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DNA Sequencing in Smoldering Multiple Myeloma Offers Clues to Risk of Progression to Full-Blown Multiple Myeloma

Researchers at the Dana-Farber Cancer Institute (DFCI) in Boston have carried out the largest genomic analysis of patients with smoldering multiple myeloma (SMM), a precursor to full-blown blood cancer that doesn't show outward symptoms. The next-generation sequencing project "will help to explain the biology of the disease and how it unfolds through time from asymptomatic stages to symptomatic ones," said Mark Bustoros, MD, a postdoctoral fellow in the lab of Irene Ghobrial, MD, at DFCI. "This research also will help us to understand which patients with SMM are at a high risk of progression, and eventually how we can target early stages of the disease, so that we don't wait to treat them until the cancer cells are spread everywhere in the body and cause major organ damage," said Dr. Bustoros, who presented results of the study at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta (December 9-12, 2017). The title of his presentation was “Next Generation Sequencing Identifies Smoldering Multiple Myeloma Patients with a High Risk of Disease Progression” (see link below). The scientists, led by Dr. Ghobrial, sequenced 186 bone marrow biopsies from patients with SMM, some of whom progressed to multiple myeloma and some of whom did not. The scientists then matched up the genomic data with standard analyses of risks of progression provided by current non-genetic clinical biomarkers. "We found that mutations were more frequent in the high-risk group of patients with SMM," Dr. Bustoros said. "We also found that certain mutations that are known to be drivers for cancer progression were more enriched in that group." Many of the mutations were among genes in the MAPK and NF-kB molecular pathways, while others were MYC gene aberrations that are known to be altered in multiple myeloma.

Tracking How Multiple Myeloma Evolves by Sequencing Cell-Free DNA (cfDNA) Found in Blood

Although people with multiple myeloma usually respond well to treatment, the blood cancer generally keeps coming back. Following genetic changes in how the disease evolves over time will help tscientists/physicians to understand the disease and, eventually, deliver more effective treatments. Researchers have now successfully demonstrated techniques to track these alterations over time by analyzing cell-free DNA (cfDNA) found in blood, according to Jens Lohr, MD, PhD, a hematologist and oncologist at the Dana-Farber Cancer Institute in Boston. Traditionally, multiple myeloma progress is monitored by painful and invasive bone marrow biopsies, but those biopsies are impractical to perform repeatedly, said Dr. Lohr, who presented study results at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta (December 9-12, 2017). The title of Dr. Lohr’s presentation was “Genomic Discovery and Clonal Tracking in Multiple Myeloma by Cell Free DNA Sequencing” (see link below). "We asked if you could get equivalent genetic information by monitoring cell-free DNA," he said. "The short answer is yes, in principle, all this information actually is in the blood." The scientists began by performing whole genome sequencing of 110 blood samples from 75 randomly selected multiple myeloma patients for cfDNA, and used the resulting data to predict the utility of deeper whole exome sequencing of the cfDNA. They also obtained cfDNA, matched normal blood cells, and bone marrow myeloma cells from ten myeloma patients at the same time point, and demonstrated that cfDNA whole exome sequencing robustly identified genetic mutations and these mutations matched up well with those found in sequencing bone marrow cells. The vast majority of clonal mutations and copy number variations in the bone marrow were also identified in cfDNA.

“Old Wives’ Tale” Link Between Morning Sickness & Healthy Pregnancy Supported by New Review, Special Hazards of Smoking for Pregnancy Also Possibly Explained by Role of Endokinin Hormone

A link between the “old wives’ tale” that morning sickness may indicate a healthy pregnancy, and the reason smoking is so detrimental has been found, according to a review published in the Journal of Molecular Endocrinology. The open-access article, published online on December 6, 2017, is titled “Morning Sickness Is Just the Side-Effect of a New Tachykinin That the Placenta Secretes to Improve Local Blood Flow.” The article discusses the importance of the hormone endokinin (a tachykinin) for healthy pregnancies, its role in causing morning sickness, and how its normal function may be adversely affected by smoking, leading to poor outcomes in pregnancy. Successful and effective implantation of the placenta is essential for a healthy pregnancy, but how this is achieved remains to be firmly established. In particular, the role of peptide hormones and the placenta in causing morning sickness is unclear. In this article, Professor Philip Lowry and Dr. Russell Woods from the University of Reading review the critical roles that peptide hormones have in ensuring successful implantation of the placenta, discuss how endokinin can indirectly lead to the development of morning sickness symptoms, and how its normal hormone function can be impaired by smoking. Endokinin is a peptide hormone found throughout the body that can affect blood supply to organs locally. Placental endokinin, even at low levels, appears to be capable of improving local blood flow, which is a key factor for ensuring successful implantation. Endokinin also acts on the brain to induce nausea and vomiting. This is why drugs that block the actions of endokinin in the brain are often used to treat nausea associated with chemotherapy.

Much Increased Incidence of Certain Cancers Associated with Evolutionary Adaptation to Extreme Cold Environments, According to New Hypothesis Based on Extensive Data Analysis

It is well known that cancer incidence is increasing worldwide, with pockets of human populations and geographical locations seemingly at higher risk than others. Researcher Konstantinos Voskarides, PhD, of the University of Cyrpus Medical School, noted that populations living in very low temperatures, like in Denmark and Norway, had among the highest incidences of cancer in the world. Now, in a new paper published online on December 5, 2017 in Molecular Biology and Evolution, he has advanced a new hypothesis: there is an evolutionary relationship that exists between adaptation at extreme environmental conditions -- like cold and high altitude -- and increased cancer risk in humans. "The findings of this study provide evidence that genetic variants found to be beneficial in extreme environments, can also predispose for cancer," said Dr. Voskarides. "Cell resistance at low temperatures and at high altitude probably increases the probability for malignancy. This effect hardly could be filtered out by natural selection because most cancers appear later on in age after most people have their children." The article is titled “Combination of 247 Genome-Wide Association Studies Reveals High Cancer Risk As a Result ff Evolutionary Adaptation.” Dr. Voskarides focused on the effect of low temperatures, either within Arctic/Scandinavian climates or at high altitudes. Dr. Voskarides' analyses focused on the relationship between cancer risk and local average annual temperatures. He concluded that the extremely cold environment contributed to the cancer risk. To do so, Dr.

Gene Therapy Advance in Hemophilia: Small Clinical Trial Using Gene for Hyperactive Clotting Factor Shows Impressive Success; Results Published in NEJM

A team of gene therapy researchers has reported positive results in a phase 1/2 clinical trial for the inherited bleeding disorder hemophilia B. A single intravenous infusion of a novel bioengineered gene therapy treatment enabled adult participants to safely produce sustained levels of clotting factor that prevented debilitating bleeding episodes. Patients were able to terminate prophylactic treatments--the gene therapy nearly universally eliminated their need for intravenous infusions of manufactured clotting factor. "A one-time therapy sufficient to prevent bleeding without further medical intervention is the ideal treatment goal for patients with hemophilia," said lead investigator Lindsey A. George (photo), MD, a hematologist at Children's Hospital of Philadelphia (CHOP). "This cohort of 10 patients all safely experienced sustained clinical benefit after one infusion." Dr. George and colleagues published their findings in the December 7, 2017 issue of the New England Journal of Medicine (online December 6). The article is titled “Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant.” The team previously reported preliminary results from the trial in December 2016 at the plenary session of the American Society of Hematology annual meeting. Dr. George is a member of CHOP's Division of Hematology as well as the Raymond G. Perelman Center for Cellular and Molecular Therapeutics. That center is part of CHOP's Roberts Collaborative for Genetics and Individualized Medicine. The phase 1/2 clinical trial, involving ten adult male participants, was sponsored by Spark Therapeutics of Philadelphia. The study's senior author is gene therapy pioneer Katherine High, MD, President and Head of Research and Development at Spark Therapeutics. Starting in the 1990s, Dr.

CLOCK Gene May Hold Clues to Human Brain Evolution

Scientists have long sought to unravel the molecular mysteries that make the human brain special: What processes drove its evolution through the millennia? Which genes are critical to cognitive development? A new study provides insight on the matter by demonstrating that a gene controlling our biological clocks also plays a vital role in regulating human-specific genes important to brain evolution. The findings from the University of Texas (UT)) Southwestern O’Donnell Brain Institute open new paths of research into how CLOCK proteins produced by the CLOCK gene affect brain function and the processes by which neurons find their proper place in the brain. “People have been searching for genes that are important for brain evolution, within the context of our larger, folded brains,” said Dr. Genevieve Konopka (photo), a neuroscientist with UT Southwestern’s Peter O’Donnell Jr. Brain Institute. “We now have evidence that CLOCK regulates many genes outside of circadian rhythms, so we can place it as a key point in the hierarchy of important molecular pathways for human brain development and evolution.” Human brains are notably bigger than the brains of our closest relative, the chimpanzee. But because size alone doesn’t account for cognitive abilities – mammals such as whales and dolphins have larger brains than humans – scientists have sought to understand what makes the human brain smarter. Dr. Konopka’s research has focused on the neocortex, an area of the brain with distinctive folds that is associated with sight and hearing and considered the most recently evolved part of the cortex. Her lab released a study in 2012 that found CLOCK has increased expression in the human neocortex compared to that seen in other primate brains.

Lemur Study Highlights Importance of Diet in Shaping Gut Microbiome

A study of the bacteria in the guts of three lemur species offers new insights into the role of diet in shaping these microbial ecosystems - and how these microbes may relate to primate health. "We wanted to know which microbes were present and what they were doing," says Dr. Erin McKenney, a postdoctoral researcher at North Carolina State University and lead author of a paper on the work. "We found, among other things, some similarities between lemurs and humans - their distant primate cousins - which raise questions about microbes we have associated with health problems in humans." The researchers looked at three species of lemur: ruffed lemurs (Varecia variegata) and ringtail lemurs (Lemur catta), which eat an identical diet of fruits and vegetables at the Duke Lemur Center (where the study animals were located); and sifakas (Propithecus coquereli), which eat leaves. The researchers collected data on the nutritional composition of each species' diet in captivity. They then used genetic sequencing techniques to identify the bacterial makeup of the gut microbiome, based on fecal samples taken from representatives of each species. The researchers also used nuclear magnetic resonance spectroscopy on fecal samples to determine which chemical products were produced in the gut. By analyzing the bacteria present and the chemicals being produced, the researchers could determine how the gut microbes were making use of each lemur's diet. To put this work in context, it's important to know that ruffed and ringtail lemurs have very different guts, physically. Ruffed lemurs have very simple guts - they're pretty much a straight line. Ringtails have guts that resemble human intestines - lots of twists and turns. But both species have identical diets in captivity. And researchers found that they also had almost identical gut microbiomes.

Steroid Hormone Suppresses Lethal Form of Parasitic Worm Infection in Mouse Model of Human Disease

University of Texas (UT) Southwestern Medical Center researchers have identified a chemical that suppresses the lethal form of a parasitic infection caused by roundworms that affects up to 100 million people and usually causes only mild symptoms. “The approach we used could be applied generally to any nematode parasite, not just this one type,” said Dr. David Mangelsdorf, Chair of Pharmacology, an Investigator in the Howard Hughes Medical Institute (HHMI), and one of three corresponding authors of the study published online on December 4, 2017 in PNAS. The study’s other corresponding authors are at two universities in Philadelphia. The article is titled “Methylprednisolone Acetate Induces, and Δ7-dafachronic Acid Suppresses, Strongyloides stercoralis Hyperinfection in NSG Mice.” “The plan is to develop better compounds that mimic the Δ7-dafachronic acid used in this study and eventually to treat the host to stop parasitic infection,” he added. The Centers for Disease Control and Prevention (CDC) reports that the soil-dwelling Strongyloides stercoralis nematode, or roundworm, is the primary strongyloides species that infects humans. Experts estimate that between 30 million and 100 million people are infected worldwide, and most of them are unaware of it because their symptoms are so mild. The parasite can persist for decades in the body because of the nematode’s unique ability to reinfect the host, repeatedly going through the early stages of its life cycle. The nematode that causes the original infection exists in dirt on all continents except Antarctica, and it is most common in warmer regions, particularly remote rural areas in the tropics and subtropics where walking barefoot, combined with poor sanitation, leads to infection.

Bottle Gourd Genome Sequence Provides Insights into Cucurbitaceae Evolution and Facilitates Mapping of a Papaya Ring-Spot Virus Resistance Locus

Researchers from the Boyce Thompson Institute (BTI), the United States Department of Agriculture (USDA), and collaborators in China and France have produced the first high-quality genome sequence for the bottle gourd (Lagenaria siceraria) and a reconstructed genome of the most recent Cucurbitaceae ancestor. Also known as calabash, the bottle gourd is valued for its numerous practical and culturally-significant uses in food, medicine, and novelties such as musical instruments, utensils, containers, and decorations. As a rootstock for other cucurbit crops, the bottle gourd also serves as a target for genomic research interests. Despite this, a high-quality sequence of the bottle gourd genome has not been available and much of the evolutionary history of modern cucurbits and their genetic relationships has remained largely unknown. In their findings, researchers compared the sequenced bottle gourd genome to those of other cucurbit species, allowing them to reconstruct the ancient genomic history of the Cucurbitaceae family. "Using this genome and other available genomes of cucurbit species including watermelon, melon, cucumber and pumpkin, we reconstructed the genome of the most recent common ancestor of Cucurbitaceae, which provides insights into the paleohistory of the Cucurbitaceae genome evolution," according to Dr. Zhangjun Fei, Associate Professor at BTI. The high-quality bottle gourd genome sequence also provides a comprehensive collection of the genetic relationships between the bottle gourd and other Cucurbitaceae species, which can be used to accelerate improvements in cucurbit quality and tolerance to stressors such as disease and cold.

Pigeons Can Discriminate Both Space and Time

New research at the University of Iowa (UI) shows that pigeons can discriminate the abstract concepts of space and time--and seem to use a different region of the brain than humans and primates to do so. In experiments, pigeons were shown on a computer screen a static horizontal line and had to judge its length or the amount of time it was visible to them. Pigeons judged longer lines to also have longer duration and judged lines longer in duration to also be longer in length. What that means, says Dr. Edward Wasserman, Stuit Professor of Experimental Psychology in the Department of Psychological and Brain Sciences at UI, is that pigeons use a common area of the brain to judge space and time, suggesting that these abstract concepts are not processed separately. Similar results have been found with humans and other primates. The finding adds to growing recognition in the scientific community that lower-order animal species -- such as birds, reptiles, and fish -- are capable of high-level, abstract decision-making. "Indeed, the cognitive prowess of birds is now deemed to be ever closer to that of both human and nonhuman primates," says Dr. Wasserman, who has studied intelligence in pigeons, crows, baboons, and other animals for more than four decades. "Those avian nervous systems are capable of far greater achievements than the pejorative term 'bird brain' would suggest." Humans are able to perceive space and time, even without the aid of inventions such as a watch or a ruler. The region of the brain that helps humans make those abstract concepts more tangible is the parietal cortex, part of the cerebral cortex and the outermost layer of the brain.

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