The prespecified exploratory analyses of the secondary survival endpoint demonstrated a >90% reduction in risk of death alone or in risk of death/permanently assisted ventilation at 24 weeks, when adjusted for baseline imbalances in risk (p=0.028 to p=0.075, unadjusted for multiple comparisons) with the CNM-Au8 30 mg dose. These survival results were statistically consistent for the 30 mg dose between the regimen only and full analysis sets, which included shared placebo from other regimens participating in the Healey ALS Platform trial (Regimens A, B, and D). This survival signal is consistent with results previously reported by Clene in the Phase 2 RESCUE-ALS trial with CNM-Au8.

The full analyses, including data on biomarkers of neurodegeneration and exploratory efficacy results, are expected later in 2022. The open-label extension will continue to follow participants and provide data updates in the future. Clene is in discussions with the Healey & AMG ALS Center to offer a broader EAP of CNM-Au8 30 mg for eligible participants of closed regimens and others.

Based on these topline findings, Clene has selected the CNM-Au8 30 mg dose for continued development in ALS. The CNM-Au8 60 mg dose did not demonstrate a survival benefit. CNM-Au8 was well-tolerated, and there were no drug-related serious adverse events or significant safety findings reported.

"There remains a high unmet medical need for treatments for people living with ALS. The potential survival benefit with CNM-Au8 at 30 mg is encouraging. Additional pre-specified exploratory analyses of both the RCT and open-label extension part of the study will be shared once available," said Merit Cudkowicz, M.D., MSc, principal investigator and sponsor of the Healey ALS Platform Trial, director of the Sean M. Healey & AMG Center for ALS, chief of the Department of Neurology at Massachusetts General Hospital, and the Julieanne Dorn Professor of Neurology at Harvard Medical School. "We are thankful to the many people who participated in this study. We will learn from these results and continue to use these data to inform future advances in ALS trial design," she concluded.

Robert Glanzman, M.D., FAAN, Clene's Chief Medical Officer, said, "We are very pleased to see a survival benefit in a broad population of people who had already been living with ALS for up to three years. Importantly, this is the second Phase 2 study demonstrating a survival benefit following CNM-Au8 treatment. CNM-Au8's mechanism of enabling energy metabolism and efficiency may not be reflected in the slope of ALSFRS-R change after only 24 weeks of treatment. These Healey ALS Platform Trial results support advancement of the CNM-Au8 30 mg dose. We look forward to discussions with U.S. regulatory authorities at an End of Phase 2 meeting for our CNM-Au8 development program in ALS."

Rob Etherington, Clene's President and CEO, added, "The survival results from this trial together with the consistent benefit seen in the open-label extension of the Phase 2 RESCUE-ALS trial, based on up to 31.5 months of long-term follow-up, support the rationale for treating neuronal and glial energetic failure with CNM-Au8. We have now completed multiple Phase 2 studies in ALS and MS, building a body of evidence demonstrating that CNM-Au8 supports cellular energy production, improving myelination and neuronal viability. We believe supporting brain energetic capacity translates to patient benefit, including survival. We will work closely with regulatory health authorities, ALS experts, and patient representatives to determine the proper path for FDA and EMA approval. Clene remains committed to advancing CNM-Au8 clinical programs to the ultimate goal of FDA approval. To support this effort, Clene is pursuing paths, including strategic partnerships, and is in dialogue with various potential partners."

Michael Hotchkin, Clene's Chief Development Officer, concluded, "We thank the ALS community for its support of the Healey ALS Platform trial. Furthermore, we thank the site investigators for their research excellence and dedication to patients, and we thank Dr. Cudkowicz and the team at the Healey & AMG ALS center for their leadership and for the development of the platform trial. Most importantly, we thank people living with ALS who participated in the study and their families for their effort and willingness to engage in clinical research."

Conference Call and Webcast Information

Clene will host a conference call and webcast at 8:30 am EDT to discuss the Healey ALS Platform trial topline results for CNM-Au8. Members of Clene's executive team will lead the discussion.

Time and Date: 8:30 a.m. EDT on Oct. 3, 2022 Investors: 1 (888) 660-6179 (toll-free) or 1 (929) 203-1946 (toll) Conference ID: 5318408 Press *1 to ask or withdraw a question, or *0 for operator assistance .

To access the live webcast, please register online at this link . Participants are requested to register at a minimum 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. A live audio webcast of the call will be available on the Investors section of the Company's website Events page. An archived webcast will be available on the Company's website approximately two hours after the event.

About the Healey ALS Platform Trial The Healey ALS Platform Trial is a perpetual multi-center, randomized, double-blind, placebo-controlled program designed to evaluate the efficacy and safety of multiple investigational products utilizing a shared placebo group in people living with amyotrophic lateral sclerosis (ALS). In the CNM-Au8 regimen, 161 participants were randomized to 30 mg CNM-Au8, 60 mg CNM-Au8, or placebo as adjunct to standard of care for a 24-week treatment period. Active drug was offered to all participants who were eligible and elected to continue into the open-label extension. The primary outcome of the trial was the change in disease severity over time as measured by ALSFRS-R through 24 weeks accounting for mortality (analyzed using a Bayesian shared parameter model). Prespecified secondary efficacy endpoints included the Combined Assessment of Function and Survival joint rank test (CAFS), change in respiratory function as measured by slow vital capacity (SVC), and overall survival. For more information, please see ClinicalTrials.gov Identifier: NCT04297683 .

About CNM-Au8 CNM-Au8 is Clene's lead asset in mid- and late-stage clinical development for the treatment of multiple sclerosis and amyotrophic lateral sclerosis. An oral suspension of gold nanocrystals, CNM-Au8 was developed to protect neuronal health and function by increasing energy production and utilization. The catalytically active nanocrystals of CNM-Au8 drive critical cellular energy producing reactions that enable neuroprotection and remyelination by increasing neuronal and glial resilience to disease-relevant stressors. CNM-Au8 is a federally registered trademark of Clene Nanomedicine, Inc.

About Clene Clene is a clinical-stage biopharmaceutical company focused on revolutionizing the treatment of neurodegenerative disease by targeting energetic failure, an underlying cause of many neurological diseases. The company is based in Salt Lake City, Utah, with R&D and manufacturing operations in Maryland. For more information, please visit http://www.clene.com or follow us on Twitter , LinkedIn and Facebook.

Forward-Looking Statements This press release contains "forward-looking statements" within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended, which are intended to be covered by the "safe harbor" provisions created by those laws. Clene's forward-looking statements include, but are not limited to, statements regarding our or our management team's expectations, hopes, beliefs, intentions or strategies regarding our future operations. In addition, any statements that refer to projections, forecasts or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The words "anticipate," "believe," "contemplate," "continue," "estimate," "expect," "intends," "may," "might," "plan," "possible," "potential," "predict," "project," "should," "will," "would," and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. These forward-looking statements represent our views as of the date of this press release and involve a number of judgments, risks and uncertainties. We anticipate that subsequent events and developments will cause our views to change. We undertake no obligation to update forward-looking statements to reflect events or circumstances after the date they were made, whether as a result of new information, future events or otherwise, except as may be required under applicable securities laws. Accordingly, forward-looking statements should not be relied upon as representing our views as of any subsequent date. As a result of a number of known and unknown risks and uncertainties, our actual results or performance may be materially different from those expressed or implied by these forward-looking statements. Some factors that could cause actual results to differ include our ability to demonstrate the efficacy and safety of our drug candidates; the clinical results for our drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; our ability to achieve commercial success for our drug candidates, if approved; uncertainty regarding whether potential strategic partnerships will result in any agreements or transactions, or, if completed, any agreements or transactions will be successful or on attractive terms; our limited operating history and our ability to obtain additional funding for operations and to complete the development and commercialization of our drug candidates; and other risks and uncertainties set forth in "Risk Factors" in our most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q. In addition, statements that "we believe" and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this press release, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain and you are cautioned not to rely unduly upon these statements. All information in this press release is as of the date of this press release. The information contained in any website referenced herein is not, and shall not be deemed to be, part of or incorporated into this press release.

Source: Clene Inc.

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Ginkgo Bioworks Acquires Circularis to Strengthen Capabilities in Cell and Gene Therapy - Investing News Network

Recommendation and review posted by Bethany Smith

DetailsCategory: DNA RNA and CellsPublished on Friday, 07 October 2022 11:34Hits: 395

Enrollment continues in clinical trial of MB-106 under Mustangs IND; next data disclosure anticipated 4Q 2022

Ongoing clinical trial of MB-106 at Fred Hutch continues to demonstrate high efficacy, durable responses, and favorable safety profile across wide range of hematologic malignancies

WORCESTER, MA, USA I October 06, 2022 I Mustang Bio, Inc. (Mustang) (Nasdaq: MBIO), a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, today announced that the first patient has been treated in its multicenter, open-label, non-randomized Phase 1/2 clinical trial evaluating the safety and efficacy of MB-106, Mustangs first-in-class CD20-targeted, autologous CAR T cell therapy for the treatment of relapsed or refractory B-cell non-Hodgkin lymphomas (B-NHL) and chronic lymphocytic leukemia (CLL). The patient did not experience cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). MB-106 is being developed in a collaboration between Mustang and Fred Hutchinson Cancer Center (Fred Hutch). The multicenter trial under Mustangs Investigational New Drug Application (IND) builds upon the initial, ongoing Phase 1/2 clinical trial taking place at Fred Hutch in a single-center study under Fred Hutchs IND.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang said, The first clinical trial under Mustangs IND is an important milestone in the ongoing development and evaluation of MB-106. Data presented at several prestigious medical meetings earlier this year from the initial, ongoing Phase 1/2 clinical trial at Fred Hutch show that MB-106 continues to demonstrate high efficacy and a favorable safety profile across patients with a wide range of hematologic malignancies. We look forward to providing updates on our multicenter MB-106 clinical trial as it progresses and anticipate reporting efficacy data in the fourth quarter of this year.

Interim data from 28 patients treated in the initial, ongoing Phase 1/2 investigator-sponsored clinical trial at Fred Hutch continue to support MB-106 as a viable CAR T cell therapy for B-NHLs and CLL. As of September 9, 2022, the interim data show:

We are excited to broaden the evaluation of MB-106 with this multicenter clinical trial under Mustangs IND. To date, the data from the initial, ongoing clinical trial at Fred Hutch continue to demonstrate a high rate of complete and durable responses, said Mazyar Shadman, M.D., M.P.H., Study Chair, Associate Professor and physician at Fred Hutch and University of Washington. In addition, MB-106 has shown potential to treat patients in an outpatient setting and provide another immunotherapy option for patients treated previously with CD19-directed CAR T cell therapy.

About Mustangs Multicenter MB-106 Phase 1/2 clinical trialThe six-center Phase 1/2 clinical trial is a three-arm study targeting CLL and B-NHL including FL, diffuse large B-cell lymphoma and mantle cell lymphoma. Included in the eligibility criteria are patients who have relapsed after treatment with CD19 CAR-T cell therapy. Additionally, the FL arm will evaluate other indolent histologies including Waldenstrom macroglobulinemia, a rare type of B-NHL for which the U.S. Food and Drug Administration recently granted MB-106 Orphan Drug Designation. Since the Mustang-sponsored multicenter clinical trial is using the same lentiviral vector as the Fred Hutch-sponsored single-center trial, the FDA has allowed dose escalation to begin at a higher dose than what was originally conducted at Fred Hutch.

An estimated 287 patients are anticipated to be enrolled in the trial. All patients must have evidence of CD20 expression in both phases of the clinical trial. In Phase 1, escalating MB-106 dose levels will be tested independently in each arm using a 3+3 design. Patients will be enrolled in one of three arms, based on their primary diagnosis.

A total of up to 18 patients are anticipated to be treated in each Phase 1 arm, including six patients at the maximum tolerated dose, prior to proceeding to the Phase 2 portion of the study for each respective arm, where a total of up to 71 patients will participate in each independent arm. Safety of each dose level will be reviewed for each arm until the maximum tolerated dose has been reached and the recommended Phase 2 dose (RP2D) has been established for each arm. An assessment of the safety and tolerability of the dose will be made by the Safety Review Committee based on the data from the 28-day dose-limiting toxicity observation period.

In Phase 2, specific arms of relapsed or refractory CD20-positive B-cell NHL or CLL patients will be treated with MB-106 at the respective RP2D for each arm. Each arm will initially include up to 20 patients. Based on the results of the interim analysis, up to an additional 51 patients may be added to each of the arms.

Additional information about the trial can be found on clinicaltrials.gov using the identifier NCT05360238.

About MB-106 (CD20-targeted autologous CAR T Cell Therapy)CD20 is a membrane-embedded surface molecule which plays a role in the differentiation of B-cells into plasma cells. The CAR T was developed by Mustangs research collaborator, Fred Hutch, in the laboratories of the late Oliver Press, M.D., Ph.D., and Brian Till, M.D., Associate Professor in the Clinical Research Division at Fred Hutch, and was exclusively licensed to Mustang in 2017. The lentiviral vector drug substance used to transduce patients cells to create the MB-106 drug product produced at Fred Hutch has been optimized as a third-generation CAR derived from a fully human antibody. MB-106 is currently in a Phase 1/2 open-label, dose-escalation trial at Fred Hutch in patients with B-NHLs and CLL. The same lentiviral vector drug substance produced at Fred Hutch will be used to transduce patients cells to create the MB-106 drug product produced at Mustang Bios Worcester, MA, cell processing facility for administration in the multicenter Phase 1/2 clinical trial under Mustang Bios IND. It should be noted that Mustang Bio has introduced minor improvements to its cell processing to facilitate eventual commercial launch of the product. In addition, prior to commercial launch, Mustang Bio will replace the Fred Hutch lentiviral vector drug substance with vector produced at a commercial manufacturer. Additional information on these trials can be found athttp://www.clinicaltrials.govusing the identifierNCT05360238for the Mustang multicenter trial andNCT03277729for the ongoing trial at Fred Hutch.

About Mustang BioMustang Bio, Inc. is a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR T therapies across multiple cancers, as well as lentiviral gene therapies for severe combined immunodeficiency. Mustang is registered under the Securities Exchange Act of 1934, as amended, and files periodic reports with the U.S. Securities and Exchange Commission (SEC). Mustang was founded by Fortress Biotech, Inc. (Nasdaq: FBIO). For more information, visit http://www.mustangbio.com.

SOURE: Mustang Bio

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Mustang Bio Announces First Patient Treated in Its Multicenter Phase 1/2 Clinical Trial of MB-106, a First-in-Class CD20-targeted, Autologous CAR T...

Recommendation and review posted by Bethany Smith

LONDON, Oct. 04, 2022 (GLOBE NEWSWIRE) -- Freeline Therapeutics Holdings plc (Nasdaq: FRLN) today announced that the first patient has been dosed in the second dose cohort of the Phase 1/2 MARVEL-1 clinical trial of FLT190 in Fabry disease, a debilitating inherited disorder that leads to progressive organ damage and can result in early death as a result of a harmful build-up of fat in cells due to an enzyme deficiency.

We believe FLT190 has the potential to be a life-changing therapy for people with Fabry disease by providing durable enzyme activity above the normal range with a one-time treatment, and we are excited to have initiated this cohort in MARVEL-1, said Pamela Foulds, MD, Chief Medical Officer at Freeline. We have multiple trial sites now open across five countries with more expected to open by year-end. We look forward to reporting updated safety and efficacy data in the first half of next year.

Freeline recently reached alignment with the U.S. Food and Drug Administration to dose patients in MARVEL-1 in the United States. Efficacy and safety data from the first dose cohort of MARVEL-1 (in which patients received 7.5e11 vg/kg of FLT190) supported progression to the second, mid-dose cohort (1.5e12 vg/kg).

MARVEL-1 is an international, multicenter, adaptive dose-escalation and dose-expansion Phase1/2 clinical trial in adult men ( 18 years) with classic Fabry disease. The trial is evaluating the safety and efficacy of one-time treatment with FLT190 in up to four dose cohorts. Efficacy measures include-GalA activity levels and clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) as measured in plasma and urine. In the dose-escalation part, patient dosing is staggered to allow for adequate monitoring of both safety and efficacy. Patients will be monitored for nine months after dosing and will be eligible to participate in a long-term follow-up study for at least five years (MARVEL-2).

About Fabry Disease

Fabry disease is caused by a mutation in the GLA gene, which encodes for the enzyme -galactosidase A (-Gal A) that is required to metabolize a certain type of fat called globotriaosylceramide 3 (Gb3). As a result of deficient -Gal A production or function, Gb3 accumulates in the lysosome of various cell types and causes damage, commonly leading to a variety of painful and debilitating renal, cardiac, skin, neurological, and gastrointestinal conditions. A Gb3 metabolite, called lyso-Gb3, is considered a good biomarker for Fabry disease and may contribute to disease pathogenesis. Fabry disease can lead to premature death with renal failure and cardiac disease being the most common causes of death. Fabry disease affects approximately 16,000 people in the United States, European Union and Japan.

About FLT190 for Fabry Disease

FLT190 is a gene therapy candidate designed to generate durable plasma -Gal A levels above the normal range to enable sufficient enzyme activity in relevant tissues with a one-time treatment. FLT190 uses Freelines proprietary AAVS3 capsid to introduce a functional GLA gene into liver cells to produce functional -Gal A. AAVS3 has been rationally designed to enable effective liver cell transduction and strong and durable enzyme production at low doses and with a good safety profile. From the liver, -Gal A can circulate in the blood and be taken up by various tissues in the body, where it is transported to the cells and lysosomes and can break down Gb3.

About Freeline Therapeutics

Freeline is a clinical-stage biotechnology company developing transformative adeno-associated virus (AAV) vector-mediated systemic gene therapies. The company is dedicated to improving patient lives through innovative, one-time treatments that may provide functional cures for inherited, systemic debilitating diseases. Freeline uses its proprietary, rationally designed AAV vector and capsid (AAVS3), along with novel promoters and transgenes, to deliver a functional copy of a therapeutic gene into human liver cells, thereby expressing a persistent functional level of the missing or dysfunctional protein into the patients bloodstream. The company has clinical programs in hemophilia B, Fabry disease, and Gaucher disease Type 1. Freeline is headquartered in the UK and has operations in Germany and the U.S.

Forward-Looking Statements

This press release contains statements that constitute forward-looking statements as that term is defined in the United States Private Securities Litigation Reform Act of 1995, including statements that express the opinions, expectations, beliefs, plans, objectives, assumptions or projections of Freeline Therapeutics Holdings plc (the Company) regarding future events or future results, in contrast with statements that reflect historical facts. All statements, other than historical facts, including statements regarding FLT190s potential to be a life-changing therapy for people with Fabry disease by providing durable enzyme activity above the normal range with a one-time treatment and that the Company expects to open more sites in its MARVEL-1 clinical trial by year end and plans to report updated safety and efficacy data from such trial in the first half of next year, are forward-looking statements. In some cases, you can identify such forward-looking statements by terminology such as anticipate, intend, believe, estimate, plan, seek, project, expect, may, will, would, could or should, the negative of these terms or similar expressions. Forward-looking statements are based on managements current beliefs and assumptions and on information currently available to the Company, and you should not place undue reliance on such statements. Forward-looking statements are subject to many risks and uncertainties, including the Companys recurring losses from operations; the uncertainties inherent in research and development of the Companys product candidates, including statements regarding the timing of initiation, enrollment, continuation, completion and the outcome of clinical studies or trials and related preparatory work and regulatory review, regulatory submission dates, regulatory approval dates and/or launch dates, as well as risks associated with preclinical and clinical data, including the possibility of unfavorable new preclinical, clinical or safety data and further analyses of existing preclinical, clinical or safety data; the Companys ability to design and implement successful clinical trials for its product candidates; whether the Companys cash resources will be sufficient to fund the Companys foreseeable and unforeseeable operating expenses and capital expenditure requirements for the Companys expected timeline; the potential for a pandemic, epidemic or outbreak of infectious diseases in the United States, United Kingdom or European Union, including the COVID-19 pandemic, to disrupt and delay the Companys clinical trial pipeline; the Companys failure to demonstrate the safety and efficacy of its product candidates; business interruptions resulting from geopolitical actions, including global hostilities, war and terrorism, global pandemics or natural disasters, including earthquakes, typhoons, floods and fires; the fact that results obtained in earlier stage clinical testing may not be indicative of results in future clinical trials; the Companys ability to enroll patients in clinical trials for its product candidates; the possibility that one or more of the Companys product candidates may cause serious adverse, undesirable or unacceptable side effects or have other properties that could delay or prevent their regulatory approval or limit their commercial potential; the Companys ability to obtain and maintain regulatory approval of its product candidates; the Companys limited manufacturing history, which could result in delays in the development, regulatory approval or commercialization of its product candidates; and the Companys ability to identify or discover additional product candidates, or failure to capitalize on programs or product candidates. Such risks and uncertainties may cause the statements to be inaccurate and readers are cautioned not to place undue reliance on such statements. The Company cannot guarantee that any forward-looking statement will be realized. Should known or unknown risks or uncertainties materialize or should underlying assumptions prove inaccurate, actual results could vary materially from past results and those anticipated, estimated, or projected. Investors are cautioned not to put undue reliance on forward-looking statements. A further list and description of risks, uncertainties, and other matters can be found in the Companys Annual Report on Form 20-F for the fiscal year ended December 31, 2021, and in subsequent reports on Form 6-K, in each case including in the sections thereof captioned Cautionary Statement Regarding Forward-Looking Statements and Item 3.D. Risk factors. Many of these risks are outside of the Companys control and could cause its actual results to differ materially from those it thought would occur. The forward-looking statements included in this press release are made only as of the date hereof. The Company does not undertake, and specifically declines, any obligation to update any such statements or to publicly announce the results of any revisions to any such statements to reflect future events or developments, except as required by law. For further information, please reference the Companys reports and documents filed with the U.S. Securities and Exchange Commission (the SEC). You may review these documents by visiting EDGAR on the SEC website at http://www.sec.gov.

Media Contact:

Arne Naeveke, PhDVice President, Head of Corporate Communicationsarne.naeveke@freeline.life+1 617 312 2521

IR Contact:

Naomi Aokinaomi.aoki@freeline.lifeSenior Vice President, Head of Investor Relations & Communications+ 1 617 283 4298

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Freeline Initiates Dosing of Second Cohort in MARVEL-1 Trial of FLT190 Gene Therapy Candidate for People with Fabry Disease - GlobeNewswire

Recommendation and review posted by Bethany Smith

For medical geneticist Dr. Xiao-Ru Yang, BSc 13, MD16, few things are more rewarding than helping a patient understand what caused their mysterious, unexplained illness answers those patients often seek for many years.

Thanks to a new University of Calgary fellowship generously supported by Albertas only neurogeneticist, Dr. Oksana Suchowersky, MD 78, and her partner, the board chair of the Alberta Cancer Foundation, Dr. Chris Eagle, BSc 73, MD 77, Yang is poised to help sleuth out new diseases and improve health while adding Canadian capacity in the rapidly advancing field of neurogenetics.

There are so many diagnostic odyssey families, who get tests and investigations done for many years, but still have no diagnosis. To be able to tell these families, I think we actually have the answer now and see their reaction, is really incredible, she says.

Every case is different. It's really like solving a puzzle and you're motivated to continue to work and study these things until you do.

Yang is the first recipient of Canadas first clinical fellowship in neurogenetics and medical genetics, the 12-month Dr. Oksana Suchowersky and Dr. Chris Eagle Clinical Fellowships, offered alternating years at UCalgary and the University of Alberta.

The fellowship provides up to $100,000 to support training for exceptional clinical fellows who have completed residency in neurology or medical genetics. It allows trainees to conduct clinical or translational research or advanced subspecialty training in the area of neurogenetics (the study of the role of genetics in the development and function of the nervous system) or genetics (the diagnosis and management of genetic disorders).

Cumming School of Medicine alumni and UCalgary philanthropists, Oksana Suchowersky and Chris Eagle.

Courtesy Oksana Suchowersky and Chris Eagle

Over the past number of years, genetics has mushroomed its becoming an important point in how we diagnose and even treat patients. We're starting to use gene therapy in a lot of different specialties, says Suchowersky.

And yet in medical school, students receive only about seven hours of general training in genetics, and funding for clinical fellowships is very limited. That started the discussions between Chris and myself about the importance in developing expertise in genetics.

The donors have worn many hats in Albertas health care and education communities. Suchowersky is an adjunct professor and former department head of medical genetics at UCalgary. She is a professor in the departments of Medicine (Neurology), Medical Genetics and Paediatrics at the University of Alberta and director of the Neurogenetics and Huntington disease program.

Eagle is a past president and CEO of Alberta Health Services and past CEO of Calgary Health Trust. He is also a professor emeritus, former department head of anesthesiology and assistant dean of medical education at UCalgarys Cumming School of Medicine (CSM). He says:

We've watched generations of talented young physicians leave Alberta to get training elsewhere sometimes they return, sometimes they don't. This fellowship is an opportunity to keep or bring people here. Its also about making the care thats given in Alberta the best in the world.

Yang started her training this summer under the supervision of Dr. Francois Bernier, MD, Dr. Billie Au, MD, PhD and Dr. Mike Innes, MD, at the Alberta Childrens Hospital (ACH) all international leaders in their field. Shell learn how to analyze genomic data and how to ultimately apply emerging genetic sequencing technologies in the clinic.

The funding of this fellowship is transformational, supporting advanced training of the some of the best physicians in one of most rapidly advancing fields of medicine. Canada desperately needs academic and physician leaders to maximize the impact of genomic medicine and neurogenetics and UCalgary have consistently been at the forefront of these fields, says Bernier, professor and head of Medical Genetics.

Dr. Yang will be among the new generation of leaders in genomics thanks to this fellowship.

Rapid advances in genomics the study of genes and their functions are allowing researchers and physicians to customize health care and treat individuals according to their genetic makeup. This precision medicine approach is giving physicians more tools to understand what their patients need and to provide highly personalized, precise care.

There are more than 4,800 known, rare syndromes, affecting between one and two million Canadians. More accessible gene sequencing has allowed UCalgary geneticists to diagnose many previously undiagnosed, complex chronic diseases, which has a positive impact on families as well as the health-care system.

The cost to sequence the full genome in one single person used to be $100 million, but now costs about $1,000.

Yang moved from Halifax to Calgary with her family as a teenager and completed her five-year residency in medical genetics at the CSM earlier this year. During the COVID-19 pandemic, she became a mom to a now two-year-old boy. She previously had the opportunity to spend time during her residency in clinic with Suchowersky, who teaches at both UCalgary and UAlberta, and Yang looks forward to learning from the neurogeneticist again as part of the fellowship.

"I'm so grateful for this investment that Dr. Suchowersky and Dr. Eagle are making into training the next generation of physicians in the fields of genetics and neurology. I get to train with some really fantastic physicians and scientists and it wouldn't happen without their generosity, Yang says.

I hope through the course of my career that I can pay it forward by furthering the education of other trainees, like they're doing for me right now.

See the article here:
Clinical fellowship offers opportunity to diagnose previously undiagnosable diseases through genetic 'detective' work - University of Calgary

Recommendation and review posted by Bethany Smith

Around 80% survive their cancer for one year or more, and almost 60% survive their cancer for five years or more.

Early-stage colon cancer can often be identified and treated with a colonoscopy. A colonoscopy employs a tiny camera mounted on a small, flexible tube to look for indications of colon cancer.

During a colonoscopy, small, early-stage malignancies may also be removed. Surgery is typically required for larger tumors. It is occasionally used with radiation, chemotherapy, targeted therapy, and/or immunotherapy. These therapies reduce tumor size and stop their spread.

Breast cancer can kill both men and women.

Cancerous cells in the lining of the breast's lobules or ducts are what cause breast cancer. While the vast majority of cases are found in women, men make up around 1% of all breast cancer cases. The process through which cells become cancerous and infiltrate other body tissues takes time.

Surgical treatments for breast cancer may include removal of the breast tissue and associated lymph glands (mastectomy) or lumpectomy.

Other than surgery, there are other methods to help treat this type of cancer. These include, but are not limited to: -

Few people ever survive pancreatic cancer.

Pancreatic cancer, once it starts, tends to be one of the most aggressive of all cancers. It frequently kills rapidly and produces uncomfortable symptoms like these:

Despite its aggressive nature, there aren't many reliable screening options for pancreatic cancer yet. But, regular ultrasound and MRI/CT imaging tests should be performed on people who are at increased risk.

Aggressive chemotherapy and surgery are frequently required for people with this kind of cancer. When tumors cannot be removed, radiation may be used to reduce their size.

Only 10% to 20% of cancer patients are candidates for surgery. In the U.S., five-year survival rates for localized pancreatic cancer are around 42%, but for all stages of pancreatic cancer, this drops to 11%.

Prostate cancer is big killer of older men.

The prostate is located between the rectum and bladder in the center of the lower pelvis. Its main purpose is to produce the fluid that nourishes sperm in men.

Since the prostate is a gland rather than an organ, per se, it is an example of something called adenocarcinoma. It typically affects older men, is more prevalent in black men, and is more likely to run in families.

Prostate tumors typically grow slowly. This form of cancer may not immediately show signs in its victims, and in older men, in particular, it may move so slowly that only minimal treatment is recommended. Doctors might opt for a wait-and-see approach to treatment as a result. Interestingly, many people with prostate cancer die of unrelated causes, such as a heart attack or stroke.

Even if they have no symptoms, older men should be frequently checked for prostate cancer using a digital rectal exam and prostate-specific antigen (PSA) testing, although many professionals today dispute the usefulness of prostate screening.

Prostate cancer treatment usually involves one or more of the following:

Cancer of the esophagus also kills alot of people.

The esophagus is the muscular tube that carries food from the throat to the stomach. Older age, being a man, smoking, consuming alcohol, and having severe acid reflux (where stomach acid rises into the lower esophagus), are risk factors for esophageal cancer.

Depending on how far along the cancer is, there are a variety of possible treatments, such as surgery, chemotherapy, radiation, immunotherapy, and targeted therapies.

Liver cancer is sadly on the rise.

One of the most prevalent types of cancer in the world is liver cancer. Although liver cancer is not widespread in the U.S., it has been on the rise since the 1980s, with its incidence more than doubling.

Chronic hepatitis B or hepatitis C infections are the main cause of liver cancer. Blood and semen are just two body fluids that can spread either of these illnesses. Although there is no vaccine for hepatitis C, the CDC advises that all children receive the hepatitis B vaccine.

Intrahepatic bile duct cancer, which develops in the ducts that transfer bile from the liver and gallbladder to the small intestine, where the bile aids in the digestion of lipids from the diet, is a closely related cancer.

Brain cancer is less common, but very deadly.

In adults, brain tumors rarely begin in the brain.Instead, they usually spread there from other malignancies.

However, as malignancies are classified according to their location of origin, brain tumors that are caused by tumors that began elsewhere in the body are generally excluded from brain cancer survival statistics.

If a person passed away from cancer that started in the lung and spread to the brain, for instance, the death would have an impact on lung cancer survival numbers rather than brain cancer survival statistics.

According to the Mayo Clinic, most brain tumors in children, however, do start in the brain. Family history and radiation exposure to the head are risk factors for brain tumors. Typically, radiation exposure occurs while undergoing treatment for another cancer.

Treatment options for brain tumors can range from surgery to radiation to chemotherapy to immunotherapies to targeted medicines, depending on the tumor type and the extent of the malignancy at the time of diagnosis.

Leukemia is also a big killer.

Leukemias develop from stem cells in the bone marrow, which differentiate into different blood-cell precursors and eventually blood cells. It is caused by a rise in the number of white blood cells in your body. Those excess white blood cells don't work properly, and they crowd out the red blood cells and platelets your body needs.

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Here are the 9 most common types of cancer - Interesting Engineering

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As cancer treatments continue to advance and new therapies are introduced, it's easy to get lost in your search for information. To help you better understand the differences between specific cancer treatments and how they work, we spoke with medical oncologist Bhavina Sharma, MD, MPH.

"Chemotherapy are drugs designed to directly attack all rapidly dividing cells in the body, including cancer cells," explains Dr. Sharma. "It relies on the idea that cancer cells reproduce much faster than most healthy cells in our body."

Chemotherapy drugs can be given by infusion or in pill form. Unfortunately, these drugs can't tell the difference between cancerous cells and fast-growing healthy cells like the gastrointestinal tract and hair follicles, leading to side effects such as diarrhea and hair loss. Thankfully, recent advancements in chemotherapy have helped lessen side effects such as nausea, pain and lethargy.

Targeted therapy are special drugs designed to target differences within cancer cells that help them thrive. Unlike chemotherapy, targeted therapy drugs actually change the inner workings of the cancer cell. Because targeted therapy focuses on the part of the cancer cell that makes it different from the normal, healthy cell, it often has fewer side effects than standard chemotherapy treatments.

Immunotherapy is very different than chemotherapy in that it helps our immune system to find and kill cancer cells.

"Cancer cells are abnormal cells that have formed in our body because of cell damage or mutations," explains Dr. Sharma. "Cancer cells hide from your immune system by shutting down certain pathways of the immune response. Immunotherapy unlocks those pathways so your immune system can recognize and remove the cancer cells."

Cellular therapies are treatments that improve the body's ability to fight cancer. "Stem cell therapy falls under the umbrella of cellular therapy," explains Dr. Sharma. "It uses stem cells to mount an immune response to attack your cancer cells."

Stem cells from blood and bone marrow can be used in transplants. These stem cells can either come from a matched donor (allogeneic) or from the patient themselves (autologous).

Chimeric antigen receptor therapy or CAR T-cell, is a type of cellular therapy.

"T cells are white blood cells that help our bodies fight infection and cancer," explains Dr. Sharma. "With CAR T-cell therapy, your own T cells are collected from your blood. These T cells are modified to recognize cancer as a foreign cell and attack it."

CAR T-cell therapy has been approved by the Food and Drug Administration to treat lymphoma, leukemia and multiple myeloma.

Hormone therapy slows or stops the growth of cancer that uses hormones to grow. It is also called hormonal therapy, hormone treatment or endocrine therapy. Hormone therapy is recommended for cancers that are hormone-receptor positive, such as certain breast and prostate cancers. It can't be used in cancers that don't carry hormone receptors.

"Hormone therapy can be used for both early stage and metastatic hormone-receptor positive breast cancers," explains Dr. Sharma. "In patients with early-stage breast cancer, it is used after surgery to help reduce the risk of the cancer coming back."

Chemotherapy, immunotherapy, targeted therapy, and hormone therapy are just a few of the treatments we use to treat cancer. Many of these cancer treatments can be combined with others like cancer surgery and radiation therapy. Every person's journey through cancer is different. Your oncology team will help you sort through the best therapies available to create your treatment plan.

The information in this article is for information purposes only. For specific questions regarding your medical condition or treatment plan, please consult with your doctor directly. To schedule an appointment with a Nebraska Medicine cancer specialist, call 402.559.5600.

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Are immunotherapy and chemotherapy the same thing? How cancer treatments work - Nebraska Medicine

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ReportLinker

Global Cord Blood Banking Market By Service (Sample Preservation & Storage, Sample Analysis, Sample Processing, Sample Collection & Transportation), By Component (Cord Blood v/s Cord Tissue), By Application (Cancer Disease, Diabetes, Blood Disease, Immune Disorders, Metabolic Disorders, Others), By Sector (Public Cord Blood Banks v/s Private cord Blood Banks), By Company, and By Region, Competition Forecast and Opportunities, 2027

New York, Oct. 07, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Cord Blood Banking Market - Competition Forecast and Opportunities, 2027" - https://www.reportlinker.com/p06325897/?utm_source=GNW

The global cord blood banking market is anticipated to observe impressive growth during the forecast period, 2023-2027.The major factors include the increase in genetic diseases and the growing awareness among parental population.

Cord blood stem cells treat various invasive diseases such as leukemia, anemia, and blood cancer.Moreover, there is an upsurge in the utilization of cord blood banking services for the treatment of immunodeficiency disorders across the world.

This, coupled with the growing awareness among masses about the benefits and broad availability of cord blood banking service donors, is impelling the growth of the market. The other factors supporting the markets growth are extensive investments by governments of different countries in research and development (R&D) activities to expedite clinical trials of cord blood stem cells, and expansion of healthcare industry.Increasing Prevalence of Hematological DisordersNowadays, more and more people are suffering from various hematological disorders and chronic diseases due to which storing of cord blood stem cells is very crucial.Cord blood holds a rich source of stem cells, which can cure hematological disorders such as leukemia, thalassemia, hemophilia, sickle cell anemia, lymphoma, and others.

The growing occurrence of different cancers, such as leukemia and lymphoma, due to longer working hours, hectic lives, and excessive smoking and alcohol intake signifies one of the key factors driving the cord blood banking market.Cord blood stem cells can cure chronic diseases such as cancer, blood diseases, diabetes, and immune diseases due to which an increase in the utilization of cord blood banking services for the treatment of these diseases is becoming more common.

For instance, in 2020, CIBMTR reported 4,864 unrelated and 4,160 related bone marrow and cord blood transplants which were performed in the United States.Growing Awareness regarding the Therapeutic Potential of Stem cellsStem cells have been proven to treat over 80 genetic diseases and other chronic diseases due to which people are becoming more aware regarding the therapeutic potential of stem cells across the globe.Parental as well as expectant populations are becoming more aware as health professionals are starting to educate them about the importance and benefits of storing cord blood stem cells which is driving the growth of the market, globally.

Additionally, increase in awareness among the public regarding the massive availability of service providers is likely to propel the growth of cord blood banking market.For instance, in the United States, the donor registry contains more than 9 million potential donors.

Also, the donor registry includes 266,000 cord blood units from which 115,000 units are from National Cord Blood Inventory (NCBI), with over 4000 NCBI units added in 2021.Increasing Investments for Cord Blood Banking SectorIncrease in fundings and initiatives by government for R&D, technological advancements and expansion of healthcare infrastructure is propelling the growth of the cord blood banking market, globally. Increasing investments in research and development for treating life threatening diseases and clinical trials for cord blood stem cells are expected to drive the market.Market SegmentationThe global cord blood banking market is segmented into service, component, application, sector, and company.Based on service, the market is divided into sample preservation & storage, sample analysis, sample processing, and sample collection & transportation.

Based on component, the market is divided into cord blood and cord tissue.Based on application, the market is divided into cancer disease, diabetes, blood disease, immune disorders, metabolic disorders, and others.

Based on sector, the market is divided into public cord blood banks and private cord blood banks. In terms of country, the United States is expected to be a lucrative market in the forecast period due to growing prevalence of hematological disorders and increasing R&D activities in the country.Market PlayersAmericord Registry LLC, Covis Group, Cordlife Group Limited, Cryo-Cell International, Inc., FamiCord Group, Cordvida, Perkinelmer Inc., Lifecell International Pvt. Ltd., ViaCord LLC, Global Cord Blood Corporation, and StemCyte Inc. are some of the leading companies operating in the market.

Report Scope:

In this report, global cord blood banking market has been segmented into following categories, in addition to the industry trends which have also been detailed below: Cord Blood Banking Market, By Service:o Sample Preservation & Storageo Sample Analysiso Sample Processingo Sample Collection & Transportation Cord Blood Banking Market, By Component:o Cord Bloodo Cord Tissue Cord Blood Banking, By Application:o Cancer Diseaseo Diabeteso Blood Diseaseo Immune Disorderso Metabolic Disorderso Others Cord Blood Banking Market, By Sector:o Public Cord Blood Bankso Private Cord Blood Banks Cord Blood Banking Market, By Region:o North AmericaUnited StatesCanadaMexicoo Asia-PacificChinaIndiaJapanAustraliaSouth Koreao Europe & CISGermanyFranceUnited KingdomSpainItalyo South AmericaBrazilArgentinaColombiao Middle East & AfricaSouth AfricaSaudi ArabiaUAE

Competitive Landscape

Company Profiles: Detailed analysis of the major companies present in Cord Blood Banking Market

Available Customizations:

With the given market data, we offers customizations according to a companys specific needs. The following customization options are available for the report:

Company Information

Detailed analysis and profiling of additional market players (up to five).Read the full report: https://www.reportlinker.com/p06325897/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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Global Cord Blood Banking Market - Competition Forecast and Opportunities, 2027 - Yahoo Finance

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MCARH109, a CAR T-cell therapy targeting the enigmatic GPRC5D antigen, generated remissions in 70.6% of patients with relapsed/refractory multiple myeloma.

MCARH109, a CAR T-cell therapy targeting the enigmatic GPRC5D antigen, generated remissions in 70.6% of patients with relapsed/refractory multiple myeloma, according to data from a first-in-human phase 1 trial (NCT04555551).1

Twelve of 17 patients experienced a measurable decline in their cancer after receiving MCARH109 CAR T cells. Six patients (35%) achieved complete response, and 10 patients (59%) had very good partial response or better. Eight patients (47%) had minimal residual disease negativity in bone marrow.

Although the study population was small, coauthor Renier Brentjens, MD, PhD, The Katherine Anne Gioia Endowed Chair in Cancer Medicine, chair of the department of medicine, and deputy director at Roswell Park Comprehensive Cancer Center; said these findings open up a new plan of attack for treating multiple myeloma.

Whats scientifically exciting is that we now have 2 populations of targeted cells which we think we can now feasibly treat patients with concomitantly, potentially, and that is very exciting, he explained in an interview with OncLive. That will certainly help set a proof of principle for other malignancies that we will target with CAR T cells, including solid tumor malignancies. It really is a significant step forward in the field. Its still to be seen how meaningful this iswhether its an opportunity to prolong responsesor to potentially enhance responses. Were very excited about that part of it.

Physicians have achieved deep, durable responses using B-cell maturation antigen (BCMA)targeting CAR T-cell therapies in patients with multiple myeloma. However, data from some studies show that progression-free survival is less than 12 months, an indicator of myeloma recurrence despite the persistence of CAR T cells.2 Relapse is common, and mechanisms of resistance are not fully defined, although recent data suggests that the identification of BCMA expression, copy number variation, and point mutations appeared to be key indicators of resistance for patients receiving BCMA-targeting CAR T-cell therapy or T-cell engagers.3

Investigators at Roswell Park developed MCARH109 in partnership with Memorial Sloan Kettering Cancer Center (MSKCC) and Dana-Farber Cancer Institute. Brentjens said investigators began exploring cellular therapeutic targets for multiple myeloma about 10 years ago. They identified 3 targets including BCMA, which is now FDA approved in the form of drugs, such as ciltacabtagene autoleucel (Carvykti), and the antigen GPRC5D.

GPRC5D is an intriguing target because its really nicely upregulated on multiple myeloma cells, but not expressed in most normal tissues, with some exceptions in the skin, for example, he explained. We knew even back then that we were likely going to have to go after more than 1 target.

Duration is limited for BCMA-directed therapy and there are few treatment options for patients who relapse. In preclinical models, investigators found in vitro and in vivo antitumor efficacy with GPRC5D CAR T cells in multiple myeloma, including in a BCMA antigen escape model. GPRC5D is highly expressed in myeloma cell lines and in bone marrow plasma cells of patients with multiple myeloma. The antigen is found less often in plasma cells in normal tissue and has low expression in a subset of cells in the hair follicles and hard keratinizing tissue.

The 17 patients in the phase 1 trial, conducted at MSKCC, had undergone a median of 6 prior treatments for myeloma, including CAR T-cell therapy targeting BCMA, proteasome inhibitors, immunomodulatory agents (IMiDs), and anti-CD38 antibodybased therapies. Eligible patients had an ECOG score of 0 or 1 and adequate organ function. Baseline GPRC5D expression in the bone marrow was not required for enrollment.

Patients could receive bridging therapy following apheresis but had to discontinue at least 2 weeks before initiating lymphodepleting chemotherapy. Lymphodepletion consisted of daily 300 mg/m2 cyclophosphamide plus 30 mg/m2 fludarabine for 3 consecutive days. Two days after the completion of lymphodepletion, investigators administered MCARH109 at 4 dose levels: 25 106, 50 106, 150 106, and 450 106 CAR T cells.

Investigators followed all patients until disease progression. Long-term follow-up continued until death or withdrawal of consent.

The median patient age was 60 years (range, 38-76). All patients received previous treatment with 2 proteasome inhibitors, 2 IMiDs, and 1 anti-CD38 antibody. Sixteen patients (94%) had triple-refractory disease.

Ten patients (59%) had received previous treatment with BCMA-targeted therapies, including 8 (47%) who received previous BCMA CAR T-cell therapy. Nine responded to BCMA-targeted therapy and 2 were refractory to the treatment. The median time from last BCMA therapy to MCARH109 infusion was 16.4 months (range, 4.4-36.6).

All patients had previously received high-dose melphalan and undergone an autologous stem cell transplantation. Three patients (18%) had previously received allogeneic transplantation.

Fourteen patients (82%) were refractory to their last line of therapy. Sixteen patients (94%) received bridging therapy after leukapheresis; 15 were refractory to bridging therapy.

Three patients (18%) had nonsecretory myeloma at baseline, and 8 (47%) had extramedullary plasmacytoma. Thirteen (76%) had one or more high-risk cytogenetic features, defined by the presence of 1q gain, del(17p), t(4;14), or t(14;16).

At a median follow-up of 10.1 months (95% CI, 8.5not reached [NR]), 6 of 12 patients (50%) with a partial response or better remained progression free. Two patients have completed more than 1 year of follow-up after MCARH109 infusion.

The median duration of response (DOR) was 7.8 months (95% CI, 5.7-NR) in the entire cohort. The median DOR was also 7.8 months (95% CI, 4.6-NR) in patients who received 25 106 to 150 106 CAR T cells.

At the maximum tolerated dose of 150106 cells, 58% of patients had a response.

Seven of 10 patients who received previous BCMA-targeted therapies had partial response or better. The same was true for 3 of 6 patients (50%) treated at doses of 25 106 to 150 106 cells.

Fourteen patients experienced grade 1/2 cytokine release syndrome (CRS). One patient at the highest dose level (450 106 CAR T cells) had a grade 4 CRS event. Investigators said this patient had grade 4 immune effector cellassociated neurotoxicity syndrome (ICANS) and grade 4 macrophage activation syndrome, which constituted a dose-limiting toxic effect. No other patients had ICANS or macrophage activation syndrome.

Two other patients at the highest dose level experienced a grade 3 cerebellar disorder that investigators determined was possibly related to MCARH109 and constituted a dose-limiting toxic effect for this dose.

The most common grade 3 or higher adverse effects (AEs) included neutropenia (94%), thrombocytopenia (65%), and anemia (35%). Nonhematologic grade 3 or higher events were uncommon.

Three patients (18%) experienced infections. Two experienced grade 3 events (bacterial infection and parvovirus infection, respectively).

Twelve patients were treated at dose levels that did not produce unacceptable AEs (25 106 to 150 106 CAR T cells). Seven of those (58%; 95% CI, 28%-85%) had an objective response.

They had relapsed or been refractory to BCMA-targeted CAR T cells, and yet we are still able to demonstrate clinical meaningfully clinical responses using the GPRC5D CAR T cells, Brentjens said. We now actually have 2 targets for patients with multiple myeloma rather than just 1. We can start to potentially explore [targeting 2] different antigens on the multiple myeloma tumor cell, either sequentially or concurrently, which is really exciting to potentially utilize this dual targeted approach to get more durable and long-term remissions in patients.

To the best of my knowledge, this the first time that we really have identified 2 targets on 1 tumor cell, both of which demonstrate really promising and significant responses. That really begs the question of, if we put the 2 populations together, will there be a synergistic benefit when assessing durability of response?

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GPRC5D AntigenTargeted CAR T-cell Therapy Induces Strong Response in Resistant Multiple Myeloma - OncLive

Recommendation and review posted by Bethany Smith

Over the past year, news of two new people cured of HIV grabbed headlines, stirring hopeful talk of what these scientific wonders might portend for the four-decade fight against the virus.

To researchers working in the HIV cure arena, these cases are inspiring because they prove it is in fact possible to eradicate this extraordinarily complex virus from the body.

That said, such cures are the result of treatments too toxic to attempt on all but a select few. So while they provide a scientific roadmap toward success, they do not necessarily make researchers job any easier as they work to develop alternatives: safe, effective and, crucially, scalable therapies to cure HIV.

HIV has been a tough nut to track, says Marshall Glesby, an infectious disease specialist at Weill Cornell Medicine in New York City and a coauthor of one of the recent HIV cure case studies. But there is incremental progress being made in terms of our understanding of where the virus hides within the body and potential ways to purge it from those sites.

The HIV cure research field is yet quite young. And it likely never would have ballooned as it has in recent years were it not for the very first successful cureone that served as a catalyst and guiding light for scientists.

During the late 1990s and early 2000s, the HIV research establishment focused the lions share of its energy and resources on treatment and prevention of the virus. Actually curing HIV was generally regarded as a distant dream, with only a small set of researchers pursuing such a goal.

Then, in 2008, German scientists announced the first case of what would ultimately be deemed a successful cure of the virus. This proof of concept ignited the field and sent financial investment soaringto $337 million in nonpharmaceutical industry funding in 2020, according to the HIV nonprofit AVAC.

Clinicians were able to cure HIV in an American man living in Berlin named Timothy Ray Brown, by exploiting the fact that he had also been diagnosed with acute myeloid leukemia, or AML. This made Brown a candidate for a stem cell (bone marrow) transplant to treat his blood cancer.

Browns treatment team relied on the existence of a rare genetic abnormality found among people with northern European ancestry. Known as the CCR5-delta32 mutation, it gives rise to immune cells lacking a certain coreceptor called CCR5 on their surface. This is a hook to which HIV typically latches to begin the process of infecting an immune cell and hijacking its machinery to manufacture new copies of the virus.

The clinicians found a stem cell donor who was not only a good genetic match for Brown, but who also had the CCR5-delta32 mutation. First they destroyed Browns immune system with full-dose chemotherapy and full-body radiation. Then they effectively gave him the donors immune system through the stem cell transplant. This cured his HIV by ensuring that any remaining virus in his body was incapable of infecting his new immune cells.

Variations of this method have yielded cures, or likely cures, in four other people during the years since. These cases provide researchers with increasing certainty that it is possible to achieve the ultimate goal: a sterilizing cure, in which the body has been rid of every last copy of virus capable of producing viable new copies of itself.

It was not a given that if you completely replace the immune system, even with a purportedly non-susceptible immune system, that you would cure infection, says Louis Picker, associate director of the Vaccine and Gene Therapy Institute at the Oregon Health & Science University. It was possible that HIV could be hiding in non-immune cells, like endothelial cells, and still find targets to infect.

But the small cohort of people who have been cured or likely cured to date, Picker says, show thats not the case.

Nevertheless, these successes have not opened the door to a cure for HIV available to much more than a few of the estimated 38 million people living with the virus worldwide. Critically, it is unethical to provide such a dangerous and toxic treatment to anyone who does not already qualify for a stem cell transplant to treat blood cancer or another health condition.

Brown, for one, nearly died from his treatment. And a number of efforts to repeat his case have failed.

Highly effective treatment for HIV hit the market in 1996, transforming what was once a death sentence into a manageable health condition. Today, the therapy, a combination of drugs called antiretrovirals, is so safe, tolerable and effective, that it has extended recipients life expectancy to near normal. But despite the fact that these medications can inhibit viral replication to such a degree that its undetectable by standard tests, they cannot eradicate HIV from the body.

Standing in the way is whats known as the HIV reservoir.

This viral reservoir is composed in large part of long-lived immune cells that enter a resting, or latent, state. Antiretrovirals only target cells that are actively producing new copies of the virus. So when HIV has infected a cell that is in a non-replicating state, the virus remains under the radar of these medications. Stop the treatment, and at any moment, any of these cells, which clone themselves, can restart their engines and repopulate the body with HIV.

This phenomenon is why people with HIV typically experience a viral rebound within a few weeks of stopping their antiretrovirals. And it is the reason why, given the harm such viral replication causes the body, those living with HIV must remain on treatment for the virus indefinitely to mitigate the deleterious impacts of the infection.

A key new advance is the finding that those cells which harbor the virus seem resistant to dying, a problem with cancer cells, HIV cure researcher Steven Deeks, a professor of medicine at University of California, San Francisco, says of the viral reservoir. We will be leveraging new cancer therapies aimed at targeting these resilient, hard-to-kill cells.

Brown stood alone on his pedestal for over a decade.

Then, at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, researchers announced two new case studies of men with blood cancer and HIV who had received treatments similar to Browns. The men, known as the Dsseldorf and London patients, were treated for Hodgkin lymphoma and AML, respectively. By the time of the conference, both had spent extended periods off of antiretroviral treatment without a viral rebound.

To this day, neither man has experienced a viral reboundleading the authors of the London and Dsseldorf case studies recently to assert that they are definitely and almost definitely cured, respectively.

In February 2022, a team of researchers reported at CROI, held virtually, the first possible case of an HIV cure in a woman. The treatment she received for her leukemia represented an important scientific advance.

Called a haplo-cord transplant, this cutting-edge approach to treating blood cancer was developed to compensate for the difficulty of finding a close genetic match in the stem cell donorwhich is traditionally needed to provide the best chance that the stem cell transplant will work properly. Such an effort is made even more challenging when attempting to cure HIV, because the CCR5-delta32 mutation is so rare.

The American woman received a transplant of umbilical cord blood from a baby, who had the genetic mutation, followed by a transplant of stem cells from an adult, who did not. While each donor was only a partial match, the combination of the two transplants was meant to compensate for this less-than-ideal scenario. The result was the successful blooming of a new, HIV-resistant immune system.

The authors of the womans case study, including Weill Cornells Marshall Glesby, estimate that this new method could expand the number of candidates for HIV cure treatment to about 50 per year.

A variety of antiretroviral drugs used to treat HIV infection. Image Credit: NIAID, Flickr

In July, at the International AIDS Conference in Montreal, researchers announced the case of a fifth person possibly cured of HIV. Diagnosed with the virus in 1988 and 63 years old at the time of his stem cell transplant three years ago, the American man is the oldest to have achieved potential success with such a treatment and the one living with the virus for the longest. Because of his age, he received reduced intensity chemotherapy to treat his AML. Promisingly, he still beat both the cancer and the virus.

The lead author of this mans case study, Jana K. Dickter, an associate clinical professor of infectious disease at City of Hope in Duarte, California, says that such cases provide a guide for researchers. If we are able to successfully modify the CCR5 receptors from T cells for people living with HIV, she says, then there is a possibility we can cure a person from their HIV infection.

Scientists also know of two women whose own immune systems, in an extraordinary feat, appear to have cured them of HIV. Both are among the approximately 1 in 200 people with HIV, known as elite controllers, whose immune systems are able to suppress replication of the virus to low levels without antiretroviral treatment.

Researchers believe that these womens immune systems managed to preferentially eliminate immune cells infected with viral DNA capable of producing viable new virus, ultimately succeeding in eradicating every last such copy.

As they seek safer and more broadly applicable therapeutic options than the stem cell transplant approach, HIV cure researchers are pursuing a variety of avenues.

Some investigators are developing genetic treatments in which, for example, they attempt to edit an individuals own immune cells to make them lack the CCR5 coreceptor.

The science that I am particularly excited about and that we and others are working on is to make this treatment as an in vivo deliverable therapy that would not rely on transplant centers and could ultimately be given in an outpatient setting, says Hans-Peter Kiem, director of the stem cell and gene therapy program at the Fred Hutchinson Cancer Center in Seattle.

Then there is whats known as the shock and kill method, in which drugs are used to flush the virus from the reservoir and other treatments are then used to kill off the infected cells. Conversely, block and lock attempts to freeze the reservoir cells in a latent state for good. Researchers are also developing therapeutic vaccines that would augment the immune response to the virus.

Progress will be incremental and slow, Picker predicts, unless there is a discovery from left fieldan unpredictable advance that revolutionizes the field. I do think it will happen. My personal goal is to be a very good left fielder.

This reporting was supported by the Global Health Reporting Center.

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How a select few people have been cured of HIV - PBS

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Diagnosis, Treatment, and Prevention of Blood Cancer By Dr Gaurav Kharya

Written by Tavishi Dogra | Updated : October 4, 2022 9:56 PM IST

In India, the increase in cancer cases over the past ten years has become a significant public health problem for the country. These cases have a long latent period, are primarily lifestyle-related and require specialised infrastructure and human resources to be treated. Cancer's physical, psychological and financial toll on people, families, communities and health systems keeps rising. The prevalence of cancer varies across India's regions, making prevention and management extremely difficult. Due to cancer not being a notifiable disease, the national burden assessment is still a task for which many developing nations, including India, rely on statistical models. The estimated number of cancer-related Disability-adjusted life years (DALYs) (AMI) in India in 2021 was 26.7 million, and that number was predicted to rise to 29.8 million in 2025.

Each year, 1.24 million new instances of blood cancer are reported worldwide, making up about 6% of all cancer cases. Blood cancer develops in the bone marrow, tissues that create blood and compromise the immune system. According to incidence rates, there are primarily three different forms of blood cancers: lymphoma/leukaemia, multiple myeloma, myelodysplastic syndromes (MDS)/myeloproliferative neoplasms (MPN). In addition, blood cancer may arise when the body produces abnormal White Blood Cells (WBCs). It typically starts in the bone marrow, which produces blood in our body. This malignancy impairs the normal development, growth and functioning of blood cells that fight infection and produce healthy blood cells.

White blood cells produced by the body during leukaemia are incapable of battling infections. Depending on the type of blood cell involved and whether it is fast-growing or slow-growing (acute or chronic), leukaemia is divided into distinct forms (myeloid or lymphoid). Consequently, it can be broadly divided into four subtypes: acute lymphocytic leukaemia (ALL), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML). Apart from these are some rare blood cancers such as Juvenile myelomonocytic leukaemia (JMML).

Diagnosis, Treatment, and Prevention of Blood Cancer By Dr Gaurav Kharya, Clinical Lead Apollo Center & Indraprastha Apollo Hospital

Various diagnostic techniques are used to identify blood cancer, including clinical examination, blood testing, bone marrow tests, cytogenetic/karyotyping, molecular analyses, and flow cytometry. Most pediatric patients diagnosed with ALL or AML can be treated by chemotherapy. However, a smaller percentage of patients who don't respond well to chemotherapy are candidates for Bone marrow transplant to offer a long-term cure to these patients. In contrast, almost half of adult patients need BMT as consolidation to provide long-term treatment. If required, BMT can safely be done now using half HLA identical donors in case HLA matching donors are unavailable in experienced centres.

In most cases, the doctor will make a treatment recommendation based on research on the most effective treatments and national recommendations developed by experts. They will assess the type of blood cancer, the outcomes of any tests the patient has had, the state of the overall health, the available therapies, their effectiveness, and any potential risks or side effects.

There is a range of different treatments for blood cancer. But the most common ones include:

The cost of blood cancer therapy in India has several significant advantages. First, the most outstanding hospitals in India, equipped with the most cutting-edge equipment and a staff of oncologists and doctors with years of experience, are accessible to offer blood cancer patients comprehensive care.

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Prevalence Of Blood Cancer In India: Know Its Prevention And Management | TheHealthSite.com - TheHealthSite

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An operation that has its roots, conceptually, in the earliest history of mankind (it was first spoken about by Chinese doctors), it is nevertheless a very recent therapeutic solution: the knowledge that made it possible (immunology, study of antigens) was only acquired at the beginning of the 20th century.

From 1950 onwards, transplantation became an established choice in the treatment of those pathologies that lead to the irreparable destruction of the organ and, therefore, to the death of the patient.

But transplantation is not only the last prospect for those whose lives are in danger: this operation also makes it possible to improve the quality of life for those patients suffering from chronic disabling diseases (e.g. kidney transplantation for dialysed patients).

The future of transplantation is still to be sketched out, but is very clear in the minds of scientists and doctors engaged in research: implantation of artificial organs or organs taken from genetically modified animals (xenotransplantation), cloning and implantation of stem cells are just some of the directions in which the worlds scientific landscape is moving.

The word transplant often indicates, in a reductive way, the operation of replacing a diseased organ with a healthy one.

In reality, there is a whole organisation and preparation behind this operation that involves extreme precision and synchronisation of people and instruments.

The practice of the operation differs depending on the donor: if the organ removal is from a living person, in fact, it is possible to plan the operation; which is obviously not feasible if the organs come from a cadaveric donor, who died of accidental and unforeseeable causes.

Once the medical committee has obtained the familys consent and declares the potential donors brain death to have occurred, the evaluation of his data begins: compatibility with potential recipients on the waiting lists, medical history, immune characteristics, blood group, etc.

PHASE 1

A person with injuries that could be a donor (for example, a very serious head injury) is admitted to intensive care.

A doctor speaks to the family about the possibility of donating his or her organs; if they are available, the coordination centre is immediately alerted, which is responsible for reporting the potential donor and identifying the potential recipient.

Meanwhile, the donor patients data are assessed: compatibility with potential recipients on the list, medical history, immune characteristics. The 6-hour observation period begins, which is mandatory before the certification of brain death.

PHASE 2

The explantation team is activated and must be available in a very short time.

The doctors usually reach the facility by helicopter. Meanwhile, at the hospital where the transplant will be performed, the recipient is called in to undergo various examinations and to assess his or her state of health.

Numerous checks are also carried out on the organs to be donated to prevent the transmission of infectious diseases or tumours from donor to recipient.

PHASE 3

At the end of the observation period, if all indications point to a diagnosis of irreversible brain death, explantation can begin (approximately 2 hours).

The recipient enters the operating theatre and is prepared for the operation. The administration of immunosuppressive drugs starts now to prevent the lymphocytes from recognising the organ as foreign and causing rejection.

PHASE 4

The organ finally arrives, immersed in a special solution to protect its cells and transported in a special container filled with ice to slow down its cellular activity.

One team of doctors prepares the recipient, the other takes care of cleaning the organ to be transplanted.

PHASE 5

The transplant can now begin: the blood vessels are connected, the bleeding is controlled.

STEP 6

The patient comes out of the operating theatre, but is still under anaesthesia, which will be prolonged for at least another 6 to 8 hours to allow the new organ to get used to the temperature difference between the container with the ice and the body and, of course, to the organ itself.

The patient remains connected to the machine to breathe.

STEP 7

The patient wakes up in the intensive care unit; if his general condition is good, he is taken off the artificial respirator.

After about 4 days, he starts walking again and eating.

After about 10 days, he will be able to leave the hospital and live with his new organ.

Initially, he will have to return to the hospital every day for immunological checks; after a year, he will be able to return once every two months.

Once brain death has been ascertained and the familys consent obtained (in the case of a lack of explicit donor wishes), the potential donor is no longer assisted by the mechanical respirator and the organs can be harvested for transplantation in the same hospital that established suitability.

The previously alerted team enters the operating theatre for the removal operation.

Opposing the removal never means helping the patient to have better care; care, in fact, ends the moment brain death is established; opposing it would therefore only mean depriving someone else of a better life thanks to a new organ.

Today, another type of transplant is also gaining ground, that from living people.

Indeed, it is now possible to take a kidney, liver or lung lobe for transplantation in particularly at-risk people who would not survive on the waiting list.

These are usually children, both because of the shortage of paediatric transplant organs and because of the small size, which also means that the donor does not face too high a risk.

Once taken, organs require special procedures to preserve them for transplantation.

There is, for each organ, a maximum preservation time, beyond which the tissues, no longer receiving blood, and therefore oxygen, go into necrosis, i.e. their cells die, and are therefore unusable.

These times vary from organ to organ: heart (4-6 hours), lung (4-6 hours), liver (12-18 hours), kidney 48-72 hours, pancreas (12-24 hours).

Rejection is the reaction that the recipient organism has towards the transplanted organ or tissue.

In fact, the recipients immune system recognises the organ as foreign and attacks it as if it were a pathogen.

There are four types of rejection

Experiencing rejection of the transplanted organ does not necessarily mean inevitably losing it; on the contrary, rejection is successfully treated if action is taken within a reasonable time frame through the use of immunosuppressive drugs.

The immunosuppressants that the doctor prescribes after the transplant will help the transplanted organ not to risk rejection and to remain healthy.

Since the cells of the immune system are different, the drugs prescribed for immunosuppression will also be different.

The largest and most immediate indication for transplantation is irreversible failure of vital organs such as kidneys, liver, lungs, pancreas, but also corneas, bone marrow, intestines.

Indeed, in these cases, transplantation is the only effective treatment to ensure survival.

Therefore, any pathological condition that prevents the organ from functioning in such a way as to threaten the patients survival is to be considered an indication for transplantation.

After transplantation, recipients are admitted for the first few days to a ward equipped for intensive care, where immunosuppressive therapy is started.

The immunosuppressed patient requires isolation in sterile rooms, specially created to avoid contamination of any kind from the outside environment.

The box in which the recipient is admitted after the transplant operation is completely isolated from the rest of the resuscitation unit used for conventional surgery.

The condition of strict isolation persists for as long as it takes for the patient to overcome the critical post-surgical phase (usually 5-6 days), or in cases where anti-rejection therapy is required.

In the immediate post-surgical period, visits to close relatives are permitted as long as they are appropriately dressed (according to the clean room entry procedures).

Each person is admitted to the filter zone one at a time and, of course, persons with suspicion and/or evidence of infectious diseases may not be admitted.

The most serious issues in transplant medicine are, on the one hand, the rejection of the transplanted organ and, on the other, the insufficiency of donated organs compared to those needed.

In both directions, research is experimenting with various solutions to overcome these problems.

With regard to rejection, attempts are being made to create solutions that manage to trick the immune system, thus reducing the immunosuppressive therapy currently in use, or that protect the transplanted organ from attack by T lymphocytes, which are responsible for eliminating agents outside the body.

On the other front, that of organ shortage, artificial organs, tissue engineering or xenotransplantation are being experimented with that can replace human organs.

Through gene therapy, it is possible to go to the source of the problem and eliminate genetic defects directly in the affected cells, tissues or organs.

The healthy gene is introduced directly into the affected spot, where it begins to produce those substances that the diseased body cannot produce on its own.

However, gene therapy is still far from being used. In order to be able to transport foreign DNA into the cell nucleus, special vectors are needed viruses that have lost their infectious characteristics, but are still able to attack cells and transmit their genetic heritage to them.

To avoid rejection, the organ to be transplanted would have to be treated in the laboratory, transferring genes into it that would make it capable of defending itself against the recipients immune system.

Now the genes are known, but they are not yet handled with the necessary precision. The next step will be to search for the perfect combination of genes that prevents the action of all the recipients immunological mechanisms.

The aim of this type of therapy is to find an alternative to human organs.

Already now, researchers are able to produce tissues such as blood vessels, heart valves, cartilage and skin in the laboratory.

It has been possible to overcome this new frontier thanks to the fact that cells tend to aggregate to form organs and tissues.

Stem cells are the undifferentiated cells found in human embryos one week after fertilisation.

They are also the starting cells from which the tissues and organs of the child to be born will develop.

Their function is to regulate the turnover of blood cells (red blood cells, white blood cells and platelets) and those of the immune system (lymphocytes).

Today, computerised machines, separators, are used to collect these cells, allowing the selection of the necessary cells. The recipients of the cells are patients suffering from skin diseases, blood diseases or solid tumours.

In addition to the fact that stem cells are still largely unknown, there is also an ethical problem: harvesting embryonic stem cells implies the death of the embryo.

That is why the way to harvest stem cells from adults is being perfected.

The cloning technique would make it possible to circumvent the problem of organ rejection altogether.

It would involve introducing the patients cell nucleus, with all its genetic heritage, into the stem cell of a human embryo or oocyte that previously had no nucleus of its own.

Cultivated in vitro in the laboratory, these modified cells would be genetically identical to those of the patients immune system, which would not recognise them as foreign.

This technique is not a viable option at present because both cloning, stem cell harvesting and the indiscriminate use of oocytes are prohibited by law.

Xenotransplantation, i.e. the transplantation of animal cells, tissues and organs into humans, seems to be the future solution to the shortage of organs for transplantation.

Experiments in this field are numerous and face ethical, psychological and, last but not least, immune problems.

The few attempts that have been made, in fact (a pig liver and a baboon heart transplanted into two different human beings) have not yielded the desired results.

The rejection crisis, in fact, was particularly violent and impossible to control.

Yet this technique could really be the solution to the organ shortage.

In fact, what is most feared is the development of typically animal infections, transferred to humans via pathogens present in the organ to be transplanted, which could prove disastrous.

A possible alternative to this handicap could be genetic modifications on donor animals; in practice, the animals would be bred in a sterile environment and genetically modified to make their organs more compatible with the recipients organism.

For the time being, however, some milestones have been achieved; these are cell xenotransplants and not organ xenotransplants, such as pig embryo cells for the treatment of Parkinsons disease, baboon marrow cells transplanted into terminally ill AIDS patients in an attempt to recover the patients immune system, or pancreas insulae still from pigs in the stimulation of insulin production as a therapy against diabetes.

Another solution to organ failure such as rejection is artificial organs.

The main problem is biological compatibility; these are, after all, mechanical organs that have to adapt to a biological organism.

Biocompatibility must cover all morphological, physical, chemical and functional characteristics that are able to provide for the organs functionality and, at the same time, its survival without the risk of rejection.

It is all these implications that make the production of artificial organs capable of completely and perfectly replacing natural organs in their functions complex.

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As the world observed World Chronic Myeloid Leukemia Day recently, leading medical experts emphasized the need of creating awareness aboutthe condition, a relatively uncommon type of bone marrow and blood cancer.

Chronic Myeloid Leukemia (CML) occurs with an incidence rate of 0.4 to 3.9 per 100,000 patients, which increases with age and has a slight male preponderance. It is a chronic disease in which patients must take lifelong treatment and hence, experts stress its appropriate management and adherence to treatment.

CML occurs due to spontaneous chromosome mutation which causes diseased white blood cells to build up in huge numbers, crowding out healthy blood cells and damaging the bone marrow.

Dr. Ankit Jitani - Hematologist, Hemato-Oncologist, and BMT Physician, Ahmedabad says, CML is caused by secondary passenger mutations in the stem cells. The most common way that patients present symptoms of CML is leukocytosis or have respiratory discomfort and hence go to a cardiologist, or have gastric discomfort, and then visit a gastroenterologist who then refers the patients to us. However, post COVID-19 awareness of CML has increased amongst all patients, they are now actively doing blood tests and measuring CBC.

He further stated that For CML, regular monitoring and adherence to treatment are essential. We are actively working more toward treatment-free-remission. Regular monitoring and adherence to treatment if done actively, only then the patient is a suitable candidate for treatment-free-remission. A lack of adherence to treatment protocols can make the condition severe.

Therefore, it is recommended that patients continue to take medication as prescribed by their healthcare professional. CML management and treatment require a lot of patience and discipline. It is a great thing that cancer gets cured with a drug, hence regular check-ups, and sticking to your schedule with your doctor is important.

Dr. Abhishek Dudhatra, Haematology Consultant & BMT Specialist, HCG Oncology, Ahmedabad mentions, Tyrosine kinase inhibitors (TKIs) are the initial treatment of choice for CML, and more than two-thirds of patients achieve long-term control of the disease with this.

Regular monitoring of the condition is equally critical as it enables the physician to prescribe the appropriate dose and hence, keep the condition under control. Monitoring is done through a blood test, primarily to check the quantification of BCR-ABL transcript in the blood. When the condition is initially diagnosed, monitoring is recommended to be done every 3 months and later, the frequency can be 6 months. While these are the recommended periods, the frequency of monitoring also depends on individual cases. One should adhere to what is suggested by the physician.

While CML is caused by a genetic mutation in the stem cells, its exact cause is not known. The condition is not hereditary and cannot be passed on to future generations.

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Experts emphasize appropriate management and adherence to treatment for Chronic Myeloid Leukemia - First India

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Neuron generation trajectories. Credit: BGI Genomics

Because of its distinctive and adorable look, the axolotl Ambystoma mexicanum is a popular pet. Unlike other metamorphosing salamanders, axolotls (pronounced ACK-suh-LAH-tuhl) never outgrow their larval, juvenile stage, a trait known as neoteny. Its also recognized for its ability to regenerate missing limbs and other tissues including the brain, spinal cord, tail, skin, limbs, liver, skeletal muscle, heart, upper and lower jaw, and ocular tissues like the retina, cornea, and lens.

Mammals, including humans, are almost incapable of rebuilding damaged tissue after a brain injury. Some species, such as fish and axolotls, on the other hand, may replenish wounded brain regions with new neurons.

Tissue types the axolotl can regenerate as shown in red. Credit: Debuque and Godwin, 2016

Brain regeneration necessitates the coordination of complex responses in a time and region-specific way. In a paper published on the cover of Science, BGI and its research partners used Stereo-seq technology to recreate the axolotl brain architecture throughout developing and regenerative processes at single-cell resolution. Examining the genes and cell types that enable axolotls to renew their brains might lead to better treatments for severe injuries and unlock human regeneration potential.

Cell regeneration images at seven different time points following an injury; the control image is on the left. Credit: BGI Genomics

The research team collected axolotl samples from six development stages and seven regeneration phases with corresponding spatiotemporal Stereo-seq data. The six developmental stages include:

Through the systematic study of cell types in various developmental stages, researchers found that during the early development stage neural stem cells located in the VZ region are difficult to distinguish between subtypes, and with specialized neural stem cell subtypes with spatial regional characteristics from adolescence, thus suggesting that various subtypes may have different functions during regeneration.

In the third part of the study, the researchers generated a group of spatial transcriptomic data of telencephalon sections that covered seven injury-induced regenerative stages. After 15 days, a new subtype of neural stem cells, reaEGC (reactive ependymoglial cells), appeared in the wound area.

Axolotl brain developmental and regeneration processes. Credit: BGI Genomics

Partial tissue connection appeared at the wound, and after 20 to 30 days, new tissue had been regenerated, but the cell type composition was significantly different from the non-injured tissue. The cell types and distribution in the damaged area did not return to the state of the non-injured tissue until 60 days post-injury.

The key neural stem cell subtype (reaEGC) involved in this process was derived from the activation and transformation of quiescent neural stem cell subtypes (wntEGC and sfrpEGC) near the wound after being stimulated by injury.

What are the similarities and differences between neuron formation during development and regeneration? Researchers discovered a similar pattern between development and regeneration, which is from neural stem cells to progenitor cells, subsequently into immature neurons and finally to mature neurons.

Spatial and temporal distribution of axolotl brain development. Credit: BGI Genomics

By comparing the molecular characteristics of the two processes, the researchers found that the neuron formation process is highly similar during regeneration and development, indicating that injury induces neural stem cells to transform themselves into a rejuvenated state of development to initiate the regeneration process.

Our team analyzed the important cell types in the process of axolotl brain regeneration, and tracked the changes in its spatial cell lineage, said Dr. Xiaoyu Wei, the first author of this paper and BGI-Research senior researcher. The spatiotemporal dynamics of key cell types revealed by Stereo-seq provide us a powerful tool to pave new research directions in life sciences.

Corresponding author Xun Xu, Director of Life Sciences at BGI-Research, noted that In nature, there are many self-regenerating species, and the mechanisms of regeneration are pretty diverse. With multi-omics methods, scientists around the world may work together more systematically.

Reference: Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration by Xiaoyu Wei, Sulei Fu, Hanbo Li, Yang Liu, Shuai Wang, Weimin Feng, Yunzhi Yang, Xiawei Liu, Yan-Yun Zeng, Mengnan Cheng, Yiwei Lai, Xiaojie Qiu, Liang Wu, Nannan Zhang, Yujia Jiang, Jiangshan Xu, Xiaoshan Su, Cheng Peng, Lei Han, Wilson Pak-Kin Lou, Chuanyu Liu, Yue Yuan, Kailong Ma, Tao Yang, Xiangyu Pan, Shang Gao, Ao Chen, Miguel A. Esteban, Huanming Yang, Jian Wang, Guangyi Fan, Longqi Liu, Liang Chen, Xun Xu, Ji-Feng Fei and Ying Gu, 2 September 2022, Science.DOI: 10.1126/science.abp9444

This study has passed ethical reviews and follows the corresponding regulations and ethical guidelines.

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Unlocking the Mysteries of Brain Regeneration Groundbreaking Study Offers New Insight - SciTechDaily

Recommendation and review posted by Bethany Smith

Formulated as a rich cream, this product acts as a lightweight veil ideal for concealing, correcting, brightening, and contouring. Because of its texture, the Sweetener Concealer is especially a plus for dry-to-normal skin types craving added moisture in their makeup regimen. Whats more, as with other skincare-makeup hybrids, this has skin-nourishing ingredients at its corepacked with hyaluronic acid, vitamin E, raspberry stem cells, and ashwagandha for not only hydration, but protection against environmental stressors.

According to Thomas, a good pot concealer should offer a double pay-off, optimal coverage that acts as a foundation and concealer. She recommends applying under the eyes, around the nose, and on top of any spots or blemishes; blend with fingers, a sponge, or a brush.

For daily use, I prime with a hydrating mist and makeup primer. Then, I place a bit of the concealer on my skin, immediately buffing with a Beautyblender or complexion brush. Despite its rich texture, I find that it blends seamlessly, so I often wear it on its own instead of foundation for a skin-like finish, just as Thomas indicated. Because this leans towards full coverage, it instantly veils my dark spots and under-eye bags without any heavy layering.

Keep in mind, though, that this can crease easily on some skin types, so a good setting powder is essential for long-wear. My advice is to start with a small amount, building up to your desired coverage. A little goes a long way! Otherwise, this layers well with other products on top (think: cream blushes or Chanels bronzer) without feeling cakeyan ideal concealer for the cooler months ahead.

r.e.m. beauty Sweetener Concealer

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TikTok Made Me Buy It: The Creamy Concealer That Instantly Veils Dark Circles and Hyperpigmentation - Vogue

Recommendation and review posted by Bethany Smith

You probably know what hormones are, and you may have at least heard about stem cells, but what is a growth factor? According to Britannica, it is a protein that stimulates growth in specific tissues. There are many types of growth factors, each with the job of repairing certain body parts. Some growth factors include epidermal growth factor (responsible for skin repair), platelet-derived growth factor (responsible for repairing muscles and connective tissues), and nerve growth factor (responsible for stimulating brain cell growth and repair).

According to a 2020 mini-review in Frontiers in Bioengineering and Biotechnology, growth factors are critical for tissue repair and regeneration. In short, growth factors help maintain skin health and heal wounds. As you age and fewer growth factors are available to help with repair and regeneration, injuries take longer to heal. Stem cells factor in because they release growth factors to instigate wound healing, according to a 2010 study in theInternational Journal of Stem Cells.

And the sex hormones estrogen and testosterone play a part in wound healing too. Low estrogen levels or high amounts of testosterone can slow healing. For women, estrogen levels drop after menopause, resulting in slowed healing time (via Wounds).

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Here Is Why You Heal Slower As You Age - Health Digest

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By Dr Chytra V Anand

The fascination with beauty and skincare in India has grown leaps and bounds in recent times, and understandably so, given that the culture of beauty is deeply rooted in the country. The days when beauty was an aspect of social class and the cosmetic treatments and products you access gave away your economic status are long gone, as are the days when cosmetic treatments were considered a girl thing. With cosmetic treatments becoming more accessible and sought-after, the Indian skincare and derma cosmetics market generated an estimated revenue of a whopping USD 188.2 million in 2021. The same is projected to grow at a CAGR of 10.2% between 2021 and 2030.

Today, with changing lifestyles, demographic growth, cutting-edge technology, and improving economic and social conditions thanks to rising per capita and disposable income, India is quickly heading towards becoming a leader in the global cosmetics industry. But for a bit of self-introspection, what are Indian consumers looking for when it comes to cosmetic treatments? What does their consumption tell industry players?

Body hair removal has become one of the most popular cosmetic procedures done across the world today. But compared to shaving, waxing, or using an epilator or a trimmer, laser hair removal is a more permanent hair removal method that has gained immense traction of late. Especially in urban India, laser hair removal has quickly gained popularity, with mothers even bringing their 16-year-olds for Laser hair removal.

In 2021, the global laser hair removal market was valued atUSD 798.6 million, with an estimated CAGR of 18.4% from 2022 to 2030. Given that laser hair removal is a one-time procedure, although one has to sit through multiple sessions, the results, when done by a reliable cosmetic professional, are impressive. The Asia Pacific is projected to be the fastest-growing segment for laser hair removal, especially in countries like India and China.

A cosmetic procedure where a chemical solution is applied to your skin to remove the top layers, Chemical Peels ensure that the skin becomes smoother and clearer, making it radiant. On the other hand, a Medical Clean-up, in the simplest terms, is the procedure of cleaning your skin, ridding impurities like blackheads and white head spots to clear clogged pores. Besides, Medical Clean-ups are also beneficial for people struggling with acne scars, making it a popular procedure that an increasing number of people are choosing. For Chemical Peels, the market size is expected to touch USD 68.81 million between 2021 to 2025, making their popularity surge.

As we grow older, our skin begins to age too, and wrinkles and fine lines begin to appear on our face. Cosmetic procedures like Hydra Facials and skin maintenance with Laser Photofacials are a weekly must-do for 30-45-year-olds to ensure their skin is supple and glowing. Apart from this, the perception of Indian consumers when it comes to cosmetic treatments like Botox and Fillers has begun to change. These are no longer viewed as taboo as people now realise that they give your skin a lift.

Such treatments are also no longer only available for a certain section of society, like the wealthy. Botox and Fillers are now available to everyone, and consumers are looking at them from a skin maintenance standpoint rather than as a luxury, unnecessary treatment. Annually, the Botox segment is registering 20-25% growth in the country proof of evolving consumer preferences and the rising popularity of such treatments. Besides these, derma cosmetics and medical skin care have also gained a fair amount of traction, with skincare aficionados looking for effective and efficient skin care procedures that are non-surgical.

Alongside our skincare, taking care of our mane is equally important. For people struggling with hair fall, flaky and dry scalp, and other issues that affect your hair, stem cell therapy is the answer. Often done annually, stem cell therapy helps rejuvenate your hair cells to retain hair and repair damage. And with the global hair restoration market standing at over USD 4.2 billion in 2020, we can safely say its here to stay.

With consumerism changing face gradually and Indian consumers gaining access to world-class cosmetic treatments that are non-surgical, which still trump surgical procedures, the future of the Indian cosmetic treatments market shines bright. As long as the procedures are done by qualified and experienced professionals and are reliable and effective, the demand for such cosmetic procedures will continue to grow.

(The author isfounder ofKosmoderma Healthcare Pvt. Ltd.Views expressed are personal and do not reflect the official position or policy of the FinancialExpress.com.)

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A glimpse into Indian consumers expectations for cosmetic treatments and consumption insights - The Financial Express

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MELBOURNE, Australia--(BUSINESS WIRE)--Propanc Biopharma, Inc. (OTC Pink: PPCB) (Propanc or the Company), a biopharmaceutical company developing novel cancer treatments for patients suffering from recurring and metastatic cancer, today announced that Chief Scientific Officer and Co-Founder, Dr Julian Kenyon, MD, MB, ChB, explains why pancreatic and ovarian cancers are selected as the primary target therapeutic indications for planned PRP human studies. According to Dr Kenyon, target indications were selected based on in vitro and in vivo data, as well as clinical observations from a compassionate use study investigating the effects of two proenzymes, trypsinogen and chymotrypsinogen against a range of malignant tumors. Overall, proenzymes appeared to exert significant effects against more aggressive, less differentiated tumor types, like pancreatic and ovarian tumors. Patients from the compassionate use study suffering from cancers of the GI tract, or endocrine tumors, such as pancreatic and ovarian cancers, benefited most from treatment. The world market for pancreatic and ovarian cancer drugs is projected to grow to $4.2 Billion in 2025 according to Grandview Research and $10.1 Billion by 2027 according to iHealthcareAnalyst, respectively, resulting in a combined global market of $14.3 Billion over the next 5-year period.

Extensive laboratory analysis confirmed that PRP reduced the main characteristics of cancer spread, namely angiogenesis (blood vessel formation), which is a critical step in tumor development, as well as the spreading of tumor metastases. In addition, assays revealed that the migration capacity of ovarian, pancreatic, melanoma and colon cancer cells was suppressed after incubation with PRP. Furthermore, evidence suggests the epithelial to mesenchymal transition (EMT), a biological process associated with wound healing and cell migration, which causes cancer stem cells (CSCs) to become motile and invasive, is associated with metastasis and inducing drug resistance in many cancers, such as pancreatic and ovarian cancers. Studies in pancreatic and cancer cell lines after PRP treatment demonstrated a significant reduction in EMT markers and genes and in fact, a reversal of the EMT process so that CSCs become benign and less resistant to standard treatments.

The in vivo effects of PRP at different doses on tumor weight in implanted pancreatic and ovary tumors was evaluated. In the pancreatic tumor model, there was significant reduction in mean tumor weight in animals treated for 26 days with PRP with more than 85% tumor growth inhibition compared with the control. Furthermore, ovary tumor-bearing mice showed a significant reduction in mean tumor weight in animals treated for 21 days with two different doses of PRP, resulting in a 46 52% tumor growth inhibition compared with the control.

The clinical efficacy of a suppository formulation containing bovine pancreatic proenzymes trypsinogen and chymotrypsinogen was evaluated in the context of a UK Pharmaceuticals Special Scheme and the results were published in Scientific Reports. Clinical effects were studied in 46 patients with advanced metastatic cancers of different origin (prostate, breast, ovarian, pancreatic, colorectal, stomach, non-small cell lung, bowel cancer and melanoma) after treatment with a rectal formulation of both pancreatic proenzymes. No severe or serious adverse events related to the rectal administration were observed. Patients did not experience any hematological side effects as typically seen with classical chemotherapy regimens.

In order to assess the therapeutic activity, overall survival of patients under treatment was compared to the life expectancy assigned to a patient prior to treatment start. Nineteen from 46 patients (41.3%) with advanced malignant diseases, most of them suffering from metastases, had a survival time significantly longer than their expected, in fact, for the whole set of cancer types, mean survival (9.0 months) was significantly higher than mean life expectancy (5.6 months). In the case of pancreatic and ovarian cancers, 2 from 4 pancreatic cancer patients and 4 from 7 ovarian cancer patients significantly exceeded life expectancy.

As a result of the extensive studies undertaken, particularly in pancreatic cancer, the Company applied for and received Orphan Drug Designation (ODD) from the US Food and Drug Administration (USFDA) for the use of its lead product, PRP, for the treatment of pancreatic cancer. The approved indication is one of the most lethal malignancies with a median survival of 6 months and a 5-year survival rate of less than 5%. The lethal nature of this disease stems from its propensity to rapidly disseminate to the lymphatic system and distant organs, and is a major unmet medical issue. Under the Orphan Drug Act (ODA), drugs, vaccines, and diagnostic agents qualify for orphan status if they are intended to treat a disease affecting less than 200,000 American citizens. Under the ODA, orphan drug sponsors qualify for seven-year FDA-administered market Orphan Drug Exclusivity (ODE), tax credits of up to 50% of R&D costs, R&D grants, waived FDA fees, protocol assistance and may get clinical trial tax incentives.

Over the past 15 years, our extensive research has uncovered a truly unique and exciting technology that selectively targets and eradicates cancer stem cells, whilst leaving healthy cells alone, making it less toxic compared with standard treatment approaches, said Dr Kenyon. Furthermore, our technology appears to be effective against more aggressive, less differentiated tumor types where few treatment options exist, and prognosis is poor, especially in the case of pancreatic and ovarian cancers. I look forward to advancing PRP to human studies where we can fully assess the clinical efficacy of PRP in a controlled setting.

Propanc plans to undertake a First-In-Human study in 30 to 40 advanced cancer patients suffering from solid tumors to determine a maximum tolerated dose for PRP treatment, followed by two proof of concept studies in pancreatic and ovarian cancers, 60 patients in each study, to confirm the clinical efficacy of PRP in the selected target therapeutic indications.

PRP is a mixture of two proenzymes, trypsinogen and chymotrypsinogen from bovine pancreas administered by intravenous injection. A synergistic ratio of 1:6 inhibits growth of most tumor cells. Examples include kidney, ovarian, breast, brain, prostate, colorectal, lung, liver, uterine and skin cancers.

About Propanc Biopharma, Inc.

Propanc Biopharma, Inc. (the Company) is developing a novel approach to prevent recurrence and metastasis of solid tumors by using pancreatic proenzymes that target and eradicate cancer stem cells in patients suffering from pancreatic, ovarian and colorectal cancers. For more information, please visit http://www.propanc.com.

The Companys novel proenzyme therapy is based on the science that enzymes stimulate biological reactions in the body, especially enzymes secreted by the pancreas. These pancreatic enzymes could represent the bodys primary defense against cancer.

To view the Companys Mechanism of Action video on its anti-cancer lead product candidate, PRP, please click on the following link: http://www.propanc.com/news-media/video

Forward-Looking Statements

All statements other than statements of historical facts contained in this press release are forward-looking statements, which may often, but not always, be identified by the use of such words as may, might, will, will likely result, would, should, estimate, plan, project, forecast, intend, expect, anticipate, believe, seek, continue, target or the negative of such terms or other similar expressions. These statements involve known and unknown risks, uncertainties and other factors, which may cause actual results, performance or achievements to differ materially from those expressed or implied by such statements. These factors include uncertainties as to the Companys ability to continue as a going concern absent new debt or equity financings; the Companys current reliance on substantial debt financing that it is unable to repay in cash; the Companys ability to successfully remediate material weaknesses in its internal controls; the Companys ability to reach research and development milestones as planned and within proposed budgets; the Companys ability to control costs; the Companys ability to obtain adequate new financing on reasonable terms; the Companys ability to successfully initiate and complete clinical trials and its ability to successful develop PRP, its lead product candidate; the Companys ability to obtain and maintain patent protection; the Companys ability to recruit employees and directors with accounting and finance expertise; the Companys dependence on third parties for services; the Companys dependence on key executives; the impact of government regulations, including FDA regulations; the impact of any future litigation; the availability of capital; changes in economic conditions, competition; and other risks, including, but not limited to, those described in the Companys periodic reports that are filed with the Securities and Exchange Commission and available on its website at http://www.sec.gov. These forward-looking statements speak only as of the date hereof and the Company disclaims any obligations to update these statements except as may be required by law.

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Propanc Biopharma Targets Pancreatic & Ovarian Cancers for PRP Clinical Studies with Combined Markets to Reach Over $14.3 Billion by 2027 -...

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Expression of genes depending on parentage

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the mother or the father.[1][2][3][4][5] Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele.[6] Forms of genomic imprinting have been demonstrated in fungi, plants and animals.[7][8] In 2014, there were about 150 imprinted genes known in mice and about half that in humans.[9] As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.[10]

Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence. These epigenetic marks are established ("imprinted") in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism.[11]

Appropriate imprinting of certain genes is important for normal development. Human diseases involving genomic imprinting include Angelman syndrome, PraderWilli syndrome and male infertility.[3]

In diploid organisms (like humans), the somatic cells possess two copies of the genome, one inherited from the father and one from the mother. Each autosomal gene is therefore represented by two copies, or alleles, with one copy inherited from each parent at fertilization. The expressed allele is dependent upon its parental origin. For example, the gene encoding insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father. Although imprinting accounts for a small proportion of mammalian genes they play an important role in embryogenesis particularly in the formation of visceral structures and the nervous system.[12]

The term "imprinting" was first used to describe events in the insect Pseudococcus nipae.[13] In Pseudococcids (mealybugs) (Hemiptera, Coccoidea) both the male and female develop from a fertilised egg. In females, all chromosomes remain euchromatic and functional. In embryos destined to become males, one haploid set of chromosomes becomes heterochromatinised after the sixth cleavage division and remains so in most tissues; males are thus functionally haploid.[14][15][16]

That imprinting might be a feature of mammalian development was suggested in breeding experiments in mice carrying reciprocal chromosomal translocations.[17] Nucleus transplantation experiments in mouse zygotes in the early 1980s confirmed that normal development requires the contribution of both the maternal and paternal genomes. The vast majority of mouse embryos derived from parthenogenesis (called parthenogenones, with two maternal or egg genomes) and androgenesis (called androgenones, with two paternal or sperm genomes) die at or before the blastocyst/implantation stage. In the rare instances that they develop to postimplantation stages, gynogenetic embryos show better embryonic development relative to placental development, while for androgenones, the reverse is true. Nevertheless, for the latter, only a few have been described (in a 1984 paper).[18][19][20]

No naturally occurring cases of parthenogenesis exist in mammals because of imprinted genes. However, in 2004, experimental manipulation by Japanese researchers of a paternal methylation imprint controlling the Igf2 gene led to the birth of a mouse (named Kaguya) with two maternal sets of chromosomes, though it is not a true parthenogenone since cells from two different female mice were used. The researchers were able to succeed by using one egg from an immature parent, thus reducing maternal imprinting, and modifying it to express the gene Igf2, which is normally only expressed by the paternal copy of the gene.

Parthenogenetic/gynogenetic embryos have twice the normal expression level of maternally derived genes, and lack expression of paternally expressed genes, while the reverse is true for androgenetic embryos. It is now known that there are at least 80 imprinted genes in humans and mice, many of which are involved in embryonic and placental growth and development.[11][21][22][23] Hybrid offspring of two species may exhibit unusual growth due to the novel combination of imprinted genes.[24]

Various methods have been used to identify imprinted genes. In swine, Bischoff et al. compared transcriptional profiles using DNA microarrays to survey differentially expressed genes between parthenotes (2 maternal genomes) and control fetuses (1 maternal, 1 paternal genome).[25] An intriguing study surveying the transcriptome of murine brain tissues revealed over 1300 imprinted gene loci (approximately 10-fold more than previously reported) by RNA-sequencing from F1 hybrids resulting from reciprocal crosses.[26] The result however has been challenged by others who claimed that this is an overestimation by an order of magnitude due to flawed statistical analysis.[27][28]

In domesticated livestock, single-nucleotide polymorphisms in imprinted genes influencing foetal growth and development have been shown to be associated with economically important production traits in cattle, sheep and pigs.[29][30]

At the same time as the generation of the gynogenetic and androgenetic embryos discussed above, mouse embryos were also being generated that contained only small regions that were derived from either a paternal or maternal source.[31][32] The generation of a series of such uniparental disomies, which together span the entire genome, allowed the creation of an imprinting map.[33] Those regions which when inherited from a single parent result in a discernible phenotype contain imprinted gene(s). Further research showed that within these regions there were often numerous imprinted genes.[34] Around 80% of imprinted genes are found in clusters such as these, called imprinted domains, suggesting a level of co-ordinated control.[35] More recently, genome-wide screens to identify imprinted genes have used differential expression of mRNAs from control fetuses and parthenogenetic or androgenetic fetuses hybridized to gene expression profiling microarrays,[36] allele-specific gene expression using SNP genotyping microarrays,[37] transcriptome sequencing,[38] and in silico prediction pipelines.[39]

Imprinting is a dynamic process. It must be possible to erase and re-establish imprints through each generation so that genes that are imprinted in an adult may still be expressed in that adult's offspring. (For example, the maternal genes that control insulin production will be imprinted in a male but will be expressed in any of the male's offspring that inherit these genes.) The nature of imprinting must therefore be epigenetic rather than DNA sequence dependent. In germline cells the imprint is erased and then re-established according to the sex of the individual, i.e. in the developing sperm (during spermatogenesis), a paternal imprint is established, whereas in developing oocytes (oogenesis), a maternal imprint is established. This process of erasure and reprogramming[40] is necessary such that the germ cell imprinting status is relevant to the sex of the individual. In both plants and mammals there are two major mechanisms that are involved in establishing the imprint; these are DNA methylation and histone modifications.

Recently, a new study[41] has suggested a novel inheritable imprinting mechanism in humans that would be specific of placental tissue and that is independent of DNA methylation (the main and classical mechanism for genomic imprinting). This was observed in humans, but not in mice, suggesting development after the evolutionary divergence of humans and mice, ~80 Mya. Among the hypothetical explanations for this novel phenomenon, two possible mechanisms have been proposed: either a histone modification that confers imprinting at novel placental-specific imprinted loci or, alternatively, a recruitment of DNMTs to these loci by a specific and unknown transcription factor that would be expressed during early trophoblast differentiation.

The grouping of imprinted genes within clusters allows them to share common regulatory elements, such as non-coding RNAs and differentially methylated regions (DMRs). When these regulatory elements control the imprinting of one or more genes, they are known as imprinting control regions (ICR). The expression of non-coding RNAs, such as antisense Igf2r RNA (Air) on mouse chromosome 17 and KCNQ1OT1 on human chromosome 11p15.5, have been shown to be essential for the imprinting of genes in their corresponding regions.[42]

Differentially methylated regions are generally segments of DNA rich in cytosine and guanine nucleotides, with the cytosine nucleotides methylated on one copy but not on the other. Contrary to expectation, methylation does not necessarily mean silencing; instead, the effect of methylation depends upon the default state of the region.[43]

The control of expression of specific genes by genomic imprinting is unique to therian mammals (placental mammals and marsupials) and flowering plants. Imprinting of whole chromosomes has been reported in mealybugs (Genus: Pseudococcus)[13][14][15][16] and a fungus gnat (Sciara).[44] It has also been established that X-chromosome inactivation occurs in an imprinted manner in the extra-embryonic tissues of mice and all tissues in marsupials, where it is always the paternal X-chromosome which is silenced.[35][45]

The majority of imprinted genes in mammals have been found to have roles in the control of embryonic growth and development, including development of the placenta.[21][46] Other imprinted genes are involved in post-natal development, with roles affecting suckling and metabolism.[46][47]

A widely accepted hypothesis for the evolution of genomic imprinting is the "parental conflict hypothesis".[48] Also known as the kinship theory of genomic imprinting, this hypothesis states that the inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of the evolutionary fitness of their genes.[49][50] The father's genes that encode for imprinting gain greater fitness through the success of the offspring, at the expense of the mother. The mother's evolutionary imperative is often to conserve resources for her own survival while providing sufficient nourishment to current and subsequent litters. Accordingly, paternally expressed genes tend to be growth-promoting whereas maternally expressed genes tend to be growth-limiting.[48] In support of this hypothesis, genomic imprinting has been found in all placental mammals, where post-fertilisation offspring resource consumption at the expense of the mother is high; although it has also been found in oviparous birds[51][52] where there is relatively little post-fertilisation resource transfer and therefore less parental conflict. A small number of imprinted genes are fast evolving under positive Darwinian selection possibly due to antagonistic co-evolution.[53] The majority of imprinted genes display high levels of micro-synteny conservation and have undergone very few duplications in placental mammalian lineages.[53]

However, our understanding of the molecular mechanisms behind genomic imprinting show that it is the maternal genome that controls much of the imprinting of both its own and the paternally-derived genes in the zygote, making it difficult to explain why the maternal genes would willingly relinquish their dominance to that of the paternally-derived genes in light of the conflict hypothesis.[54]

Another hypothesis proposed is that some imprinted genes act coadaptively to improve both fetal development and maternal provisioning for nutrition and care.[9][54][55] In it, a subset of paternally expressed genes are co-expressed in both the placenta and the mother's hypothalamus. This would come about through selective pressure from parent-infant coadaptation to improve infant survival. Paternally expressed 3 (PEG3) is a gene for which this hypothesis may apply.[9]

Others have approached their study of the origins of genomic imprinting from a different side, arguing that natural selection is operating on the role of epigenetic marks as machinery for homologous chromosome recognition during meiosis, rather than on their role in differential expression.[56] This argument centers on the existence of epigenetic effects on chromosomes that do not directly affect gene expression, but do depend on which parent the chromosome originated from.[57] This group of epigenetic changes that depend on the chromosome's parent of origin (including both those that affect gene expression and those that do not) are called parental origin effects, and include phenomena such as paternal X inactivation in the marsupials, nonrandom parental chromatid distribution in the ferns, and even mating type switching in yeast.[57] This diversity in organisms that show parental origin effects has prompted theorists to place the evolutionary origin of genomic imprinting before the last common ancestor of plants and animals, over a billion years ago.[56]

Natural selection for genomic imprinting requires genetic variation in a population. A hypothesis for the origin of this genetic variation states that the host-defense system responsible for silencing foreign DNA elements, such as genes of viral origin, mistakenly silenced genes whose silencing turned out to be beneficial for the organism.[58] There appears to be an over-representation of retrotransposed genes, that is to say genes that are inserted into the genome by viruses, among imprinted genes. It has also been postulated that if the retrotransposed gene is inserted close to another imprinted gene, it may just acquire this imprint.[59]

Unfortunately, the relationship between the phenotype and genotype of imprinted genes is solely conceptual. The idea is frameworked using two alleles on a single locus and hosts three different possible classes of genotypes.[60] The reciprocal heterozygotes genotype class contributes to understanding how imprinting will impact genotype to phenotype relationship. Reciprocal heterozygotes have a genetically equivalent, but they are phenotypically nonequivalent.[61] Their phenotype may not be dependent on the equivalence of the genotype. This can ultimately increase diversity in genetic classes, expanding flexibility of imprinted genes.[62] This increase will also force a higher degree in testing capabilities and assortment of tests to determine the presences of imprinting.

When a locus is identified as imprinted, two different classes express different alleles.[60] Inherited imprinted genes of offspring are believed to be monoallelic expressions. A single locus will entirely produce one's phenotype although two alleles are inherited. This genotype class is called parental imprinting, as well as dominant imprinting.[63] Phenotypic patterns are variant to possible expressions from paternal and maternal genotypes. Different alleles inherited from different parents will host different phenotypic qualities. One allele will have a larger phenotypic value and the other allele will be silenced.[60] Underdominance of the locus is another possibility of phenotypic expression. Both maternal and paternal phenotypes will have a small value rather than one hosting a large value and silencing the other.

Statistical frameworks and mapping models are used to identify imprinting effects on genes and complex traits. Allelic parent-of -origin influences the vary in phenotype that derive from the imprinting of genotype classes.[60] These models of mapping and identifying imprinting effects include using unordered genotypes to build mapping models.[62] These models will show classic quantitative genetics and the effects of dominance of the imprinted genes.

Imprinting may cause problems in cloning, with clones having DNA that is not methylated in the correct positions. It is possible that this is due to a lack of time for reprogramming to be completely achieved. When a nucleus is added to an egg during somatic cell nuclear transfer, the egg starts dividing in minutes, as compared to the days or months it takes for reprogramming during embryonic development. If time is the responsible factor, it may be possible to delay cell division in clones, giving time for proper reprogramming to occur.[citation needed]

An allele of the "callipyge" (from the Greek for "beautiful buttocks"), or CLPG, gene in sheep produces large buttocks consisting of muscle with very little fat. The large-buttocked phenotype only occurs when the allele is present on the copy of chromosome 18 inherited from a sheep's father and is not on the copy of chromosome 18 inherited from that sheep's mother.[64]

In vitro fertilisation, including ICSI, is associated with an increased risk of imprinting disorders, with an odds ratio of 3.7 (95% confidence interval 1.4 to 9.7).[65]

Epigenetic deregulations at H19 imprinted gene in sperm have been observed associated with male infertility.[66] Indeed, methylation loss at H19 imprinted gene has been observed associated with MTHFR gene promoter hypermethylation in semen samples from infertile males. [66]

The first imprinted genetic disorders to be described in humans were the reciprocally inherited Prader-Willi syndrome and Angelman syndrome. Both syndromes are associated with loss of the chromosomal region 15q11-13 (band 11 of the long arm of chromosome 15). This region contains the paternally expressed genes SNRPN and NDN and the maternally expressed gene UBE3A.

DIRAS3 is a paternally expressed and maternally imprinted gene located on chromosome 1 in humans. Reduced DIRAS3 expression is linked to an increased risk of ovarian and breast cancers; in 41% of breast and ovarian cancers the protein encoded by DIRAS3 is not expressed, suggesting that it functions as a tumor suppressor gene.[67] Therefore, if uniparental disomy occurs and a person inherits both chromosomes from the mother, the gene will not be expressed and the individual is put at a greater risk for breast and ovarian cancer.

Other conditions involving imprinting include Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism.[68]

Transient neonatal diabetes mellitus can also involve imprinting.[69]

The "imprinted brain hypothesis" argues that unbalanced imprinting may be a cause of autism and psychosis.

In insects, imprinting affects entire chromosomes. In some insects the entire paternal genome is silenced in male offspring, and thus is involved in sex determination. The imprinting produces effects similar to the mechanisms in other insects that eliminate paternally inherited chromosomes in male offspring, including arrhenotoky.[70]

In placental species, parent-offspring conflict can result in the evolution of strategies, such as genomic imprinting, for embryos to subvert maternal nutrient provisioning. Despite several attempts to find it, genomic imprinting has not been found in the platypus, reptiles, birds, or fish. The absence of genomic imprinting in a placental reptile, the Pseudemoia entrecasteauxii, is interesting as genomic imprinting was thought to be associated with the evolution of viviparity and placental nutrient transport.[71]

Studies in domestic livestock, such as dairy and beef cattle, have implicated imprinted genes (e.g. IGF2) in a range of economic traits,[72][73][29] including dairy performance in Holstein-Friesian cattle.[74]

A study published in March, 2022,[75] documents that foraging behavior in mice studied was influenced by a sexually dimorphic allele expression implicating a cross-gender imprinting influence that varies throughout the body and may dominate expression and shape a behavior.[76]

A similar imprinting phenomenon has also been described in flowering plants (angiosperms).[77] During fertilization of the egg cell, a second, separate fertilization event gives rise to the endosperm, an extraembryonic structure that nourishes the embryo in a manner analogous to the mammalian placenta. Unlike the embryo, the endosperm is often formed from the fusion of two maternal cells with a male gamete. This results in a triploid genome. The 2:1 ratio of maternal to paternal genomes appears to be critical for seed development. Some genes are found to be expressed from both maternal genomes while others are expressed exclusively from the lone paternal copy.[78] It has been suggested that these imprinted genes are responsible for the triploid block effect in flowering plants that prevents hybridization between diploids and autotetraploids.[79] Several computational methods to detect imprinting genes in plants from reciprocal crosses have been proposed. [80][81][82]

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When a doctor recommended to Steven Kalister that he get screened for genes associated with breast cancer a few years ago, the Columbus Northwest Side resident was surprised.

Kalister, 50, did not have breast cancer a disease uncommon (though not unheard of) among men or any form of malignancy, for that matter. But his father had died from metastatic prostate cancer, so Steve was seeking precautions besides common tests like digital rectal exams and prostate-specific antigen screenings.

The oncologist, Dr. Steven Clinton at Ohio State Universitys comprehensive cancer care center, explained to Kalister that mutations in two genes, known as BRCA1 and BRCA2, could have caused his fathers cancer, and might have been passed down to him. BRCA stands for Breast Cancer Gene, because that is what researchers first found it to be associated it with.However, science has since connected the BRCA genes with a range of malignant tumors that affect men and women, from melanoma to pancreatic, ovarian, and prostate cancers.

Kalister decided to take a simple blood test and learned that, indeed, he had a mutation in the BRCA2 gene.Since then, he has undertaken a variety of precautions that could help him ward off any significant tumor, and he shared the news with family members who also got tested.

Kalister said he would encourage anyone who is thinking about genetic testing to go seea counselor.

My wife thought maybe Id get paranoid or have a lot of anxiety from these results. But thats not the case at all.Knowledge is power, he said.

'Pay it forward': One testicular cancer survivor raises funds for research

Researchers and clinicians say that the publics understanding of BRCA genes needs updating.Because of the genes association with breast cancer and therefore cisgender women, until recently BRCA testing was not covered by insurance or encouraged for men diagnosed with prostate cancer but with no family history of the disease.

However, recent research has shown that men with mutations to BRCA2 have a three-times higher risk of prostate cancer than the general population, and people with mutations in BRCA1 and BRCA2 are six and 14 times more susceptible to pancreatic cancer, respectively. Today, genetic counselors recommend that certain male cancer patients and men with family histories of cancer get tested for mutations in BRCA and a suite of other cancer-associated genes.

The BRCA genes code for proteins that help prevent cancer by fixing damaged DNA.

Like everything in our bodies, DNA is susceptible to damage from radiation, chemicals, or other factors, like random chance during the process of creating new cells. Cells containing damaged DNA can become cancerous if fixes are not made by DNA-repairing proteins. Mutations in the BRCA genes can create proteins that are less effective at fixing DNA damage, thus upping cancer risk.

Everyone has two copies of each BRCA gene one from each parent but only some people have harmful mutations in the gene. If a parent has a harmful mutation in either gene, each of their children has a 50% chance of inheriting it, according to Lindsey Byrne, a licensed genetic counselor at Ohio State University's Wexner Medical Center.

More: United we ride: Pelotonia brings cancer survivors, loved ones together to find a cure

Byrne leads a genetics clinic at the OSU Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. As a licensed genetic counselor, she helps patients decide whether to undergo genetic screening, how to interpret results, and next steps.

Byrne encourages genetic testing for anyone with a strong family history of cancer, and for patients who have cancer at an early age or particularly aggressive cancers.

That includes prostate cancer.

I think there hasnt been enough messaging to say: prostate cancer is something you should have genetic testing (for). There is a lot of media and coverage about breast cancer and genetics, but the message was not as strong for prostate cancer until recently, she said.

Certain people may want to consider genetic screening based on their ethnicity.While only one in 400 individuals in the general population has a harmful BRCA mutation, that statistic rises to about one in 50 among Ashkenazi Jews, who trace their ancestry to central and eastern Europe.

Kalister works at The James as a service line administrator, but he said there was a lot he didnt understand about cancer and genes until he sought out genetic counseling.

Knowing he is positive for a BRCA2 mutation has helped him take precautionary measures. He is more careful about sun exposure than he used to be (because BRCA2 is linked with melanoma), and tries to eat more healthful foods.

Byrne also helped him connect with an ongoing National Cancer Institute study, which takes MRIs of his prostate on a regular basis to detect any abnormalities.

So far, so good, he said.

Kalister plans to encourage his twin 9-year-old sons, Ian and Colin, to get genetic screening as well when the time comes.

Ill tell them about how its not scary its about how you use that knowledge to your advantage, he said.

Insurance covers most patients for genetic cancer screenings, but it depends on the policy and ones medical and family cancer history, said Byrne.

Testing is very low out of pocket,and for Medicare and Medicaid patients, its usually zero out-of-pocket, she said. Medicaid and Medicare have covered genetic screening for metastatic prostate cancer patients since 2018.

Even if one were to self-pay, the cost of screening is just a few hundred dollars, compared to several thousand dollars a decade or more ago.

Although BRCA is a common genetic cause of cancer, it is not the only one.Byrne says she typically tests for a suite of 12 other genes, in addition to the two BRCAs.

Some genes that cause cancer including prostate cancer may have yet to be discovered.

For example, Black men, who are 60% to 80% more likely than white men to be diagnosed with prostate cancer, do not have higher-than-normal incidences of BRCA.

There must be something else going on, said Byrne.

It could be a combination of a whole bunch of small risk factors, or it could be a gene we havent discovered, and its because we havent studied genetics as much in individuals who are Black as we have in whites. The problem with some research is its not validated for all populations, and thats a huge equity issue.

Byrne says some patients come to her with privacy concerns over genetic testing, but she is usually able to allay their fears.

Unlike some companies that test DNA to identify relatives, none of OSUs genetic testing partners share information with the police, she told The Dispatch.

Individuals are also protected by the 2008 Genetic Information Nondiscrimination Act (GINA), which prevents employers and health insurers from asking about genetic information when making decisions.However, exceptions are made for life insurance and long-term care insurers, who can ask for such information. It is often best to buy such coverage before undergoing genetic testing, said Byrne.

Kalister said that for at-risk individuals like himself, genetic counseling should be a no-brainer.

The counselors are really really good, he said.This is what they do they talk to people about this kind of testing, these results, theyre there to answer questions.

OSU also provides Family HealthLink, a free online tool that estimates cancer risk by reviewing family patterns.

Peter Gill covers immigration and new American communities for The Dispatch in partnership with Report for America. You can support work like his with a tax-deductible donation to Report for Americahere:bit.ly/3fNsGaZ.

pgill@dispatch.com

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BRCA beyond breast cancer: links to prostate, pancreatic, other tumors - The Columbus Dispatch

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A retrospective study that analyzed sex disparities in patients with COVID-19 and rheumatoid arthritis found that men had more baseline comorbidities and increased risk of COVID-19related outcomes, compared with females.

Differences in genetics between sex and sex steroid hormones may play a role in predisposition to COVID-19 infection as well as modulating the disease progression, according to Xiaofeng Zhou, PhD, senior director at Pfizer, New York, and the studys lead author.

Zhou presented her findings at The Lancet Summit: Sex and gender in rheumatology in late September.

Patients with chronic rheumatic diseases treated with immunomodulatory therapies may be at higher risk for more severe COVID-19 outcomes, including hospitalization, complications, and death. Research on sex-based disparities in RA patients with COVID-19 in the United States is limited, said Zhou, who embarked on a retrospective cohort study to examine the demographic and clinical characteristics of RA patients with COVID-19 and estimate the risk of possible COVID-19 outcomes by sex.

Zhou and colleagues used U.S. COVID-19 data collected through electronic health records by Optum during 2020 to June 2021. The study included adult patients with RA and a COVID-19 diagnosis ( 1 diagnosis code or positive SARS-CoV-2 laboratory test) and 183 days of database enrollment who received treatment with immunomodulatory therapies prior to the diagnosis date. They were stratified by sex.

Investigators used logistic regression to estimate the risk of 11 possible COVID-19related outcomes within 30 days of the COVID-19 diagnosis (hospitalization, ICU admission, pneumonia, kidney failure, thrombotic event, heart failure, acute respiratory distress syndrome [ARDS], sepsis/septic shock, mechanical ventilation/extracorporeal membrane oxygenation [ECMO], in-hospital death, and all-cause mortality), adjusting for demographics and baseline clinical covariates.

A total of 4476 COVID-19 patients with RA (78% females) took part in the study. Male patients trended older (64 vs 60 years) and had lower African American representation and Medicaid enrollment than females, but they had more baseline comorbidities such as hypertension (55% vs 45%), hyperlipidemia (45% vs 33%), diabetes (25% vs 20%), coronary artery disease (28% vs 12%), and chronic kidney disease (20% vs 15%).

Eight of the 11 COVID-19 outcomes were significantly more likely to occur in men than women (hospitalization: odds ratio [OR], 1.32 [95% CI, 1.11-1.56]; ICU admission: OR, 1.80 [95% CI, 1.36-2.40]; mechanical ventilation/ECMO: OR, 1.48 [95% CI, 1.04-2.11]; in-hospital death: OR, 1.53 [95% CI, 1.13-2.07]; all-cause mortality: OR, 1.42 [95% CI, 1.09-1.86]; sepsis: OR, 1.55 [95% CI, 1.20-2.02]; kidney failure: OR, 1.46 [95% CI, 1.15-1.85]; ARDS: OR, 1.39 [95% CI, 1.15-1.69]).

The data illustrated that men with RA had more baseline comorbidities and increased risk of COVID-19 outcomes than females.

Sex hormones regulate virus entry into host cells, respiratory function, immune response, the cardiovascular system, and coagulation, explained Zhou.

Estrogen and progesterone in women could help develop stronger and efficient immune responses to viruses and reduce virus entry into the host cells. Also, larger number of copies of ACE2 genes in women, [which] is linked with protection in the lungs against edema, permeability, and pulmonary damage, could be associated with lower incidence of severe COVID-19 outcomes, such as respiratory-related mortality and mortality, Zhou said.

By comparison, androgens in men may increase virus entry into the host cells and promote unfavorable immune response through the induction of cytokine production and reducing the antibody response to the virus. This could lead to severe infection, Zhou said.

Sex-based differences in steroid hormones may also explain the higher incidence of morbidity and fatality thats been observed in other studies of male patients with other infectious diseases, such as severe acute respiratory syndrome and Middle East respiratory syndrome.

The results add real-world evidence to the limited literature on sex disparities in COVID-19 outcomes among patients with RA in the United States, Zhou said. The differential role in sex steroid hormones among women and men may shed light on clinical management of COVID-19 patients and the need to consider sex-specific approaches in clinical trials in preventing and treating COVID-19 patients, she said.

Considering that all patients are recommended to get COVID-19 vaccinations, It is difficult to say how this impacts clinical practice, said Janet Pope, MD, MPH, professor of medicine in the division of rheumatology at the University of Western Ontario, London, Ontario, Canada, who was not involved with the study.

Sharing results with some patients may help to encourage vaccination, thus reducing risk of poor COVID-19 outcomes, Pope said.

In future studies, Zhou suggests using multiple databases and considering other geographies beyond the United States to further understand the etiology of sexual dimorphism in COVID-19 and expand generalizability. In addition, future research will seek to provide insights into health equity gaps in the management of COVID-19. This may inform development of precision medicines and vaccines, especially among patients on immunosuppressive treatments, she said.

The study was sponsored by Pfizer. Zhou and other study authors are Pfizer employees and hold Pfizer stock.

The Lancet Summit: Sex and gender in rheumatology: Abstract P.37. Presented Sept. 22, 2022.

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There is something about bees that in all ages has taken men captive.Brother Adam, Beekeeping at Buckfast Abbey*

On isolated, swampy Thorah Island in Lake Simcoe, Ontario, researchers bring virgin queen bees to take their mating flights. Each year, the Honey Bee Research Centre at the University of Guelph brings Buckfast queens to this mating station, which restricts the queens options. Thorah Island is situated far enough from the mainland that queens can only breed with the finest male Buckfast drone (male) bees, also brought by the researchers, who express the traits theyve selected for; here, mainland bees wont fly over water at such a distance.

Researchers and beekeepers work intensely to maintain the Buckfast honeybee genes because the strain is valued for its gentle nature, its hardiness in challenging climates, and its ability to produce high amounts of honey. Today, the Honey Bee Research Centre follows the same breeding program to preserve the bee lines developed in the early twentieth century by a monk named Brother Adam Kehrle.

A Benedictine monk of Buckfast Abbey in England, Br. Adam studied and bred the first Buckfast bee lines around 1920, and over the course of his nearly eighty-year beekeeping career wrote three books regarded as classics on the subject: Beekeeping at Buckfast Abbey, In Search of the Best Strains of Bees, and Breeding the Honeybee.

These texts remain important references for beekeepers and those interested in breeding bee species, and while they offer poetic and meticulous practical detailsqueen selection for optimum fecundity, fertilization, and pest controlBrother Adams writing reveals his deep admiration for honeybees, as well as the more esoteric aims and considerations in the practice of beekeeping.

Their extraordinary sense of order and precision, their ability to adapt themselves to anything and everything, their amazing versatility, these and many other characteristics provide an inexhaustible source of interest and delight for the professional bee-keeper with his 2,000 stocks as well as for the amateur with his few hives in the corner of his garden.

One of Br. Adams most enigmatic instructions with regard to what bees may need from those who tend to them was to Let the bees tell you. Still, while seemingly inscrutable, this idea holds important weight among even expert beekeepers. Many elements of beekeeping cannot be learned by text or even detailed instruction, or by applying past experience to current colonies, whose behavior is as changeable as weather patterns.

As Br. Adams advice suggests, its only with keen and patient attention that beekeepers can understand what may be happening inside a hive; and with this observation, beekeepers need to be attuned to how they contribute to, not engineer, the outcome of a colony; as he says, not attempting the impossible of mastering her, but rather doing all we can to serve her needs.

Honeybees must be, in a sense, decoded. In a failing hive, many would expect the bees foraging to be weak or that a queen is placed into a hive with limited capacity, but Brother Adam emphasized that, all too often, it is the beekeeper who is at fault for failing to serve the bees needs. Certain codes exist even within the beekeeping lexicon.

In one of the more obvious instances, in the world of queen bee breeding and rearinga competitive industry involving larvae graftingqueens are marked with a specific color for the year theyre bred. There are five queen bee marking colors that follow the recognized color sequenceas queens do not live more than a maximum of five years, the color code starts over in the sixth year. A common mnemonic to remember the colors is Will you raise good bees (white yellow red green blue).

On beekeeping message boards one sees speculations about brood patterns, whether a colony is thriving, signs of swarming (abandoning a hive), and, if a colony dies, beekeepers perform hive autopsies, assessing mysteries which can largely only be identified through experience; watching and interpreting, in other words, is letting the bees tell you. The beekeeper must, Br. Adam writes, with his signature esteem for the insects, at all times heed the instincts and highly developed organisation of the bees.

Brother Adam wrote this specific advice in Beekeeping at Buckfast Abbey. You may envision Br. Adam as hes depicted in the many photos featured in this text: a seemingly gentle, gray-haired and fastidious man, dressed not in white suit or a veil, but in a monks dark habitperhaps not the first visual that comes to mind with regard to honeybees and their keepers.

While the history of beekeeping is vast and worldwide, in Europe, beekeeping was taken on regularly by abbeys and monasteries during the Middle Ages; different regions established their traditional forms of housing for bee hives, or skeps, which resemble overturned baskets, some woven and others made from pottery, wood, or cork. Traditionally, skeps were used to house bees and their honeycomb, but harvesting the honey required the destruction of the colony, killing the bees.

Up to a hundred years before Brother Adam was writing, honeybee breeding was the exclusive prerogative of nature, and harvests were challenging. Humans, he writes, had little influence before the movable frame hive became common in the 19th century, borrowed, its said, from top-bar (movable honeycomb) hives in Greece, which preserve the bees. Later, the Langstroth hivethe most popular among apiarists, those recognizable, stackable boxes opened from the topprovided perfect amounts of bee space between frames of comb to keep both honeybees and their honey harvesting stewards content.

As many of us become aware of the dangers of human intervention with honeybeesrelying on industrial beekeeping to support the pollination of monoculture crops, and the (likely) connected colony collapse disorderits important to clarify that apiculture, like agriculture, holds much diversity and nuance. Some contemporary beekeepers support Buckfast strains of bees for the same reasons Br. Adam developed them: gentle temperament (a bonus for keepers), low swarm tendencies, and stability in unpredictable climates.

University of Guelph Honeybee Research Centre brings around a hundred Buckfast mating nucleus colonies to Thorah Island each year; colorful nucs piled like blocks get ferried across the water on a beater pickup truck. From this isolated place, after their lofty mating flights with Buckfast drones, mated queens are harvested on a two-week cycle. These young, fertile Buckfast queens, who will each lay thousands of eggs and populate their own Buckfast colonies, are then used to re-queen HBRC colonies or sold to beekeepers.

The careful steps involved in maintaining these lines of bees requires a commitment to Brother Adams breeding system, and only registered Buckfast breeders are allowed to use the term Buckfast when advertising colonies or queens for sale. Similarly, in Br. Adams pedigree bee-breeding, he isolated his colonies to ensure queens could only mate with selected drones. Buckfast Abbey was relatively close to the wilds of Dartmoor, a relatively treeless expanse utterly inhospitable to bees, which ensured that the only honeybees interbreeding would be Br. Adams Buckfast strain.

Honeybees provided materials that became integrated into the material life of the Catholic Church: fermented honey was used medicinally, and to make mead in areas where grapes could not be grown for wine; beeswax was highly prized for making candles for church services, as they give a purer, longer burn than typical animal tallow candles.

Further, the candles themselves were considered sacred: The wick denoted the soul and mortality of Christ, the light the divine person of the Saviour, writes Hilda Ransome in The Sacred Bee in Ancient Times and Folklore. Apparently, beeswax candles were the preferred method for lighting in Catholic Churches, a practice which survived into the 20th century when the requirement was ended by the Pope.

Aside from the practical usage of their wax and honey, beekeeping among monks and religious communities has long been seen as a meditative, even holy practice. Beekeeping was the responsibility of many monks and nuns, and some religious, like Br. Adam, held positions entirely devoted to working with the bees.

Its not a huge leap to transpose the widely held cultural view of honeybee coloniesas intelligent, industrious, sweet, working in harmony for the greater goodonto religious communities like Buckfast Abbey. In Brother Adams writing, we find admiration for his colonys collective work, its rituals and devotion to a higher power, and his desire to emulate it in his work at the abbey.

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Karle Kehrle arrived at Buckfast Abbey from Germany in 1909, at just 11 years of age, to join the order, taking the name Brother Adam. Lay monks typically learned practical skills, evidently vital to Buckfast as it was still undergoing a revitalization begun in the late 19th century. As he wasnt suited for stonemasonry, Adam started as an assistant in the apiary with Br. Columban.

At the time, the abbey kept two breeds of honeybees: the native English black beeshardy and well suited for the unpredictable British weatherand Italian honeybees. Soon after Br. Adam joined, thirty of the Abbeys forty-six honeybee colonies (or hives) were lost to what experts thought to be a disease caused by tracheal mites known as acarine. All of the bees that died were of the native black bee variety. The bees that survived were of Italian origin, a discrepancy that struck Br. Adam, and led him to study the importance of species and genetics in apiculture.

Upon Br. Columbans retirement in 1919, Br. Adam took on the apiarist role and slowly rebuilt the lost colonies. His pursuit of a successful strain of honeybee came at an opportune time. As he took on the role at Buckfast Abbey, the Isle of Wight Disease, as it was then called, had brought native bees in England practically to extinction. Italian honeybees could not be managed in the same way as the indigenous variety; the beekeeping practices used elsewhere, in more temperate climates with longer flowering seasons, were unsuitable for the British Isles. Br. Adam sought to use cross-breeding between the English native black bee and the Italian honeybee to develop a new species that would be tough like the black bee, pest- and disease-resistant like the Italian bee, gentle, and, of course, an intrepid producer of honey.

Br. Adam found that providing the hybrid bees with a larger brood chamber (ample breeding space, that is), made way for bees to thrive. In undertaking this breeding of an ideal honeybee, Br. Adam looked to heterosis, also known as hybrid vigor, to develop the superior qualities of genetic lineages; inevitable, though, in hybridizing animals is the persistence of undesirable qualities. In honeybees, this can look like aggression (stinging), slow honey production, or weakly fertile queen lines. The resultant Buckfast bee is more industrious, more thrifty, less disposed to swarm, more resistant to disease, particularly acarine As for temper, she is unusually docile and will tolerate handling in unfavourable weather.

As queen bee genetics determine generations of their own colony, breeding them was vital, and soon Br. Adam was consumed by the search for an ideal bee. Bee breeding typically requires isolation; unlike other livestock, its difficult to predict bee crosses, and, even more difficult to control their pairings. Queens mate while flying, and so bee breeders face the time-consuming task of ensuring queens are limited to top-choice drones.

Directed breeding looks to the best qualities in honeybees, which according to Br. Adam are: fecundity (honey-gathering and brood-rearing abilities), industry (boundless capacity to work), resistance to disease, and disinclination to swarm. He also outlines the charmingly named qualities of indirect value, which do not influence honey production, but facilitate the beekeepers tasks. These involve bees exhibiting good temper, calm behavior, and a keen sense of orientation back to their home hive (for bees that wont drift to neighboring colonies).

There is no perfect or ideal bee, Br. Adam wrote, though he traveled extensively throughout the world to be sure. In his research trips he studied and sourced breeding stock for his bee program. He concentrated on countries with distinct indigenous species of bees, going chiefly to isolated rural regions where the purity of the native strains had been maintained. According to the Buckfast Abbey website, over the years, he traveled more than 100,000 miles in search of the best strains of bees, which of course he documented in In Search of the Best Strains of Bees.

In Beekeeping at Buckfast Abbey, Br. Adam discusses the preferred structure of hives, apiary location (a southerly sunny aspect and shelter from the prevailing wind), and the aims of beekeeping itself. These aims outline objectives, as Brother Adam saw them: over years spent with apiaries and bees, the beekeeper will gain a knowledge and insight into the mysterious ways of the honeybee, usually denied to the scientist in the laboratory. This surrender to natures mystery is likely what compels readers and beekeepers alike.

Br. Adams ongoing acknowledgement of our inability to control honeybees is heartening, especially in the context of genetic selection. He concedes that breeding bees is a blind-mans game and the honeybee will, despite genetic expectations and human interference, follow her instincts regardless of our wishes. The tasks of the modern beekeeper might more aptly be described as a service; in fact, we are more truly servants than masters.

While many others had bred bees before him, it is Brother Adams reverential, poetic writing that makes him a particularly captivating figure. Upon his death in 1996, the Washington Post called his creation the legendary Buckfast Superbee. Adams research led to a breed of honeybee which is exclusive yet popular, highly productive, and more resistant to parasites and the pervasive varroa mites that trouble beekeepers and decimate bee colonies.

Brother Adams hybrid queens, foundational for todays Buckfast honeybees, were so highly valued that in 1982 thieves stole two queens from the Buckfast Abbey apiaries. Police circulated a description of the bees: three-quarters of an inch in length, with dark brown and dark gray stripes.

Buckfast bees are treasured by commercial beekeepers and honey fanatics alike; and, of course, they contribute to their surrounding environment by doing what honeybees do: visiting flowers and pollinating plants that enhance our farming and our ecosystems.

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Let the Bees Tell You. On the Holy Bible (For Beekeepers) of Buckfast Abbey - Literary Hub

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What if people who need regular injections to treat chronic diseases could instead take a pill that precisely controls the production of the right proteins and hormones inside their bodies?

A promising new gene therapy technology that aims to turn the human body into such a medicine-making factory could, if successful, push the boundaries of medicine and make certain treatments much more convenient and potentially less expensive.

MeiraGTx, a gene therapy company, is working to make this futuristic vision a reality.

The British company already develops traditional gene therapy, which replaces missing or broken genes in people with inherited disorders. That side of business is booming, and the firm just opened a manufacturing facility in Ireland that could employ up to 300 people.

But MeiraGTx is also making strides in what it calls gene regulation therapy, which it says could help control much more precisely the genes that instruct cells to make or stop making certain proteins.

Its no easy feat and the technology would take years to bring to market, but it has the potential to make gene therapy even more life-changing for patients.

When you put a gene or replace a missing gene into a cell today, you put the gene in and it is expressed for the rest of that cell's life, MeiraGTx CEO Alexandria Forbes told Euronews Next.

Its very hard to build a gene therapy that is switched on and off when it's needed, particularly in a disease. And what's even harder is to create a gene therapy which is switched on or off when you, the doctor or patient, want it to be.

MeiraGTx says it has developed a switch of this sort that could help make patients lives much easier: rather than injecting synthetic hormones and proteins into them, it could insert the gene that tells their body to make those, while a pill activates the gene only when the specific protein or hormone is needed.

Take Epogen (epoetin alfa) a well-known injectable drug that helps create more red blood cells when you're anaemic, with kidney disease or you're being treated for cancer.

What you can do, for example, is put the gene for Epogen into the body, into the muscle, and have a switching system that only allows your body to make the natural form of Epogen when you take a pill, Forbes explained.

So we don't have to make unnatural forms of these drugs because what we're doing is we're providing the body with the message to make the drug, and that message is only switched on when we give the body a pill.

MeiraGTx told Euronews Next it has already tested this technology in animals and is hoping to start trialling it on humans in 2023.

If successful, it could have huge, broad-ranging implications, Forbes said.

This isn't only for gene therapy. It allows you to control cell therapy, immuno-oncology, antibody production anything that is a protein or peptide that can be made by the body.

Many traditional drugs involve making a protein outside the body, like insulin to fight diabetes or antibodies to fight cancer. That protein is manufactured in cells or bacteria outside the body and then is injected into the body on a regular basis as a treatment.

Gene therapy, by contrast, involves putting into the body a gene encoding the therapeutic protein: rather than injecting the protein over and over and over again, you put the gene for the protein into the person and the protein is made in the person's body.

Gene therapies are typically used against inherited diseases, where a gene is missing or not functioning well. Gene therapy inserts into a patient a perfect copy of that gene to replace the missing or broken one.

So our drugs are actually genes - DNA - and they're delivered into the body by being encapsulated in viral proteins which act like a little spaceship and insert those genes that we've made into the appropriate cell, Forbes said.

This type of technology requires a very specific manufacturing process to ensure through rigorous testing that every single batch of these genes always has the same identical quality, safety and potency, she explained.

MeiraGTx controls this manufacturing in-house and has just inaugurated a new commercial-scale facility in Shannon, Ireland, thats set to employ 100 people initially and up to 300 as business grows.

The company hopes the new site will help accelerate its development and delivery of gene therapy treatments to patients with an initial focus on rare inherited disorders affecting the eye, central nervous system, and salivary gland.

But MeiraGTx argues that adding a switch to be able to fine-tune gene therapy has the potential to considerably expand this range to also tackle non-hereditary diseases that affect hundreds of millions of people worldwide, including heart disease, cancer and diabetes.

It says it could even help fight obesity, arguably one of the biggest global health challenges.

The causes behind obesity are complex and multi-faceted, genetic factors mean some people are more at risk than others, and the hormones that control appetite are very unstable and short-lasting.

A class of injectable diabetes drugs currently proving highly effective against obesity are GLP- 1 drugs, which help control blood sugar levels. But they work better in combination with several other gut peptides that affect metabolism.

The challenge, once again, is to precisely control the levels of these peptides.

MeiraGTx claims its technology may someday allow those hoping to lose weight to switch on the combination of genes that produce the hormones and peptides controlling their appetite, blood sugar levels and ultimately their fat.

We can now put the genes for three natural gut peptides that control metabolism into the body and give a pill when we want those drugs, Forbes said.

In theory, if clinical trials go well, the potential applications for other diseases are dizzying and they directly raise the question of extending human life expectancy. But that should not be the priority right now, Forbes said.

I think that currently we have really big problems with obesity, with Alzheimer's, with ways of living that mean we are young and living poorly, she said.

And these sorts of products can be used to help address those really large indications, not just the rare gene replacements.

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This gene therapy company is testing new tech to 'switch off' diabetes and obesity with a pill - Euronews

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CNN Travel recently published a heartwarming story about a unique world tour by Canadian couple Edith Lemay and Sebastian Pelletier and their four children. The couple wishes to give incredible moments that would enrich visual memories of their children before it is too late. Three of their childrenMia, Colin and Laurentare affected by a rare genetic condition named retinitis pigmentosawhich causes blindness over time. It is a condition that does not have a cure so far, and Lemay and Pelletiers aim is to help their children have better coping mechanisms that would prepare them for their future.

What is retinitis pigmentosa?

Retinitis pigmentosa is a condition where the cells in the retina break down slowly over time. The condition would result in vision loss. RP is caused by mutations in certain genes that control the cells that form the retina. These mutated genes are passed down from parents to children.

Symptoms of RP would typically appear in childhood itself. Loss of night vision is the most common early symptom. Children with RP may have issues adjusting to dim light and walking in darkness. The condition would cause loss of peripheral vision, too. Over time, a person with RP will have trouble seeing things out of the corners of the eyes. Eventually, they would lose this tunnel vision, too. Some others may experience loss of central vision, which would hamper their ability to do tasks such as reading or threading a needle.

RP-affected people will exhibit sensitivity to bright light and may also experience loss of colour vision. The type and speed of vision loss associated with RP would vary from person to person. Global estimates say that RP affects about one in 3,000 to one in 4,000 people. In India, the prevalence of RP is high. A study published in 2012 found that the prevalence of retinitis pigmentosa was about 1:1750 in the adult population of rural central India.

How is RP detected?

The most common method for the detection of RP is a comprehensive dilated eye exam. Here the doctor would give the patient some eye drops to widen his pupil and examine for RP. Electroretinography, optical coherence tomography and fundus autofluorescence imaging are other tests that used to detect RP.

Can RP be treated?

There is no cure for most types of RP so far. But low vision aids and rehabilitation programmes may help those with RP to manage their lives. Those with RP are advised to use sunglasses and other means to avoid exposure to too much light. Voretigene neparvovec-ryzl, a gene therapy product, is now being used to treat a specific type of RPcases in which the disease develops because of mutations in the RP65 genes. Researchers believe that advancements in gene therapy, cell therapy, and medications would bring changes in RP treatment soon.

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What's retinitis pigmentosa, a rare genetic condition that causes blindness over time - The Week

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When she was younger, Daisha Dillon was told she couldnt have a baby. Or that it would be dangerous to get pregnant. That she could put her life or her babys at risk.

Dillon has sickle cell disease.

Despite the warnings, Dillon gave birth to Kinley Dillon on Aug. 19, a healthy girl who does not have sickle cell disease, although she does have one of the associated traits.

Dillon has the New England Sickle Cell Institute at UConn Health to thank, but, even more, she can be proud of her own courage and willingness to do what it took to have a baby.

They really worked with me, she said of the staff at NESCI. And to be honest, I had an amazing pregnancy. It was hard sometimes, but to sum it up altogether, I will say it was great, you know, for someone like me that has sickle cell.

On Aug. 19, Daisha Dillon gave birth to her daughter, Kinley Dillon, but it wasn't a normal pregnancy. Dillons pregnancy was high risk because she has sickle cell disease so she required blood transfusions and other measures. Her daughter does not have sickle cell. (Douglas Hook / Hartford Courant) (Douglas Hook)

Dillon said it took a lot for her to decide to become pregnant.

Growing up, I always heard since I had sickle cell I couldnt have kids, she said. It wasnt good for me to have kids. And if I did have kids I would have to have a C-section; it would send me into a pain crisis. Ive heard all this stuff.

Theyre oftentimes discouraged by their physicians as well as their family members who love them that are worried about their health to not have children, said Dr. Biree Andemariam, founder and director of NESCI, whom Dillon met when she was 17. So, you know, it takes a bit of courage and resilience to push on and have a baby despite being told that youre taking significant risks.

Dillon said she felt some fear, but she went ahead because of her lifelong dream to be a mother and because of her faith.

I know God is not going to put anything on me that I cant handle, and if I pray about things and continue to serve him, itll be fine, she said.

Kinley Dillon was born Aug. 19. Her mother, Daisha Dillon, has sickle cell disease but said she set aside her fears to reach her lifelong dream of being a mother. (Douglas Hook / Hartford Courant) (Douglas Hook)

Dillon, 32, a Manchester resident, was required to get monthly blood transfusions throughout her pregnancy, and she had to deal with the pain crises that come with the disease, as well as chronic pain.

When she needed to go to the hospital, I couldnt go to the ER; I had to go to labor and delivery because they had to watch me and the baby, Dillon said. I was automatically a high-risk pregnancy. So automatically I had to go to the doctor more frequently than anyone else.

She was also on Lovenox, a blood thinner that doesnt pass through to the placenta.

I had to shoot myself with a needle every day. Twice a day, she said.

On Aug. 19, Daisha Dillon gave birth to her daughter, Kinley Dillon, but Daishas pregnancy was high risk because she has sickle cell disease so she required blood transfusions and other measures. Her daughter does not have sickle cell. (Douglas Hook / Hartford Courant) (Douglas Hook)

While the doctors had hoped to have Dillon deliver at 37 weeks, she developed preeclampsia, so she had her C-section a couple of days early. It would have been sooner, but she had to be off the blood thinner before they could deliver Kinley.

She stayed at John Dempsey Hospital for 24 hours, and then they did the C-section the next morning, Dillon said. I had an amazing doctor who did it. She was awesome. The whole team was awesome.

September is designated Sickle Cell Disease Month in order to increase awareness of the blood disorder, which affects mostly Blacks and Hispanics but also, to a lesser extent, groups such as South Asians and those from the Mediterranean.

The disease is characterized by misshapen red blood cells, which are flat and curved, resembling a farmers sickle, larger than a normal cell. They dont carry hemoglobin well and will clog up small blood vessels, which can cause the pain crises associated with the disease.

Bone marrow transplants can cure the disease, but not many with sickle cell disease undergo the procedure, partly because of the risks, including infertility, dealing with the required chemotherapy, and because people with sickle cell can live for decades, Andemariam said.

Also, finding a donor who matches a sickle cell patient is difficult, she said. Parents often will defer the decision of having a bone marrow transplant for their child until the child can make the decision for herself, she said.

Another technique, now in clinical trials, is gene therapy, in which the patients own stem cells are edited or corrected and returned to the patient. NESCI doesnt do transplants at this point, Andemariam said, but is gearing up to do gene therapy once its approved.

On Aug. 19, Daisha Dillon gave birth to her daughter, Kinley Dillon, but it wasn't a normal pregnancy. Dillons pregnancy was high risk because she has sickle cell disease so she required blood transfusions and other measures. Her daughter does not have sickle cell. (Douglas Hook / Hartford Courant) (Douglas Hook)

Dillon said she met Andemariam in the hospital and talked to her about the specialized care NESCI could give her.

I was able to ask her all the questions that I had, and she made me feel very comfortable about going to UConn, Dillon said. So when I did come over here, I felt very comfortable. And then when I got over here, it was even better. All the nurses were great.

Genice Nelson, a doctor of nursing practice, also has been really influential in my care, Dillon said.

Andemariam said there are several risks for both the mother with sickle cell and her baby.

There can be increased complications like something called preeclampsia, increased risk of preterm delivery, increased risk of low birthweight an increased number of pain crises, an increased risk of a very serious lung complication called acute chest syndrome, an increased risk of being hospitalized during the pregnancy, Andemariam said. Death of the mother is also a risk.

For the baby, premature birth and miscarriage are the main risk factors, she said.

Dillon said the idea of not being at NESCI is scary and that she has gotten healthier to the point of not having to go to the hospital as often.

When I go to the ER now, people [say], Oh my God, its been so long, rather than before, they think, Oh, you dont feel well again, Dillon said. That feels good to put some spacing between hospitalizations and come in for regular routine doctor visits rather than come in for pain crises. Whatever were doing, its working.

She credits her caregivers at NESCI for letting her know that she would be OK, even when she had to come off a medication during her pregnancy that helped her avoid pain crises.

They told her, Im not the first person to have a baby with sickle cell, and Im not the last, she said.

Andemariam said NESCI plays an important role in caring for patients with sickle cell disease.

Research has shown us that your odds of doing well in pregnancy with underlying sickle cell disease are dramatically improved if youre receiving care at a place where you have experts in sickle cell disease and you have experts in high-risk pregnancies, Andemariam said.

And this gets to her courage, she said of Dillon. This is her resiliency. She was going to do whatever it took to get that care.

On Aug. 19, Daisha Dillon gave birth to her daughter, Kinley Dillon, but it wasn't a normal pregnancy. Dillons pregnancy was high risk because she has sickle cell disease so she required blood transfusions and other measures. Her daughter does not have sickle cell. (Douglas Hook / Hartford Courant) (Douglas Hook)

She said the center, staffed by fantastic nurses, social workers and assistants, has cared for almost 100 pregnant women, with no serious problems, offering blood transfusions, prenatal diagnostic testing and genetic counseling.

More help may be on the way, as a bill has been introduced in Congress to create a $535 million annual grant program to hospitals with sickle cell disease programs to expand services to community health and outpatient centers. Andemariam is on one of the councils that helped develop the bill.

Dillon has always wanted to be a mother, Andemariam said. She actually shares a very special relationship and bond with her own mother, Carmen, who has always been by her side and supportive of her in everything that shes done, and I can only see that Dashia will want to be able to replicate what Carmen has given to her to her own child.

Since sickle cell is individualized there are a number of variations of the disease Dillon has a written and signed pain plan that she can present to any doctor if she has a pain crisis. It spells out the best treatment for her.

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It takes the guessing game out, she said. The doctor doesnt have to ask you all of the questions. Its all written down, ABC type of things. If a doctor questions the plan, Dillons doctors phone number is there.

It reassures me and reassures the doctor that a hematologist is watching me and she knows what shes doing, Dillon said.

As for Kinley, Shes such a good baby. Honestly, I am blessed. God is so good. I prayed because I do take pain medication. I thought that she would have withdrawal symptoms from the pain medication. And she had no withdrawal symptoms. She was born a happy, healthy baby. When she wakes up she opens her eyes wide and looks at me. I know that everythings going to be OK.

Dillon said Kinleys father keeps his privacy and doesnt want to be named. She said he doesnt have sickle cell or the genetic traits. Theyre not married, but hopefully there will be an engagement soon, Dillon said.

Dillon works as care coordinator in the detox unit at InterCommunity Health Care in Hartford and is working on a masters degree in social work, hoping to work with people with substance use disorder.

Daisha, no matter how sick she has been, and she has been sick throughout her life, always perseveres, Andemariam said. She is always holding down at least two jobs. She is always taking care of herself, providing for herself. She was always a support to her family. So it doesnt surprise me that she would have the courage to take the risk to try to accomplish one of her lifelong goals, which is to be a mother.

Ed Stannard can be reached at estannard@courant.com or 860-993-8190.

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CT woman with painful, life altering disease relies on faith, 'perseveres' to have a baby - Hartford Courant

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Sex- and age-dependent genetics of longevity in a heterogeneous mouse population - Science

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