PHILADELPHIA, Dec. 17, 2020 /PRNewswire/ --Immunotherapies, such as checkpoint inhibitor drugs, have made worlds of difference for the treatment of cancer. Most clinicians and scientists understand these drugs act on what's known as the adaptive immune system, the T cells and B cells that respond to specific threats to the body.

New research from a team co-led by Penn Dental Medicine's George Hajishengallis suggests that the innate immune system, which responds more generally to bodily invaders, may be an important yet overlooked component of immunotherapy's success.

Their work, published in the journal Cell, found that "training" the innate immune system with -glucan, a compound derived from fungus, inspired the production of innate immune cells, specifically neutrophils, that were programmed to prevent or attack tumors in an animal model.

"The focus in immunotherapy is placed on adaptive immunity, like checkpoint inhibitors inhibit the interaction between cancer cells and T cells," says Hajishengallis. "The innate immune cells, or myeloid cells, have not been considered so important. Yet our work suggests the myeloid cells can play a critical role in regulating tumor behavior."

The current study builds on earlier work by Hajishengallis and a multi-institutional team of collaborators, which showed that trained immunity, elicited through exposure to the fungus-derived compound -glucan, could improve immune recovery after chemotherapy in a mouse model.

In that previous study, the researchers also showed that the "memory" of the innate immune system was held within the bone marrow, in hematopoietic stem cells that serve as precursors of myeloid cells, such as neutrophils, monocytes, and macrophages.

The team next wanted to get at the details of the mechanism by which this memory was encoded. "The fact that -glucan helps you fight tumors doesn't necessarily mean it was through trained immunity," says Hajishengallis.

To confirm that link, the researchers isolated neutrophils from mice that had received the innate immune training via exposure to -glucan and transferred them, along with cells that grow into melanoma tumors, to mice that had not received -glucan. Tumor growth was significantly dampened in animals that received cells from mice that had been trained.

-glucan is already in clinical trials for cancer immunotherapy, but the researchers say this finding suggests a novel mechanism of action with new treatment approaches.

"This is a breakthrough concept that can be therapeutically exploited for cancer immunotherapy in humans," Hajishengallis says, "specifically by transferring neutrophils from -glucan-trained donors to cancer patients who would be recipients."

Contact: Beth Adams, [emailprotected]

SOURCE Penn Dental Medicine

http://www.dental.upenn.edu

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Priming the Immune System to Fight Cancer - PRNewswire

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Most kids with peanut allergies do not outgrow them. But, with a little help, some might be able to better tolerate accidental exposures.

In January, the Food and Drug Administration approved Palforzia, a new drug designed to help kids who are allergic to peanuts react better, if they are accidentally exposed.

"Because there is no cure, allergic individuals must strictly avoid exposure to prevent severe and potentially life-threatening reactions," Dr. Peter Marks, director of the FDA's Center for Biologics Evaluation and Research said at the time in a news release. "When used in conjunction with peanut avoidance, Palforzia provides an FDA-approved treatment option to help reduce the risk of these allergic reactions."

Palforzia is not designed to be administered during an allergic reaction, instead it works as an allergy exposure therapy: children ages 4 through 17 receive daily doses of peanut powder under clinical supervision, and slowly up-dose it over time.

In clinical trials, the strategy worked well, but not perfectly. When peanut-allergic kids were fed 600 milligrams of peanut protein, 67.2% of Palforzia recipients who'd been using the medication for six months tolerated it, while only 4% of the control group did.

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The 11 most mind-blowing, awe-inspiring health discoveries and innovations of 2020 - Business Insider - Business Insider

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First gene therapy to receivefull EU marketing authorization for eligible MLD patients

One-time treatment with Libmeldy has been shown to preserve motor and cognitive function

Achievement shared with research alliance partners Fondazione Telethon and Ospedale San Raffaele

BOSTON and LONDON and MILAN, Italy, Dec. 21, 2020 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, and its research alliance partners Fondazione Telethon and Ospedale San Raffaele, today announced that the European Commission (EC) granted full (standard) market authorization for Libmeldy (autologous CD34+ cells encoding the ARSA gene), a lentiviral vector-based gene therapy approved for the treatment of metachromatic leukodystrophy (MLD), characterized by biallelic mutations in theARSAgene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

MLD is a very rare, fatal genetic disorder caused by mutations in the ARSA gene which lead to neurological damage and developmental regression. In its most severe and common forms, young children rapidly lose the ability to walk, talk and interact with the world around them, and most pass away before adolescence. Libmeldy is designed as a one-time therapy that aims to correct the underlying genetic cause of MLD, offering eligible young patients the potential for long-term positive effects on cognitive development and maintenance of motor function at ages at which untreated patients show severe motor and cognitive impairments.

Todays EC approval of Libmeldy opens up tremendous new possibilities for eligible MLD children faced with this devastating disease where previously no approved treatment options existed, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. Libmeldy is Orchards first product approval as a company, and I am extremely proud of the entire team who helped achieve this milestone. We are grateful for and humbled by the opportunity to bring this remarkable innovation to young eligible patients in the EU.

With Libmeldy, a patients own hematopoietic stem cells (HSCs) are selected, and functional copies of the ARSA gene are inserted into the genome of the HSCs using a self-inactivating (SIN) lentiviral vector before these genetically modified cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate across the blood-brain barrier into the brain, engraft, and express the functional enzyme has the potential to persistently correct the underlying disease with a single treatment.

The EC approval of Libmeldy comes more than a decade after the first patient was treated in clinical trials performed at our Institute, and ushers in a remarkable and long-awaited shift in the treatment landscape for eligible MLD patients, said Luigi Naldini, M.D, Ph.D., director of the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. Our team at SR-Tiget has been instrumental in advancing the discovery and early-stage research of this potentially transformative therapy to clinical trials in support of its registration through more than 15 years of studies supported by Fondazione Telethon and Ospedale San Raffaele, and we are extremely proud of this achievement and what it means for patients and the field of HSC gene therapy.

MLD is a heart-breaking disease that causes immeasurable suffering and robs children of the chance of life, said Georgina Morton, chairperson of ArchAngel MLD Trust. As a community, we have been desperate for a treatment for young MLD patients, and we are incredibly excited to now have such a ground-breaking option approved in the EU.

The marketing authorization for Libmeldy is valid in all 27 member states of the EU as well as the UK, Iceland, Liechtenstein and Norway. Orchard is currently undertaking EU launch preparations related to commercial drug manufacturing, treatment site qualification and market access.

Data Supporting the Clinical and Safety Profile of Libmeldy

The marketing authorization for Libmeldy is supported by clinical studies in both pre- and early- symptomatic, early-onset MLD patients performed at the SR-Tiget. Early-onset MLD encompasses the disease variants often referred to as late infantile (LI) and early juvenile (EJ). Clinical efficacy was based on the integrated data analysis from 29 patients with early-onset MLD who were treated with Libmeldy prepared as a fresh (non-cryopreserved) formulation. Results of this analysis indicate that a single-dose intravenous administration of Libmeldy is effective in modifying the disease course of early-onset MLD in most patients.

Clinical safety was evaluated in 35 patients with MLD (the 29 patients from the integrated efficacy analysis as well as six additional patients treated with the cryopreserved formulation of Libmeldy). Safety data indicate that Libmeldy was generally well-tolerated. The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies (AAA) reported in five out of 35 patients. Antibody titers in all five patients were generally low and no negative effects were observed in post-treatment ARSA activity in the peripheral blood or bone marrow cellular subpopulations, nor in the ARSA activity within the cerebrospinal fluid. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For further details, please see the Summary of Product Characteristics (SmPC).

About MLD and Libmeldy

MLD is a rare and life-threatening inherited disease of the bodys metabolic system occurring in approximately one in every 100,000 live births. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. In its late infantile form, mortality at five years from onset is estimated at 50% and 44% at 10 years for juvenile patients.1

Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), also known as OTL-200, is approved in the European Union for the treatment of MLD in eligible early-onset patients. In the U.S., OTL-200 is an investigational therapy which has not been approved by the U.S. Food and Drug Administration (FDA) for any use. Libmeldy was acquired from GSK in April 2018 and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and Fondazione Telethon, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan, initiated in 2010.

About Orchard

Orchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S.headquarters inBoston. For more information, please visitwww.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About Orchard

Investors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter andLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

About Fondazione Telethon, Ospedale San Raffaele and the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget)

Based in Milan, Italy, the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) is a joint venture between the Ospedale San Raffaele, a clinical-research-university hospital established in 1971 to provide international-level specialized care for the most complex and difficult health conditions, and Fondazione Telethon, an Italian biomedical charity born in 1990 and focused on rare genetic diseases. SR-Tiget was established in 1995 to perform research on gene transfer and cell transplantation and translate its results into clinical applications of gene and cell therapies for different genetic diseases. Over the years, the Institute hasgiven a pioneering contribution to the field with relevant discoveries in vector design, gene transfer strategies, stem cell biology, identity and mechanism of action of innate immune cells. SR-Tiget has also established the resources and framework for translating these advances into novel experimental therapies and has implemented several successful gene therapy clinical trials for inherited immunodeficiencies, blood and storage disorders, which have already treated >115 patients and have led through collaboration with industrial partners to the filing and approval of novel advanced gene therapy medicines.

For more information:

Forward-Looking Statements

This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, plans, intends, projects, and future or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, including its plans and expectations for the commercialization of Libmeldy, and the therapeutic potential of Libmeldy, including the potential implications of clinical data for eligible patients. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation:: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials of Libmeldy will not continue or be repeated in our ongoing or planned clinical trials of Libmeldy, will be insufficient to support regulatory submissions or marketing approval in the US or to maintain marketing approval in the EU, or that long-term adverse safety findings may be discovered; the inability or risk of delays in Orchards ability to commercialize Libmeldy, including the risk that we may not secure adequate pricing or reimbursement to support continued development or commercialization of Libmeldy; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2020, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaChristine HarrisonVice President, Corporate Affairs+1 202-415-0137media@orchard-tx.com

1 Mahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature.Journal of Child Neurology2010, DOI:http://doi.org/10.1177/0883073809341669

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Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD) - GlobeNewswire

Recommendation and review posted by Bethany Smith

The stock price of Creative Medical Technology Holdings Inc (OTCMKTS: CELZ) a company that engages in stem cell research and developing applications to treat male sexual dysfunction and related issues increased by 80.77% yesterday as it went from $0.0026 to $0.0047 per share. One of the biggest triggers for the stock price increase is an announcement about the company announcing the successful application of ImmCelz immunotherapy for treatment of stroke.

In an animal model of ischemia stroke, the middle cerebral artery ligation model, administration of ImmCelz resulted in 34% reduction in infarct volume, whereas control bone marrow mesenchymal stem cells reduced infarct volume by 21%. And there were improvements in functional recovery were observed using the Rotarod test.

At 28 days after induction of stroke the animals receiving ImmCelz had superior running time (92% of non-stroke controls) compared to animals that received bone marrow mesenchymal stem cells (73% of non-stroke control). And animals that received saline had a running time that was 50% of non-stroke controls.

KEY QUOTES:

The regenerative potential of immune cells that have been programmed by stem cells is a fascinating and novel area of research. Conceptual advantages of using reprogrammed T cells include higher migratory ability due to smaller size, as well as ability to replicate and potentially formregenerative memory cells.

Dr.Amit Patel, coinventor of ImmCelz

This data, which is covered by our previous filed patents, such as no. 15/987739,Generation of autologous immune modulatory cells for treatment of neurological conditions, demonstrate that immune modulation via this stem cell based method may be a novel and superior way of addressing the$30 billion dollarmarket for stroke therapeutics. The fact that this technology, which has priority back to 2017, is demonstrating such stunning results, motivates us to consider filing an Investigational New Drug Application for use in stroke.

Dr.Thomas Ichim, coinventor of the patent and Chief Scientific Officer of Creative Medical Technology

While stroke historically has been a major area of unmet medical need, the rise in stroke cases , as well as the fact that younger people are increasingly falling victim to stroke, strongly motivates us to accelerate our developmental programs and to continue to explore participation of Big Pharma in this space. We are eager to replicate the existing experiments start compiling the dossier needed to take ImmCelz into humans using the Investigational New Drug Application (IND) route through the FDA.

Timothy Warbington, President and CEO of Creative Medical Technology

Disclaimer: This content is intended for informational purposes. Before making any investment, you should do your own analysis.

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Creative Medical Technology Stock Price Increased 80.77%: Why It Happened - Pulse 2.0

Recommendation and review posted by Bethany Smith

Abstract

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5/Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

Reactive aldehydes, such as acetaldehyde and formaldehyde, are cytotoxic and carcinogenic because they damage DNA and interfere with transcription and replication. Whereas acetaldehyde is mostly produced by oxidative degradation of ingested alcohol, formaldehyde is an ordinary one-carbon (1C) metabolite that is generated from various in vivo biochemical reactions, including enzymatic demethylation of histones and nucleic acids (1, 2). These free aldehydes are swiftly oxidized to innocuous carboxylic acids by cellular dehydrogenases. Aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde into acetate, but this enzyme is inactivated in ~50% of the population in East Asian countries because of a functional single-nucleotide polymorphism, rs671 [ALDH2*2, c.1510G>A, p.E504K; MAF (minor allele frequency) = 0.27 in Japanese]. Rs671 is known to cause alcohol flushing response after drinking (36). Apparently, alcohol flushing is not a disease; however, the rs671 defective (A) allele is protective against alcoholism and is also associated with an increased risk of various clinical conditions, including cardiovascular disorders (7, 8) and certain types of cancer (4, 912). In particular, the incidence of gastrointestinal cancers, represented by esophageal squamous cell carcinoma, is significantly higher in individuals with the rs671 defective allele when they regularly drink alcohol (1012). Despite a multitude of known genetic associations, no disease with a true digenic/oligogenic inheritance (1315), under complete penetrance, due to rs671 has been reported. With regard to the formaldehyde elimination, alcohol dehydrogenase 5 (also known as formaldehyde dehydrogenase or S-nitrosoglutathione reductase, ADH5/FDH/GSNOR) is the principal enzyme converting formaldehyde to formic acid in a glutathione-dependent manner (16). Because GSNOR is also a key enzyme for the modulation of cellular nitric oxide signaling, thereby regulating circulatory functions, ADH5 polymorphisms are known to be associated with an increased risk of cardiovascular disorders (16). Nevertheless, to date, no congenital disorders due to the loss of ADH5 function has been reported.

When the metabolic processes of aldehyde clearance become uncapable or the capacity overflows, various types of endogenous DNA damage increase. Aldehydes primarily produce DNA interstrand cross-links (ICL) and nonenzymatic DNA-protein cross-links (DPC) (17). These DNA lesions prevent replication fork progression; therefore, they are thought to be largely repaired by the following replication-coupled DNA repair mechanisms: (i) ICL repair pathway involves FANC proteins that are mutated in Fanconi anemia (FA), a rare inherited bone marrow failure syndrome (IBMFS) (18, 19). This pathway (otherwise known as FA pathway) is activated in S phase and eliminates ICL, by unhooking of covalently bridged Watson/Crick strands with structure-specific endonucleases, followed by sequential actions involving translesion synthesis (TLS), homologous recombination, and nucleotide excision repair (NER). (ii) DPC repair is similarly initiated by the stalling of DNA polymerases at replication forks, where metalloproteases, such as SPRTN, degrade DNA-bound proteins to remnant peptides before TLS and further excision of remaining lesions by NER. Mutations in the SPRTN gene also cause a rare disorder, Ruijs-Aalfs syndrome (RJALS), characterized by segmental progeria and early-onset hepatocellular carcinoma (20).

In this study, we report a number of families with a new form of IBMFS cases. On the basis of genome analysis of the patients, we identified disease-causing digenic mutations in the ALDH2 and ADH5 genes. Cellular and animal studies demonstrate that the simultaneous loss of ALDH2 and ADH5 activities leads to an increase of cellular formaldehyde sensitivity and multisystem abnormalities including hematopoietic failure. Our results suggest that the formaldehyde clearance is as important as the DNA repair system for normal development of both humans and mice.

We report 10 cases in eight unrelated families, presenting a previously unclassified trait, characterized by aplastic anemia (AA), mental retardation, and short stature and microcephaly (dwarfism), termed AMeD syndrome (AMeDS). Pedigrees of the families (Fig. 1A), summaries of clinical manifestations (Table 1), and hematological complications (Table 2) of the affected individuals are shown (see also detailed clinical episodes below). Each of the cases was initially diagnosed as AA, FA, refractory anemia (RA), Bloom syndrome (BS) or Dubowitz syndrome (DS), largely based on their facial appearance and hematological manifestations (18, 21, 22). All cases developed myelodysplasia during infancy to childhood, and of seven cases with detailed clinical records, four patients received bone marrow transplants (BMTs). The possibility of FA is often considered in the differential diagnosis of IBMFS. Notably, severe dwarfism (height and head circumference < 4.0 SD) and intellectual disabilities both typical in AMeDS cases are uncommon in FA; these additional symptoms rather resemble those of patients with transcription-coupled NER deficiency, Cockayne syndrome (CS) (23), and its related disorders [cerebro-oculo-facio-skeletal syndrome (COFS) and XFE progeroid syndrome (XFEPS)] (24, 25). Also in contrast to typical FA cases, neither polydactyly nor chromosome fragility was observed in any of the AMeDS cases. Dyskeratosis congenita (DC) was also excluded by normal telomere length tested in some of the cases. These families and cases were extracted from the Genome Instability Syndrome Diagnosis Project, a part of the Rare/Intractable Disease (nanbyo) Project of Japan, as well as from a collection of undiagnosed IBMFS children analyzed by the central review system of the Japanese Society of Pediatric Hematology and Oncology and the targeted sequencing system for IBMFS at Nagoya University Pediatrics Department.

(A) Pedigrees of AMeDS families 4 to 8. (B) Pathogenic variants identified in ADH5 and ALDH2. (C) Immunoblots of ADH5 and ALDH2 in primary fibroblasts from normal (1BR) and patients with AMeDS (N0608, N0611, and N0614). SMC3 is a loading control. (D) ADH5 transcript of normal (1BR) and AMeDS (N0608, N0611, and N0614) cells. The relative transcript levels analyzed by the CT method are shown for triplicate experiments. (E) Cell viability after continuous 30 M formaldehyde treatment. Results from triplicate experiments (means SD) are shown. **P < 0.01, two-tailed unpaired t test. (F) Immunoblots showing a reduced stability of ADH5 p.S75N identified in a healthy individual, NAG16714. Gene-edited hTERT-immortalized RPE1 (RPE1 hTERT) cells expressing the homozygous ADH5 p.S75N alleles (clones no. 10 and no. 52), and ADH5 cells are examined. (G) Stable expression of the p.S75N mRNA. (H) Cell viability after continuous 40 M formaldehyde treatment. Results from triplicate experiments (means SD) are shown. ***P < 0.001, two-tailed unpaired t test. (I) ADH5 p.S75N is unstable as with p.A278P. U2OS cells transfected with V5-tagged ADH5 WT (wild type), p.A278P, or p.S75N were harvested at the indicated times following cycloheximide (CHX) treatment. Cell lysates were immunoblotted with V5 and ACTB antibodies. (J) Quantification of ADH5-V5 levels in (I) by image analysis, normalized to ACTB levels. Means ( SD) from triplicate experiments are shown. *P < 0.05; one-way analysis of variance (ANOVA) with Tukeys multiple comparisons test.

NA, not analyzed. WBC, white blood cells; Neut, neutrophils; Mon, monocytes; Hb, hemoglobin; MCV, mean corpuscular volume; Ret, reticulocytes; Plt, platelets; HbF, fetal hemoglobin; PB, peripheral blood; BM, bone marrow; RCMD, refractory cytopenia with multilineage dysplasia; RAEB-1, refractory anemia with excess blasts-1.

N1254 (Family4), the first daughter of nonconsanguineous Japanese parents, was born at 39 weeks and 3 days with a birth weight of 2880 g (0.12 SD), after an uneventful antenatal period. She had neither obvious malformations nor abnormalities at birth. At 3 weeks of age, she had poor weight gain (Kaup index of 13) and presented with telecanthus and broad nasal tip. At 1 year of age, she was repeatedly admitted to the hospital because of prolonged fever and pancytopenia. Skin hyperpigmentation and displacement of the left third toe were pointed out. She was initially diagnosed with RA. At 2 years of age, she had severe growth retardation (height: 71 cm, 2.3 SD; weight: 6850 g, 2.7 SD), delayed motor and language development (spoke only two or three meaningful words), and was diagnosed with acute myeloid leukemia (AML; monosomy 7). She received a cord blood stem cell transplant from an unrelated donor. She had successful engraftment of neutrophils, but the thrombocyte levels did not return to normal. She had leukoencephalopathy and cerebral abscess and died at 2 years and 10 months of age. She had no episode of sunburn.

N1037 (Family4), a younger sister of N1254, was born at 41 weeks and 3 days with a birth weight of 2870 g (1.27 SD), after an uneventful antenatal period. She had neither obvious malformations nor abnormalities at birth. At 1 year of age, she was repeatedly admitted to the hospital because of prolonged fever and thrombocytopenia. At 5 years of age, she was initially diagnosed with possible BS based on her facial characteristics and hematological abnormalities. She presented with short stature, microcephaly, delayed motor and language developments (spoke only two or three meaningful words), analgia, hypohidrosis, hypothyroidism, and displacement of the left third toe. She died of interstitial pneumonia at 9 years and 8 months of age. She had no episode of sunburn.

N1267 (Family5), the second child of nonconsanguineous Japanese parents, was born at 40 weeks and 5 days with a birth weight of 2606 g (1.81 SD), after an uneventful antenatal period. No physical abnormalities were noted at birth. She was undergoing medical follow-up care because of low birth weight, failure to thrive, and short stature. She presented with pancytopenia at 7 years of age. She was initially diagnosed with DS. Bone marrow examination showed trilineage dysplasia with an abnormal karyotype: 46,XX,+1,der(1:21)(q10;q10) [7/20]; 46,idem,add(18)(p11.2) [13/20]. Regular bone marrow examination performed 1 year after the diagnosis revealed monosomy 7 clonal evolution. BMT from a human leukocyte antigen (HLA)matched sibling donor (sibling5-1) appeared to be successful; however, the disease relapsed 3 months after the transplant. She underwent her second BMT from an HLA-matched unrelated donor. She is alive and disease-free 5 years after the transplant.

N1269 (Family6), the second daughter of nonconsanguineous Japanese parents, was born at 39 weeks and 2 days with a birth weight of 2442 g (1.72 SD), after an uneventful antenatal period. No physical abnormalities were noted at birth. At 2 years of age, she presented with thrombocytopenia, short stature, and developmental delay. Following a transient elevation in platelet count, her thrombocytopenia and anemia subsequently progressed and she was diagnosed with myelodysplastic syndrome (MDS) with trilineage dysplasia at 3 years of age. Cytogenetic analysis revealed a complex karyotype with trisomy 8: 46,XX,der(5;17)(p10;q10),+8 [4/20]; 45,idem,add(7)(p11.2),-8,add(19)(p13) [14/20]; 46,XX,ins(1;?)(q12;?) [2/20]. BMT from an HLA-matched sibling donor was successful, and she is alive 6 years after the transplant.

N1270 (Family6), a younger brother of N1269, was born at 39 weeks and 0 days with a birth weight of 2366 g (2.14 SD), after an uneventful antenatal period. No physical abnormalities were noted at birth. At 3 months of age, he was admitted to the hospital because of poor weight gain and possible developmental abnormalities. He had bicytopenia (thrombocytopenia and anemia), hypothyroidism, skin hyperpigmentation, agenesis of corpus callosal, and recurrent epileptic seizures. Bone marrow examination showed MDS with a normal karyotype. His motor and intellectual disabilities were severe. He needed a gastrostomy tube for feeding at 1 year and 8 months of age. He died of infection at 2 years of age: height, 76.7 cm (4.5 SD); weight, 8.85 kg (3.0 SD); and head circumference, 40 cm (5.8 SD). Telecanthus, displacement of the right fourth toe, and low-set ears were pointed out. He had hypertrophic cardiomyopathy and frontal lobe atrophy.

N1275 (Family7), the first daughter of nonconsanguineous Japanese parents, was born at 41 weeks and 5 days with a birth weight of 2984 g (0.65 SD). She had initially presented with pancytopenia at 8 years of age. Bone marrow examination revealed hypoplastic MDS with the following abnormal karyotype: 46,XX,+1,der(1;22) (q10;q10) [2/20]; 47,idem,del(7)(q?),add(17)(p11.2),+mar1 [9/20]; 47,idem,add(17),del(20)(q1?),+mar1 [5/20]. She presented with FA-like physical anomalies, such as short stature, skin hyperpigmentation, and developmental delay. However, her chromosomal breakage test and FANCD2 ubiquitination were normal. BMT from a mismatched unrelated donor with reduced intensity conditioning was successful. She is alive 5 years after transplant.

N1329 (Family8), the second son of nonconsanguineous Japanese parents, was born at around 40 weeks with a birth weight of 3480 g (0.72 SD), after an uneventful antenatal period. He presented with short stature (2.52 SD) and had a delayed bone age at 6 years of age. He had Tanner stage 4 and an advanced bone age and was diagnosed with precocious puberty at 10 years of age. He had bicytopenia (anemia and leukopenia), and his bone marrow examination revealed MDS with an abnormal karyotype: 46,XY,+1,der(1;15)(q10;q10),add(17)(p11.2)x2 at 12 years of age. He was initially diagnosed with FA. At 15 years of age, he had short stature (height: 149.7 cm, 3.2 SD; weight: 31.35 kg, 2.7 SD), microcephaly (head circumference: 51.5 cm, 4.7 SD), and intellectual disability. He has no episode of sunburn.

We have implemented whole-exome sequencing (WES) for genetic screening of undiagnosed cases (standard WES procedure, see Materials and Methods). From the WES and follow-up studies, we identified biallelic mutations in the ADH5 gene in all of the AMeDS cases. By the WES analyses, we did not find any other potential causative genes shared among more than two of the cases under an autosomal recessive model of inheritance; we were not aware of any reported pathogenic variants of known disorders in any of the identified potential causative genes; no biallelic variants were detected in known FA-associated genes (table S1) (18). The patients were homozygous or compound heterozygous for the following ADH5 variant alleles: c.966delG, p.W322*; c.G832C, p.A278P; c.564+1G>A, 5 splice site (Fig. 1B and Table 1). Immunoblot analysis of AMeDS fibroblasts demonstrated a significant reduction of the ADH5 protein levels, indicating that the identified variants led to loss-of-function (LOF) changes causing a lack of gene expression or involving a severe protein destabilization (Fig. 1, C and D).

Previous animal studies demonstrated that combined inactivation of the endogenous aldehydes detoxification and the FA pathway leads to very severe attrition of hematopoietic stem and progenitor cells (HSPCs) and abnormal fetal development (2630). In these processes, ADH5 is the key enzyme in the protection against DNA damage induction, by eliminating endogenous formaldehyde (30). Consistent with this notion, ADH5-deficient AMeDS cells exhibited increased sensitivity to formaldehyde treatment (Fig. 1E), although the cells displayed normal ubiquitination of FANCD2 and resistance to ICL-inducing mitomycin C, indicating that the FA pathway is proficient in the AMeDS cases (fig. S1, A to C). From these results, we anticipated that the ADH5 deficiency was the primary cause of AMeDS.

In contrary, Adh5 null mice did not show any devastating phenotype that causes a survival disadvantage (31). To further evaluate the pathogenicity of the ADH5 deficiency in humans, we first searched for individuals with biallelic ADH5 rare variants in genotype-available databases. No homozygous ADH5 LOF variants were detected within ~140,000 individuals in gnomAD (v.2.1.1). Because all the AMeDS cases were of Japanese origin, we conducted an additional search of ~5600 Japanese individuals within ToMMo (Tohoku Medical Megabank; 2036 individuals), HGVD (Human Genetic Variation Database, Kyoto University; 300 individuals), BBJ (BioBank Japan, RIKEN Institute; 1006 individuals), and Nagahama Study (Nagahama Prospective Cohort for Comprehensive Human Bioscience, Kyoto University; 1321 individuals) datasets, as well as in-house genome databases. Furthermore, we genotyped the ADH5 pathogenic variant alleles (p.W322*, p.A278P, and c.564+1G>A) in ~26,000 Japanese individuals (Hospital-Based Epidemiologic Research Program at Aichi Cancer Center, Aichi Cancer Center). From these screenings, we identified a healthy individual (female, age 55, no preexisting conditions) with a homozygous mutation, c.G224A (p.S75N) in the ADH5 gene (NAG16714 in Nagahama Study; Table 1). As we could not obtain cellular materials from this individual, we generated hTERT-immortalized RPE1 (RPE1 hTERT) and U2OS cells with ADH5 and with the site-specific ADH5 p.S75N homozygous mutation using the CRISPR-Cas9based gene editing technique (without silent mutations, see Materials and Methods; table S2). Immunoblot analysis revealed severely decreased levels of the ADH5-p.S75N protein in the mutant cells (Fig. 1F and fig. S1D), although the ADH5 mRNA expression was unaffected (Fig. 1G). The ADH5-p.S75N mutant cells were as sensitive to formaldehyde as ADH5 cells (Fig. 1H and fig. S1E) due to destabilization of the ADH5 protein (Fig. 1, I and J). These initial results indicate that the loss of ADH5 expression or deficiency in formaldehyde detoxification is not associated with any obvious disease phenotype. These data suggest that the ADH5 monogenic deficiency is not sufficient to cause AMeDS.

We therefore considered a possibility of digenic/oligogenic inheritance. We focused on the ALDH2 gene and rs671 because ALDH2 retains a weak catabolic activity for formaldehyde (32) and for various endogenous active aldehyde species, such as 4-hydroxy-2-nonenal (4-HNE) that arises from membrane lipid peroxidation products (33), in addition to its primary function of detoxifying acetaldehyde. These active aldehydes generate ICL-DNA damage (17); consequently, they can put loads on the FA pathway and other DNA repair pathways, such as base excision repair and DPC repair. Therefore, the phenotypes of patients with AMeDS may result from the lack of enzymatic activity of ALDH2 in combination with the loss of ADH5 function for endogenous aldehydes.

Individuals harboring either one or two copies of the ALDH2 rs671 defective allele display a severe deficiency in acetaldehyde catabolic activity because the active enzyme complex requires the wild-type ALDH2 homotetramer (5, 34). By examining the ALDH2 rs671 genotype, we indeed found that all 10 patients with AMeDS carry at least one copy of the defective allele (G/A or A/A) (Table 1). Despite the high allele frequency in Japanese population, appearance of the rs671 defective allele in the AMeDS cases deviates substantially from the Hardy-Weinberg equilibrium (Pearsons 2 test; P = 0.0007), suggesting that this locus is strongly associated with the disease development. The healthy individual, NAG16714 with the homozygous ADH5 p.S75N defective variant, harbors the homozygous rs671 wild-type (G/G) alleles (Table 1). Furthermore, all three cases homozygous for the rs671 defective alleles (N1037, N1254, and N1270) manifested more severe phenotypes, including neurological abnormalities, prominent motor deterioration (confined to a wheelchair or bed), and early death (Tables 1 and 2). This suggests that the aldehyde detoxification activity determined by the rs671 genotype underlies the severity of AMeDS clinical features. Collectively, we conclude that the ALDH2 rs671 defective allele in combination with biallelic LOF mutations in the ADH5 gene is necessary and sufficient to cause a true digenic disorder, AMeDS, classified as IBMFS.

To determine potential substrates of the ADH5 and ALDH2 enzymes, we have measured growth inhibition profiles of ADH5- and/or ALDH2-deficient U2OS cells after treatments with various active aldehydes (fig. S2, A to C). Nine major endogenous aldehydesincluding ,-unsaturated aldehydes [4-hydroxyhexenal, (4-HHE), 4-HNE, 4-oxononenal, acrolein, and crotonaldehyde], the simplest aldehyde (formaldehyde), dialdehydes (glyoxal and methylglyoxal), and a saturated aldehyde (heptanal)whose chemical properties have been widely studied, were chosen for the proliferation assay.

While the treatments with ,-unsaturated aldehydes (4-HHE, 4-HNE, and acrolein) inhibited cell proliferation of ALDH2E504K U2OS cells, ADH5/ cells were not affected by the same treatment (fig. S2D); this may imply that these aldehydes are preferentially metabolized and detoxified by the ALDH2 enzyme. We found that formaldehyde and methylglyoxal treatments suppressed cell proliferation of ADH5/ALDH2E504K double-deficient U2OS cells compared to single-deficient ADH5/ or ALDH2E504K cells, indicating that these aldehydes are possible substrates of both ADH5 and ALDH2 enzymes (fig. S2D). The concentration of formaldehyde in human plasma is estimated to be ~100 M (35, 36), while that of methylglyoxal is much less than 1 M (37), which implies that near physiological levels of formaldehyde, but not methylglyoxal, can perturb cell proliferation. To further investigate the effects of formaldehyde treatment in ADH5/ALDH2E504K double-deficient U2OS cells more precisely, we analyzed replication inhibitory profiles by flow cytometry (Fig. 2A). While either LOF of ADH5 or ALDH2 modestly attenuated the progression of cell cycle compared to wild-type cells, digenic loss of ADH5 and ALDH2 led to the significant inhibition of DNA replication after formaldehyde treatment (Fig. 2, A and B).

(A) Formaldehyde treatment inhibits DNA replication in ADH5 and ALDH2 double-deficient cells. 5-ethynyl-2-deoxyuridine (EdU) incorporation in WT, ADH5, ALDH2E504K, or ADH5 ALDH2E504K double-mutant U2OS cells after formaldehyde treatment is measured by fluorescence-activated cell sorting (FACS) analysis. Cells were incubated with indicated concentration of formaldehyde or 10 mM hydroxyurea (HU) as a positive control for 8 hours followed by EdU incorporation for 1 hour. Then, cells were fixed with 70% ethanol and analyzed by FACS for Alexa Fluor 488labeled EdU and DNA stained with 7-aminoactinomycin D (7-AAD). Representative FACS images are shown. (B) Quantification of data in (A). Graph shows the percentage of EdU-positive cells. Means ( SD) from three independent experiments are shown. *P < 0.05, **P < 0.01, and ***P < 0.001, one-way ANOVA with Tukeys multiple comparisons test. (C) Formaldehyde treatment induces DNA damage in cells from AMeDS-affected individuals. Immunoblots showing phospho-Ser139 histone H2AX (H2AX), a DNA damage marker, and PARP1, an apoptosis marker in normal (1BR) and AMeDS (N0608 and N0611) cells. KU70 is a loading control. (D) EdU incorporation in normal and AMeDS cells after formaldehyde treatment measured by FACS analysis. Cells were incubated with indicated concentration of formaldehyde for 22 hours followed by EdU incorporation for 2 hours. Then, cells were fixed with 70% ethanol and analyzed by FACS for Alexa Fluor 488labeled EdU and DNA stained with propidium iodide (PI). (E) Formaldehyde-induced DNA damage in AMeDS cells (N0611) is ameliorated with expression of either the wild-type ADH5 or ALDH2 cDNA. Green fluorescent protein as a mock control.

We next studied the cooperative actions of ADH5 and ALDH2 on the prevention of DNA damage induction. We assessed increased cellular DNA damage levels as a consequence of diminished formaldehyde processing activity in patients with AMeDS cells. We measured formaldehyde-induced DNA damage by immunoblotting of histone H2AX Ser139 phosphorylation (H2AX) as a DNA damage marker. AMeDS cells (N0608 and N0611) showed significant increase of H2AX levels after 200 M formaldehyde treatment, although normal cells were resistant to even such a high dose, indicating that unrepairable DNA damage are indeed increased in the AMeDS cells supposedly because of the lack of formaldehyde processing capacity (Fig. 2C). Similar to ADH5/ALDH2E504K double-deficient U2OS cells, significant inhibition of DNA replication after formaldehyde treatment was also confirmed in patient with AMeDS cells (Fig. 2D). Ectopic expression of either of the wild-type ADH5 or ALDH2 complementary DNA (cDNA) in the AMeDS cells completely eliminated the induction of formaldehyde-induced DNA damage, suggesting that both ADH5 and ALDH2 deficiencies underlie the decrease of formaldehyde detoxification capacity (Fig. 2E and fig. S2, E and F). Together, formaldehyde is metabolized by both ADH5 and ALDH2, and even naturally occurring concentration of formaldehyde may have a negative effect on cell proliferation and genome integrity in ADH5 and ALDH2 double-deficient cells.

We next investigated the effects of ADH5 and ALDH2 digenic deficiency on the progenitor cell capacity of HSPCs in humans. We performed colony-forming unit (CFU) assays of CD34+ umbilical cord bloodderived HSPCs, which were prepared from healthy Japanese donors (RIKEN BRC). The ALDH2 rs671 genotype was confirmed in each HSPC pool, and the ADH5 expression was eliminated by the CRISPR-Cas9based gene editing with specific single-guide RNAs (sgRNAs) (Fig. 3A and fig. S3, A and B). The loss of ADH5 did not induce unexpected DNA damage (determined by H2AX induction shown in fig. S3B), and it did not affect the proliferation of HSPCs regardless of the rs671 genotype during culture in hematopoietic maintenance medium (fig. S3C), suggesting that decrease in the formaldehyde detoxification capacity does not involve any growth disadvantage of HSPCs in ex vivo conditions. However, the differentiation and proliferation potential of HSPCs was severely compromised when ADH5 was deleted in HSPCs with the ALDH2 rs671 defective (G/A) but not with the wild-type (G/G) alleles (Fig. 3, B and C). In addition, these ADH5 and ALDH2 rs671 double-deficient HSPCs had reduced capacity to differentiate into common progenitor cells and/or their progeny cells (fig. S3D), suggesting that formaldehyde detoxification deficiency causes a wide range of hematopoietic abnormalities in humans.

(A) Schematic representation of CFU assay. CD34+ HSPCs are derived from umbilical cord blood of Japanese healthy donors. The numbers of HSPC pools with the designated ALDH2 rs671 alleles are shown. ADH5 was deleted in each HSPC pool by CRISPR-Cas9based gene editing. (B) CFU assay of gene-edited CD34+ HSPCs was performed using a methylcellulose medium. Representative images are shown. Scale bar, 3 mm. (C) Total number of colonies after 14-day CFU assay of gene-edited CD34+ HSPCs. The number of colonies was normalized to untreated control. Statistical analysis was performed using one-way ANOVA with Tukeys multiple comparisons test (***P < 0.001; ns, not significant). Lines represent median.

To investigate the consequences of the ADH5 and ALDH2 digenic deficiency for the development of multisystem abnormalities in AMeDS, we generated gene-edited mice with Adh5/ and Aldh2-E506K (equivalent to the human ALDH2-E504K and hereafter called Aldh2-KI) double mutation using the CRISPR-Cas9 technique. Adh5+/Aldh2+/KI female mice were interbred with Adh5+/Aldh2KI/KI male mice, and the offspring genotypes were measured. Adh5/Aldh2KI/KI mice were born at near Mendelian ratios (Fig. 4A). The weight and size of the Adh5/Aldh2KI/KI double-deficient neonates were indistinguishable from those of their littermates, indicating of no prenatal growth retardation, which is similar to human AMeDS cases (Fig. 4, B and C). Severe growth failure with poor weight gain was prominent in all of the Adh5/Aldh2KI/KI mice at 1 to 2 weeks after birth (Fig. 4, B and C); computed tomography (CT) and dissection analyses also revealed multisystem abnormalities, including small body size, extremely shrunken organs, diminished muscle and subcutaneous fat volumes, and kyphosis at 3 weeks after birth (fig. S4A), although all the animals received breast-feeding from their mothers without problem. Intriguingly, all the Adh5/Aldh2KI/KI mice displayed anemia and severe debility and eventually died, possibly due to cachexia or overall weakness, within 4 weeks after birth before weaning, although Adh5/Aldh2+/KI mice or mice with other genotypes did not show any survival disadvantage during this period (Fig. 4D). Notably, Adh5/ or Aldh2KI/KI animals did not show any obvious developmental defects, which is consistent with previous reports (31, 38).

(A) Observed and expected frequencies of mice at 2 weeks of age from intercrossed of Adh5+/Aldh2+/KI female mice with Adh5+/Aldh2KI/KI male mice. Chi-square test shows no significant difference between observed and expected (P = 0.17). (B) Postnatal growth defects of Adh5/Aldh2KI/KI mice. Representative pictures are shown. Blue arrows indicate Adh5/Aldh2KI/KI mice. Photo credit: Yasuyoshi Oka, Nagoya University. (C) Body weights of individual mice at 0 days, 2 weeks, or 6 weeks of age. **P < 0.01 and ***P < 0.001, one-way ANOVA with Tukeys multiple comparisons test. (D) Kaplan-Meier curves with log-rank (Mantel-Cox) test show a significant decrease in survival of Adh5/Aldh2KI/KI compared to the mice with other genotypes (P < 0.0001). (E) Quantification of nucleated bone marrow cells in bilateral femurs and tibias from 3-week-old mice is shown (means SD; n = at least 5 animals). *P < 0.05 and ***P < 0.001; one-way ANOVA with Tukeys multiple comparisons test. (F and G) Quantification of hematopoietic subset: LKS (Linc-Kit+Sca-1+), HSC (Linc-Kit+Sca-1+CD150+CD48), MPP (Linc-Kit+Sca-1+CD150CD48), HPC1 (Linc-Kit+Sca-1+CD150CD48+), HPC2 (Linc-Kit+Sca-1+CD150+CD48+), CLP (Linc-KitlowSca-1lowCD127+CD135+), CMP (Linc-Kit+Sca-1CD34+CD16/32), MEP (Linc-Kit+Sca-1CD34CD16/32), and GMP (Linc-Kit+Sca-1CD34+CD16/32+) in individual mice at 3 weeks of age in (F) and at 8 to 9 months of age in (G). Means SD; n = at least 5 animals. *P < 0.05, **P < 0.01, and ***P < 0.001, one-way ANOVA with Tukeys multiple comparisons test.

Adh5/Aldh2+/KI mice also displayed smaller body weight compared to that of Adh5/ or Aldh2KI/KI animals from 2 to 6 weeks after birth (Fig. 4C). Similar but much milder manifestations compared to the Adh5/Aldh2KI/KI mice were also detected in the Adh5/Aldh2+/KI animals at 6 months (fig. S4B). Furthermore, we noticed that all middle-aged Adh5/Aldh2+/KI animals (8 to 9 months) displayed skin hyperpigmentation on the tails, indicative of FA-like features (fig. S4C). A previous report described a skin hyperpigmentation induced in Aldh2/ mice continuously administrated with ethanol (acetaldehyde precursor) (39). The Adh5/Aldh2+/KI male and female animals were fertile.

To study hematopoietic functions of the Adh5 and Aldh2 double-deficient mice in detail, we examined peripheral blood hematological parameters. Adh5/Aldh2KI/KI mice at the moribund stage (3 weeks of age) exhibited decreased red blood cells (RBCs), hemoglobin (HGB) levels, hematocrit (HCT) values, and increased levels of mean corpuscular volume (MCV), indicating macrocytic anemia, although age-matched Adh5/Aldh2+/KI mice did not present apparent hematopoietic defects at this point (fig. S4D). The Adh5/Aldh2+/KI mice eventually displayed similar abnormalities of erythrocytes at 8 to 9 months after birth (fig. S4E).

We further investigated the maintenance of HSPCs in the Adh5 and Aldh2 double-deficient mice. In Adh5/Aldh2KI/KI mice at the moribund stage (3 weeks of age), total number of nucleated bone marrow cells from tibiae and femora significantly decreased compared with that of other animals (Fig. 4E). Consistently, the number of multipotent self-renewing HSCs defined by Linc-Kit+Sca-1+ CD150+CD48 (CD150+ long-term HSCs) was significantly reduced in Adh5/Aldh2KI/KI mice (Fig. 4F and fig. S4I); similar trends were observed for immature hematopoietic progenitors, including Linc-Kit+Sca-1+CD150CD48 [CD150 multipotent progenitors (MPPs)] and Linc-Kit+Sca-1+CD150CD48+ [CD48+ restricted progenitors (HPC1)] cells. We found that the number of further differentiated progenitor cellsincluding Linc-KitlowSca-1low CD127+CD135+ [common lymphoid progenitors (CLPs)], Linc-Kit+ Sca-1CD34+CD16/32 [CD34+ common myeloid progenitors (CMPs)], and Linc-Kit+Sca-1CD34CD16/32 [bipotent megakaryocyte/erythrocyte lineage-restricted progenitors (MEPs)]was also significantly diminished in Adh5/Aldh2KI/KI mice. In connection with the decrease of CLPs in Adh5/Aldh2KI/KI mice, the number of lymphocytes in peripheral blood and the weights of thymus and spleen were reduced without any significant alteration of lymphocyte distribution in these organs (fig. S4, F to H). Although Adh5/Aldh2+/KI mice did not show any anomaly of bone marrow cells at 3 weeks of age (Fig. 4F), the number of MPPs and CLPs was significantly decreased compared with that of Adh5 or Aldh2 single-deficient mice at 8 to 9 months of age (Fig. 4G). Collectively, hematopoietic abnormalities in the Adh5 and Aldh2 double-deficient animals are due to exhaustion of HSPCs. These findings demonstrate that the combined LOFs in the Adh5 and Aldh2 genes cause multisystem abnormalities potentially due to the lack of formaldehyde clearance capacity in the double-deficient animals, and the Aldh2-E506K allele defines the severities of manifestations, which clearly mimic the major clinical features of AMeDS in humans.

Digenic inheritance (DI) is the simplest genetic trait describing complex oligogenic disorders caused by the malfunctions of two or more genes (1315). In the past human genetics studies, thousands of monogenic disorders have been identified. However, to date, only tens of diseases with solid evidence for DI have been reported (1315). Moreover, even in well-documented DI disorders, such as retinitis pigmentosa and Bardet-Biedl syndrome, affected individuals often display heterogeneous clinical features because of incomplete penetrance, and unexplained pedigrees are frequently observed (40, 41). Our AMeDS cases all develop generally uniform clinical symptoms (AA, mental retardation, and dwarfism), and they are genetically characterized by true DI, i.e., mutations in two distinct genes are necessary and sufficient to cause a disease, with no exception. The ALDH2 rs671 defective allele is also involved in the severity of AMeDS clinical features; however, unlike other coinheriting genetic modifiers, it is essential for the disease development in addition with the ADH5 deficiency.

The accumulation of unrepaired endogenous DNA damage ultimately triggers cancer and aging through a failure in the essential functions of various cellular processes (4244). DNA lesions may induce mutations and chromosomal aberrations that cause genome instability and an increased risk of cancer. In parallel, major DNA lesions can also interfere with transcription and replication, resulting in the loss of accurate gene expression profiles, delay of cell cycle progression, and induction of cell death, which contribute to aging. The cellular defense against DNA damage involves serial mechanisms (two-tier protection): (tier 1) enzymatic detoxification processes of highly reactive genotoxic chemicals, such as reactive oxygen species (ROS) and active aldehydes, and (tier 2) DNA repair processes to eliminate various types of DNA damage and restore genetic information. In this regard, dysfunctions in either of these mechanisms may result in carcinogenesis and aging-related phenotypes. In particular, cancer predisposition and progeroid symptoms are naturally observed in a variety of human genetic disorders due to mutations in DNA repair genes (tier 2) (45). In contrast, there is only a small number of congenital diseases that are caused by abnormalities in the detoxification systems of chemical compounds that induce DNA damage (tier 1). Recent clinical reports have shown that a complete absence of the superoxide dismutase 1 (SOD1) enzyme, which is involved in the removal of ROS, causes an extreme oxygen sensitivity in patients cells and is associated with autosomal recessive progressive spastic tetraplegia and axial hypotonia (STAHP), characterized by severe and progressive psychomotor retardation in humans (46, 47). Note that mutations in the SOD1 gene usually cause autosomal dominant amyotrophic lateral sclerosis because of the toxic effects of protein aggregation rather than by the loss of enzymatic activity (48). The STAHP phenotype with the lack of SOD1 may be due to an overload of oxidative DNA damage in the single-strand break (SSB) repair pathway; this postulation is corroborated by a report that SSB repair deficiency by the XRCC1 gene mutation causes spinocerebellar ataxia (SCA) (49). Our AMeDS cases and the animal model further support the idea that malfunctions in the detoxification systems of active genotoxic compounds cause symptoms of cancer predisposition and accelerated aging.

Patients with AMeDS display many characteristic clinical features that overlap with other DNA repair deficiency disorders (table S3). Here, we propose that FA-like hematopoietic abnormalities observed in AMeDS may result from the overload of the FA pathway (ICL repair pathway) due to limitations of cellular detoxification properties against endogenous formaldehyde. During differentiation including hematopoiesis, various histone demethylases erase methyl marks on lysine residues of histones associated with gene regulation, leading to the release of active formaldehyde (50). Under a limited capacity of the FA pathway, the rs671 defective allele would significantly contribute to the increase of unrepaired formaldehyde-induced DNA lesions during hematopoiesis. This idea is consistent with previous reports that rs671 is a genetic modifier of the severity of BMF in Japanese FA cases (51), as well as in children with sporadic AA (52); this is also true for the FA pathwayproficient AMeDS cases, as rs671 genotype defines the severity of AMeDS clinical features. AMeDS cases display premalignant MDS or leukemia, indicative of cancer predisposition, although no solid tumor is present at the moment. Adulthood patients with FA commonly develop solid tumors including head and neck squamous cell carcinoma, in addition to MDS and leukemia (53). Because the ages of AMeDS cases with clinical records range from 2 to 16 years, follow-up studies are necessary to investigate the etiology of cancers. On the other hand, in canonical FA, severe dwarfism and neurological abnormalities, as well as psychomotor retardation, are uncommon. In this respect, AMeDS clinical features have substantial similarities to those of segmental progeroid disorders, RJALS and CS (and its severe forms, COFS and XFEPS). Since RJALS cells with mutations in the SPRTN gene display hypersensitivity to DPC-inducing chemicals, including formaldehyde (54), the phenotypes of AMeDS that overlap with RJALS could be explained from the overload of DPC repair pathway. From these perspectives, the severe phenotypes of AMeDS may be due to a combined failure of multiple DNA repair processes as represented by BRCA1 (FANCS) or XPF (FANCQ)deficient atypical FA cases, as well as by patients with ERCC1/XPF-deficient COFS/XFEPS (25, 5557), because BRCA1 and the ERCC1/XPF complex, respectively, contribute to DNA double-strand break repair and NER, together with the FA pathway. ADH5 and ALDH2 double deficiency would also induce various types of DNA damage apart from ICL and DPC, such as simple aldehyde base adducts, which can be repaired independently of the ICL and DPC repair pathways (5860). Consequently, in AMeDS cases, these synergistic effects may trigger the severe clinical features. Likewise, CS-like clinical features observed in AMeDS rather suggest an additional failure in TCR; further analyses will address this possibility. In conclusion, our data propose that the combined deficiency in formaldehyde metabolic processes, by harboring the prevalent polymorphism rs671 in ALDH2 together with biallelic mutations in ADH5, overburdens the multiple DNA repair pathways and leads to a true digenic disorder, AMeDS, which is similar both in the clinical features and molecular pathogenesis but distinct from other DNA repair deficiency disorders.

Affected individuals and normal control samples were obtained with local ethical approvals (the Ethics Committee for Human Genome Studies in Research Institute of Environmental Medicine, Nagoya University; the ethics committee of the Nagoya University Graduate School of Medicine). Written informed consent was obtained from the patients.

Next-generation sequencing (NGS) was performed in-house or by macrogen. Genomic DNA of the individuals was enriched by using the Agilent SureSelect Human All Exon Kit version 5/6 (Agilent, Santa Clara, CA, USA). The captured genomic fragments were sequenced on the Illumina HiSeq 2500 sequencer (Illumina, San Diego CA, USA) using paired-end (PE) flow cells to obtain 100 to 150base pair PE reads of 100 to 200 coverage.

The NGS data were analyzed by our standard exome pipeline. Briefly, low-quality reads were trimmed out by Trimmomatic (version 3.36) (61). The reads were then aligned to the human reference genome (GRC h37/hg19) with the Burrows-Wheeler Aligner (version 0.7.12-r1039) (https://arxiv.org/abs/1303.3997). Duplicate reads were removed using Biobambam2 (version 2.0.72) (doi: 10.1186/1751-0473-9-13). The aligned reads were locally realigned, and base quality scores were recalibrated using the IndelRealigner and BaseRecalibrator programs in Genome Analysis Toolkit (GATK; version 3.5) (62). Single-nucleotide variants were identified by the HaplotypeCaller program in GATK. All the variants were annotated with ANNOVAR (63) based on the GENCODE release 19 (GRCh37.p13). To further determine potentially pathogenic changes, commonly observed variants (MAF > 0.01) were excluded using public databases and functionally significant changes were extracted. According to an autosomal recessive inheritance model, genes that carried homozygous or compound heterozygous changes were determined. We considered 2 to 18 potential causative genes in each of the affected individuals (table S1), and we identified ADH5 as only pathogenic candidate gene shared among any subset of the affected individuals.

The following cell lines were used in this study: U2OS; RPE1 hTERT; HEK293 (human embryonic kidney293), immortalized normal human embryonic kidney cells; 1BR, normal human primary fibroblast; and FA20P, primary fibroblast from an FA-A individual. N0608, N0611, and N0614 were obtained from JCRB Cell Bank. All cells were maintained in Dulbeccos modified Eagles medium (DMEM) (Wako) supplemented with 10% fetal bovine serum (FBS; Invitrogen) and antibiotics, unless otherwise noted. Mycoplasma testing was performed routinely.

For plasmid-based genome editing experiments, a guide RNA (gRNA) coding sequence was cloned into the pX459 vector. The designated plasmid was transfected into U2OS cells using X-tremeGENE HP DNA Transfection Reagent (Merck). Cells were selected for 48 hours with puromycin (1 g/ml) in DMEM with 10% FBS. Single clones were isolated by limiting dilution. For ribonucleoprotein-based genome editing experiments, HiFi Cas9 Nuclease V3 (Integrated DNA Technologies) was mixed with crRNA (CRISPR RNA):tracrRNA (trans-activating CRISPR RNA) complex and single-stranded oligodeoxynucleotide (ssODN). The mixture was electroporated into U2OS or RPE1 hTERT cells using 4D-Nucleofector (Lonza). Cells were recovered by DMEM with 10% FBS and cultured on a 35-mm dish for 24 hours. Single-cell clones were isolated using a limiting dilution in 96-well plates. All gRNA and ssODN sequence information are listed in table S2.

Genomic DNA was extracted from gene-edited cells using the MightyAmp Genotyping Kit (Takara) according to the manufacturers instruction. Mutations and indel frequencies of gene-edited cells (CD34+ HSPCs, U2OS cells, RPE1 hTERT cells, and mice) were confirmed by Sanger sequencing and TIDE (tracking of indels by decomposition) analysis (64). Untreated cells were always used as a negative control for calculating indel frequencies with TIDE. All primer sequence information are listed in table S2.

Total RNA was isolated using an RNeasy mini kit (Qiagen), according to the manufacturers instructions, and cDNA was generated with SuperScript IV (Thermo Fisher Scientific), according to the manufacturers instructions. The quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed using LightCycler 96 System (Roche). For the detection of target genes, SYBR green (Qiagen) was used according to the manufacturers instructions. Expression of mRNAs was quantitated using the following set of primers: ADH5 (forward, 5-CCAGCACATTTTCTGAATACAC-3; reverse, 5-ACCAAAGACGGCACAAAC-3) and ACTB (forward, 5-TCACCCACACTGTGCCCATCTACGA-3; reverse, 5-CAGCGGAACCGCTCATTGCCAATGG-3). The LightCycler was programmed to run an initial heat-denaturing step at 95C for 15 min, 45 cycles at 94C for 15 s, an annealing step for 20 s at 58C, and an extension step for 10 s at 72C coupled with fluorescence measurements. Following amplification, melting curves of the PCR products were monitored from 65 to 97C to determine the specificity of amplification. Each sample was run in triplicate, and expression of target genes was normalized against ACTB.

Cells were lysed in EBC buffer [50 mM tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 0.5% NP-40, and 1 mM dithiothreitol (DTT)] or denaturing buffer [20 mM tris (pH 7.5), 50 mM NaCl, 1 mM EDTA, 0.5% NP-40, 0.5% SDS, 0.5% sodium deoxycholate, and 1 mM DTT] supplemented with protease inhibitor cocktail (Roche) and phosphatase inhibitor cocktail (Nacalai Tesque) and incubated on ice, cleared by centrifugation. Purified proteins were resolved by 6, 12.5, or 5 to 20% gradient SDSpolyacrylamide gel electrophoresis. Resolved protein samples were transferred to polyvinylidene difluoride membrane for immunodetection. Antibodies used for immunochemical experiments were as follows: rabbit monoclonal anti-ADH5 (ab174283, Abcam), rabbit polyclonal anti-ADH5 (HPA044578, Atlas Antibodies), mouse monoclonal anti-ALDH2 (MA5-17029, Invitrogen), rabbit polyclonal anti-SMC3 (A300-060A, Bethyl Laboratories), rabbit polyclonal anti-H2AX (no. 2577, Cell Signaling Technology), rabbit monoclonal anti-KU70 (no. 4588, Cell Signaling Technology), rabbit monoclonal anti-FANCD2 (ab108928, Abcam), rabbit polyclonal anti-FANCA (A301-980A, Bethyl Laboratories), mouse monoclonal antiACTB (sc-47778, Santa Cruz Biotechnology), rabbit polyclonal antiV5-tag (PM003, MBL), and mouse monoclonal anti-PARP1 (sc-8007, Santa Cruz Biotechnology).

U2OS cells were seeded in 96-well plates (10,000 cells per well) and treated with the following aldehydes for 8 hours: 4-HHE (Cayman Chemical), 4-hydroxynonenal (Cayman Chemical), 4-oxononenal (Cayman Chemical), acrolein (Wako), crotonaldehyde (Tokyo Chemical Industry), formaldehyde (Nacalai Tesque), glyoxal (Tokyo Chemical Industry), heptanal (Tokyo Chemical Industry), or methylglyoxal (Sigma-Aldrich). After incorporation of 5 M 5-ethynyl-2-deoxyuridine (EdU) for 1 hour, cells were fixed and permeabilized for 20 min in phosphate-buffered saline (PBS) containing 2% formaldehyde and 0.5% Triton X-100. After washing with PBS, cells were then incubated with coupling buffer with 10 M Alexa Fluor 488 azide (Invitrogen), 50 mM tris-HCl (pH 7.3), 4 mM CuSO4, 10 mM sodium ascorbate, and 4,6-diamidino-2-phenylindole (DAPI) for 60 min, followed by washing with PBST (PBS + 0.05% Tween 20). Fluorescent image acquisition and data processing were automated using CellInsight NXT (Thermo Fisher Scientific).

Cells were labeled with 5 M EdU for 1 hour (U2OS cells) or 2 hours (primary fibroblasts) followed by fixing in 70% ethanol overnight at 30C. Cells were incubated with coupling buffer with 10 M Alexa Fluor 488 azide (Invitrogen), 50 mM tris-HCl (pH 7.3), 4 mM CuSO4, and 10 mM sodium ascorbate for 60 min. DNA was stained with 7-aminoactinomycin D (7-AAD) or propidium iodide. Data were acquired on a Cytomics FC500 FACS analyzer (Beckman Coulter) or CytoFLEX S FACS analyzer (Beckman Coulter) and analyzed with FlowJo version 10.6.2.

For gene expression, HEK293 cells were transfected with the pLenti6.3 construct encoding gene of interest together with ViraPower Packaging Mix (Invitrogen) using Lipofectamine 2000 (Invitrogen). Viral particles were collected 48 hours after transfection and concentrated using PEG-it Virus Precipitation Solution (System Biosciences). For virus complementation experiments, viral particles produced by transfection of pLenti6.3 were used to infect cells. Selectin under blasticidin (5 g/ml) was carried out.

Cells were seeded in 96-well plates (500 to 1000 cells per well) and fixed and stained with 2% formaldehyde and DAPI at 4 days (U2OS and RPE1 hTERT cells) or 7 days (primary fibroblasts) after formaldehyde treatment. Cells were identified and quantified on the basis of DAPI signal using CellInsight NXT (Thermo Fisher Scientific).

The ALDH2 activity was analyzed using the colorimetric ALDH2 Activity Assay Kit (Abcam) according to the manufacturers instruction.

CD34+ HSPCs from normal cord blood were procured from RIKEN BioResource Center (RIKEN BRC). Frozen CD34+ HSPCs were thawed and cultured in StemSpan SFEM II medium supplemented with StemSpan CC110 cocktail (STEMCELL Technologies) for 48 hours before electroporation. CD34+ HSPCs were electroporated using 4D-Nucleofector (Lonza). The following conditions were used: 50,000 cells were pelleted and resuspended in Lonza P3 solution containing TrueCut Cas9 protein v2 (Thermo Fisher Scientific) complexed with synthetic chemically modified sgRNA (ADH5#1, 5-UCAGGGUAUAGGCAUCGGUG-3; ADH5#2, 5-CUGAUAGAUCAUUGCCACUG-3; Synthego) at a 1:3 molar ratio. This mixture was electroporated using the Lonza 4D-Nucleofector (program EH-100). Electroporated cells were recovered and transferred to culture in StemSpan SFEM II medium supplemented with StemSpan CC110 cocktail.

CD34+ HSPCs at 2 days after electroporation were resuspended in Iscoves MDM (modified Dulbeccos medium) and plated on methylcellulose-based media (MethoCult Optimum, STEMCELL Technologies) according to the manufacturers instruction. Cells were plated onto 35-mm petri dishes, in duplicate, and incubated for 14 days at 37C with 5% CO2 and 95% humidity. CFU-erythroid; burst-forming uniterythroid; CFU granulocyte and macrophage; and CFU granulocyte, erythroid, macrophage and megakaryocyte were classified and counted according to standard morphological criteria under microscopy in a blind fashion.

All the animal studies were conducted in compliance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. The experiments using genetically modified mice were approved by the Animal Care and Use Committee and the recombinant DNA experiment committee of Nagoya University and Osaka University.

C57BL/6JJcl mice were purchased from CLEA Japan. The animals were kept under conditions of 50% humidity and a 12-hour light/12-hour dark cycle. They were fed a standard pellet diet (MF, Oriental Yeast) and tap water ad libitum, unless otherwise noted.

The following reagents were purchased: HiFi Cas9 Nuclease V3, tracrRNA, crRNA, and ssODN (Integrated DNA Technologies). To design gRNA sequence, software tools (http://crispor.tefor.net/ and https://crispr.dbcls.jp/) predicting unique target sites throughout the mouse genome were used. Pronuclear-stage mouse embryos were prepared by thawing frozen embryos (CLEA Japan) and cultured in a KSOM (potassium simplex optimization medium) (ARK Resource). For electroporation, 100 to 150 embryos at 1 hour after thawing were placed into a chamber with 40 l of serum-free media (Opti-MEM, Thermo Fisher Scientific) containing HiFi Cas9 Nuclease V3 (100 ng/l), Adh5 gRNA (100 ng/l), Aldh2 gRNA (100 ng/l), and ssODN (300 ng/l). They were electroporated with a 5-mm gap electrode (CUY505P5, Nepa Gene) in a NEPA21 super electroporator (Nepa Gene). The poring pulses for the electroporation were voltage of 225 V, pulse width of 1 ms for mouse embryos, pulse interval of 50 ms, and number of pulses of 4. The first and second transfer pulses were voltage of 20 V, pulse width of 50 ms, pulse interval of 50 ms, and number of pulses of 5. Mouse embryos that developed to the two-cell stage after the electroporation were transferred into the oviducts of female surrogates anesthetized with sevoflurane or isoflurane (Mylan). All gRNA and ssODN sequence information are listed in table S2.

CT analysis was performed on anesthetized mice using a CosmoScan FX system (RIGAKU), with the following parameters: x-ray tube (90 kV), current (88 A), FOV (field of view) (60 mm), and voxel size (240 m). Data were analyzed and visualized by 3D Slicer version 4.10.2.

Peripheral blood from the animals was subjected to complete blood cell count analysis. RBC, platelet (Plt), white blood cell (WBC), HGB, HCT, MCV, mean corpuscular hemoglobin concentration, and lymphocyte were measured using an IDEXX ProCyte Dx (IDEXX Laboratories).

Bone marrow cells were flushed from femurs and tibias using a 26-gauge needle, and spleens and thymuses were dissociated by crushing followed by passing through a cell strainer in Ca2+- and Mg2+-free Hanks buffered salt solution (Gibco) supplemented with 1% heat-inactivated bovine serum (Gibco). RBCs were lysed by resuspending the cells in RBC lysis buffer (eBioscience) for 5 min at room temperature. Cells were filtered through a 70-m cell strainer to obtain a single-cell suspension. Number of cells was measured with a hemocytometer. Antibodies used for fluorescence-activated cell sorting (FACS) analysis were as follows: fluorescein isothiocyanate (FITC)conjugated lineage cocktail (no. 133302, BioLegend), CD41 (FITC, no. 133903, BioLegend), FcRI (FITC, no. 134305, BioLegend), CD117 (APC, no. 105811, BioLegend), Sca-1 (PE, no. 108107, BioLegend), CD48 (Brilliant Violet 421, no. 103428, BioLegend), CD150 (APC/Fire 750, no. 115940, BioLegend), CD135 (Brilliant Violet 421, no. 135313, BioLegend), CD127 (PE/Cy7, no. 135014, BioLegend), CD16/32 (Brilliant Violet 421, no. 135313, BioLegend), CD34 (APC/Fire 750, no. 135014, BioLegend), CD3 (Alexa Fluor 488, no. 100321, BioLegend), CD19 (APC, no. 152410, BioLegend), CD4 (PE, no. 130310, BioLegend), and CD8a (APC, no. 100712, BioLegend). Antibody staining was performed at 4C for 20 min. Dead cells were excluded by staining with 7-AAD (BioLegend). Data were acquired on a CytoFLEX S FACS analyzer (Beckman Coulter) and analyzed with FlowJo version 10.6.2.

Acknowledgments: We would like to thank the families and clinicians for their involvement and participation. We are grateful to A. Lehmann for helpful comments and discussions on the manuscript. We thank M. Nakashima for comments on the animal analyses. We are grateful to S. Hashimoto, M. Isono, and K. Horiba, as well as M. Toyama, Y. He, and K. Katoh for the technical assistance. We thank JCRB Cell Bank (Osaka, Japan) for primary fibroblasts from patients, RIKEN BioResource Center (Tukuba, Japan) for fresh CD34+ umbilical cord blood cells and NIH for the use of dbGaP repositories (project no. 19720). Funding: This work was supported by the Special Coordination Funds for Rare and Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, and JP18kk020501 to N.Ma. and JP19ek0109281, JP19ek0109229, and JP19ek0109301 to T.O.); Grants in Aid for Scientific Research KAKENHI from the Japan Society for the Promotion of Science (JP16K21084 and JP18H03372 to Y. Oka, JP17K07255 and JP17KT0125 to K.Hi., JP17H01539 to N.Ma., 26253041, 15H02524, 16H06277, 18H03045, and 19K19425 to K.M., and JP15H02654 and JP17H00783 to T.O.); Grants in Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture, and Technology of Japan, consisting of Priority Areas of Cancer (17015018), Innovative Areas (221S0001), and a Grant-in-Aid for the Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour, and Welfare of Japan to K.M.; a medical research grant from Daiichi Sankyo Foundation of Life Science to Y. Oka; a grant from Daiko Foundation to T.O.; Science Research Grants from Uehara Memorial foundation to Y. Oka and T.O.; and medical research grants from Takeda Science Foundation to Y. Oka and T.O. Author contributions: Y. Oka and T.O. designed the study and the experiments. Y. Oka, Y.Oku., K.Hi., N.Mit., Y.H., N.Miy., Y.Kaw., K.T., M.N., N.Ma., F.M., K.M., and T.O. analyzed the genetics data. Y. Oka, Y.N., Y.Oku., K.Ha., H.T., M.S., Y.Kas., S.N., and T.O. performed molecular and cell biological experiments. Y. Oka, M.S., Y.Ko., M.Y., M.T., T.S., S.Ki., and T.M. performed animal studies. Y. Oka., M.H., H.M., Y.Oku., K.Hi., K.Ha., T.H., T.K., H.S., T.I., S.O., K.Y., Y.W., K.K., S.M., K.I., M.O., H.K., F.M., Y.T., S.K., and T.O. analyzed clinical manifestations of the affected individuals and healthy control cases. M.H., H.M., K.Ha., T.K., H.S., T.I., S.O., K.Y., Y.W., K.I., M.O., H.K., F.M., K.M., Y.T., and S.K. contributed the patients and control samples. Y. Oka and T.O. wrote the manuscript. M.H., Y.N., H.M., Y.Oku., and K.Hi. contributed equally to the study. All authors commented on the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome - Science Advances

Recommendation and review posted by Bethany Smith

Cancer cells pose an uncanny ability to make new cells and dodge drugs, "somewhat like would-be robbers hacking the bank's alarm code," one doctor explains. But researchers at Cincinnati Children's Hospital Medical Center have figured out how cancer cells rewire themselves and, in turn, how to possibly overcome drug resistance.

This drug resistance may explain why some acute myeloid leukemia (AML) and other cancer patients suffer fatal relapses despite many improvements in leukemia outcomes over the years, according to a Children's news release.

"Overcoming resistance to therapy remains a holy grail of leukemia treatment," says Yi Zheng, Ph.D., director, experimental hematology and cancer biology at Cincinnati Children's. Zheng and his colleagues have now discovered a way to boost the effectiveness ofmTOR inhibitors, which prohibit unwanted cell proliferation.

"While the latest study is based on mouse models, building upon the findingspublished Dec. 21, 2020, in PNASeventually could improve outcomes for people with AML, and possibly other forms of cancer," a release says.

What Happens When Treatments Target mTOR?

"Using a novel mouse model, we have learned that deleting the mTOR gene prompts blood stem cells to multiply rapidly to open other pathways to continue producing new blood cells," says Zheng, the study's senior author. "We also found that leukemia cells use a similar response to continue multiplying despite mTOR-inhibiting treatments."

He says attacking mTOR essentially sets off alarms among hemopoietic stem cells (HSCs), which act like blood cell factories deep in bone marrow. Then the cells themselves produce a flood of new, re-wired blood cells. These re-wired stem cells, treated with mTOR inhibitors, can begin multiplying, rendering mTOR inhibitor drugs useless.

The co-authors say mTOR treatment resistance can be counteracted by inhibiting activity of the MNK, CDK9 or c-Myc genes. So-called BET inhibitors can act against c-Myc activity. Other inhibitors that are in clinical trials can act against CDK9.

Next Steps

Scientists at Cincinnati Childrens have already launched some of the research needed to prepare the combination therapies for in vivo test leading to human clinical trials, the news release says. That process will take time, but since mTOR inhibitors have been widely tested in clinical trials, investigators have a head start on exploring combination therapies.

Longer term, the findings may extend beyond AML, Zheng says, because mTOR has been a recognized target in most human cancers, including solid tumors like brain tumors.

Link:
New Combination Therapy Tested By Children's May Offer Hope For Leukemia Patients - WVXU

Recommendation and review posted by Bethany Smith

Meet John.

Hes 6. He lives with his family on a small farm in Washington, Iowa. He likes to fish he can bait his own hook and take off his own catch. He likes to climb trees. Hes as solid as any 40-pound wrestler youll meet.

And hes walking down a path thats just as bright as it may be dark.

Johns losing his vision and his hearing. Its happening slowly, and could take years.

So for now, Johns practicing single-leg takedowns and sprawls. Hes building elaborate train sets and playing oranges and lemons on the piano. Hes sitting on his dads lap to help drive the tractor.

We want him to get as much experience in certain things as he can while he can soak them up, his mom, Heather Koch, told The Gazette.

Because this isnt a story about a medical miracle. It isnt a story about some novel discovery sparking new hope for John and his family although discovery is happening.

Its a story about a more remarkable kind of hope. The kind that persists without groundbreaking advancements. The kind that isnt reliant on good news.

The kind that lives in the stark reality that is theirs.

He was born Feb. 4, 2014, and he was perfect.

His older brother, Gus, had died five years earlier at just 1 month old on Jan. 8, 2009, from Zellweger syndrome, a rare congenital disorder. His older sister was born healthy in 2012. And John came after.

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He was totally normal, Heather said. Everything was fine. He passed his newborn hearing screen.

But as John grew, she and her husband, Greg Koch, began wondering if something was off. As their 18-month-old John would go toddling down the hall in the predawn hours, Heather would try whispering him to her.

I would poke my head out of my room and I would say, quietly because everyone else was still sleeping, John, John, come here, come here, and he would keep on walking, she said. He just wasnt hearing me.

John would press musical toys hard against his ear desperate to hear their song. He also wasnt saying much besides mama, dada, and uh oh.

So when John was 2, they drove him to Cincinnati Childrens Hospital and learned he had moderate hearing loss. Because the cause was unknown, the family had John checked for a catalog of possible culprits.

Usher syndrome was on that list, Heather said.

Results would take a while, so the family returned home and eased back into their routine. Until eight weeks later, on June 23, 2016, when Heathers phone rang. She was by herself, on her way to meet her mom and sister to go shopping.

It was gut-wrenching, she said. I called Greg right away, but there was no hiding it from my mom and sister a few minutes later. So they and the rest of our families all knew that day also.

John had genetic mutations amounting to Usher syndrome type 2A.

They said he will slowly lose his hearing and his vision for the rest of his life, Heather said.

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Before getting the news, she hadnt done a lot of research on all the possible causes of Johns hearing loss.

Were not the panic type of people, so we were praying, she said. But not panicking.

They carried that mentality with them into their new reality with John which, while devastating, enabled a deeper understanding of how they could support him.

Like giving him new hearing aids. The moment John put them in, Heather said, he could hear their whispers.

He looked right at us, she said, adding, Those next few days were amazing. He could hear the chickens for the first time. And he could hear the airplanes in the sky for the first time. Big things for a 2-year-old.

The family addressed his vision troubles with new glasses, which opened to some degree a new world for John, who spent the next two years in speech therapy learning to talk like everyone else.

Once I caught seven fish in a row, John told The Gazette, showing off his storytelling skills. First cast, I caught one. Second cast, I caught one. Third cast, caught one. Fourth cast, caught one. Fifth cast, caught one. Sixth cast, caught one. Seventh cast, caught one. Like, I just cast it and reeled it in, and I just kept catching fish.

The Kochs dont have a precise picture of Johns long-term prognosis, but University of Iowa ophthalmic genetics professor Arlene Drack said patients with Ushers develop retinitis pigmentosa, a progressive type of vision loss, typically in their teens.

She reported a huge amount of research going on at the University of Iowa and around the world on how to replace or repair the genes that cause (retinitis pigmentosa).

We hope there will be a gene therapy that will help John in the future, Drack said.

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World-renowned UI Institute for Vision Research Director Edwin Stone is among those paving the way in groundbreaking research that he believes will work for patients like John.

Were hoping to have some gene and stem cell therapy that will work for this condition in this childs lifetime, he said. So I think that theres reason for optimism.

For now, Heather and Greg are heeding doctor warnings that Johns hearing and vision will continue to fade.

Theyre telling us it probably will, Heather said. Theyve been given symptoms to watch out for like trouble seeing at night.

They said he will start stumbling over things in the dark, he wont be able to see the stars in the sky, Heather said. And we have just started seeing some of the night vision symptoms.

The guessing is hard. John might trip over something in the garage and Greg will find himself wondering if its the syndrome.

How do you know? he said. Is he a 6-year-old kid whose mind gets ahead of where his feet are going? Or is it part of it? You just dont know what is what, and youre always thinking, Is that a sign?

They fight off paranoia with hope, like hope for expanding research and new technology, and by homing in on their vision for a normal life.

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Hes going to have some things to overcome, Heather said. Our job, I think, is to teach him to be tough enough to overcome those things. Because whats the alternative?

They acknowledged some things might be different or difficult for their son like driving.

So he drives now, Greg joked about his co-pilot in the field.

But theyre not raising John differently from their four other kids all of whom have tested negative for Ushers.

And, being so young, John doesnt yet know the full weight of his diagnosis.

I think one thing we probably will say is, this is just the hand you were dealt. And its not going to stop you from living your life, or accomplishing anything, or being the best person that you can be, Heather said. We will expect the same out of him that we do of all our other kids.

But they acknowledged, someday John will ask.

And he deserves to know, Greg said. But its not fair to make a 6-year-old carry that burden in its full weight like we have to carry it.

And they do.

If theres a day where hes displaying a symptom of something, thats heavy, Heather said. So you just carry that on that day.

But largely they stay optimistic.

Johns going to have the best life no matter what, she said, citing his involvement in a sport they believe will help make that possible. Thats part of wrestling.

John has been wrestling since age 3. And hes good.

He goes to Husky Wrestling Club in Riverside and started going to Big Game Wrestling Club in North Liberty, too, around age 5.

John is a light, said Big Game Chief Executive Officer and Coach Dylan Carew. His fight, courage, and personality are inspiring.

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The family is close friends with Mike Zadick, a UI All-American wrestler in the early 2000s who went on to have a successful international wrestling career.

Zadick was Heathers neighbor when they both lived in Solon and, Heather said, He and his family have become family to us.

Having seen John in matches and meets, Zadick told The Gazette, hes got a natural feel for the sport.

At a young age, 4 or 5 years old, he had real natural movement, Zadick said. It was like, Wow, look at this. You can tell when a kid has a natural feel.

Not only is John well-suited for the sport, its well-suited for him in the skills it instills might become particularly relevant as he ages.

Wrestling, the word itself, its constant work and battle and struggle, Zadick said.

Echoing that sentiment, Carew said, Adversity is every day with wrestling.

So when it comes to someone with a challenge beyond normal, what better sport?

Johns physical obstacles which may be seen by some as disabilities have actually given him an edge on the mat, according to Carew.

You can tell he focuses a lot more to details, he said. He pays more attention because he needs to.

John has to wrestle without his hearing aids or glasses leaving him reliant on skills hell increasingly lean on as he loses more of his sight and hearing.

Without those supports, Greg before matches warns officials his son cant hear them.

They need to communicate with him by touching him and using hand signals, Heather said. He usually cant hear the whistle.

But largely, when Johns on the mat, hes like any other kid. Hes fighting for take downs and escapes. Hes learning to accept losses a skill that could become especially helpful as John matures into a braver understanding of the hand hes been dealt.

Were going to make him as mentally strong as possible, so he can carry it to when he gets big enough to carry that burden, Heather said.

Take last spring, when a 38-pound John found himself in the third-place bout in the kindergarten bracket at AAU Super Pee Wee State.

I was so tired I almost fell asleep during the match, John said.

Exhausted and hurting, he barely made it into his stance before the official whistled the start of the overtime period.

But I kept wrestling, wrestling, wrestling, John said.

From the side of the mat, Heather shouted, John, youre tough bud.

And he was, holding off his opponents shot and getting behind him for two points, before jumping into his moms arms with a well-deserved sense of accomplishment one sense hes in no danger of losing.

Comments: (319) 339-3158; vanessa.miller@thegazette.com

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This 6-year-old Iowa boy is losing his vision and hearing. But his family holds on to hope. - The Gazette

Recommendation and review posted by Bethany Smith

There is no proven way to permanently thicken hair if you are healthy and have no underlying health conditions. But, there are lifestyle adjustments to improve your overall hair health and prevent breakage.

Here are common causes of thin hair and five tips for healthier, thicker hair.

"The earlier someone starts therapies, the more likely they are to be effective," Wasserbauer says. "If you are losing more than 100 hairs per day, or if your hair is less thick when you run your hand through it, it is worth seeing a hair expert."

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If your hair loss is not due to an underlying health condition, you may be able to thicken your hair with the following lifestyle changes:

Cortisol, the stress hormone, disrupts the functioning of the hair follicle and contributes to thinning hair. A 2016 study found high levels of cortisol can cause certain proteins in hair to break down.

It is important to differentiate between different types of stress, Wasserbauer says. If you experience a stressful event, you may notice a period of hair loss and accelerated thinning, but the hair usually recovers within a year. Ongoing hair loss is more serious, and unless it is caught, diagnosed, and treated, it may result in permanent loss.

A hormone imbalance, such as during pregnancy or menopause, can cause thinning hair. A decrease in estrogen or an increase in testosterone levels can thin hair as well, Umar says.

Research found an imbalance of hormones like estrogen, progesterone, and prolactin can all contribute to hair loss. Hair loss can also be due to an imbalance of thyroid hormones, Umar says.

Heat styling products, like blow dryers, straighteners, and curling irons all weaken the hair shaft and fiber, Umar says. These products damage the cuticle on the outer layer of the hair, especially if the heat setting is set too high or you use a heating product daily.

A 2004 study found using a curling iron causes hair to weaken and break, though hair treated with a conditioner showed less damage than hair that was not.

Sulfates are chemicals found in most shampoos and soaps that provide the "sudsy" effect when you lather them up.

Sulfates also strip hair of its natural oils and moisture, Umar says, causing it to become dry and brittle, which makes it break more easily.

If you have no underlying health conditions causing hair loss, there is no proven way to thicken your hair. However, you can improve overall hair health by eating a nutritious diet, limiting heat styling, and using a sulfate-free shampoo. Healthier hair means less damage and breakage, which can help hair grow longer and thicker.

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5 tips to get thicker hair and common causes of hair loss or thinning - Business Insider India

Recommendation and review posted by Bethany Smith

Menstruation or monthly period is the most familiar phenomenon of a female body going through the reproductive age. At a particular time of each month, our uterus sheds off the ovarys unfertilized egg and all other residual chemical and biological waste materials. Usually, every healthy female has a menstrual cycle of twenty days, and it lasts for three to seven days. The time may come forward or halt for two to five days due to normal physiological conditions. But, if it exceeds more than a week or goes over a month, there is a reason to worry. What do you think first when you miss a period date? Most appropriately, a married female will think about pregnancy. Pregnancy causes a physiological halt of the menstrual cycle for nine months. But, other than that, there several more reasons for a . Here in this article, we will focus on some critical health conditions that may cause delayed menstruation in females. These conditions require immediate physicians attention.

Pregnancy

We already mentioned earlier that if your cycle is one or two days different from the last process, it is not a menstruation delay. But, some legit health conditions push the menstruation future later. For example, suspected pregnancy is one of the most common causes. If you are a married or sexually active female and miss more than seven days after the expected menstruation date, there is a good chance of pregnancy. You may complete the strip test to detect pregnancy at home. But, these procedures do not give accurate results all the time. So, taking a physicians advice will be the best option. Because taking any step without the right precaution can harm your health.

PCOS

Polycystic ovary syndrome or PCOS is one of the most common gynecological problems nowadays in the world. There are multiple cysts of bulge formation on the wall of the uterus, both inside and outside. Cysts or these bulges remain harmless initially, but they suck out blood from the surroundings to ensure the nutrients. That is why the patients body does not get enough blood supply or fails to excrete the unfertilized egg. Delayed menstruation and anemia is an overall presentation of a patient with PCOS.

Obesity

Obesity is the main culprit for most of the diseases in the human body. Extra fat accumulation alters the enzymatic and hormonal activities in the body that may cause delayed menstruation or complete amenorrhea at some time. Low body weight (LBW) is another major cause of delayed menstruation, similar to obesity. Eating disorders such as anorexia nervosa or bulimia, are pervasive in people, especially teenagers and models. But, trying to be thinner than ever may cost you more than the external beauty.

Stress

Stress and tension throw your hormones into a frenzy. Excessive cortisol, also known as the stress hormone, causes alterations in estrogen and progesterone secretion. Rhythmical alteration in the concentration of these two hormones is essential to keep up the normal menstruation cycle. The same thing goes with alcohol consumption and smoking too. These narcotic objects cause delayed and painful menstruation very often. Hormonal imbalances like thyroid storm, thyrotoxicosis, and low thyroid hormone are also responsible for delayed menstruation.

Delayed menstruation brings a lot of tension with it. It can be due to regular physiological alternation or merely a change in food habits. But, there can be deadly underlying diseases behind it. You cant be sure without proper examination and tests. So, consult your doctor if you are facing delayed menstruation frequently.

Laila Azzahra is a professional writer and blogger that loves to write about technology, business, entertainment, science, and health.

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A late period: things that might happen to your body - Omega Underground

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Heavy menstrual bleeding (HMB) or menorrhagia is one of the most common reasons for which women seek a Gynaecologists help. There are over 355 million menstruating women in India and about 60% of them may need medical help at some time in their lives to deal with heavy periods.Why do women have periods?Imagine a life without periods - no bleeding, no pain, no sanitary napkins and no tampons .freedom. Before you get too carried away with that utopian thought have you ever wondered why women have periods? Well, because we are special of course! Every month the womb prepares for a possible pregnancy and when this does not happen it sheds the lining of the womb which results in a period or menses. This usually happens once a month and a woman bleeds on an average for 5 days. The normal cycle varies from 21 to 35 days and the bleeding can last from 2 to 7 days. So, having a regular period most often indicates that a woman is ovulating every month. So ladies the next time you moan about your periods remember it is your monthly reminder that you are capable of having a baby!

How do I know if I have HMB?Do have heavy periods, needing constant change of menstrual hygiene wear, staining of clothes, cramps and severe pain in your tummy? Are you personal and professional life affected during your period days such that you cannot maintain your usual activities? Do you dread that time of the month? If the answer to most of the questions is yes, you are suffering from heavy periods and you need to see a doctor.

Symptoms of HMB

If you have any of the following symptoms you may be suffering from heavy menstrual bleeding and may need medical help:Soaking through one or more sanitary pads or tampons every hour for several consecutive hoursNeeding to use double sanitary protection to control your menstrual flowNeeding to wake up to change sanitary protection during the nightBleeding for longer than a weekPassing blood clots larger than a quarterRestricting daily activities due to heavy menstrual flowSymptoms of anemia, such as tiredness, fatigue or shortness of breath

What are the causes of HMB?About 60% of the women who consult me, do so because they have a menstrual problem. Heavy periods can be caused by hormone problems, uterine problems and other causes. Given below is a brief overview of the causes of heavy bleeding.

Hormone imbalanceIn a normal menstrual cycle, a balance between the hormones estrogen and progesterone regulates the buildup of the lining of the uterus (endometrium), which is shed during menstruation. If a hormone imbalance occurs, the endometrium develops in excess and eventually sheds by way of heavy menstrual bleeding.A number of conditions can cause hormone imbalances, including polycystic ovary syndrome (PCOS), obesity, insulin resistance and thyroid problems.Uterine fibroids - These are benign tumors of the uterus which may cause heavier than normal or prolonged menstrual bleeding.

Uterine Polyps - Small, benign growths on the lining of the womb cause heavy or prolonged or irregular menstrual bleeding.Adenomyosis - This condition usually affects women in their forties. Glands of the lining of the uterus become embedded in the muscle of the uterus and cause heavy, painful periodsIntrauterine device (IUD) - Menorrhagia is a side effect of using a nonhormonal intrauterine device for birth control.

Cancer - Uterine cancer and cervical cancer can cause excessive menstrual bleeding, especially if you are postmenopausal or have had an abnormal Pap test in the past.Inherited bleeding disorders - Some bleeding disorders such as von Willebrand's disease, a condition in which an important blood-clotting factor is deficient or impaired can cause abnormal menstrual bleeding.Medications - Certain medications like anticoagulants or blood thinners, can cause heavy menstrual bleeding.

Other medical conditions - A number of other medical conditions, including liver or kidney disease, may be associated with menorrhagia.

HMB Treatment options in the 21st Century

Treatment depends on the under lying cause of HMB can be divided into Medical, Surgical and Non-Surgical Procedures.

Medical

Drugs: The most commonly used non-hormonal drugs are Tranexamic Acid and Mefenamic Acid.

The Combined oral Contraceptive pill and Progesterones are hormonal drugswhich are used to treat this condition.

A hormonal Intra uterine device or system (IUS) has a small amount of progesterone hormone impregnated into it and releases it locally. It is inserted into the uterus and acts by thinning the lining of the womb, thus reducing the amount of blood lost during menstruation. Research has shown that this is the most effective form of medical treatment in suitable women.

Surgical and non-surgical proceduresHysteroscopy and/or Laparoscopy: If the HMB is due to fibroids or polyps these can be surgically removed by Hysteroscopy and/or Laparoscopy or by the traditional open method.

Endometrial Ablation: This procedure involves destroying (ablating) the lining of the womb (endometrium). The procedure uses a laser, radiofrequency or heat applied to the endometrium to destroy the tissue.

Endometrial resection: In this procedure an electrosurgical wire loop is used to remove the lining of the womb.This results in lighter bleeding. However, in women considering a pregnancy this procedure is not recommended.

Uterine artery embolization: When HMB is caused by large fibroids (more than 3 cm) this procedure helps shrink the fibroids (in selected cases) by blocking the uterine arteries and cutting off the blood supply to the fibroids. During this procedure, the doctor passes a catheter through the large artery in the thigh (femoral artery) and guides it to the uterine arteries, where the blood vessel is injected with materials that decrease blood flow to the fibroid.

HIFU: High Intensity Focused ultrasound is a non-invasive way to treat uterine fibroids. Using this treatment method in conjunction with image guidance, the physician directs a focused beam of energy through the patients skin, superficial fat layer, and abdominal muscles to heat and destroy the fibroid tissue without damaging nearby tissue or the tissues that the beam passes through on its way to the target.The treatment is conducted with the patient awake and uses either magnetic resonance (MR) or ultrasound (US) guidance.

Link:
Heavy menstrual bleeding What you should know - Times of India

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When the long summer days begin to slip away and temperatures begin to drop, its not uncommon to feel down in the dumps. Many may begin to feel resigned and sad as early as the fall when facing bone-chilling weather and increased isolation during the darkest time of any year, but its possible many more may feel affected by the challenges that this winter may bring.

The lethargy and cabin fever can range from mild winter blues to seasonal episodes of depression called seasonal affective disorder (SAD)

There are certain people who are susceptible to these changes when you get to the autumn and winter when the daylight gets shorter and its darker, explains Dr. Norman Rosenthal, a clinical professor of psychology at Georgetown University School of Medicine who lead the team that first described SAD in 1984 at the National Institute of Mental Health.

Rosenthal, who wrote a book about the seasonal depression titled Winter Blues, says that people in winter often over-eat, over-sleep and experience loss of energy, interest and more as the days grow shorter.

They can have difficulty in their relationships because they get socially withdrawn. They can have trouble at work because they dont concentrate and function as well. And this can all accumulate to the point that they feel quite depressed, Rosenthal tells TIME.

While many are able to stave off these creeping seasonal mood swings by spending quality time with loved ones or participating in activities that boost their mood, looming COVID-19 restrictions and lockdowns may make this years winter blues the most brutal yet. To help keep your mental health at its best, here are some possible, expert-approved ways to lift your spirits during the darkest time of year.

Lack of light is widely recognized as a trigger that affects peoples moods as they get less exposure to natural sunlight. A study of North America found that the prevalence of SAD increased the further north the subjects lived, as the hours of daylight decrease the further away one lives from the equator.

Both Rosenthal and Dr. Kelly Rohan, a professor and director of clinical training at the University of Vermont, recommend increasing your exposure to light every day, whether its inside or outside of your home.

Walk or do activities outside

Instead of staying cooped up at home, Rohan advises that you bundle up and get outside before those fleeting rays of sunshine disappear.

As long as youre not in a complete lockdown, get outside and walk, spending some time in nature breathing fresh air, Rohan advises, adding that you should make sure to adhere to CDC and local public health guidelines.

Seeing color in nature, like the little bit of greenery and getting direct sunlight exposure, all of these things are good for mental health. You just need to maintain a reasonable amount of distance between yourself and other people, she says.

If youre looking for a way to stay warm, dont forget to add layers. Windbreaker jackets for men or women can keep the chill out of your bones outside, and a reusable face mask will help protect you and everyone around you from infection.

Bright Light Therapy

If going for a walk outside simply isnt enough or you cant leave your home, Rosenthal recommends getting your daily dose of light with therapeutic light boxes.

Bring light into your home, Rosenthal advises. Use them for as little as 20 to 30 minutes in the morning, and you can start to feel a lot better.

Rosenthal, who pioneered bright light therapy after studying seasonal affective disorder, noted that its important to do your research before purchasing any bright light therapy lamp.

Lux is a measurement of light; 10,000 lux is how much was used in the research studies that showed the beneficial effects of lux. And [the bright light therapy lamps] need to be from established companies and screen out the ultraviolet light, Rosenthal explains. According to Rosenthal, the lights used in research studies often measure about one-foot by 18 inches. Having a larger lamp gives you more room to move around and ensures you get enough light exposure, he adds.

I like ones that are angled down towards the eyes, theyre the most comfortable he notes.

If youre in the market for a therapeutic lamp, the Carex Day-Light Classic is a way to bring extra light into your life.

Many experts believe that we can often feel deflated and lethargic during the darkest time of year because of lights influence over our sleep and circadian rhythms.

The most popular theory is that a later dawn in the winter triggers a slower-running circadian clock that is out of sync with the dark and light cycle, Rohan explains. This is our central biological timekeeper in the brain that changes and regulates our bodys 24-hour circadian rhythm which includes sleep, our core body temperature and melatonin releasethe hormone of darkness, she adds.

For this reason, Rohan and Rosenthal emphasize that regulating sleep is vital to getting your winter blues under control.

Natural sleeping aids

If you have trouble falling asleep at night, many people take melatonin supplements, a hormone your brain produces in response to darkness, to help get them on a regular sleeping schedule. Rosenthal recommends taking between one to three milligrams at night. If youd rather not ingest a sleeping aid, slip a lavender sachet inside your pillow covers to help you fall fast asleep.

Dawn simulator

Rosenthal also recommends a dawn simulator to help regulate your sleep cycle. A daylight or dawn simulator helps you wake up in the morning, says Rosenthal. I find it much nicer to awaken to an illuminated room than to awaken to darkness.

But the Hatch Restore, one of TIMEs Best Inventions of 2020, does more than just getting you up in the morning. Its designed to help you establish a sleep routine from the morning to night. During your waking hours, a dawn simulator helps you get out of bed and start your day. And at night, the device has a soft light to help you read and relax before bed or you can listen to soothing, meditative sounds to gently lull yourself to sleep.

Another way to reset your circadian rhythms is to establish and maintain a routine, says Rohan. Maintain a sense of normalcy as much as possible by following a schedule. Get up. Shower. Get dressed. Make your meals at the times that you usually do, she advises. Maintaining a schedule in this way can help regulate the circadian clock.

Keeping a daily planner, for example, might help you establish a schedule and hold yourself accountable for sticking with it.

Panda Planner Pro Daily Planner

Rohan also notes that its important to make time to do a hobby or something that you can enjoy.

This is really important for mental health because theres a very strong relationship between doing fun things and mood, Rohan says. She recommends finding simple pleasures that you can enjoy inside like playing a game or reading a book.

In addition to light, Rosenthal adds that stress also has a major impact on feeling down in the winter.

Add stress to the equation, and you will bring out the symptoms, Rosenthal says. As COVID-19 continues to affect so many lives and communities, stress and anxiety may feel inescapable this winter. And individuals who struggle with seasonal affective disorder are particularly sensitive to life events.

I think its the perfect storm because, by definition, their issue is recurrent depression, Rohan says. And then you couple that with a global pandemic, anxiety and very real issues that are associated with that uncertainty over jobs, finances, health, themselves and other people, and familyits kind of a double whammy.

Exercise

Rohan and Rosenthal recommended one easy stress-reliever that anyone can do at home: exercise.

Exercises are a wonderful way to decrease stress and so is meditation, Rosenthal says. Whether youre doing an hour-long workout or a quick 15-minute session, here are some home-workouts for a long and socially distant winter, recommended by fitness experts.

Skipping rope or using non-slip resistance bands are an excellent way to get some quick movement and keep the cabin fever at bay.

Yoga and meditation

Rosenthal also recommended yoga and meditation as a way to fight stress and find serenity during these turbulent times. So hit the mat for several sun salutations every day or if youre new to yoga and are looking for a guided practice, a monthly membership with Glo will fit your meditation and yoga needs. Additionally, if you need a comfortable way to move on the floor, Ewedoos has a great, eco-friendly yoga mat.

Read More: The Best At-Home Workouts for a Long and Socially-Distant Winter, According to Fitness Experts

If youre familiar with the winter blues, you may know people who swear by taking a daily dose of vitamin D. With less exposure to the sun, many have equated their seasonal mood swings to a deficiency in the essential vitamin. However, theres not a lot of data that shows that vitamin D improves mood.

There is surprisingly little research on vitamin D and seasonal affective disorder. And most of them have a teeny tiny sample size, Rohan says.

Most people in the U.S. have insufficient levels of vitamin D. Interestingly, researchers have noted that the groups who are at risk for vitamin D deficiency are also groups that are at risk of suffering from major depressive disorders. Rosenthal believes its the placebo effect of taking natural supplements and feeling healthy that lifts our spirits. While there may not be evidence of its efficacy as a mood booster, he says it cant hurt to take a supplement.

A lot of these vitamins may have a placebo, Rosenthal says. But, I wouldnt discount it if somethings making you feel better. It certainly shouldnt hurt you in the long run. If you do decide to take some supplements, Rosenthal recommends having your physician monitor your levels and intake. Vitamin D supplements are relatively inexpensive and available on Amazon.

Some self-help for the winter blues is necessary, especially during a time when mental health professionals are in high demand due to anxiety around the pandemic. However, Rohan stresses that you should seek out help if you are struggling to get your depression under control.

There are psychiatrists, psychologists, community health and mental health workers who are prepared to recommend an effective treatment because seasonal depression is very treatable, Rohan says.

Like many other major depressive disorders, antidepressant medications that require a prescription from a physician are proven to help treat SAD. Rohan has found that certain methods of cognitive-behavioral talk therapy can be extremely effective in treating SAD, a field that she herself has developed and studied.

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Dec. 22The coronavirus has so far killed about 325,000 people in this country, but that staggering toll does not include the multitudes who have died because of disruptions, isolation, and destitution related to the pandemic.

People with diabetes or Alzheimer's disease are particularly vulnerable.

An Inquirer analysis of federal data found that from mid-March through November, Pennsylvania had 753 more deaths attributed to Alzheimer's and diabetes than would be expected based on the last four years, a 14% increase for each cause. In New Jersey, there were 634 more deaths than expected for the two causes, an increase of 11% for Alzheimer's and 33% for diabetes.

The same trends occurred across the country, according to the Inquirer analysis, which aligns with other studies this year of "excess deaths" the gap between actual and expected deaths. The biggest deviation from the norm for Alzheimer's and diabetes was in April, but every month had excess deaths attributed to these causes.

Even in the best of times, diabetes can be a costly, complex, frustrating condition to manage. Sugar builds up in the blood, either because the body can't properly use or doesn't make enough insulin, the hormone that regulates sugar. If not controlled with diet, exercise, and often, medication, diabetes can cause devastating complications including heart disease, blindness, kidney failure, and lower-extremity amputations. Diabetes is the seventh leading cause of death in the United States.

Because Type 2 diabetes, the most common type, is closely linked to obesity, incidence has been soaring over the last decade. About 34 million American adults and children just over one in 10 have diabetes, and 88 million more adults about one in three have higher than normal blood sugar, called prediabetes.

Barbara Simon, an endocrinologist at Thomas Jefferson University Hospital, sees "multiple layers and multiple factors" related to the pandemic eroding the health and welfare of her diabetes patients.

"From my experience, the No. 1 issue is economic stress," she said. "Many are out of work and not able to afford their already expensive medicines."

Even the price of insulin, a decades-old generic drug, has increased dramatically over the last decade. (For those with Medicare, some Part D plans will cap the monthly copay for insulin at $35 beginning in January.)

"Studies have shown that prior to the COVID pandemic, up to 25% of insulin-dependent diabetics rationed supplies to save money," area physician Jennifer N. Goldstein wrote in September in The Inquirer. "The dramatic rise in unemployment and the loss of employer-sponsored health insurance due to the COVID-19 pandemic is likely to bring this crisis to a breaking point. This is particularly true in Pennsylvania, where unemployment rates hover around 13%, and almost 700,000 residents are uninsured."

As the U.S. Postal Service has struggled with pandemic-related turmoil including historic volumes of mail and funding gaps lost and late mail has been an issue for people ordering diabetes medication or blood sugar test strips. In June, when Cherry Hill resident Gerald Katz went to his local post office to ask what happened to his box of strips, he was told, "Well, we can't find out."

At the same time, the civil unrest and vandalism that led some Philadelphia pharmacies to shut down for weeks in the spring left many patients struggling to get their medications, said Simon at Jefferson.

People with diabetes are at elevated risk of severe COVID-19 if they get infected. But the isolation of staying home to avoid the virus also has dangers.

"Patients who used to go to the gym can't anymore," Simon said. "So they are more sedentary. Their eating habits have also changed. A lot of my patients report weight gains."

"Patients are also unsure about coming in for medical care, perhaps because of fear of traveling or overburdening the medical system," Simon added. "We try to assure them that diabetes is one of the diseases we can address well with telemedicine."

Lisa Walke, chief of geriatrics at the University of Pennsylvania's Perelman School of Medicine, said people with diabetes face a double whammy as the pandemic complicates their lives.

"Stress causes your sugars to be less well-controlled and, obviously, this has been a stressful time," Walke said.

It is possible that some of the excess deaths of Alzheimer's patients were actually due to undiagnosed COVID-19, experts said. Particularly in the early months, testing was not widespread in nursing homes, where many with advanced dementia live, and people without obvious symptoms may have been overlooked. Moreover, people with dementia were probably less likely than others to talk about feeling sick.

Walke, at Penn, said COVID-19 cases among frail dementia patients who live in the community are probably still being underdiagnosed. These patients may find it difficult to access testing, or may not be strong enough to wait in line.

Another possible factor behind the excess deaths: some Alzheimer's patients could not withstand the social isolation and changes in their routines that were meant to protect them from the virus.

"Routine is an Alzheimer's patient's best friend," said Carol Lippa, director of the Cognitive Disorders and Comprehensive Alzheimer's Disease Center at Jefferson University Hospitals. "They do better when they know what to expect."

Patients in facilities were suddenly surrounded by staff wearing masks, gowns, and face shields. People with dementia "don't have the capacity to understand that, and that's just stressful," Lippa said.

At the same time, family members have been prohibited from visiting, cutting off the interactions that mean the most. That compounds the effects of isolation. "The quality of interactions is not as good," Lippa said. "It's not with the people who love them and are familiar with them."

Walke and Lippa said dementia patients in the community also have felt their worlds shrink and change in harmful ways.

Maybe they couldn't go to adult day care or church or take their daily walk. Visiting their doctors and getting home care has been more difficult. If dementia patients needed hospitalization for an illness other than COVID-19, many hospitals still don't allow family visitors. Penn has changed that policy for dementia patients, Walke said, not only because they need loving contacts, but also because they need advocates who can communicate for them.

(c)2020 The Philadelphia Inquirer

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Pune, India, Dec. 21, 2020 (GLOBE NEWSWIRE) -- The global womens health market size is projected to reach USD 41.05 billion by 2027, exhibiting a CAGR of 3.2% during the forecast period. The COVID-19 pandemic is likely to reemphasize the importance of woman health and boost the market, observes Fortune Business Insights in its report. The infection caused by the coronavirus, which has affected more men than women across the globe, has brought the issue of health of women in the spotlight. A UN policy brief released in April 2020 stated that women hold less secure jobs and earn lower wages, which makes them highly vulnerable to the adverse effects of this pandemic. More importantly, as the pandemic intensifies, womens health will inevitably suffer.

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Increasing Prevalence of Women-centric Diseases to Aid Growth

A leading factor aiding the womens health market growth is the rising incidence of women-specific diseases and disorders around the globe. For example, the 2018 GLOBOCAN report by the International Agency for Research on Cancer (IARC) revealed that female breast cancer diagnoses stood at 2.1 million in 2018, accounting for approximately 11.6% of the total global cancer burden.

Further, female breast cancer was the fifth leading cause of death, contributing to 6.6% of the total global deaths in 2018. Another prime example is osteoporosis in women, a disease that generally afflicts menopausal women, causing reduction in bone density. The National Osteoporosis Foundation, for example, estimates that 20% of Caucasian women aged 50 and above have osteoporosis.

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As a result of their complex internal body dynamics, management of womens health, especially post-pregnancy and post-menopause, when hormone imbalances are known to occur, requires high level of efficiency and accuracy. Products designed to facilitate effective management of women-centric diseases will, thus, play a crucial in augmenting this market in the forthcoming years.

Robust Spending on Womens Healthcare to Stoke Market Growth in North America

North America is expected to emerge as a major revenue generator for this market during the forecast period, having registered a market size of USD 18.00 billion in 2019. The primary reason for the regions dominance in the market share is the large amount of funds allocated to enhance womens healthcare across the US and Canada. This is a result of the spreading awareness about health issues and the growing prevalence of women-specific diseases in the region.

Improving healthcare infrastructure, especially in Eastern European countries, is anticipated to bolster Europes position as the second-largest region in this market. Asia Pacific is expected to grow at the highest CAGR on account of the rising awareness about the importance women health.

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Launch of Digital Health Solutions for Women to Fuel Innovation

Some of the leading players in this market that specialize in female wellness and health are coming out with path-breaking digital solutions to address the unique health issues faced by women. These solutions are aimed at enabling women to take care of their independently without affecting their daily routines.

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Women's Health Market to Touch USD 41.05 Billion at 3.2% CAGR by 2027; Growing Focus on Women's Health Worldwide to Positively Impact the Market:...

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How to Find the Best CBD Gummies

When it comes to choosing the best CBD Gummies, thorough research of reputable brands and every ingredient, extracting method, and recommended dosage will undoubtedly help ensure you get precisely what you hope and pay for. Its main ingredient is cannabidiol or CBD, the most active cannabinoid in hemp plants that carries many health benefits for users.

Many health enthusiasts see CBD as a holistic health supplement. Its popularity is in part because while it is derived from a cannabis plant, it has no intoxicating side effect, unlike its sister-cannabinoid, tetrahydrocannabinol THC. You can also find it in various forms, including CBD oil tinctures, capsules, flowers, topicals, vapes, and a lot more.

If youre thinking about dipping your toes into the world of cannabis but are hesitant about the infamous marijuana high, try out hemp-derived products instead. Most of which are low in THC and wont have any undesired side effects if taken correctly. CBD gummies are a great start; they taste delicious and dont look so daunting as other products.

There are various things to look for when shopping for the best CBD gummies. Of course, it is important to always know more about a product before purchasing it and using it for yourself. Cannabidiol has been named a generally safe substance by the World Health Organization because of its lack of potential abuse and dependency.

Due to the influx of hemp products in the market recently, not everything undergoes the Food and Drug Administration (FDA). As demands go up, so does the supply, but you have to be careful not to fall into the trap of CBD oil brands selling themselves as the panacea for everyone.

Each type of CBD product is unique and can serve you differently if you know which ones to look for. Listed below are some factors to consider before making any major purchase and incorporating the cannabinoid into your daily health routine.

Not all hemp CBD products are made the same. Most use CBD oil to infuse gummies, pills, or topicals, but these extracts are also categorized into three main types: full-spectrum , broad-spectrum CBD, or CBD isolate. The first two contain many cannabinoids, with the full-spectrum containing a meager amount of THC while the broad-spectrum stays THC-free.

Isolates are potent, coming up to around 99% of pure CBD. This one is usually the most expensive out of the three because it is more challenging to produce. Full-spectrum CBD gummies are taken by those who want to experience the entourage effect. The legal limit of 0.3 percent THC by dry weight is still observed, so no worries about any psychoactive side effects.

The entourage effect gives users the benefit of enjoying the other compounds present in the raw plant material and formula, such as terpenes, flavonoids, and other cannabinoids like CBC, CBG, and CBN. Some studies suggest that using CBD and hemp extracts with these other compounds makes the cannabinoid even more effective and long-lasting.

No matter the type of hemp oil extract, the best CBD gummies or a gummy bear are always the ones you prefer. Try out all of the above by asking your local hemp store if they sell trial size products, and see which ones serve you best.

Try looking up best CBD gummies on search engine platforms, and you will usually be linked to websites of reputable cannabis or organic hemp brands. These companies pride themselves in producing the best quality of cannabidiol in the market, with impeccable customer service, and some of their buyers might be inclined to agree.

If you head on over to their product page, try and look for a section that states the CBD oil has undergone third-party laboratory testing. It is even better if there is a link to the result of said testing somewhere on the site. These tests are done by an accredited laboratory not associated with the brand for an unbiased review of the products potency and efficiency.

Third-party lab test results also make sure you are getting CBD gummies safe from unwanted chemicals, pesticides, chemical fertilizers, and toxins. The test report also states the methods used in extracting the hemp oil extract, such as Supercritical CO2 Extraction Method. This one is considered the safest standard of extraction in the industry producing high quality cannabidiol for each product.

The hemp and CBD market can be confusing, so be sure to ask questions first and purchase later. Companies or independent labs that refuse to disclose such valuable information to their customers are not worth spending a dime on, so be careful in researching a brands background and business ethics.

Most manufacturers and avid users would agree that the secret to making the best CBD gummy packs is organically home-grown hemp of the highest quality. As the raw plant material where the oil is extracted, it is important that the hemp planted, cultivated, and harvested is done using safe and sustainable farming methods.

Not only that, but all subsequent ingredients must also be as organic, GMO-free, and vegan-friendly as possible. Premium companies help hemp farmers in breeding and harvesting the best quality of raw hemp to be used in their full-spectrum and broad-spectrum CBD gummies. This practice also boosts the local farming communities income and employment rate.

In addition to this, reputable brands always put every ingredient on their labels. These labels should always be true to the products composition, and the only way to ensure this is to be vigilant at the ingredients listed therein. Youll want your gummies to contain only natural flavorings and sweeteners made possible by infusing them with real fruit juice extracts.

One hemp brand, BlosumCBD, promises all of the aforementioned good qualities and best values listed above. Blosum CBD products are made from locally and organically-grown hemp, the cannabidiol extracted using the safest and most meticulous methods, mixed only with compounds that would enhance CBDs health benefits, undergone third-party lab testing, and packed securely.

This CBD brand also offers great deals to customers and offers discounts, sales, and free shipping within the United States with a minimum amount of purchase. Depending on your preference, Blosum does not only provide the best CBD gummies but have varying products available as well. These include their flavored oil tinctures, softgels, topicals, and pet treats.

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Much like other CBD products, CBD gummies work by having the body absorb the cannabidiol compound and work with the endocannabinoid system or ECS. The ECS is responsible for maintaining an overall balance in the body that regulates your mood, pain receptors, sleep cycle, stress levels, hormone production, and other vital processes needed to keep healthy.

When orally ingested via an edible like gummies, CBD is deposited into the bloodstream and distributed throughout the body through your natural cannabinoid receptors. It may help with many seemingly inconsequential but occurring conditions in your body, such as backaches, inflammation, migraines, difficulty sleeping, and anxiety symptoms.

There are several ways to take CBD edibles, as you may be well-informed by now. As mentioned before, CBD is considered a generally safe substance as there has been no recorded overdose on the compound to date. However, it is important to note that there is no universal dosage for any hemp product, including CBD gummies.

On average, users take one to two of the soft candies per dose, sometimes up to three times a day. This does not mean that you need to go dose it up this high, especially if it is your first time introducing the cannabinoid into your system. There are other factors to consider when doing the dosing guesswork, including your body mass and the products bioavailability.

The amount of CBD in each gummy could also affect how your body will metabolize the compound, along with its other ingredients. Different studies suggest varying dosages but listen to how your body reacts and work from there at the end of the day. Increase or decrease intake according to your desired effect.

Although it may take longer even for the best CBD gummy candy to start working, stay consistent in your product. Stay with a routine for at least 4-6 weeks. Compared to oil tinctures taken via sublingual absorption, gummies need to be digested so their absorption will be gradual. Take one gummy for your first dose and see how long it takes to take effect.

Most hemp products are relatively new to the market. Admittedly, even the science behind cannabis side effects and health benefits are fairly new and young in theory at best. There has been substantial evidence regarding CBDs anti-inflammatory, antibacterial, and antioxidant properties, but these still need a wider test audience and clinical trials.

This resulted from the decades-long cannabis ban worldwide that put a screeching halt to many scientific studies on the plant and its great potential. It is only recently that policymakers have started listening to their constituents and health experts that hemp, marijuana, and its many cannabinoids contain many modern medicine possibilities.

Now, CBD is used to help treat many conditions such as chronic pain, anxiety, and stress symptoms, sleeping difficulties, skin problems, among many others. In a more controlled space, hemp and CBD have also been used and are currently being used to help treat the symptoms of

long-term conditions like Dravet syndrome, certain types of cancer, and multiple sclerosis.

With the passage of the 2018 Farm Bill, industrial hemp was declared legal on a federal level. This comes with a restriction that no product must contain more than 0.3% THC by dry weight to be allowed for manufacturing and distribution to local stores and groceries. The hemp industry was also handed over to the jurisdiction of the Department of Agriculture and the FDA.

While federally legal, some states still abide by their strict medical marijuana programs. They prohibit any cannabis-derived products open use unless they have qualifying conditions that need the plants benefits for treatment and medicine.

Additionally, the FDA added its own set of safety nets that both hemp sellers and consumers should keep in mind. These included being aware that no CBD product in existence has been approved nor evaluated by the FDA, and any brand claiming so is playing their customers false. No hemp product is also intended to treat, cure, or diagnose any medical condition.

If you are thinking of adding the best CBD gummies to your wellness routine, it may very well be the best thing you do, considering its many wondrous health benefits. Gummies are a delicious and discreet way of trying out CBD and seeing if it agrees with you. You can take them anywhere, eat them at any time of the day, and not worry about any harsh side effects.

CBD oil is also a good, long-term supplement that is organic and all-natural. It could help maintain homeostasis in the body, give your immune system a good boost, and help with any discomforts you may be currently experiencing. The added support to the body could do you wonders, but only if you take heed of the information and tips listed above.

Be sure to inform your attending physician first before making any significant changes to your diet and health routines. Pregnant, nursing, or people with complicated medical histories may react to CBD. Cannabidiol gummies may not be for everyone but try them to find out for yourself.

Original post:
How to Find the Best CBD Gummies - Cincinnati CityBeat

Recommendation and review posted by Bethany Smith

Dublin, Dec. 21, 2020 (GLOBE NEWSWIRE) -- The "Genetic Testing. Global Market Forecasts for Applications and Technologies. Updated for COVID-19 Pandemic Impact with Executive and Consultant Guides 2021 to 2025" report has been added to ResearchAndMarkets.com's offering.

The role of genetics in health and disease is just now being understood. This new knowledge, combined with lower pricing is driving the Genetic Testing industry to record growth. New drugs may only work for people with a certain genetic makeup, and this too is driving the Genetic Testing Industry.

The traditional genetic testing market is growing in volume and growing in the breadth of tests creating a new life for the industry. The report forecasts the market size out to 2025. The report includes detailed breakouts for 14 countries and 5 regions.

Predictive Diagnostics? Pharmacogenomic Testing? Direct to Consumer? Find out about the technology in readily understood terms that explain the jargon. What are the issues? Find the opportunities and the pitfalls. Understand growth expectations and the ultimate market forecasts for the next five years.

Key Topics Covered:

Genetic Testing - Strategic Situation Analysis & Impact of COVID-19 Pandemic

1. Introduction and Market Definition 1.1 Genetic Testing Definition in This Report 1.2 The Genomics Revolution 1.3 Market Definition 1.3.1 Revenue Market Size1.3.1 Newborn Screening 1.3.2 Non Invasise Pregnancy Testing 1.3.3 Predictive 1.3.4 Oncology 1.3.5 Direct to Consumer 1.3.6 Other Application1.3.7 PCR 1.3.4 NGS 1.3.5 Cytogenetic1.3.6 Other Technology 1.4 U.S. Medical Market and laboratory Testing - Perspective 1.4.1 U.S. Medicare Expenditures for Laboratory Testing

2. Market Overview 2.1 Market Participants Play Different Roles 2.1.1 Supplier/pharmaceutical 2.1.2 Independent lab specialized/esoteric 2.1.3 Independent lab national/regional2.1.4 Independent lab analytical 2.1.5 Public National/regional lab 2.1.6 Hospital lab 2.1.7 Physician lab 2.1.8 DTC Lab2.1.9 Independent Genetic Testing Lab2.1.10 Audit Body2.2 Genetic Tests -Types, Examples and Discussion 2.2.1 Preimplantation Genetic Diagnosis- An Emerging Market 2.2.2 Prenatal Diagnosis - New Technologies Create Opportunity 2.2.3 Newborn Screening 2.2.2 Diagnostic Testing 2.2.3 Carrier Testing 2.2.6 Predictive and Presymptomatic Testing 2.2.7 Pharmacogenomics 2.2.8 Forensic Testing2.2.9 Parental Testing 2.2.10 Ancestral Testing2.3 Industry Structure 2.3.1 Hospital's Testing Share 2.3.2 Economies of Scale2.3.2.1 Hospital vs. Central Lab 2.3.3 Physician Office Lab's 2.3.4 Physician's and POCT 2.4 Market Shares of Key Genetics Players - Analysis

3. Market Trends3.1 Factors Driving Growth3.1.1 Genetic Discoveries Creating New Diagnostic Markets 3.1.2 Aging Population a Boon for Diagnostics3.1.3 Pharmacogenomics Drives Further Growth3.1.4 Oncology and Liquid Biopsy Enter New Era3.1.5 Fertility Practice Growth drives market 3.1.6 Direct to Consumer begins to break out 3.2 Factors Limiting Growth3.2.1 Increased Competition Lowers Price 3.2.2 Lower Costs3.2.3 Testing usage analysis curtailing growth3.2.4 Wellness has a downside 3.3 Instrumentation and Automation 3.3.1 Instruments Key to Market Share 3.3.2 Bioinformatics Plays a Role3.4 Diagnostic Technology Development3.4.1 Next Generation Sequencing Fuels a Revolution3.4.2 Impact of NGS on pricing 3.4.3 POCT/Self Testing Disruptive Force3.4.4 Pharmacogenomics Blurs Diagnosis and Treatment 3.4.5 CGES Testing, A Brave New World 3.4.6 Biochips/Giant magneto resistance based assay

4. Genetic Testing Recent Developments4.1.1 Importance of This Section 4.1.2 How to Use This Section

5. Profiles of Key Companies

6. Global Market Size6.1 Global Market by Country 6.1.1 Table - Global Market by Country6.1.2 Chart - Country Market Shares 6.2 Global Market by Application 6.2.1 Table - Global Market by Application 6.2.2 Chart - Application Share by Year 6.2.3 Chart - Application Segment Growth Rates 6.2.4 Chart - Application Segment Share Shifts6.2.5 Chart - Application Segment Share Base Year 6.2.6 Chart - Application Segment Share Final Year 6.3 Global Market by Technology 6.3.1 Table - Global Market by Technology 6.3.2 Chart - Technology Share by Year 6.3.3 Chart - Technology Segment Growth Rates 6.3.4 Chart - Technology Segment Share Shifts6.3.5 Chart - Technology Segment Share Base Year 6.3.6 Chart - Technology Segment Share Final Year

7. Market Sizes by Application 7.1 Newborn Testing Market 7.1.1 Table Newborn - by Country7.1.2 Chart - Newborn Growth 7.2 NIPT Market 7.2.1 Table NIPT - by Country 7.2.2 Chart - NIPT Growth 7.3 Predictive Testing Market7.3.1 Table Predictive - by Country 7.3.2 Chart - Predictive Growth 7.4 Oncology Testing Market7.4.1 Table Oncology - by Country 7.4.2 Chart - Oncology Growth 7.5 DTC Testing Market 7.5.1 Table DTC - by Country 7.5.2 Chart - DTC Growth 7.6 Other Testing Market 7.6.1 Table Other - by Country 7.6.2 Chart - Other Growth

8. Global Genetic Testing Market by Technology 8.1 PCR Testing Market 8.1.1 Table PCR - by Country 8.1.2 Chart - PCR Growth 8.2 NGS Market 8.2.1 Table NGS - by Country8.2.2 Chart - NGS Growth8.3 Cytogenetic Testing Market 8.3.1 Table Cytogenetic - by Country8.3.2 Cytogenetic - Predictive Growth 8.4 Other Testing Market 8.4.1 Table Other - by Country 8.4.2 Chart - Other Growth

9. The Future of Genetic Testing

10. Appendices

For more information about this report visit https://www.researchandmarkets.com/r/z52i9s

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

Read the original:
Insights on the Genetic Testing Global Market (2021 to 2025) - Updated for COVID-19 Pandemic Impact - GlobeNewswire

Recommendation and review posted by Bethany Smith

A Perth researcher is hoping to make a case for the upfront use of advanced DNA testing in patients with two of the most common forms of leukaemia.

Sir Charles Gairdner Hospital haematologist Dr Xuan Ni Tan is one of five cancer researchers awarded a State Government fellowship in the latest round of the WA Cancer and Palliative Care Network Fellowship program.

She will use her fellowship to determine whether the benefits of more targeted treatment can justify the costs of using advanced gene-sequencing technology to screen patients before they start treatment.

Dr Tans retrospective study will investigate the extent to which such sequencing would have altered the course and cost of treatment of 150 WA patients with Acute Myeloid Leukaemia (AML) and Chronic Lymphocytic Leukaemia (CLL).

These two cancers are the most prevalent forms of leukaemia in adults, affecting about 2600 Australians annually.

Patients involved in Dr Tans research have already completed their treatment which they were given in accordance with contemporary treatment guidelines.

Treatment for AML typically begins with one or two rounds of intense chemotherapy (designed to achieve remission by killing as many abnormal white blood cells as possible) followed by a further four rounds to consolidate the gains of their earlier therapy.

Genetic testing currently offered to these patients flags a proportion as high-risk, requiring a bone marrow transplant for best survival. But it is estimated that up to 25 per cent of high-risk patients are missed.

These undetected patients face not only delays in accessing alternative treatments but exposure to potentially harmful therapy.

Dr Tan will see how the use of massively parallel sequencing where multiple genes are sequenced simultaneously would have influenced the treatments of her patient cohort (100 AML and 50 CLL patients) and the difference it would have made to the overall costs of their treatment.

Although the technique is more expensive than the genetic testing currently offered, Dr Tan will see if the extra cost would have been offset by the savings made from patients getting more suitable treatment earlier.

Dr Tans study is focusing on AML and CLL because of their prevalence among adults and because of the ability of advanced sequencing to detect mutations in these cancers that would change treatment selection.

Evidence of significant patient benefit without substantial additional costs would provide a case for offering the advanced sequencing upfront to all AML and CLL patients.

While 75 per cent of AML patients achieve remission from chemotherapy, most will relapse within three years. For some CLL patients, treatment will not only be ineffective but could also put them at risk of life-threatening infections and secondary cancers.

The Department of Healths Assistant Director General (Clinical Excellence) Dr James Williamson said Dr Tans research highlighted the opportunities arising from advances in human genomics that were enabling doctors to provide treatments tailored to patients individual genetics and the genetics of their cancer.

What is important about this project is that it has the potential to prevent cancer patients being subjected to unnecessary, ineffective and potentially harmful treatments while hastening their access to alternative options, he said.

The full list of fellowship recipients is

Media contact: 9222 4333Follow us on Twitter: @WAHealth

Read the original post:
Researcher to test value of tailored gene testing - WA Health

Recommendation and review posted by Bethany Smith

Genomic and ancestry analyses published in Cancer Discovery revealed that among patients with lung cancer from Latin America, Native American ancestry was associated with increased mutations in the EGFR gene, independent of smoking status.1

Researchers indicated that these findings suggest that germline genetics, rather than environmental disparities, underlie these observed disparities.

Lung cancer is the leading cause of cancer mortality, both in the United States and globally, and understanding inherited risk factors for this disease may help us to identify populations that would benefit from increased screening efforts, Matthew Meyerson, MD, PhD, director of the Center for Cancer Genomics at Dana-Farber Cancer Institute in Boston, said in a press release.2

To explore the landscape of somatic cancer mutation in lung cancers from Latin America and to evaluate the influence of germline ancestry of genetically amalgamated patient populations on these somatic alterations, the study investigators performed genomic analysis of 601 lung cancer cases from Mexico and 552 from Colombia, including 499 self-reported non-smokers. Next-generation sequencing targeting a panel of 547 cancer genes plus intronic regions of 60 cancer genes was used to identify single nucleotide variants (SNVs), indels, somatic copy number alterations (SCNAs), and gene fusions; importantly, this gene panel covered all currently known lung cancer drivers.

It was discovered that 48% of all samples harbored oncogenic mutations in EGFR, KRAS, BRAF, ERBB2, or MET, or fusions in ALK, ROS1, or RET. Moreover, 785 of 1153 samples harbored at least 1 detectable alteration in a broader set of known lung cancer driver genes also including TP53, STK11, KEAP1, SMARCA4, SETD2, MYC, and MDM2. The detected mutation frequencies of EGFR and KRAS were 30% and 10%, respectively, in the tested lung cancer samples from Mexican patients, and 23% and 13%, respectively, in the tested lung cancer samples from Colombian patients.

Using a new method developed by Jian Carrot-Zhang, PhD, and Alexander Gusev, PhD, ancestry analyses from the tumor samples was also performed in this admixed population of patients. Further, global ancestry analysis was performed to measure proportions of African, European, and Native American ancestry across the genome. In addition, local ancestry analysis was performed, which evaluates genetic ancestry at a particular chromosomal location.

After obtaining data on both somatic alteration and genetic ancestry, the next step for the researchers was assessing the correlation of these features. After adjusting for various factors, including self-reported smoking status and sample-specific tumor mutational burden, it was discovered that global Native American ancestry was positively correlated with mutations in the EGFR gene. Even further, the researchers determined that Native American ancestry was predominantly associated with oncogenic mutations in the EGFR gene, but not with non-oncogenic mutations.

Patients were then stratified by their self-reported smoking status and evaluated to determine the association between global ancestry and mutations in target genes. In both individuals who were never smokers and smokers, global Native American ancestry was found to be associated with mutations in the EGFR gene, indicating that the genomic differences associated with Native American ancestry are independent of smoking status.

Smoking increases the risk for KRAS-mutant lung cancers, while patients with lung cancer who are non-smokers more often develop EGFR-mutant lung cancer, Meyerson explained. However, we show in our study that EGFR-mutant lung cancer is also elevated among smokers with Native American ancestry.

Lastly, the investigators developed a local Native American ancestry risk score to assess the association of ancestry with EGFR mutation frequency across multiple distinct sites in the genome. In doing so, it was revealed that the correlation between ancestry and increased mutation frequency in the EGFR gene was stronger at the local genome level than the global genome level.

These results suggest that germline genetics in addition to environmental factors or socioeconomic status may have an influence on the risk of EGFR-mutant lung cancer among those with Native American ancestry, said Meyerson.

Many lung cancers are now treatable with targeted therapy or immunotherapy, Meyerson added. It is very important for patients with lung cancer to undergo somatic genetic testing to determine which treatments are most likely to be effective for their particular cancer.

Moving forward, the researchers suggested that future studies will still be necessary to comprehensively characterize lung cancer genomes from Latin American patients.

References:

1. Carrot-Zhang J, Soca-Chafre G, Patterson N, et al. Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations. Cancer Discovery. doi: 10.1158/2159-8290.CD-20-1165

2. Native American Ancestry Associated With Increased Mutations in EGFR Gene Among Latin American Patients With Lung Cancer [news release]. Philadelphia. Published December 2, 2020. Accessed December 4, 2020.

Continue reading here:
Latin American Patients with Lung Cancer and Native American Ancestry See Increased EGFR Mutations - Cancer Network

Recommendation and review posted by Bethany Smith

BOYNTON BEACH, Fla. While all of us wait to reunite with family members once the pandemic eases up, five family members are excited to unite for the very first time.

A few months ago, with the help of genetic results from 23andMe, five siblings in five different states learned of their relationship and connected using Zoom calls and text messages.

"Those feelings, still to this day, are still so top-notch. When I talk about it or think about it I still get goosebumps," Jennilyn Hamm said.

Elaine Otway lives in Lake Kiowa, Texas. John Schiavo lives in Boynton Beach, Florida. They grew up with their shared parents and eventually welcomed half-sister Irene Schiavo, who lives in Denver, Colorado.

23andMe revealed a set of twin sisters who shared their father, John, Senior. Karla Lynch who lives in Strasburg, Pennsylvania, and Jennilyn Hamm, who lives in Smithtown, New York. The twin sisters didnt know the man they called dad their whole life wasnt of blood relation.

"There are still a million questions, but those well never get the answers to, and we just have to accept what it is, and we happily accept what this is. And Im very happy to have found our siblings and to know that we have this whole other side to our family that we never even knew about, Lynch said.

The twins say theyve remarked to each other many times through the years that it felt there was a piece missing.

Growing up both me and my sister felt like we were missing something, we werent whole. And that feeling had carried on into adulthood. And once this was discovered, I felt like there was huge healing. That hole was filling up and I no longer feel like theres something else out there. That I really feel complete now, Hamm said.

The siblings said they have several hobbies in common, and all share a deep love for animals.

"For us, it was just an instant warm connection that we all felt and it just felt normal. Very fortunate for that as well, Karla Lynch said.

Some of the siblings share a passion for cooking and baking. Theyre now shuttling homemade cookies across the country, swapping old photos, and trying to catch up face to face on Zoom.

"It's crazy to be able to look at them and be able to see my dad. Our dad. Right there, John Schiavo, Jr. said.

The physical similarities stem from mannerisms. The family has even taken time to compare photos at different stages of life.

"I think the first time we were all on Zoom, we were all playing with our hair and it was just very interesting to see these little mannerisms that you see where you come from you see the similarities, Lynch said.

While there were inklings of some kind of a story about siblings to the two eldest children through other relatives, it wasnt until August when the pieces came together.

The genetic testing and analysis company 23andMe notified the group of some new possible genetic matches in their family tree. One conversation led to another, with seemingly countless questions.

"When all this happened there was all this confusion. Did he know, how could he know, did he not know, how could he know and not be there? And all of these questions were bombarding me, explained the youngest sibling Irene Schiavo.

Irene questioned extended family members and beyond hoping for more insight. She says the result helped her heal.

"I called old neighbors, who maybe they were having a conversation in the street one day. And out of that, I got a myriad of incredible stories about our dad that I just never knew. Things that he said to a cousin, things that he said to a neighbor, she said.

The shared father, John Sr, passed away in 1990. The mother of the two eldest siblings, who grew up with their shared father, and the mother of the twins have both passed away. They are left to try to put the pieces together of what happened and why. They still havent figured out how the parents had met, and they may never know.

"It's 50 years of not being with them, around them, and their families. So it's a little disappointing. But I'm happy that were able to find this out through this wonderful thing called 23andMe," John Schiavo, Jr. said.

Hamm shares a different shade of the same emotions.

"As a little girl, I was upset not growing up with a dad. Knowing today that I did have a father who could have stepped up and been that role model father figure for me, and I was denied. My twin sister and I were denied that. [It] was hard. It was a hard pill to swallow in the beginning," Hamm said.

As the discovery unfolded in the middle of a pandemic, they have kept their meetings to a virtual setting until the time comes when they can physically hug and greet each other.

"We're just so excited that we want to get together somewhere and soon," Otway laughed.

Now, they meet for a Zoom call for two hours every Sunday, and text each other day, sharing a sense of closeness and communication.

Genetic site 23andMe says this type of reunion story is growing more common with their services.

"Although 23andMe was not designed specifically to help people confirm parentage or find biological parents, our DNA Relatives tool does help people find and connect with participating genetic relatives. This feature is completely optional, meaning customers must actively choose to participate and are informed upfront that by using the tool, they may discover unexpected relationships, according to Communications Director Andy Kill.

23andMe also said it offers additional support, information, and resources to customers who are navigating new roads.

"We've created a specific help page as a resource for those looking for more information on the accuracy of our relationship predictions, stories from others who may have experienced a similar situation, and suggested resources for additional counseling support such as BetterHelp and Talkspace," Kill said.

The siblings cant wait until their in-person reunion.

"It's a wonderful thing that that question mark was always inside me is no longer a question," Hamm said.

This story was first reported by Ashleigh Walters at WPTV in West Palm Beach, Florida.

Originally posted here:
'For us, it was just an instant warm connection:' 5 siblings to unite for the first time - KXLH Helena News

Recommendation and review posted by Bethany Smith

A recent comprehensive study called Global Preimplantation Genetic Testing Market 2020 by companies, regions, types and applications with a forecast up to 2025 makes a serious attempt to identify current market and competitive ideas, as well as information about regions and consumers. The report focuses on analyzing market size, trends, share, growth and driving forces. The report covers all aspects related to current trends, profitability, regional valuation and plans to expand the business of key players in the global Preimplantation Genetic Testing market The study provides an overview of the market, scale of development, market dynamics, growth challenges and influencing factors. The report includes an analysis of the key moments of the global market by major key players, by type, by applications and leading regions, as well as by segment.

Get A Sample Copy of Research Report at: https://www.adroitmarketresearch.com/contacts/request-sample/1483?utm_source=bh

This part of the study looks at the events and future opportunities that are estimated to emerge in the global Preimplantation Genetic Testing industry. The report also sheds light on the competitive landscape by highlighting the corporate strategies that established players across geographic regions have used to move the industry forward. The research focuses on business consulting, industry chain research and consumer research to help clients propose non-linear revenue models in this market.

The Prominent Players of the Preimplantation Genetic Testing Market Are:

Thermo Fisher Scientific, Inc., Agilent Technologies, Inc., PerkinElmer, Inc., CooperSurgical, Inc., Beijing Genomics Institute (BGI), Abbott Laboratories, Natera, Inc., Genea Limited, Rubicon Genomics, Inc. and Oxford Gene Technology

Market Analysis:

The report examines the market potential of key regions, as well as the advantages, opportunities and challenges, constraints and risks faced by key players in this industry. The report covers prominent players in the global Preimplantation Genetic Testing market with detailed SWOT analysis, financial overview and key events. Other information was also included such as company profiles, product images and specifications, sales revenue, price, gross margin, market share. The market overview broadly presents different types of products, applications, players and regions. The segmentation included in the report helps readers benefit from the selection of appropriate segments for the sector.

Competitive Analysis:

The report provides a clear overview of the competitive landscape and prospects, including global analysis of new products in the Preimplantation Genetic Testing market, financial overview, strategies and marketing trends. The analysts of the report offered a progressive look at various factors contributing or limiting market growth. The detailed information provided in the report includes a description of the company, core business, total company revenue, manufacturing capacity, price, revenue, as well as product presentation and recent developments.

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Research Methodology

The market Research Methodology is based on both primary and secondary research data sources. It takes into account various factors affecting the Preimplantation Genetic Testing industry such as historical data and market trends, various government policies, market environment, market risk factors, market constraints, technological advances, upcoming innovations, and industry barriers.

Impact of Coronavirus (COVID-19) on Global Preimplantation Genetic Testing Market

Coronavirus (COVID-19) is spreading around the world, having a serious impact on the economy and the global market. The report examines the impact of COVID-19 on the global Preimplantation Genetic Testing market across all segments, regions, countries and key players. North America and Europe are the countries hardest hit by the coronavirus and are key players in the global economy. The report provides a detailed analysis of market impact, growth strategies, supply disruptions in China, consumption patterns in the global Preimplantation Genetic Testing market

Global Preimplantation Genetic Testing Market Segmentation

Segmentation by Type:

by Test Type (Aneuploidy, Structural Chromosomal Abnormalities, Single Gene Disorders, X-linked Disorders, HLA Typing, Gender Identification) and Technology (Next Generation Sequencing, Polymerase Chain Reaction, Fluorescent In-Situ Hybridization, Comparative Genomic Hybridization, Single Nucleotide Polymorphism)

Regional and Country- Level Analysis:

Various geographic areas have been comprehensively explored and an economic scenario has been proposed that will help new entrants, leading market players and investors regulate emerging economies. Leading manufacturers and consumers pay attention to production, production capacity, cost, consumption, growth opportunities and market share in these key regions, covering: North America (USA, Canada, Mexico), Asia-Pacific region (China, Japan, South Korea. .. India, Australia, Indonesia, Thailand, Malaysia, Philippines, Vietnam), Europe (Germany, France, Great Britain, Italy, Russia, the rest of Europe), Central and South America (Brazil, the rest of South America), the Middle East and Africa (GCC, Turkey, Egypt, South Africa, Middle East and Africa)

Access full Report Description, TOC, Table of Figure, Chart, etc. @ https://www.adroitmarketresearch.com/industry-reports/preimplantation-genetic-testing-market?utm_source=bh

1. Executive Summary2. Assumptions and Acronyms Used3. Research Methodology4. Market Overview5. Global Market Analysis and Forecast, by Types6. Global Market Analysis and Forecast, by Applications7. Global Market Analysis and Forecast, by Regions8. North America Market Analysis and Forecast9. Latin America Market Analysis and Forecast10. Europe Market Analysis and Forecast11. Asia Pacific Market Analysis and Forecast12. Middle East & Africa Market Analysis and Forecast13. Competition Landscape

To identify correctly major underlying market forces that gradually underpin growth To comprehend future growth potential of the mentioned segments, inclusive of geographical outlook. A thorough evaluation of the entire competitive landscape gamut has been analyzed, isolating growth rendering strategies and industry forerunners To correctly isolate growth enablement determinants. The report lends clarity in understanding the commercial viability of the Preimplantation Genetic Testing market ecosystem.

Read the original:
Preimplantation Genetic Testing Market 2020 Top Countries Market Analysis and Opportunity Assessment 2025 Research Report - Farming Sector

Recommendation and review posted by Bethany Smith

The decision to take hormone therapy (HT) to tame symptoms of menopause can be complex. There are benefits and risksthat you must weigh with your healthcare provider. One area of emerging research is the relationship between hearing loss, menopause and hormonetherapy.

Researchers are still teasing out how menopause affects hearing. The same is true of HT:Research with mice and preliminaryhuman studies suggest that taking estrogen can have protective effects on your hearing. However, ananalysis with the largest data pool to date on the topic actually found the opposite.

If you dont currently have hearing loss, HT could increase your risk, according to a team led by Dr. Sharon Curhan, MD, a physician and epidemiologist at Brigham and Womens Hospital in Boston. This was true for both pills and patches, and for formulas with estrogen onlyor combined with progesterone.

To get down to the numbers: When Curhans team analyzed data for more than 47,000 female nurses spanning 22 years, theyconcluded that a course of HT for five to ten years increased a woman'srisk of hearing loss by 15 percent compared to a woman not taking HT.

Risk increased the longer a woman stayed on HT. The analysis also found thatwomen who undergo menopause at an older age have a higher risk of hearing loss.

Youve probably heard that drops in estrogen can trigger symptoms like hot flashes. Estrogen, a hormone, plays a role throughout the bodyin your muscles and bones, heart and brain as well as reproductive system. Scientists know we have estrogen receptors in ear cellsand in auditory pathways, but its still unknown exactly how estrogen affects hearing.

Sex hormone levels change during a menstrual cycle, and during menstruation, your hearing can become less sensitive.During perimenopausethe years before your ovaries stop releasing eggs and your period endsyour ovaries gradually produce less estrogen. In the last one to two years of perimenopause, the drop in estrogen speeds up. After your period ends, typically after age 45, the ovaries produce little estrogen but you still get some from your adrenal glands and fat tissue.

As Curhans team reports, both human and animal studies have shown that low estrogen levels can impair hearing, possibly through alterations in blood flow to the cochlea, the hollow tube in the inner ear. A separate study that measured hearing and blood levels of estradiol (a form of estrogen) in 1,830 post-menopausal women found that the volunteers with less estradiol were more likely to have hearing loss.

Another key reproductive hormone, progesterone, begins to drop in your thirties. Progesterone, which regulates pregnancy, is the yin to estrogens yang: It reduces receptor cells for estrogen. Progesterone doesnt affect the cochlea directly but it could by reducing estrogen receptors and therefore blood flow to the ear.

The link between low estrogen and impaired hearing suggests that women who arrive at menopause later, at 50 or older51 is the average age of menopause in the United Statesmight have a lower risk of hearing loss. After all, it would make sense that women who reach menopause sooner experienced earlier drops in estrogen.

However, when Curhans team looked at a pool of data on nearly 81,000 nurses, the opposite was true: The women with late natural menopause surprisingly had a 10 percent higher chance of hearing loss. The reason for this finding is unclear, since we dont have a full picture of all the factors that affect the age of menopause, Dr. Curhan told Healthy Hearing.

If you are about to start hormone therapyDr. Curhan suggests monitoring your hearing and taking HT only as long as needed.Some women have reacted to HT with sudden hearing loss, tinnitus and vertigo. Contact your provider right away if this happens to you.

If youre considering HT, youre likely to be offered a combination with progestin (a medication like progesterone) if you still have your uterus.Estrogen alone could stimulate growth of the uterus lining and increases your risk of endometrial cancer, so it's more commonly used for women who have had a hysterectomy.

If you do opt for HT, Dr. Curhan suggests monitoring your hearing and taking HT only as long as needed.Some people have reacted to HT with sudden hearing loss, tinnitus and vertigo.

The relationship between menopause, hormone replacement therapy and tinnitus is a topic that also needs more study. Some women may experience tinnitus when starting hormone therapy for perimenopause. Butstudies have also shown that hormone therapy can actually lower the rate of tinnitus in women who are perimenopausal.

We are looking forward to understanding more about risk factors for tinnitus, Dr. Curhan told Healthy Hearing. She is studying its relation to menopause and HT.

Diet, exercise, and maintaining a healthy weight all count. We found that people who ate diets that most closely resembled the Mediterranean or DASH [Dietary Approaches to Stop Hypertension] patterns had a substantially lower risk of hearing loss, Dr. Curhan said. That means eating more fish, vegetables, and whole grainsand less meat and junk food. More: How a healthy diet helps your hearing.

Also be mindful of medications linked to hearing loss. Curhans research with the same big data pool found that using the over-the-counter pain-relievers ibuprofen and acetaminophen two or more times a week may be linked to hearing loss (aspirin is OK). But there was no tie to alcohol.

Lastly, steer clear of loud or constant background noise, get your hearing checked and wear prescribed hearing aids regularly, and youll know youve done your best to prevent hearing lossas you age.

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Hearing loss, hormone therapy and menopause - Healthy Hearing

Recommendation and review posted by Bethany Smith

by Adrienne Berard | December 18, 2020

As we head into the holidays, W&M News spoke with Dr. Elizabeth De Falcon to learn about ways relieve stress and practice self-care over winter break, to strengthen our collective immune systems. Dr. De Falcon is a practicing physician with William & Marys Health Services. She is a licensed pediatrician and Fellow of the American Academy of Pediatrics.

In the simplest terms, stress is just your body's reaction to any change that requires response. So, it could be anything: a mental strain, a physical strain or even an emotional strain. Honestly, it's different for every person. What stresses me out may not stress you out, but if were talking about physiology, then our stress response would be mostly the same.

Without going into the specific names of all the different parts of your brain, it's just that your brain perceives stress or danger or threat. Then it sends out a signal from what is essentially the command center of your brain to the rest of your body, through the nervous system. Then the nervous system starts acting on a fight or flight response and all these different neurotransmitters and hormones get released. All these different substances start flowing through your body just to get you prepared to respond to that stressor.

A lot of times, you're not even aware of it. Most of the time the threat comes and goes, and as the threat goes away, the stress response decreases. Think of a car whizzing past you on the street. Its stressful for a second, but the feeling is very short-lived. Its important to understand that not all stress is bad. It serves an important biological purpose. The stress response has been vital to our survival and evolution. When the saber-toothed tigers were hunting us down, our bodies learned how to respond to that.

If you translate that to now, lets say you're taking a test and you feel a little bit stressed. You're supposed to have a certain level of stress, because its your bodys way of motivating you to focus on something important. After the test is done, theres this sigh of relief because that stress is gone and your body just goes back to a kind of homeostasis where it's feeling ok.

But sometimes that stress hangs around for a little while. Thats when you start running into problems. You may find that even though the threat is gone, youre not feeling better. You may be experiencing increased heart rate and breathing or generally feeling edgy all the time. Thats a sign that you're bumping over into a low-level, acute stress or chronic stress state.

Thats when we start to think about cortisol. Youve probably heard about cortisol as a stress hormone. In the moment, it actually helps your body boost its immune system and decrease inflammation, but if it's there for a long time, then you start to get into different problems.

I always tell people to seek medical help if they start seeing signs of chronic stress. Some of the red flags would be that you feel in a low mood all the time. You may stop hanging out with your friends or your family. You're just kind of retreating and not interested in the things you used to be interested in. You may be sleeping too much or too little. Some people experience physical symptoms. They have an upset stomach or heartburn or headaches, because their blood pressure is up. They might feel a knot in their chest. All of those things could be signs that you're experiencing anxiety, so you would definitely want to see your doctor at that point.

It comes down to the basics of general healthy living. For example, if youve not been on a good sleep schedule over the semester, you really need to prioritize getting on a healthy sleep scheduleand make it a realistic schedule that you can keep doing once we get back on campus. If you were not addressing your dietary needs during the semester, start to incorporate healthy, nutrient-dense types of foods into your diet.

Also, exercise is super important. Just from a perspective of improving your cardiovascular health and improving your circulation, regular exercise will help get all those immune cells pumped around your body. You don't want to smoke and try to minimize your alcohol intake.

Then, of course, what weve all been focused on over these last nine month is taking steps to minimize infections. So, being very diligent about washing your hands, keeping your distance from pretty much anyone who doesn't live in your house, and wearing a mask if you have to go out and about.

When you have a healthy immune system, when it's functional, you don't even know it's there. It's protecting you from things that are trying to kill you, viruses and bacterial infections, but you arent even aware of it.

But just like a car runs out of gas when left idling, if you are not fully addressing the things that boost your immune system, eventually that car will run out of gas and then that leads to a whole host of problems. You might start noticing that you're getting more colds or struggling to get over minor illnesses. Thats really just because when your stress response is revved up all the time, it has the opposite effect on your health and it starts down-regulating your immune system.

This is something I always recommend to my patients: practice gratitude. Its such a simple, easy thing that anyone can do. It doesn't have to be complicated. Just get a little notebook, or even make mental notes, and focus on three things that you're grateful for in a day. No matter how crummy the day is, there's always something that we can find that we can be grateful for.

Studies show that if you practice gratitude, there are positive changes in your brain that actually change your outlook on things. Along those lines, the Wellness Center has all kinds of wonderful mindfulness, meditation and exercise resources available online. They make it really easy to access, so Id also recommend trying out some of those offerings.

More here:
Tips for staying healthy and managing stress over the holidays - William & Mary News

Recommendation and review posted by Bethany Smith

DUBLIN, Dec. 18, 2020 /PRNewswire/ -- The "Prostate Cancer Disease Coverage Forecast and Market Analysis to 2036" report has been added to ResearchAndMarkets.com's offering.

Newly approved therapies for castration-resistant prostate cancer are set to create a shift in the way that the disease is treated, while creating a competitive environment for new market entrants.

Latest Key Takeaways

The report estimates that in 2018, there were 1.3 million incident cases of prostate cancer worldwide in males aged 40 years and older, and forecasts that number to increase to 1.5 million cases by 2027.

In the US, prostate cancer is the most common non-cutaneous malignancy diagnosed in men, and is the second-leading cause of cancer mortality in men behind lung cancer.

The overall likelihood of approval of a Phase I prostate cancer asset is 4.9%, and the average probability a drug advances from Phase III is 51.5%. Prostate cancer drugs, on average, take 9.0 years from Phase I to approval, compared to 9.5 years in the overall oncology space.

Pfizer's next-generation androgen receptor (AR) inhibitor Xtandi is the market leader in prostate cancer due to its established efficacy across prostate cancer segmentations and a lack of near-term generic competition. Bolstered by recent and planned expansions into additional prostate cancer segments, Xtandi will continue to be the leading option in this indication. Future expansion opportunities include potential use in combination with PARP inhibitors Talzenna or Rubraca in metastatic castration-resistant prostate cancer (mCRPC) patients.

Xtandi is also being trialed in combination with leuprolide in the Phase III EMBARK study for non-metastatic hormone-sensitive prostate cancer patients progressing on definitive therapy. Potential expansion into this segment represents a significant opportunity to improve outcomes earlier in the treatment paradigm, but the combination will have to demonstrate a significant benefit over existing localized treatment options to justify the additional clinical and financial toxicity of Xtandi treatment.

Since the launch of generic abiraterone in the US in November 2018, sales of Johnson & Johnson's cytochrome P450c17 inhibitor Zytiga have begun to erode. Further generic erosion is expected in the EU and Japanese markets in the next few years, decimating sales of the multi-blockbuster. Although branded Zytiga will continue to decrease in market share, use of abiraterone as part of standard regimens will continue and may expand to include several novel combinations.

The PARP inhibitors Rubraca and Lynparza were both approved in the US in May 2020 for the treatment of mCRPC patients following AR inhibitor therapy. Rubraca received accelerated conditional approval in mCRPC with a deleterious BRCA mutation (germline and/or somatic), while Lynparza received full approval for use in the broader homologous recombination deficient (HRD) population. To potentially differentiate the PARP assets, both are being trialed in the first-line setting of mCRPC; Rubraca in combination with Xtandi against Xtandi alone, and Lynparza with abiraterone against abiraterone alone. There is potential synergy with these combinations as its hypothesized that AR inhibitors may sensitize tumors to PARP treatment by reducing DNA damage repair (DDR) expression.

Late-phase PARP inhibitors Zejula and Talzenna are also being developed in combination with next-generation treatments and will join a crowded PARP treatment space. Zejula is being tested in combination with abiraterone against abiraterone alone as first-line therapy for mCRPC patients. Similarly, Talzenna is being studied in combination with physician's choice of Xtandi or enzalutamide in mCRPC patients, also as a first-line option. The potential synergy of the PARP inhibitors with AR modulators is promising, but a strong benefit will have to be seen to justify use in the front-line setting of mCRPC. If approved, it is likely that these regimens will be limited to the HRD or even BRCA populations, where they will have strong utility but somewhat limited commercial impact due to the relatively small prevalence of these biomarkers.

Next-generation AR inhibitors Nubeqa and Erleada have shifted the treatment paradigm to include these therapies in earlier segments of disease such as non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). Expansion into earlier segments and lines of therapy is ongoing. Bayer is looking to expand Nubeqa's label to include use in very high-risk localized patients and metastatic hormone-sensitive patients. Johnson & Johnson will continue to try and differentiate Erleada with an aggressive development plan that includes potential expansions into chemotherapy-naive mCRPC patients as part of a combination with abiraterone, as well as into the localized setting for patients treated with prostatectomy or radiation therapy.

Akt inhibitors ipatasertib and capivasertib are a potential new mechanistic addition to the prostate cancer space, but the efficacy/tolerability profile of these PI3K/Akt/mTOR pathway inhibitors may prevent approval and potential usage. Ipatasertib is a pan-Akt inhibitor from Roche currently in development for asymptomatic or mildly symptomatic mCRPC patients with PTEN loss as part of a combination with abiraterone. PTEN loss is not a standard target in this indication, but represents a significant market opportunity as it is estimated to occur in approximately 20% of primary prostate cancers and up to 50% of castration-resistant tumors. However, ipatasertib is beset by known class toxicities of PI3K/Akt/mTOR pathway inhibitors such as diarrhea, rash, and ALT/AST elevations that could be detrimental to its regulatory chances. AstraZeneca's Akt inhibitor capivasertib has also demonstrated mixed results in prostate cancer.

In the Phase I/II ProCAID trial, capivasertib in combination with docetaxel failed to meet the primary endpoint of improved progression-free survival in mCRPC patients. However, the combination did improve overall survival in these patients irrespective of PI3K/Akt/mTOR pathway mutations. This has led to initiation of the Phase III CAPItello-281 trial testing capivasertib in combination with abiraterone in de novo mHSPC with PTEN loss.

Several checkpoint inhibitors are in development for prostate cancer, but late-phase data from ongoing combination trials are needed to fully determine their relative outlook in the indication. Merck is pursuing an aggressive late-phase development strategy for Keytruda in prostate cancer that includes combinations with Lynparza, Xtandi, and docetaxel for the treatment of mCRPC patients. Opdivo is also in late-phase development as part of a combination with docetaxel in mCRPC patients after failure on a next-generation hormone therapy. Finally, Roche's Tecentriq, the lone anti-PD-L1 antibody in late-phase development for prostate cancer, is currently in Phase III development in combination with Xtandi or in combination with Cabometyx in mCRPC patients after failing on a next-generation hormone therapy.

Myovant's relugolix is a GnRH receptor antagonist that is differentiated from available GnRH antagonist Firmagon by its oral formulation, which will facilitate use in patients undergoing localized definitive therapy who also need ADT and may also allow use of an intermittent ADT option in advanced hormone-sensitive patients looking to mitigate side effects and maintain quality of life.

Key Topics Covered:

OVERVIEW

DISEASE BACKGROUND

TREATMENT

EPIDEMIOLOGY

MARKETED DRUGS

PIPELINE DRUGS

KEY REGULATORY EVENTS

PROBABILITY OF SUCCESS

LICENSING AND ASSET ACQUISITION DEALS

CLINICAL TRIAL LANDSCAPE

DRUG ASSESSMENT MODEL

MARKET DYNAMICS

FUTURE TRENDS

CONSENSUS FORECASTS

RECENT EVENTS AND ANALYST OPINION

KEY UPCOMING EVENTS

KEY OPINION LEADER INSIGHTS

BIBLIOGRAPHY

APPENDIX

For more information about this report visit https://www.researchandmarkets.com/r/z438b

Research and Markets also offers Custom Research services providing focused, comprehensive and tailored research.

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900

U.S. Fax: 646-607-1904 Fax (outside U.S.): +353-1-481-1716

SOURCE Research and Markets

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Global Prostate Cancer Disease Forecast and Market Analysis 2020-2036: Prescribing of Next-Generation Hormone Therapies in Earlier Treatment Settings...

Recommendation and review posted by Bethany Smith

A long lasting birth control option, IUDs can remain inside your body for anywhere between 3 and 10 years, depending on the type.

But when times up, that sucker has to come out! Ditto goes if you decide you want to get pregnant.

IUD removal is usually easy-freaking-peasy. Typically, a healthcare provider just pulls on the string that hangs from the device, the T arms fold in, and the little bugger comes out.

Given that, you may be wondering if its OK to remove the device on your own at home.

The short answer: Its best to have your IUD removed by a healthcare provider.

As Kimberly Langdon, an OB-GYN and medical adviser at telehealth provider Medzino puts it, IUD removal is a medical procedure.

But if thats not feasible, at-home removal can be an option.

PSA: Its possible to get your IUD removed for free or low cost, and by an affirming provider. And that stands even if your IUD insertion was costly or done by a provider who was not (ugh sorry, loves) affirming.

To find an affordable and affirming provider, check out your local:

That said, if getting to a provider isnt possible because you cant afford the removal or child care for when youre at the appointment, or some other reason, there are safe and less safe ways to remove the IUD at home.

Well walk you through how to do it as safely as possible below.

Just know before going into it that should a complication occur, youre going to have to get to a doctor ASAP.

Quick refresher: The IUD is a T-shaped device (about the size of a quarter) that gets inserted into the uterus through the cervix.

The cervix is known as the anatomical stopping point of the vagina. Its what you or your partner bumps up against when it feels like youre as deep as can be during sex.

Its also as far back as youll need to reach to grab the IUD string thats attached.

If youre squeamish about reaching that far back, you may consider asking a trusted friend or partner to lend a hand.

Due to the angle of entry, their hand will likely be able to reach further into your vagina than youd be able to.

Yes, youll need a set of hands.

But youll also probably want:

If your pal or partner is the one doing the removal, youll also probably want nitrile gloves, ring forceps, or both, which can help The Remover do said removal.

When the IUD is safely out, youll probably want some downtime.

So, be sure to have some comfy clothes, blankets and pillows, and your fave book or TV show within reach. Oh, and youll probably want some additional ibuprofen, water, and snacks, and a heating pad, too.

If theres anything that living through a pandemic has taught you, hopefully its how to wash your hands. Welp, time to draw on that new skill set, babes!

Wash your hands with warm water and fragrance-free soap. Keep on washing them until youve finished singing Happy Birthday. K?

Fail to wash your hands correctly and you could introduce bacteria to your bits that disrupt your pH, which could lead to:

Hard pass.

When your hands are dry, slip those nitrile gloves on.

Youve got two options: reclined or standing.

Which you choose will depend on a variety of factors, such as:

Lie on your back. If youre going to be removing the device yourself, pop your firmest pillow under your hips. This will bring your vaginal opening closer to your hands.

(Even better: Use a sex wedge, which will be even firmer than your sleeping pillow.)

Next, spread your knees wide and tuck them in toward your belly, suggests Langdon.

From a standing position, prop one of your feet on a tub ledge or toilet. Then take a stance similar to the one youd usually use to insert a tampon, Langdon says.

Once you get into position, youre going to bare down, which is going to bring your cervix (and uterus) closer to the vaginal opening.

To bare down, think about pushing a fart out of your vagina. Seriously, it works.

When your provider first inserted the IUD, they likely left 1 to 2 inches of string hanging for the purposes of removal, explains Kecia Gaither, MD, whos double board certified in OB-GYN and maternal fetal medicine, and the director of perinatal services at NYC Health + Hospitals/Lincoln.

Youre going to pull this string straight down in one fluid motion when you find it.

Ready to go fishing? Slide one finger into your vagina and see if you can feel the string.

The string is very, very thin. Its not like a tampon string, Langdon says. So dont be discouraged if it takes you a minute to locate.

Really cant find the string? Stop.

IUD strings can sometimes work their way up to the uterus. If this happens, removal must be done by a healthcare provider.

While rare, a missing IUD string could also be a sign of a larger issue like expulsion or perforation.

Once you find it, slide your forefinger and middle finger together and pinch the string between them. Pull straight down.

IUDs are supposed to come out pretty darn easily. If its not, something could be wrong.

The IUD, for example, could have become embedded into the uterus tissue or traveled outside of where it was initially planted, says Felice Gersh, MD, author of PCOS SOS: A Gynecologists Lifeline to Naturally Restore Your Rhythms, Hormones, and Happiness.

The doctor will know exactly how to navigate these slight complications, but you at home cant, she says.

If you try to, you risk really injuring yourself. You could tear or puncture the uterus, says Langdon.

This could result in scarring and make an infection, such a pelvic inflammatory disease, more likely to occur, Langdon says.

Yep!

Orgasms can cause muscle contractions in the pelvic floor. Those contractions may help the uterus release the IUD more easily.

The cervix naturally opens slightly during ovulation and menstruation. Removing the device during these moments in your cycle may be easier.

Just note: As soon as the IUD is removed, pregnancy is possible, Gersh says.

So, if youre going to have P-in-V intercourse and dont want to get pregnant, avoid removing the device around ovulation, which is when pregnancy is most likely.

As the IUD passes out of the uterus and into the cervix, you may experience cramping.

Expect that! Dont be alarmed by it.

Instead, keep pulling the device out. Slight cramping isnt a sign that something is wrong.

Congrats! Your uterus is free! But before you junk the little bugger, though, look at it.

Like, really look at it.

Are all the parts still there? Google the brand of device you have and compare your IUD to pictures to make sure.

Its possible for a part of the IUD to snap off and remain in the body, says Huong Nghiem-Eilbeck, MD, MPH, a provider at Pandia Health and board certified OB-GYN in Los Angeles, California.

Save all of the parts of the IUD that did come out in a baggie and then come in for an evaluation by a doctor, Nghiem-Eilbeck says.

The missing pieces can get embedded into the uterus or travel elsewhere in the reproductive tract causing things like discomfort, scarring, or even internal bleeding.

Very mild discomfort, mild cramping, and maybe some spotting are normal symptoms after removal, Nghiem-Eilbeck says. Typically, these last a few hours.

If you do experience cramping, Gaither says another dose of an NSAID like ibuprofen should be enough to relieve the pain.

Without a prescription, you can easily get and start using:

If youre looking to avoid a doctors office, you can still get access to certain prescription birth control options like the pill, patch, or ring via telemedicine companies.

Any persistent discomfort, uncomfortable symptoms, fever, or changes in your discharge arent normal, Nghiem-Eilbeck says.

If you experience these symptoms, avoid penetrative sex and see a doctor ASAP.

Its best to go to a medical professional to get your IUD removed if at all possible.

But as Nghiem-Eilbeck says, While typically not advised, self-removal is something that can be done, so long as the patient can learn how and reach the device.

Gabrielle Kassel is a New York-based sex and wellness writer and CrossFit Level 1 Trainer. Shes become a morning person, tested over 200 vibrators, and eaten, drunk, and brushed with charcoal all in the name of journalism. In her free time, she can be found reading self-help books and romance novels, bench-pressing, or pole dancing. Follow her on Instagram.

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Need to Remove Your IUD at Home? These 18 Safety Tips Will Help - Healthline

Recommendation and review posted by Bethany Smith

CARLSBAD, Calif., Dec. 15, 2020 /PRNewswire/ --Qualigen Therapeutics, Inc. (Nasdaq: QLGN),a biotechnology company focused on developing novel therapeutics for the treatment of cancer and infectious diseases, today announced that the United States Patent and Trademark Office has issued a patent entitled "Anti-Nucleolin Agent-Conjugated Nanoparticles as Radio-Sensitizers and/or MRI Contrast Agents" regarding the Company's ALAN (Aptamer-Linked Anti-Nucleolin) technology. This patent issued to the University of Louisville (UofL) protects the ALAN technology for use with cancer radiation therapy and for imaging tumors utilizing magnetic resonance imaging (MRI). The novel ALAN technology has several other potential applications, including its use as a monotherapy for the treatment of cancer and as a vehicle to deliver other anticancer compounds directly to tumors. In 2018, Qualigen obtained exclusive worldwide rights from the UofL for the use of the ALAN technology.

The gold nanoparticle component of ALAN is believed to enhance radiation therapy by "magnifying" the effects of radiation on the targeted tumor cells with the potential to justify lower radiation exposure and, in turn, decrease side effects. ALAN may also potentially be used in combination with MRIs to provide higher-resolution images of solid tumors and tumor cells as special imaging dyes attach to the gold nanoparticle compound.

"With the issuance of this patent, we continue to build our intellectual property portfolio as a key component to protect our technologies under development," stated Michael Poirier, Qualigen's Chairman, Chief Executive Officer and President. "ALAN is a valuable therapeutic platform technology that may be applied in numerous indications. Currently, we are evaluating strategic options on how to develop and monetize these additional applications while we continue to advance ALAN in our development pipeline against acute myeloid leukemia."

ALAN is a DNA aptamer-based anticancer drug candidate that combines the DNA aptamer AS1411 with a gold nanoparticle to dramatically increase its potency. This drug candidate has the potential to target and destroy tumor cells in a wide variety of cancer types with minimal side effects. The Company plans to commence Phase 1 human trials with ALAN in 2021 in patients with acute myeloid leukemia, its lead indication.

"The issuance of this patent for ALAN further protects this technology's potential broad applicability as a treatment for cancer," added Paula Bates, PhD, Professor of Medicine at UofL. "We look forward to our continued collaboration with Qualigen as we plan to enter this drug candidate into clinical trials as a therapeutic next year. We believe ALAN has the potential to be more targeted than available cancer treatments with the ability not to harm normal healthy cells resulting in less side effects for the patient."

Qualigen currently has 58 issued and pending patents and has in-licensed rights to a further 42 issued and pending patents.

About Qualigen Therapeutics, Inc. Qualigen Therapeutics, Inc. is a biotechnology company focused on developing novel therapeutics for the treatment of cancer and infectious diseases, as well as maintaining and expanding its core FDA-approved FastPack System, which has been used successfully in diagnostics for 20 years. The Company's cancer therapeutics pipeline includes ALAN (AS1411-GNP), RAS-F and STARS. ALAN (AS1411-GNP) is a DNA coated gold nanoparticle cancer drug candidate that has the potential to target various types of cancer with minimal side effects. The foundational nucleolin-targeting DNA aptamer of ALAN, AS1411, is also a drug candidatefor use in treating COVID-19 and other viral-based infectious diseases. RAS-F is a family of RAS oncogene protein-protein interaction inhibitor small molecules for preventing mutated RAS genes' proteins from binding to their effector proteins; preventing this binding could stop tumor growth, especially in pancreatic, colorectal and lung cancers. STARS is a DNA/RNA-based treatment device candidate for removal from circulating blood of precisely targeted tumor-produced and viral compounds. Because Qualigen's therapeutic candidates are still in the development stage, Qualigen's only products that are currently commercially available are FastPack System diagnostic instruments and test kits, used in physician offices, clinics and small hospitals around the world. The FastPack System menu includes rapid point-of-care diagnostic tests for cancer, men's health, hormone function, vitamin D status and antibodies against SARS-CoV-2. Qualigen's facility in Carlsbad, California is FDA and ISO Certified and its FastPack product line is sold worldwide by its commercial partner Sekisui Diagnostics, LLC. For more information on Qualigen Therapeutics, Inc., please visit https://www.qualigeninc.com/.

Forward-Looking Statements This news release contains forward-looking statements by the Company that involve risks and uncertainties and reflect the Company's judgment as of the date of this release. These statements include those related to prospects for ALAN, and the timing of the Company's proposed Phase 1 clinical trial of ALAN against acute myeloid leukemia. Actual events or results may differ from the Company's expectations. For example, there can be no assurance that clinical trials will be approved to begin by or will proceed as contemplated by any projected timeline; that the Company will successfully develop any drugs or therapeutic devices (or ALAN for imaging); that preclinical or clinical development of the Company's drugs or therapeutic devices (or ALAN for imaging) will be successful; that future clinical trial data will be favorable or that such trials will confirm any improvements over other products or lack negative impacts; that any drugs or therapeutic devices (or ALAN for imaging) will receive required regulatory approvals or that they will be commercially successful; that patents will issue on the Company's owned and in-licensed patent applications; that such patents, if any, and the Company's current owned and in-licensed patents would prevent competition; that the Company will be able to procure or earn sufficient working capital to complete the development, testing and launch of the Company's prospective therapeutic products (or ALAN for imaging); that the Company will be able to maintain or expand market demand and/or market share for the Company's FastPack diagnostic products generally, particularly in view of COVID-19-related deferral of patients' physician-office visits and FastPack reimbursement pricing challenges; that adoption and placement of FastPack PRO System instruments (which are the only FastPackinstruments on which the Company's SARS-CoV-2 IgGtest kits can be run) will be widespread; that the Company will be able to manufacture the FastPack PRO System instruments and SARS-CoV-2 IgGtest kits successfully; that any commercialization of the FastPack PRO System instruments and SARS-CoV-2 IgGtest kits will be profitable; or that the FDA will ultimately approve an Emergency Use Authorization for the Company's SARS-CoV-2 IgG test. The Company's stock price could be harmed if any of the events or trends contemplated by the forward-looking statements fails to occur or is delayed or if any actual future event otherwise differs from expectations. Additional information concerning these and other risk factors affecting the Company's business (including events beyond the Company's control, such as epidemics and resulting changes) can be found in the Company's prior filings with the Securities and Exchange Commission, available atwww.sec.gov. The Company disclaims any intent or obligation to update these forward-looking statements beyond the date of this news release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

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Qualigen Therapeutics Announces Issuance of US Patent for Expanded Applications of ALAN Anticancer Platform Technology - PRNewswire

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KENILWORTH, N.J. & WOODCLIFF LAKE, N.J.--(BUSINESS WIRE)--

KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Combination Demonstrated Statistically Significant Improvement in Overall Survival, Progression-Free Survival and Objective Response Rate Versus Chemotherapy in Patients With Advanced Endometrial Cancer Following Prior Systemic Therapy in Phase 3 Study

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced that the pivotal Phase 3 KEYNOTE-775/Study 309 trial evaluating the investigational use of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) and its secondary efficacy endpoint of objective response rate (ORR) in patients with advanced endometrial cancer following at least one prior platinum-based regimen. These positive results were observed in the mismatch repair proficient (pMMR) subgroup and the intention-to-treat (ITT) study population, which includes both patients with endometrial carcinoma that is pMMR as well as patients whose disease is microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR). Based on an analysis conducted by an independent Data Monitoring Committee, KEYTRUDA plus LENVIMA demonstrated a statistically significant and clinically meaningful improvement in OS, PFS and ORR versus chemotherapy (treatment of physicians choice [TPC] of doxorubicin or paclitaxel). The safety profile of the KEYTRUDA plus LENVIMA combination was consistent with previously reported studies. Merck and Eisai will discuss these data with regulatory authorities worldwide, with the intent to submit marketing authorization applications based on these results, and plan to present these results at an upcoming medical meeting.

Women with advanced endometrial cancer are faced with high mortality rates and limited treatment options following initial systemic therapy, said Dr. Gregory Lubiniecki, Associate Vice President, Oncology Clinical Research, Merck Research Laboratories. These are the first results from a Phase 3 trial of a combination regimen including immunotherapy in advanced endometrial carcinoma that have shown a statistically significant improvement in overall survival, progression-free survival and objective response rate versus chemotherapy. Merck and Eisai are dedicated to continuing to research the KEYTRUDA plus LENVIMA combination and discover new approaches to address unmet needs for devastating diseases such as endometrial carcinoma.

We are encouraged by the data observed in KEYNOTE-775/Study 309, which represent a possible step forward for patients impacted by advanced endometrial carcinoma and support the results seen in the advanced endometrial cancer cohort of KEYNOTE-146/Study 111, said Dr. Takashi Owa, Vice President, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. As more clinical data from the LEAP (LEnvatinib And Pembrolizumab) program are revealed, we cannot help but be energized by the trajectory of our collaboration with Merck and the benefits we hope to provide to patients together. Most importantly, we are grateful for the trust that the patients and healthcare professionals who participated in this trial have shown us.

KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported the U.S. Food and Drug Administrations (FDA) 2019 accelerated approval of the KEYTRUDA plus LENVIMA combination for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This accelerated approval was based on tumor response rate and durability of response and was the first approval granted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. Under Project Orbis, Health Canada and Australias Therapeutic Goods Administration (TGA) granted conditional and provisional approvals, respectively, for this indication.

Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in 13 different tumor types across 20 clinical trials, including a Phase 3 trial evaluating the combination in the first-line setting for patients with advanced endometrial carcinoma (LEAP-001).

About KEYNOTE-775/Study 309

KEYNOTE-775/Study 309 is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT03517449) evaluating KEYTRUDA in combination with LENVIMA in patients with advanced endometrial cancer following at least one prior platinum-based regimen. The dual primary endpoints are OS and PFS, as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors Version (RECIST) v1.1. Select secondary endpoints include objective response rate (ORR) by BICR per RECIST v1.1 and safety/tolerability. Of the 827 patients enrolled, 697 patients had tumors that were non-MSI-H or pMMR, and 130 patients had tumors that were MSI-H or dMMR. Patients were randomized 1:1 to receive:

About Endometrial Cancer

Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. In 2018, it was estimated there were more than 382,000 new cases and nearly 90,000 deaths from uterine body cancers worldwide (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In the U.S., it is estimated there will be almost 66,000 new cases of uterine body cancer and nearly 13,000 deaths from the disease in 2020. The five-year survival rate for advanced or metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,300 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

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KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Combination Demonstrated Statistically Significant Improvement in Overall Survival,...

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