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Archive - 2016

December 9th

Unique Visual Stimulation Reduces Beta-Amyloid Plaques in Mouse Model of Alzheimer’s Disease

Using LED lights flickering at a specific frequency, MIT researchers have shown that they can substantially reduce the beta amyloid plaques seen in Alzheimer’s disease, in the visual cortex of mice. This treatment appears to work by inducing brain waves known as gamma oscillations, which the researchers discovered help the brain suppress beta amyloid production and invigorate cells responsible for destroying the plaques. Further research will be needed to determine if a similar approach could help Alzheimer’s patients, says Li-Huei Tsai (photo), Ph.D., the Picower Professor of Neuroscience, Director of MIT’s Picower Institute for Learning and Memory, and senior author of the study, which appeared online on December 7, 2016 in Nature. The article is titled “Gamma Frequency Entrainment Attenuates Amyloid Load and Modifies Microglia.” “It’s a big ‘if,’ because so many things have been shown to work in mice, only to fail in humans,” Dr. Tsai says. “But if humans behave similarly to mice in response to this treatment, I would say the potential is just enormous, because it’s so noninvasive, and it’s so accessible.” Dr. Tsai and Dr. Ed Boyden, an Associate Professor of Biological Engineering and Brain and Cognitive Sciences at the MIT Media Lab and the McGovern Institute for Brain Research, who is also an author of the Nature paper, have started a company called Cognito Therapeutics to pursue tests in humans. The paper’s lead authors are graduate student Hannah Iaccarino and Media Lab research affiliate Annabelle Singer.

Scientists Identify Genetic Mechanism for Rapid Adaptation to Normally Lethal Levels of Toxic Pollution in Wild Atlantic Killfish

A new report identifies the genetic mechanism responsible for evolutionary adaptation to toxic pollution observed in wild Atlantic killifish populations. The Atlantic killifish is renowned for its ability to tolerate large fluctuations in temperature, salinity, and oxygen levels. However, its rapid adaptation to the normally lethal levels of toxic pollution found in some urban estuaries in the United States is unusual, even for such a hardy species. A report, published in the December 9, 2016 issue of Science. journal Science by a collaborative team of research institutions including the University of Birmingham, found that some populations of killifish are up to 8,000 times more resistant than others to highly toxic industrial pollutants such as dioxins, heavy metals, and hydrocarbons. The article is titled “The Genomic Landscape of Rapid Repeated Evolutionary Adaptation to Toxic Pollution in Wild Fish.” The team analyzed the genomes of four wild populations of pollution-tolerant killifish compared with four non-tolerant populations, to identify the mechanism behind this adaptation. The scientists found that the genes responsible for the trait were those involved in the aryl hydrocarbon receptor (AHR) signling pathway, which, combined with observations of desensitization of this pathway in tolerant populations, led them to conclude that the AHR pathway is a key target of natural selection. The team also showed that the potentially negative effects of desensitization of the AHR pathway were ameliorated through compensatory adaptations in terms of cell cycle regulation and immune system function. This, combined with the diversity of pollutants present in estuaries, results in a relatively complex adaptive genotype in wild populations compared to that of laboratory models.

December 9th

New Biomarker Found for Glioma

Researchers at the University of Texas (UT) Southwestern Medical Center have found a new biomarker for glioma, a common type of brain cancer, that can help doctors determine how aggressive a cancer is and that could eventually help determine the best course of treatment. Researchers from the Harold C. Simmons Comprehensive Cancer Center found that high expression of a gene called SHOX2 predicted poor survival in intermediate grade gliomas. “As an independent biomarker, SHOX2 expression is as potent as the currently best and widely used marker known as IDH mutations,” said Dr. Adi Gazdar (photo), Professor of Pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology and a member of the Simmons Cancer Center. According to the National Cancer Institute (NCI), cancers of the brain and nervous system affect nearly 24,000 people annually. In 2013, there were an estimated 152,751 people living with brain and other nervous system cancer in the United States. The overall 5-year survival rate is 33.8 percent. Knowing the probable survival status of an individual patient may help physicians choose the best treatment. In combination with IDH mutations or several other biomarkers, SHOX2 expression helped to identify subgroups of patients with a good prognosis even though other biomarkers had predicted a bad prognosis. “Our findings are based on analysis of previously published studies. They will have to be confirmed in prospective studies, and their clinical contribution and method of use remain to be determined,” said Dr. Gazdar, who holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research at UT Southwestern.

Evolutionary Adaptation of ALOX15 Enzyme Optimizes Biosynthesis of Anti-Inflammatory and Pro-Resolving Lipoxins

The enzyme known as ALOX15 plays a crucial role in the production of anti-inflammatory and pro-resolving lipid mediators. As mammals have evolved, this enzyme has undergone changes to both its structure and function. Researchers from Charité - Universitätsmedizin Berlin have found that human ALOX15 appears to have developed a much higher capacity to stimulate the production of these lipid mediators than the enzyme variant found in lower primates. This discovery might suggest that the enzyme's structure has evolved to enable it to better control inflammation and to speed up the healing process. Results from this study were published online on July 13, 2016 in PNAS. The article is titled “Evolutionary Alteration of ALOX15 Specificity Optimizes the Biosynthesis of Antiinflammatory and Proresolving Lipoxins.” Working under the leadership of Professor Dr. Hartmut Kühn, Head of Charité's Lipoxygenase Research Laboratory, the researchers started by comparing the amino acid sequence of ALOX15 isoforms in different mammals. They found that, in lower mammals, the enzyme appeared to be structurally different from that found in higher primates such as chimpanzees, orangutans, and humans. The researchers then expressed the different ALOX15 isoforms as recombinant proteins in bacteria and explored the impact of the structural differences on enzyme functionality. "This allowed us to conclude the functional alterations ALOX15 has experienced during late primate evolution. One major functional consequence of this developmental process is that the enzyme of higher primates exhibits an improved capacity for the production of lipoxins, a special type of anti-inflammatory and pro-resolving mediator" explains Dr. Kühn.

Scientists ID Naturally Occurring Off-Switches for CRISPR/Cas9 Editing; Switches Can Provide More Efficient Control of Process

CRISPR/Cas9 genome editing is quickly revolutionizing biomedical research, but the new technology is not yet exact. The technique can inadvertently make excessive or unwanted changes in the genome and create off-target mutations, limiting safety and efficacy in therapeutic applications. Now, researchers at the University of Massachusetts (UMass) Medical School and the University of Toronto have discovered the first known "off-switches" for CRISPR/Cas9 activity, providing much greater control over the edits, according to a new study published online on December 8, 2016 in Cell. The Cell article is titled “Naturally Occurring Off-Switches for CRISPR-Cas9.” Erik J. Sontheimer (photo), Ph.D., Professor in the RNA Therapeutics Institute at UMass Medical School, and Alan Davidson, Ph.D., Professor of Molecular Genetics, and Karen Maxwell, Ph.D., Assistant Professor of Biochemistry, at the University of Toronto, identified three naturally-occurring proteins that inhibit the Cas9 enzyme. These proteins, known as anti-CRISPRs, have the ability to block DNA cleavage by the Cas9 nuclease. "CRISPR/Cas9 is a good thing because it introduces specific chromosome breaks that can be exploited to create genome edits, but because chromosome breakage can be hazardous, it is possible to have too much of a good thing, or to have it go on for too long," Dr. Sontheimer said. "There is a current shortage of reliable ways to turn off Cas9 once it has already been delivered to a cell. If you can trip an off-switch after the correct editing is done, then the problem is relieved. We report the first known natural inhibitors of Cas9 activity." "CRISPR is very powerful, but we have to be able to turn it off," Dr. Davidson said. "This is a very fundamental addition to the toolbox, which should give researchers more confidence to use gene editing."

New Research Argues Strongly for Increased Focus on Anti-Death Protein Bfl-1 As a Cancer Drug Target

Cancer researchers and drug companies may have been too quick to ignore a promising line of inquiry that targets a specific cell protein, according to a research team led by a biomedical scientist in the School of Medicine at the University of California, Riverside. Every cell in our body produces pro-death proteins and anti-death proteins, which interact with each other, negating each other's function. A healthy balance between them is a natural process. A damaged cell, for example, produces more pro-death proteins than anti-death proteins, resulting in a natural elimination of the diseased cell, a process also known as apoptosis. Pro- and anti-death proteins are therefore termed pro- and anti-apoptotic proteins, respectively. In cancer cells, genetic alterations result in an overproduction of anti-apoptotic proteins. As a result, such cancer cells keep surviving and become resistant to treatment (chemotherapy or radiation) instead of dying, resulting in uncontrolled proliferation. Anti-apoptotic proteins, therefore, have been the target for developing drugs that restore apoptosis in cancer cells. Bcl-2 is a member of a family of six anti-apoptotic proteins. It is the most studied of the six proteins, and the drug Venetoclax, approved by the Food and Drug Administration in 2016, targets it. But what if cancer cells develop resistance to this drug, which targets only one anti-death protein? Based on studies using mouse proteins, academics and pharmaceutical companies have been focusing on the next anti-apoptotic protein in the line-up: Mcl-1.

Aggressive Form of Leukemia Associated with Defective Ribosomes

Twenty to forty percent of the patients with multiple myeloma - a type of leukemia - have a defect in the ribosomes, the protein factories of the cell. Patients with the defect have a poorer prognosis than patients with intact ribosomes. At the same time, these patients respond better to a drug that already exists. These are the findings of a study by the Laboratory for Disease Mechanisms in Cancer at KU Leuven (University of Leuven), Belgium, and collaborators, and published online on December 2, 2016 in the journal Leukemia. The article is titled “RPL5 on 1p22.1 Is Recurrently Deleted in Multiple Myeloma and Its Expression Is Linked to Bortezomib Response. Multiple myeloma (MM, also known as Kahler's disease) is a blood cancer in which the plasma cells in the bone marrow start proliferating malignantly. MM cannot be cured and is most common among older people. Various treatments exist to temporarily suppress the disease, but the challenge is determining to which treatment the patient will respond best. Doctoral student Isabel Hofman (KU Leuven) discovered defects in the ribosomes of MM patients. “In MM patients, one part of the ribosome is produced less in 20 to 40 percent of the patients, depending on how aggressive the cancer is. We suspect that their cells are still producing protein, but that the balance is somewhat disrupted. In any case, we found that these people have a poorer prognosis than MM patients with an intact ribosome," explained Professor Kim De Keersmaecker (photo), head of the KU Leuven Laboratory for Disease Mechanisms in Cancer. One possible treatment for MM is the use of proteasome inhibitors. "The proteasome is the protein demolition machine in a cell,” Dr. Keersmaecker said. “There's a type of drug, including bortezomib, that inhibits its functioning.

ASHG Awards Teens for Their Genetics Videos

On December 9, 2016, the American Society of Human Genetics (ASHG) announced Beryl Zhou and Cindy Xu, students at BASIS Independent Silicon Valley in Fremont, California, as the first-place winners of the ASHG's 2016 Teen Genes Video Challenge. Guohang Zhang, of John A. Rowland High School in Rowland Heights, California; Samuel Catania, of Harriton High School in Rosemont, Pennsylvania; and Joan Fernandez, Sergio Augusto Sanchez, and Jose Rodolfo Romain, of Colegio Loyola in Santo Domingo, Dominican Republic, received honorable mentions. “It’s exciting to see the level of student interest in genomics, and the quality of their video entries was terrific,” said Michael Dougherty, Ph.D., Director of Education for ASHG. “ASHG is pleased to provide students this opportunity to creatively explore the impact of genetics on their lives and society.” Entrants were asked to submit a 3-5 minute video that describes any current application of genetics and explains how it works. After the videos were reviewed for appropriateness, ASHG members were invited to view the entries and use a predetermined set of judging criteria to vote for a winner. First-place winners Zhou and Xu, whose clay stop-motion video described how CRISPR genome editing works, will share a $1,500 monetary prize. In addition, they will participate in a video chat with Rick Guidotti, an award-winning former fashion photographer and founder of Positive Exposure. Honorable mention recipients will each receive a $150 monetary prize. For additional details on the contest winners, including the winning videos, see: http://www.ashg.org/education/TeenGenes_Winners_2016.shtml.

[ASHG press release] [See more information and view videos]

Winners of 2016 ASCB Video Awards Take Viewers Inside Miraculous World of Living Cells

Riding a wave of powerful new imaging technologies, three American Society of Cell Biology (ASCB) member labs will take you inside the world of living cells with the release, December 5, of three short 2016 Celldance videos at the ASCB Annual Meeting in San Francisco. Scientists, students, and the public attended the video releases to follow a dendritic immune cell as it races to heal a wound or get up close as cells divide or explore the native environment of secretory cells pushing out vital enzymes. Celldance Studios (also known as the ASCB's Public Information Committee) selected an international mix of three ASCB member labs to produce this year's "Tell Your Own Cell Story" videos. All three Celldance 2016 video are now available for public viewing and free downloading for non-profit and educational purposes from the Vimeo links provided below. "Cell Division: Live & Up Close" from Daniela Cimini's group at Virginia Tech's Biocomplexity Institute in Blacksburg, Virginia, challenges viewers to "Close your eyes and try to picture yourself dividing." The film shreds old high school textbook diagrams of cell division and replaces them with a pulsing, action-packed mystery story with "high stakes" health impacts. (Daniela Cimini: https://vimeo.com/193753945/38c3a4a14a) "The Big Squeeze: What Dendritic Cells Do to Fight Infection" is from the lab team of Matthieu Piel at the Institut Curie and the Institut Pierre-Gilles des Gennes in Paris, France. It follows dendritic cells as they squeeze their way through the tangled extra-cellular matrix to alert the body's immune system to an open wound. (Matthieu Piel: https://vimeo.com/193754229/305f258b22).

December 6th

Researchers ID Transcriptome Signature Shared by Circulating Large Oncosomes and Exosomes from Breast Cancer Patients; This mRNA Signature May Be Noninvasive Biomarker for Diagnosing and Monitoring Breast Cancer

An international team, led by Dolores Di Vizio (photo), M.D., Ph.D., Associate Professor of Surgery, Pathology and Laboratory Medicine, and Biomedical Sciences at Cedars-Sinai Medical Center in Los Angeles, California, has demonstrated, for the first time, the existence of a shared breast cancer-associated mRNA signature, as detected by whole transcriptome analysis (carried out by RNA-Seq) of two types of extracellular vesicles (EVs) circulating in the plasma of breast cancer patients versus controls. Such detection may prove useful as a tool for noninvasive diagnosis and monitoring of breast cancer, and perhaps other cancers as well. This new study is also the first to carry out global mRNA characterization on two different types of EVs (large oncosomes and exosomes). In addition, the work represents the first attempt to use expression data to determine what factors influence the abundance of different mRNAs in EVs, as demonstrated by co-first authors Andrew Conley, Ph.D., and Valentina Minciacchi, Ph.D.