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Archive - Apr 11, 2015

G Proteins Also Signal on Internal Cell Membranes (Golgi Body); Finding May Have Relevance to Solid Tumor Cancer Metastasis

A family of proteins called G proteins are a recognized component of the communication system the human body uses to sense hormones and other chemicals in the bloodstream and to send messages to cells. In work that further illuminates how cells work, researchers at the University of California, San Diego (UCSD) School of Medicine have discovered a new role for G proteins that may have relevance to halting solid tumor cancer metastasis. The study was reported online on April 9, 2015 in Developmental Cell. The article is titled “Activation of Gαi at the Golgi by GIV/Girdin Imposes Finiteness in Arf1 Signaling.” "Our work provides the first direct evidence that G proteins are signaling on membranes inside cells, not just at the cell surface as has been widely believed for several decades," said Pradipta Ghosh, M.D., Associate Professor and senior author. "This is significant because the G-protein pathway is a target of at least 30 percent of all current drugs on the market." Specifically, the UCSD-led team used live cell imaging of fluorescent proteins and other biological assays to show that G proteins in cultured human cells are active on a series of pancake-shaped membranes, called the Golgi body. The Golgi body sorts, packages, and directs the distribution of newly synthesized proteins to various locations within a cell. It also secretes enzymes, including matrix metalloproteases that enable cancer cells to digest surrounding tissue, escape, and spread. In addition to documenting G protein activity on the Golgi, the scientists also identified the protein that turns on G proteins as the GIV protein, which is widely recognized in the cancer research community for its role in facilitating metastasis.

Spider Web Protein Perfect Substrate for Culturing Heart Tissue Cells

Genetically engineered fibers of the protein spidroin, which is the construction material for spider webs, has proven to be a perfect substrate for cultivating heart tissue cells, researchers at the Moscow Institute of Physics and Technology (MIPT) have found. The scientists discuss their findings in an article that was published online on March 23, 2015 in PLOS ONE. The article is titled “Functional Analysis of the Engineered Cardiac Tissue Grown on Recombinant Spidroin Fiber Meshes.” The cultivation of organs and tissues from a patient's cells is the bleeding edge of medical research--regenerative methods can solve the problem of transplant rejection, for instance. However, it's quite a challenge to find a suitable frame, or substrate, to grow cells on. The material should be non-toxic and elastic and should not be rejected by the body or impede cell growth. A group of researchers led by Professor Konstantin Agladze, who heads the Laboratory of the Biophysics of Excitable Systems at MIPT, works on cardiac tissue engineering. The group has been cultivating fully functional cardiac tissues, able to contract and conduct excitation waves, from cells called cardiomyocytes. Previously, the group used synthetic polymeric nanofibers, but recently decided to assay another material--electrospunfibers of spidroin, the cobweb protein. Cobweb strands are incredibly lightand durable. They're five times stronger than steel, twice more elastic than nylon, and are capable of stretching a third of their length. The structure of spidroin molecules that make up cobweb drag lines is similar to that of the silk protein, fibroin, but is much more durable. Researchers would normally use artificial spidroin fiber matrices as a substrate to grow implants like bones, tendons, and cartilages, as well as dressings.

New Technology Allows More Rapid Discovery of Aptamers, Particularly for Use As Diagnostic and Therapeutic Agents

Researchers at University of British Columbia (UBC) have developed a new technology that enables rapid discovery of aptamers, one of the fastest growing classes of diagnostic and therapeutic agents. Aptamers (see image) are short sequences of genetic material that fold into precise 3-D structures that bind target molecules and inhibit their biological functions. In an article published online on April 9, 2015 in Biotechnology and Bioengineering, the UBC investigators describe their aptamer selection platform, called high-fidelity systematic evolution of ligands by exponential enrichment (Hi-Fi SELEX), that accelerates and improves selection of DNA aptamers by ameliorating several limitations of current methods used for aptamer discovery. The platform is engineered to greatly enhance the diversity of the starting collection of aptamers and the ability to rapidly enrich aptamers of therapeutic relevance, while also enabling their high-fidelity amplification and regeneration. The article is titled “Hi-Fi SELEX: A High-Fidelity Digital-PCR-Based Therapeutic Aptamer Discovery Platform.” "As a technology development lab, we looked under-the-hood of available aptamer discovery platforms to determine precisely why they often do not yield functionally or therapeutically useful reagents. Through that effort we identified a number of issues that greatly limit performance and then worked to ameliorate those impediments using a combination of chemical modification methods and advanced enzymatic and processing strategies available in our labs," said senior author Dr. Charles Haynes. "One of the great strengths of the resulting Hi-Fi SELEX platform is its ability to enhance the functional diversity of the library, which greatly improves the odds of discovering useful molecules."

Study Associates Genes for Shorter Telomeres with Decreased Cancer Mortality

Telomeres are short stretches of repeated nucleotides that protect the ends of chromosomes. In somatic cells, these protective sequences become shorter with each cellular replication until a critical length is reached, which can trigger cell death. In actively replicating cells such as germ cells, embryonic stem cells, and blood stem cells of the bone marrow, the enzyme telomerase replenishes these protective caps to ensure adequate replication. Cancer cells also seem to have the ability to activate telomerase, which allows them to keep dividing indefinitely, with dire consequences for the patient. However, according to a study published online on April 10, 2015 in the Journal of the National Cancer Institute (JNCI), the extent to which cancer cells can utilize telomerase may depend on which variants of the genes related to telomerase activity are expressed in an individual's cells. The article is titled “Peripheral Blood Leukocyte Telomere Length and Mortality Among 64,637 Individuals from the General Population.” Telomere shortening is an inevitable, age-related process, but it can also be exacerbated by lifestyle factors such as obesity and smoking. Thus, some previous studies have found an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association found between short telomeres and increased cancer mortality was correlational, but other factors (age and lifestyle), not adjusted for in previous studies, were the real causes. Genetic variation in several genes associated with telomere length (TERC, TERT, OBFC1) is independent of age and lifestyle.

New UCLA Device Enables Massive Parallel Delivery of Particles into Cells at Rate of 100,000 Cells Per Minute; Previous Technology Worked at Rate of 1 Cell Per Minute

A new device (represented in image) developed by UCLA engineers and doctors may eventually help scientists study the development of disease, enable them to capture improved images of the inside of cells, and lead to other improvements in medical and biological research. The researchers created a highly efficient automated tool that delivers nanoparticles, enzymes, antibodies, bacteria and other "large-sized" cargo into mammalian cells at the rate of 100,000 cells per minute -- significantly faster than current technology, which works at about one cell per minute. The research, published online in Nature Methods on April 6, 2015, was led by Dr. Eric Pei-Yu Chiou, Associate Professor of Mechanical and Aerospace Engineering and of Bioengineering at the Henry Samueli School of Engineering and Applied Science at UCLA. Collaborators included students, staff, and faculty members from the engineering school and the David Geffen School of Medicine at UCLA. Currently, the only way to deliver so-called “large cargo,” particles up to 1 micrometer in size, into cells is by using micropipettes, syringe-like tools common in laboratories, which is much slower than the new method. Other approaches for injecting materials into cells -- such as using viruses as delivery vehicles or chemical methods -- are only useful for small molecules, which are typically several nanometers in length. The new device, called a biophotonic laser-assisted surgery tool (BLAST), is a silicon chip with an array of micrometer-wide holes, each surrounded by an asymmetric, semicircular coating of titanium. Underneath the holes is a well of liquid that includes the particles to be delivered. Researchers use a laser pulse to heat the titanium coating, which instantly boils the water layer adjacent to parts of the cell.

FOUNTAIN OF YOUTH: Removal of Two Tissue Inhibitors of Metalloproteinases (TIMP1 & TIMP3) Leads to Rise in Mammary Stem Cell Number and Preserves Youthful Breast Tissue in Aging Mice; No Cancer Increase Observed with Greater Number of Stem Cells

In a study carried out in the mammary glands of genetically modified mice, a research team led by Professor Rama Khokha, Ph.D., of the University of Toronton (U of T) has found that when two factors [TIMP1 (image) and TIMP3] that control tissue development are removed, the normal impact of aging on breast tissue does not occur and the tissue remained youthful in aged mice. Think of tissue as a building that is constantly under renovation. The contractors would be "metalloproteinases," which are constantly working to demolish and reconstruct the tissue. The architects in this case, who are trying to reign in and direct the contractors, are known as "tissue inhibitors of metalloproteinases" -- or TIMPs. When the architect and the contractors don't communicate well, a building can fall down. In the case of tissue, the result can be cancer. To understand how metalloproteinases and TIMPs interact, medical researchers breed mice that have one or more of the four different types of TIMPs removed. Dr. Khokha's team examined the different combinations and found that when TIMP1 and TIMP3 were removed, breast tissue remained youthful in aged mice. The results were published online on February 23, 2015 in Nature Cell Biology. The article is titled “Expansion of Stem Cells Counteracts Age-Related Mammary Regression in Compound Timp1/Timp3 Null Mice.” In the normal course of aging, tissue loses its ability to develop and repair as quickly as it did in youth. That's because stem cells, which are abundant in youth, decline in number with the passing of time. The U of T team found that with the TIMP1 and TIMP3 “architects” missing, the pool of stem cells expanded and remained functional throughout the lifetime of these mice.

Comprehensive Genetic Analysis Supports Precision Approach to Treatment of Pancreatic Cancer

A genetic analysis led by University of Texas (UT) Southwestern Medical Center researchers suggests that most pancreatic cancers harbor genetic alterations that could be targeted by existing drugs, using their genetic features as a roadmap for treatment. The findings support a precision approach to treating pancreatic cancer, the fourth deadliest cancer for both men and women. A comprehensive DNA sequencing of pancreatic cancer cases revealed, not only a plethora of damaged genes, but potential diagnostic biomarkers that could help identify those with longer or shorter survival times, and also provide opportunity for new therapeutic interventions. The new findings were published online on April 9, 2015 in an open-access article in Nature Communications. "We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic cancer--an important step in gaining a better understanding of this difficult and particularly deadly disease," said lead author Dr. Agnieszka Witkiewicz, Associate Professor of Pathology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "Importantly, the team was able to identify several genes that may be able to help us to predict outcomes in certain circumstances or serve as good candidates for therapeutic efforts." Researchers have long hoped that genetic analysis would provide insight into the biology of pancreatic cancer and define new targets for more effective treatment. Achieving this goal has been hampered by the technical difficulty of isolating pure cancer cells out of the tumor tissue that contains both tumor cells as well as normal cells. The new study overcame this limitation by selectively dissecting cancer cells from pieces of tumor tissue.

Possible Crop-Threatening New Plant Virus Found in North America

The switchgrass exhibited mosaic symptoms--splotchy, discolored leaves--characteristic of a viral infection, yet tested negative for known infections. Deep sequencing, a new technology, revealed the plants were infected with a new virus in the genus mastrevirus, the first of its kind found in North America. University of Illinois scientists reported in in the May 2015 issue of the Archives of Virology evidence of the new mastrevirus, tentatively named switchgrass mosaic-associated virus 1 (SgMaV-1). The article is titled “Detection and Characterization of the First North American Mastrevirus in Switchgrass." Other members of the mastrevirus genus, a group of DNA viruses, are known to be responsible for decimating yields in staple food crops (including corn, wheat, and sugarcane) throughout Africa, Europe, Asia, and Australia. It has never before been reported in North America. Many mastreviruses are transmitted from plant to plant by leafhoppers. The rate of infection rises with leafhopper populations, which can cause widespread epidemics and complete yield loss in some crops. Researchers are not sure what vector transmits SgMaV-1 and the impacts of the virus on switchgrass biomass yield, nor do they know what other crops the new virus affects. "My fear is that this virus is in corn and wheat, and we are not even aware of it," said first author Dr. Bright Agindotan, a former postdoctoral researcher at the Energy Biosciences Institute (EBI), housed within the Carl R. Woese Institute for Genomic Biology (IGB) at the Universtity of Illionois at Urbana-Champaign. Dr. Agindotan is now a Research Assistant Professor at Montana State University "It's like when you are sick and go to the hospital, but the doctors say nothing is wrong with you because they only test for what they know."