Study describes the sequencing of 64 full human genomes

Researchers at the University of Maryland School of Medicine (UMSOM) co-authored a study, published today in the journal Science, that details the sequencing of 64 full human genomes. This reference data includes individuals from around the world and better captures the genetic diversity of the human species.

Among other applications, the work will enable population-specific studies on genetic predispositions to human diseases as well as the discovery of more complex forms of genetic variation.

Twenty years ago this month, the International Human Genome Sequencing Consortium announced the first draft of the human genome reference sequence.

The Human Genome Project, as it was called, required 11 years of work and involved more than 1000 scientists from 40 countries. This reference, however, did not represent a single individual, but instead was a composite of humans that could not accurately capture the complexity of human genetic variation.

Building on this, scientists have conducted several sequencing projects over the last 20 years to identify and catalog genetic differences between an individual and the reference genome. Those differences usually focused on small single base changes and missed larger genetic alterations.

Current technologies now are beginning to detect and characterize larger differences – called structural variants – such as insertions of new genetic material. Structural variants are more likely than smaller genetic differences to interfere with gene function.

The new finding in Science announced a new and significantly more comprehensive reference dataset that was obtained using a combination of advanced sequencing and mapping technologies.

The new reference dataset reflects 64 assembled human genomes, representing 25 different human populations from across the globe. Importantly, each of the genomes was assembled without guidance from the first human genome composite. As a result, the new dataset better captures genetic differences from different human populations.

We've entered a new era in genomics where whole human genomes can be sequenced with exciting new technologies that provide more substantial and accurate reads of the DNA bases. This is allowing researchers to study areas of the genome that previously were not accessible but are relevant to human traits and diseases."

Scott Devine, PhD, Study Co-Author and Associate Professor, Medicine, University of Maryland School of Medicine

Scott Devine is also the Faculty Member of IGS. Institute of Genome Science (IGS)'s Genome Resource Center (GRC) was one of three sequencing centers, along with Jackson Labs and the University of Washington, that generated the data using a new sequencing technology that was developed recently by Pacific Biosciences. The GRC was one of only five early access centers that was asked to test the new platform.

Dr. Devine helped to lead the sequencing efforts for this study and also led the sub-group of authors who discovered the presence of "mobile elements" (i.e., pieces of DNA that can move around and get inserted into other areas of the genome).

Other members of the Institute for Genome Sciences (IGS) at the University of Maryland School of Medicine are among the 65 co-authors. Luke Tallon, PhD, Scientific Director of the Genomic Resource Center, worked with Dr. Devine to generate one of the first human genome sequences on the Pacific Bioscences platform that was contributed to this study. Nelson Chuang, a graduate student in Dr. Devine's lab also contributed to the project.

"The landmark new research demonstrates a giant step forward in our understanding of the underpinnings of genetically-driven health conditions," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "This advance will hopefully fuel future studies aimed at understanding the impact of human genome variation on human diseases."

Source:

University of Maryland School of Medicine

Journal reference:

Ebert, P., et al. (2021) Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Science. doi.org/10.1126/science.abf7117.

Posted in: Molecular & Structural Biology | Genomics

Tags: Bases, DNA, Gene, Genetic, Genome, Genomic, Genomics, Medical Research, Medical School, Medicine, Research

Comments (0)

Source: Read Full Article

Electronic doctors’ notes could help hospitals plan for surges in COVID-19 cases

A new study, published today in Nature Digital Medicine, found that 'natural language processing' (NLP) of information routinely recorded by doctors – as part of patients' electronic health records – reveal vital trends that could help clinical teams forecast and plan for surges in patients.

The researchers from King's College London, King's College Hospital NHS Foundation Trust (KCH), and Guy's and St Thomas' Hospital NHS Foundation Trust (GSTT), used NLP algorithms to translate the electronic notes made by doctors into a standardized, structured set of medical terms that could be analyzed by a computer.

Tracking trends in patients

In the same way social media posts can be tracked and aggregated by 'hashtags', the researchers detected words or phrases that were 'trending' in electronic health records at KCH and GSTT, during key stages of the COVID-19 pandemic last year. For instance, they tracked the number of patient records containing keywords for symptomatic COVID-19, such as 'dry cough', 'fever' or 'pneumonia'. Throughout the pandemic, hospital doctors have entered patient symptoms and test results into electronic health records, which are used to track the spread of COVID-19 at a national level.

However, these records often contain incomplete and unstructured data, that is difficult to access and analyze.

By analyzing the text as a 'bag of words', the researchers were able to produce real-time maps of trending 'signals' (i.e., symptoms that were most frequently recorded by doctors), and these signals closely mirrored patterns of positive laboratory tests reported by each hospital. Clear spikes were visible in March 2020, for instance, during the first wave of COVID-19 cases, and in subsequent waves.

Providing advance warning for hospitals

The study indicates that these signals provide a real-time situational report of reflecting current activity levels in a hospital and up to four days advance warning for hospitals helping them to prepare for surges in COVID-19 admissions.

The study authors also reported a strong association between the trending signals and regional tracking of COVID-19 admissions in London hospitals. In addition, they found that as new COVID-19 symptoms emerged nationally, these symptoms were also recorded more frequently by doctors at KCH and GSTT.

Dr James Teo, Clinical Director of AI at King's College Hospital and Guy's and St Thomas' Hospital, said: "By teaching computers how to read and understand doctors' notes, we hope to reveal important patterns and trends that could help in the fight against COVID-19 and other diseases.

Tracking word trends in electronic health records offers an additional method for studying disease and healthcare activity, in a way that is very easy and cost-effective to run. While this method was shown to be effective in two individual hospital Trusts, the approach could be scaled up to a regional or even national level with the right privacy safeguards".

CogStack

The CogStack platform used in this study allows researchers to interrogate complex sets of data extremely rapidly, providing a real-time feed of what is happening in a particular hospital, allowing clinical teams to prepare for incoming patients.

The CogStack platform allows us to extract information from deep within hospital records at King's College Hospital NHS Foundation Trust in near real time. This means we can anticipate likely increases in pressure on the system before receiving information such as test results, giving clinical teams time to react and prepare in advance."

Professor Richard Dobson, Head of the Department of Biostatistics & Health Informatics, NIHR Maudsley BRC

Source:

NIHR Maudsley Biomedical Research Centre

Journal reference:

Teo, J.T.H., et al. (2021) Real-time clinician text feeds from electronic health records. npj Digital Medicine. doi.org/10.1038/s41746-021-00406-7.

Posted in: Device / Technology News | Disease/Infection News | Healthcare News

Tags: Artificial Intelligence, Cough, Fever, Healthcare, Hospital, Imaging, Laboratory, Language, Medical Imaging, Medicine, Pandemic, Pneumonia, Research

Comments (0)

Source: Read Full Article

Three decades-old antibiotics could offer an alternative to opioid-based painkillers

Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.

Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it's caused by damage to pain-sensing nerves.

To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.

Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher – explored the potential of drugs already approved by the Food and Drug Administration (FDA).

The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1's promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.

Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.

To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1's activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein's catalytic domain, a key portion necessary for EphB1 to function.

In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.

Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic. This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

Enas S. Kandil, M.D., Associate Professor, Anesthesiology and Pain Management, UT Southwestern

Source:

UT Southwestern Medical Center

Posted in: Medical Science News | Medical Research News | Pharmaceutical News

Tags: Anesthesiology, Animal Model, Antibiotic, Cancer, Cardiology, Chronic, Chronic Pain, Crystallography, Diabetes, Drugs, Education, heat, Medicine, Minocycline, Molecular Biology, Nerve, Neuropathic Pain, Neuroscience, Opioids, Pain, Pain Management, pH, Prescription Drug, Protein, Receptor, Research, Tetracycline, Trauma, X-Ray

Comments (0)

Source: Read Full Article

Hydrogel injection could help repair damage to the heart muscle after heart attack

Researchers at CÚRAM, the SFI Research Centre for Medical Devices based at NUI Galway, and BIOFORGE Lab, at the University of Valladolid in Spain, have developed an injectable hydrogel that could help repair and prevent further damage to the heart muscle after a heart attack event.

The results of their research have just been published in the prestigious journal Science Translational Medicine.

Myocardial infarction or heart disease is a leading cause of death due to the irreversible damage caused to the heart muscle (cardiac tissue) during a heart attack. The regeneration of cardiac tissue is minimal so that the damage caused cannot be repaired by itself.

Current treatments lack an effective method to prevent death and subsequent cardiac tissue repair following a heart attack.

"This project involved the development and testing of an elastin-based hydrogel derived from a naturally occurring biomaterial in the human body", explains Professor Abhay Pandit, Scientific Director of CÚRAM and project lead. The hydrogel is based on a family of unique biomaterials, called elastin-like recombinamers, that BIOFORGE-UVa had developed in the search for advanced hydrogels for regenerative medicine.

"The hydrogel was developed to mimic the environment around the heart following an infarction and then customized to have the ability to protect and promote regeneration of the cardiac tissue", he explains.

The therapeutic effect of multiple injections of this hydrogel into the cardiac tissue was assessed during the first-ever preclinical study of its kind, demonstrating its efficacy for cardiac tissue remodeling following a heart attack.

The international research team, which included researchers from Ireland, Spain, Sweden, France and Italy, were able to show that if their hydrogel was injected into the heart muscle shortly after a heart attack, it resulted in less fibrosis (scarring of the cardiac tissue) and an increase in the generation of new blood vessels in the area.

They were also able to observe the rise in the preservation and survival of cardiomyocytes, a type of cell that allows the heart to beat, in the affected area.

Professor Pandit added: "This project demonstrates the efficacy of a unique biomaterial-only system able to induce a positive healing effect on cardiac tissue following a heart attack event. The functional benefits obtained by the timely injection of the hydrogel supports and highlight the potential use of this treatment in the clinic. The next step will be to develop a prototype for a delivery system for the hydrogel."
 

In this study, we employed a model to specifically look at a type of heart attack that has increased in incidence and is not often treated until the acute phase resolves. Scar tissue that forms after the heart attack often remodels negatively, causing future problems like heart failure. The timely injection of this hydrogel appears to change the way the heart muscle heals after a heart attack. There is a significant positive histological, biological and functional recovery of the injured heart muscle. Work is progressing now to deliver this to the sites of injury in different clinical settings and will be followed with translation into a clinical trial."

Mark Da Costa, Study Senior Co-Author and Professor and Cardiothoracic Surgeon

CÚRAM's research focuses on developing diagnostic devices, biomedical implants, cell-device and drug-device combination products to address unmet clinical needs. The recent announcement of a €46M reinvestment in CÚRAM by Science Foundation Ireland in February 2021, demonstrates the Government's strong commitment to the MedTech industry in Ireland, supporting the continuation of substantial academic, industry and clinical collaborations that are central to CÚRAM's work.

Source:

Science Foundation Ireland (SFI)

Journal reference:

Contessotto, P., et al. (2021) Elastin-like recombinamers-based hydrogel modulates post-ischemic remodeling in a non-transmural myocardial infarction in sheep. Science Translational Medicine. doi.org/10.1126/scitranslmed.aaz5380

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Blood, Blood Vessels, Cell, Clinical Trial, Diagnostic, Efficacy, Elastin, Fibrosis, Heart, Heart Attack, Heart Disease, Heart Failure, Hydrogel, Implants, Laboratory, Medicine, Muscle, Myocardial Infarction, Preclinical, Research, Scar, Translation

Comments (0)

Source: Read Full Article

Combination therapy produces clinical benefit for early stage non-small cell lung cancer

The first randomized Phase II clinical trial to report on single and combined neoadjuvant immune checkpoint inhibitor therapy in stage I-III non-small cell lung cancer (NSCLC) found combination therapy produced a significant clinical benefit, as assessed by major pathologic response (MPR) rate, as well as enhanced tumor immune cell infiltration and immunological memory. Researchers from The University of Texas MD Anderson Cancer Center published the study results today in Nature Medicine.

The NEOSTAR trial tested combined neoadjuvant therapy of nivolumab plus ipilimumab, as well as neoadjuvant nivolumab monotherapy in patients with operable NSCLC. The trial met its prespecified primary endpoint efficacy threshold in the combination arm, with eight of 21 treated patients (38%) achieving major pathological response, defined as ≤10% viable tumor at surgery.

MPR has been shown to correlate with improved survival outcomes after neoadjuvant chemotherapy in NSCLC. The prespecified efficacy boundary for each treatment to be considered promising for further testing was six or more MPRs in 21 evaluable patients. With MPR in five of 23 treated patients (22%), monotherapy did not meet the efficacy boundary.

While combination immunotherapy has been approved for a subset of patients with metastatic NSCLC, this is the first randomized study to report on the role of combination checkpoint inhibitors for operable, early stage disease.

More than 50% of patients with localized non-small cell lung cancer will relapse if treated with surgery alone. Adding chemotherapy produces only a modest improvement in overall survival, and it comes with toxicity. The results from our study with neoadjuvant combination immunotherapy are particularly encouraging in that we found that this dual treatment can induce higher pathologic responses and trigger immunological memory. This may translate into a reduced risk for tumor relapse in more patients with early stage non-small cell lung cancer."

Tina Cascone, MD., Ph.D., Assistant Professor, Thoracic/Head & Neck Medical Oncology and Study Lead Author

Study design and secondary endpoints

The Phase II single-institution study enrolled 44 patients with surgically resectable stage IA to IIIA NSCLC between June 2017 and November 2018. The median age of trial participants was 66 years old, and 64% were male. Participants were 84% white, 9% Black and 5% Asian. Most participants had a history of smoking: 23% identified as current smokers and 59% as former smokers.

Patients were randomized to one of two treatment arms with immune checkpoint inhibitors prior to surgery: 23 received three doses of nivolumab alone and 21 received three doses of nivolumab plus one dose of ipilimumab. Each arm was compared against historical controls of neoadjuvant chemotherapy. Overall, 41 patients completed the planned three doses of therapies, 37 patients had surgery on trial and two patients underwent surgery off trial after additional therapies.

Among the 37 patients who had surgical resection on the study, the combination arm showed higher MPR rates (50% versus 24%) and fewer viable tumor cells at resection than monotherapy (a median of 9% versus 50%). Combination therapy also showed better pathological complete response rates than monotherapy (38% versus 10%). After a median follow-up of 22 months, median overall survival and lung cancer-related recurrence-free survival were not reached.

Toxicities were manageable overall, with no new safety concerns compared to known adverse event profiles of either drug. The median time to surgery was 31 days after the last dose of nivolumab. Some patients experienced nodal immune flare (NIF), or the appearance of nodal disease progression on radiographic imaging, which invasive node biopsy revealed to be immune cell infiltration rather than malignant disease.

Exploratory analyses reveal immune impact, potential biomarkers

In an exploratory analysis of resected tissues, investigators found — and reported for the first time — higher levels of immune cell infiltration in tumors treated with combination therapy, including an abundance of CD3+ and CD3+CD8+ T lymphocytes, tissue-resident memory and effector memory T cells. Tumors that responded better to treatment had higher PD-L1 expression at baseline, but responses were also observed in those without PD-L1 expression in tumor cells.

The researchers analyzed the gut microbiome, as well, and found that pathologic response to combination therapy was associated with the presence of certain fecal microbes that also have been correlated with immunotherapy response in melanoma and other cancers. Immune checkpoint inhibitor therapy did not significantly affect the diversity or composition of the microbiome in this study.

"Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer," Cascone said. "The immune microenvironment findings also give us an opportunity to look at immune cell populations and potential biomarkers that can be evaluated in the future to identify those patients who are most likely to benefit from these agents in new prospective trials."

The NEOSTAR trial has been amended to a modular platform design, which provides the opportunity to add treatment arms to rapidly test and advance promising new neoadjuvant therapeutic combinations. Results from a third arm testing neoadjuvant nivolumab plus chemotherapy are expected later this year. A fourth arm testing the combination of dual immunotherapy plus chemotherapy is ongoing.

"The NEOSTAR trial results set the stage for evaluating the role of dual immunotherapy added to neoadjuvant chemotherapy, which we are currently exploring, and expediting the investigation of novel agents in the perioperative setting," Cascone said. "This is a population with potentially curable disease. We should do whatever it takes to minimize the risk of relapse and increase the cure rates for these patients."

The NEOSTAR trial was supported by the Lung Cancer Moon Shot®, part of MD Anderson's Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients' lives. Boris Sepesi, M.D., associate professor of Thoracic and Cardiovascular Surgery, served as co-principal investigator of the study. A full list of co-authors and author disclosures can be found in the paper.

Source:

University of Texas M. D. Anderson Cancer Center

Journal reference:

Cascone, T., et al. (2021) Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nature Medicine. doi.org/10.1038/s41591-020-01224-2.

Posted in: Drug Trial News | Medical Condition News

Tags: Biopsy, Cancer, Cardiovascular Surgery, CD3, Cell, Chemotherapy, Clinical Trial, Efficacy, Imaging, Immunotherapy, Laboratory, Lung Cancer, Malignant, Medicine, Melanoma, Microbiome, Neck, Non-Small Cell Lung Cancer, Oncology, PD-L1, Perioperative, pH, Research, Small Cell Lung Cancer, Smoking, Surgery, Translation, Tumor

Comments (0)

Source: Read Full Article

Study sheds light on pathological characteristics behind sudden cardiac death

Nearly a half-million people a year die from sudden cardiac death (SCD) in the U.S. — the result of malfunctions in the heart's electrical system.

A leading cause of SCD in young athletes is arrhythmogenic cardiomyopathy (ACM), a genetic disease in which healthy heart muscle is replaced over time by scar tissue (fibrosis) and fat.

Stephen Chelko, an assistant professor of biomedical sciences at the Florida State University College of Medicine, has developed a better understanding of the pathological characteristics behind the disease, as well as promising avenues for prevention. His findings are published in the current issue of Science Translational Medicine.

Individuals with ACM possess a mutation causing arrhythmias, which ordinarily are non-fatal if managed and treated properly. However, Chelko shows that exercise not only amplifies those arrhythmias, but causes extensive cell death. Their only option is to avoid taking part in what should be a healthy and worthwhile endeavor: exercise.

There is some awful irony in that exercise, a known health benefit for the heart, leads to cell death in ACM subjects. Now, we know that endurance exercise, in particular, leads to large-scale myocyte cell death due to mitochondrial dysfunction in those who suffer from this inherited heart disease."

Stephen Chelko, Assistant Professor of Biomedical Sciences, College of Medicine, Florida State University

Several thousand mitochondria are in nearly every cell in the body, processing oxygen and converting food into energy. Considered the powerhouse of all cells (they produce 90 percent of the energy our bodies need to function properly), they also play another important role as a protective antioxidant.

As mitochondria fail to function properly, and myocyte cells in the heart die, healthy muscles are replaced by scar tissue and fatty cells. Eventually, the heart's normal electrical signals are reduced to an erratic and disorganized firing of impulses from the lower chambers, leading to an inability to properly pump blood during heavy exercise. Without immediate medical treatment, death occurs within minutes.

Chelko's research gets to the heart of the process involved in mitochondrial dysfunction.

"Ultimately, mitochondria become overwhelmed and expel 'death signals' that are sent to the nucleus, initiating large-scale DNA fragmentation and cell death," Chelko said. "This novel study unravels a pathogenic role for exercise-induced, mitochondrial-mediated cell death in ACM hearts."

In addition to providing a better understanding of the process involved, Chelko discovered that cell death can be prevented by inhibiting two different mitochondrial proteins. One such approach utilizes a novel targeting peptide developed for Chelko's research by the National Research Council in Padova, Italy.

That discovery opens avenues for the development of new therapeutic options to prevent myocyte cell death, cardiac dysfunction and the pathological progression leading to deadly consequences for people living with ACM.

Source:

Florida State University

Journal reference:

Chelko, S. P., et al. (2021) Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy. Science Translational Medicine. doi.org/10.1126/scitranslmed.abf0891.

Posted in: Medical Research News | Medical Condition News

Tags: Antioxidant, Blood, Cardiomyopathy, Cell, Cell Death, DNA, Exercise, Fibrosis, Genetic, Heart, Heart Disease, Laboratory, Medicine, Mitochondria, Muscle, Mutation, Oxygen, Research, Scar, Sudden Cardiac Death

Comments (0)

Source: Read Full Article

Scientists discover two unique subtypes of a prominent mutation in patients with AML

Using advanced RNA sequencing, scientists have identified two unique subtypes of a prominent mutation present in many patients with Acute Myeloid Leukemia (AML) called NPM1 that could help predict survival and improve treatment response for patients whose leukemic cells bear the mutation.

In research published Feb. 16, in Nature Communications, a team led by Princess Margaret Cancer Centre Senior Scientists, Drs. Benjamin Haibe-Kains, Aaron Schimmer and Mark Minden, have discovered that within the NPM1 mutation of AML there exists two unique subtypes, one of which can be effectively treated with drugs already in use.

It is the first study to classify within the common NPM1 mutant form of AML two subtypes, one being "primitive" and the other "committed." Furthermore, the research shows that each subtype has a different response to treatment and long-term survival, cracking open opportunities to personalize treatment plans and introduce new targeted therapies in the future.

"Patients with NPM1 mutated AML face a relapse rate of around 40 per cent," says Dr. Schimmer, Research Director and acute leukemia physician at the Princess Margaret, which is part of University Health Network. "While we're getting better at incorporating new monitoring techniques, we're still not at a point where we can adequately predict what side of the curve a patient might fall.

By going deeper with our sequencing, we can better predict outcomes and adjust treatment accordingly for each patient."

NPM1 mutated AML makes up around 30 per cent of all AML cases, but therapeutic discoveries for these patients have been limited.

While the NPM1 mutation is relatively common, AML is a rare disease to begin with. Generating enough data to be able to sequence and understand the biology of this mutation is very challenging."

Dr Haibe-Kains,  Associate Professor, Medical Biophysics, University of Toronto

This was made possible in large part thanks to a team led by Dr. Minden, Senior Scientist and medical oncologist, and Andrea Arruda, staff scientist at the Princess Margaret Cancer, who have been collecting samples to enable deeper learning since the mid-1980s thanks to the willingness, generosity and foresight of patients.

"Recognizing those 'needles in a haystack'the small groups of patients that don't benefit from certain treatments is critically important for improving personalized medicine," says Dr. Minden. "Now we can start to improve outcomes for this more discreet patient population."

An advanced computational model was custom-built to analyze RNA from patient leukemic cells obtained from the Leukemia Live Cell Tissue Bank, along with other data published from NPM1 mutant leukemia studies.

"We developed a unique machine-learning model that was able to clearly discriminate two subtypes of NPM1 mutant AML in datasets collected from patients," says Dr. Haibe-Kains.

These two subtypes both contain mutant AML but they express different genes that can now separate them into two clear subtypes based on their RNA.

The study also suggests that certain drugs already used to treat other types of cancer could be effective in the primitive subtype.

"Once we were able to identify the pattern of each subtype, we analyzed existing pharmacogenomics data to narrow a list of drugs that might be able to target one subtype or the other," explained Dr. Haibe-Kains. "We found two drugs that seemed to effectively target the primitive subtype in the lab, with potential to move to clinical trials in the future."

"This finding could change the way we treat patients," says Dr. Schimmer. "It opens up the opportunity to better refine and time treatmentswhether it's the decision for a stem cell transplant early on, or choosing more effective and less toxic therapies throughout the course of treatment.

Our goal with all of our patients is to get better and better outcomes. This is one step towards doing better."

Source:

University Health Network

Posted in: Medical Science News | Medical Research News | Medical Condition News

Tags: Cancer, Cell, Drugs, Education, Genes, Hospital, Leukemia, Medicine, Mutation, Pharmaceuticals, Rare Disease, Research, RNA, Transplant

Comments (0)

Source: Read Full Article

HIV self-testing increases testing uptake and frequency in trans people

HIV self-testing could reduce the time between HIV infection and HIV diagnosis amongst trans people when compared to standard testing services, suggests new research in EClinicalMedicine.

The project was a collaboration between the London School of Hygiene & Tropical Medicine (LSHTM), University College London (UCL), and the Medical Research Council Clinical Trials Unit. It involved more than 100 trans men and trans women in England and Wales, and is the largest HIV self-testing trial in this community to be reported.

Participants were first randomized into two groups, one was given one self-test for HIV, the other group was offered a link to find standard testing services, and no self-tests. Some of the self-testing arm were randomized a second time and offered either repeat self-testing (an additional self-test every three months) or standard testing services. They were then followed up for two years.

More than 93% of participants in the self-testing group tested for HIV compared to 26% in the standard care group. HIV testing frequency was also increased by three times in the repeat testing group. Importantly there were no negative impacts on STI testing, but uptake of these services was very low across all arms in the trial.

Accompanying qualitative research led by the London School of Hygiene & Tropical Medicine revealed that the main reason HIV self-testing was so popular was because most sexual health services do not meet the needs of trans people. Services were reported to be often set-up and run in a way that did not recognize their unique needs.

Trans people are at increased risk of HIV and poor sexual health compared to other groups. They tend to test less often and have worse clinical outcomes when they are diagnosed with HIV.

The researchers say rolling out self-testing more widely and making sure it is accessible to trans people will increase HIV testing rates, and that staff require training aimed at improving the experiences of trans people when they access sexual health services.

Charles Witzel from LSHTM who led the qualitative study, said: "HIV has changed enormously. Thanks to effective treatment people with HIV can now live long and full lives. However, stigma and inappropriately designed services still act as a major barrier for individuals to access testing, the critical first step towards treatment for those with undiagnosed HIV and an important prevention opportunity for those who are HIV negative.

"Despite increased vulnerability for trans people, they are seldom included in HIV testing or prevention research, and when they are their data is rarely presented separately from other priority groups such as gay and bisexual men. Our research aimed to shed new light on how best to meet the HIV testing needs of trans men and trans women."

HIV self-testing was legalized in the UK in 2014 but has not been made widely available on the NHS. Instead, self-testing has mostly been provided in fits and starts through pilot projects run by the voluntary sector and through a large clinical trial in England and Wales.

An HIV Self-testing Public Health Intervention (SELPHI) study was a large randomized trial of HIV self-testing in England and Wales which recruited men (cis and trans) and trans women, all who have sex with men.

The trial assessed whether providing free self-testing would increase HIV testing uptake and frequency, and if it had any impacts on STI testing.

Acceptability of the HIV self-test kit was very high: 97% found the instructions easy to understand, 97% found the test easy to use and 100% reported a good overall experience.

The qualitative peer-interview study sourced additional insights of the experiences of trans people when accessing HIV testing services, including HIV self-testing. It found staff working in sexual health clinics frequently misgendered them or provided stigmatizing care which wasn't respectful of their gender identity and/or their sexual orientation.

However, participants who had accessed sexual health services specifically designed for and by trans people said that these services were excellent.

Alison Rodger from UCL who co-led the trial said: "Put together, the results of our study clearly show the potential HIV self-testing has to meet some of the immediate HIV testing needs for trans men and trans women. This could mean more people with HIV receive treatment earlier which will have benefits for their health and will also reduce onward transmissions."

It is critical that sexual health clinics adapt to be more inclusive, welcoming and to make sure they meet the diverse needs of these groups. Trans people must be actively included in these initiatives to make them successful."

Talen Wright, Researcher

The authors acknowledge limitations of the study, including that the main trial did not include non-binary people, and their experiences while accessing HIV testing remains a significant research gap. Given the findings on inappropriately designed services, future sexual health research and service improvement initiatives for non-binary people is a critical priority.

Source:

London School of Hygiene & Tropical Medicine

Journal reference:

Witzel, T.C., et al. (2021) Impact and acceptability of HIV self-testing for trans men and trans women: A mixed-methods subgroup analysis of the SELPHI randomised controlled trial and process evaluation in England and Wales. EClinicalMedicine. doi.org/10.1016/j.eclinm.2020.100700.

Posted in: Disease/Infection News | Healthcare News

Tags: Clinical Trial, Education, Frequency, HIV, Hygiene, Medical Research, Medicine, Public Health, Research, Sexual Health, Social Care, students, Translation

Comments (0)

Source: Read Full Article

Analysis finds racial and ethnic disparities in the odds of testing positive for COVID-19

An analysis of Kaiser Permanente members in Northern California early in the COVID-19 pandemic found racial and ethnic disparities in the likelihood of testing positive for the coronavirus, but no significant disparities in mortality among those who were hospitalized.

According to the study published Feb. 8 in Annals of Internal Medicine, Latino patients were nearly 4 times as likely as white patients to become infected with the virus, while Asian and Black patients were 2 times as likely to get COVID-19 as white patients. The odds of hospitalization were also higher for Latino, Asian, and Black patients with COVID-19 than for white patients. However, the study did not find racial disparities in mortality among patients hospitalized after infection.

The authors of the study said the findings reinforce the urgent message to health systems to mitigate the spread of COVID-19 in their highest-risk communities by seeking to reduce transmission among the most vulnerable.

"We need to continue to explore the reasons why some communities have higher infection rates, which in a pandemic can be deadly," said lead author Gabriel Escobar, MD, an investigator with the Kaiser Permanente Northern California Division of Research. "It's also our responsibility as clinicians and health care leaders to improve the way we reach out to these communities."

While research from other health systems has also found racial disparities related to COVID-19, this analysis was the first to follow a cohort of patients from virus testing through the complete course of the disease, the authors said.

"COVID-19 has dramatically altered the patterns of health care delivery across the world making it more difficult than ever to trace patients' experiences and outcomes," said coauthor Vincent Liu, MD, MS, a research scientist with the Northern California Division of Research and critical care specialist with The Permanente Medical Group. "Kaiser Permanente's comprehensive health data from testing to medical care and hospitalization allow us to carefully assess the impact of racial and ethnic differences at each stage."

The study examined a total of 3.5 million Kaiser Permanente members in Northern California, 2.6% of whom, or 91,212 people, received a COVID-19 test between Feb. 1 and May 31, 2020. Of the total, 4%, or 3,686, tested positive.

The study confirmed other research linking specific comorbidities with increased mortality from COVID-19, and that nonwhite patients were more likely to have chronic health conditions. However, the authors noted that there are complex reasons why that might be. "Many factors may contribute to comorbidity and intrinsic risk, including the totality of ways in which societies foster racial discrimination, through mutually reinforcing inequitable systems (structural racism)," they wrote.

Unadjusted hospital mortality rates were highest among white patients (17%), followed by Black patients (12.7%), Asian patients (10.5%), and Hispanic patients (9.7%). After adjusting for age, severity of illness, and comorbidities, racial and ethnic differences were no longer significantly different.

Neighborhood and age as risk factors

Along with following the outcomes for those who tested positive, the analysis also looked at the role of geographic location, finding infections clustered in areas with higher proportions of nonwhite members, regardless of their health risks for COVID-19.

The researchers found race was a major factor in likelihood of infection, but contributed in a minor way to hospitalization, admission, and death. For those adverse outcomes, age was the major predictor.

The findings bring an important message to health care leaders, said coauthor Stephen Parodi, MD, associate executive director of The Permanente Medical Group and national infectious disease leader at Kaiser Permanente. "Health care systems are in a position to take action in their communities in response to these inequities," Dr. Parodi said. "Specifically, we must continue to pursue initiatives such as community education, contact tracing, and public health partnerships. We are deepening community connections to address social determinants in response to an unprecedented health threat that is taking an unequal toll."

Clinicians also have a role in reducing inequities, and Kaiser Permanente has taken steps to support clinicians in doing so, said coauthor Yi-Fen "Irene" Chen, MD, associate executive director of The Permanente Medical Group. "The pandemic has moved many medical visits to telehealth, which has many benefits, but we must remain aware of the digital divide that could make this technology harder to access in some traditionally underrepresented communities," Dr. Chen said. "Addressing such issues is part of Kaiser Permanente's longstanding commitment to health equity."

Dr. Chen noted the importance of addressing equity in vaccination. "Now that COVID-19 vaccines are available, physicians and health care providers must employ culturally tailored messaging for communities that experience health disparities, to make sure they are optimally informed and protected," she said.

Source:

Kaiser Permanente

Posted in: Medical Research News | Disease/Infection News | Healthcare News

Tags: Chronic, Chronic Disease, Coronavirus, Critical Care, Education, Health Care, Health Disparities, Health Systems, Hospital, Medicine, Mortality, Pandemic, Public Health, Research, Virus

Comments (0)

Source: Read Full Article

Plants depend on LEAFY protein that enables cells to change their fate

Cells don't express all the genes they contain all the time. The portion of our genome that encodes eye color, for example, doesn't need to be turned on in liver cells. In plants, genes encoding the structure of a flower can be turned off in cells that will form a leaf.

These unneeded genes are kept from becoming active by being stowed in dense chromatin, a tightly packed bundle of genetic material laced with proteins.

In a new study in the journal Nature Communications, biologists from the University of Pennsylvania identified a protein that enables plant cells to reach these otherwise inaccessible genes in order to switch between different identities.

Called a "pioneer transcription factor," the LEAFY protein gets a foothold in particular portions of the chromatin bundle, loosening the structure and recruiting other proteins that eventually allow genes to first be transcribed into RNA and then translated into proteins.

The programs that are not needed in a given cell or tissue or condition are effectively shut off by various chromatin modifications that make them very inaccessible. The question has always been, How do you go from shut to open? We found that LEAFY, this protein that we already knew was important in reprogramming plant cells, is one of these pioneer transcription factors that get a foot in the door, as it were, to alter the program of cells."

Doris Wagner, Study Senior Author and Biologist, School of Arts & Sciences, University of Pennsylvania

Pioneer transcription factors were first characterized by Penn faculty member Kenneth Zaret of the Perelman School of Medicine, whose own work has examined these regulatory proteins in animals, such as in the context of liver development.

Early in her time at Penn, Wagner heard Zaret give a talk about his work in this area and grew curious about looking for similar factors in plants, given that flexible gene expression is so critical to their survival.

Indeed, plants must switch between expressing whole sets of different genes all the time. In rich soils, they may grow more branches to get bigger, while in a drought they may express more genes associated with developing flowers, so they can set seed and reproduce before they succumb.

How plant cells determine their identity and fate has been a focus of Wagner's work since the start of her career, and so has LEAFY. During her postdoc days, Wagner showed that LEAFY could reprogram root cells to produce flowers. "That gave us a good clue that LEAFY might have this 'pioneer' activity, but we had to look more closely to prove it," she says.

To do so, Wagner and colleagues first used isolated protein and strands of genetic material to show that LEAFY, though not other transcription factors, bound to nucleosomes, subunits of chromatin where DNA spools on a cluster of proteins called histones. Specifically, the binding occurred at the gene AP1, which is known to be activated by LEAFY to prompt plants to make flowers.

To confirm that this connection was true in a living organism, the researchers took plant roots and applied a compound that causes them to flower spontaneously. When flowering, they found that not only did LEAFY bind strongly to AP1 but that the binding site was also occupied by a histone. "This tells us that the histones and LEAFY are really occupying the same portion of DNA," Wagner says.

Furthermore, they showed that chromatin structure began to open up at the AP1 region when LEAFY was activated, a key facet of what pioneer transcription factors do.

This opening was limited, and full loosening of chromatin took days. What did happen quickly, the researchers found, was that LEAFY displaced a linker histone protein, creating a small local opening that also allowed other transcription factors to nose their way into the DNA.

Though pioneer transcription factors had been proposed to exist in plants, the new work provides the first concrete support backing this conception for LEAFY. And Wagner believes there are others. "If necessary, plants can alter their entire body plan or generate an entire plant from a little piece of leaf," she says.

"We predict setting this in motion will require pioneer transcription factors. So plants may actually have more of these factors than animals."

In upcoming work, she and her team hope to delve more deeply into the processes that precede and follow this "pioneering" activity of LEAFY: Does anything restrict its activity, and how do the other factors that it recruits fully unpack the hidden-away genes? "It would be great to find out both sides of this equation," Wagner says.

The findings have significance in agriculture and breeding, where LEAFY is already manipulated to encourage earlier flowering, for example. And as more is understood about pioneer transcription factors in plants, Wagner can envision a fine-tuning of other aspects of plant growth and activity, which could be leveraged to help crops adapt to new environmental conditions, such as those being ushered in by climate change.

Source:

University of Pennsylvania

Journal reference:

Jin, R., et al. (2021) LEAFY is a pioneer transcription factor and licenses cell reprogramming to floral fate. Nature Communications. doi.org/10.1038/s41467-020-20883-w.

Source: Read Full Article