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Archive - Dec 8, 2014

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HIF Inhibitor May Make Triple-Negative Breast Cancer Vulnerable to Chemotherapy, Hopkins Study Shows

Triple-negative breast cancer is as bad as it sounds. The cells that form these tumors lack three proteins that would make the cancer respond to powerful, customized treatments. Instead, doctors are left with treating these patients with traditional chemotherapy drugs that only show long-term effectiveness in 20 percent of women with triple-negative breast cancer. Now, researchers at The Johns Hopkins University have discovered a way that breast cancer cells are able to resist the effects of chemotherapy -- and they have found a way to reverse that process. A report of their findings was published online in PNAS on December 1, 2014. Triple-negative breast cancers account for about 20 percent of all breast cancers in the United States, and 30 percent of all breast cancers in African-American women. In addition to being resistant to chemotherapy, these cancers are known to include a high number of breast cancer stem cells, which are responsible for relapses and for producing the metastatic tumors that lead to the death of patients with cancer. Previous research revealed that triple-negative breast cancer cells show a marked increase in the activity of many genes known to be controlled by the protein hypoxia-inducible factor (HIF). Given these past results, a research team directed by Gregg Semenza, M.D., Ph.D., of Johns Hopkins, decided to test whether HIF inhibitors could improve the effectiveness of chemotherapy. "Our study showed that chemotherapy turns on HIF and that HIF enhances the survival of breast cancer stem cells, which are the cancer cells that must be killed to prevent relapse and metastasis," says Dr. Semenza, the C. Michael Armstrong Professor of Medicine at Johns Hopkins and a Johns Hopkins Kimmel Cancer Center expert. "The good news is that we have drugs that block HIF from acting."

3D Nanostructure-Forming Biomaterial May Be Used to Boost Immune Response to Cancer and Infectious Diseases

Scientists at the Institute for Biologically Inspired Engineering at Harvard University and Harvard's School of Engineering and Applied Sciences (SEAS) have shown that a non–surgical injection of programmable biomaterial that spontaneously assembles in vivo into a 3D structure could fight and even help prevent cancer and also infectious diseases such as HIV. Their findings were reported online on December 8, 2014 in Nature Biotechnology. "We can create 3D structures using minimally–invasive delivery to enrich and activate a host's immune cells to target and attack harmful cells in vivo," said the study's senior author David Mooney, Ph.D., who is a Wyss Institute Core Faculty member and the Robert P. Pinkas Professor of Bioengineering at Harvard’s SEAS. Tiny biodegradable rod–like structures made from silica, known as mesoporous silica rods (MSRs) (see image), can be loaded with biological and chemical drug components and then delivered by needle just underneath the skin. The rods spontaneously assemble at the vaccination site to form a three–dimensional scaffold, like pouring a box of matchsticks into a pile on a table. The porous spaces in the stack of MSRs are large enough to recruit and fill up with dendritic cells, which are "surveillance" cells that monitor the body and trigger an immune response when a harmful presence is detected. "Nano–sized mesoporous silica particles have already been established as useful for manipulating individual cells from the inside, but this is the first time that larger particles, in the micron–sized range, have been used to create a 3D in vivo scaffold that can recruit and attract tens of millions of immune cells," said co-lead author Jaeyun Kim, Ph.D., an Assistant Professor of Chemical Engineering at Sungkyunkwan University and a former Wyss Institute Postdoctoral Fellow.

New Model for Snake Venom Evolution Is Proposed

Technology that can map out the genes at work in a snake or lizard’s mouth has, in many cases, changed the way scientists define an animal as venomous. If oral glands show expression of some of the 20 gene families associated with “venom toxins,” that species gets the venomous label. But, a new study from The University of Texas at Arlington (UT-Arlington) challenges that practice, while also developing a new model for how snake venoms came to be. The work, which was published online on October 21, 2014 in the journal Molecular Biology and Evolution, is based on a painstaking analysis comparing groups of related genes or “gene families” in tissue from different parts of the Burmese python, or Python molurus bivittatus. A team led by assistant professor of biology Dr. Todd Castoe, and including researchers from Colorado and the United Kingdom, found similar levels of these so-called toxic gene families in python oral glands and in tissue from the python brain, liver, stomach, and several other organs. Scientists say those findings demonstrate much about the functions of venom genes before they evolved into venoms. It also shows that just the expression of genes related to venom toxins in oral glands of snakes and lizards isn’t enough information to close the book on whether something is venomous. “Research on venom is widespread because of its obvious importance to treating and understanding snakebite, as well as the potential of venoms to be used as drugs, but, up until now, everything was focused in the venom gland, where venom is produced before it is injected,” Dr. Castoe said. “There was no examination of what’s happening in other parts of the snake’s body.

Three Hormones in One Molecule May Offer Powerful New Treatment for Adult-Onset Diabetes

A new treatment for adult-onset diabetes and obesity developed by researchers at Indiana University (IU) and the German Research Center for Environmental Health has essentially cured lab animals of obesity, diabetes, and associated lipid abnormalities through improved glucose sensitivity, reduced appetite, and enhanced calorie burning. In preclinical trials, the new peptide (image)-- a molecular integration of three gastrointestinal hormones -- lowered blood sugar levels and reduced body fat beyond all existing drugs, according to the work co-led by IU Distinguished Professor of Chemistry Dr. Richard DiMarchi and Dr. Matthias Tschöp, Director of the Institute for Diabetes and Obesity at the German Research Center for Environmental Health. The new findings were published online on December 8, 2014 in in Nature Medicine. These preclinical results advance the clinical work the team announced last year that a peptide combining the properties of two endocrine hormones, GLP-1 and GIP, was an effective treatment for adult-onset diabetes. This new molecule includes a third hormone activity, glucagon. "This triple hormone effect in a single molecule shows results never achieved before,” said co-first author Dr. Brian Finan, a scientist at the Helmholtz Diabetes Center who earned his Ph.D. in biochemistry at IU in Dr. DiMarchi’s lab. “A number of metabolic control centers are influenced simultaneously, namely in the pancreas, liver, fat depots, and brain.” In constructing the new single-cell molecules with triple-hormone action, the researchers found they could reduce body weight in rodents by about 30 percent, almost twice as much as the GLP-1/GIP double hormone. The molecules are called triple agonists -- three hormones combined molecularly that can bind to and activate receptors to produce certain biological responses.

Orchid Genome Is Sequenced

As one of the most diverse plant families, the orchid now has had its first whole genome sequenced and the result will ultimately appear as a cover story in Nature Genetics and was published, in advance, online, on November 24, 2014, in an open-access article in Nature Genetics. This study was an international collaboration, including the National Orchid Conservation Center of China (NOCCC), BGI-Shenzhen, Tsinghua University, Ghent University, Chengkong University, and Institute of Botany Chinese Academy of Sciences. The research team carried out the whole genome sequencing of Phalaenopsis equestris (image), which is an important parental species for breeding of commercial phalaenopsis strains. P. equestris is also the first plant sequenced that has crassulacean acid metabolism (CAM). The assembled genome contains 29,431 predicted protein-coding genes. The average intron length is 2,922 base pairs, which is much longer than seen in any sequenced plant genomes. Further analysis indicated that transposable elements in introns are the major reason for the large size of introns in the orchid genome. The orchid genome contains a high degree of heterozygosity, thus posing a great challenge for the whole genome sequencing and assembly. In this study, researchers found that due to heterozygosity, the derived contigs were likely to be under-assembled and may be enriched for genes involved in self-incompatibility pathways. Those genes could be candidates for further research on the mechanism of self-incompatibility in the orchid. It was also reported that the evidence was found for an orchid-specific paleopolyploidy event that preceded the radiation of most orchid clades, which explained why orchid developed into one of the largest plant families on earth.

PiggyBack Transposons Reveal Genes Newly Associated with Pancreatic Cancer

A technique that can identify causes of cancer invisible to genetic sequencing has uncovered large sets of previously unknown pancreatic cancer genes. It is hoped that this study will boost research into a disease that is still poorly understood and for which five-year survival rates have stood at approximately 5 per cent for the past four decades. The technique works by introducing sections of DNA called PiggyBac transposons into the mouse genome. Transposons jump around within the genome, reinserting themselves at random spots and causing a different mutation in each cell of the mouse. This triggers cancer development, and tracking the transposon´s fingerprints in the tumors allows discovery of the affected cancer-causing genes. The PiggyBac tool was engineered for the first time to allow cancer induction in individual tissues within the mouse, and the method can now be used to study any type of cancer. While genome sequencing can identify all categories of genetic alterations with high accuracy, some of these changes are difficult to interpret. For example, hundreds or thousands of genes are found to be transcriptionally or epigenetically dysregulated within a cancer, meaning that they are not mutated but just being turned on or off. Pinpointing the few cancer-causing events among these large gene sets is extremely difficult. PiggyBac screening can facilitate this search for the needle in the haystack because transposons jump directly into the relevant genes. Moreover, the tool monitors tumor development in mice and, therefore, researchers are also able to see the consequences of cancerous mutations and how they help the disease to progress. "Recent advances in cancer genome sequencing have given extraordinary insights into the genetic events underlying cancer.