Syndicate content

Archive - 2021

Date

March 4th

Proteomics Analysis Identifies Potential Drug Targets for Aggressive Human Cancers

Researchers at Baylor College of Medicine have shown that analysis of the proteomics, or all the protein data, from aggressive human cancers is a useful approach to identify potential novel therapeutic targets. The scientists reported their findings in an article published online on February 24, 2021 in Oncogene (https://www.nature.com/articles/s41388-021-01681-0), the identification of "proteomic signatures" that are associated with clinical measures of aggressive disease for each of the seven cancer types studied. Some signatures were shared between different types of cancer and included cellular pathways of altered metabolism. Importantly, experimental results provided proof-of-concept that their proteomics analysis approach is a valuable strategy to identify potential therapeutic targets. The Oncogene article is titled “Mass-Spectrometry-Based Proteomic Correlates of Grade and Stage Reveal Pathways and Kinases Associated With Aggressive Human Cancers.” "There are two notable aspects of this study. One is that we explored the proteomic landscape of cancer looking for proteins that were expressed in association with aggressive forms of cancer," said co-corresponding author Chad Creighton (photo), PhD, Professor of Medicine and Co-Director of Cancer Bioinformatics at the Dan L. Duncan Comprehensive Cancer Center at Baylor. "We analyzed protein data that included tens of thousands of proteins from about 800 tumors including seven different cancer types--breast, colon, lung, renal, ovarian, uterine, and pediatric glioma--made available by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) mass-spectrometry-based proteomics datasets."

Novel Drug May Prevent Alzheimer’s Disease by Modulating, Rather Than Inhibiting, Key Enzyme (γ-Secretase) Involved in Amyloid Plaque Formation; Drug Proves Successful and Safe in Animal Models

Amyloid plaques are pathological hallmarks of Alzheimer's disease (AD)--clumps of misfolded proteins that accumulate in the brain, disrupting and killing neurons and resulting in the progressive cognitive impairment that is characteristic of the widespread neurological disorder. In a new study, published online on March 2, 2021 in the Journal of Experimental Medicine (JEM) (https://rupress.org/jem/article/218/4/e20202560/211838/Preclinical-valid...), researchers at University of California (UC) San Diego School of Medicine, Massachusetts General Hospital, and elsewhere have identified a new drug that could prevent AD by modulating, rather than inhibiting, a key enzyme involved in forming amyloid plaques. The open-access article is titled “Preclinical Validation of a Potent γ-Secretase Modulator for Alzheimer’s Disease Prevention.” In studies using rodents and monkeys, the researchers report that the drug was found to be safe and effective, paving the way for possible clinical trials in humans. "Alzheimer's disease is an extraordinarily complex and multi-faceted condition that has, so far, defied effective treatment, let alone prevention," said senior author Steven L. Wagner, PhD, Professor in the Department of Neurosciences at UC San Diego School of Medicine. "Our findings suggest a potential therapy that might prevent one of the key elements of AD." Amyloid plaques are composed of small protein fragments called amyloid beta (Aβ) peptides. These peptides are generated by enzymes called β-secretase and γ-secretase, which sequentially cleave a protein called amyloid precursor protein on the surfaces of neurons to release Aβ fragments of varying lengths. Some of these fragments, such as Aβ42, are particularly prone to forming plaques, and their production is elevated in patients with mutations predisposing them to early-onset AD.

March 3rd

Immunotherapy Drug Delays Onset of Type 1 Diabetes in At-Risk Group

More than five years after receiving an experimental immunotherapy drug, 50% of a group of people at high risk of developing Type 1 diabetes remained disease-free compared with 22% of those who received a placebo, according to a new trial overseen by Yale School of Medicine researchers. And those who developed diabetes did so on average about five years after receiving the new drug, called teplizumab, compared with 27 months for those who received the placebo. The study, which was done in collaboration with researchers from Indiana University, was published online on March 3, 2021 in Science Translational Medicine (https://stm.sciencemag.org/content/13/583/eabc8980). The open-access article is titled “Teplizumab Improves and Stabilizes Beta Cell Function in Antibody-Positive High-Risk Individuals.” "If approved for use, this will be the first drug to delay or prevent Type 1 diabetes," said Kevan Herold, MD, the C.N.H. Long Professor of Immunobiology and of Medicine (Endocrinology) at Yale School of Medicine and co-senior author of the paper. The drug, developed by biotechnology company Provention, has been awarded breakthrough status by the U.S. Food and Drug Administration and could be approved for general use by summer, Dr.Herold said. In the trial, an analysis of the 76 subjects showed reduced levels of damage caused by T cells in response to the drug and improved functioning of insulin-producing beta cells in those who received teplizumab. The subjects in the trial had a median age of 13 years and relatives with Type 1 diabetes. The new study is the result of 30 years of work by Dr. Herold's lab to find new treatments for Type 1 diabetes. The findings are a follow-up to another clinical study organized by TrialNet, an international coalition dedicated to the study of the disease.

February 26th

Research Reveals Mechanism by Which Bacteria May Defeat Drugs That Fight Cystic Fibrosis

University of Montana (UM) researchers and their partners have discovered a strategy used by bacteria to defeat antibiotics and other drugs used to combat infections afflicting people with cystic fibrosis. The research was published online on February 23, 2021 in Cell Reports. The open-access paper is titled "P. aeruginosa Aggregates in Cystic-Fibrosis Sputum Produce Exopolysaccharides That Likely Impede Current Therapies." Cystic fibrosis is a life-threatening disease that causes persistent lung infections and limits a person's ability to breathe over time. A common strain of bacteria, Pseudomonas aeruginosa, often thrives in the lungs of people with cystic fibrosis, as well as in wounds from burns or diabetic ulcers. Once a P. aeruginosa infection is established, it can be incredibly difficult to cure, despite repeated courses of antibiotics. Laura Jennings (photo), PhD, a Research Assistant Professor in UM's Division of Biological Sciences and an affiliate with the University's Center for Translational Medicine, said her research, conducted with colleagues, showed that the stubborn germs living in the lungs of cystic fibrosis patients create a self-produced carbohydrate slime. And this slime makes the bacteria more resistant to the antibiotics prescribed by doctors, as well as drugs that reduce the thickness of mucus. "We found the first direct evidence that these carbohydrates are produced at the sites of infection," Dr. Jennings said. "We showed that one of the carbohydrates, called Pel, sticks to extracellular DNA, which is abundant in the thick mucus secretions prominent in cystic fibrosis lungs.”

New Tools May Identify COVID Patients at Highest Risk of Mechanical Ventilation and of Death; May Permit Better Allocation of Scarce Resources

Two novel calculators for predicting which patients admitted to the hospital with COVID-19 are at greatest risk of requiring mechanical ventilation or of in-hospital death have been developed and validated by Massachusetts General Hospital (MGH). In a study published in the March 2021 issue The Lancet's EClinicalMedicine (https://www.sciencedirect.com/science/article/pii/S2589537021000456), researchers describe how these models could enable clinicians to better stratify risk in COVID-infected patients to optimize care and resource utilization in hospitals faced with ICU capacity constraints. The open-access article is titled “Estimating Risk of Mechanical Ventilation and In-Hospital Mortality Among Adult COVID-19 patients Admitted to Mass General Brigham: The VICE and DICE Scores.” "Information that can accurately predict severity of the clinical course at the time of hospital admission has been limited," says senior author Rajeev Malhotra, MD, a cardiologist at MGH and investigator in the MGH Cardiovascular Research Center. "Using a combination of past medical history, vital signs, and laboratory results at the time of patient admission, we developed models that can differentiate between risk for mechanical ventilation and risk for in-hospital mortality. While other studies have focused on 30-day hospital outcomes, we followed all COVID-19 patients to the end of their hospital course because a significant number are hospitalized well beyond 30 days." The research team compiled this clinical information from 1,042 patients confirmed with COVID-19 who were admitted to five hospitals in the Mass General Brigham health care system during the first three months of the pandemic.

Dynamic Light Scattering (DLS) Technique May Help Elucidate Mysteries of Exosomes

Despite great progress in understanding various cellular mechanisms over the last decades, many of mysteries remain. Such is the case for exosomes, small cell-released vesicles that can contain various molecules, including RNAs, DNA, proteins, and lipids. The roles of exosomes are believed to be quite varied and important, both for normal bodily functions and also in the spreading of diseases like cancer. However, exosomes are so small that studying them is challenging and typically calls for costly and time-consuming techniques, such as electron microscopy (EM). To tackle this difficulty, a team of undergraduate students from Daegu Gyeongbuk Institute of Science and Technology (DGIST), Korea, explored a different and promising method for analyzing exosomes. In their study, which was published in PLOS One (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231994), the students focused on dynamic light scattering (DLS), a laser-based technique that can be used to easily determine statistical parameters about the sizes of a large number of vesicles. What was admirable, according to Professor Jung-Ah Cho (corresponding author of the study), was that "the undergraduate students independently conducted the whole study under DGIST's Undergraduate Group Research Program with no external help." The open-access PLOS One article is titled “The Characterization of Exosomes from Fibrosarcoma Cell and the Useful Usage of Dynamic Light Scattering (DLS) for Their Evaluation.” First, the students compared the exosomes of two types of cancer cells: a well-studied breast cancer cell line and a mouse fibrosarcoma cell line. The exosomes secreted by cancer cells of the latter type had rarely been studied before.

February 24th

Whale Sharks Show Remarkable Capacity to Recover from Injuries

A new study has, for the first time, explored the rate at which the world's largest fish, the endangered whale shark, can recover from its injuries. The findings reveal that lacerations and abrasions, increasingly caused through collisions with boats, can heal in a matter of weeks and researchers found evidence of partially removed dorsal fins re-growing. This work, published online on February 4, 2021 in Conservation Physiology, comes at a critical time for these large sharks, that can reach lengths of up to 18 meters (~59 feet). The open-access article is titled “Wound-Healing Capabilities of Whale Sharks (Rhincodon typus) and Implications for Conservation Management” (https://academic.oup.com/conphys/article/9/1/coaa120/6102284). Other recent studies have shown that, as their popularity within the wildlife tourism sector increases, so do interactions with humans and boat traffic. As a result, these sharks face an additional source of injury on top of natural threats, and some of these ocean giants exhibit scars caused by boat collisions. Until now, very little was known about the impact from such injuries and how they can recover. "These baseline findings provide us with a preliminary understanding of wound healing in this species" says lead author Freya Womersley, a PhD student with University of Southampton based at the Marine Biological Association, UK. "We wanted to determine if there was a way of quantifying what many researchers were anecdotally witnessing in the field, and so we came up with a technique of monitoring and analyzing injuries over time.”

Lou Gehrig’s Disease (ALS) Neuron Damage Reversed with New Compound In Mouse Model

Northwestern University scientists have identified the first compound that eliminates the ongoing degeneration of upper motor neurons that become diseased and are a key contributor to ALS (amyotrophic lateral sclerosis) (also known as Lou Gehrig’s disease), a swift and fatal neurodegenerative disease that paralyzes its victims. In addition to ALS, upper motor neuron degeneration also results in other motor neuron diseases, such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). In ALS, movement-initiating nerve cells in the brain (upper motor neurons) and muscle-controlling nerve cells in the spinal cord (lower motor neurons) die. The disease results in rapidly progressing paralysis and death. So far, there has been no drug or treatment for the brain component of ALS, and no drug for HSP or PLS patients. "Even though the upper motor neurons are responsible for the initiation and modulation of movement, and their degeneration is an early event in ALS, so far there has been no treatment option to improve their health," said senior author Hande Ozdinler, PhD, Associate Professor of Neurology at Northwestern University Feinberg School of Medicine. "We have identified the first compound that improves the health of upper motor neurons that become diseased." The study was published online on February 23, 2021 in Clinical and Translational Medicine. The open-access article is titled “Improving Mitochondria and ER Stability Helps Eliminate Upper Motor Neuron Degeneration That Occurs Due to mSOD1 toxicity and TDP‐43 Pathology (https://onlinelibrary.wiley.com/doi/10.1002/ctm2.336). Dr. Ozdinler collaborated on the research with study author Richard B. Silverman, PhD, the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern.

Seeing Schizophrenia: X-Rays Shed Light on Neural Differences

Schizophrenia, a chronic, neurological brain disorder, affects millions of people around the world. It causes a fracture between a person's thoughts, feelings and behavior. Symptoms include delusions, hallucinations, difficulty processing thoughts and an overall lack of motivation. Schizophrenia patients have a higher suicide rate and more health problems than the general population, and a shorter life expectancy. There is no cure for schizophrenia, but a key to treating it more effectively is to better understand how it arises. And that, according to Ryuta Mizutani, PhD, Professor of Applied Biochemistry at Tokai University in Japan, means studying the structure of brain tissue. Specifically, it means comparing the brain tissues of schizophrenia patients with those of people in good mental health, to see the differences as clearly as possible. "The current treatment for schizophrenia is based on many hypotheses we don't know how to confirm," Dr. Mizutani said. "The first step is to analyze the brain and see how it is constituted differently." To do that, Dr. Mizutani and his colleagues from several international institutions collected eight small samples of brain tissue -- four from healthy brains and four from those of schizophrenia patients, all collected post-mortem--and brought them to beamline 32-ID of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE's Argonne National Laboratory. At the APS, the team used powerful X-rays and high-resolution optics to capture three-dimensional images of those tissues.

February 23rd

Kittens Could Hold Key to Understanding Deadly Diarrheal Disease in Children

Kittens could be the model for understanding infectious, sometimes deadly, diarrheal disease in both animals and children, according to new research from North Carolina (NC) State University. Diarrheagenic Escherichia coli (DEC) bacteria cause lethal diarrheal disease in children worldwide, killing up to 120,000 children under the age of five annually. Atypical enteropathic Escherichia coli (aEPEC) are a form of DEC increasingly associated with diarrheal disease in humans and in kittens. "We were looking for causes of infectious diarrhea in kittens, which has a high mortality rate, and came across this pathogen," says Jody Gookin, DVM, PhD, FluoroScience Distinguished Professor in Veterinary Scholars Research Education at NC State and corresponding author of the research. "The interesting thing about aEPEC is that you can find it in both healthy and sick individuals. Having it in your intestinal tract doesn't mean you're sick, but those that are sick have a higher burden, or amount of the bacteria, in their bodies." Dr. Gookin and Victoria Watson, DVM, PhD, a former PhD student at NC State, lead author of the study, and now a veterinary pathologist at Michigan State University, performed a genomic analysis of aEPEC isolates from both healthy kittens that were colonized by the bacteria and kittens with lethal infections to try to determine why aEPEC causes illness in some kittens but remains dormant in others. With collaborators at the University of Maryland, Dr. Gookin and Dr. Watson then compared the genomic data from both groups of kittens to human aEPEC isolates. However, there were no specific genetic markers that allowed the researchers to distinguish between the groups of isolates.