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Archive - Aug 3, 2017

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Mysterious Children’s Neurological Disease Traced to Single Base Error in One Gene; Deep Sequencing Is Key to Discovery of Mutation Affecting Ribosomal RNA Metabolism

In a new study published on August 3, 2017 in The American Journal of Human Genetics, a multinational team of researchers describes, for the first time, the biological basis of a severe neurological disorder in children. The extremely rare disorder is characterized by developmental regression and neurodegeneration. At first, the children lead normal lives and seem identical to their age-matched peers. However, beginning at around 3 to 6 years of age, the children present with neurological deterioration, gradually losing motor, cognitive, and speech functions. Although the condition progresses slowly, most patients are completely dependent on their caretakers by 15-20 years of age. Researchers from the Hadassah Medical Center and the Hebrew University of Jerusalem’s Faculty of Medicine, working with colleagues from the Pennsylvania State University College of Medicine and a multinational research team, have now identified and studied seven children — from Canada, France, Israel, Russia, and the United States — who suffer from the disorder. The researchers found in all patients the same spontaneously occurring, non-inherited genetic change in a gene (named “UBTF”) responsible for ribosomal RNA formation. Because of this small change, the patients’ cells are flooded with ribosomal RNA and are poisoned by it. (Ribosomes are responsible for the translation and production of cell proteins; themselves, they are made up of ribosomal proteins and of ribosomal RNA in a precise ratio). The researchers found an identical error in the same gene in all the patients tested, representing a difference of one letter among the roughly 3 billion letters that make up human DNA.

Autism May Reflect Excitation-Inhibition Imbalance in Brain, Stanford Study Finds

A study by Stanford University investigators suggests that key features of autism reflect an imbalance in signaling from excitatory and inhibitory neurons in a portion of the forebrain, and that reversing the imbalance could alleviate some of its hallmark symptoms. In a series of experiments conducted on a mouse model of the disorder, the scientists showed that reducing the ratio of excitatory to inhibitory signaling countered hyperactivity and deficits in social ability, two classic symptoms of autism in humans. The study was published in the August 2, 2017 issue of Science Translational Medicine. Dr. Karl Deisseroth, Professor of Bioengineering and of Psychiatry and Behavioral Sciences, is the study's senior author. The lead author is former graduate student Aslihan Selimbeyoglu, PhD. The article is titled “Modulation of Prefrontal Cortex Excitation/Inhibition Balance Rescues Social Behavior In CNTNAP2-Deficient Mice.” In 2011, Dr. Deisseroth's group published a study in Nature showing that autism-like behavioral deficits could be induced in ordinary mice by elevating the ratio of excitatory to inhibitory neuronal firing patterns in the mice's medial prefrontal cortex. The new study shows that decreasing that ratio restores normal behavior patterns in a strain of lab mice bioengineered to mimic human autism. These mice carry a mutation equivalent to a corresponding mutation in humans that is associated with autism spectrum disorder. For reasons that are not understood, the incidence of autism spectrum disorder has increased steadily in recent years, said Dr. Deisseroth, a practicing psychiatrist. Approximately 1 in 80 American children may be diagnosed with the disorder, which is characterized by repetitive behaviors and difficulty with social interaction.

Gladstone Study Reveals How to Reprogram Cells in Our Immune System; Discovery Could Improve Treatments for Autoimmune Diseases and Cancer

When the immune system is imbalanced, either due to overly-active cells or cells that suppress its function, it causes a wide range of diseases, from psoriasis to cancer. By manipulating the function of certain immune cells, called T cells, researchers could help restore the system's balance and create new treatments to target these diseases. Scientists at the Gladstone Institutes in San Francisco revealed, for the first time, a method to reprogram specific T cells. More precisely, they discovered how to turn pro-inflammatory cells that boost the immune system into anti-inflammatory cells that suppress it, and vice versa. The researchers studied two types of cells called effector T cells, which activate the immune system to defend our body against different pathogens, and regulatory T cells, which help control the immune system and prevent it from attacking healthy parts of its environment. "Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies," said Gladstone Senior Investigator Sheng Ding, PhD, who is also a Professor of Pharmaceutical Chemistry at the University of California, San Francisco. By drawing on their expertise in drug discovery, Dr. Ding's team identified a small-molecule drug that can successfully reprogram effector T cells into regulatory T cells. Their study, published online on August 2, 2017 in Nature, describes, in detail, a metabolic mechanism that helps convert one cell type into another. The article is titled “Metabolic Control of TH17 and Induced Treg Cell Balance By An Epigenetic Mechanism.” This new approach to reprogram T cells could have several medical applications. For instance, in autoimmune disease, effector T cells are overly activated and cause damage to body.

Serum Exosomal miR-125b Is a Novel Prognostic Marker For Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with high mortality. Circulating miRNA has been demonstrated as a novel noninvasive biomarker for many tumors. A new study by collaborators in China sought to investigate the potential of circulating miR-125b as a prognostic marker of HCC. In the work, exosomes were extracted from serum samples collected from two independent cohorts: cohort 1: HCC (n=30), chronic hepatitis B (CHB, n=30), liver cirrhosis (LC, n=30); cohort 2: HCC (n=128). The researchers found that miR-125b levels were remarkably increased in exosomes compared to those in serum from patients with CHB, LC, and HCC (P<0.01, respectively). However, miR-125b levels in exosomes and the serum from HCC patients were inferior to that of CHB (P<0.01 and P=0.06) and LC patients (P<0.01 for all). Additionally, miR-125b levels in exosomes were associated with tumor number (P=0.02), encapsulation (P<0.01), and TNM stage (P<0.01). In TMN, T describes the size of the original tumor and whether it has invaded nearby tissue; N describes nearby (regional) lymph nodes that are involved; and M describes distant metastasis. Kaplan–Meier analysis indicated that HCC patients with lower exosomal miR-125b levels showed reduced time to recurrence (TTR) (P<0.01) and overall survival (OS) (P<0.01). Furthermore, multivariate analysis revealed that miR-125b level in exosomes, but not in serum, was an independent predictive factor for TTR (P<0.001) and OS (P=0.011). Exosomal miR-125b levels predicted the recurrence and survival of HCC patients with an area under the ROC curve of 0.739 (83.0% sensitivity and 67.9% specificity) and 0.702 (82.5% sensitivity and 53.4% specificity). In conclusion, the researchers believe that exosomal miR-125b could serve as a promising prognostic marker for HCC.