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Archive - Jun 22, 2017

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Five-Gene Assay Detects Neuroblastoma with Greater Sensitivity; Improved Disease Assessment Aids Prediction of Relapse in Children

Investigators at The Saban Research Institute of Children's Hospital Los Angeles have developed and tested a new biomarker assay for quantifying disease and detecting the presence of neuroblastoma even when standard evaluations yield negative results for the disease. In a study, led by Araz Marachelian, MD, of the Children's Center for Cancer and Blood Diseases, researchers provide the first systematic comparison of standard imaging evaluations versus the new assay that screens for five different neuroblastoma-associated genes and determine that the new assay improves disease assessment and provides prediction of disease progression. Results of the study were published on May 30, 2017 in Clinical Cancer Research. The article is titled “Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis.” Neuroblastoma is a cancer of the nervous system that exists outside the brain and typically is diagnosed in children 5 years or age or younger. Forty-five percent of patients have high-risk, metastatic tumors (stage 4) when diagnosed. While children with neuroblastoma often respond to therapy and many are declared to be in a "remission" based on standard tests, many will still relapse. "Clearly, there is some remaining tumor in the body that we cannot detect with standard tests and physicians have a hard time predicting if a patient is likely to relapse," said Dr. Marachelian, who is Medical Director of the New Approaches to Neuroblastoma (NANT) consortium, headquartered at CHLA. The new assay, which was developed in the laboratories of Robert Seeger, MD, and Shahab Asgharzadeh, MD, at CHLA, tests for five different genes (CHGA, DCX, DDC, PHOX2B, and TH) that are specific to neuroblastoma.

Study of Parasitic Wasp Venom Reveals Novel & Possibly Widespread Mechanism for Genes to Evolve New Functions; Parasitoid Venoms May Offer “Immense Untapped Cornucopia for Drug Discovery”

Amid the incredible diversity of living things on our planet, there is a common theme. Organisms need to acquire new genes, or change the functions of existing genes, in order to adapt and survive. How does that happen? A common view is that genes are duplicated, with one of the copies picking up a new function while the other copy continues to function as before. However, by studying tiny parasitic Jewel Wasps and their rapidly changing venom repertoires, the Werren Lab at the University of Rochester in New York has uncovered a different process that may be widespread in other species as well. The process involves co-opting single-copy genes to take on new functions. In some cases, these genes appear to continue their previous function as well, in other parts of the wasp's anatomy besides the venom gland. The findings are published in Current Biology. The article is titled “The Evolution of Venom by Co-option of Single-Copy Genes.” "It is almost as if they are now moonlighting," says John (Jack) Werren, Professor of Biology. "They've got a day job, and then take on a night job as well. Over time, if the night job works out, they may give up the day job and evolve as a venom specialist. However, in other cases, we have found that they stop moonlighting as venom genes, but appear to retain their day job." How is a gene co-opted? And what determines which job (or combination of jobs) it performs? In the case of Jewel Wasps, the process called gene regulation is key. As the researchers explain, the rapid turnover in venom genes is accomplished mostly by changes in regulatory regions adjacent to the genes. These regulatory regions control how the genes are expressed--that is, whether the genes are turned "on" or "off" in different tissues. When a gene is turned on, it provides instructions for manufacturing proteins.

Exosomes As “Reconfigurable Therapeutic Systems” Are Focus of New Review; Exosomes Said to Offer “Enormous Potential”

Exosomes - tiny biological nanoparticles that can transfer information between cells - offer significant potential in detecting and treating disease, according to the most comprehensive overview so far of research in the field. Areas that could benefit include cancer treatment and regenerative medicine, say Dr. Steven Conlan from Swansea University (UK), Dr. Mauro Ferrari of Houston Methodist Research Institute in Texas, and Dr. Inês Mendes Pinto from the International Iberian Nanotechnology Laboratory in Portugal. Their commissioned paper, “Exosomes As Reconfigurable Therapeutic Systems,” was published on June 22, 2017 in Trends in Molecular Medicine. Exosomes are sub-cellular particles produced by all cells in the body and are from 30-130 nanometers in size. They act as biological signaling systems, communicating between cells, carrying proteins, lipids, DNA, and RNA. They drive biological processes, from modulating gene expression to transmitting information through breast milk. Though discovered in 1983, the full potential of exosomes is only gradually being revealed. The reviewers show that the possible medical benefits of exosomes fall into three broad categories: detecting disease - by acting as disease-specific biomarkers; activating immune responses to boost immunity; and treating diseases - serving as the vehicle for drugs, for example bearing cancer therapies as their payload, to target tumors. One of the most useful properties of exosomes is that they are able to cross barriers such as the plasma membrane of cells, or the blood/brain barrier. This makes exosomes well-suited to delivering therapeutic molecules in a very targeted way.

Stanford Collaborates with Pacific Biosystems to Carry Out Long-Read Sequencing to Confirm Diagnosis of Very Rare Mendelian Disease; First Use of Long-Read Sequencing in Clinical Setting Is in Synch with Stanford’s Focus on Precision Health

When Ricky Ramon was 7, he went for a routine checkup. The pediatrician, who lingered over his heartbeat, sent him for a chest X-ray, which revealed a benign tumor in the top-left chamber of his heart. For Ramon, it was the beginning of a long series of medical appointments, procedures, and surgeries that would span nearly two decades. During this time, noncancerous tumors kept reappearing in Ramon's heart and throughout his body -- in his pituitary gland, adrenal glands above his kidneys, nodules in his thyroid. When Ramon was 18, doctors thought his symptoms were suggestive of Carney complex, a genetic condition caused by mutations in a gene called PRKAR1A. However, evaluation of Ramon's DNA revealed no disease-causing variations in this gene. Now, eight years later, researchers at the Stanford University School of Medicine have used a next-generation technology -- long-read sequencing -- to secure a diagnosis for Ramon. It is the first time long-read, whole-genome sequencing has been used in a clinical setting, the researchers report in a paper published online on June 22, 2017 in Genetics in Medicine. The article is titled Long-Read Genome Sequencing Identifies Causal Structural Variation in a Mendelian Disease.” Genome sequencing involves snipping DNA into pieces, reading the fragments, and then using a computer to patch the sequence together. DNA carries our genetic blueprint in a double-stranded string of molecular "letters" called nucleotides, or base pairs. The four types of nucleotides are each represented by a letter -- C for cytosine and G for guanine, for example -- and they form links across the two strands to hold DNA together.

Study Answers Why Ketamine Helps Depression, Suggests Target For Safer Therapy

University of Texas (UT) Southwestern Medical Center scientists have identified a key protein that helps trigger ketamine’s rapid antidepressant effects in the brain, a crucial step to developing alternative treatments to the controversial drug being dispensed in a growing number of clinics across the country. Ketamine is drawing intense interest in the psychiatric field after multiple studies have demonstrated it can quickly stabilize severely depressed patients. But ketamine – sometimes illicitly used for its psychedelic properties – could also impede memory and other brain functions, spurring scientists to identify new drugs that would safely replicate ketamine’s antidepressant response without the unwanted side effects. A new study from the Peter O’Donnell Jr. Brain Institute at UT Southwestern has jump-started this effort in earnest by answering a question vital to guiding future research: what proteins in the brain does ketamine target to achieve its effects? “Now that we have a target in place, we can study the pathway and develop drugs that safely induce the antidepressant effect,” said Dr. Lisa Monteggia (photo), Professor of Neuroscience at UT Southwestern’s O’Donnell Brain Institute. The study, published online on June 21, 2017 in Nature, shows that ketamine blocks a protein responsible for a range of normal brain functions. The blocking of the N-methyl-D-aspartate (NMDA) receptor creates the initial antidepressant reaction, and a metabolite of ketamine is responsible for extending the duration of the effect. The Nature article is titled “Effects of a Ketamine Metabolite on Synaptic NMDAR Function.” The blocking of the NMDA receptor also induces many of ketamine’s hallucinogenic responses. The drug – used for decades as an anesthetic – can distort the senses and impair coordination.