Archive for December, 2020

When I was 68, I went on a safari holiday in Namibia. My wife and I were bouncing around in the back of a Land Rover for two weeks and I felt a soreness on my nipple. I thought it was just the seatbelt rubbing against it so I didnt take much notice.

But I was still sore a month or so after we got back, and then I felt a small lump.

I knew men could get breast cancer, but I thought the likelihood of me having it was so low that I didnt do anything about it. It wasnt until a few months later when my wife playfully slapped me on the chest and felt the lump, which had grown substantially larger by this point, that I visited the GP.

My GP didnt think it was anything to worry about either, but he referred me to the hospital just in case, and a biopsy then confirmed I had stage 3 breast cancer.

I was treated pretty quickly. Just two weeks after my diagnosis, Id had a mastectomy, and then I went on to have chemotherapy and a lymph node clearance, followed by radiotherapy.

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With all the treatment over, I was getting back on the road to fitness and starting to move on, but it was then recommended I go for genetic testing.

Although we didnt know anything further back in the family history, my sister had recently had breast cancer and so the team in the breast clinic, and the nurse in particular, were very keen for me to get checked out.

The nurse explained what it all meant, and I thought it would be a good thing to do. I had the test and, when the results came back, they showed I had the BRCA2 mutation.

I called my sister straightaway, and she immediately decided to get tested.

The BRCA2 gene was discovered by scientists at the ICRin the 1990s and found to increase the risk of prostate and ovarian cancer, as well as breast cancer in both men and women.

My sister and her daughter have now both tested positive for the BRCA2 mutation, and my niece has chosen to get a double mastectomy as a preventative measure, which I think is incredibly brave of her.

When I got my test results back, it was explained to me that I was now at an increased risk of developing prostate cancer, and my consultant encouraged me to join the IMPACT study,which offers regular screening to men carrying mutations in BRCA1, BRCA2 or the Lynch Syndrome genes MSH2, MSH6 or MLH1.

Since joining the study, Ive been going for annual PSA checks, and just over two years ago it was discovered my PSA had gone up to 3.8, whereas normally it was 2.4.

Our scientists are renowned for their success in improving treatments for men with prostate cancer. Our wide-ranging programme of research has delivered huge benefits for patients helping men to live longer, improving their quality of life and increasing cure rates. Learn more about the latest updates on our prostate cancer research:

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The result wasnt that high but, because I was on the IMPACT study, I was referred straightaway and I then got a diagnosis of prostate cancer.

Ive since had 37 sessions of radiotherapy for my prostate cancer and am now on the hormone therapy goserelin, which Ill have every 12 weeks for the next three years.

Being told I had the BRCA2 mutation effectively saved my life. I dont think a PSA of 3.8 would have been enough for my GP to have referred me, and the prostate cancer could have been too far gone by the time it showed itself in symptoms.

I feel pretty lucky. Thanks to discovering I had the BRCA2 mutation, my prostate cancer was caught early, and I was able to receive the treatment I needed and get straight back to my normal life.

At the start of this year, my wife and I were travelling around New Zealand. The outbreak of coronavirus has obviously put a stop to any further travels since then, but were already planning our next adventures together and Im looking forward to carry on living the life I want with her by my side.

Our researchers identified the BRCA2 gene, which enabled families with a history of cancer to be assessed for future risk, and laid the groundwork for developing novel forms of therapy for BRCA-associated cancers. Learn more about our work related to BRCA genes:

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Science Talk - Being told I had the BRCA2 mutation effectively saved my life Tony's story - The - The Institute of Cancer Research

A new and versatile research presentation depicting key milestone developments in the global Predictive Genetic Testing Market has been added to the recent fast-growing data archive, which provides players with descriptive inputs on key market developments, trends and high revenue generation and overall guiding supplier activity. The report is carefully contrasted to cover all important aspects of the market development, continuing to strengthen the vitality of participants in the global Predictive Genetic Testing Market and to encourage unbiased market decisions amid fierce competition. The report maintains and leads the market by investing in strategic planning and investment discretion, maximizing high returns, balancing various market-specific developments such as inventory management, consumption and production development design, and motivating accurate advertising and promotional content. Designed to defend. Position in the fierce competition of the global Predictive Genetic Testing Market.

Essential Key Players involved in Global Predictive Genetic Testing Market are:

Agilent, Technologies, Inc., BGI Genomics, F.Hoffman-La Roche Ltd., Genes In Life., Invitae Corporation, Illumina, Inc., 23andMe, Myriad Genetics, Inc., Pathway Genomics and Thermo Fisher Scientific, Inc.

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Predictive Genetic Testing Market SegmentationType Analysis of Predictive Genetic Testing Market:

by Types (Predispositional Testing and Presymptomatic Testing), by Demographics (<35, 35 ? 64 and 65+)

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Global Predictive Genetic Testing Market: Key Products1. Overall Predictive Genetic Testing Market Overview Summary2. Comprehensive Analysis Survey3. A systematic reference to recent and past market developments4. Growth prognosis by dominant segment and area completed with sub-segment presentation5. Clear view of current and past growth milestones through Predictive Genetic Testing Market size estimates6. Details of company references and strategic recommendations to diversify market presence.

Major Topics Covered in this Report:1. Study Coverage2. Executive Summary3. Predictive Genetic Testing Market Size by Manufacturers4. Production by Regions5. Consumption by Regions6. Predictive Genetic Testing Market Size by Type7. Predictive Genetic Testing Market Size by Application8. Manufacturers Profiles9. Production Forecasts10. Consumption Forecast11. Upstream, Industry Chain and Downstream Customers Analysis12. Opportunities and Challenges, Threat and Affecting Factors13. Key Findings14. Appendix

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Predictive Genetic Testing Market Business Opportunities, Leading Players, Trends Outlook Up to 2025Agilent, Technologies, Inc., BGI Genomics,...

SAN DIEGO, Dec. 23, 2020 (GLOBE NEWSWIRE) -- Bionano Genomics, Inc. (Nasdaq: BNGO) announced the publication of a study by the Human Genome Structural Variation Consortium (HGSVC) revealing that their sequencing method based on PacBio HiFi reads detected only 72% of the large SVs that Bionanos optical genome mapping (OGM) detected across 32 different human genomes. The consortium developed its custom sequencing method by combining sequencing with PacBio and the single-strand prep and sequencing method StrandSeq to establish a comprehensive catalog of human SVs with base-pair and haplotype resolution. The cost of this method is estimated, based on list pricing, to be between $10,000 and $20,000 per genome. OGM with Saphyr, which costs less than $500 per genome, was shown to be significantly more sensitive than the sequencing method.

Many of the SVs missed by the sequencing technologies overlapped with complex regions of the genome that cause microdeletion and microduplication syndromes, which are highly relevant clinically owing to their involvement in neurodevelopmental disorders. The analysis primarily focused on insertions and deletions, which are considered to be easier for sequencing to detect. Other studies have shown that OGM significantly outperforms sequencing for detection of other SVs, such as inversions and translocations, which are also highly clinically relevant, especially in cancer.

The publication did classify some large SVs as being uniquely detected by the sequencing-based method based on PacBio HiFi. Upon further analysis, however, most of these SVs were in fact identified by OGM, but classified differently. Overall, less than 2% of the large SVs detected by PacBio were missed by OGM.

Erik Holmlin, Ph.D., CEO of Bionano Genomics commented, This publication outlines one of the most comprehensive side-by-side comparisons of PacBio sequencing and Bionanos OGM for large SV detection. The unparalleled performance of Saphyr is remarkable because the Bionano data were generated on our commercially available Saphyr system and analyzed using its automated pipeline for a variable cost per genome of less than $500. With the latest update to Saphyrs software released this week, the instrument can now generate clinical quality SV calls on 12 samples per day per instrument and up to 96 samples per week.

Something else worth noting in these studies is that longer read lengths improve the accuracy of SV calls. With PacBios focus on matching Illumina-like read quality, their HiFi reads are significantly shorter than their traditional long-reads. By contrast, Saphyr images molecules that are consistently 20 to 30 times longer than PacBio reads. Sequencing reads are not getting longer, which we believe implies that Saphyr will remain the only effective and affordable technology currently capable of detecting the structural rearrangements in the genome that are involved in disease.

The publication is available at https://www.biorxiv.org/content/10.1101/2020.12.16.423102v1

About Bionano GenomicsBionano is a genome analysis company providing tools and services based on its Saphyr system to scientists and clinicians conducting genetic research and patient testing, and providing diagnostic testing for those with autism spectrum disorder (ASD) and other neurodevelopmental disabilities through its Lineagen business. Bionanos Saphyr system is a platform for ultra-sensitive and ultra-specific structural variation detection that enables researchers and clinicians to accelerate the search for new diagnostics and therapeutic targets and to streamline the study of changes in chromosomes, which is known as cytogenetics. The Saphyr system is comprised of an instrument, chip consumables, reagents and a suite of data analysis tools, and genome analysis services to provide access to data generated by the Saphyr system for researchers who prefer not to adopt the Saphyr system in their labs. Lineagen has been providing genetic testing services to families and their healthcare providers for over nine years and has performed over 65,000 tests for those with neurodevelopmental concerns. For more information, visitwww.bionanogenomics.com or http://www.lineagen.com.

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) convey uncertainty of future events or outcomes and are intended to identify these forward-looking statements. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, Saphyrs continued position as the only effective and affordable technology capable of detecting structural variations in the genome that are involved in disease. Each of these forward-looking statements involves risks and uncertainties. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks and uncertainties associated with: the impact of the COVID-19 pandemic on our business and the global economy; general market conditions; changes in the competitive landscape and the introduction of competitive products; changes in our strategic and commercial plans; our ability to obtain sufficient financing to fund our strategic plans and commercialization efforts; the ability of medical and research institutions to obtain funding to support adoption or continued use of our technologies; the loss of key members of management and our commercial team; and the risks and uncertainties associated withour business and financial condition in general, including the risks and uncertainties described in our filings with the Securities and Exchange Commission, including, without limitation, our Annual Report on Form 10-K for the year ended December 31, 2019 and in other filings subsequently made by us with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management's assumptions and estimates as of such date. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.

CONTACTSCompany Contact:Erik Holmlin, CEOBionano Genomics, Inc.+1 (858) 888-7610eholmlin@bionanogenomics.com

Investor Relations Contact:Ashley R. RobinsonLifeSci Advisors, LLC+1 (617) 430-7577arr@lifesciadvisors.com

Media Contact:Darren Opland, PhDLifeSci Communications+1 (617) 733-7668darren@lifescicomms.com

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Publication Reveals in Side-by-Side Comparison that Method Using PacBio Sequencing Detects Only 72% of the Large Structural Variants Detected by...

The primary aim of the globalDTC Genetic Testing Marketresearch report is to evaluate, describe, and forecast the DTC Genetic Testing market globally based on the various factors like organization size, region, service, application, segments, deployment mode, and verticals. The global DTC Genetic Testing market research report distinctly evaluates every segment {Disease Risk and Health, Ancestry or Genealogy, Kinship, Lifestyle}; {On-line Sales, Doctors Office} influencing the growth factors, restraining factors for the growth, contribution to the total DTC Genetic Testing market and the future developments.

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DTC Genetic Testing Market COVID-19 Impact Analysis

The outbreak of COVID-19 was sudden and was not at all considered so dangerous when it first struck at Wuhan city of China. Although, everything in that city was closed but the coronavirus infection had wide spread in China as a wild fire. Within months it spread to the neighboring countries and then to every single country in the world. The World Health Organization announced it as a pandemic and till then it had created huge losses in several countries.

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Summary

The global DTC Genetic Testing market research report gives a comprehensive data and analysis about the worldwide market. The report further gives the data that one could rely on; which comes with in-depth analysis of DTC Genetic Testing market. Different factors like in-depth description of DTC Genetic Testing market, growth factors, segmentation, regional analysis, sales, supply, demand, manufacture analysis, recent trends, and competing companies are included in the DTC Genetic Testing report. The exquisite data provided in global DTC Genetic Testing market research report is explanatory in terms of quantity as well as quality.

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All the major players Color Genomics, Laboratory Corporation of America, MapMyGenome, Gene by Gene, 23andMe, African Ancestry, Helix, WeGene, Myriad Genetics, Pathway Genomics, Quest Diagnostics, Thermo Fisher leading in the DTC Genetic Testing market are mentioned in the report along with their regions-wise dominance.

A detail region-wise segmentation is also been involved in the global DTC Genetic Testing market research report to make a clear.

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Global DTC Genetic Testing Market Growth Graph To Demonstrate Inclination Towards Positive Axis By 2026 - The Courier

FIRTH The annual Adams Connection Snake River Valley Genetics Bull Sale has evolved over five decades, but what remains constant is the continued commitment to raising high-quality Black Angus and Lim-Flex registered cattle.

The first sale was held in 1969 by Bob and Opal Adams in Leadore. Their son Chet and his wife Phyllis joined the sale in the mid-1970s. After the untimely death from a drowning accident of the elder Adams, Chet and Phyllis carried on the tradition and moved the sale to Blackfoot, near their Firth-area ranch.

In the years since, Chet and Phyllis labored to improve each years sale. Their commitment to integrity and raising top quality cattle became their main focus. Sadly, Phyllis passed away last year after a long battle with Alzheimers.

She was an integral part of the ranch and sale. Ours was a team effort. Her unwavering contribution and partnership is greatly missed, Chet said.

Eight years ago, the Arnold and Teresa Callison family of Rimrock Angus in Blackfoot and the Wade and Vicki Beckman family of Beckman Livestock in Roberts joined the Adams Connection Snake River Genetics Bull Sale.

The 2021 sale will be Wednesday March 3, beginning at 1 p.m., at the Blackfoot Livestock Auction Company at 93 Rich Lane. Producers can also bid online at LiveAuctionsTV. The sale attracts producers from around Idaho and surrounding states. Seventy-six Black Angus Bulls and 22 Lim-Flex Bulls will be sold. Lim-Flex bulls are a cross between a Limousin and a Red or Black Angus.

Until last fall, heifers and cows were sold during the annual sale in Blackfoot. Last October, Adams, Callison and Beckman started their first annual all-female sale called, The Gems of Idaho Female Sale, featuring 42 head of Lim-Flex and Black Angus open heifers, bred heifers and cows.

The 2021 sale will be held at the new Bonneville County Fairgrounds at 1542 East 73rd South in Idaho Falls on Saturday October 30th.

Our first female fall sale was a success. Cattle sold into seven states as well as locally, Adams said.

Each animal has behind him or her years of genetic improvement, which is proved out with DNA, ultrasound and performance testing, Adams said.

Technology has really changed the whole schematics of breeding and is another tool to help us. We put a lot of emphasis on performance and balanced expected progeny differences (EPD), including strong maternal values. As we continue to forge the genetic link, our goal is to breed sound cattle with a lot of capacity, length, good feet and udders, Adams said, and Beckman added, And with the access we have to artificial insemination, its unlimited in what genetics we can try, and we do.

Altogether the families represent about 150 years of experience in the seed stock livestock business. Each grew up on ranches, were in 4-H, FFA and Junior Angus shows.

We were all born and raised on ranches. We all work closely together and have the same philosophies of raising quality seed stock. They are all really good people to work with, Chet Adams said, and Arnold Callison added, We like cattle, and its a bad addiction that we cant get out of.

The secret to their success is improved genetics which helps to improve the herds of the commercial cattle producer, along with an emphasis on personal integrity.

If a buyer has a problem with one of our bulls, we fix it. We take care of our customers, Adams said.

For more than 30 years, Adams was a teacher and administrator in schools in Firth, Alaska and Shelley. Along the way, he and Phyllis purchased neighboring ranches, expanding their land holdings and cow herd in East Idaho.

We lived on my principals salary, and put all the profit we made from the ranch back into it. Its something we enjoyed. We had a goal and we went after it, Adams said.

Callison worked on the Pat Goggins family's Vermillion Ranch in Billings for several years before returning to lease Adams ranch while the Adams were in Alaska. Today, hes the vice president and a loan officer at the Bank of Commerce in Blackfoot.

The Pat Goggins family's Vermillion Ranch is the largest Angus operation in the world and theyre great people, Callison said. Were still friends, and I picked up auctioneering from them too.

Each year, Callison volunteers his auctioneering talents to about 10 4-H and FFA auctions and about 25-35 community fundraisers like the annual Christmas Tree Fantasy in Blackfoot.

The opportunity to lease Chets place gave us a chance to come back here where Teresa and I are from. Weve always stayed close and have worked together quite a bit, he said. And auctioneering has been really fun, I really enjoy it.

Their children are activity involved in the cattle operation. Tiffany and Jered Hansen are in charge of marketing, Darrell and Jenny Callison help with the cattle, and have their own herd called Western Skies Angus. Mark and Charissa Callison are the computer experts, Callison said.

Our kids and grandkids have never been to Disneyland or Disney World, but they have been to every livestock show there is, Callison said. Our grandkids Angie and Conner are very active in the operation and our newest granddaughters, twins Maisy and Elaina will have the same opportunity.

The Beckmans have raised both commercial and registered cattle in the Roberts area and also raise cattle for 4-H and FFA exhibitors. In 1979 the Beckmans purchased their first Limousin bull and were so impressed they found themselves in the purebred industry, Wade said. In 2000, they incorporated Lim-Flex cattle into their operation.

The hybrid advantage is huge. These genetics have helped us to create the ultimate beef machine, the feeders and packers love them, Beckman said. This is something we take a lot of pride in. Were not high-end guys who dont know which end of the cow the hay goes in.

Wade currently serves on the board of the North American Limousin Foundation and his wife Vicki Beckman manages the day-to-day cattle operation along with their son Sedar. Sedar and his wife

Danna Beckman along with daughter Winston are partners in the operation. Sedar and Danna have degrees in Sustainable Agriculture from the University of Wyoming in Laramie, WY. Danna Beckman is the manager of the DL Evans Bank in Rigby.

Their daughter Devori has a masters degree in breeding and genetics from Colorado State University. Shes a co-manager of a Walmart store in Nebraska. Shes married to Dr. Matt Spangler, a professor of Animal Science and Beef Genetics Extension Specialist at the University of Nebraska in Lincoln, NE., and along with their son Jack, contribute the latest genetic research to the ranch operation.

Chet and Phyllis dont have an heir to take over the family business. Their youngest son who was the most interested in ranching died in a plane crash in 2000. Their daughter, Lisa Adams lives in Boise and another son, Eric Adams, is a doctor of chiropractic medicine in Idaho Falls.

I love this business. I always have. Im not ready to quit yet, Chet Adams said, and Callison added, Wade and I are increasing our herds so that when Chet cuts down we can pick up a bit.

All three families look forward to the annual auction.

One of our favorite days of the year is sale day, Callison said. If I could work as hard as my wife Teresa, I could run two ranches on the side. Its enjoyable to be surrounded by family and visit with old friends, and we serve the best lunch and cookies in the land.

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East Idaho ranchers find strength in unified bull auction - Post Register

People who experience a burning sensation in the lower abdomen may have a condition of the urological, gynecological, or digestive system.

Causes of a burning sensation in the lower abdomen may include gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), kidney stones, certain gynecological conditions, and cancer.

People should note that a burning sensation in the lower abdomen is not common. It is more common in the upper abdomen, where the pain is usually associated with GERD or PUD.

A burning sensation in the lower abdomen often comes with urination, which means that it may be a urinary tract infection (UTI). However, a UTI may not present with any abdominal pain. For females, there are multiple gynecological conditions associated with lower abdominal pain that might feel similar to burning.

There are other conditions that could be associated with a burning sensation in the lower abdomen. People should talk with a doctor about their symptoms.

Keep reading to learn more about the possible causes of a burning sensation in the lower abdomen, including any associated symptoms and how to treat them.

A burning sensation in the abdomen may be a symptom of GERD, which is a chronic condition affecting the digestive system. It is one of the most common digestive conditions in the United States.

Doctors can identify certain risk factors for developing GERD. For example, some people have motor anomalies that affect the movements of the esophagus. This can affect the ability of the esophagus to clear its contents.

Another possible risk factor is dysfunction of the lower esophageal sphincter, which can allow acidic stomach contents to rise up through the esophagus.

Aside from a burning sensation in the abdomen, people with GERD may experience:

Doctors may recommend several strategies to treat GERD, including certain lifestyle changes, medications, surgery, and endoluminal therapy.

They may first recommend the following self-care strategies:

It may also help to avoid the following potential trigger items, though the research into the effectiveness of avoiding them is limited:

Instead, a doctor may simply advise a person to avoid foods and beverages that they know worsen their symptoms.

Some medications that can help treat GERD include histamine blockers and proton pump inhibitors (PPIs).

For people with severe symptoms that do not respond to the above self-care strategies or medications, surgery or endoluminal therapy may be necessary.

People with PUD may also experience a burning sensation in the abdomen.

Doctors will diagnose PUD when the inner lining of the stomach, small intestine, or lower esophagus becomes compromised by stomach acid secretions or pepsin. This is an enzyme that breaks down protein.

Doctors have identified several factors that may cause PUD, including:

Smoking may also play a role in intestinal ulcers, while alcohol consumption can irritate the stomach and promote gastric acid release into the stomach.

People with PUD experience upper abdominal pain, right below the ribs, about 1530 minutes after eating a meal. If the person has an ulcer in the small intestine, the pain may only begin 23 hours after a meal.

Some other signs and symptoms of PUD include:

The following warning signs require immediate emergency care and a consultation with a gastroenterologist:

Doctors will treat PUD with medications or surgery. The options for medication therapy include the same drugs often recommended for GERD. PPIs are the preferred treatment because their action is superior to that of histamine receptor antagonists.

If a person tests positive for H. pylori infection, they may require antibiotics. The treatment for H. pylori infection includes two antibiotics and a PPI. People whose conditions do not respond to this protocol may require a quadruple therapy with bismuth and different antibiotics.

If possible, some doctors may recommend that people stop taking medications that contribute to PUD. However, people should not stop taking any medications without first seeking the advice of a doctor.

People with refractory disease that does not respond to medication may require surgery.

People develop kidney stones when a crystal, usually comprising calcium, travels from the kidney through the urinary tract. Kidney stones do not always cause problems and health complications, but some can get stuck and lead to medical issues.

Some risk factors for kidney stones include:

People with kidney stones may not experience any symptoms. The most common symptom of kidney stones is a sharp pain radiating to the groin when the stone begins traveling down the ureter. People may describe this pain as dull, colicky, sharp, or severe.

Some individuals may feel nauseous or vomit because of the pain. Blood in the urine is also common. Some people may also report a burning sensation when urinating.

Doctors may need to prescribe pain relief medications, since passing a kidney stone is often very painful. People may also take NSAIDs to help with pain. Increasing fluid intake is also important.

Tamsulosin is a drug that helps people pass kidney stones; it reduces the stimulation of the smooth muscle in the urethra.

If a doctor finds a kidney stone that is 6 millimeters or larger, they may need to intervene to manually remove it from the urinary tract.

UTIs are bacterial infections of the urinary bladder. Doctors categorize UTIs as either complicated or uncomplicated. An uncomplicated UTI occurs in people who are otherwise healthy and not pregnant.

The most common bacteria that cause UTIs include:

People with a UTI may experience:

People who are very young or old may experience subtle or unusual symptoms. For example, older adults with a UTI may present with confusion or an altered mental state.

The symptoms of a complicated UTI are usually similar to those of an uncomplicated UTI.

Doctors treat UTIs with antibiotics. To select the most appropriate antibiotic to treat the infection, the doctor will consider the persons risk factors for infection with a pathogen that is resistant to multiple drugs.

People with a low risk may receive a first-line therapy such as:

Learn more about UTIs here.

Different gynecological conditions can cause pain in the lower abdomen that might feel like a burning sensation. These conditions may include:

During ovulation, a fluid filled sac, or cyst, may form on an ovary. Most are benign, but they can sometimes rupture and require intervention.

Painful menstruation, or dysmenorrhea, refers to pain during menstruation without a disease of the pelvis. Sometimes, other conditions can cause painful periods.

Endometriosis is a chronic condition of the female reproductive system wherein the tissue that normally lines the uterus grows in other parts of the abdomen.

The following table lists some of the symptoms associated with ruptured cysts, painful menstruation, and endometriosis.

Depending on the diagnosis of a burning sensation in the lower abdomen with a gynecological cause, a doctor will select the most appropriate treatment.

The following table lists some treatment options for causes of a burning sensation in the lower abdomen.

Certain cancers of the digestive, urological, and gynecological tracts may present with pain in the lower abdomen.

Depending on the type of cancer, people may experience different symptoms. However, the condition may also go unnoticed.

Although cancer is more common in older adults, anyone with troubling symptoms should arrange an evaluation by a doctor.

The following table lists some warning signs and symptoms of urological, digestive, and gynecological cancers.

Different types of cancer require different treatments. These may include surgery, radiation therapy, and chemotherapy. Surgery aims to remove the cancer tissue, whereas chemotherapy and radiation therapy use medications or high energy rays to kill cancer cells.

Doctors may select a treatment based on the cancers location and stage. Sometimes, people may require a combination of treatments.

People with digestive cancers may also receive targeted therapies and immunotherapy.

People who experience a burning sensation in the lower abdomen may have a digestive, gynecological, or urological condition.

By investigating the other associated symptoms and the persons medical history, doctors can diagnose a burning sensation in the lower abdomen and choose the most appropriate treatment option for it.

A doctor may also consider some other abdominal conditions, especially in older adults. These may include cancers of the gastrointestinal, gynecological, or urological systems.

Be sure to contact a doctor for a complete evaluation to determine the correct diagnosis and receive the appropriate treatment.

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Burning sensation in lower abdomen: Causes and treatments - Medical News Today

A Council Grove native who took down a mountain goat earlier this fall in southeast Alaska can now lay claim to a world record.

Kaleb Baird, 33, a Council Grove High School graduate, shot the massivebilly goat on Sept. 11 of this year. On Dec. 5, the Pope and Young Club convened a special panel of judges in Prescott, Ariz., to measure the potential world record, and the judges scored the goat at53 4/8 inches, making it the largest bow-harvested mountain goat in North America by just two-eighths of an inch.

The previous record was set just10months prior, on Feb. 15, by fellow Alaskan Rosey Roseland. Roseland'sgoat was taken onRevillagigedo Island in Alaska and measured53 2/8 inches officially.

"Congratulations to Kaleb Baird on his very special Rocky Mountain Goat, and the Pope and Young Club's new World Record," Eli Randall, director of records for the Pope and Young Club, said in a news release shortly after Baird'srecord goatwas scored.

Randall said Baird's goat was the third Rocky Mountain goat to meet the criteria to go through a special panel in the last 12 1/2 months.

Baird's goat will be on display at the Pope and Young's Biennial Awards Convention from April 14-17, 2021, in Reno, Nev. The event marks the 60th anniversary of the club.

Baird now joins Paslie Werth, of Cimarron, and Brian Butcher, of Andover, as recent Kansans to harvest world-class animals.

Werth, 14, set a Boone and Crockett world record with her 42-point whitetail buck shot Sept. 6, pulling in a net score of 271 4/8 inches following a mandatory 60-day drying periodto secure her deer's place in history as the largest nontypical whitetail harvested by a female in the world, as well as making her the youngest record holder in Kansas. The deer is currently the fifth-largest buck of any kind taken in state history, and broke Jamie Remmers' 23-year-old state record for largest nontypical whitetail harvested by a female at 257 1/8 inches.

"The Butcher Buck," meanwhile, is perhaps the most legendary rackin the state. The gnarly, 67-point nontypical spread unofficially measured an astounding 321 3/8 inches last October when it was taken in Chase County. The deer is set to be officially measured in 2022 and is thought to be good for the fourth-largest nontypical deer ever taken.

Kaleb's father Ken Baird, a 1969 Topeka High graduate who now lives in Manhattan, got him started on the sport at a young age when they lived in Council Grove.

"When he was knee-high to a grasshopper, I'd take him pheasant hunting," Ken said. "He started real young."

Council Grove also was where Kaleb got his start in bowhunting, as he would go deer hunting each year. But the Bairds soon began to expand their journeys as Ken started working in Alaska.

"I had a fishing boat for quite a few years up in Alaska and I thought I'd start taking him up there in southeast Alaska, and he just has always loved to hunt," Ken said. " ... How I got started up in Alaska is when I graduated from Topeka High, I went to the University of Alaska, and I met a bunch of guys up there. Always kept going back up there."

He said there's nothing else quite like the wilderness in the 49th state.

"They call it the Last Frontier, and it really is," Ken said. "It's beautiful country."

Kaleb joined his father in the Alaska fishing industry in 2014, and would go back and forth from Council Grove for nearly fiveyears before moving up to Petersburg, Alaska, early last year as a full-time resident. He said he mainly fishes commercially for salmon.

After gaining residency, Kaleb put in for a lottery permit for a "pretty unique" mountain goat herd. About 150 hunters applied for the permit last year, and the stategave out just two billy tags. And as luck would have it, Kaleb got a tag.

Mountain goat season in Alaska runs Aug. 1 through the end of the year, meaning he had some time to plan his goat hunt.

Between COVID-19, his hectic work schedule and the uncertain weather, however, Kaleb couldn't line anybody up to go with him, so he decided to go alone in the second week of September.

That meant when he finallydid shoot his trophy billy goat in September, he had a long haul to get it back home a journey that lasted about almost three days in bear country, according to Kaleb's father.

Kaleb, who lives on a remoteisland in the southeast part of Alaska, had to get a water transporter to get to the even more remote hunting area a stretch of mainland just north of Ketchikan. He said the ride was about two hours from his island.

He hiked up the mountain with about eight days of supplies on his back.

"I hadn't been in this country before," Kaleb said. "I'd talked to some biologists and guys who had hunted it years and years ago. This hunt was closed for a lot of years and this was the reinitiation, I guess, was these two billy tags they allowed for this year.

"I didn't really know what to expect."

On the fourth day, Kaleb spotted his goat. It took him about a half-day to get up the mountain to where he needed to be. By the time he got where the goat was when he started, it had already relocated, meaning he had to keep moving.

"I did find him and another smaller billy together late in the afternoon when I was about to give up," Kaleb said. "It worked out, I just kind of stumbled into him at 30 yards. Put a good shot on him, and he decided he was going to dive off into a big avalanche chute and dropped about seven- or eight-hundred foot in elevation probably in a matter of seconds."

It took Kaleb a couple hours to get down to the goat after it fell. Once he reached it, he was able to quarter it up and pack away the meat. In Alaska, he said, you've got to salvage all the edible meat, which includes "neck meat, tenderloins, backstraps, ribs, everything."

"Then the real work began," Kaleb said.

From where the goat ended up after getting shot in the avalanche chute, Kaleb said, there was another 600- to 700-foot decline that was quite treacherous.

"I knew I couldn't go back up the hill with him, my only option was to go down, but I didn't know exactly what was below," Kaleb said. "So I took him all at once. What I did was, I basically just tied all the meat bags together and I would kind of throw them in front of me a little ways and then I'd step down a couple steps and lower the meat down."

To make matters worse, he was trying to get down the mountain in darkness, as he had reachedthe goat around5 p.m. and the sun set around 7:30 p.m. He began running out of steam, and decided to set up camp for the night on a ledge with his meat. The next morning, when he resumed his descent, he was met with an unexpected visitor.

"That's when I came across a black bear that had found the carcass up above me from the night before," Kaleb said. "The chute was super narrow and steep, and it was inevitable that we were going to cross paths.

"But he didn't give me too much of an issue. I let him know I was around and he went on his way and I went on mine."

Before his trip, Kaleb had joked with his friends that he was going to shoot a record goat.

While it may seem like a premonition, it was actually just an educated guess.

"This particular goat herd, it had been known back 20, 30 years ago for some of the biggest billies to come out of the state of Alaska," Kaleb said. "And then they closed the hunt. It was kind of an isolated herd that they wanted to do some studies on and monitor for a while. There was some logging going on in the area and a few other reasons.

"This herd just has abnormally large horn genetics, so going in I knew with the caveat it hadn't been huntedin 16, 18 yearsit was kind of a double whammy that the potential was there for a really big billy."

As this was his first real mountain goat hunt, he said he was by no means a field judge and really didn't know when he saw the goat that it was a potential world record. He said the smaller billy that was with his goat gave him some perspective as far as it being a good-sizedgoat, but other than that he didn't know for sure.

However, before he went on his hunt, he had to study up, taking an online course on identification and studying online what he was looking for in a trophy goat.

"It was obvious this billy had some incredible mass when I first found him," Kaleb said. "... I had a pretty good idea this was a pretty substantial billy."

And as massive as the goat's horns were, they were actually damaged a little by the fall, as Kaleb said it clippedabout an inch off the right side.

Aside from mountain goats, Alaska has a variety of big game species to pursue, including bear, moose, Sitka black-tailed deer and elk.

And as luck would have it, Kaleb actually drew an elk tag this year, as well as his goat tag.

"Because of this goat hunt, that was kind of first and foremost," Kaleb said. "It took up most of my free time. I'd love to get another crack at hunting elk here, it's kind of neat. It's a really tough area to hunt."

Read more:
World-record mountain goat shot with bow by Kansas native in Alaska - The Topeka Capital-Journal

A well attended online Campus course staged by the SIG Reproductive Genetics heard that the expansion of sequencing analysis is poised to push forward the development of cost-effective preconception tests able to identify several underlying genetic causes of infertility

The everyday implications of preconceptional medicine have so far been largely evident in lifestyle advice conducive to successful pregnancy, but a well attended online Campus meeting staged in December suggests that genomic medicine has an increasingly important role to play. Sessions at the meeting not only covered the much debated subject of genetic risk assessment by expanded carrier screening, but explored the application of genome-wide sequencing in recurrent miscarriage, in predicting ART outcomes from parental genome analysis, and even in explaining the different responses to ovarian stimulation with gonadotrophins. Such subjects, especially expanded carrier screening, are not without their ethical problems, notably in the disclosure (or not) of secondary findings, so it was also appropriate at this meeting to hear a preview of ESHREs forthcoming recommendations on expanded carrier screening in ART.

In his opening lecture Stphane Viville, a former coordinator of ESHREs SIG Reproductive Genetics, said that known genetic and chromosomal factors account for around 20% of all infertility cases, with three additional (and relatively unknown) phenotypes now moving into active research: POI, oocyte maturation defect, and preimplantation embryonic lethality, all of which were covered at this meeting. Viville added that so far at least 21 genes have been implicated in POI and advised that genetics is now getting more and more into IVF labs and no longer confined to chromosomal aberrations or microdeletions on the Y chromosome.

Much of the content of this Campus course has been explored in detail in a recent Human Reproduction Update review, whose first author, Antonio Capalbo, is deputy of ESHREs SIG Reproductive Genetics and an organiser of this course.(1) In the review, as was repeatedly implied at this meeting, Capalbo et al note that the expansion of sequencing analysis may enable the development of cost-effective preconception tests capable of identifying underlying genetic causes of infertility, which until now have largely been defined as idiopathic.

One such step in this move towards a more positive and personalised approach to preconceptional medicine is in genetic risk assessment by expanded carrier screening, which occupied a large section of this meeting. James Goldberg, prominent in the development of ECS, said its availability now steps beyond the disparities and restrictions of ethnicity-specific screening and aims to inform couples about their risk of having children with autosomal recessive and X-linked recessive disorders and thereby to support informed decision making. Nevertheless, two of the current guidance statements on ECS cited by Goldberg both from the USA are largely based on ethnicity screening with an emphasis on cystic fibrosis and spinal muscular dystrophy. ECS, said Goldberg, represents a more equitable approach to identifying risk. Such risk assessment in both the general population and IVF couples - will allow identification of those who carry recessive mutations, and thereby provide increased reproductive autonomy to couples deemed at risk and where PGT is available for embryo selection.

However, when a publicly provided ECS programme was set up in Amsterdam offering a test panel of 50 genes (at a cost of 650 euro per test) and following the guidance of the European Society of Human Genetics, there was a relatively quiet response (20%) from the general risk population, and higher (80%) from the high risk population.(2) Nevertheless, assessment of the programme, began in 2016, appeared to raise more questions than answers, and no clear resolution of how such a programme might be best provided. Capalbo and his fellow Update reviewers concluded that ECS represents one of the most effective and advanced applications of preconception genomic medicine worldwide today and is expected to grow in application in coming years.

The preview of recommendations from ESHREs Ethics Committee was specifically about ECS ahead of ART (and not just involving gamete donors). Thus, asked Dutch bioethicist Guido de Wert, would the offer of ECS to all such applicants be proportionate, and if so, for what kinds of disorders and under what conditions? Applying the three ethicists principles of proportionality, respect for autonomy and justice, De Wert firstly noted that any possible benefits should clearly outweigh any possible harms, that ECS should still be embedded in a research framework, and that a couples access to ECS should only be on condition that they take preventive measures and apply for PGT, donor gametes, or, maybe, prenatal diagnosis.

Even the outcome of fertility treatments may well be affected by genetic mutations, and such extreme outcomes as oocyte maturation failure and embryonic developmental arrest are now investigated as a genetic cause of infertility. Indeed, Semra Kahraman from theIstanbul Memorial Hospital reported that variants in more than 2000 genes are now predicted to be involved in various infertility pathways. She described her own study in which 22 IVF patients whose repeated failure was attributed to oocyte maturation failure and embryo development arrest and who were investigated using whole exome sequencing panels. Family history analysis had also identified infertility and early menopause in the family of nine of the subjects. The analysis identified genomic variants in eight of the 22 subjects, including four genes known to be lethal at the embryonic stage.

With ovarian ageing identified as one of todays most frequent causes of infertility, John Berry, an MRC investigator from Cambridge, reported in a keynote lecture that ten years ago population studies had identified four common genetic variants associated with menopause. Today, he added, there are now more than 300 loci identified, which explain around 10% of the heritable component. Too few to be clinically useful? he asked. Again, there appeared more questions than answers, notably if POI can be explained solely by monogenic alleles and if menopausal age can indeed be predicted by genetics.

The conclusions from this meeting, as well as the increasing number of genes and variants identified, suggest that genomic assessment ahead of conception may have real clinical benefits at both the individual (in identifying genetic risks in the male and female partner) and the couple level (in allowing a specific reproductive prognosis). Information at this early stage may thus lay the basis for personalised interventions, and certainly make at-risk couples better informed of their reproductive choices.

1. Capalbo A, Poli M, Riera-Escamilla A, et al. Preconception genome medicine: current state and future perspectives to improve infertility diagnosis and reproductive and health outcomes based on individual genomic data, Hum Reprod Update 2020; doi:10.1093/humupd/dmaa044

2. Henneman L, Borry P, Chokoshvili D, et al. Responsible implementation of expanded carrier screening. Eur J Hum Genet 2016; 24: e1-e12. doi:10.1038/ejhg.2015.27

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The expanding role of genomics in preconceptional 'personalised' medicine - ESHRE

21 December 2020

Session three of the Progress Educational Trust (PET) annual conference explored the genetic and genomic links to susceptibility to severe COVID-19. Sarah Norcross, director at PET, opened the session with the unfortunate news that one of the speakers Dr Kri Stefnsson was unable to participate in the session due to illness.

The session was chaired by Dr Roger Highfield, science director at the Science Museum Group mild-mannered and a clear speaker, he chaired the session with ease. Dr Highfield introduced the first speaker Dr Sharon Moalem a scientist and physician who specialises in genetics. Dr Moalem is a bestselling author, with titles including: 'How Sex Works', 'Inheritance: How Our Genes Change Our Lives and Our Lives Change Our Genes', and 'The Better Half: On the Genetic Superiority of Women' (see BioNews 1050).

Dr Moalem focused his talk on the law of homogameity, and whether COVID-19 illustrates the genetic/genomic resiliency of women. He began by briefing the audience on the basics of mammalian genetics, how we have 46 chromosomes, one pair of which is sex chromosomes, containing either XX for a female, termed homogametic, or XY for a male, termed heterogametic. A system has arisen in females, where in each cell one X chromosomes is 'turned off', called X-inactivation or silencing. However, it has now been discovered that X-inactivation is not complete, and that about 25 percent of the second X chromosome is still active. Dr Moalem explained that this allows females to have more 'genetic horse power' within each of her cells.

X-linked conditions, such as fragile X, red-green colour blindness and Duchene muscular dystrophy, are more common in males, as men do not have another X chromosome. Females do not simply have a 'back up X', but in some cases their non-faulty gene produces and shares the required protein, essentially rescuing the cells containing the faulty gene, which would have died. In other cases, cells with such a mutation do not survive, but cell lines with the healthy X proliferate to compensate. This leads to tissues with an uneven distribution of active Xs, called X-skewing.

Moving onto COVID-19, why is the mortality rate for males higher than that for females? Dr Moalem proposed the law of homogameity, which predicts that the homogametic sex has a survival advantage across the life course. Females have a greater genetic diversity due to having an extra X-chromosome, which equates to 1000 more genes. The X chromosome contains many immune-related genes eg, TLR7 which is used by certain cells in the body to detect for single-stranded RNA viruses, like SARS-CoV-2, the virus which leads to COVID-19. As females have two variations of TLR7 they have two different immune cell populations to help detect the virus. However, there is a cost to homogameity increased autoimmunity, with 'long COVID' proving to be four times more common in women.

In the USA there is currently no requirement for drug approval from the FDA to use both male and female cells. Scientists can use just one sex, yet females' cells work in a corporative way. Dr Moalem believes there should be a completely separate drug approval process as many drugs behave differently in men and women.

Dr Highfield returned to introduce the second speaker Dr Qian Zhang a research associate at the St Giles Laboratory of Human Genetics of Infectious Diseases, at Rockefeller University in New York City. Dr Zhang's research specialises in inborn errors of immunity (IEIs) inherited disorders that impair normal immune development and function.

Dr Zhang focused her talk on type I interferon immunity in patients with life-threatening COVID-19 and began by explaining how early on in the pandemic it became clear that people infected with SARS-CoV-2 responded differently. Most were asymptomatic and developed either no or very mild clinical symptoms. A small proportion of patients developed life-threatening disease. This phenomenon is seen in all infectious diseases from bacteria, fungi and viruses.

Dr Zhang and her research team studied whether the same genetic mutations already known to be associated with life-threatening influenza infections also increase the risk of life-threatening COVID-19 pneumonia. There are three genes, TLR3, IRF7 and IRF9, in the type I interferon pathway that are mutated in people who develop life-threatening influenza. In addition, ten further genes, IFNAR1, IFNAR2, STAT1, STAT2, IRF3, UNC93B, TRIF, NEMO, TRAF3 and TBK1, are reported to affect severity of other viral infections.

Type I interferon is a cytokine and has 17 different subtypes, which lead to the stimulation of several hundred interferon-stimulated genes that have an antiviral function. Hence, if this pathway is disrupted by a genetic mutation, viruses are able to gain a foothold more easily.

Dr Zhang's team sequenced the whole of the genome of over 600 severe COVID-19 patients to determine whether they had mutations in any of these 13 genes and discovered over 118 variants, of which, 24 resulted in loss of function.

Four patients with autosomal recessive mutations causing a complete loss of function in IRF7 and IFNAR1had never been hospitalised before contracting COVID-19, much to Dr Zhang's surprise. IRF7 is a transcription factor that amplifies the antiviral signal of type I interferon, and IFNAR1 is one of two proteins that make the receptor for type I interferons. Patients with these mutations are unable to mount an interferon response to COVID-19 infection.

Dr Zhang reassuringly explained that these mutations are rare, less than one in 1000 in the population, as such they cannot explain why there are so many people dying of COVID-19. This led Dr Zhang to the second part of her research: studying whether auto-antibodies against type I interferons lead to the same phenotype as these rare mutations.

Over ten percent of patients with life-threatening COVID-19 make auto-antibodies against two of the type I interferons. These neutralising auto-antibodies can entirely block the protective effect of type I interferons, which may be the cause of severe COVID-19.

Surprisingly, 95 percent of patients with these auto-antibodies were male and only six were female. One of these female patients had incontinentia pigmenti (IP), which is caused by a NEMO mutation on the X chromosome, leading to skewed X-inactivation a perfect example of the genetic diseases Dr Moalem was discussing earlier in the session. Even though such patients have two X chromosomes, most of the tissues in their bodies express just one X chromosome, and so these females are more similar to males in terms of susceptibility.

Combining both parts of her research, Dr Zhang's team discovered that selected patients with TLR3 and IRF7 mutations could simply be treated with type I interferon. However, this treatment did not work for patients with IFNAR1 mutations because the receptor is absent, but treatment with wildtype IFNAR1 was successful. Unfortunately, neither treatment worked for patients with auto-antibodies.

In her opinion COVID-19 could be considered an X-linked disease, even though the candidate on the X-chromosome has yet to be discovered and furthermore, type I interferon immunity is essential to control COVID-19 infection.

Dr Highfield returned to update the audience on Dr Stefnsson's research, investigating the genetic code of each COVID-19 infection in Iceland, giving an insight into the origins, and how the infection was caught, spread and mutated. Surprisingly, a large number of cases came from the UK. Similar research in the UK has detected 1356 independent introductions of the virus, mostly due to inbound international travel a third came from Spain, over a quarter from France and 14 percent from Italy.

The session provoked interesting discussions within the Q&As, with the first asking Dr Moalem whether females are less severely affected by other viruses, which he concluded as true, particularly for influenza. But even for HIV-1, women are much better at clearing the virus and have a much lower viral load.

With a personal interest, I took the opportunity to ask Dr Zhang whether patients with type I interferon IEIs were more susceptible to severe COVID-19, as such a disease affects members of my own family. Dr Zhang confirmed that such patients are more likely to suffer with severe COVID-19 and had now tested 20 IP patients discovering at least a quarter had high levels of autoantibodies to type I interferons. She warned that these females should be very cautious and shield as much as possible, as any patient with auto-antibodies is very difficult to treat. Reassuringly, patients with certain genetic mutations that do not have high levels of autoantibodies to type I interferon can simply be treated early with interferon injections.

I will leave with a final comment from Dr Moalem: 'Men are more biologically fragile when compared to women.' Whoever said that women were the weaker sex?

PET would like to thank the sponsor of this session, the Anne McLaren Memorial Trust Fund, and the other sponsors of its conference - the Edwards and Steptoe Research Trust Fund, ESHRE, Wellcome, the European Sperm Bank, Ferring Pharmaceuticals, the London Women's Clinic, Merck, Theramex, Vitrolife and the Institute of Medical Ethics.

Originally posted here:
Correlation and Causation: What Can Genetics and Genomics Tell Us about COVID-19? - BioNews

PHOENIX, Dec. 16, 2020 /PRNewswire/ --Creative Medical Technology Holdings Inc., (OTC CELZ) announced today positive preclinical data supporting the utilization of its ImmCelz cell based immunotherapy for treatment of stroke. In an animal model of ischemia stroke, the middle cerebral artery ligation model, administration of ImmCelz resulted in 34% reduction in infarct volume, whereas control bone marrow mesenchymal stem cells reduced infarct volume by 21%. Additionally, improvements in functional recovery where observed using the Rotarod test. At 28 days after induction of stroke the animals receiving ImmCelz had superior running time (92% of non-stroke controls) compared to animals which received bone marrow mesenchymal stem cells (73% of non-stroke control). Animals that received saline had a running time that was 50% of non-stroke controls.

"The regenerative potential of immune cells that have been programmed by stem cells is a fascinating and novel area of research." Said Dr. Amit Patel, coinventor of ImmCelz, and board member of the Company. "Conceptual advantages of using reprogrammed T cells include higher migratory ability due to smaller size, as well as ability to replicate and potentially form "regenerative memory cells."

"This data, which is covered by our previous filed patents, such as no. 15/987739, Generation of autologous immune modulatory cells for treatment of neurological conditions, demonstrate that immune modulation via this stem cell based method may be a novel and superior way of addressing the $30 billion dollar market for stroke therapeutics1." Said Dr. Thomas Ichim, coinventor of the patent and Chief Scientific Officer of the Company. "The fact that this technology, which has priority back to 2017, is demonstrating such stunning results, motivates us to consider filing an Investigational New Drug Application for use in stroke."

Creative Medical Technology Holdings possesses numerous issued patents in the area of cellular therapy including patent no. 10,842,815 covering use of T regulatory cells for spinal disc regeneration, patent no. 9,598,673 covering stem cell therapy for disc regeneration, patent no. 10,792,310 covering regeneration of ovaries using endothelial progenitor cells and mesenchymal stem cells, patent no. 8,372,797 covering use of stem cells for erectile dysfunction, and patent no. 7,569,385 licensed from the University of California covering a novel stem cell type.

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

About Creative Medical Technology Holdings

Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in stem cell technology in the fields of urology, neurology and orthopedics and trades on the OTC under the ticker symbol CELZ. For further information about the company, please visitwww.creativemedicaltechnology.com.

Forward Looking Statements

OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website atwww.sec.gov.

Timothy Warbington, CEO[emailprotected] CreativeMedicalHealth.com

Creativemedicaltechnology.comwww.StemSpine.comwww.Caverstem.comwww.Femcelz.com

1 Stroke Management Market Size Forecasts 2026 | Statistics Report (gminsights.com)

SOURCE Creative Medical Technology Holdings, Inc.

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Creative Medical Technology Holdings Announces Successful Application of ImmCelz Immunotherapy for Treatment of Stroke - PRNewswire

New York, Dec. 21, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Organ and Tissue Transplantation and Alternatives" - https://www.reportlinker.com/p096592/?utm_source=GNW g., kidneys, liver, heart-lung, pancreas, intestines) and the tissue transplantation (e.g., bone, skin, cornea, heart valve) markets, along with the pharmaceuticals that accompany each market.

Also included are experimental xenografts and artificial organs; tissue transplants; and cell transplants (e.g., bone marrow, cord blood, peripheral blood, islet cell). The report touches on the use of fetal cells, stem cells and altered cancer cells.

The arrangement of this report offers an overview of the key elements in the transplantation process: tissue typing, procurement and preservation, immunosuppressants for solid organ and tissue transplants, and postoperative monitoring. International markets are discussed, and information is provided on industry structure and the regulatory environment.

Within each section are discussions of commercialization opportunities for each segment of the market. New or emerging devices, techniques and pharmaceuticals are highlighted.

Profiles of leading companies involved with solid organ transplantation, tissue transplantation, and alternative technologies are included. The report provides information on company placement within the market and strategic analyses of the companies available and emerging products.

An appendix featuring various terms and processes used in transplantation is provided at the end of the report.

This report cites autologous products only in relation to their impact on the market for allografts. It does not include blood products, except for peripheral and umbilical cord blood as a source of stem cells.

By geography, the market has been segmented into the North America, Europe, Asia-Pacific, and Rest of the World regions. Detailed analysis of the market in major countries such as the U.S., Germany, the U.K., Italy, France, Spain, Japan, China, India, Brazil, Mexico, GCC countries and South Africa will be covered in the regional segment. For market estimates, data will be provided for 2019 as the base year, with estimates for 2020 and forecast value for 2024.

Report Includes:- 26 data tables and 37 additional tables- An overview of the global organ and tissue transplantation and alternatives market- Estimation of the market size and analyses of market trends, with data from 2018 to 2019, estimates for 2020 and projection of CAGR through 2024- Details about organ and tissue transplantation and alternatives, their pathophysiology and affects, and major advancement and latest trends- A look at the regulatory scenarios and initiatives by government organization- Analysis of current and future market dynamics and identification of key drivers, restraints and opportunities such as increasing incidence of organ donations, improved awareness about organ donations, side effects of organ and tissue transplantation and antibiotic resistance infections- Coverage of emerging procedures and products in development and discussion on prevalence of major chronic diseases which initiates organ damage or donation- Discussion on the role of the organ procurement organization and information on transplantation process and preparation and coverage of issues like black market donors- Impact analysis of COVID-19 on organ and tissue transplantation and alternatives market- Market share analysis of the key companies of the industry and coverage of events like mergers & acquisitions, joint ventures, collaborations or partnerships, and other key market strategies- Company profiles of major players of the industry, including Abiomed Inc., Bayer AG, F. Hoffmann-La Roche & Co., Johnson & Johnson, Novartis AG, Pfizer Inc. and XVIVO Perfusion

Summary:The global organ and tissue transplantation and alternatives market was valued at REDACTED in 2019.The market is expected to grow at a compound annual growth rate (CAGR) of REDACTED to reach approximately REDACTED by 2024.

Growth of the global market is attributed to factors such as the growing prevalence of obesity, diabetes, cancer, and other chronic diseases which leads to organ damage, a strong product regulatory scenario, and strong investment in research and development activities by key market players including Abbott Laboratories, Cryolife Inc., Bristol-Myers Squibb, Novartis Ag, F. Hoffmann-La Roche Ltd., Medtronic, Arthrex Inc., Depuy Synthes (Johnson & Johnson), and Allosource.

Although various factors facilitate the global market for organ and tissue transplantation and alternatives, certain parameters such as challenges in HLA sequencing and gaps in supply and demand can constrain market growth.For instance, although there is an increasing need for organ transplants, the shortage of organs worldwide limits the number of transplant procedures performed, and in turn creates an impact on transplant diagnostics procedures.

An increasing number of candidates on the waiting list for organ transplant procedures worldwide further widens this gap of availability and requirement of organs for transplant purposes.

Successful organ and tissue transplantation began to arrive in the mid-1970s when tissue typing coupled with the use of cyclosporine provided more successful graft and patient survival. Today, patient and graft survival for kidney transplants is higher than 90% for the first year post-transplant, and often the success rate is 80% to 90% for five years post-transplant, with some recipients living more than 20 years after their transplant.

Continuing developments in organ procurement, organ preservation, tissue typing, and immunosuppressant use have bolstered successful transplantation surgical techniques. Evolving posttransplant drug and testing regimens have added to the success rate with close post-transplant monitoring and immunosuppressant dosage review.Read the full report: https://www.reportlinker.com/p096592/?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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Organ and Tissue Transplantation and Alternatives - GlobeNewswire

Image: UN/Unsplash.

One of the astonishing aspects of the human response to the COVID-19 pandemic has been how quickly scientists pivoted to studying every facet of the virus in order to mitigate the loss of life and plan for a return to normalcy. At the same time, a lot of non-coronavirus research ground to a near halt.

With research labs and offices shuttered for all but essential workers, many scientists were stuck at home, their fieldwork and meetings canceled and planned experiments kicked down the road as they struggled to figure out how to keep their research programs going. Many took the opportunity to catch up on writing grants and papers; some in between caring for kids came up with strategic workarounds to keep the scientific juices flowing.

To gauge how researchers in different fields are managing,Knowable Magazine spoke with an array of scientists and technical staff among them a specialist keeping alive genetically important strains of fruit flies, the maintenance chief of an astronomical observatory working to keep telescopes safe and on standby during the lockdown, and a paediatrician struggling to manage clinical trials for a rare genetic disease. Here are a few slices of scientific life during the pandemic.

Agnieszka Czechowicz, Stanford University School of Medicine

Czechowicz is a paediatrician in Stanfords division of stem cell transplantation and regenerative medicine, where she manages a research group that develops new therapies and conducts clinical trials on rare genetic diseases.

Agnieszka Czechowiczs father suffers from severe Parkinsons disease. The coronavirus pandemic forced him to remain indoors and away from people, robbing him of the physical conditioning and social interactions he needs to cope with his disease. A recent fall left him in the hospital, bringing the additional worry that he might contract COVID-19 there and isolating him further.

For Czechowicz, his situation brought into sharp relief the challenges the coronavirus has forced upon those carrying out clinical trials, including those she is running, which involve patients traveling to hospitals around the country. Would I have him travel to any clinical site right now for a new Parkinsons treatment? she says. Absolutely not.

The pandemic forced Czechowicz to halt clinical trials she oversees for a rare genetic disease of children called Fanconi anAemia, a condition that impairs the bodys ability to repair damaged DNA and often leads to bone marrow failure and cancer. The treatment Czechowicz and colleagues are testing involves extracting blood-forming stem cells from the patients bone marrow, inserting a healthy copy of a missing or malfunctioning gene and then reinfusing those cells back into the patient.

Every aspect of what I do is massively impacted by the pandemic, Czechowicz says. One of her early-stage clinical trials involves testing the safety of the therapy. But during the initial shutdown which started in mid-March and lasted for two months her patients could not readily travel to Stanford for the necessary follow-up visits, and remote monitoring was difficult.

Theres special blood testing and bone marrow testing that we need to do. In particular, its critical to get the samples to make sure the patients, for example, arent developing leukAemia, she says. Theres no way to know that without really checking the bone marrow. She had to clear large hurdles to get her patients evaluated.

Another early-stage trial, designed to determine the effectiveness of the therapy, also had to stop enrolling new patients. Because speed is important when it comes to treating Fanconi anaemia the children are likely losing stem cells all the time any delay in treatment can be a source of great anxiety for their parents. Czechowicz had to explain to them why the trials were temporarily halted. It was really challenging to have these discussions with the families, she says.

With the easing of travel and workplace restrictions, the families began traveling to Stanford in June but with infections back on the rise, many families are becoming hesitant again, says Czechowicz. Fortunately, her trials are small, so she can guide each family through the process of safely resuming the trials and continuing with follow-up. Her own team also has to follow strict safety protocols. For example, even though her lab has 10 members, only two can be in the lab at any one time, and only one parent is allowed into the clinic with the child.

Not all clinical trials can pay such close attention to individual patients. Large trials with hundreds of patients can involve multiple sites and require much more monitoring, so resuming those remains difficult. Also, restrictions on working full bore are slowing the pipeline for new therapies. The impact of that, were not going to see for many years to come, Czechowicz says.

Abolhassan Jawahery, University of Maryland, College Park

Jawahery is a particle physicist and a member of LHCb, one of the main experiments at the Large Hadron Collider (LHC) at CERN, the particle physics laboratory near Geneva.

In December 2018, well before the coronavirus pandemic began, the LHC shut down for upgrades. Housed in a 27-kilometre-long tunnel about 100 meters underground, the LHC accelerates two beams of protons, one clockwise and one counterclockwise, and makes them collide head-on at four locations. There, four gigantic subterranean detectors ATLAS, CMS, LHCb and ALICE sift through the debris of particles created by the collisions, looking for evidence of new physics. (For example, ATLAS and CMS found the Higgs boson, the fundamental particle of the Higgs field, which gives all elementary particles their mass.)

For its next set of experiments, which aim to probe the properties of subatomic particles with greater precision, the LHC needed to increase the intensity of its proton beams. Consequently, the four detectors needed to be upgraded too, to handle the resultant higher temperatures and increased radiation at the sites of the particle collisions. The work was on track for a restart around May 2021 until the pandemic swept all the scientists careful plans away.

The LHC and its four detectors are each run by a separate collaboration. CERN, which manages the LHC, is hopeful it can restart the collider by February 2022. They think that they can get the accelerator going if there are no more major catastrophic events, says physicist Abolhassan Jawahery. But the impact on the four detectors is less clear.

For the LHCb upgrade, Jawaherys team at the University of Maryland had been working on building about 4,000 extremely sensitive electronic circuit boards. These boards have to be burned in before they can be sent to CERN. We put them in an oven, literally cooking the boards and then running extensive tests in order to get them ready so that we can put them in the accelerator and run them for 10 to 20 years, says Jawahery. And none of that could be done during the pandemic shutdown.

The team resumed its work in June, but with restrictions put in place by the state of Maryland. Jawahery runs two labs, and for months was allowed only two people at a time in one lab and three in the other, making progress extremely slow. Still, his team is fortunate that it does not depend on supplies from countries hit hard by the coronavirus. Other labs werent so lucky. Scientists in Milan, for example, built some electronics and detector components for the LHCb, and a lab at Syracuse University in New York built sensors that relied on shipments from Milan. When Milan was completely closed down at the height of the pandemic, Syracuse, too, stopped working on Milan-dependent components.

For Jawahery the lockdown had a silver lining. The LHCs most recent run had produced about 25 gigabytes of data per second but his team had found little time to analyse any of it before the pandemic. We were complaining that we were spending all our time building the new instrument and the data keeps on coming, he says. When he and his team were locked out of their labs, they turned to their data backlog. We could do actual physics, he says. We are already getting ready to publish some papers.

Gordon Gray, Princeton University

Gray is a professionalDrosophila specialist in the department of molecular biology.

Gordon Gray has been called the chef de cuisine of Princetons fly kitchen, where he has been feeding flies for 46 years. He concocts meals for millions of fruit flies, at least 150 litres each week. When the pandemic hit in March and universities around the world shut down, Princeton deemed Grays work an essential service: The Drosophilafruit flies could not be allowed to die off.

Princetons flies include mutant and transgenic strains everything from ones that allow researchers to study the genes that influence normal development of a fly embryos organs, to those that have cancer-causing mutations. If the flies starved, researchers would need months or years to recreate these strains, says Princeton molecular biologist Elizabeth Gavis. And often, as techniques in molecular biology improve, the biologists reexamine flies they had studied earlier to get a more fine-grained understanding, making it worthwhile to preserve the strains.

Normally, if a lab had to shut down, researchers would send their flies to stock centres, such as one at Bowling Green State University in Ohio, that preserve the flies as part of their genetic library. But the stock centres couldnt handle Princetons flies, so Gray found himself on his own. Its basically catch as catch can with regards to the various labs here, just to keep things operational, he says.

For months, university pandemic restrictions have allowed only one person to be in Grays kitchen at a time. This has caused problems. Before the pandemic began, Gray, who is in his late 60s, had started training someone as a backup. But because of the one-person restriction, Gray and his trainee havent been able to work together. Gray envisions doing so soon, while wearing masks, keeping nearly 12 feet apart and communicating using hand signals.

To whip up a batch of fly food, or media, Gray uses a 50-litre steel cauldron, to which is attached a mixer that looks like an outboard motor. Gray fills the cauldron with water and adds agar, sugars, yeasts, salts and cornmeal, then brings it to a boil, all the while stirring watchfully. You dont want it to boil over, because when it does you wind up with a gigantic pancake on the floor, which you have to scoop up immediately because it gels, he says. Once the suspension cools to the right temperature, Gray adds an acid to inhibit mould, then dispenses precise amounts of the media into bottles and vials.

Even before the pandemic, Grays kitchen was isolated, to keep errant fruit flies from contaminating the pristine media. But at least he could work regular hours, because he knew the rhythms of the 10 or so fly labs he cooked for. That has changed. Labs, restricted to two occupants at a time, are now working seven days a week on rotating shifts. Gray comes in to work at all hours, because he cannot predict when each batch of fly food will run out and hell need to cook more.

He tries to work mostly at night to avoid coming into contact with others. But he still worries for his health, given his asthma and age-related risk. The relentless pandemic is taking a toll. Its exhausting, he says. It doesnt help not knowing when we will return to a sense of normalcy.

Celeste Kidd, University of California, Berkeley

Kidd is a child developmental psychologist who uses behavioural tests and computational methods to understand how children acquire knowledge.

When UC Berkeley locked down in March, Celeste Kidd found herself closeted at home, dealing simultaneously with virtual meetings and her three-year-old son. During the early days of the pandemic, Kidd kept a supply of treats handy, and when her toddler came up to her during a meeting shed sneak him some under the desk. But she hadnt accounted for how long the pandemic would last. It turns out thats not a good strategy, long term, she says. I was very literally rewarding him for bad behaviour.

Kidds son soon learned that acting up during her meetings meant more candy. I knew that would happen. I did it anyway because I didnt have the bandwidth to come up with a better solution, she says. But Kidd knew from her own research that children are also extremely flexible and can unlearn behaviours. Eventually, she had a chat with her son. First, she admitted to him that she had made a mistake by giving him candy when he disrupted her meetings, and that was bad of her. Then she brought in new rules: no candy for misbehaving and misbehaviour could even mean no treats for the rest of day. We had some meltdown moments, says Kidd. But he gets it now and he doesnt do those things.

Her son may be the only child Kidd gets to interact with during the pandemic. Thats a huge loss for her research, because the bulk of her work focuses on young children. In normal times, families would bring their children to her lab, where her research team would track their gaze as they watched videos. In one study, for example, infants about seven to nine months old would look away (demonstrating lack of interest) when the events in the video were either too complex or too simple, suggesting that infants use their cognitive resources for stimuli that have just the right amount of information.

Such work, of course, requires the presence of parent, child and researchers, all in the same room. None of that is going to happen anytime soon, she says. Those families are not going to feel comfortable coming in for a while.

Kidd is also concerned about the impact of the pandemic on younger scientists. One of her undergraduate students had spent six months working on a study aimed at exploring the complexity of kids play patterns using physical objects and their relation to working memory and other cognitive resources. The university had approved the protocol, but shelter-in-place orders went into effect the week the first child was to come for the experiment. I feel so bad for her as a young scientist, to have done all this hard work and then right when you get to the fun part, which is collecting the data and finding out if her ideas have lasting merit, she doesnt get to do that part, Kidd says.

The situation might be even worse for grad students and postdocs. All of them are experiencing a big blow to morale in general, because there is so much uncertainty about what the future holds, she says. University budget cuts mean fewer slots for graduate students and fewer jobs for postdocs. Its very hard to stay motivated and get things done when youre not sure if there will be a payoff in the future, says Kidd. Thats literally a study that we ran in the lab so were all acutely aware of it.

Maxime Boccas, ESO Paranal Observatory

Boccas is the head of maintenance, support and engineering at the European Southern Observatorys Paranal Observatory in Chile.

When the massive domes of the Very Large Telescope, a constellation of four 8-meter-class telescopes atop Mount Paranal in Chiles Atacama Desert, open to the night sky each evening and the telescopes get ready for observations, its like a dragon waking up.

When the pandemic hit in March, the dragon on Mount Paranal closed its eyes to the cosmos and slept the first shutdown in its 20-year history, which included a major earthquake in 2010 that paralyzed much of the rest of Chile. For those who had to leave Paranal, it was like being sent away from home. We spend 40% of our life here, says Maxime Boccas, who oversaw the process of ensuring an orderly shutdown of the sites scientific and technical facilities. We work and sleep here, and we stay here eight days in a row. Some of Boccass colleagues have been doing that for 20 to 25 years. Leaving Paranal was like leaving their second home. That was a weird feeling.

The skeleton staff just 20 of the normal 150 or so people remained on site kept the observatory safe, ensuring that essential systems continued working: computers that astronomers were accessing remotely, the fire detection system and the earthquake protection system essential for protecting the 8-meter-wide primary mirrors from Chiles frequent quakes. The mirrors will likely never be made again, says Boccas. All the factories that cast and polished them are dismantled. If we lost a mirror, it would take between 5 and 10 years to build up the factory again and fabricate it. So each mirror has an airbag a tube that inflates around it when the system detects tremors and other protections.

During the shutdown, astronomers kept their fingers crossed. They were anxious that no big thing, like a supernova in our galaxy, would explode, Boccas says. The heavens have been quiet, but the six-month shutdown harmed research that involves continuously monitoring the same patch of the sky for transient phenomena such as gamma ray bursts. It creates a hole in their science program, says Boccas.

The observatory began a slow return to normalcy on September 9. Boccas is overseeing the reawakening of each telescope, one at a time. The staff still less than full strength is now working in shifts that have doubled from 8 to 15 days to limit the amount of travel to and from the site. The four large telescopes are now up and running again, and Boccas hopes they will be back to working together as one by the end of January.

Boccas, his crew and a few lucky astronomers are glad to be back at Paranal. It really feels like a family and I think everyone has noticed that, he says. Even in the kitchen, they have to cook for 30 people instead of 150, so the quality of the food is different, its slightly better.

But even as people return to the observatory, Boccas worries about long-term effects of the shutdown. Given the reduced staff, he has had to cut down on the frequency of preventive maintenance tasks, such as changing belts and lubricating motors, potentially shortening the lifetime of some components. We will not know until six months, a year or three years from now, he says.

This article is part ofReset: The Science of Crisis & Recovery, an ongoing series exploring how the world is navigating the coronavirus pandemic, its consequences and the way forward. Reset is supported by a grant from the Alfred P. Sloan Foundation.

Anil Ananthaswamy is a science journalist who enjoys writing about cosmology, consciousness and climate change. Hes a 2019-20 MIT Knight Science Journalism fellow. His latest book is Through Two Doors at Once. http://www.anilananthaswamy.com.

This article originally appeared in Knowable Magazine, an independent journalistic endeavour from Annual Reviews.

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How Researchers Are Making Do in the Time of COVID-19 - The Wire Science

FDAs decision will enable CytoDyn to respond to ongoing requests for leronlimab until Phase 3 trial data is unblinded

VANCOUVER, Washington, Dec. 22, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company"), a late-stage biotechnology company developing Vyrologix (leronlimab-PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced today a treating physician has received authorization from the U.S. Food and Drug Administration (FDA) to administer leronlimab for a COVID-19 patient under emergency IND (eIND).

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn, commented, We are very thankful the FDA is allowing severe-to-critical COVID-19 patients access to Vyrologix (leronlimab) again under eIND while we await the unblinding of data from our recently completed Phase 3 registrational trial. We are receiving daily requests from families seeking our drug for a loved one with COVID-19. In recent months, leronlimab received more than 60 eIND authorizations from the FDA, and during the pendency of our COVID-19 trials, we deferred seeking authorizations for eINDs in order to accelerate the pace of enrollment. Now that enrollment has been completed, we are pleased to be able to assist once again and remain hopeful the upcoming results of our Phase 3 trial will enable leronlimab to be more readily available for severe-to-critical COVID-19 patients.

CytoDyns Phase 2b/3 trial to evaluate the efficacy and safety ofleronlimabfor patients with severe-to-critical COVID-19 indications is a two-arm, randomized, double blind, placebo controlled, adaptive design multicenter study. Patients are randomized to receive weekly doses of 700 mg leronlimab, or placebo. Leronlimab and placebo are administered via subcutaneous injection. The study has three phases: Screening Period, Treatment Period, and Follow-Up Period. The primary outcome measured in this study is: all-cause mortality at Day 28. Secondary outcomes measured are: (1) all-cause mortality at Day 14, (2) change in clinical status of subject at Day 14, (3) change in clinical status of subject at Day 28, and (4) change from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 14.

About Coronavirus Disease 2019 CytoDyn completed its Phase 2 clinical trial (CD10) for COVID-19, a double-blinded, randomized clinical trial for mild-to-moderate patients in the U.S. which produced statistically significant results for NEWS2. CytoDyn completed enrollment of 390 patients in its Phase 2b/3 randomized clinical trial for the severe-to-critically ill COVID-19 population and expects to release results in mid-January 2021.

About Leronlimab (PRO 140) The FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for critical illnesses. The first indication is a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer. Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH.Leronlimab has completed nine clinical trials in over 800 people and met its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use.

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting a Phase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells.CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD. Due to the lack of patients during the COVID-19 pandemic, the Company is closing down its Phase 2 trial for acute GvHD.

About CytoDyn CytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells. The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH.

CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. The FDA met telephonically with Company key personnel and its clinical research organization and provided written responses to the Companys questions concerning its recent Biologics License Application (BLA) for this HIV combination therapy in order to expedite the resubmission of its BLA filing for this indication.

CytoDyn has completed a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV. No drug-related serious site injection reactions reported in about 800 patients treated with leronlimab and no drug-related SAEs reported in patients treated with 700 mg dose of leronlimab. Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than six years.

CytoDyn is also conducting a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is at http://www.cytodyn.com.

Forward-Looking StatementsThis press release contains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as "believes," "hopes," "intends," "estimates," "expects," "projects," "plans," "anticipates" and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. Forward-looking statements specifically include statements about leronlimab, its ability to have positive health outcomes, the possible results of clinical trials, studies or other programs or ability to continue those programs, the ability to obtain regulatory approval for commercial sales, and the market for actual commercial sales. The Company's forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i) the sufficiency of the Company's cash position, (ii) the Company's ability to raise additional capital to fund its operations, (iii) the Company's ability to meet its debt obligations, if any, (iv) the Company's ability to enter into partnership or licensing arrangements with third parties, (v) the Company's ability to identify patients to enroll in its clinical trials in a timely fashion, (vi) the Company's ability to achieve approval of a marketable product, (vii) the design, implementation and conduct of the Company's clinical trials, (viii) the results of the Company's clinical trials, including the possibility of unfavorable clinical trial results, (ix) the market for, and marketability of, any product that is approved, (x) the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Company's products, (xi) regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii) general economic and business conditions, (xiii) changes in foreign, political, and social conditions, and (xiv) various other matters, many of which are beyond the Company's control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and any risk factors or cautionary statements included in any subsequent Form 10-Q or Form 8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CONTACTSInvestors: Michael MulhollandOffice: 360.980.8524, ext. 102mmulholland@cytodyn.com

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FDA Resumes eIND Approval for Severe-to-Critical COVID-19 Patients Use of Vyrologix (leronlimab) Following Full Enrollment in CytoDyn's Phase 3 Trial...

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

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

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

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

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

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

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

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

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

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

Contact: Beth Adams, [emailprotected]

SOURCE Penn Dental Medicine

http://www.dental.upenn.edu

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Priming the Immune System to Fight Cancer - PRNewswire

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Data Supporting the Clinical and Safety Profile of Libmeldy

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

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

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

About MLD and Libmeldy

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

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

About Orchard

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

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

Availability of Other Information About Orchard

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

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

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

For more information:

Forward-Looking Statements

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

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

Contacts

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

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

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

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

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

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

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

KEY QUOTES:

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

Dr.Amit Patel, coinventor of ImmCelz

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

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

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

Timothy Warbington, President and CEO of Creative Medical Technology

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

The rest is here:
Creative Medical Technology Stock Price Increased 80.77%: Why It Happened - Pulse 2.0

Abstract

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What Happens When Treatments Target mTOR?

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

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

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

Next Steps

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

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

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

Meet John.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Usher syndrome was on that list, Heather said.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

But they acknowledged, someday John will ask.

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

And they do.

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

But largely they stay optimistic.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pregnancy

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

PCOS

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

Obesity

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

Stress

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

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

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

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

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

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

Symptoms of HMB

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

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

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

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

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

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

HMB Treatment options in the 21st Century

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

Medical

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Walk or do activities outside

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

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

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

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

Bright Light Therapy

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

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

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

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

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

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

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

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

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

Natural sleeping aids

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

Dawn simulator

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

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

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

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

Panda Planner Pro Daily Planner

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

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

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

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

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

Exercise

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

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

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

Yoga and meditation

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

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

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

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

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

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

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

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

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

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Winter Got You Down? Here's How to Combat Seasonal Blues, According to Experts - TIME

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(c)2020 The Philadelphia Inquirer

Visit The Philadelphia Inquirer at http://www.inquirer.com

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The coronavirus pandemic is killing people with diabetes or Alzheimer's who didn't even contract the virus - LancasterOnline