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Fecal Microbiota Transplants Help Patients with Advanced Melanoma Respond to Immunotherapy, Science Article Reports

For patients with cancers that do not respond to immunotherapy drugs, adjusting the composition of microorganisms in the intestines—known as the gut microbiome—through the use of stool, or fecal, transplants may help some of these individuals respond to the immunotherapy drugs, a new study suggests. Researchers at the National Cancer Institute (NCI) Center for Cancer Research, part of the National Institutes of Health, conducted the study in collaboration with investigators from the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center at the University of Pittsburgh. In the study, some patients with advanced melanoma who initially did not respond to treatment with an immune checkpoint inhibitor, a type of immunotherapy, did respond to the drug after receiving a transplant of fecal microbiota from a patient who had responded to the drug. The results suggest that introducing certain fecal microorganisms into a patient’s colon may help the patient respond to drugs that enhance the immune system’s ability to recognize and kill tumor cells. The findings were published in the February 5, 2021 issue of Science. The article is titled “Fecal Microbiota Transplant Overcomes Resistance to Anti–PD-1 Therapy in Melanoma Patients” (https://science.sciencemag.org/content/371/6529/595). “In recent years, immunotherapy drugs called PD-1 and PD-L1 inhibitors have benefited many patients with certain types of cancer, but we need new strategies to help patients whose cancers do not respond,” said study co-leader Giorgio Trinchieri, MD, Chief of the Laboratory of Integrative Cancer Immunology in NCI’s Center for Cancer Research. “Our study is one of the first to demonstrate in patients that altering the composition of the gut microbiome can improve the response to immunotherapy.

Avian Version of Autism Gene FOXP1 Plays Key Role in Birds Remembering Songs; Finding Could Change Focus of Speech Therapies for FOXP1-Related Autism Spectrum Disorder (ASD); Other ASD-Related Genes Might Also Be Studied in Songbird Model

Inactivating a gene (FoxP1) in young songbirds that’s closely linked with autism spectrum disorder (ASD) prevents the birds from forming memories necessary to accurately reproduce their fathers’ songs, a new study led by University of Texas Southwestern (UTSW) shows. The findings, published online on February 3, 2021 in Science Advances, may help explain the deficits in speech and language that often accompany ASD and could eventually lead to new treatments specifically targeting this aspect of the disorder. The open-access article is titled “Autism-Linked Gene FoxP1 Selectively Regulates the Cultural Transmission of Learned Vocalizations.” Study leader Todd Roberts, PhD, a Thomas O. Hicks Scholar in Medical Research at UTSW, explains that learning vocalizations for both songbirds and humans consists of two different stages: First, birds and humans must form a memory of sounds. Next, they practice the sounds through imitation. Juvenile zebra finches typically practice their fathers’ song thousands of times a day over three months, rehearsing it approximately 100,000 times until it’s a close match. These birds can memorize the song 20 to 60 days after hatching, but they don’t start to practice singing it until approximately 35 to 40 days after hatching. To better understand the role FoxP1 might play in both parts of this process, the researchers separated young zebra finches into two groups: Half the birds spent their early lives in contact with their singing fathers and continued to live with them while they practiced their songs; the other half spent their early lives with their songless mothers and later joined their fathers during the practice phase.

IncellDx Files Patents for Two Distinct Algorithms for COVID Long-Hauler Index and Active COVID-19 Severity Score; Algorithms Built on Tailored Panel of Cytokines & Chemokines Specific for Cytokine Storm Conditions and Chronic COVID Long-Haulers

On February 3, 2021, IncellDx, a leading precision medicine diagnostics company, announced that it had filed patents for algorithms identifying immunologic profiles unique to COVID long-haulers and patients with severe COVID. IncellDx has developed and patented two distinct algorithms using machine learning, built on a tailored panel of cytokines and chemokines specific for abnormalities in cytokine storm conditions and in chronic COVID patients (often referred to as COVID "long-haulers"). These have been submitted for publication (pre-print available through BioRxiv https://www.biorxiv.org/content/10.1101/2020.12.16.423122v1). The preprint is titled “Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning.” The first algorithm generates a severity score based on analysis of hundreds of COVID-19 patients spanning the spectrum of disease severity from mild to critical. The second algorithm derived from the same cytokine/chemokine immune panel, demonstrates that the immunology of long-haulers is distinct from active COVID-19. This objective algorithm offers the opportunity for precision medicine to be used by physicians as a guide in the care of COVID-19 patients. Bruce Patterson, MD, CEO of IncellDx, commented that "Since the beginning of the COVID-19 pandemic, IncellDx has led the way in using biomarkers to develop precision medicine approaches to therapy including the post-COVID-19 long-haulers. A recent preprint of a meta-analysis suggests as many as 80% of individuals infected by COVID-19 may have at least one symptom long after infection." IncellDx, in collaboration with Ram Yogendra, MD, and Purvi Parikh, MD, launched the website http://www.covidlonghaulers.com on January 29, 2021.

New Work Reveals How Tau Protein “Tangles” Develop in Alzheimer’s Brain; Lysosomal Enzymes Permeabilize Membranes of Endosomes and of Tau-Containing Exosomes in Endolysosomes Releasing Tau into the Cytosol

University of Queensland (UQ) (Australia) researchers have discovered a new “seeding” process in brain cells that could be a cause of dementia and Alzheimer's disease. UQ’s Queensland Brain Institute (https://qbi.uq.edu.au/) dementia researcher Professor Jürgen Götz, PhD, said the study revealed that tangled neurons, a hallmark sign of dementia, form in part by a cellular process that has gone astray and allows a toxic protein, tau, to leak into healthy brain cells. “These leaks create a damaging seeding process that causes tau tangles and ultimately lead to memory loss and other impairments,” Professor Götz said. Professor Götz said, until now, researchers did not understand how tau seeds were able to escape after their uptake into healthy cells. “In people with Alzheimer’s disease, it seems the tiny sacs transporting messages within or outside the cells, called exosomes, trigger a reaction which punches holes in their own cell membrane and allows the toxic seeds to escape,” he said. "As more tau builds up in the brain, it eventually forms tangles, and together with abnormally configured proteins known as amyloid plaque, they form the key features of these neurological diseases." The new results are described in an article published online on January 8, 2021 in Acta Pathologica (https://link.springer.com/article/10.1007/s00401-020-02254-3). The open-access article is titled “Exosomes Induce Endolysosomal Permeabilization As a Gateway by Which Exosomal Tau Seeds Escape into the Cytosol.” In their abstract, the authors state the following.

How European Hibernating Bats Cope with White-Nose Syndrome, Which Kills Millions of North American Bats

Fungal diseases are a major threat to wildlife, sometimes resulting in significant population declines or even causing the extirpation of populations or species. White-nose syndrome, caused by the cold-loving fungus Pseudogymnoascus destructans, has become a major cause of death for hibernating bats in North America. European bats survive when infected by the same fungus during hibernation. What are the reasons for such a contrast in outcomes? A scientist team led by the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) has now analyzed the humoral innate immune defense of European greater mouse-eared bats to the fungus. In contrast to North American bats, European bats have sufficient baseline levels of key immune parameters and thus tolerate a certain level of infection throughout hibernation. The results were published online on January 18, 2021 in Developmental and Comparative Immunology. He article is titled “Determinants of Defence Strategies of a Hibernating European Bat Species Towards the Fungal Pathogen Pseudogymnoascus destructans.” During infections caused by the fungus P. destructans (Pd), the causative agent of white-nose syndrome, North American bats arouse frequently from hibernation to trigger a more elaborate immune response, whereas European bats remain in dormancy, owing, as the new results reveal, to their competent baseline immunity. Not being able to deal with the fungus by baseline immunity causes North American bats to deplete fat stores before the end of winter because of the need for additional and energetically expensive arousals, which ultimately leads to their starvation. European bats may also arouse once in a while when infected, but their strong baseline immunity allows them to balance the tight energy budget better during winter hibernation.

Genetic Screening Before Prescribing Could Benefit Millions

Four million UK patients could benefit annually from genetic testing before being prescribed common medicines, according to new research from the University of East Anglia (UEA) in collaboration with Boots UK and Leiden University (Netherlands). The research results were published online on January 19, 2021 in the British Journal of Clinical Pharmacology. The open-access article is titled “'Estimating the Potential Impact of Implementing Pre-Emptive Pharmacogenetic Testing in Primary Care Across The UK.” Researchers looked through 2019 National Health Service (NHS) dispensing data across the UK to see how many patients are started on new prescriptions each year that could be potentially optimized by genetic testing. The scientists studied 56 medicines, including antidepressants, antibiotics, stomach ulcer treatments, and painkillers where there are known drug-gene interactions. And they found that in more than one in five occasions (21.1%) there was the potential for a doctor or pharmacist to take action under international pharmacogenetic guidelines. If this screening was applied to all new prescriptions, an estimated one in 11 (9.1%) would lead to a change of drug or dose, affecting over five million dispensed items. Depending on the results of individual pharmacogenetic tests, patients might receive either a higher or lower starting dose than normal or be more closely monitored during the early stages of treatment. Pharmacogenomic testing services already working in the Netherlands show that specially-trained general practitioners and pharmacists can carry out pre-prescribing tests and use the results to give advice on safer and more effective prescribing, delivering better patient outcomes.

Scientists Publish Blueprint to Apply Artificial Intelligence (AI) to Extend Human Longevity

On January 27, 2021, Deep Longevity, a fully-owned subsidiary of Regent Pacific (HKEX: 0575), specializing in the development and the application of next-generation artificial intelligence (AI) for aging and longevity research, announced the January 14, 2021 online publication of an open-access article in Nature Aging titled "Artificial Intelligence in Longevity Medicine” (https://www.nature.com/articles/s43587-020-00020-4). In the article, the authors describe a new field of study converging AI, basic research, and medicine referred to as Longevity Medicine. Another definition for Longevity Medicine is the preventative and restorative medicine enabled by the deep-aging clocks and artificial intelligence. The article was authored by Alex Zhavoronkov, PhD, the Founder and Chief Longevity Officer of Deep Longevity, a computer scientist with a doctoral degree in biophysics; Evelyne Yehudit Bischof, MD, MPH, a practicing medical doctor trained in the top European and the US medical schools actively engaged in aging research and gero-oncology at the University Hospital Basel in Switzerland, and at Shanghai University of Medicine and Health Sciences; and Kai-Fu Lee, PhD, one of the most prolific scientists and entrepreneurs in artificial intelligence, and Chairman and CEO of Sinovation Ventures (https://www.sinovationventures.com/). The traditional approach to medicine is to treat diseases. However, scientists estimate (Cutler and Mattson, 2006) that complete elimination of cancer would result in only a 2.3-year increase in life expectancy in the US at birth and 1.3-year gain at age 65. Complete elimination of influenza and pneumonia would yield gains of 0.5 years and 0.2 years in life expectancy in general.

Scientists Identify Protein (KIF18A) Key to Cancer Cells’ Ability to Replicate Despite Aneuploidy

An international research team, co-led by the Technische Universität Kaiserslautern (TUK), has identified a vulnerability in most cancer cells that could help lead to drugs that target tumors regardless of cancer type. Cancer cells with an abnormally high number of chromosomes appear to rely on a particular protein (KIF18A) for cell division and largely die when that protein is blocked, researchers in Germany, Israel, Italy, and the US report in an online publication on January 27,2021 in Nature (https://www.nature.com/articles/s41586-020-03114-6). The article is titled “Aneuploidy Renders Cancer Cells Vulnerable to Mitotic Checkpoint Inhibition.” Because more than 90 percent of tumors, regardless of tissue type, contain extra chromosomes, this protein could present an effective target for treating a wide range of cancers. “We think we have found a possible vulnerability of cancer cells with abnormal chromosome numbers,” says Zuzana Storchová, PhD, a Professor of Molecular Genetics at the Technische Universität Kaiserslautern (TUK) in Germany, and a co-senior author of the Nature article. Normal, healthy human cells have 46 chromosomes, but malignant tumors often consist of highly abnormal cancer cells that can have deviant chromosome numbers, usually ranging between 60 to 90 chromosomes. They are called aneuploid cancer cells. For a long time, researchers thought aneuploidy was a side-effect of cells turning cancerous, but in the last 15 years, more suspect this might be one of the driving forces of cancer. Finding a common feature associated with this aberrant number of chromosomes could be critical for targeting cancer, regardless of where it develops in the body. Dr. Storchová and collaborators conducted extensive experiments with nearly 1,000 cell lines from human cancer patients and model cancer cells cultured in the lab.

Scientists Gain New Insight into How Remdesivir Interacts with SARS-CoV-2 RNA Polymerase; Findings Could Be Basis for Developing Better Anti-Virals

More effective antiviral treatments could be on the way after research from The University of Texas at Austin (UT-Austin) sheds new light on the COVID-19 antiviral drug remdesivir, the only treatment of its kind currently approved in the U.S. for the coronavirus SARS-CoV-2. The study was published online on January 28, 2021 in Molecular Cell. The article is titled “Remdesivir Is a Delayed Translocation Inhibitor of SARS CoV-2 Replication.” Remdesivir targets a part of the coronavirus that allows it to make copies of itself and spread through the body. For the first time, scientists identified a critical mechanism that the drug uses and unearthed information that drug companies can use to develop new and improved antivirals to take advantage of the same trick. According to co-author Kenneth Johnson, PhD, Professor of Biochemistry at UT-Austin, the finding could also lead to more potent drugs, meaning a patient could take less of a dose, see fewer side effects, and experience faster relief. "Right now, it's a five-day regimen of taking quite a bit of remdesivir," said Dr. Johnson. "That's inconvenient and comes with side effects. What if you could take just one pill and that was all you needed to do? That would make a huge difference in terms of the here and now."Study co-author David Taylor, PhD, Assistant Professor of Molecular Biosciences at UT-Austin, likens the trick the team identified to a paper jam in the virus's photocopier. Remdesivir shuts down this photocopier--called an RNA polymerase--by preventing copying of the virus's genetic code and its ability to churn out duplicates and spread through the body. The team detected where the drug manages to gum up the gears, grinding the machine to a halt. "We were able to identify the point where that paper jam happens," said Dr. Taylor. "We know now exactly what's creating this block.

Parkinson’s Disease Risk & Severity Are Tied to Activity of Potassium Ion Channel in Lysosomes; Genetic Variations in TMEM175 Trans-Membrane Protein Are Associated With Both Increases & Reductions in Risk of This Neurodegenerative Disease

Many genetic mutations have been found to be associated with a person’s risk of developing Parkinson’s disease. Yet, for most of these variants, the mechanism through which they act remains unclear. Now a new study in Nature (https://www.nature.com/articles/s41586-021-03185-z) published online on January 27, 2021, and led by a team from the University of Pennsylvania (Penn), has revealed how two different variations—one that increases disease risk and leads to more severe disease in people who develop Parkinson’s and another that reduces risk—manifest in the body. The work, led by Dejian Ren (photo)(https://www.bio.upenn.edu/people/dejian-ren), PhD, Professor of Biology in the School of Arts & Sciences’ Department of Biology at Penn, showed that the variation that raises disease risk, which about 17% of people possess, causes a reduction in function of an ion channel in cellular organelles called lysosomes, also known as cells’ waste removal and recycling centers. Meanwhile, a different variation that reduces Parkinson’s disease risk by about 20% and is present in 7% of the general population enhances the activity of the same ion channel. The Nature article is titled “A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology.” “We started with the basic biology, wanting to understand how these lysosomal channels are controlled,” says Dr. Ren. “But here we found this clear connection with Parkinson’s disease. To see that you can have a variation in an ion channel gene that can change the odds of developing Parkinson’s both ways—increasing and decreasing it—is highly novel.” The fact that the channel seems to play a crucial role in Parkinson’s also makes it an appealing potential target for a drug that could slow the disease’s progression, the researchers note.

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