Syndicate content

Archive - 2020

December 28th

Gut Cells (Enterocytes) Sound First Alarm When Cryptosporidium Parasites Invade; Inflammasome Is Key

To effectively combat an infection, the body first has to sense it's been invaded, then the affected tissue must send out signals to marshal resources to fight the intruder. Knowing more about these early stages of pathogen recognition and response may provide scientists with crucial clues when it comes to preventing infections or treating inflammatory diseases resulting from overactive immunity. That was the intent behind a new study, led by researchers at the University of Pennsylvania School of Veterinary Medicine (Penn Vet), examining infection with the parasite Cryptosporidium (image). When the team looked for the very first "danger" signals emitted by a host infected with the parasite, they traced them not to an immune cell, as might have been expected, but to epithelial cells lining the intestines, where Cryptosporidium sets up shop during an infection. Known as enterocytes, these cells take up nutrients from the gut, and here they were shown to alert the body to danger via the molecular receptor NLRP6, which is a component of what's known as the inflammasome (https://en.wikipedia.org/wiki/Inflammasome). "You can think about the inflammasome as an alarm system in a house," says Boris Striepen, PhD, a Professor in the Department of Pathobiology at Penn Vet and senior author on the paper, which was published online on December 28, 2020 in PNAS. "It has various components--like a camera that watches the door, and sensors on the windows--and once triggered it amplifies those first signals to warn of danger and send a call for help.

New England Journal of Medicine Publishes Positive Initial Regeneron Antibody Cocktail Results in Non-Hospitalized Patients with COVID-19

On December 17, 2020, Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced that the New England Journal of Medicine (NEJM) has published initial clinical data from an ongoing seamless Phase 1/2/3 trial of the Regeneron antibody cocktail casirivimab and imdevimab in non-hospitalized patients with COVID-19 (https://www.nejm.org/doi/full/10.1056/NEJMoa2035002). "The peer-reviewed NEJM publication of our first set of clinical data in recently infected COVID-19 patients showed that casirivimab and imdevimab effectively reduced viral load and the need for medically-attended visits, with the greatest benefit in patients who had not yet mounted their own effective immune response or had high viral load at baseline," said David Weinreich, MD, Senior Vice President and Head of Global Clinical Development at Regeneron and lead author of the publication. "The investigational cocktail is now available to indicated high-risk U.S. patients under an Emergency Use Authorization, and we also continue a robust clinical development program." "Building on these initial findings, we were gratified to recently report follow-on data from the next-stage analysis of this ongoing trial, which prospectively replicated these results in a rigorous and statistically significant manner. These follow-on data provided the first definitive prospective evidence demonstrating anti-viral activity for a treatment regimen now available for COVID-19, and also further documented the ability of this treatment to decrease the need for further medical attention," said George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer at Regeneron.

Discovery About How Cancer Cells Evade Immune Defenses Inspires New Treatment Approach; Inhibiting Action of Scissor-Like ENPP1 Protein May Strike at Cancer in Two Different Ways, Sloan-Kettering Study Indicates

Cancer cells are known for spreading genetic chaos. As cancer cells divide, DNA segments and even whole chromosomes can be duplicated, mutated, or lost altogether. This is called chromosomal instability, and scientists at Memorial Sloan Kettering Cancer Center (MSKCC) have learned that it is associated with cancer's aggressiveness. The more unstable chromosomes are, the more likely that bits of DNA from these chromosomes will end up where they don't belong: outside of a cell's central nucleus and floating in the cytoplasm. Cells interpret these rogue bits of DNA as evidence of viral invaders, which sets off their internal alarm bells and leads to inflammation. Immune cells travel to the site of the tumor and churn out defensive chemicals. A mystery has been why this immune reaction, triggered by the cancer cells, does not spell their downfall. "The elephant in the room is that we didn't really understand how cancer cells were able to survive and thrive in this inflammatory environment," says Samuel Bakhoum (https://www.mskcc.org/research-areas/labs/samuel-bakhoum),MD, PhD, a physician-scientist at MSKCC and a member of the Human Oncology and Pathogenesis Program. According to a new study from Dr. Bakhoum's lab, published online on December 28, 2020 in Cancer Discovery (https://cancerdiscovery.aacrjournals.org/content/early/2020/12/23/2159-8...), the reason has to do, in part, with a molecule sitting on the outside of the cancer cells that destroys the warning signals before they ever reach neighboring immune cells. The findings help to explain why some tumors do not respond to immunotherapy, and--equally important--suggest ways to sensitize them to immunotherapy. The warning system Dr.

Big Bumblebees Take Time to Memorize Locations of Best Flowers; Big Bumblebees Have Longer Flight Range and Higher Carrying Capacity Than Smaller Bumblebees, Which Do Not Alter Their Location Learning Efforts on Basis of Flower’s Nectar Richness

Big bumblebees take time to learn the locations of the best flowers, new research shows. Meanwhile, smaller bumblebees--which have a shorter flight range and less carrying capacity--don't pay special attention to flowers with the richest nectar. University of Exeter (UK) scientists examined the "learning flights" which most bees perform after leaving flowers. Honeybees are known to perform such flights-- and the study shows bumblebees do the same, repeatedly looking back to memorize a flower's location. "It might not be widely known that pollinating insects learn and develop individual flower preferences, but, in fact, bumblebees are selective," said Natalie Hempel de Ibarra, PhD, Associate Professor of Neuroethology at Exeter's Centre for Research in Animal Behavior (https://psychology.exeter.ac.uk/staff/profile/index.php?web_id=Natalie_H...). "On leaving a flower, they can actively decide how much effort to put into remembering its location. The surprising finding of our study is that a bee's size determines this decision-making and the learning behavior." In the study, captive bees visited artificial flowers containing sucrose (sugar) solution of varying concentrations. The larger the bee, the more its learning behavior varied depending on the richness of the sucrose solution. Smaller bees invested the same amount of effort in learning the locations of the artificial flowers, regardless of whether sucrose concentration was high or low. "The differences we found reflect the different roles of bees in their colonies," said Professor Hempel de Ibarra. "Large bumblebees can carry larger loads and explore further from the nest than smaller ones.

Discovery Boosts Theory That Life on Earth Arose from RNA-DNA Mix; Undercuts “RNA World” Hypothesis & Suggests Enzyme-Free Chemical Reactions That May Prove Superior to PCR in Some Cases

Chemists at Scripps Research in La Jolla, California, have made a discovery that supports a surprising new view of how life originated on our planet. In a study published online on December 15, 2020 in the chemistry journal Angewandte Chemie, the scientists demonstrated that a simple compound called diamidophosphate (DAP), which was plausibly present on Earth before life arose, could have chemically knitted together tiny DNA building blocks called deoxynucleosides into strands of primordial DNA. The finding is the latest in a series of discoveries, over the past several years, pointing to the possibility that DNA and its close chemical cousin RNA arose together as products of similar chemical reactions, and that the first self-replicating molecules--the first life forms on Earth--were mixes of the two. The discovery may also lead to new practical applications in chemistry and biology, but its main significance is that it addresses the age-old question of how life on Earth first arose. In particular, it paves the way for more extensive studies of how self-replicating DNA-RNA mixes could have evolved and spread on the primordial Earth and ultimately seeded the more mature biology of modern organisms. The Angewandte Chemie article is titled “Prebiotic Phosphorylation and Concomitant Oligomerization of Deoxynucleosides to form DNA.” "This finding is an important step toward the development of a detailed chemical model of how the first life forms originated on Earth," says study senior author Ramanarayanan Krishnamurthy, PhD, Associate Professor of Chemistry at Scripps Research.

QUAZAR Global Trial of Drug (Oral Azacytidine, CC-486) Shows Significantly Extended Survival of Patients Over 55 with Acute Myeloid Leukemia; Drug “Likely to Establish New Standard of Care for Older Patients with AML,” First Author of NEJM Article States

A landmark paper published online on December 23, 2020 in the New England Journal of Medicine describes the results from a global trial across 148 sites in 23 countries, showing a 30 per cent improvement in survival in patients with acute myeloid leukemia (AML). The Phase 3 clinical trial called QUAZAR, showed that a drug, called CC-486 (oral azacytidine) (image), significantly improved survival in older patients, over the age of 55, with the disease. AML is the most acute blood cancer in adults and its incidence increases with age, with a poor prognosis. With current treatments, the majority of older patients will die of their disease within 2 years of diagnosis. Approximately 20,000 people in the United States are diagnosed with AML every year. The global trial, led by Professor Andrew Wei from Monash University's Australian Centre for Blood Diseases and a hematologist at Alfred Health, focused on people with AML over 55 years of age, "because of an unmet need to identify new agents able to improve outcome in patients after completing chemotherapy," he said. "After intensive chemotherapy, the risk of AML relapse is high. Many older patients are not eligible to receive a stem cell transplant and so a less toxic option to reduce disease recurrence is desirable, rather than just being monitored and waiting for the disease to come back," he said. "Based on the results of the QUAZAR study, it is very exciting to think that, by taking a tablet that is relatively well-tolerated, we can help reduce relapse risk and improve survival." The NEJM article was published online on December 24, 2020 and is titled “Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission.” The trial involved 472 patients, with an average age 68 years, who were either given CC-486 or a placebo.

December 27th

Frameshifting ID’d in Protein Synthesis by Ribosomes of Melanoma Cells Missing the Amino Acid Tryptophan; First Time Such Frameshifting Observed in Human Cells; Aberrant Proteins Produced As Result; Findings May Offer Therapeutic Insights

Cancers like melanoma are hard to treat, not least because they have a varied bag of tricks for defeating or evading treatments. A combined research effort by scientists at the Weizmann Institute of Science in Israel and researchers in the Netherlands Cancer Institute in Amsterdam and the University of Oslo, Norway, shows exactly how tumors, in their battles to survive, will go so far as to starve themselves in order to keep the immune cells that would eradicate them from functioning. The new work was published online on December 16 in Nature (https://www.nature.com/articles/s41586-020-03054-1). The article is titled “Anti-Tumour Immunity Induces Aberrant Peptide Presentation in Melanoma.” The immunotherapies currently administered for melanomas work by removing obstacles that keep immune cells called T-cells from identifying and killing tumor cells. Recent research suggested that in melanoma, another blocker could assist the T-cells, this one to stop an enzyme called IDO1 that is overproduced by the cancer cells. IDO1 breaks down an essential amino acid, tryptophan, which is needed to make proteins, in the process leaving behind tryptophan breakdown byproducts that suppress the immune response. But IDO1 blockers did not fare well in clinical trials, suggesting more knowledge was needed--including how the cancer cells, which also require tryptophan, can function after they have destroyed this resource. The research team, including the group of Professor Yardena Samuels (http://www.weizmann.ac.il/mcb/Samuels/) of Weizmann’s Molecular Cell Biology Department, members of the lab of Professor Reuven Agami (https://www.nki.nl/research/research-groups/reuven-agami/) of the Netherlands Cancer Institute; Dr.

PACS-1 Gene Could Help Predict Response to Cervical Cancer Treatment

UCLA researchers have identified a potential diagnostic marker that could help predict how likely someone with cervical cancer is to respond to the standard treatment of chemotherapy and radiation. The scientists found that PACS-1 (phosphofurin acidic cluster sorting protein 1), a gene that resides on a small segment of the long arm of chromosome 11, is overexpressed in cancer tissues, which can result in cancer growth and spread. Further, they discovered that translocation of the PACS-1 protein from outside to inside the cell nucleus — a function required for normal cell growth — plays a role in the development of cervical cancer that is resistant to chemotherapy and radiation. Higher levels of PACS-1 expression in the nucleus could indicate resistance to the treatment, the researchers say. Cervical cancer is the second leading cause of cancer-related death among women worldwide. While infection with human papillomaviruses plays a significant role in cervical cancer development, the presence of a virus alone is not enough to cause cancer; genetics and environmental factors such as smoking and poor eating habits also play a role. Therefore, it is important to identify biological markers as targeting agents for diagnosis and treatment. The researchers performed a Western blot, a technique for detecting specific protein molecules from among a mixture of proteins, on cervical tumors and healthy cervical tissue and discovered an overexpression of PACS-1 in the tumor tissues. The team then developed in vitro human cell line models to assess the protein’s role in cell growth. Finally, they used a fluorescence-activated sorter analysis to help determine if the overexpression of the PACS-1 protein was associated with cancer chemotherapy resistance.

December 26th

Study Identifies Divergent Gene Activity Between Healthy and Damaged Skeletal Muscle in Mouse Model of Duchenne Muscular Dystrophy; Work “Opens Door to New Approaches for Ameliorating the Severe Pathological Consequences of This Disease,” Eric Olson Says

Understanding the activity of genes can shed light on pathologies that affect different tissues in the body. However, says Rhonda Bassell-Duby, PhD, a Professor of Molecular Biology at the University of Texas Southwestern (UTSW), studying skeletal muscle has been a challenge because of a key difference from other tissue types; rather than containing a single nucleus that controls the activity of the genes, a skeletal muscle fiber can contain hundreds of nuclei. And it was unknown which genes were activated in all these nuclei, making it unclear how gene expression differs between healthy skeletal muscle tissue and tissue affected by Duchenne muscular dystrophy (DMD). To answer these questions, Eric Olson, PhD, Chairman and Professor of Molecular Biology at UTSW, Dr. Bassel-Duby, and their colleagues isolated tissue from the tibialis anterior, a muscle in mice similar to one in humans that runs down the shin. They took these samples from both healthy animals and from a mouse model of DMD that they generated using gene-editing technology to introduce a mutation that commonly causes DMD in people. The researchers then isolated muscle tissue from both sets of animals, separated the nuclei, and analyzed their gene activity using a tool known as single-nucleus RNA sequencing. The results were published online on November 4, 2020 in PNAS. The article is titled “Degenerative and Regenerative Pathways Underlying Duchenne Muscular Dystrophy Revealed By Single-Nucleus RNA Sequencing.” In muscle fibers from both groups, the scientists identified 14 types of nuclei based on similar gene profiles. These nuclei appear to perform different jobs based on their predominant gene activity, such as maintaining mature muscle, liaising with neurons or tendons, or regenerating new muscle fibers.

Scientists Develop Molecular Classification of Zebrafish Retinal Ganglion Cells (RGCs) Linking Molecularly Described RGC Type to Specific Structure, Function, and Behavioral Response

Retinal ganglion cells (RGCs) are the bottleneck through which all visual impressions flow from the retina to the brain. A team from the Max Planck Institute of Neurobiology, the University of California (UC) Berkeley, and Harvard University created a molecular catalog that describes the different types of these neurons. In this way, individual RGC types could be systematically studied and linked to a specific connection, function and behavioral response. When zebrafish see light, they often swim towards it. Same with prey, although the signals are entirely different. A predator, on the other hand, prompts the fish to escape. That's good, because a mix-up would have fatal consequences. But how does the brain manage to react to a visual stimulus with the proper behavior? Optical signals are generated by photons that bombard the retina of the eye. Neurons in the retina collect and process these impressions. While doing so, the retina focuses on the important details: Is there contrast or color? Are there small or large objects? Is something moving? Once these details are filtered out, retinal ganglion cells (RGCs) send them to the brain, where they are translated into a specific behavior. As the only connection between the retina and the brain, RGCs play a central role in the visual system. We already knew that specific RGC types sends different details to different regions of the brain. However, it has been unclear how RGC types differ on the molecular level, what their respective functions are, and how they help to regulate context-dependent behavior. To begin to solve this puzzle, a team led by Yvonne Kölsch (photo), PhD, from Herwig Baier's (PhD) laboratory analyzed the genetic diversity of RGCs. Dr. Baier is Director of the Max Planck Institute of Neurobiology.