Scientists have isolated cancer stem cells that lead to the growth of Wilms’ tumors, a type of cancer typically found in the kidneys of young children. The researchers have used these cancer stem cells to test a new therapeutic approach that one day might be used to treat some of the more aggressive types of this disease. The results were published online on December 13, 2012 in EMBO Molecular Medicine. “In earlier studies, cancer stem cells were isolated from adult cancers of the breast, pancreas, and brain, but so far much less is known about stem cells in pediatric cancers,” remarked Professor Benjamin Dekel, head of the Pediatric Stem Cell Research Institute and a senior physician at the Sheba Medical Center and the Sackler School of Medicine at Tel Aviv University in Israel. “Cancer stem cells contain the complete genetic machinery necessary to start, sustain, and propagate tumour growth and they are often referred to as cancer-initiating cells. As such, they not only represent a useful system to study cancer development, but they also serve as a way to study new drug targets and potential treatments designed to stop the growth and spread of different types of cancer.” He added: “We have demonstrated for the first time the presence of cancer stem cells in a type of tumor that is often found in the kidneys of young children.” Wilms’ tumors are the most prevalent type of tumor found in the kidneys of children. While many patients respond well if the tumors are removed early by surgery and if patients are given chemotherapy, recurrences may occur and the cancer can spread to other tissues increasing the risks to the health of the patient. Conventional chemotherapy is toxic to all cells in the body and if given to children may lead to the development of secondary cancers when they become adults.
Using synthetic foam type materials to mimic the natural process of creating the extracellular matrix or ECM – scientists, from the University of Sheffield and the University of California San Diego, have created the random stickiness required for stem cells to properly adhere. The findings will better inform researchers across the world of how to make their biomaterials appropriately sticky for stem cells to grow. Previous attempts to recreate the process have managed only a uniform spread of sticky cells meaning there isn’t the maximum, hindering the stem cells maturation into tissue cells. Professor Giuseppe Battaglia of the University’s Department of Biomedical Science said: “We used two polymers, one that is sticky and one that is not, which separate from each other in solution. Just like with balsamic vinaigrette, we shook these two polymers up sufficiently to form randomly distributed nano-scopic patches of the sticky material – the balsamic vinegar –in a non-sticky material, just like the olive oil. To put it another way, these two materials phase separate within the foam to give you regions distinctly of one material or the other.” At the appropriate ratio of sticky and non-sticky polymer, the researchers found that it is possible to tune the size and distribution of the foam’s adhesive regions: having less sticky polymer in the foam made its adhesive patches smaller and more dispersed, just as in the human body with natural ECM. Professor Battaglia and Dr. Priyalakshmi Viswanathan, who performed most of the experimental work, added: “What was surprising to the team was that when we allowed stem cells to adhere to the foams, we found that random stickiness versus uniform stickiness was required for stem cells to properly adhere.
A specific pattern of neuronal firing in a brain reward circuit instantly rendered mice vulnerable to depression-like behavior induced by acute severe stress, a study supported by the National Institutes of Health has found. When researchers used a high-tech method to mimic the pattern, previously resilient mice instantly succumbed to a depression-like syndrome of social withdrawal and reduced pleasure-seeking – they avoided other animals and lost their sweet tooth. When the firing pattern was inhibited in vulnerable mice, they instantly became resilient. “For the first time, we have shown that split-second control of specific brain circuitry can switch depression-related behavior on and off with flashes of an LED light,” explained Ming-Hu Han, Ph.D., of the Mount Sinai School of Medicine, New York City, a grantee of NIH’s National Institute of Mental Health (NIMH). “These results add to mounting clues about the mechanism of fast-acting antidepressant responses.” Dr. Han, Eric Nestler, M.D., Ph.D., of Mount Sinai, and colleagues, reported the results of their study online on December 12, 2012, in Nature. In a companion article, NIMH grantees Kay Tye, Ph.D., of the Massachusetts Institute of Technology, Cambridge, Massacusetts, and Karl Deisseroth, M.D., Ph.D., of Stanford University, Stanford, California, used the same cutting-edge technique to control mouse brain activity in real time. Their study reveals that the same reward circuit neuronal activity pattern had the opposite effect when the depression-like behavior was induced by daily presentations of chronic, unpredictable mild physical stressors, instead of by shorter-term exposure to severe social stress. Prior to the new studies, Dr.
Long ago, when life on Earth was in its infancy, a group of small single-celled algae propelled themselves through the vast prehistoric ocean by beating whip-like tails called flagella. It’s a relatively unremarkable story, except that now, more than 800 million years later, these organisms have evolved into parasites that threaten human health, and their algal past in the ocean may be the key to stopping them. The organisms are called apicomplexa, but people know them better as the parasites that cause malaria and toxoplasmosis, serious diseases that infect millions of people every year, particularly in the developing world. Now, researchers at the University of Georgia (UGA) have discovered how an important structure inside these parasitic cells, which evolved from the algal ancestor millions of years ago, allows the cells to replicate and spread inside their hosts. The research may soon lead to new therapies to halt these deadly pathogens before they cause disease. In order to survive, the parasitic apicomplexa must invade an animal or human and force its way into the cells of its host. Once inside the host cell, the parasite begins to replicate into numerous daughter cells that in turn create additional copies, spreading the infection throughout the body. In their study, published December 11, 2012 in PLoS Biology, the researchers demonstrate that, during the process of replication, the parasite cell loads genetic material into its daughter cells via a strand of fiber that connects the two. By altering the genes for the components of the fiber in the laboratory, the researchers discovered that they could prevent parasite replication, making the parasite essentially harmless.
Epigenetics – how gene expression is regulated by temporary switches, called epi-marks – appears to be a critical and overlooked factor contributing to the long-standing puzzle of why homosexuality occurs. According to a study, published online December 11, 2012 in The Quarterly Review of Biology, sex-specific epi-marks, which normally do not pass between generations and are thus “erased,” can lead to homosexuality when they escape erasure and are transmitted from father to daughter or mother to son. From an evolutionary standpoint, homosexuality is a trait that would not be expected to develop and persist in the face of Darwinian natural selection. Homosexuality is nevertheless common for men and women in most cultures. Previous studies have shown that homosexuality runs in families, leading most researchers to presume a genetic underpinning of sexual preference. However, no major gene for homosexuality has been found despite numerous studies searching for a genetic connection. In the current study, researchers from the Working Group on Intragenomic Conflict at the National Institute for Mathematical and Biological Synthesis (NIMBioS) integrated evolutionary theory with recent advances in the molecular regulation of gene expression and androgen-dependent sexual development to produce a biological and mathematical model that delineates the role of epigenetics in homosexuality. Epi-marks constitute an extra layer of information attached to our genes’ backbones that regulates their expression. While genes hold the instructions, epi-marks direct how those instructions are carried out – when, where, and to what extent a gene is expressed during development.
Highlanders in Tibet and Ethiopia share a biological adaptation that enables them to thrive in the low oxygen of high altitudes, but the ability to pass on the trait appears to be linked to different genes in the two groups, research from a Case Western Reserve University scientist and colleagues shows. The adaptation is the ability to maintain a relatively low (for high altitudes) level of hemoglobin, the oxygen-carrying protein in red blood cells. Members of ethnic populations – such as most Americans – who historically live at low altitudes naturally respond to the thin air by increasing hemoglobin levels. The response can help draw oxygen into the body, but increases blood viscosity and the risks for thrombosis, stroke, and difficulties with pregnancies. By revealing how populations can live in severe environments, the research may provide insight for managing high-altitude sickness and for treating low blood-oxygen conditions such as asthma, sleep apnea, and heart problems among all people. How long such physiological and genetic changes take remains a question. The researchers found the adaptation in an ethnic group that has lived high in mountains of Ethiopia for at least 5,000 years, but not among a related group that has lived high in the mountains for 500 years. The findings were reported on December 6, 2012 in the open-access online journal PLoS Genetics. In their first comparison, the researchers found that the genes responsible for hemoglobin levels in Tibetans don’t influence an ethnic group called the Amhara. The Amhara have lived more than a mile high in the Semien Mountains of northern Ethiopia for 5,000 to 70,000 years. A different variant on the Amhara genome, far away from the location of the Tibetan variant, is significantly associated with their low hemoglobin levels.
Researchers using novel approaches and methodologies of identifying genes that contribute to the development of autism have found evidence that disturbances in several immune-system-related pathways contribute to development of autism spectrum disorders. The report published December 4, 2012 in the open-access journal PLoS ONE powerfully supports a role for the immune function in autism by integrating analysis of autism-associated DNA sequence variations with that of markers identified in studies of families affected by autism. “Others have talked about immune function contributions to autism, but in our study immune involvement has been identified through a completely nonbiased approach,” says Vishal Saxena, Ph.D., of the Massachusetts General Hospital (MGH) Department of Neurology, first, corresponding, and co-senior author of the PLoS ONE paper. “We let the data tell us what was most important; and most tellingly, viral infection pathways were most important in this immune-related mechanism behind autism.” Genetic studies of families including individuals with autism have indentified linkages with different locations in the genome. Since traditional interpretation methods implicate the gene closest to a marker site as the cause of a condition, those studies appeared to point to different genes affecting different families. However, Saxena’s team realized that, because autism has typical symptoms and affects the same biological processes, a common molecular physiology must be affecting the different families studied. To search for genetic pathways incorporating these autism-associated sites, they developed a methodology called Linkage-ordered Gene Sets (LoGS) that analyzes all of the genes within a particular distance from marker sites and ranks them according to their distance from the marker. Dr.
A team of researchers from the Spanish National Cancer Research Centre (CNIO), led by Dr. Manuel Serrano, from the Tumour Suppression Group, together with scientists from London and Santiago de Compostela, has discovered that the cellular reprogramming gene SOX2, which is involved in several types of cancers, such as lung cancer and pituitary cancer, is directly regulated by the tumor suppressor CDKN1B(p27) gene, which is also associated with these types of cancer. The same December 7, 2012 edition of Cell Stem Cell also includes a study led by Dr. Massimo Squatrito, who recently joined the CNIO to direct the Seve Ballesteros Foundation Brain Tumour Group. This study, carried out in Dr. Eric C. Holland’s laboratory, at the Memorial Sloan Kettering Cancer Center (MSKCC), in New York, shows the relationship between MEF, a gene regulator involved in glioblastomas – the most aggressive and common brain tumors -, and SOX2. The cell reprogramming process, discovered by this year’s Nobel Prize co-winner, Dr. Shinya Yamanaka, has become a powerful tool for researchers. Via the introduction of a cocktail of four genes, among them SOX2, into cells, scientists can reprogram cells and transform them into stem cells which can be used to study a variety of processes, including cancer. The research team led by Dr. Serrano and Dr. Manuel Collado was interested in the possible role of the tumor suppressor gene CDKN1B(p27) in reprogramming. During the course of these studies, Dr. Han Li, first author of the study, unexpectedly discovered that cells deficient in the CDKN1B(p27) gene could be reprogrammed without the need to introduce SOX2. This observation was the starting point to unravel the functional relationship between the two genes. The work led by Dr. Squatrito, in which Dr.
Genomic sequencing has revealed therapeutic drug targets for difficult-to-treat, metastatic triple-negative breast cancer (TNBC), according to an unprecedented study by the Translational Genomic Research Institute (TGen) and US Oncology Research. The study was published online on November 19, 2012 in the journal Molecular Cancer Therapeutics. By sequencing, or spelling out, the billions of letters contained in the genomes of 14 tumors from ethnically diverse metastatic TNBC patients, TGen and US Oncology Research investigators found recurring significant mutations and other changes in more than a dozen genes. In addition, the investigators identified mutations previously unseen in metastatic TNBC and took the sequencing data into account in selection of therapeutic protocols specific to each patient’s genetic profile. “This study stands as a one-of-a-kind effort that has already led to potentially beneficial clinical trials, and sets the stage for future investigations,” said Dr. John Carpten, Ph.D., TGen’s Deputy Director of Basic Science and Director of TGen’s Integrated Cancer Genomics Division, and the study’s senior author. The most frequently mutated gene among the tumors (7 of 14) was the TP53 tumor suppressor, and aberrations were observed in additional tumor suppressor genes including CTNNA1, which was detected in two of six African-American patients (who typically have more aggressive and treatment-resistant disease). Alterations were also seen in the ERBB4 gene, known to be involved in mammary-gland maturation during pregnancy and lactation, but not previously linked to metastatic TNBC. The study included an “outlier analysis,” which assessed expression patterns for each tumor when compared against the other tumors examined in the study.
Each year, approximately 610,000 Americans suffer their first heart attack, according to the Centers for Disease Control and Prevention. Heart attacks and other symptoms of cardiovascular disease can be caused when blockage occurs in the arteries. In a new study from the University of Missouri (MU), a scientist has discovered a natural defense against arterial blockage: bilirubin. Bilirubin is typically something parents of newborns hear about when their children are diagnosed with jaundice. Generated during the body’s process to recycle worn-out red blood cells, bilirubin is metabolized by the liver and, usually, leaves the body harmlessly. (Many babies’ livers are not developed enough to metabolize the bilirubin, which results in the infants being diagnosed with jaundice, or high levels of bilirubin in their systems.) Now MU scientists have found that bilirubin can be used to inhibit the clogging of arteries, and thus prevent the deadly consequences often experienced by individuals with cardiovascular disease. “Bilirubin is generated daily in the human body, but it’s not a waste product; it has important functions, including being an antioxidant,” said Dr. William Durante, professor of medical pharmacology and physiology and lead author on the study. “What we found in our study is that bilirubin can prevent or limit the damage that occurs to blood vessels in individuals who have, or are at risk for, cardiovascular diseases, such as atherosclerosis.” When arteries are damaged, smooth muscle cells in blood vessels become activated and grow at the injury sites creating lesions inside the arteries. These lesions can block the flow of blood in arteries of the heart leading to chest pains or deadly heart attacks, Dr. Durante said.