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Archive - May 2020

Date

May 31st

Study Shows Ketamine Combats Depression by Targeting Serotonin 1B Receptors, Increasing Their Number, and Increasing Dopamine Levels

The anaesthetic drug ketamine has been shown, in low doses, to have a rapid effect on difficult-to-treat depression. Researchers at the Karolinska Institutet in Sweden now report that they have identified a key target for the drug: specific serotonin receptors in the brain. Their findings, which were published online on June 1, 2020 in Translational Psychiatry, give hope of new, effective antidepressants. The open-access article is titled “A Randomized Placebo-Controlled PET Study of Ketamine´s Effect on Serotonin1b Receptor Binding in Patients with SSRI-Resistant Depression.” Depression is the most common psychiatric diagnosis in Sweden, affecting one in ten men and one in five women at some point during their lives. Between 15 and 30 per cent of patients are not helped by the first two attempts at therapy, in which case the depression is designated difficult to treat. Studies have shown that low doses of the anaesthetic drug ketamine are rapid-acting on certain sufferers, but exactly how it works is unknown. A nasal spray containing ketamine has recently been approved in the USA and EU for patients with treatment-resistant depression. Researchers at the Karolinska Institutet have now imaged the brains of study participants using a PET (positron emission tomography) camera in connection with ketamine treatment.

New Understanding of mRNA/microRNA Interactions May Enable New Approaches to Treating Cancer

Research from Sweden’s Karolinska Institutet, published on March 27, 2020 in Nature, shows that an RNA molecule involved in preventing tumor formation can change its structure and thereby control protein production in the cell. The article is titled “Base-Pair Conformational Switch Modulates miR-34a Targeting of Sirt1 mRNA.” The finding may have important clinical implications as it [suggests the possibility of new strategies to treat different types of cancer. Short RNA molecules in our cells, called microRNAs, are important regulators of messenger RNAs (mRNAs) – the molecules that code for the building blocks of our body, the proteins. The exact mechanism of this regulation remains elusive, but it is known that microRNAs can silence mRNA molecules and thereby prevent protein production. Therefore, they have the potential to be used as tools or targets for drugs. “It’s important to increase our understanding of how microRNA regulates protein production because this process is disturbed in many different types of diseases, including cancer,” says Katja Petzold, PhD, Associate Professor in the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, who led the study. “We show for the first time that a microRNA-mRNA complex has a structure that changes and that this movement has an effect on the biological outcome, i.e., the amount of protein produced in the cell.” The researchers studied a microRNA known as miR-34a, which plays an important role in cancer by indirectly regulating the activity of the p53 protein, known as the “guardian of the genome” for its ability to prevent cancer formation. Changes in the function of p53 are very common in human cancers. miR-34a downregulates the mRNA that codes for Sirt1, a protein that deactivates p53.

Modified Adenoviruses Better Able to Target and Kill Cancer Cells Due to Addition of AU-Rich Elements That Hasten mRNA Breakdown in Normal Cells, But Which Result in Stabilized mRNA in Cancer Cells, Thus Enhancing Cancer Cell-Specific Killing by the Virus

Hokkaido University scientists have made an adenovirus (graphic image of an adenovirus) that specifically replicates inside and kills cancer cells by employing special RNA-stabilizing elements. The details of the research were published online on May 11, 2020 in the journal Cancers. The open-access article is titled “Conditionally Replicative Adenovirus Controlled by the Stabilization System of AU-Rich Elements Containing mRNA.” Much research in recent years has investigated genetically modifying adenoviruses to kill cancers, with some of these modified viruses currently being tested in clinical trials. When injected, these adenoviruses replicate inside cancer cells and kill them. Scientists are trying to design more efficient viruses, which are better able to target cancer cells, while leaving normal cells alone. Hokkaido University molecular oncologist Fumihiro Higashino, PhD, led a team of scientists to make two new adenoviruses that specifically target cancer cells. To do this, they used ‘adenylate-uridylate-rich elements’ (AREs or AU-rich elements), which are signals in RNA molecules known to enhance the rapid decay of messenger RNAs (mRNAs) in human cells. “AREs make sure that mRNAs don’t continue to code for proteins unnecessarily in cells,” explains Dr. Higashino. “Genes required for cell growth and proliferation tend to have AREs.” Under certain stress conditions, however, ARE-containing mRNAs can become temporarily stabilized allowing the maintenance of some necessary cell processes. ARE-mRNAs are also stabilized in cancer cells, supporting their continuous proliferation. Dr. Higashino and his team inserted AREs from two human genes into an adenovirus replicating gene, making the new adenoviruses: AdARET and AdAREF.

SARS-CoV-2 May Ultimately Be a Blood Vessel Disease, Which Might Explain Everything

In April 2020, blood clots (https://coronavirus.medium.com/doctors-want-to-know-could-blood-thinners...) emerged as one of the many mysterious symptoms attributed to COVID-19, a disease that had initially been thought to largely affect the lungs in the form of pneumonia. Quickly after this, came reports of young people dying due to coronavirus-related strokes. Next it was COVID toes — painful red or purple digits. What do all of these symptoms have in common? An impairment in blood circulation. Add in the fact that 40% of deaths (https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.120.317055) from COVID-19 are related to cardiovascular complications, and the disease starts to look like a vascular infection instead of a purely respiratory one. Months into the pandemic, there is now a growing body of evidence to support the theory that the novel coronavirus can infect blood vessels, which could explain, not only the high prevalence of blood clots, strokes, and heart attacks, but also provide an answer for the diverse set of head-to-toe symptoms that have emerged. “All these COVID-associated complications were a mystery.

FDA Publishes Comprehensive Review of What’s Known to Date on SARS-CoV-2; Outlines Roadmap for Effective Treatment of COVID-19; Proposes Range of Existing Drugs That Might Be Repurposed to Treat the Disease

Due to the devastating worldwide impact of COVID-19, the illness caused by the SARS-CoV-2 virus, there have been unprecedented efforts by clinicians and researchers from around the world to quickly develop safe and effective treatments and vaccines. Given that COVID-19 is a complex new disease with no existing vaccine or specific treatment, much effort is being made to investigate the repurposing of approved and available drugs, as well as those under development. In an article published online on May 29, 2020 in Frontiers in Immunology (https://www.frontiersin.org/articles/10.3389/fimmu.2020.01131/full) , a team of researchers from the U.S. Food and Drug Administration (FDA) review all of the COVID-19 clinical and research findings to date. They provide a breakdown of key immunological factors underlying the clinical stages of COVID-19 illness that could potentially be targeted by existing therapeutic drugs. The open-access review is titled “Lessons Learned to Date on COVID-19 Hyperinflammatory Syndrome: Considerations for Interventions to Mitigate SARS-CoV-2 Viral Infection and Detrimental Hyperinflammation.” Montserrat Puig (photo) (https://www.fda.gov/science-research/fda-science-jobs-and-scientific-pro...), PhD, of the FDA, senior author of the review, stated that "there are multiple factors involved in determining if the patient's immune response will be insufficient or successful in combating the infection. Our review is an overview of these factors and how they can be considered to define the context in which medications currently used for other diseases, or development of novel agents, can be utilized to prevent, ameliorate, or cure COVID-19." We know that during the early stage of COVID-19 people can show no symptoms or mild symptoms, and, for many, the disease resolves.

May 30th

First Evidence Inherited Genetics Can Drive Cancer's Spread; In Melanoma Model, Rockefeller Scientists Show That APOE4 Variant Is Most Protective Against Metastasis by Enhancing Anti-Tumor Immune Response

Sometimes cancer stays put, but often it metastasizes, spreading to new locations in the body. It has long been suspected that genetic mutations arising inside tumor cells drive this potentially devastating turn of events. Now, researchers at The Rockefeller University have shown for the first time that our own pre-existing genetics may promote metastasis. A new study, published online on May 25, 2020 in Nature Medicine, suggests that differences in a single gene (APOE), carried within someone's genome from birth, can alter progression of melanoma, a type of skin cancer. The researchers suspect these inherited variations may have the same effect on other types of cancer as well. Their article is titled “Common Germline Variants of the Human APOE Gene Modulate Melanoma Progression and Survival.” "Patients often ask 'Why am I so unlucky? Why did my cancer spread?' As doctors, we never had an answer," says lead investigator Sohail Tavazoie, MD, PhD, Leon Hess Professor and Senior Attending Physician at The Rockefeller University. "This research provides an explanation." The discovery may transform how scientists think about cancer metastasis, and lead to a better understanding of patients' risks in order to inform treatment decisions,” Dr. Tavazoie says. Metastasis occurs when cancer cells escape the original tissue to establish new tumors elsewhere in the body, a phenomenon that leads to the majority of cancer deaths. Scientists have suspected that cancer cells, which initially emerge due to mutations inside normal cells, gain their travelling ability following further mutations. But after decades of searching, they have yet to find such a genetic change that could be proven to encourage metastasis. Previous research (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753115/) in Dr.

Fearful Great Danes Provide New Insights to Genetic Causes of Fear

A novel genomic region on chromosome 11 has been associated with fearfulness in dogs in a study of Great Danes by researchers at the University of Helsinki and the University of Oahu, both in Finland. The identified genomic region includes several candidate genes associated with brain development and function, as well as anxiety, whose further analysis may reveal new neural mechanisms related to fear. For the purposes of the study, led by the University of Helsinki’s Professor Hannes Lohi's (https://researchportal.helsinki.fi/en/persons/hannes-lohi) research group (https://www.koirangeenit.fi/english/) and published online on May 28, 2020 in Translational Psychiatry, data from a total of 120 Great Danes was collected. The article is titled “A Novel Genomic Region on Chromosome 11 Associated with Fearfulness in Dogs.” [Editor’s Note: Dogs have 38 pairs of somatic chromosomes, and the X and Y sex chromosomes, compared to the human complement of 22 pairs of somatic chromosomes and the X and Y sex chromosomes.] The Great Dane breed is among the largest breeds of dog in the world. The project was launched after a number of Great Dane owners approached the research group to tell them about their dogs' disturbing fearfulness towards unfamiliar human beings in particular. "Fear in itself produces a natural and vital reaction, but excessive fear can be disturbing and results in behavioral disorders. Especially in the case of large dogs, strongly expressed fearfulness is often problematic, as it makes it more difficult to handle and control the dog," says Riika Sarviaho, PhD, from the University of Helsinki. In dogs, behavioral disorders associated with anxiety and fearfulness include generalized anxiety disorder and a range of phobias.

May 29th

Eight-Protein Blood Test Can ID Those at Risk of Carrying Hidden Malaria Parasites (Hypnozoites) within Nine Months of Active Infection with Plasmodium vivax; Test Offers Possibility of Reducing P. vivax Prevalence by As Much As 69%; 2 Billion Now at Risk

Plasmodium vivax is the most widespread malaria parasite worldwide, with up to 2,000,000,000 people at risk of infection. As well as causing illness and death in its “active” stage of infection, the parasite can hide as hypnozoites, a dormant stage, in the liver, and is a significant cause of “relapsing” malaria. These hypnozoites, undetectable with current diagnostics, can be responsible for >80% of all blood-stage infections. Identifying and targeting individuals with hypnozoites is thus essential for accelerating and achieving malaria elimination. A major gap in the P. vivax elimination toolkit is the identification of individuals carrying clinically silent and undetectable hypnozoites. The current study developed a panel of serological exposure markers capable of classifying individuals with P. vivax infections within the previous nine months who have a high likelihood of harboring hypnozoites. Using the Perkin-Elmer AlphaScreen system (https://www.perkinelmer.com/Content/RelatedMaterials/Brochures/BRO_Alpha...), the researchers measured IgG antibody responses to 342 P. vivax proteins expressed by a wheat germ cell-free system, invented at Ehime University in Japan, in longitudinal clinical cohorts conducted in Thailand and Brazil, and identified 60 candidate serological markers of exposure. Candidate markers were then validated using samples from year-long observational cohorts conducted in Thailand, Brazil, and the Solomon Islands and antibody responses to eight P. vivax proteins classified P. vivax infections in the previous 9 months with 80% sensitivity and specificity. Mathematical models demonstrate that a serological testing and treatment strategy based on testing for responses to these eight P.

Przewalski’s Horse: The Long Way Home

Przewalski’s Horse (Equus ferus przewalskii) (see also photos at end) is the last surviving species of wild horse – however, since 1969, it has been considered extinct in the wild. Because it was possible to continue breeding the remaining animals in captivity, the species could be preserved until today. “The current population goes back to a mere twelve horses that produced offspring while kept in zoos--a genetic bottleneck that carries the risk of diseases caused by inbreeding, such as a reduced resistance or shortened life expectancy,” explains Professor Hermann Ansorge, PhD, of the Senckenberg Research Institute and Natural History Museum in Görlitz, Germany, and he continues, “Under these conditions, attempts to reintroduce the Przewalski’s Horses into the wild pose a serious challenge. A species can only react to environmental changes if it has a high level of genetic variability!” In 1992, the first successful attempts began to reintroduce the Przewalski’s Horse into its former home, the Mongolian steppe. Today, about 746 individual horses can be found there in the wild again. In recent years, an international team took a closer look at the reintroduced Przewalski’s Horses and at historic collection materials. The researchers examined a total of 130 skulls from a period of 110 years. The comparison of non-metric characteristics revealed insights into the genetic variability. “This involves defined manifestations on the skull whose appearance can be differentiated qualitatively,” explains Dr. Ansorge, and he adds, “For example, these can be small natural openings that serve as passageways for blood vessels or nerves.

One in Three British Women Have Inherited Neandertal Variant of Gene for Progesterone—Variant Associated with More Siblings, Fewer Bleedings in Early Pregnancy, and Fewer Miscarriages, Suggesting Neandertal Variant Promotes Fertility

New data analysis indicates that almost one in three women in the UK Biobank have inherited the gene variant receptor for progesterone from Neandertals—and that this gene variant is associated with greater number of siblings, fewer bleedings during early pregnancy, and fewer miscarriages—suggesting increased fertility. This is according to a study published online on May 21, 2020 in Molecular Biology and Evolution by researchers at the Max Planck Institute for Evolutionary Anthropology in Germany and Karolinska Institutet in Sweden. The article is titled “The Neandertal Progesterone Receptor.” "The progesterone receptor is an example of how favorable genetic variants that were introduced into modern humans by mixing with Neandertals can have effects in people living today," says Hugo Zeberg, PhD, Assistant Professor in the Department of Neuroscience at Karolinska Institutet and researcher with the Max Planck Institute for Evolutionary Anthropology, who performed the study with colleagues Janet Kelso, PhD, Group leader of the Minerva Research Group for Bioinformatics at the Max Planck Institute for Evolutionary Anthropology, and Svante Pääbo (photo), PhD, Director, Max Planck Institute for Evolutionary Anthropology. Progesterone is a hormone that plays an important role in the menstrual cycle and in pregnancy. Analyses of biobank data from more than 450,000 participants--among them 244,000 women--show that almost one in three women in Europe have inherited the progesterone receptor from Neandertals. 29 percent carry one copy of the Neandertal receptor and three percent have two copies. "The proportion of women who inherited this gene is about ten times greater than for most Neandertal gene variants," says Dr. Zeberg.