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Researchers may have found a way to prevent Duchenne muscular dystrophy-related heart disease, the leading cause of death in patients living with the disease.

The study examines the role of Connexin-43 (Cx43), a protein that regulates heart function. The researchers found that Cx43 was dysfunctional in both human and mouse Duchenne muscular dystrophy (DMD) hearts, so they modified the Cx43 protein in the hopes of alleviating heart disease.

They discovered that altering the Cx43 protein through a process called phosphorylation protected DMD mice against irregular heart beat and late-stage failure.

DMD, a genetic disorder characterized by progressive muscle degeneration, is the most common type of muscular dystrophy, affecting about one in 5,000 males and typically beginning at about age 4. The average life expectancy is 26.

For many DMD patients, the heart muscles gradually break down, leading to death. Our findings may help give hope to millions of patients, says study coauthor Diego Fraidenraich, an assistant professor of cell biology and molecular medicine at Rutgers University New Jersey Medical School.

Medical advances have managed to slow down the disease progression in most muscles in the body, but there are yet to be any discoveries that target or prevent deterioration of the DMD heart, which remains the number one killer among these patients, says coauthor Eric Himelman, a PhD candidate. Therapies based on our finding may help prolong the lives of muscular dystrophy and other heart disease patients.

Next steps include developing drugs that directly target Cx43 in DMD hearts, with a goal of potentially introducing clinical trials using Cx43 modification as a therapy for DMD patients.

The study appears in the Journal of Clinical Investigation. Another study in JCI Insight also examined Cx43 activity in the heart.

The National Institutes of Health, the Muscular Dystrophy Association, and the American Heart Association funded the work.

Additional researchers are from Rutgers, the Fred Hutchinson Cancer Research Center, New York University, and Baylor College of Medicine.

Source: Rutgers University

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Protein tweak may prevent DMD-related heart disease - Futurity: Research News

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Research focuses on precisely how the disease develops in the brain

Anne Fagan, PhD, supervises staff scientist Matthew R. Amos as he analyzes samples for molecular signs of Alzheimer's disease. Fagan leads one arm of a long-running, international Alzheimers study aimed at understanding how the disease develops and progresses. Researchers at Washington University School of Medicine in St. Louis have received $29 million to continue the study known as the Dominantly Inherited Alzheimer Network for another five years.

For more than a decade, Washington University School of Medicine in St. Louis has led an international effort to better understand Alzheimers disease by studying people with rare genetic mutations that cause the disease to develop in their 50s, 40s or even 30s. The researchers have shown that the disease begins developing two decades or more before peoples memories begin to fade, as damaging proteins silently accumulate in the brain.

Now, the National Institute on Aging of the National Institutes of Health (NIH) has committed $29 million to support the effort known as the Dominantly Inherited Alzheimer Network (DIAN) for another five years, pending availability of funds. With the new funding, the network will add three new research initiatives to investigate more closely the changes that occur in the brain as the disease develops, which could lead to new ways to diagnose or treat Alzheimers.

The extraordinary accomplishments of the DIAN investigators and participants over the past decade have set the stage to understand the molecular changes that can cause Alzheimers disease, said DIAN director Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. The three new scientific projects will provide deep insights into how Alzheimers disease begins and progresses to dementia.

DIAN follows families with genetic mutations that all but guarantee that those who inherit the mutations will develop Alzheimers disease at young ages. While devastating for families, this genetic form of Alzheimers disease creates a rare opportunity for researchers to look for brain changes long before symptoms appear in people who carry such mutations, compared with their relatives who dont have the mutation.

Although the study follows only people with a rare genetic form of Alzheimers, its findings could apply to the millions of people living with the much more common late-onset Alzheimers, which appears after age 65. The brain changes that lead to memory loss and confusion are thought to be much the same in early- and late-onset Alzheimers.

Since the network was established in 2008, DIAN researchers have established 19 sites in eight countries representing North and South America, Europe, Asia and Australia with another five sites in four Latin American countries in the works. People from families with genetic forms of Alzheimers take part in observational studies to track changes to their brains over time. The network also has established a clinical trials unit to test investigational therapies to prevent or treat the disease.

Participants undergo assessments of their memory and thinking skills, provide DNA for genetic analysis, undergo brain scans, and give blood and cerebrospinal fluid so researchers can look for molecular signs of Alzheimers disease. With the help of such participants, researchers have begun to piece together a timeline of the brain changes that culminate in cognitive decline and dementia. First, the protein amyloid beta starts forming plaques in the brain up to two decades before symptoms arise. Later, tangles of tau protein form, and the brain begins to shrink. Only then do signs of confusion and forgetfulness appear.

In addition to supporting ongoing research efforts, the grant funds three new projects:

The study described in this press release is supported by the National Institute on Aging of the National Institutes of Health (NIH) under award number U19AG032438. The grant from the National Institute on Aging provides 95.4% of the funding for this study, with the remainder provided by the Alzheimers Association (3.3%) and a consortium of pharmaceutical companies (1.3%). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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$29 million for new phase of international Alzheimer's study Washington University School of Medicine in St. Louis - Washington University School of...

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Culprit identified in bone loss from cancer therapy

Red and green lines represent new bone in this image of a normal mouse bone. Exposure to chemotherapy and radiation during cancer treatment leads to bone loss and increases the risk of osteoporosis and fractures. A new study from Washington University School of Medicine in St. Louis identifies the trigger for this bone loss and suggests ways to prevent it.

Bone loss that can lead to osteoporosis and fractures is a major problem for cancer patients who receive chemotherapy and radiation. Since the hormone estrogen plays an important role in maintaining bone health, bone loss is especially pronounced among postmenopausal women with breast cancer who are treated using therapies aimed at eliminating estrogen.

Men and children treated for other cancers also experience bone loss, suggesting that eliminating estrogen is not the only trigger leading to bone degeneration.

Studying mice, researchers from Washington University School of Medicine in St. Louis have found a driver of bone loss related to cancer treatment. They have shown that radiation and chemotherapy can halt cell division in bone, which results in a stress response referred to as senescence. According to the new study, cell senescence drives bone loss in female mice beyond that seen from the absence of estrogen alone. The researchers further found that this process occurs in males and females and is independent of cancer type. And perhaps most importantly, the researchers showed that such bone loss can be stopped by treating the mice with either of two investigational drugs already being evaluated in clinical trials.

The study appears Jan. 13 in Cancer Research, a journal of the American Association for Cancer Research.

Researchers have understood that this bone loss has to be due to more than just hormone loss, said senior author Sheila A. Stewart, PhD, a professor of cell biology & physiology. Cancer patients who receive chemotherapy and radiation lose a lot more bone than women with breast cancer treated with aromatase inhibitors, which eliminate estrogen. And children who have not yet gone through puberty, and arent making much estrogen, also lose bone. We wanted to understand what causes bone loss beyond a lack of estrogen and whether we can do anything to stop it.

Stopping bone loss could improve quality of life for cancer patients. Bone loss leads to an increased risk of fractures that continues many years after treatment. This loss of bone density makes it much more likely that patients will develop fractures in the pelvis, hips and spine, which affect mobility and increase the risk of death.

The researchers studied bone loss in mice treated with two common chemotherapy drugs doxorubicin and paclitaxel as well as in mice that received radiation to one limb, to understand whether the bone loss effects were similar in different types of cancer therapies. In all situations, the treatments induced the process of cellular senescence.

Senescence is a chronic stress response in a cell that stops it from dividing and also results in the release of many molecules, some of which we showed drive bone loss, said Stewart, who is also the associate director for basic sciences at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

The cells in mouse bones that were most affected by the cancer therapies included those responsible for bone remodeling. These are sets of cells that strike a vital balance between dismantling old bone and building new bone in its place. This balance is disturbed in conditions such as osteoporosis, in which the bone-building cells can no longer keep up with the bone-dismantling cells. The new study suggests that the balance is even more off-kilter following cancer therapy: Bone-building cell activity slows down, and the activity of cells that remove old bone actually accelerates.

The researchers showed they could prevent bone loss in the mice if they took steps to remove the cells that are no longer dividing, thus eliminating the molecular signals that the cells produce that drive bone loss. Toward possible therapies, Stewart and her colleagues then showed they could achieve a similar effect with two different types of compounds that block these molecular signals.

The investigational drugs, a p38MAPK inhibitor and a MK2 inhibitor, block different parts of the same pathway leading to bone loss. Stewart and her colleagues also published a study in 2018 showing that the two inhibitors slowed the growth of metastatic breast cancer in mice. The p38MAPK inhibitor is being tested in U.S. clinical trials for inflammatory diseases, such as chronic obstructive pulmonary disease (COPD). And the MK2 inhibitor is about to be evaluated as atherapy for rheumatoid arthritis.

Cancer patients at risk of bone loss often are treated with drugs for osteoporosis, including bisphosphonates and denosumab. Both have some undesirable side effects, such as muscle and bone pain and, because of the way they work, they may be less desirable for children whose bones are still growing.

The inhibitors we studied have extremely low toxicity, so we are interested in exploring whether they could be an improved option to stop bone loss in children receiving cancer therapy, Stewart said. Were also interested in pursuing a clinical trial to evaluate these drugs in women with metastatic breast cancer to see if we can slow metastatic growth and also preserve bone health in these patients.

This work was supported by the National Institutes of Health (NIH), grant numbers P30 AR074992, NS086741 and P30 CA91842; Washington University School of Medicine; and The Childrens Discovery Institute of Washington University and St. Louis Childrens Hospital, grant number CDI-CORE-2015-505.

Yao Z, Murali B, Ren Q, Luo X, Faget DV, Cole T, Ricci B, Thotala D, Monahan JB, van Deursen J, Baker D, Faccio R, Schwarz J, Stewart SA. Therapy-induced senescence drives bone loss. Cancer Research. Jan. 13, 2020.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Investigational drugs block bone loss in mice receiving chemotherapy - Washington University School of Medicine in St. Louis

Scientists from the University of Zurich and the Max Planck Institute for Molecular Genetics, as well as the Icahn School of Medicine at Mount Sinai have come together to summarize recent evidence has challenged our working theory on the origin of life. Previously, scientists thought early life may have arisen from proteins or other chemical reactions important for life reacting in the hot soup of early Earth before there were actually cells. Then, it has been thought that these chemical reactions may have later been taken over by early cells.

However, long ago, after discovering large amounts of amino acids, DNA, and RNA on meteorites in our cosmic neighborhood, researchers again had to shift their train of thought. This paper explained that experiments that mimicked the temperature, acidity, pressure, and energy of an Early earth provided evidence that life may have come from random assortments of RNA and other small molecules. Then, the authors continued, a hypothesis was developed that RNA may have been the primordial first lifeform which took shape on our planet and may have already formed on others. The authors claim that this led to this most recent and widely accepted theory: our world may have been a RNA world at one point in its development; one in which life was composed of a few self-reproducing RNA molecules that worked to spread information as rapidly as possible and combined with amino acids to make proteins which could assist it. The problem with this idea is that researchers are still struggling to engineer RNA molecules that create themselves; a necessary condition if RNA is to reproduce and be able to evolve. Enter the viroid viroids are, essentially, a piece of RNA that can copy itself. Viroids can also insert themselves into a hosts DNA using normal cell processes.

A study highlighted in this article attempted to imitate RNA. Researchers showed that, in solutions of rich in salts and sugars, RNA can spontaneously regrow quite rapidly. These molecules were able to reproduce across 74 generations. From looking at how the sequences changed over these generations, it was determined that viroids replicated fast and continually became smaller and smaller strands of RNA.

The authors conclude that, given what we know about viroids, the idea of a viroid-first origin-of-life theory should be seriously considered, though there is not yet enough evidence to be confident. The good news is that detecting small organic molecules and viroid particles in the depths of space and below the surface of other planets is a lot easier to do than finding evidence to support other origin of life theories, since this theory uses techniques and science that are already familiar to biologists. Genetic engineers are still struggling to create self-copying RNA outside of a viroid-like model and proteins and metabolic chemicals havent turned up in our observations of the space beyond our solar system.

Evidence of organic molecules such as pieces of RNA, DNA, and proteins have been found on recent meteorites. This demonstrates that space already has the conditions to allow for these chemical reactions to take place beyond Earth. The authors suggest that the beginning of life must have been simple, and the search for signatures of viruses, viroids, and small RNA and the modeling of these life forms may be where we need to turn our attention next to answer the questions about life in our Universe.

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How Colds Are Unlocking Secrets About Life on Other Planets - Sciworthy

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January 4, 2020 -Most viral respiratory infections, like the common cold, usually come and go within a few days, with no lasting effects. But influenza (flu) is a disease that can cause serious health problems and can result in hospitalization or death.

You can fight back by adopting healthy habits and by using medicines and vaccines approved by the U.S. Food and Drug Administration to combat and help prevent the flu.If you are generally healthy, heres how to tell if you have a cold or the flu, and when to seek medical care.

Flu and cold viruses spread mainly by droplets, when infected people cough, sneeze, or talk. You also can get infected by touching a surface or object that has flu viruses on it, such as a door handle, and then touching your eyes, nose, or mouth. Flu season in the United States may begin as early as October and can last as late as May, and generally peaks between December and February.

Colds:Symptoms of colds usually are a stuffy or runny nose and sneezing. Other symptoms include coughing, a scratchy throat, and watery eyes. There is no vaccine to prevent colds, which come on gradually and often spread through everyday contact.

Flu:Symptoms of the flu come on suddenly and can include fever, headache, chills, dry cough, sore throat, body or muscle aches, tiredness, and feeling generally miserable. Like the viruses that cause a cold, flu viruses can cause a stuffy or runny nose, sneezing, and watery eyes. Young children also may experience nausea and vomiting.

Check with your health care provider promptly if you are at high risk for flu-related complications and you have flu symptoms or if you have flu symptoms that do not improve.People at high riskinclude:

Some health care providers can give you an FDA-cleared rapid flu test. There are 17 rapid flu tests (11 antigen-based and six molecular-based) on the market with updated performance criteria that the FDA created to provide reasonable assurance that the test is accurate, reliable, and clinically valid.

According to the Centers for Disease Control and Preventions flu testing guidelines, you dont need testing or to await test results before your health care provider can prescribe antiviral medication. Your health care provider will decide what to prescribe based on the signs and symptoms you have.

Colds usually run their course. When youre sick, limit exposing yourself to other people. Cover your mouth and nose when you cough or sneeze. Also, stay hydrated and rested. Avoid alcohol and caffeinated products.

There are FDA-approved prescription medications called antivirals for treating flu. Also, a cold or flu may lead to a bacterial infection (such as bronchitis, sinusitis, ear infections, and pneumonia) that could require antibiotics.

Most people with the flu who aren't at high risk have mild illness and do not need medical care or antiviral drugs. Still, your symptoms may last up to two weeks.

Read medicine labels carefully and follow the directions.People with certain health conditions, such as high blood pressure or diabetes, should check with a doctor or pharmacist before taking a new cough or cold medicine.

Choose the right over-the-counter (OTC, or non-prescription) medicines for your symptoms.

Check the medicines side effects.Medications can cause drowsiness and interact with food, alcohol, dietary supplements, and other medicines. Tell your doctor and pharmacist about every medical product and supplement you are taking.

Check with a health care professional before giving medicine to children.

Get vaccinated against the flu.The best way to prevent the flu is by getting vaccinated every year. The vaccine changes each year and contains flu virus strains that are expected to be prevalent during the upcoming flu season. The protection from the previous years vaccine will diminish over time and may be too low to protect you into the next year, even if the flu virus strains circulating the next year are the same as those contained in the previous years vaccine.

With rare exceptions, the CDC recommends that everyone ages 6 months and older should be vaccinated against flu. The flu vaccine provides protection from the flu and its potential complications, which can result in hospitalization and sometimes death.

Annual vaccination is especially important for people at high risk for developing serious complications from flu: health care workers, and anyone who lives with or cares for people at high risk for serious flu-related complications.

Although children younger than 6 months are too young to be vaccinated, they have the highest risk for being hospitalized because of flu and flu-related complications compared to children of other ages. Therefore, the CDC recommends that parents, grandparents, caregivers, and all household members 6 months or older should be vaccinated because they will be less likely to get the flu and spread it to the unvaccinated child. If possible, keep infants away from crowds for the first few months of life.

Wash your hands often.Teach children to do the same. Both colds and flu can be passed through contaminated surfaces, including the hands. Wash hands with warm water and soap for at least 20 seconds. Try not to touch your eyes, nose, or mouth. Clean and disinfect frequently touched surfaces, especially when someone is ill.

Limit exposure to infected people.Cover your nose and mouth with a tissue when you cough or sneeze. Throw the tissue in the trash after you use it.Source: FDA

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FDA: Is It a Cold or the Flu? Prevention, Symptoms, Treatments - Sierra Sun Times

Roswell completed the development and prototyping of the first of its kind molecular-electronic chips, which used all the latest achievements from the fields of semiconductor technology, nanotechnology, biosensors, etc. All this made it possible to create an integrated CMOS chip, which contains a huge number of elements of molecular sensors, which, at a chip price of $ 100, can read information from the entire human genome in just one hour.

In 2019, Roswell Biotechnologies, Inc, whose management managed to attract $ 32 million of investments, completed the development of a number of key technologies necessary for implementing direct, high-speed and accurate reading of genetic data and other information of biological origin.

As mentioned above, Roswells first molecular-electronic chip is designed to quickly read genetic information from DNA. The chips that the company plans to create in the near future will be much more complicated and they will be able to perform more complex functions, such as detecting certain types of proteins, biomarkers of various diseases, which can be used in field infectious medicine, environmental monitoring, or to identify biological samples of various nature.

Currently, the ENDSeq System (Electronic Nano-Device Sequencing) technology, which can reduce the time it takes to read genetic information from a few days to tens of minutes, can become a drastic reduction in the cost of this procedure. This, in turn, can serve as a strong impetus for the further development of the relevant areas of medicine. In addition, on the basis of the new chip, Roswell plans to launch the first device, Data Reader, which will provide high speed information reading using synthetic DNA molecules as an information carrier.

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Roswell Biotechnologies created a chip capable of reading biological information from human DNA - FREE NEWS

Zendesk (NYSE:ZEN) and NantHealth (NASDAQ:NH) are both computer and technology companies, but which is the better investment? We will contrast the two businesses based on the strength of their risk, analyst recommendations, profitability, dividends, valuation, institutional ownership and earnings.

Insider and Institutional Ownership

95.9% of Zendesk shares are held by institutional investors. Comparatively, 2.8% of NantHealth shares are held by institutional investors. 4.6% of Zendesk shares are held by company insiders. Comparatively, 64.5% of NantHealth shares are held by company insiders. Strong institutional ownership is an indication that endowments, large money managers and hedge funds believe a stock is poised for long-term growth.

Risk & Volatility

Zendesk has a beta of 1.22, indicating that its share price is 22% more volatile than the S&P 500. Comparatively, NantHealth has a beta of 1.53, indicating that its share price is 53% more volatile than the S&P 500.

Profitability

This table compares Zendesk and NantHealths net margins, return on equity and return on assets.

Analyst Recommendations

This is a summary of recent recommendations and price targets for Zendesk and NantHealth, as reported by MarketBeat.

Zendesk presently has a consensus target price of $94.94, indicating a potential upside of 21.17%. NantHealth has a consensus target price of $1.00, indicating a potential downside of 1.96%. Given Zendesks higher probable upside, analysts clearly believe Zendesk is more favorable than NantHealth.

Valuation & Earnings

This table compares Zendesk and NantHealths top-line revenue, earnings per share (EPS) and valuation.

Zendesk has higher revenue and earnings than NantHealth. Zendesk is trading at a lower price-to-earnings ratio than NantHealth, indicating that it is currently the more affordable of the two stocks.

Summary

Zendesk beats NantHealth on 10 of the 14 factors compared between the two stocks.

Zendesk Company Profile

Zendesk, Inc., a software development company, provides SaaS products for organizations. Its flagship product is Zendesk Support, a system for tracking, prioritizing, and solving customer support tickets across various channels. The company also offers Zendesk Chat, a live chat software to connect with customers on Websites, applications, and mobile devices; Zendesk Talk, a cloud-based call center software; Zendesk Guide, a knowledge base that powers customer self-service and support agent productivity; Zendesk Sell, a sales force automation software to enhance productivity, processes, and pipeline visibility for sales teams; Zendesk Connect that manages customer communication across channels; and Zendesk Explore, which provides analytics for businesses to measure and enhance the customer experience. In addition, it provides Zendesk Sunshine, a customer relationship management platform; Zendesk Embeddables, which allow developers to embed support, chat, and guide experiences on the Web and within mobile applications; and Zendesk application platform interfaces and Apps. The company has operations in North America, Latin America, Europe, the Middle East, Africa, Australia, Asia, and South America. Zendesk, Inc. was founded in 2007 and is headquartered in San Francisco, California.

NantHealth Company Profile

NantHealth, Inc., together with its subsidiaries, operates as a healthcare technology company in the United States and internationally. The company engages in converging science and technology through an integrated clinical platform to provide health information at the point of care. It develops NantHealth solutions, including molecular profiling solutions, software, and hardware systems infrastructure, which integrates patient data management, bioinformatics, and molecular medicine to enable value-based care and evidence-based clinical practice. The company's products include GPS Cancer, a molecular profile that integrates whole genome sequencing of tumor and normal germline samples, as well as whole transcriptome sequencing; GPS Cancer Report, a GPS cancer solution; GPS in rare diseases and chronic illnesses; Liquid GPS, a blood-based molecular test; and Eviti, a decision support solution. It also provides Web-based and mobile software solutions, such as Device Connectivity Suite, a device connectivity and near real-time biometric software and hardware suite; DeviceConX, a device data normalization software; HBox, an Internet of Medical Things and Internet of Things hardware hub; and VitalsConX, a tablet-optimized application. In addition, NantHealth, Inc. offers NaviNet Open, a payer-provider collaboration platform comprising plan central, eligibility and benefit, claims status inquiry, claims management, referral, authorization, document exchange, and AllPayer services; and cloud-based computing, storage, and transport infrastructure-as-a-service solutions. The company was formerly known as Nant Health, LLC and changed its name to NantHealth, Inc. in June 2016. The company was founded in 2010 and is headquartered in Culver City, California. NantHealth, Inc. is as a subsidiary of NantWorks, LLC.

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Head-To-Head Survey: NantHealth (NASDAQ:NH) and Zendesk (NASDAQ:ZEN) - Riverton Roll

Wenxiang Bai,1,2,* Honghua Wang,1,* Hua Bai1,3

1Comprehensive Cancer Center, Xiangshui Peoples Hospital, Xiangshui 224600, Peoples Republic of China; 2Department of Respiratory Medicine, Xiangshui Peoples Hospital, Xiangshui, 224600, Peoples Republic of China; 3Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Hua BaiComprehensive Cancer Center, Xiangshui Peoples Hospital, Xiangshui 224600, Peoples Republic of ChinaEmail baihua92@126.com

Objective: Systemic amyloid light chain (AL) amyloidosis is a rare plasma cell disease. However, the regulatory mechanisms of AL amyloidosis have not been thoroughly uncovered, identification of candidate genes and therapeutic agents for this disease is crucial to provide novel insights into exploring the regulatory mechanisms underlying AL amyloidosis.Methods: The gene expression profile of GSE73040, including 9 specimens from AL amyloidosis patients and 5 specimens from normal control, was downloaded from GEO datasets. Differentially expressed genes (DEGs) were sorted with regard to AL amyloidosis versus normal control group using Limma package. The gene enrichment analyses including GO and KEGG pathway were performed using DAVID website subsequently. Furthermore, the proteinprotein interaction (PPI) network for DEGs was constructed by Cytoscape software and STRING database. DEGs were mapped to the connectivity map datasets to identify potential molecular agents of AL amyloidosis.Results: A total of 1464 DEGs (727 up-regulated, 737 down-regulated) were identified in AL amyloidosis samples versus control samples, these dysregulated genes were associated with the dysfunction of ribosome biogenesis and immune response. PPI network and module analysis uncovered that several crucial genes were defined as candidate genes, including ITGAM, ITGB2, ITGAX, IMP3 and FBL. More importantly, we identified the small molecular agents (AT-9283, Ritonavir and PKC beta-inhibitor) as the potential drugs for AL amyloidosis.Conclusion: Using bioinformatics approach, we have identified candidate genes and pathways in AL amyloidosis, which can extend our understanding of the cause and molecular mechanisms, and these crucial genes and pathways could act as biomarkers and therapeutic targets for AL amyloidosis.

Keywords: light chain amyloidosis, bioinformatics approach, differentially expressed genes, candidate genes, therapeutic agent

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Identification of Candidate Genes and Therapeutic Agents for Light Cha | PGPM - Dove Medical Press

Brain imaging of pathological tau-protein tangles reliably predicts the location of future brain atrophy in Alzheimers patients a year or more in advance, according to a new study by scientists at the UC San Francisco Memory and Aging Center. In contrast, the location of amyloid plaques, which have been the focus of Alzheimers research and drug development for decades, was found to be of little utility in predicting how damage would unfold as the disease progressed.

The results, published Jan. 1, 2020, in Science Translational Medicine, support researchers growing recognition that tau drives brain degeneration in Alzheimers disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimers clinical trials and improve individualized patient care.

The match between the spread of tau and what happened to the brain in the following year was really striking, said neurologist Gil Rabinovici, MD, the Edward Fein and Pearl Landrith Distinguished Professor in Memory and Aging and leader of the PET imaging program at the UCSF Memory and Aging Center. Tau PET imaging predicted not only how much atrophy we would see, but also where it would happen. These predictions were much more powerful than anything weve been able to do with other imaging tools, and add to evidence that tau is a major driver of the disease.

Alzheimers researchers have long debated the relative importance of amyloid plaques and tau tangles two kinds of misfolded protein clusters seen in postmortem studies of patients brains, both first identified by Alois Alzheimer in the early 20th century. For decades, the amyloid camp has dominated, leading to multiple high-profile efforts to slow Alzheimers with amyloid-targeting drugs, all with disappointing or mixed results.

Many researchers are now taking a second look at tau protein, once dismissed as simply a tombstone marking dying cells, and investigating whether tau may in fact be an important biological driver of the disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimers patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients symptoms (in language-related areas vs. memory-related regions, for example).

No one doubts that amyloid plays a role in Alzheimers disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease, explained Renaud La Joie, PhD, a postdoctoral researcher in Rabinovicis In Vivo Molecular Neuroimaging Lab, and lead author of the new study. Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our groups key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration.

Despite early misgivings that tau might be impossible to measure in the living brain, scientists recently developed an injectable molecule called flortaucipir currently under review by the FDA which binds to misfolded tau in the brain and emits a mild radioactive signal that can be picked up by PET scans.

Rabinovici and collaborator William Jagust, MD, of UC Berkeley and Lawrence Berkeley National Laboratory, have been among the first to adopt tau PET imaging to study the distribution of tau tangles in the normally aging brain and in a smaller cross-sectional study of Alzheimers patients. Their new study represents the first attempt to test whether tau levels in Alzheimers patients can predict future brain degeneration.

La Joie recruited 32 participants with early clinical stage Alzheimers disease through the UCSF Memory and Aging Center, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brains structural integrity, both at the start of the study, and again in follow-up visits one to two years later.

The researchers found that overall tau levels in participants brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration.

Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimers disease, La Joie said.

Notably, PET scans revealed that younger study participants had higher overall levels of tau in their brains, as well as a stronger link between baseline tau and subsequent brain atrophy, compared to older participants. This suggests that other factors likely other abnormal proteins or vascular injuries may play a larger role in late-onset Alzheimers, the researchers say.

The results add to hopes that tau-targeting drugs currently under study at the UCSF Memory and Aging Center and elsewhere may provide clinical benefits to patients by blocking this key driver of neurodegeneration in the disease. At the same time, the ability to use tau PET to predict later brain degeneration could enable more personalized dementia care and speed ongoing clinical trials, the authors say.

One of the first things people want to know when they hear a diagnosis of Alzheimers disease is simply what the future holds for themselves or their loved ones. Will it be a long fading of memory, or a quick decline into dementia? How long will the patient be able to live independently? Will they lose the ability to speak or get around on their own? These are questions we cant currently answer, except in the most general terms, Rabinovici said. Now, for the first time, this tool could let us give patients a sense of what to expect by revealing the biological process underlying their disease.

Rabinovici and his team also anticipate that the ability to predict future brain atrophy based on tau PET imaging will allow Alzheimers clinical trials to quickly assess whether an experimental treatment can alter the specific trajectory predicted for an individual patient, which is currently impossible due to the wide variability in how the disease progresses from individual to individual. Such insights could make it possible to adjust dosage or switch to a different experimental compound if the first treatment is not affecting tau levels or altering a patients predicted trajectory of brain atrophy.

Tau PET could be an extremely valuable precision medicine tool for future clinical trials, Rabinovici said. The ability to sensitively track tau accumulation in living patients would for the first time let clinical researchers seek out treatments that can slow down or even prevent the specific pattern of brain atrophy predicted for each patient.

Authors: La Joie is corresponding author on the study; Rabinovici is senior author. Additional authors on the study are Adrienne V. Visani, Jesse A. Brown, Viktoriya Bourakova, Jungho Cha, Kiran Chaudhary, Lauren Edwards, Leonardo Iaccarino, Orit Lesman-Segev, Zachary Miller, David C. Perry, Julie Pham, Julio C. Rojas, Howard J. Rosen, William W. Seeley, Richard M. Tsai, and Bruce L. Miller, all of UCSF; Suzanne L. Baker, Mustafa Janabi, and James P. ONeil, of Lawrence Berkeley National Laboratory (LBNL); and Jagust, of LBNL and UC Berkeley.

Funding: The study was supported by the Alzheimers Association (AARF-16-443577), the National Institute on Aging (NIA) of the US National Institutes of Health (R01-AG045611, P50-AG023501, P01-AG19724), the Tau Consortium, and an Alzheimers Disease Research Center of California grant (04-33516) from the California Department of Health Services.

Disclosures: Rabinovici receives research support from Avid Radiopharmaceuticals, GE Healthcare, and Life Molecular Imaging, and has received consulting fees or speaking honoraria from Axon Neurosciences, Roche, Eisai, Genentech, Merck. La Joie reports no conflicts of interest. See study online for a full list of conflict of interest disclosures.

The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.UCSF Health, whichserves as UCSFs primary academic medical center, includestop-ranked specialty hospitalsandother clinical programs,and has affiliations throughout the Bay Area.

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Alzheimer 'Tau' Protein Far Surpasses Amyloid in Predicting Toll on Brain Tissue - UCSF News Services

A group led by researchers at Baylor College of Medicine has identified significant differences at the epigenetic level the chemical tags in DNA that help regulate gene expression between two clinically distinct forms of acute childhood malnutrition known as edematous severe acute malnutrition (ESAM) and non-edematous SAM (NESAM).

The researchers report in the journal Nature Communications that ESAM, but not NESAM, is characterized by a reduction in methyl chemical tags in DNA and complex changes in gene activity, including both enhanced and reduced gene expression. Some of the genes that lost their methyl tags have been linked to other disorders of nutrition and metabolism, such as abnormal blood sugar and fatty liver disease, conditions that also have been observed in ESAM. The findings support consideration of methyl-group supplementation in ESAM.

Severe acute childhood malnutrition presents in two clinically distinct forms: ESAM and NESAM, said corresponding author Dr. Neil Hanchard, assistant professor of molecular and human genetics and the USDA/ARS Children's Nutrition Research Center at Baylor. ESAM is characterized by body swelling and extensive dysfunction of multiple organs, including liver, blood cells and the gut, as well as skin and hair abnormalities. NESAM, on the other hand, typically presents with weight loss and wasting.

The differences between ESAM and NESAM are still not fully explained despite decades of studies addressing this question. In the current study, Hanchard and his colleagues looked to better understand the conditions by investigating whether there were differences at the molecular level, specifically on DNA methylation.

The decision to look at DNA methylation was partly driven by previous studies looking at biochemical markers in these individuals. In particular, the turnover of a particular amino acid called methionine, said Hanchard.

Previous work has shown that methionine turnover is slower in ESAM than in NESAM. Methionine is a central ingredient of 1-carbon metabolism, a metabolic pathway that is key to DNA methylation. Lower methionine turnover suggested the possibility of alterations in DNA methylation.

First, we conducted a genome-wide analysis of DNA methylation. When we found in children acutely ill with ESAM genes with levels of DNA methylation that were significantly different from those in NESAM patients, the levels were always lower. Of the genes analyzed, 161 showed a highly significant reduced level of methylation in ESAM, when compared to the same genes in NESAM, Hanchard said.

Interestingly, a group of adults who had recovered from having ESAM malnutrition in their childhood did not show the same reduction in DNA methylation the researchers observed in childhood acute cases. This suggested that lower DNA methylation was probably related to acute ESAM.

Knowing that DNA methylation helps regulate gene expression, Hanchard and his colleagues next investigated whether there were differences in gene expression between ESAM and NESAM. They found that reduced overall methylation in ESAM resulted in a complex pattern of gene expression changes. For some genes, having reduced methylation enhanced their expression, while for others it reduced it.

Among the genes that were highly affected by reduced methylation were some of those related to conditions such as blood sugar regulation, fatty liver disease and other metabolic problems, which are also commonly seen more often in ESAM than NESAM.

Our findings contribute to a better understanding of the molecular events that likely result in the differences between ESAM and NESAM, Hanchard said. Although we still dont know why malnutrition leads to ESAM in some children, while it results in NESAM in others, our findings suggest that, once ESAM gets on its way, methylation changes are likely involved in the clinical signs and symptoms of the condition. There is also evidence that individual genetic variation also influences the level of DNA methylation. Furthermore, I am excited about the possibility that altering the molecular outcome of malnutrition with specific interventions could one day help alter the clinical outcome.

Other contributors to this work include first author Katharina V. Schulze, Shanker Swaminathan, Sharon Howell, Aarti Jajoo, Natasha C. Lie, Orgen Brown, Roa Sadat, Nancy Hall, Liang Zhao, Kwesi Marshall, Thaddaeus May, Marvin E. Reid, Carolyn Taylor-Bryan, Xueqing Wang, John W. Belmont, Yongtao Guan, Mark J. Manary, Indi Trehan and Colin A. McKenzie.

See a complete list of author affiliations and financial support for this study.

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Form of severe malnutrition linked to DNA modification - Baylor College of Medicine News