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PREMIER NEWS SOURCE FOR LIFE SCIENCE RESEARCHERS WORLDWIDE ISSN 1939-4470 Vol.16 No.
4 7-8/2011
DNA Sequencing from Small or Degraded RNA Samples
Next-Generation Sequencers Essential Tools in Biomedical Research

ext-generation sequencers (NGSs) are moving into the service sector and the global biomedical research community where they are increasingly being seen as indispensable tools. Recent scientific developments that are an outcome of next-generation sequencing technology demonstrate
New Insights into Protein Molecular Structure
company with expertise in DNA and RNA sample preparation has joined forces with a major manufacturer of DNA sequencing equipment to develop a unique sample preparation method and high-throughput sequencing solution for small and degraded RNA samples.
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the impact of masively parallel platforms, according to new market research. The declining cost of genomic sequencing has made way for the clinical application of this technology. The remarkable growth in drug discovery and molecular diagnostics will promote the uptake of this technology.
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tool has been designed to determine the molecular configuration of proteins. An international collaboration has led to a new, high-performance application that rapidly determines the structure of protein molecules in several cases where previous techniques had failed.
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Biosensor to Speed Up Drug Development T

Image: Courtesy of Sebastian Osterfeld / Stanford University
Protein Regulator of Blood Vessel Formation Identified

he molecular processes leading to formation of blood vessels from undifferentiated endothelial cells are apparently under the direct control of the Ras interacting protein 1 (Rasip1). Investigators at the University of Texas Southwestern Medical Center (Dallas, USA; www.utsouthwestern.edu)
he study of the kinetics of protein interactions is essential to the process of drug development. Magnetically responsive nanosensors scaled to more than 100,000 sensors per square centimeter could be used to monitor the kinetics of protein interactions with highresolution, overcoming current detection limits.
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INSIDE
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Image: Image: A A microchip microchip with with an an array array of of 64 64 nanosensors nanosensors
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Color-Coded Freezer Boxes Enhance Cryogenic Storage
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new line of colored cryogenic storage boxes was designed to be a key component in a series of solutions for problems relating to organizing and retrieving samples held in deep freezers and under liquid nitrogen.
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Genomics Proteomics Drug Discovery Biochemistry Therapeutics Diagnostics Lab Techniques Industry News
Product News . . . . . . 14-26 Technical Literature . . . . 30 International Calendar . . 34
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Research Management System Improves Study Effectiveness
Nanowire Technology Could Lead to Research Breakthroughs
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new clinical research management system (CRMS) will help improve the efficiency and efficacy of clinical research studies, enterprise-wide, by driving better management of treatment plans, processes, and protocols while supporting research-billing compliance.
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team of Danish investigators has been able to combine nanoscale materials and technologies that are conventionally used for electronic devices with individual living cells. The researchers have shown that cells can grow and function on a carpet of small upright
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Nanowire Technology Could Lead to Research Breakthroughs

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Image: Scanning electron microscope (SEM) image of nanowires growing on an untreated metal surface (Photo courtesy of the University of California, San Diego).
needles made of semiconductors so-called nanowires. We have developed a new method that makes it possible for us to see how the cells function when they are impaled on carpets of nanowires. We think that the technique has great potential and that it could be used in laboratories within a couple of years to develop. For example, it could be used by the pharmaceutical industry to test new drugs for a variety of diseases including neurological problems, cancer and heart disease, explained Dr. Karen Martinez, who is group leader of the BioNano group, department of neu-
roscience and pharmacology at the University of Copenhagen (Denmark; www.ku.dk). With this advance, the Danish research group is now at the top of international research in this interdisciplinary field of research, together with a few groups from Harvard University (Cambridge, USA), University of California, Berkeley (USA), and Lund University (Sweden). The [University of Copenhagen] Nano-Science Center brings together biologists, physicists, pharmacologists, and chemists who are working together across traditional research boundaries, and this breakthrough at the Nano-Science Center is a direct result of the cultivation of this interdisciplinarity in the long-term strategic focus at the Nano-Science Center, explained the new director of the NanoScience Center Prof. Morten Meldal. Nanophysicists Jesper Nygrd and Claus Srensen are in charge of the development of nanowires with a diameter of approximately 100 nm and Dr. Martinez is responsible for the knowledge of the function and handling of cells. The project benefits considerably from the interdisciplinary background of Trine Berthing, a PhD student in nanoscience, who has been working on this project since the beginning of her graduate studies in nanoscience in 2007. We have come much further than I would have predicted just a few years back when the research resembled science fiction. Actually, we took a bit of a chance when Trine started, but soon discovered that there was research potential. Now we have a method that makes it possible to incorporate several nanowires in a cell while the cell functions, explained associate professor, Dr. Martinez, who will continue to investigate the techniques industrial potential, for example, with the help of the start-up company inXell bionics, created by researchers from the University of Copenhagen.
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Bio Research International July-August/2011
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New Insights to Protein Molecular Structure

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The effectiveness of the new method was reported online May 1, 2011, in the journal Nature. The lead authors were Dr. Frank DiMaio of the University of Washington (UW; Seattle, USA; www.washington.edu) and Dr. Thomas C. Terwilliger of Los Alamos [US] National Laboratory (NM, USA; www.lanl.gov). The senior author was Dr. David Baker, from the UW department of biochemistry. A proteins molecular structure shapes its functions. In biomedical and health research, for example, scientists are interested in the molecular structure of specific proteins for many reasons, a few of which are (1) to design drugs that selectively target, at the molecular level, specific biochemical reactions in the body; (2) to understand abnormal human proteins in disease, and how these abnormal proteins cause malfunctions; (3) to learn the shape and function of virus particles and how they act to cause infections; (4) to see how the chains of amino acids, decoded from the DNA in genes, fold and twist into normally or abnormally shaped protein molecules; (5) to design new proteins not found in the nature; (6) to find ways to replace malfunctioning molecular parts of proteins that are vital to health; (7) lastly, to devise nanoscale tools. The important new method describedin Nature highlights the value of computational modeling in helping scientists to determine the structures and functions of molecules that are difficult to study using current techniques, said Dr. Peter Preusch, who oversees Dr. Bakers research grant and other structural biology grants at the US National Institutes of Health (NIH; Bethesda, MD, USA). The methods devised by the group overcome some of the limitations of X-ray crystallography in determining the molecular structure of a protein. Xray crystallography obtains data about the positions of atoms, chemical bonds, the density of electrons and other arrangements within a protein molecule. The information is gleaned by striking protein crystals with X-ray beams, which bounce off in several directions. Measuring the angles and intensities of these diffracted beams enables scientists to generate a three-dimensional (3D) image of electron density. However, information about the molecular structure can be lost in taking the measurements, due to restraints posed by physics. Scientists attempt to avoid this problem by comparing the crystallography results to previously solved protein structures that resemble the unknown structure. The technique to fill in the blanks is called molecular replacement. Molecular replacement has its own limitations in understanding the electron density maps produced by X-ray crystallography, according to the authors of the paper. Techniques such as automatic chain tracing frequently follow the comparative model more closely than the actual structure of the protein under question. These errors lead to failure to obtain an accurate configuration of the molecule. The researchers demonstrated that this limitation could be considerably reduced by combining computer algorithms for protein structure modeling
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with those for determining structure via X-ray crystallography. Several years ago, University of Washington researchers and their colleagues developed a structure prediction method called Rosetta. This program takes a chain of amino acids and searches for the lowest energy conformation possible from folding, twisting, and packing the chain into a 3D molecule. The researchers discovered that even very poor electron density maps from molecular replacement solutions could be useful. These maps could guide Rosetta structural prediction searches that are based on energy optimization. By taking these energyoptimized predicted models, and searching for consistency with the electron density data contained in the X-ray crystallography, new maps were generated. The new maps were then subjected to automatic chain tracing to generate 3D models of the protein molecular structure. The models were checked with an advanced monitoring technique to see if any are successful. To evaluate the performance of their new integrated method, the researchers looked at 13 sets of X-ray crystallography data on molecules whose structures could not be solved by expert crystallographers. These structures remained unsolved even after the application of an extensive array of other approaches. The new integrated method was able to yield high-resolution structures for eight of these 13 highly challenging models. The results show that structural prediction methods such as Rosetta can be even more powerful when combined with X-ray crystallography data, the researchers noted. They added that the integrated approach likely outperforms others because it provides physical chemistry and protein structural information that can guide the massive sampling of candidate configurations. These data eliminate most conformations that are not physically possible. These procedures, the authors noted, required significant computation, as up to several thousand Rosetta model predictions are generated for each structure. The researchers have developed automated procedures that potentially could taper down the possibilities and lessen the number of times a model is rebuilt to make corrections. This automation could reduce computing time. Through Dr. Bakers laboratory, many members of the general public contribute their unused home computer time to help in the effort to obtain structural models of proteins that are biologically and medically significant. The scientific discovery game is called Fold It, which can be accessed at http://fold.it/portal).
Image: Folded up Puzzle 48 (Photo courtesy of Foldit).
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Color-Coded Freezer Boxes Enhance Cryogenic Storage

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The Wheaton (Millville, NJ, USA; www.wheaton.com) KeepIT Freezer Boxes complement Wheatons line of CryoELITE Cryogenic Vials. Both boxes and vials are colored, which allows color-coding to enable faster batching and easier sample identification. For digital traceability, the KeepIT boxes have openings in the bottom tray that allow for scanning of barcode bottom inserts on the CryoELITE vials. The bottom openings also allow for the quick draining of liquid nitrogen. The KeepIT boxes are constructed of Eastman Tritan, a bisphenol-A (BPA) free, shatter resistant resin that withstands extreme freeze/thaw cycles, moisture, and exposure to solvents such as DMSO. The transparent cover permits easy viewing of sample vials while closed. Wheaton currently offers the KeepIT-100, which stores up to 100 internal-threaded, 1.2 mL - 2 mL CryoELITE vials, and the KeepIT-81, which accommodates up to 81 external-threaded, 1.2 mL - 2 mL CryoELITE vials. Both boxes fit the standard footprint used with most liquid nitrogen storage shelves and freezer drawers. The KeepIT Freezer Box and CryoELITE vials are components of Wheaton BioBanking Solutions, a comprehensive offering of products and customized services for research that also includes glass or plastic cryogenic containers, biobank storage boxes, barcoding, and scanners. We work closely with scientific innovators to develop containment solutions that accommodate their lifes work, said Stephen R. Drozdow, president of Wheaton. These products are designed to support researchers who want to build a secure biorepository with confidence right from the start.
Clinical Research Management System Improves Study Effectiveness

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Centricity Research, developed by GE Healthcare (Chalfont St. Giles, UK; www.gehealthcare.com), a global developer of healthcare information technology (HIT), is the industrys first enterprise-class clinical research management solution. Centricity Research helps institutions conducting clinical or translational research manage the growing complexity of research processes and compliance requirements. Centricity Research has robust functionality, built on the foundation of the currently available Centricity Patient Protocol Management solution, to support both the institutions and researchers efforts in achieving compliance, enhancing safety, increasing subject recruitment, and facilitating agency audits. Moreover, GE Healthcare has developed a strategic partnership with mdlogix (Medical Decision Logic, Inc.; Baltimore, MD, USA; www.mdlogix.com), which developed its CRMS in collaboration with the Johns Hopkins University School of Medicine (Baltimore, MD, USA) and other leading clinical research institutions. The enterprise deployment of CRMS at Johns Hopkins includes all departments in the School of Medicine, said Dr. Dan Ford, vicedean of clinical research at the Johns Hopkins School of Medicine. We have over 4,000 protocols currently in CRMS, with over 1,100 of those being active, and approximately 25% of those protocols using CRMS solely at the discretion of the researchers themselves because of the value they gain from the system. CRMS has helped us more efficiently manage the 30% increase we have achieved in the number of research studies conducted at the Johns Hopkins School of Medicine since 2007.
Approach Devised to Trigger Immune System Using Nanovaults to Deliver Drugs

cientists have found a new way to wake up the immune system using nanovaults to deliver drugs. The University of California, Los Angeles (UCLA; USA; www.ucla.edu) scientists have discovered a way to trigger the immune system to combat cancer by delivering an immune systemstimulating protein in a nanoscale container called a vault directly into lung cancer tumors. The vaults, barrel-shaped nanoscale capsules found in the cytoplasm of all mammalian cells, were engineered to release slowly a protein, the chemokine CCL21, into the tumor. Preclinical studies in mice with lung cancer revealed that the protein stimulated the immune system to recognize and attack the cancer cells, potently inhibiting cancer growth, according to Dr. Leonard Rome, a researcher at UCLAs Jonsson Comprehensive Cancer Center, associate director of the California NanoSystems Institutes, and cosenior author of the study. The study was published in the May 3, 2011, issue of the journal PLoS One, a peer-reviewed journal of the Public Library of Science. The new vault delivery system, which Dr. Rome characterized as just a dream three years ago, is based on a 10-year, on-going research effort focusing on using a patients white blood cells to create dendritic cells, cells of the immune system that process antigen material and present it on the surface to other immune system cells. A phase I study that is part of the effort, led by UCLAs Dr. Steven Dubinett, used a replication-deficient adenovirus to infect the dendritic cells and prompt them to over-secrete CCL21, the first time the chemokine has been administered to humans. The engineered cells 10 million at a time were then injected directly into the patients lung cancer to stimulate an immune response. The early phase study has shown the dendritic cell method is safe, has no side effects, and seems to boost the immune response Dr. Dubinett and his team found T lymphocytes circulating in the blood stream with specific cytokine signatures, indicating that the lymphocytes were recognizing the cancer as a foreign invader. However, the process to generate dendritic cells from the white blood cells and engineer them to over-secrete CCL21 is cumbersome, expensive, and time-consuming. It also requires a Good Manufacturing Practice (GMP) suite, a specialized laboratory critical for the safe growth and manipulation of cells, which many research institutions do not have. It gets complicated, said Dr. Dubinett, director of the Lung Cancer Program at UCLAs Jonsson Comprehensive Cancer Center, a professor of pathology and laboratory medicine, member of the California NanoSystems Institute (CNSI; www.cnsi.ucla.edu), and a cosenior author of the article. You have to have a confluence of things happen the patient has to be clinically eligible for the study and healthy enough to participate, we have to be able to grow the cells and then genetically modify them and give them back. There also was the challenge of patient-to-patient variability, according to Dr. Sherven Sharma, a researcher at the California NanoSystems Institute,
professor of pulmonary and critical care medicine, and cosenior author of the study. It was easier to isolate and grow the dendritic cells in some patients than in others, so results were not consistent. In the phase I study, it takes more than a week to differentiate the white blood cells into dendritic cells and let them grow to the millions required for the therapy. The dendritic cells are infected with a virus modified to carry a gene that caused the cells to secrete CCL21 and then injected into the patients tumor using guided imaging. We thought if we could replace the dendritic cells with a nano-vehicle to deliver the CCL21, we would have an easier and less expensive treatment that also could be used at institutions that dont have GMP, Dr. Dubinett said. The researchers plan to assess the vault delivery method in human studies within the next three years and hope the promising results found in the preclinical animal tumor models will be
replicated. If such a study were approved, it would be the first time a vault nanoparticle is used in humans for a cancer immunotherapy. The vault nanoparticle would require only a single injection into the tumor because of the slowrelease design, and it ultimately could be designed to be patient specific by adding the individuals tumor antigens into the vault, Dr. Dubinett reported. The vaults may also be targeted by adding antibodies to their surface that recognize receptors on the tumor. The injection could then be delivered into the blood stream and the vault would navigate to the tumor, a less invasive process that would be easier on the patients. The vault could also hunt for and target tumors and metastases too small to be detected with imaging. Because a vault is naturally occurring particle, it causes no harm to the body and is potentially an ideal vehicle for use in delivery of personalized therapies, according to Dr. Rome.
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Protein Regulator of Blood Vessel Formation Identified

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have been studying the mechanisms underlying vascular tubulogenesis (the formation of biological tubular structures). These mechanisms are required during fetal development when the body forms many tubeshaped organs such as the intestines of the digestive system and the vessels of the cardiovascular system. Results from experiments conducted on mice that were published in the April 19, 2011, issue of the journal Developmental Cell revealed that endothelial tubulogenesis required the Ras interacting protein 1, Rasip1, and its binding partner, the RhoGAP Arhgap29. Mice lacking Rasip1 failed to form patent lumens in all blood vessels, including the early endocardial tube. Depletion of either Rasip1 or Arhgap29 in cultured endothelial cells blocked in vitro lumen forma-
tion, fundamentally altered the cytoskeleton, and reduced integrindependent adhesion to ECM (extracellular matrix). These defects result from increased RhoA/ROCK/ myosin II activity and blockade of Cdc42 and Rac1 signaling. What we have found is really the first factor that is important in all blood vessels for inner channel formation and tubulogenesis, i.e., the transformation of something that looks like a rope into something that looks like a garden hose, said senior author Dr. Ondine Cleaver, assistant professor of molecular biology at the University of Texas Southwestern Medical Center. Rasip1 is the first blood vessel-specific regulator of molecular switches called GTPases. The protein appears to be active only in the endothelium, the layer of cells that line the blood vessels, and is not found in the smooth
Image: Colored scanning electron micrograph (SEM) of endothelial cells lining the inside of a blood vessel (Photo courtesy of Steve Gschmeissner / Science Photo Library).
muscle cells that make up the outside of the vessels. Although this is still a mouse study, we feel that future studies of Rasip1 and the molecular processes
under its control hold great promise to provide tools and models for advancing clinical therapies aimed at blocking vessel formation in tumors, said Dr. Cleaver.
Biosensor Microchip Speeds Drug Development

esearchers have developed a new biosensor microchip that could significantly speed up the process of drug development. The microchips, stuffed with highly-sensitive nanosensors analyze how proteins bind to one another, a vital step for assessing the effectiveness and possible side effects of potential medications. A 1-cm-sized array of the nanosensors can monitor simultaneously and continuously thousands of times more protein-binding events than any existing sensor. The new sensor is also able to detect interactions with greater sensitivity and deliver the results significantly faster than the present gold standard method. You can fit thousands, even tens of thousands, of different proteins of interest on the same chip and run the protein-binding experiments in one shot, said Dr. Shan Wang, a professor of materials science and engineering, and of electrical engineering, Stanford University (Stanford, CA, USA; www.stanford.edu), who led the research effort. In theory, in one test, you could look at a drugs affinity for every protein in the human body, said Richard Gaster, MD/PhD candidate in bioengineering and medicine, who is the first author of a paper describing the research is in the April 2011 issue of Nature Nanotechnology, also available online. The power of the nanosensor array lies in two advances. First, the use of magnetic nanotags attached to the protein being studied such as a medication greatly increases the sensitivity of the monitoring. Second, an analytic model the researchers developed enables them to predict accurately the final outcome of an interaction based on only a few minutes of monitoring data. Current techniques typically monitor no more than four simultaneous interactions and the process can take
hours. I think their technology has the potential to revolutionize how we do bioassays, said Dr. P.J. Utz, associate professor of medicine (immunology and rheumatology) at Stanford University Medical Center, who was not involved in the research. Members of Dr. Wangs research group developed the magnetic nanosensor technology several years ago and demonstrated its sensitivity in research in which they demonstrated that it could detect a cancer-associated protein biomarker in mouse blood at a thousandth of the concentration that commercially available techniques could detect. That research was described in a 2009 paper in Nature Medicine. The researchers customized the nanotags to attach to the particular protein being studied. When a nanotag-equipped protein binds with another protein that is attached to a nanosensor, the magnetic nanotag alters the ambient magnetic field around the nanosensor in a small but distinct way that is sensed by the detector. Lets say we are looking at a breast cancer drug, Mr. Gaster said. The goal of the drug is to bind to the target protein on the breast cancer cells as strongly as possible. But we also want to know: How strongly does that drug aberrantly bind to other proteins in the body? To establish that, the researchers would put breast cancer proteins on the nanosensor array, along with proteins from the liver, lungs, kidneys, and any other kind of tissue about which they are concerned. Then they would add the medication with its magnetic nanotags attached and see which proteins the drug binds with and how strongly. We can see how strongly the drug binds to breast cancer cells and then also how strongly it binds to
any other cells in the human body such as your liver, kidneys, and brain, Mr. Gaster said. So we can start to predict the adverse affects to this drug without ever putting it in a human patient. It is the increased sensitivity to detection that comes with the magnetic nanotags that enables Mr. Gaster and Dr. Wang to determine not only when a bond forms, but also its strength. The rate at which a protein binds and releases, tells how strong the bond is, Mr. Gaster said. That can be an important factor with numerous medications. I am surprised at the sensitivity they achieved, Dr. Utz said. They are detecting on the order of between 10 and 1,000 molecules and that to me is quite surprising. The nanosensor is based on the same type of sensor used in computer hard drives, Wang said. Because our chip is completely based on existing microelectronics technology and procedures, the number of sensors per area is highly scalable with very little cost, he said. Although the chips used in the research described in the Nature Nanotechnology paper had a little more than 1,000 sensors per square centimeter, Dr. Wang stated it should be no problem to put tens of thousands of sensors on the same footprint. It can be scaled to over 100,000 sensors per centimeter, without even pushing the technology limits in microelectronics industry, he said. Dr. Wang reported that he sees a promising future for increasingly powerful nanosensor arrays, because the technology infrastructure for making such nanosensor arrays is in place. The next step is to marry this technology to a specific drug that is under development, he concluded. That will be the really killer application of this technology.
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New Protocol Enables DNA Sequencing from Small or Degraded RNA Samples
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454 Life Sciences (Branford, CT, USA; www.454.com), a subsidiary of Roche (Basel, Switzerland; www. roche.com), and NuGEN Technologies (San Carlos, CA, USA; www. nugeninc.com) have developed a solution to the problem of working with limited amounts of sample material using both NuGENs proprietary isothermal linear amplification (SPIA) products and the GS FLX Titanium cDNA Rapid Library Preparation protocol for the 454 GS Junior and GS FLX Systems for DNA sequencing. NuGENs innovative sample preparation solutions provide a unique and powerful tool which will enable researchers to obtain high-quality data from their less abundant samples, said Elizabeth Hutt, CEO of NuGEN Technologies. Together with 454 Sequencing Systems, the research community can perform whole transcriptome profiling on samples with as little as
500 pg of total RNA. Being able to collaborate with a leading NGS platform provider such as Roche, enables customers to leverage NuGENs linear amplification technology while obtaining long and highly accurate sequence reads. We are sensitive to the challenges many researchers face when working with precious and often irreplaceable samples, said Dr. Todd E. Arnold, vice president of development at 454 Life Sciences. By combining NuGENs amplification technology with 454 Sequencing Systems, we provide a solution that meets these researchers needs, while allowing them to leverage the power of 454 Sequencing Systems long read lengths, which are critical for both de novo transcriptome assembly and comprehensive identification of splice variants and fusion transcripts.
Image: The 454 GS Junior system for DNA sequencing (Photo courtesy of Roche).
Next-Generation Sequencers Essential Tools in Biomedical Research

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New analysis from Frost & Sullivan (Palo Alto, CA, USA; www. pharma.frost.com), an international market research company, found that the markets earned revenues of US$278.3 million in 2010 and estimates this to reach over $1 billion in 2017 due to the increased focus on human genome sequencing and the application of this technology to disease prediction. The segments covered include sequencing within the service-providing sector and academic research laboratories. NGS are rapidly replacing microarray technology in key applications, noted Frost & Sullivan research analyst Divyaa Ravishankar. Enhanced breadth of application is contributing, in turn, to wider coverage even as increased read lengths are being worked on in the new platforms. The need to sequence complex and variable human genomes has created opportunities for the growth of next-generation sequencing in areas such as gene discovery, gene expression, gene regulation studies, and clinical diagnostic applications in Europe. An increasing number of laboratories in Europe are replacing microarrays with NGS. Ongoing cancer research programs, biomarker discovery, forensics, and many funded drug discovery projects rely on NGS. Approximately 130 research centers in Europe are using this technology. However, funding and technology related issues remain areas of con-
cern. European research organizations are dependent on funding and grants. These are sometimes in short supply, posing problems for continued research. At the same time, technology overlapping by various NGS vendors raises intellectual property (IP) concerns. There is significant concern regarding technology overlap since all the market participants have common goals that include sample preparation methods, higher throughput and cost-cutting measures, explained Ms. Ravishankar. Competitors are moving towards longer reads and single molecule real-time sequencing [SMRT] and hence, the need to patent their technology is becoming a key issue. Increase in the volume of data requiring efficient data management systems poses a challenge. At the same time, interpretation of complicated data from next-generation platforms presents another challenge that market participants and end users will need to handle. Applications for next-generation sequencing can be better addressed with a multidisciplinary approach that embraces novel solutions and innovative technologies. Developing instruments that will cater to enduser needs will enable market participants to gain an edge. Concentrating on factors like greater read lengths, higher throughput and improved accuracy will help companies succeed, concluded Ms. Ravishankar. Instrument pricing can also help promote sales.
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New Optical Imaging System Has Fully Adjustable Iris-Like Aperture

newly available state-of-the-art imaging system has been designed specifically to provide a solution for cell biologists requiring an instrument capable of performing high-content cellular assays that include live cell studies, threedimensional imaging, co-localization studies, or imaging of assays with low signal output. The GE Healthcare (Little Chalfont, United Kingdom; www. gehealthcare.com) IN Cell Analyzer 6000 is a high-performance, laser-
based, confocal imaging platform designed for the most demanding live cell analysis studies. To this end, the system boasts a proprietary optical system that features a variable, iris-like aperture that mimics the action of the eye and is fully adjustable. The instrument incorporates the latest generation scientific CMOS camera, which delivers a four times larger field of view with five times less noise than traditional CCD cameras. This technology significantly
Controlled-Dose Nebulizers Show Potential for Early-Stage Drug Development

s proteins and peptides become increasingly common as inhaled drugs, the biotech industry faces the challenge of how to deliver these fragile biomolecules without damaging them. New study trials have shown that controlled-dose nebulizers might reduce formulation costs and facilitate early-stage efficacy trials. Nebulizers are frequently chosen as a delivery mechanism during biotech drug development. They are less likely to denature proteins and other large molecules, and they avoid the cost associated with formulation for dry-powder inhalers. Contract analysis and formulation company Melbourn Scientific (Melbourne, UK; www.melbournscientific.com) has developed a rapid formulation screening service for poorly soluble drugs and has been working with its clients to develop formulations that can be used in first-in-human trials. David Ward, a formulation scientist from Melbourn Scientific, stated, A drug which is only effective over a narrow dose range poses problems when used with a traditional jet nebulizer, because the dose is highly variable depending on the patients breathing patterns. Additionally, the heat generated by the motor can affect the droplet size. In early-stage development the drug needs to be accurately delivered, so for some of the most fragile compounds we have been trialing the use a controlleddose nebulizers to administer an exact dose. These nebulizers only deliver a drug during the first 80% of the in-breath, the time over which the drug is deposited in the lungs. This can be extremely valuable for accurate dose-range studies. While controlled-dose nebulizers are more expensive than jet nebuliz-
increases sensitivity and reduces exposure times in order to maximize throughput in screening settings. The imaging system is described by the manufacturer as being suitable for the most challenging applications by providing flexible imaging for multiplexed assays, enhanced sensitivity for imaging dim assays, and versatility for a wide range of sample types. The system can handle 6-, 12-, 24-, 48-, 96-, 384-, and 1536-well
microplates and is compatible with commercially available laboratory automation systems. In addition, the user can access a manual microscope mode.
Image: The IN Cell Analyzer 6000 (Photo courtesy of GE Healthcare).
ers are and may require the supervision of a clinician, they have the added advantage that the quantity of drug received by the patient can be accurately controlled and measured. Therefore, for small-scale trials they offer significant advantages. Nebulizers create a mist of medicine that can be inhaled passively, and the drug can be delivered as a solution or suspension, which increases the possibilities for formulation. They allow formulation in solution and so overcome some of the challenges of stabilizing the drug. However, fragile active pharmaceutical ingredients (APIs) can be denatured by conventional jet nebulizers. The drug is delivered as an aerosol created by a compressor blowing air through the solution or suspension at high speed. A controlled-dose nebulizer, in contrast, uses vibrating mesh technology, which is much gentler and so less likely to damage the drug. Melbourn Scientific works with leading-edge device developers and provides a fast formulation screening service. This service will accelerate the development of nebulizer formulations that are increasingly favored for early-stage evaluation. The companys screening service is supported by recent investment in a new platform technology that will allow analysts to assess a broad range of formulations. Interest in nebulizers is expected to grow. A spokesperson for one of the controlled-dose nebulizers commented, Drug instability is increasingly common so we are seeing some drug companies looking to bring a drug to market in liquid form for use with a controlled dose inhaler. This saves the time and expense of formulation for dry-powder inhalers.
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Candidate Cancer Drug Blocks Proteins That Inhibit Apoptosis

n orally deliverable drug that blocks the activity of proteins that prevent cells from entering apoptosis has been found to shrink tumors significantly in animals with only minimal side effects. The drug, AT-406, mimics the action of the protein Smac (second mitochondria-derived activator of caspases), a mitochondrial protein that enables apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. The inhibitors of apoptosis (IAP) are a family of functionally- and structurallyrelated proteins, which serve as endogenous inhibitors of programmed cell death. The human IAP family consists of at least six members, and IAP homologs have been identified in numerous organisms. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV- or gamma-irradiation. In the cytosol Smac moderates the caspase inhibition of IAPs. Investigators at the University of Michigan (Ann Arbor, USA; www.umich.edu) first synthesized AT-406 in 2006. Since then they have demonstrated that the drug blocked IAP activity
Image: Color enhanced scanning electron micrograph (SEM) of lymphocytes undergoing apoptosis (Photo courtesy of David M. Phillips / Science Photo Library).
in a variety of cell free systems. In the current study, which was published in the March 28, 2011, issue of the Journal of Medicinal Chemistry, they examined the effect of AT-406 on human cancer cells growing in culture and on tumors in animal models. They found that the drug inhibited cancer cell growth in various human cancer cell lines. It had good oral bioavailability in mice, rats, nonhuman primates, and dogs, was highly effective in induction of apoptosis in xenograft tumors, and was capable of complete inhibition of tumor growth. Removing key apoptosis blockades in tumor cells is a completely new cancer therapeutic approach and could have benefit for the treatment of many types of human tumors, said senior author Dr. Shaomeng Wang, professor of medicine at the University of Michigan. Patent applications covering the drug are exclusively licensed to Ascenta Therapeutics (Malvern, PA, USA; www.ascenta.com), a privately held, clinical stage biopharmaceutical company cofounded by Dr. Wang. After extensive testing, in 2010 Ascenta began the first clinical trial of AT406 as a potential cancer treatment.
Reduced Telomerase Activity Slows Cancer Development

nhibition of the enzyme telomerase, which is overexpressed in most human cancers, may be the method of choice for treating several common carcinomas, including breast, lung, liver, and gastrointestinal cancers. Telomerase is activated in most human cancers and is critical for cancer cell growth. However, little was known about the significance of telomerase activation in chromosome instability and cancer initiation. Investigators at Harvard University Medical School (Boston, MA, USA; www.harvard.edu) have been studying the role of the telomerase inhibitor PinX1 (PIN2/TRF1-interacting, telomerase inhibitor 1) in the metabolic processes that lead to cancer formation.
They reported in the March 23, 2011, online edition of the Journal of Clinical Investigation that reduced PinX1 activity contributed to cancer development in a mouse population that had been genetically engineered to lack one allele of the PinX1 gene. Reduced PinX1 activity in cells of these animals not only caused telomerase activation, it also triggered chromosome instability. Most of the PinX1 mutant mice spontaneously developed carcinomas. Although telomerase is activated in 85% to 90% of human cancers, little has been known about the significance of telomerase activation in chromosome instability and cancer initiation, explained
senior author Dr. Kun Ping Lu professor of medicine at Harvard Medical School. We have discovered, for the first time, a novel role for abnormal telomerase activation in cancer initiation. This suggests that telomerase inhibition using PinX1 or other small molecules may be used to treat certain cancers with activated telomerase. Going forward, we are also interested in determining the genetic changes that underlie PinX1 reduction in cancers, said Dr. Lu. This might lead to new diagnostic tools to better identify individuals who are susceptible to certain cancers, and therefore, might be suitable for treatment with telomerase inhibitors.
Granulocyte Macrophage-Colony Stimulating Factor Protects Mice from the Flu

study conducted on several different populations of mice found that that pulmonary administration of granulocyte macrophage-colony stimulating factor (GM-CSF) significantly reduced flu symptoms and prevented death after challenge with a lethal dose influenza virus. GM-CSF protein is a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. Alveolar macrophages (AM), which are enhanced by GM-CSF, are essential to the innate immune response and have been shown to contribute to host defense against flu infections in various animal models. In the current study, investigators at the University of Texas Health Science Center (Tyler, USA; www.uthscsa.edu) worked with three groups of mice: a normal wild type control group, a line that had been genetically engineered to lack the gene for GM-CSF, and a line that had the GM-CSF gene in one lung only. Animals from each group were infected with influenza virus in an initial
series of experiments. Results published in the April 7, 2011, online edition of the American Journal of Respiratory and Critical Care Medicine revealed that after progressive weight loss, all the wild type and GM-CSF null mice died within days. In contrast, all the mice carrying the GM-CSF gene survived, and these animals gained back the weight they had initially lost after a short period of time. The resistance of the transgenic mice to influenza was canceled by elimination of alveolar macrophages, but not by depletion of T-cells, B-cells, or neutrophils. In a second series of experiments, animals were given GM-CSF after having been infected with the flu virus. Delivery of intranasal GM-CSF to the wild type mice conferred resistance to influenza to these animals. This resistance was apparently due to the enhancement of innate immune mechanisms that depend on alveolar macrophages. Such unique and unambiguous results demonstrate the great potential of GM-CSF and may be the
remedy for a critical public health priority: developing strategies to reduce the morbidity and mortality from influenza, said senior author Dr. Homayoun Shams, professor of pulmonary and infectious diseases at the University of Texas Health Science Center. Improved methods to protect against influenza are sorely needed, particularly in the face of an impending pandemic. Development of such methods hinges on understanding host mechanisms that confer robust protection against influenza. Despite the widespread use of vaccines, influenza causes significant morbidity and mortality throughout the world, and those with poor immune systems are particularly more susceptible such as very young, elderly, or immunocompromised individuals. Unlike a vaccine, GM-CSF does not rely heavily on the bodys ability to mount an immune counterattack against a specific antigen or virus strain, but enhances the speed of local responses to virus infection and delicately balances the host immune responses, said Dr. Shams.
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Genotyping Chip Accelerates Workflow and Increases Throughput While Maintaining Accuracy
iotech and life science researchers now have the option of upgrading to an ultrafast genotyping system capable of providing 4,608 data points in just one hour. The Fluidigm Corporation (South San Francisco, CA, USA; www.fluidigm.com) has introduced its new 192.24 Dynamic Array IFC (integrated fluidic circuit) array chip. This microarray was designed to genotype 192 samples against 24 SNP (single nucleotide polymorphism) assays in a single run, providing 4,608 data points in just one hour. Dynamic Array IFCs have an on-chip network of microfluidic channels, chambers, and valves that automatically assemble individual PCR reactions, decreasing the number of pipetting steps required by up to 100-fold. This accelerated workflow and increased throughput enables more data
points, while the 192.24 chip retains Fluidigms 99.75% or greater call accuracy and 99% or greater call rates. The new chip can be read using either Fluidigms BioMark HD (the BioMark HD system is the newest real-time PCR system developed by Fluidigm with enhanced productivity, increased reliability, and a smaller footprint) or EP1 (the EP1 system offers the most efficient system for high sample throughput SNP genotyping and other applications using end-point reading after PCR) systems. The Fluidigm 192.24 Dynamic Array chip enables life science researchers to achieve ultralow cost, and rapid throughput while maintaining full assay and reagent flexibility. Providing the ability to use fewer SNP assays, and run a high number of samples is a format that is ideal for
some applications in agricultural biochemistry and for GWAS (genome wide association) follow-up studies, said Gajus Worthington, Fluidigm president and CEO.
Image: The 192.24 Dynamic Array IFC (integrated fluidic circuit) array chip (Photo courtesy of Fluidigm).
Imaging Technique Shows Complex Microbial Interactions

esearchers using a new form of imaging mass spectrometry were able to visualize multiplex microbial interactions. Microbes must be able to communicate, to be able to interact with its environment and with others in order to thrive. This cellular chatter comes in the form of signaling molecules and exchanged metabolites that can have effects far larger than the organism itself. Most of what is known about how microbes communicate with each other is the result of indirect observation and measurements. Until now, there has been no general or informative technique for observing the manifold metabolic exchange and signaling interactions between microbes, their hosts, and environments. In a study published May 16, 2011, in the journal Angewandte Chemie, researchers from the University of California, San Diego (UCSD; USA; www.ucsd.edu) and the Scripps Institute of Oceanography (La Jolla, CA, USA; http://scripps. ucsd.edu) reported the mass spectrometry approach clearly visualizes multiplex microbial interactions. Being able to better see and understand the metabolic interplay between microbial communities and their surrounding biology means we can better detect and characterize the molecules involved and perhaps discover new and better therapeutic and commercially viable compounds, said Pieter C. Dorrestein, PhD, associate professor at the UCSD Skaggs School of Pharmacy and
Pharmaceutical Sciences and the articles senior author. Dr. Dorrestein and colleagues used matrix-assisted laser desorption ionization (MALDI) mass spectrometry, a comparatively new application that creates two-dimensional, spatial images of microbes and biomolecules among them proteins, peptides, sugars too fragile to endure other mass spectrometry techniques. As their first subject, the scientists gathered marine microbial assemblages scraped off the surfaces of a barnacle attached to the Scripps Pier. The resulting images, generated after careful preparation, offered new insights. One of the things we see that we havent with other techniques is that the dialog between microbes is multiplexed, said Dr. Dorrestein. There are many conversations going on at the same time, many changes happening at the same time. We see competition for resources such as iron, but also that microbes secrete molecules that alter the phenotypes of neighboring organisms. Dr. Dorrestein noted that the ability to better visualize the immensely complex environment of microbial communication is changing the ways scientists examine how two or more microbes are studied and ultimately engineered. Rather than enumerating which microbes are present, as in many metagenomic efforts, our current approach is anticipated to address the why, when, and how questions of microbial interactions instead of just the who, Dr. Dorrestein concluded.
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PRODUCT NEWS
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MICROPLATE WASHER
BioTek Instruments
FLUORESCENCE SPECTROMETER
Shimadzu Scientific Instruments
BIOMARKER WORKSTATION
Avantra Biosciences
AUTOMATED SYSTEM
BD Diagnostics
The ELx405 Select deep well washer is a robot-compatible washer for automated aspirate and dispense steps in 96- and 384-well plates up to 50 mm high, as well as standard 15-mm microplates. The washer offers increased efficiency compared to manual and hand-held methods.
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The EDX-LE is designed specifically for screening elements regulated by RoHS/ELV directives. The unit is equipped with a detector that does not require liquid nitrogen, allowing for low operation costs and easier maintenance.
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The Q400 features a one-step user interface with sample preparation requiring less than five minutes. Other key benefits include walkaway operation, ease of use, automated data analysis, compact footprint, consistency, dynamic range, and cost-effectiveness.
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The BD Max is a fully automated open system for molecular testing that can perform a range of userdefined protocols and research applications. The system allows labs to operate an open molecular platform, with the ability to add new assays for a broad testing menu.
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Naturopathic Compound Suppresses Growth of Prostate Cancer Cell Cultures

paper by cancer researchers working with prostate cancer cell cultures supports claims of the efficacy of a naturopathic formulation as an anticancer treatment. Investigators at Indiana University (Indianapolis, USA; www.indiana.edu) evaluated the effects of the dietary supplement ProstaCaid (PC), which contains mycelium from medicinal mushrooms (Ganoderma lucidum, Coriolus versicolor, Phellinus linteus), saw palmetto berry, pomegranate, pumpkin seed, green tea [40% epigallocatechin-3-gallate (EGCG)], Japanese knotweed (50% resveratrol), extracts of turmeric root (BCM-95), grape skin, pygeum bark, sarsaparilla root, Scutellaria barbata, eleuthero root, Jobs tears, astragalus root, skullcap, dandelion, coptis root, broccoli, and stinging nettle, with purified vitamin C, vitamin D3, selenium, quercetin, citrus bioflavonoid complex, beta-sitosterolzinc, lycopene, alpha lipoic acid, boron, berberine and 3.3-diinodolymethane (DIM). The ingredients form a collection of the natural products best known to be rich in anti-inflammatory and antioxidant activities.
In the current study, which was published in the April 4, 2011, online edition of the International Journal of Oncology, the investigators exposed cultures of prostate cancer cells to PC and then evaluated its effects on gene expression, tumor growth, and tumor invasiveness. They reported that PC treatment inhibited cell proliferation in the population of highly invasive human hormone independent PC-3 prostate cancer cells in a dose- and time-dependent manner. PC suppressed the metastatic behavior of PC-3 cells by the inhibition of cell adhesion, cell migration, and cell invasion. DNA-microarray analysis demonstrated that PC inhibited proliferation through the modulation of expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6, and PCNA genes. Senior author Dr. Daniel Silva, associate professor of medicine at Indiana University, said, The formula we studied has been shown to inhibit growth of human androgen dependent as
well as independent prostate cancer cells, and suppresses the metastatic potential of these cells. We were able to identify specific genes, which are responsible for growth of human prostate cancer cells and show, on the molecular level, how it affects the cancer cells. Natural compounds in this formula are known to be without the side effects associated with traditional cancer chemotherapy drugs.
Image: Colored scanning electron micrograph (SEM) of prostate cancer cells in culture (Photo courtesy of Parviz M. Pour / Science Photo Library).
Aspirin Could Slash Risk of Pancreatic Cancer
he use of aspirin at least once per month is associated with a significant decrease in pancreatic cancer risk, according to results of a large case-control study. The studys findings were presented at the American Association of Cancer Research (AACR) 102nd annual meeting, held in Orlando (FL, USA) April 2-6, 2011. Xiang-Lin Tan, PhD, MD, a research fellow at Mayo Clinic (Rochester, MN, USA; www.mayoclinic.com) reported that the findings from this large collaborative study are preliminary and do not encourage widespread use of aspirin for this purpose. The results are not meant
to suggest everyone should start taking aspirin once monthly to reduce their risk of pancreatic cancer, said Dr. Tan. Individuals should discuss use of aspirin with their physicians because the drug carries some side effects. For the current study, Dr. Tan and colleagues enrolled 904 patients who had documented pancreatic cancer and compared them with 1,224 healthy patients. All patients were at least 55 years old and reported their use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen by questionnaire. The studys findings revealed that individuals
who took aspirin at least one day during a month had a 26% decreased risk of pancreatic cancer compared to those who did not take aspirin regularly. The effect was also found for those who took lowdose aspirin for heart disease prevention at 35% lower risk, according to Dr. Tan. The researchers did not find a benefit from non-aspirin NSAIDs or acetaminophen. This provides additional evidence that aspirin may have chemoprevention activity against pancreatic cancer, remarked Dr. Tan. He added that more data must be collected before they can validate a real benefit.
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Drug Pair Conquers Highly Aggressive Childhood Cancer
pair of drugs has been found to block the growth of a deadly form of childhood cancer in a mouse model of the disease. Investigators at the Oregon Health and Science University (Portland, USA; www.ohsu.edu) genetically engineered a line of mice to mimic the childhood cancer metastatic alveolar rhabdomyosarcoma (ARMS). ARMS accounts for more than 50% of all soft-tissue cancers in children, but even after extensive therapy the survival rate of patients with advanced disease is less than 20%. In the current study, the investigators worked with a prototype drug (NVP-AEW541) that inhibited the insulin-like growth factor 1 receptor (Igf1r), a protein heavily overexpressed on ARMS cells. While the drug could inhibit cell growth and induce apoptosis in vitro, drug resistance in vivo was common and was associated with increased Igf1r overexpression. Igf1r overexpression was accompanied by an increase in another tumor surface enzyme, human epidermal growth factor receptor 2 (Her2). Her2 is also found on certain types of breast tumors, and the drug lapatinib has
been approved for treating this form of breast cancer. In their paper published in the March 29, 2011, online edition of the journal Molecular Cancer Therapeutics the investigators described results of experiments in which NBP-AEW541 was used in combination with lapatinib to treat mice with ARMS. They reported that NVPAEW541 reduced tumor growth in a third of the mice before the tumors became resistant to the drug. Lapatinib alone had no effect on the tumors, but the combination of the two drugs almost completely blocked tumor growth without development of resistance. Despite our best efforts, outcomes for metastatic alveolar rhabdomyosarcoma have not improved for decades. That is why our findings are significant. Our clinical partners now have a new method of mitigating resistance to the current treatment for childhood muscle cancer, said first author Dr. Jinu Abraham, senior cancer biology research associate at the Oregon Health and Science University. Fortunately, when we treated resistant rhabdomyosarcoma cells
Image: Light micrograph of a section through a rhabdomyosarcoma, a fast-growing highly malignant tumor that arises from rhabdomyoblasts. This cancer is most common in children under 10, where it accounts for over half of the soft tissue sarcomas (Photo courtesy of CNRI).
with a combination of the Igf1r inhibitor and the Her2 inhibitor lapatinib, there was a significant increase in tumor cell killing compared with either drug alone. Our
study has shown that targeting both Igf1r and Her2 may be a very promising approach in preventing resistance to Igf1r-inhibiting drugs in rhabdomyosarcoma.
Safe Tobacco Smoke Compound Protects Against Alzheimers

esults of a recent study suggest that cotinine, the major metabolic product of nicotine, may be an excellent therapeutic candidate for the treatment of Alzheimers disease. Cotinine, which is found in high concentrations in the blood and urine of smokers, does not have the negative cardiovascular and addictive properties as nicotine. As some data has indicated that smokers have lower incidence of Alzheimers disease, investigators at the University of South Florida (Tampa, FL, USA; www.usf.edu) examined the effect of cotinine on the brains of mice that had been genetically engineered to develop a disease that closely mimics Alzheimers disease. They reported in the April 2011 online edition of the Journal of Alzheimers Disease that cotinine reduced amyloid beta plaque deposition, improved working and reference memories, and inhibited amyloid beta oligomerization in the brains of transgenic 6799 AD (Alzheimers disease) mice. Overall,
there was a 26% reduction in deposits of amyloid plaques in the brains of the treated animals. In vitro studies further confirmed the inhibitory effect of cotinine on amyloid beta aggregation. Cotinine stimulated Akt signaling, including the inhibition of glycogen synthase kinase 3-beta (GSK3-beta), which promotes neuronal survival and the synaptic plasticity processes underlying learning and memory in the hippocampus and cortex of wild type and AD mice. We found a compound that protects neurons, prevents the progression of Alzheimers disease pathology, enhances memory, and has been shown to be safe, first author Dr. Valentina Echeverria assistant professor of molecular medicine at the University of South Florida. It looks like cotinine acts on several aspects of Alzheimers pathology in the mouse model. That, combined with the drugs good safety profile in humans, makes it a very attractive potential therapy for Alzheimers disease.
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PRODUCT NEWS
SEPARATION/ESI MODULE
Beckman Coulter
SINGLE TUBE READER

BioMicroLab
POSITIVE PRESSURE MANIFOLDS

Biotage
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Eppendorf
The CESI 8000 high-performance module consists of a CESI sprayer combined with new capillary electrophoresis instrumentation specifically designed for MS. The module is designed for the detection of an expanded range of analytes, while improving overall sensitivity.
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The SampleScan Plus offers a small footprint, as well as plug-and-play functionality, with 1D and 2D scan and decode times of less than one second per tube. Other key features include a USB connection, no required power supply, and compatibility with Mac and PC formats.
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The Pressure+ manifolds offer parallel processing for 96-well plates, or 1 mL, 3 mL, or 6 mL SPE columns. Features include easy set-up and use, improved reproducibility, accuracy, and extraction efficiency, as well as built-in safety operations.
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The epMotion GxP includes an automated pipetting system, as well as software, certificates, and dedicated validation services. The GxP is designed to streamline user workflow by shortening the timeline of process validation and qualification.
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Life Science Research Will Profit from a New Hands-Free Mini Automated Cell Counter
new instrument for the life science laboratory a novel hands-free mini automated cell counter has recently been released to the marketplace. The Moxi Z mini cell counter is manufactured by ORFLO Technologies (Bothell, WA, USA; www. orflo.com) who describe it as the first portable instrument to provide cell viability without the use of reagents or dyes. The Moxi Z combines two powerful methods, the Coulter Principle which is the gold standard for cell counting, and a patented thin-film sensor technology developed by ORFLO to allow particle sizing and counting over a
broad size range (2 to 34 microns). In just eight seconds per measurement, the instrument provides accurate cell size and count determinations and an indicator of dead versus live cells based on the proprietary Moxi Viability Index. A measurement requires only 75 l of sample volume in the 3,000 cells/mL to 500,000 cells/mL range, and the Moxi Zs disposable cassettes offer superior ease of use and cost effectiveness. The instrument is small enough to fit in the palm of one hand, does not require a PC to operate, is easy to clean and does not require that a person hold it while performing a measurement, mak-
Image: The Moxi Z mini automated cell counter (Photo courtesy of ORFLO Technologies).
ing it an ideal tool for the hood. Cleaning is simple with ethanol or Isopropyl alcohol. While the Moxi Z is very robust with few moving parts and has been validated to be extremely stable over time, each unit is supplied with an Electronic Calibration Cassette to allow periodic checks of the accura-
cy of the instrument. The Moxi Z mini cell counter sets a new bar for the cell counting community, said Manju Sethi, vice president of business development at ORFLO Technologies. The instrument eliminates virtually all of the drawbacks of current cell counting methods.
Protective Protein Drastically Reduced Following Brain Injury
he protein produced by the KCC2 gene acts to prevent damage to neurons following trauma to the brain caused by head injury, stroke, or neurodegenerative diseases such as Alzheimers. KCC2 is a member of the cation-chloride cotransporter gene family. KCCs normally lower intracellular chloride concentrations below the electrochemical equilibrium potential, and depending on the chemical concentration gradients of potassium and chloride, KCC2 can operate as a net efflux or influx pathway. KCC2 is expressed at high levels in neurons throughout the nervous system and immunofluorescence has shown that the protein was localized at inhibitory synapses of the spinal cord. Previous studies had shown that the level of KCC2 dropped drastically after brain injury. Investigators at the Universit de la Mditerrane (Marseille, France; www.univmed.fr) used
primary hippocampal neuronal cultures to study KCC2 function. In this system, they could block the action of KCC2 either by an RNA interference approach or by using a dominant negative mutant. KCC2 activity was restored by gene therapy that overexpressed the active form of the KCC2, while overexpression of its nonactive mutant Y1087D was used as a control. Results published in the May 15, 2011, issue of the Journal of Physiology revealed that the experimental silencing of endogenous KCC2 reduced neuronal resistance to toxic insults. In contrast, the artificial gain of KCC2 induced by overexpression of KCC2 gene function in the same neurons protected them from death. Overexpression of the nonactive mutant Y1087D had no protective effect. The death of neurons in the brain can be triggered by an imbalance of oxygen known as oxida-
tive damage, or where cells are incorrectly instructed to die by a neurotransmitter a process known as excitotoxicity, said senior author Dr. Igor Medina, professor of medicine at the Universit de la Mditerrane. KCC2 protects against both. It is really encouraging that we have identified a means of potentially protecting the brain from these common conditions. The destiny of neurons in a damaged brain depends on a tiny equilibrium between prosurvival and prodeath signals. We wanted to know what KCC2 was signaling for was it killing neurons or protecting them after an injury? Our study has found that KCC2 actually rescues the damaged cells. Neuroprotective agents that may stem from this research would benefit the victims of car crashes, stroke, and those suffering with epilepsy, Parkinsons, and Alzheimers it is a major focus for further studies, said Dr Medina.
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Automatic Drift Compensation System Maximizes Optical Microscope Performance

new automatic drift compensation system has been released that is designed to maintain the focal position for optical microscopes over a time span ranging from hours to weeks. The Olympus (Hamburg, Germany; www.microscopy.olympus.eu) ZDC2 ZDrift compensation system operates in either continuous or one-shot mode that continually monitors the distance between the objective lens and the sample surface. Since the relationship between the sample and the cover slip tends to be consistent, this allows the microscope system to remain focused automatically in response to external factors, via the rapid adjustment of the nosepiece.
Olympus recommends using the new ZDrift compensation system with the IX81 inverted microscope. The IX81 microscope systems are highly stable, rigid, and reliable, taking advantage of proprietary UIS2 objectives, providing exceptional contrast, brightness, and resolution resulting in enhanced image clarity. The IX81 combines seamlessly with the ZDC2 Z-Drift compensation module to provide automatic focal adjustment. The complete system is compatible with a range of powerful Olympus hardware and software, including cellSens Dimension and xcellence, as well as integrating fully with environmentally isolated stage incubation systems.
Image: The IX81 microscope with ZDC2 Z-drift compensation system (Photo courtesy of Olympus).
Chronic Digoxin Use Reduces Risk of Prostate Cancer

paired laboratory and epidemiological study has identified the cardiac drug digoxin as the basis for a new chemotherapeutic approach for the treatment of prostate cancer. Investigators at Johns Hopkins University (Baltimore, MD, USA; www.jhu.edu) screened a series of recognized drug compounds for any that would inhibit the growth of prostate cancer cells growing in culture. The screen of 3,187 compounds yielded digoxin as the most potent inhibitory agent. The investigators then evaluated epidemiological data from studies where incidence of prostate cancer was linked to digoxin use. This evaluation produced a cohort of
about 47,000 men aged 40-75 who had participated in Harvards Health Professionals Follow-up Study from 1986 through 2006 and did not have a cancer diagnosis before 1986. Results published in the April 3, 2011, online edition of the journal Cancer Discovery revealed that regular digoxin users especially users for at least 10 years had a lower prostate cancer risk. Thus, digoxin was both highly potent in inhibiting prostate cancer cell growth in vitro, and its use was associated with a 25% lower prostate cancer risk. We realized that combining our laboratory and epidemiologic approaches could reduce the possibil-
ity that results on the candidate drugs might be due to chance, said first author Dr. Elizabeth Platz, professor of epidemiology, oncology, and urology at Johns Hopkins University. Adding the epidemiology study to the drug screen step provided an assessment of the drugs potential
activity in people. Despite the promising findings presented in this study, digoxin was not shown to prevent prostate cancer, and the authors do not suggest the drug be used to prevent the disease. This is not a drug you would give to healthy people, said Dr. Platz.
Lack of DNA Building Blocks Promotes Cancer Cell Formation

actors causing depletion of the nucleotide building blocks of DNA have been linked to the initiation of processes that cause normal cells to become cancerous. Investigators at the Hebrew University of Jerusalem (Israel; www.huji.ac.il) worked with cell cultures that were put under stress when the Rb-E2F signaling pathway was aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 (human papillomavirus) or cyclin E oncogenes significantly decreased the cellular nucleotide levels. The cells making up these cultures were prone to transform spontaneously into cancer cells. The investigators reported in the
April 29, 2011, issue of the journal Cell that supplying exogenously nucleosides to the cell cultures eliminated the replication stress and DNA damage and dramatically decreased oncogene-induced transformation into cancer cells. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor cmyc, increased the nucleotide pool and also rescued the replicationinduced DNA damage. The authors concluded that, This work raises the possibility for developing new approaches for protection against precancerous development, even possibly creating a kind of treatment to decrease DNA breakage.
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Vitamin A Derivative Shown to Suppress Early Forms of Breast Cancer

nutrient found in sweet potatoes and carrots may prove vital in combating breast cancer at its earliest stages. Sandra Fernandez, PhD, an assistant research professor at Fox Chase Cancer Center (Philadelphia, PA, USA), presented the studys findings at the American Association of Cancer Research (AACR) 102nd annual meeting, held in Orlando (FL, USA) on April 2-6, 2011. Retinoic acid, a derivative of vitamin A, could be a promising cancer therapy because it affects cell growth, proliferation, and survival. Although it is being evaluated in a number of clinical trials, so far its effectiveness at combating cancer has been inconsistent. However, Dr. Fernandez and her colleagues have now pinpointed critical characteristics of retinoic acids manner of action a potentially important step toward developing successful treatments for patients. Retinoic acid binds to retinoic acid receptor beta (RAR-), and it may be through this process that it can suppress tumors. A decrease in RAR- levels in tumors is associated with cancer progression, and an increase is linked to positive responses to certain clinical interventions. It is thought that the activated receptor limits cell growth by regulating gene expression, but its underlying processes are not entirely understood. To identify the specific conditions under which retinoic acid inhibits and even reverses the growth of abnormal masses in the breast, however, Dr. Fernandez developed a culture system consisting of four cell lines representing different phases of cancer: normal-like human breast cells; transformed cells (which give rise to solid masses upon exposure to carcinogens); invasive cells (which are capable of breaking through breast tissue barriers and spreading to other areas of the body); and tumor cells (which form when invasive cells are injected into the mammary fat pad of mice and show all of the characteristics of fully malignant breast cancer cells). We found that the RAR- gene was active in the two earliest stages of cancer, but silenced in the final two stages, said Dr. Fernandez. These changes in gene activation were caused by a type of chemical modification called methylation, which involves the addition of a methyl group to DNA. In three-dimensional (3D) cultures containing a collagen matrix, normal-like cells formed tubules resembling a normal mammary gland, while the transformed cells also gave rise to solid masses. The cells that generated solid masses in collagen produced tubules when they received retinoic acid for 15 days. In comparison, invasive and tumor cells did not generate tubules in response to treatment with retinoic acid, even in combination with a drug that activates RAR- by inhibiting DNA methylation. The results suggest that retinoic acid can stop tumor progression early on, but not at later timepoints because the genetic changes related to can-
cer have become too severe. There appears to be no way to revert the tumors with retinoic acid when they become too advanced, Dr. Fernandez stated. The study also revealed that the methylation status of RAR- can act as a biomarker for the early detection of breast cancer. Moreover, drugs that reactivate this receptor by decreasing DNA methylation may help breast cancer patients. These agents are already being used to treat a specific type of leukemia, offering hope that it will also be approved to treat other diseases.
Image: Polarized light micrograph of crystals of retinoic acid, one of the physiological forms of Vitamin A (Photo courtesy of Michael W. Davidson / Science Photo Library).
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Removable Cloak Designed for Nanoparticles to Target Tumors
hemical engineers have designed a new type of drug-delivery nanoparticle that exploits a trait shared by nearly all tumors: they are more acidic than healthy tissues. Such particles could target nearly any type of tumor, and can be designed to carry virtually any type of drug, according to Dr. Paula Hammond, a member of the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA; www.mit.edu) and senior author of an article describing the particles online April 23, 2011, in the journal ACS Nano. Similar to most other drug-delivering nanoparticles, the new MIT particles are cloaked in a poly-
mer layer that protects them from being degraded by the bloodstream. However, the MIT team, including lead author and postdoctoral associate Dr. Zhiyong Poon, designed this outer layer to fall off after entering the slightly more acidic environment near a tumor. That reveals another layer that is able to penetrate individual tumor cells. In the article, the researchers reported that, in mice, their particles survive in the bloodstream for up to 24 hours, accumulate at tumor sites and enter tumor cells. The new MIT approach differs from that taken by most nanoparticle designers. Typically, researchers try to target their particles to
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a tumor by decorating them with molecules that bind specifically to proteins found on the surface of cancer cells. The difficulty with that approach is that it is difficult to find the right target a molecule found on all of the cancer cells in a particular tumor, but not on healthy cells. In addition, a target that works for one type of cancer might not work for another. Dr. Hammond and her colleagues decided to exploit the properties of tumor acidity, which is a byproduct of its increased metabolism. Tumor cells grow and divide much more rapidly than normal cells, and that metabolic activity uses up a lot of oxygen, which increases acidity. As the tumor grows, the tissue becomes more and more acidic. To construct their targeted particles, the researchers used a technique called layer-by-layer assembly. This means each layer can be customized to perform a specific function. When the outer layer (comprised of polyethylene glycol [PEG]) breaks down in the tumors acidic environment, a positively charged middle layer is revealed. That positive charge helps to overcome another obstacle to nanoparticle drug delivery: Once the particles reach a tumor, it is difficult to get them to enter the cells. Particles with a positive charge can penetrate the negatively charged cell membrane, but such particles cannot be injected into the body without a cloak of some kind because they would also destroy healthy tissues. The polymer coating is shed as the particle approaches a tumor, exposing positive charges. Those charges help the particle be absorbed through the tumor cell membrane. The nanoparticles innermost layer can be a polymer that carries a cancer drug, or a quantum dot that could be used for imaging, or virtually anything else that the designer might want to deliver, according to Dr. Hammond, who is a professor of chemical engineering at MIT. Other researchers have tried to design nanoparticles that take advantage of tumors acidity, but Dr. Hammonds particles are the first that have been successfully tested in living animals. The researchers are planning to additionally develop these particles and assess their ability to deliver drugs in lab animals. Dr. Hammond expects it could take five to 10 years of development before human clinical trials could begin. Dr. Hammonds team is also working on nanoparticles that can carry multiple payloads. For example, the outer PEG layer might carry a drug or a gene that would prime the tumor cells to be susceptible to another drug carried in the particles core.
Image: The polymer coating (light blue) is shed as the particle approaches a tumor, exposing positive charges. Those charges help the particle be absorbed through the tumor cell membrane (Photo courtesy of Stephen Morton / MIT).
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PRODUCT NEWS
MAGNETIC BEADS
GE Healthcare
CELL LINE DEVELOPMENT KIT

Life Technologies
SCANNING CALORIMETER
Mettler Toledo
DNA ISOLATION KIT

MO BIO Laboratories
The Streptavidin Mag Sepharose beads offer a high binding capacity for efficient purification of biotinylated biomolecules, and enrichment of target proteins. The beads provide simplified handling, from low microlitre to high milliliter scale sample volumes.
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The PowerWater Sterivex is designed to isolate genomic DNA from filter units without the need for enzymes or hazardous chemicals. The kit enables purification of high quality DNA in just 40 minutes, from all types of water samples.
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Single-Use Bioreactor Boasts Disposable pH and Dissolved Oxygen Sensors

single-use bioreactor vessel with built-in pH and dissolved oxygen sensors suitable for work with mammalian, insect, and plant cell cultures is now available to researchers in biopharmaceuticals and other life sciences. The Sartorius Stedim Biotech (Aubagne, France; www.sartorius-stedim.com) UniVessel SU is a single-use bioreactor with two-liter working volume. The vessel is made of USP class VI conform polycarbonate and includes several ports for media addition, sampling, harvesting as well as spare ports for insertion of classical sensors or other equipment. All tubing for media transfer is thermoweldable and features common Luer or MPC connectors for fast and easy connection to peripheral equipment. Key features of the UniVessel SU are the singleuse sensors for optical measurement of pH and dissolved oxygen (DO). The determination of pH and DO with the SENSOLUX system is based on fluorescence detection. Each UniVessel SU con-
Image: The UniVessel SU single-use bioreactor (Photo courtesy of Sartorius Stedim Biotech).
tains two sensor patches for pH and DO, respectively. The actual measurement is performed optically and noninvasively from outside the vessel. The sensor patches contain fluorescent dyes, which can be excited with light of a given wavelength. Optoelectronics integrated in the vessel holder transmit light of a particular wavelength to the sensor patches. In turn, they also transmit the luminescence response from the patches to a measuring amplifier. The sensor patches inside the UniVessel SU come precalibrated. Calibration data are located on the vessel label and can be transferred manually or by barcode reader to the calibration menu of the bioreactor controller. Each UniVessel SU unit is irradiated prior to delivery and is ready-to-use out of the box. It is designed to the same safety standards that are required for classical multiuse bioreactors. The complete culture vessel is disposed after use, eliminating cleaning time, autoclaving, and reinstallation bother as well as the risk of cross-contamination.
Apigenin Slows Growth of Progestin-Induced Breast Cancer in Rat Model
he flavonoid apigenin, which is found in leafy green vegetables such as parsley and celery, blocks the spread of the form of breast cancer induced by progestin treatment by inhibiting the creation of new blood vessels that tumors require for growth and development. Investigators at the University of Missouri (Columbia, USA; www.missouri.edu) worked with a recently developed progestin-dependent mammaV I S I T
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ry cancer model in which tumors were induced in Sprague-Dawley rats by 7,12-dimethylbenz(a) anthracene (DMBA) treatment. They reported in the April 19, 2011, online edition of the journal Cancer Prevention Research that the flavonoid apigenin, which they previously had found to inhibit progestin-dependent vascular endothelial growth factor (VEGF) synthesis in human breast-cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA- (the progestin medroxyprogesterone acetate)-accelerated DMBAinduced mammary tumors in this animal model. While apigenin decreased the occurrence of such tumors, it did not completely block MPA-induced formation of cancer cells within the breast tissues of the rats.
Six to 10 million women in the United States receive hormone replacement therapy (HRT), said senior author Dr. Salman Hyder, professor of biomedical sciences at the University of Missouri. We know that certain synthetic hormones used in HRT accelerate breast tumor development. In our study, we exposed the rats to one of the chemicals used in the most common HRTs received in the United States a progestin called medroxyprogesterone acetate (MPA) which also happens to be the same synthetic hormone that accelerates breast tumor development. We do not have specific dosage for humans yet, said Dr. Hyder. However, it appears that keeping a minimal level of apigenin in the bloodstream is important to delay the onset of breast cancer that progresses in response to progestins such as MPA.
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Electrical Impedance Measures Physiological Changes in Skeletal Muscle Thickness

hanges in myotube thickness were measured by measuring cellular electrical impedance. Tracking physiological changes in skeletal muscle thickness is a direct and unbiased approach in screening therapeutic compounds that prevent skeletal muscle atrophy or induce hypertrophy. In drug screening, it would be beneficial to find novel treatments that prevent muscle atrophy and other diseases associated with any morphologic change in cell shape. Both qualitative and quantitative changes in electrical impedance as a function of cellular adhesion in real time correlated well with variation in myotube thickness caused by atrophy or hypertrophy agents. Conversely, pharmacologic blocking myotube hypertrophy prevented changes in electrical impedance. Sergey Rakhilin PhD of Novartis (Basel, Switzerland; www.novartis.com) and colleagues used the xCELLigence system from Roche (Penzberg, Germany; www.roche.com) to show
that both qualitative and quantitative changes in electrical impedance as a function of cellular adhesion in real time correlate well with variation in myotube thickness caused by atrophy or hypertrophy agents. Conversely, pharmacologic blocking myotube hypertrophy prevented changes in electrical impedance. According to the study, impedance can be used as a reliable and sensitive biomarker for myotube atrophy or hypertrophy. The study appeared online on April 14, 2011 in the Journal of Biomolecular Screening. In the past, it was difficult to estimate accurate cell thickness for a couple of reasons. One is the extreme heterogeneity of the myotube cellular population and therefore the lack of a regular distribution of perturbed myotubes. Another reason is the fact that differentiated myotubes form a confluent layer, which makes it difficult to estimate parameters of individual cells. In addition, most of the atrophy or hypertrophy-induced changes in cell thickness are relatively small (less
than twofold) and therefore hard to detect with low statistical error. Electrical impedance measurement overcomes these hurdles and offers a reliable method to determine cell thickness.
Image: Colored scanning electron micrograph (SEM) showing a bundle of skeletal muscle fibers (red) together with collagenous connective tissue fibers (yellow, bottom right) (Photo courtesy of Professors P.M. Motta, P.M. Andrews, K.R. Porter, and J. Vial).
Partnership to Develop Multiplexed Cancer Diagnostic Assays

partnership has been established to integrate multicolor fluorescence slides-technology analysis with a fluorescence biomarkeranalysis system to provide clinicians with more complete determination of the disease state. Definiens (Munich, Germany; www.definiens.com), a health image intelligence company, and Cernostics (Danville, PA, USA; www.cernostics.com), a life sciences firm specializing in advanced cancer diagnostics, announced a partnership to develop a unique multiplexed assay tool for the diagnosis of cancer. Cernostics will apply Definiens image analysis technology to develop new molecular diagnostic tests for the treatment of a variety of cancer types. Cernostics is using Definiens Tissue Studio to develop its cancer diagnostic test, which relies on highly multiplexed panels of fluorescence biomarkers, with the final goal to deploy the solution in the clinical routine. Definiens Tissue Studio enables pathologists to analyze cancers on the cellular and subcellular level. Rapid and accurate quantification of cancer characteristics will provide the Cernostics research team with data on which to build and deploy cancer diagnostic tests. Unlike some approaches that rely on single-biomarker expression, Cernostics takes a systems approach to tumor analysis, evaluating immune, stromal, stem cell and
tumor biomarkers on a single slide while preserving tissue structure. This can help clinicians better understand disease subtypes and help them choose the course of treatment most suited to each patients disease state. The partnership between Definiens and Cernostics will apply powerful technology to the field of oncology diagnostics, said Thomas Heydler, CEO of Definiens. Definiens Tissue Studio is uniquely able to evaluate multiple channels from a single sample, providing accurate data to support clinical decisions and help clinicians apply the best treatment for each patient. The collaboration with Definiens will enable Cernostics to accelerate development of its pipeline of systems biology-based diagnostic, prognostic, and predictive tests. Cernostics is in a unique position to provide unsurpassed solutions for tissue analysis and cancer diagnosis and the well validated Definiens software is a key component for extracting precise image measurements, said Rebecca Critchley-Thorne, PhD, director of biomarker and diagnostic development of Cernostics. To support its development of oncology diagnostic technology, Cernostics is working closely with Geisinger Health System, a US$2.3 billion integrated health services organization based in Pennsylvania. Supported by Geisinger, Cernostics
gains access to a clinical setting on which to create and validate pathology solutions, including a large tumor
bank linked to well-annotated, deep, and longitudinal clinical information.
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PRODUCT NEWS
FLOW CHEMISTRY SYSTEMS

Syrris
SEQUENCING SERVICE
Oxford Gene Technology
SILICON IMMERSION OBJECTIVES

Olympus
SINGLE-USE MIXER
Pall
The Asia systems feature maximum chemical resistance with wide temperature and pressure ranges. The Asia range consists of three series, each with preconfigured systems for varying levels of functionality, along with fast reaction times, and microgram to kilogram scalability.
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The service includes whole exome sequencing, as well as custom targeted sequencing of any genomic region of interest. The service allows researchers to obtain the benefits of NGS, without the need for extensive technical knowledge, equipment, or bioinformatics resources.
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The silicon oil-immersion objectives are considered ideal for live cell experiments, especially those investigating thick samples or requiring long-term imaging. The oil-based objectives offer increased brightness, resolution, and reproducibility.
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The Allegro 200L is designed for high-performance mixing in biopharmaceutical applications from pilot scale to full production. The mixer serves to improve the efficiency of critical mixing processes throughout the drug production cycle.
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New Gene May Increase Risk for Preterm Birth

volutionary changes that make people uniquely human may have driven human birth timing earlier and can be used to identify genes associated with preterm birth. Investigators from Vanderbilt University (Nashville, TN, USA; www.vanderbilt.edu), Washington University at St. Louis (MO, USA; http://wustl.edu), and the University of Helsinki (Finland; www. helsinki.fi/university) reported that variations in a gene with accelerated evolution in humans, the folliclestimulating hormone receptor (FSHR), may increase a womans risk for delivering her infant prematurely. The studys findings in the April 14, 2011, open-access journal PLoS Genetics point to a novel biologic pathway that may influence birth timing. More than half a million babies per year in the US alone one in eight are born prematurely (before 37 weeks of gestation). Premature babies face an increased risk of death and serious short-term and long-term medical complications, yet there are no adequate therapies to prevent preterm birth. Part of the problem is that we dont understand the fundamental biology of human pregnancy and birth timing, said Louis Muglia, MD, PhD, professor and vice chair for Research Affairs in the Vanderbilt department of pediatrics. We dont know if preterm birth in humans is the normal process gone awry, or if its an entirely distinct process.
Attempts to use animal models to understand human pregnancy have been of limited success, Dr. Muglia said, The signals that control pregnancy and birth timing in animal models arent able to be extended to humans; human pregnancy differs from pregnancy in other animal species. Dr. Muglia and his colleagues theorized that humans large heads and narrow pelvises have put pressure on human pregnancy to adapt and shift the time of birth to the earliest time compatible with optimal survival for both the mom and the fetus. To examine whether this notion of evolutionary pressure on birth timing had merit, the researchers compared the length of gestation in humans and nonhuman primates. They demonstrated in the current study that gestation length has decreased in the evolutionary lineage leading to modern humans. The scientists also compared body and brain sizes at birth in humans and nonhuman primates, in a process called allometric scaling, and demonstrated that human gestation is shorter than would be predicted based on this comparison. We think there is good evidence that human gestation has been pushed to shorter times, which means there should be a signature in the human genome genes with accelerated evolution to accommodate this process, Dr. Muglia remarked. Justin Fay, PhD, associate profes-
sor of genetics at Washington University and coleader of the study, developed comparative genomic techniques to identify human accelerated genes genes that are most altered in humans compared to six other animals. The researchers identified a set of 450 human accelerated genes and narrowed the list to 150 genes that were plausible candidates for having a role in human pregnancy. They examined variations in these 150 genes in a cohort of Finnish mothers and found that specific variations in the FSHR gene were more frequent in mothers who had experienced preterm birth. The same variations may also be linked to preterm birth in African-
Americans, additional study suggested. The FSHR gene has not previously been implicated in the timing for birth or preterm birth risk. Studies in larger cohorts could lead to additional accelerated genes with roles in birth timing and provide new targets for therapeutic or preventive measures, Dr. Muglia said. Ideally wed like to predict which women are at greatest risk for having preterm birth and be able to prevent it. That would really have an impact on infant mortality and the long-term complications of being born prematurely.
Image: Slightly premature baby girl pictured in a thermostat-controlled cot (Photo courtesy of Jim Stevenson / Science Photo Library).
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New Biological Safety Cabinets Boast Upgraded Ergonomic Features

n upgraded series of biological safety cabinets is now available for use in biotech and life science laboratories. The Thermo Fisher Scientific Inc. (Milford, MA, USA; www.thermoscientific.com) 1300 Series A2 line of biological safety cabinets has now been enhanced by the addition of two new models. The newly available 0.914 m and 1.52 m cabinets join the previously available
1.22 m and 1.83 m versions. The new models feature SmartPorts that provide clean, easy, and safe access for routing vacuum tubing and cables through the sidewall of the biological safety cabinet. The 1300 Series A2 biological safety cabinets are available with choices of stainless steel or SmartCoat interiors and 20.3 cm or 25.4 cm work apertures.
The standard ergonomic features of the Thermo Scientific 1300 A2 series, such as its sloped front sash, a shelf to keep waste disposal and laboratory supplies within easy reach, and a spacious, unobstructed work area, have been further enhanced by the new Ergolign laboratory saddle stool that reduces back pressure and optimizes working posture for high efficiency.
Image: The 1300 A2 series of biological safety cabinets (Photo courtesy of Thermo Fisher Scientific).
Electronic Medical Records Speed Genetic Research

new study revealed that mining data from electronic medical records (EMRs) is a faster way to get insights into disease processes. Recruiting thousands of patients to collect health data for genetic clues to disease is expensive and time consuming. However, process of collecting data for genetic studies could be faster and cheaper by instead mining patient data that already exists in electronic medical records, according to new research. In the study, researchers were able to cull patient information in EMRs from routine physicians visits at five US sites that all used different brands of medical record software. The information allowed researchers to identify accurately patients with five kinds of diseases or health disorders type 2 diabetes, dementia, peripheral arterial disease, cataracts, and cardiac conduction. The hard part of doing genetic studies has been identifying enough people to get meaningful results, said lead investigator Abel Kho, MD, an assistant professor of medicine at Northwestern University Feinberg School of Medicine (Chicago, IL, USA; www.feinberg.northwestern.edu) and a
physician at Northwestern Memorial Hospital. Now weve shown you can do it using data thats already been collected in electronic medical records and can rapidly generate large groups of patients. The studys findings were published April 20, 2011, in the journal Science Translational Medicine. To identify the diseases, Dr. Kho and colleagues searched the records using a series of criteria such as medications, diagnoses, and laboratory tests. They then tested their results against the gold standard review by physicians. The physicians validated the results, according to Dr. Kho. The electronic health records allowed researchers to identify patients diseases with 73% to 98% accuracy. The researchers also were able to reproduce previous genetic findings from prospective studies using the EMRs. The five institutions that participated in the study collected genetic samples for research. Patients agreed to the use of their records for studies. Sequencing individuals genomes is becoming faster and less expensive. It soon may be possible to include patients genomes in their medical records,
Dr. Kho noted. This would create a plentiful resource for genetic research. With permission from patients, you could search electronic health records at not just five sites but 25 or 100 different sites and identify 10,000 or 100,000 patients with diabetes, for example, Dr. Kho said. The larger the group of patients for genetic studies, the better the ability to detect rarer affects of the genes and the more detailed genetic sequences that cause a person to develop a disease. The study also revealed across-the-board weaknesses in institutions electronic medical records. The institutions didnt do a good job of capturing race and ethnicity, smoking status, and family history, all which are important areas of study, Dr. Kho reported. It shows we need to focus our efforts to use electronic medical records more meaningfully, he added. The institutions participating in the study are part of a consortium called the Electronic Medical Records and Genomics Network (eMERGE). The research was supported by the US National Human Genome Research Institute with additional funding from the US National Institute of General Medical Sciences, both based in Bethesda (MD, USA).
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IMAGING MODULE
PerkinElmer
PCR ARRAY SYSTEM

Qiagen
PCR INSTRUMENT
Roche Diagnostics
PUMP TUBING
Saint-Gobain Performance Plastics
The multispecies imaging module enables researchers to generate 3D datasets of animal models relevant to disease research. The imaging module is intended for use with fluorescence molecular tomography in vivo imaging systems FMT 1500 or FMT 2500LX.
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The qBiomarker Somatic Mutation system is designed for fast and accurate mutation profiling in basic research and drug discovery. The array consists of collections of pathway or cancer-specific assays in 96or 384-well formats, with a number of pathways and cancer types.
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The LightCycler Nano 32-well instrument offers a low variation of well-towell performance that could only be achieved previously by higher-priced instruments. The system uses PCR strips for convenient handling, and the system and its software can be used with all operating systems.
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The C-Flex ULTRA is designed for biopharmaceutical applications such as pumping, single-use assemblies, process filling, and sampling. The tubing is available in 10 standard sizes, with custom sizes, lengths, and packaging also available.
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Papillomavirus Protein Fragment Blocks Spread of the Virus in Tissue Culture
protein fragment generated from an integral human papillomavirus (HPV) protein prevents transcription of viral genes and blocks spread of the HPV virus, which is the causative agent of cervical and anogenital cancers. Investigators at Tufts University (Boston, MA, USA; www.tufts.edu) prepared a truncated version of the HPV E2 protein. This E2R fragment contained only the proteins C-terminal dimerization domain, and repressed the normal function of E2 due to formation of an inactive heterodimer. When tested in a mammalian cell cultures system, E2R and was found to inhibit the E2 protein of HPV-16, the high-risk strain of the virus that is most commonly associated with cancers. As HPV infects epithelial cells, the outermost layer of the skin, and the mucous membranes, protein
inhibitors such as E2R may be adaptable to application in a topical form. Currently, there is no cure for HPV, and the available treatment options involve destroying the affected tissue, said senior author Dr. James Baleja, associate professor of biochemistry at Tufts University. We have developed a protein inhibitor that blocks HPV protein expression in cell culture, a first step toward a topically-applied treatment for this cancer-causing virus. Vaccines are helping to lower the incidence of HPV, but vaccines will not help the millions of women and men who currently have an infection, especially those who have high-risk and persistent infections, said Dr. Baleja. Social and economic
challenges make widespread administration of a vaccine difficult, particularly in developing countries. A topical treatment for HPV could provide an economical option.
Image: Colored scanning electron micrograph (SEM) of a cervical cancer cell (Photo courtesy of Steve Gschmeissner / Science Photo Library).
Click Chemistry Yields Potent and Specific Serine Hydrolase Inhibitors

rug developers have used the principles of Click Chemistry to create a series of low molecular weight inhibitors that selectively block the activity of a large and diverse group of enzymes known as serine hydrolases. Serine hydrolases are a diverse enzyme class representing approximately 1% of all human proteins. The biological functions of most serine hydrolases remain poorly characterized owing to a lack of selective inhibitors to probe their activity in living systems. In the current study, investigators at the Scripps Research Institute (La Jolla, CA, USA; www.scripps.edu) applied the principles of Click Chemistry to the development of serine hydrolase inhibitors. Click Chemistry is a term that was introduced by K. B. Sharpless in 2001 to describe reactions that are high yielding, wide in scope, create only byproducts that can be removed without
chromatography, are stereospecific, simple to perform, and can be conducted in easily removable or benign solvents. This concept was developed in parallel with the interest within the pharmaceutical, materials, and other industries in capabilities for generating large libraries of compounds for screening in drug discovery research. In a paper published in the May 15, 2011, online edition of the journal Nature Chemical Biology the investigators described the synthesis of a series of 1,2,3-triazole ureas, which were powerful serine hydrolase inhibitors that showed negligible cross-reactivity with other protein classes. While most of the enzyme-inhibition tests described in the paper were conducted in mouse cell cultures, one of the groups inhibitor compounds, AA74-1, was tested in an animal model. Results revealed that the compound potently blocked the activity of its target serine hydrolase,
acyl-peptide hydrolase, or APEH, without significantly affecting other enzymes. There are more than 200 serine hydrolases in human cells, but for most we have lacked chemical inhibitors of their activity, said senior author Dr. Benjamin F. Cravatt III, professor of chemical physiology at the Scripps Research Institute, so we have had only a limited ability to study them in the lab or to block them to treat medical conditions. This new research allows us to greatly expand our list of these inhibitors. We are also using the techniques described in this paper to try to systematically generate more of these inhibitor compounds. We see these compounds as basic tools that enable us to determine the roles of serine hydrolases in health and disease. As we understand these enzyme roles better, we expect that some of their inhibitors could become the bases for medicines.
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Mouse Colorectal Cancer Model Demonstrates a Critical Role for P53 in Invasiveness Control
ancer researchers have highlighted the role of the p53 tumor suppressor by using a model system that blocked the activity of casein kinase I-alpha (CKI-alpha), a critical regulator of the Wnt signaling pathway, which is frequently hyperactivated in colorectal cancer. Investigators at the Hebrew University of Jerusalem (Israel; www.huji.ac.il) worked with a mouse model that had been genetically engineered to mimic human colorectal cancer. Further genetic manipulation enabled them to eliminate the gene that encodes CKIalpha, which triggered massive Wnt activation in the gut, but surprisingly without causing tumorigenesis. CKIalpha-deficient epithelium showed many of the features of human colorectal tumors in addition to Wnt activation, in particular the induction of the DNA damage response and cellular senescence, both of which are thought to provide a barrier against malignant transformation. The investigators then removed the gene encoding the tumor suppressor-protein p53. Results published in the February 17, 2011, issue of the journal Nature revealed that in the p53-deficient gut, loss of heterozygosity of the gene encoding CKI-alpha caused a highly invasive carcinoma, indicating that CKI-alpha functioned as a tumor suppressor when p53 was inactivated. A set of genes (the p53suppressed invasiveness signature, PSIS) that was activated by the loss of both p53 and CKI-alpha probably accounted for the brisk induction of invasiveness. The maintenance of intestinal homeostasis in the CKI-alpha-deficient gut required p53-mediated growth control, because the combined elimination of the CKI-alpha gene and either p53 or its target gene p21 triggered high-grade dysplasia with extensive proliferation. Inhibition of these genes also induced nonproliferating cells to invade neighboring normal tissue rapidly, producing invasive carcinomas throughout the small bowel. One of the earliest signs of cancer progression is this invasion process, said senior author Dr. Yinon BenNeriah, professor of basic cancer research at the Hebrew University of Jerusalem. Normally, it is slow. In
humans, it takes 10 to 15 years for colorectal cancer to develop. Even in mouse models, it takes at least six months. But when we knocked out p53, we started observing the malignant process within seven days, and it happens throughout the gut. There was something fundamental going on that had to do with p53.
Image: Colored scanning electron micrograph (SEM) of a colorectal cancer cell undergoing mitosis (Photo courtesy of Steve Gschmeissner / Science Photo Library).
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NUCLEIC ACID PURIFICATION SYSTEM

Thermo Fisher Scientific
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Torrey Pines Scientific
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Waters
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Carl Zeiss
The KingFisher Duo system includes the magnetic particle processor instrument, optimized DNA/RNA isolation kits, plastics consumables, and software. The low- to mediumthroughout packages provides a flexible, fully automated workflow.
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The SYNAPT G2-S high definition MS provides a 30x improvement in signal intensity for MS peaks. Additional benefits include a 5x improvement in signal-to-noise, and up to a 10-fold improvement in limits of quantitation over previous generation mass spectrometers.
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The Axio Lab.A1 features an ergonomic design with the main adjustment elements located in close proximity, including a height tube that can be swiveled from 8-33 degrees. The microscope is intended to reduce the workplace risks of muscular-skeletal conditions.
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Target for Treatment of Multiple Sclerosis Shows Damage to Nerve Cells Can Be Reversed
erman scientists have now been able to clarify how the damage from multiple sclerosis (MS) is inflicted. Their findings reveal that the inflammatory reaction can induce a previously unknown type of axonal degeneration, which is called focal axonal degeneration (FAD). In an animal model of MS, this process is reversible if it is recognized and treated early; therefore, the researchers believe that it could serve as a potential target for therapeutic intervention. The immune system recognizes and neutralizes or destroys toxins and foreign pathogens that have gained access to the body. Autoimmune diseases result when the system attacks the bodys own tissues instead. One of the most typical examples is MS. MS is a serious disorder in which nerve-cell projections, or axons, in the brain and the spinal cord are destroyed as a result of misdirected inflammatory reactions. It is frequently characterized by an unpredictable course, with periods of remission being interrupted by episodes of relapse. The team of researchers was led by Prof. Martin Kerschensteiner of the Medical Center of the University of Munich (Germany; www.en. uni-muenchen.de) and Prof. Thomas Misgeld from the Technical University of Munich (TUM; Germany; www.tum.de). Development of an effective treatment will be a long-term project, cautioned Prof. Kerschensteiner. As yet, we only have a superficial understanding of the underlying molecular mechanisms and, of course, finding effective therapies will require time-consuming screens and extensive trials of drug candidates. The studys findings were published online March 27, 2011, in the journal Nature Medicine. Commonly, it is thought that the primary target of MS is the myelin sheath, an insulating membrane that enwraps axons, and increases the speed of signal transmission. However, damage to nerve
fibers is also a central process, as whether autoimmune pathology ultimately leads to permanent disability depends largely on how many nerve fibers are damaged over the course of time. The team led by Profs. Kerschensteiner and Misgeld set out to define precisely how the damage to the nerve axons occurs. As Prof. Misgeld explained, We used an animal model in which a subset of axons is genetically marked with a fluorescent protein, allowing us to observe them directly by fluorescence microscopy. After inoculation with myelin, these mice begin to show MS-like symptoms. But the researchers found that many axons showing early signs of damage were still surrounded by an intact myelin sheath, suggesting that loss of myelin is not a prerequisite for axonal damage. Instead, a previously unrecognized mechanism, termed focal axonal degeneration (FAD), is responsible for the primary damage. FAD can damage axons that are still wrapped in their protective myelin sheath. This process could also help explain some of the spontaneous remissions of symptoms that are characteristic of MS. In its early stages, axonal damage is spontaneously reversible, said Prof. Kerschensteiner. This finding gives us a better understanding of the disease, but it may also point to a new route to therapy, as processes that are in principle reversible should be more susceptible to treatment. However, it takes years to convert findings in basic research into effective therapies. First, the process that leads to disease symptoms must be elucidated in molecular detail. In the case of MS it has already been suggested that reactive oxygen and nitrogen radicals play a significant role in facilitat-
ing the destruction of axons. These aggressive substances are generated by immune cells, and they disrupt and may ultimately destroy the mitochondria. In our animal model, at least, we can neutralize these radicals and this allows acutely damaged axons to recover, said Prof. Kerschensteiner. The findings of additional studies on human tissues, carried out in collaboration with specialists based at the Universities of Gttingen (Germany) and Geneva (Switzerland), are encouraging. The characteristic signs of the newly discovered mechanism of degeneration can also be identified in brain tissue from patients with MS, suggesting that the basic principle of treatment used in the mouse model might also be effective in humans. Even if this turns out to be the case, it would not mean that a new therapy would be ready soon. The agents utilized in the mouse research are not specific enough and not tolerated well enough to be of clinical use. Before appropriate therapeutic strategies can be developed, we need to clarify exactly how the damage arises at the molecular level, stated Prof. Kerschensteiner. We also want to investigate whether similar mechanisms play a role in later chronic stages of multiple sclerosis.
Image: Fluorescent light micrograph of a section through a spinal cord affected by multiple sclerosis (Photo courtesy of Riccardo Cassiani-Ingoni / Science Photo Library).
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Wnt Signaling Pathway Inhibitors Block Growth of Human Colon Cancer Cells
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n innovative, integrated screening platform combining RNA interference (RNAi)-technology and high-throughput chemical genetic screening was used to identify inhibitors of the Wnt signaling pathway, which is active in many types of cancer. Investigators at New York University (New York, USA; www.nyu.edu) combined RNAi-technology and high-throughput chemical genetic screening to examine the potency of 14,977 compounds on their ability to inhibit activity of the Wnt pathway. They reported in the April 12, 2011, issue of the journal Proceedings of the [US] National Academy of Sciences that three of the compounds examined were capable of blocking Wnt target genes in various mammalian cancer cell lines including human colon and breast cancer cells. Furthermore, these Wnt inhibitors were specifically cytotoxic to human colon tumor-biopsy cultures as well as colon cancer-cell lines that exhibited deregulated Wnt signaling. Our study demonstrates that the three newly identified compounds are capable of blocking cell proliferation in cancerous human tumor biopsy cells, said senior author Dr. Ramanuj DasGupta, assistant professor of pharmacology at New York University. These molecules hold a lot of promise towards future Wnt-based drug development for cancer treatments. They may allow the compounds to be used for specific therapeutic purposes in humans to induce the death of Wnt-dependent or Wnt-addicted cancer cells and tumor tissues without affecting the growth and proliferation of normal healthy cells. While more exploratory research of these promising compounds is needed, these small molecules identified in the RNAi screens can serve as prototypes for the development of future antitumor drugs targeting the Wnt signaling pathway in different Wnt-associated cancers, says Dr. DasGupta. Similar RNAi-based integrated screening technology should be widely applicable to a variety of other signaling pathways implicated in human disease.
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Biodegradable Nanoparticles Kill Drug Resistant Gram-Positive Bacteria

recent paper described the development of biodegradable nanoparticles capable of killing Gram-positive bacteria including MRSA (Methicillin-resistant Staphylococcus aureus). Investigators at the IBM Almaden Research Laboratory (San Jose, CA, USA; www.almaden.ibm.com) focused on types of nanoparticles that would be able to disrupt bacterial cell membranes. They reasoned that while it only requires one to two decades for microbes to develop resistance to traditional antibiotics that target a particular metabolic pathway inside the cell, drugs that compromise microbes cell membranes are probably less likely to evoke resistance. In the current study, they prepared polymer nanoparticles synthesized by metal-free organocatalytic ring-opening polymerization of func-
tional cyclic carbonate. These nanoparticles were biodegradable and possessed a secondary structure that could insert into and disintegrate bacterial and fungal cell membranes. Data obtained in collaboration with researchers at the Singapore Institute of Bioengineering and Nanotechnology (Singapore; www. ibn.a-star.edu.sg) was published in the April 3, 2011, online edition of the journal Nature Chemistry. Results showed that the nanoparticles disrupted microbial walls and membranes selectively and efficiently, thus inhibiting the growth of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and fungi, without inducing significant hemolysis over a wide range of concentrations. The biodegradable nanoparticles, which can be synthesized in large
Image: Colored scanning electron micrograph (SEM) of Staphylococcus aureus bacteria (yellow) on human nasal epithelial cells (Photo courtesy of Juergen Berger / Science Photo Library).
quantities and at low cost, represent a promising new class of antimicrobial drugs. We are trying to generate polymers that interact with microbes in a
very different way than traditional antibiotics, said contributing author Dr. James Hedrick, a materials scientist at the IBM Almaden Research Laboratory.
Understanding Tumor Cell Metabolism Key to Personalized Chemotherapy

ancer researchers have coined the term Metabolo-Genomics to define a new approach to personalized cancer medicine, which incorporates features of both cell metabolism and gene transcriptional profiling. Investigators at Thomas Jefferson University (Philadelphia, PA, USA; www.jefferson.edu) used this approach to study the effect of cancer cell metabolism on clinical outcome. They had previously shown that lactate and ketone utilization in cancer cells promoted the formation of a cancer stem cell phenotype, resulting in significant decreases in patient survival. In the current study, human breast cancer cells (MCF7) were cultured with lactate or ketones, and then subjected to transcriptional analysis (exon-
array). Results published in the April 15, 2011, online edition of the journal Cell Cycle revealed that treatment with these high-energy metabolites increased the transcriptional expression of gene profiles normally associated with stemness, including genes upregulated in embryonic stem (ES) cells. Similarly, the results showed that lactate and ketones promoted the growth of bonafide ES cells, providing functional validation. The lactate- and ketoneinduced gene signatures were able to predict poor clinical outcome (including recurrence and metastasis) in a cohort of human breast cancer patients. Tumors that are using the bodys own nutrients (lactate and ketones) as fuel have a poorer outcome for patient survival, a behavior that now can be used to predict if a patient is at a high-risk for
recurrence or metastasis, said senior author Dr. Michael P. Lisanti, professor of cancer biology at Thomas Jefferson University. This is getting to the heart of personalized cancer medicine. Now, we have identified a panel of biomarkers that directly links cancer metabolism with targeted cancer therapy. Just by feeding cancer cells a particular energyrich diet, it changes their character, without introducing mutations or altering their genetic profile, Dr. Lisanti said. We have only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile. It is a new biomarker for lethal cancers that we can now treat with the right drugs, such as the antioxidant metformin.
Experimental Drug Inhibits Ovarian Cancer by Blocking Two Critical Enzymes

n experimental drug that blocks two points of a crucial cancer cell signaling pathway has been shown to inhibit the growth of ovarian cancer cells, including those from cell lines that have developed resistance to conventional (cisplatin) platinum chemotherapy. Investigators at the University of California, Los Angeles (UCLA; USA; www.ucla.edu) worked with the experimental drug NVP-BEZ235. This drug is an imidazoquinoline derivative and PI3K (phosphoinositide 3-kinase) inhibitor that inhibits PI3K and mTOR (mammalian target of rapamycin) kinase activity by binding to the ATP-binding cleft of these enzymes. PI3K and mTOR are members of a molecular signaling pathway, which once activated promotes ovarian cancer growth. Tumors with this pathway are more aggressive and more likely metastasize. In their paper published in the April 15, 2011,
issue of the journal Clinical Cancer Research the investigators described the drugs effect on cell proliferation in 18 ovarian cancer cell lines, including four pairs of syngeneic cisplatin-sensitive and cisplatin-resistant cell lines. They also evaluated the in vivo effects of NVP-BEZ235 on established tumor growth using an immunocompetent, transgenic murine ovarian cancer model. Results revealed that NVP-BEZ235 decreased cell proliferation in all ovarian cancer cell lines assayed and sensitized cisplatin-resistant cells to the cytotoxic effects of cisplatin. Oral administration of NVP-BEZ235 resulted in significantly longer survival of the mice with ovarian tumors compared to control animals that were not treated. Platinum-based chemotherapy drugs are effective in treating ovarian cancers as long as the cancer cells remain sensitive to platinum, said senior
author Dr. Oliver Dorigo, assistant professor of obstetrics and gynecology at the UCLA. But once the tumor becomes resistant, treating the cancer becomes very challenging. This is a significant clinical problem, since the majority of ovarian cancer patients develop resistance at some point during treatment. Breaking chemotherapy resistance is a difficult challenge, but crucial if we want to improve long-term survival for our patients. We were very encouraged to find that NPVBEZ235 could resensitize the ovarian cancer cells to standard platinum treatment, said Dr. Dorigo. In addition, we found this drug to be more effective in inhibiting ovarian cancer cell growth than other drugs that target only one checkpoint, mTOR, in this pathway. We believe that NVPBEZ235 has superior efficacy because of the dual effect on PI3Kinase and mTOR.
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some fascinating information, he concluded, but very few proteins and other DNA products differ in any fundamental way between humans and chimps. The important difference between us and our close cousins lies in gene expressionthe basic level at which genes give rise to traits such as eye color, height, and susceptibility to a particular disease. ENCODE is helping to map the very proteins involved in gene regulation and gene expression. Our paper not only explains how to find the data, but it also explains how to apply the data to interpret the human genome. The ENCODE Project is funded, primarily, by the National Human Genome Research Institute of the US National Institutes of Health (Bethesda, MD, USA).
Decoding Human Genes the Goal of New Open-Source Encyclopedia

massive database cataloging the human genomes functional elements including genes, RNA transcripts, and other products is being made available as an open resource to the scientific community, science writers, classrooms, and the public, due to the work of an international team of researchers. In an article published in the journal PLoS Biology on April 19, 2011, the project called ENCODE (Encyclopedia Of DNA Elements) provides an overview of the teams ongoing efforts to interpret the human genome sequence, as well as a guide for using the vast amounts of data and resources produced so far by the project. Ross Hardison, a professor of biochemistry and molecular biology at Pennsylvania State University (Penn State; University Park, PA, USA; www.psu.edu) and one of the lead investigators of the ENCODE Project team, explained that the philosophy behind the project is one of scientific openness, transparency, and collaboration across subdisciplines. ENCODE comes on the heels of the now-complete Human Genome Project a 13-year effort aimed at identifying all the approximately 20,000 to 25,000 genes in human DNA which also was based on the belief in open-source data-sharing to further scientific discovery and public understanding of science. The ENCODE Project has accomplished this goal by publishing its database at http://genome.ucsc.edu/ENCODE, and by posting tools to facilitate data use at http://encodeproject.org. Dr. Hardison noted there are about 3 billion base pairs in the human genome, making the cataloging and interpretation of the information a colossal task. We have a very lofty goal: To identify the function of every nucleotide of the human genome, he said. Not only are we discovering the genes that give information to cells and make proteins, but we also want to know what determines that the proteins are made in the right cells, and at the appropriate time. Finding the DNA elements that govern this regulated expression of genes is a major goal of ENCODE. ENCODEs task is to identify the human genomes functional regions, many of which are quite esoteric, according to Dr. Hardison. Dr. Hardison stated that the ENCODE
Project supplies data such as where proteins bind to DNA and where parts of DNA are augmented by additional chemical markers. These proteins and chemical additions are keys to determining how different cells within the human body interpret the language of DNA. In the article, the scientists revealed how the ENCODE data can be immediately useful in interpreting associations between disease and DNA sequences that can vary from individual to individual single nucleotide polymorphisms (SNPs). For example, scientists know that DNA variants located upstream of a gene called MYC are associated with multiple cancers, but until recently the mechanism behind this association was a mystery. ENCODE data already have been utilized to confirm that the variants can change binding of specific proteins, leading to enhanced expression of the MYC gene, and therefore, to the development of cancer. ENCODE also has made similar studies possible for thousands of other DNA variants that may be associated with susceptibility to a variety of human diseases. Another of the principal investigators of the project, Dr. Richard Myers, president and director of the HudsonAlpha Institute for Biotechnology (Huntsville, AL, USA; www.hudsonalpha.org), explained that the ENCODE Project is unique because it requires collaboration from multiple people all over the world at the cutting edge of their fields. Scientists with the ENCODE Project also are applying up to 20 different tests in 108 commonly used cell lines to compile important data. John Stamatoyannopoulos, an assistant professor of genome sciences and medicine at the University of Washington (Seattle, USA; www.washington.edu) and another lead investigator, reported that the ENCODE Project has been responsible for producing many assays molecular-biology procedures for measuring the activity of biochemical agents that now are fundamental to biology. Widely used computational tools for processing and interpreting large-scale functional genomic data also have been developed by the project, Prof. Stamatoyannopoulos said. The depth, quality, and diversity
of the ENCODE data are unprecedented. Dr. Hardison noted that the portion of the human genome that actually codes for protein is approximately 1.1%. Thats still a lot of data, he said, and to complicate matters even more, most mechanisms for gene expression and regulation lie outside what we call the coding region of DNA. Dr. Hardison explained that scientists have a limited number of tools with which to explore the genome, and one that has been used widely is interspecies comparison. For example, we can compare humans and chimpanzees and glean
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TECHNICAL LITERATURE F R E E S E RV I C E S E RV I C E G R AT U I T K U N D E N D I E N S T G R AT I S S E RV I C I O G R AT U I TO S E RV I Z I O G R AT U I TO
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First Comprehensive Gene Map of the Human Brain Developed
new human brain atlas reveals more than 90% similarity among humans, and details genes at work throughout the brain to further scientific research and medical outcomes. The Allen Institute for Brain Science (Seattle, WA, USA; www.alleninstitute.org) has released the worlds first anatomically and genomically comprehensive human brain map, a previously improbable endeavor made possible through leading-edge technology and more than four years of demanding studies and documentation. The mappings are the foundation for the Allen Human Brain Atlas, an online public resource developed to advance the Institutes goal to accelerate understanding of how the human brain works and fuel new discovery among the global research community. In developing the Allen Human Brain Atlas, the Allen Institute has now characterized and mapped the biochemistry of two normal adult human brains, providing opportunities for scientists to study the brain with new detail and accuracy. The data reveal a remarkable 94% similarity between human brains, establishing strong patterns as a critical foundation for translational and clinical research. Moreover, data analysis from the two human brains indicate that at least 82% of all human genes are expressed in the brain, highlighting its great complexity while also providing an essential genetic blueprint to understand brain functionality better and fuel research in neurologic disease and other brain disorders. Until now, a definitive map of the human brain, at this level of detail, simply hasnt existed, said Allan Jones, PhD, chief executive officer of the Allen Institute for Brain Science. The Allen Human Brain Atlas provides never-before-seen views into our most complex and most important organ. Understanding how our genes are used in our brains will help scientists and the medical community better understand and discover new
treatments for the full spectrum of brain diseases and disorders, from mental illness and drug addiction, to Alzheimers and Parkinsons diseases, multiple sclerosis, autism, and more. Similar to a high-powered, multifunctional GPS (global positioning system) navigation system, the Allen Human Brain Atlas identifies 1,000 anatomic sites in the human brain, underscored by more than 100 million data points that indicate the particular gene expression and underlying biochemistry of each site. Scientists can utilize the Allen Human Brain Atlas to explore the human brain and identify how disease and trauma, including physical brain injuries and mental health disorders, affect specific areas of the brain. This resource makes it possible to pinpoint where a particular drug acts anatomically in the brain, to ultimately better control the successful outcome of numerous therapies. The Allen Human Brain Atlas is free and available to scientists, physicians, and the education community as an online public resource at www.brain-map.org. Previously, as its inaugural initiative, the Allen Institute for Brain Science completed mappings of the adult mouse brain in 2006, similarly making the data available free to scientists. Overall, those data have led to a number of significant research advances worldwide, including the publishing of over 500 peer-reviewed papers citing the Allen Mouse Brain Atlas to support research conclusions. A significant feature of the Atlas that makes it a powerful research tool is that it fully integrates several different kinds of data across different scales of brain exploration. Data incorporated into the Atlas include magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), as well as histology and gene expression data derived from both microarray and in situ hybridization (ISH) approaches. Users of the Allen Human Brain Atlas com-
prise a diverse range of biomedical researchers primarily neuroscientists throughout the world. They include scientists who study the human brain itself, as well as those working in mouse and other model systems, providing a rare and important opportunity for them to probe the relevance of the findings to humans. Some 4,000 unique visitors are now accessing the new Atlas each month. It is anticipated that the Allen Human Brain Atlas will be used in small and large-scale applications to examine diseases and disorders, such as obesity, Parkinsons disease, autism, schizophrenia, Alzheimers disease, and multiple sclerosis as well as those exploring how the healthy brain works. The Allen Institute for Brain Science will continue to expand the Allen Human Brain Atlas in the coming years, with new data from additional brains, as well as enhanced tools for searching, analyzing, and viewing the data. The Allen Institute for Brain Science is a medical research organization focused on accelerating understanding of the human brain by driving discovery for the broader scientific community.
Image: When complete in 2012, the Allen Human Brain Atlas will allow researchers to see where individual genes are expressed in the brain. Dots in hotter colors represent higher expression of genes, and cooler colors, lower expression (Photo courtesy of the Allen Institute for Brain Science).
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INDUSTRY NEWS
Protein That Suppresses Invadopodia Formation Prevents Spread of Breast Cancer Cells
levated activity of the adaptor protein Cdc42-interacting protein 4 (CIP4) has been found to suppress the formation of invadopodia, actin-rich membrane protrusions that promote extracellular matrix (ECM) degradation and invasiveness of tumor cells. Investigators at Queens University (Kingston, ON, Canada; www.queensu.ca) demonstrated the role of CIP4 by using RNA interference technology to block its activity in cultures of breast tumor cells. They reported in the May 15, 2011, issue of the Journal of Cell Science that these CIP4 knockdown cells degraded more ECM, had increased numbers of mature invadopodia, and were more invasive through matrigel. The inhibitory role of CIP4 was explained by the finding that CIP4 limited surface
expression of transmembrane type I matrix metalloprotease (MT1MMP), by promoting MT1-MMP internalization. By removing this enzyme complex from the cell surface CIP4 suppressed invadopodia formation and reduced the ability of the cancer cells to metastasize. Cancer researchers want to design new therapeutic strategies in which the metastasis or spreading stage of cancer can be blocked, explained senior author Dr. Andrew Craig, professor of biochemistry and cancer research at Queens University. Patients stand a much better chance of survival if the primary tumor is the only tumor that needs to be treated.
Image: Colored scanning electron micrograph (SEM) of a breast cancer cell (Photo courtesy of Steve Gschmeissner / Science Photo Library).
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Oncolytic Viruses Shown to Target and Kill Pancreatic Cancer Stem Cells
ncolytic viruses quickly infect and kill cancer stem cells, which may provide a treatment for tumors that are resistant to conventional chemotherapy and radiation, particularly pancreatic cancer, according to new research. The findings are particularly significant since pancreatic cancer has a poor prognosis and is difficult to detect and treat at early stages. Investigators led by Joyce Wong, MD, a surgical researcher with Memorial Sloan-Kettering Cancer Center (New York, NY, USA; www.mskcc. org), examined whether they could use oncolytic viruses, which are naturally occurring viruses that have been genetically engineered to be safe and express tracking genes, as a possible therapy against pancreatic cancer stem cells. These stem cells are thought to cause disease recurrence and metastasis, even after therapy, and oncolytic viruses may offer a new treatment strategy. What we learned is that oncolytic viruses have been engineered to selectively target cancer cells and have a low toxicity profile in animal studies, said Dr. Wong. Targeting the cancer stem cell may enhance our ability to eradicate tumors and prevent future recurrence of disease. While much research has been performed on isolating the cancer stem cell from various hematologic cancers, this research was based on the pres-
ence or absence of specific cell surface markers. Numerous mechanisms of how these cancer stem cells resist chemotherapy and radiation have also been examined. However, up to now, there has not been any research assessing whether genetically modified viruses can target and kill pancreatic cancer stem cells. Investigators tried to determine whether the viruses containing a marker gene that expresses green fluorescent protein could infect pancreatic cancer stem cells and ultimately kill the cancer stem cell. Their findings were promising and validated that viral activity was correlated with green fluorescent protein expression. Dr. Wong added that future studies are needed to determine whether oncolytic virus administration in vivo will help eradicate tumors and prevent future disease recurrence, and that while these initial findings are encouraging, further study is necessary to see whether oncolytic viruses will be clinically beneficial as a therapy. Dr. Wong presented the studys findings at Digestive Disease Week 2011 (DDW) May 9, 2011, in Chicago (IL, USA). DDW is the largest international gathering of physicians, researchers, and academics in the fields of gastroenterology, hepatology, endoscopy, and gastrointestinal surgery.
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Antibody-Linked Photosensitizer Eradicates Skin Tumors in Mouse Models

paper described a potential new cancer treatment based on the specific destruction of tumor blood vessels by antibodies labeled with a photosensitive drug. Investigators at the University of Hull (United Kingdom; www2.hull.ac.uk) began by synthesizing a novel porphyrin-based photosensitizer suitable for conjugation to antibodies. The photosensitizer was designed to release molecules of the DNA-damaging reactive oxygen species upon exposure to light. The photosensitizer was chemically linked to antibodies directed at the cells comprising new blood vessels, which are required for tumor growth and expansion. The investigators tested the experimental drug (based on the L19 antibody) in two mouse cancer models. They reported in the April 12, 2011, issue of the British Journal of Cancer that L19
was capable of highly selective binding to tumor blood vessels and that its conjugation with the photosensitizer allowed selective disruption of tumor vasculature upon irradiation, leading to complete and long-lasting cancer eradication. Tumors disappeared and there was no regrowth during the following 100 days. The investigators found that immune system natural killer cells were essential for complete tumor destruction. If natural killer-cell activity was inhibited, tumors were greatly reduced in size they but did not vanish completely. There are already drugs in clinical use which target tumor blood vessels, but these only inhibit growth rather than completely kill the tumor, said contributing author Dr. Ross Boyle, professor of chemistry at Hull University. By using this form of targeted photodynamic therapy, we were able to
completely kill the tumor in our models. Though this is still a long way from being used on patients, it does hold exciting potential for the treatments of some of the most common skin cancers.
Image: Light micrograph of a section through a malignant melanoma, showing red blood cells (red), connective tissue and blood vessel walls (purple) and macrophages (blue) (Photo courtesy of Steve Gschmeissner / Science Photo Library).
Dactinomycin More Effective than Methotrexate for Treating Gestational Trophoblastic Neoplasia
clinical study conducted on a population of women suffering from the low-risk cancer, gestational trophoblastic neoplasia (GTN), found that a biweekly dose of dactinomycin had a higher complete response rate than a weekly dose of methotrexate, the more commonly used drug. In a study lasting eight years, investigators at the University of Texas Southwestern Medical Center (Dallas, USA) treated a group of 216 GTN patients with either biweekly intravenous dactinomycin or weekly intramuscular (IM) methotrexate. Results published in the March 1, 2011, issue of the Journal of Clinical Oncology revealed that a biweekly dose of intravenous dactinomycin was superior to a weekly intramuscular injection of methotrexate in stopping the growth of cancerous cells in the uterus. Dactinomycin had a 70% com-
Computer Model Helps Explain Why Some Proteins Misfold

computer model that emulates the conditions that exist inside the cellular endoplasmic reticulum has provided information regarding the factors that cause proteins to misfold and aggregate, characteristics of diseases such as Alzheimers disease and diabetes. Investigators at the University of Michigan (Ann Arbor, USA; www. umich.edu) used a continuous flow reactor model of the endoplasmic reticulum to study proteins that misfold and their interaction with bystander proteins that somehow contribute to the process that lead to misfolding. This process often displays a threshold behavior characterized by a sudden shift between nontoxic to toxic levels of misfolded proteins. They reported in the April 20, 2011 issue of Biophysical Journal that slight changes in the bystander
plete response rate compared to 53% for methotrexate. Adverse effects were minimal with either drug. Both chemotherapy drugs are effective in treating this kind of neoplasia, but this trial proved that dactinomycin is the best first-line regimen, said contributing author Dr. David Scott Miller, professor of gynecologic oncology at the University of Texas Southwestern Medical Center. Minimizing toxicity is essential in low-risk GTN, because these women have a high-cure rate and usually hope to have subsequent pregnancies, Dr. Miller said. These tumors are much more common in developing countries, where access to more complicated chemotherapy regimens is limited. We have sought to develop simpler but effective regimens that would lend themselves to use in low-resource settings.
protein-residence time in the endoplasmic reticulum or the ratio of basal misfolded to bystander protein inflow rates can trigger the threshold behavior in protein misfolding. There are many diseases, including cystic fibrosis, Alzheimers disease, Huntingtons disease, Parkinsons disease, and diabetes that are products of improperly folded but potentially functional proteins, said senior author Dr. Santiago Schnell, associate professor of molecular and integrative physiology at the University of Michigan. These diseases are known as protein folding or conformational diseases. Our model proposes a couple of remedies for recovering a patients own misfolded proteins so they become correctly folded and functional proteins again, said Dr. Schnell.
PARP-1 Inhibitor Shows Promise for Treating Colorectal Cancer
he PARP-1 (poly(ADP-ribose) polymerase) inhibitor ABT-888 was found to be preferentially toxic to colon cancer cells carrying mutations in both copies of the MRE11 DNA-repair gene. Approximately 15% of all colorectal cancers (CRCs) demonstrate a type of DNA error called microsatellite instability (MSI), and about 82% of those tumors have MRE11 gene mutations. Investigators at the University of Michigan (Ann Arbor, USA; www.umich.edu) assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. They hypothesized that deficiency in MRE11 may sensitize CRC cells to PARP-1 inhibition based on the concept of synthetic lethality.
Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes does not. The investigators used two experimental approaches; including short hairpin RNA knockdown of MRE11 in the wild type and MSS (microsatellite stable) cell line SW-480 and a second cell-line model transfected with mutant MRE11 to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. They reported in the April 1, 2011, issue of the journal Cancer Research that use of the PARP-1 inhibitor ABT-888 revealed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and MSS cell lines.
Both models led to changes in proliferation, in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. University of Michigan clinicians regularly screen for microsatellite instability in patients at high risk of colorectal cancer. In addition, these markers can be easily detected in tissue samples of patients already diagnosed with colorectal cancer. This is a potential broader application for PARP inhibitors, beyond breast and ovarian cancer. This is a class of drug that has already shown safety in early clinical trials and now might benefit some colorectal cancer patients as well, said first author Dr. Eduardo Vilar-Sanchez, a fellow in hematology and oncology at the University of Michigan.
32
INDUSTRY NEWS
Introducing the Latest Generation of Low-Throughput Real-Time PCR Instruments

worldwide exclusive OEM agreement will increase the availability of the latest generation of low-throughput real-time PCR instruments for applications such as nucleic acid quantification, gene expression profiling, and detecting genetic variations. Roche Applied Science (Basel, Switzerland; www.roche.com) has signed an agreement with IT-IS Life Sciences Ltd. (Stokesley, United Kingdom; www.itisint.com) for the distribution of the new LightCycler Nano Instrument. The LightCycler Nano is a 32well format real-time PCR cycler with state of the art functionality and easy-to-use software. As it is both silent and compact, this instrument was designed to be an excellent bench-top companion for laboratory end users performing realtime PCR on a daily basis. The system uses convenient, standard PCR strips and can support all common detection dyes with its full spectrum optics. Roche is the worlds largest
Partners to Develop Complex Multilayer Films for Biopharmaceutical Applications

wo European manufacturers have signed an exclusive cooperation agreement to develop, manufacture, and supply polymer plastic films for the biopharmaceutical market. Sartorius Stedim Biotech (Aubagne, France; www.sartorius-stedim.com) - a leading provider of equipment and services for development, quality assurance, and production processes in the biopharmaceutical industry - and Sdpack Medica AG (Ochsenhausen, Germany; www.suedpack.com) - a manufacturer of innovative packaging solutions that belongs to the Sdpack Group - have agreed to form a strategic partnership for an initial term of 10 years. Sdpack will produce plastic film materials for Sartorius Stedim Biotech to be employed in the manufacture of single-use bags and systems. These single-use bags are primarily for laboratory applications by customers in the pharmaceutical industry for cell cultivation, transportation, and storage of biopharmaceutical liquids. In addition, the two companies will collaborate on the development of novel multilayer films with improved product characteristics. The first product innovations from this cooperation are expected in approximately one year from now.
biotech company with over 80,000 employees and more than nine billion Swiss francs committed to research and development. Regarding the agreement with IT-IS Life Sciences, Roches head of PCR projects, Gerd Haberhausen, said, With the LightCycler Nano Instrument, we now provide a very compact and innovative high performance PCR instrument under a worldwide exclusive agreement. The new LightCycler Nano Instrument delivers proven high quality at an affordable price and expands our qPCR business into a new segment. Customers will love the smart design of the instrument and appreciate the high quality data they can produce with it. Roderic Fuerst, CEO of IT-IS Life Sciences Ltd., said, We believe that the creative engineering capability of IT-IS and the market leadership position of Roche in real-time PCR are a perfect match for each other. The LightCycler Nano system will deliver exceptional performance, ease of use, and value due to its highly integrated solid-state design.
Takeda Pharmaceuticals to Acquire Nycomed

akeda Pharmaceutical Company (Osaka, Japan; www.takeda. com), the largest pharmaceutical company in Japan, and Nycomed (Zurich, Switzerland; www.nycomed.com) have jointly announced that Takeda will acquire Nycomed for 9.6 billion Euro on a cash-free, debt-free basis. The transaction is expected to transform Takeda's global business, in line with Takeda's sustainable growth strategy as it was outlined in its 20112013 mid-range plan. Takeda has a strong presence in the Japanese and US markets, while Nycomed has a significant business infrastructure in Europe and high-growth emerging markets that will enhance Takeda's regulatory development expertise and commercialization capability. The acquisition includes the roflumilast franchise, a first-in-class treatment for chronic obstructive pulmonary disease (COPD), which is expected to be a major source of revenue growth for Takeda. In addition, the acquisition will bring Takeda an immediate and stable increase in cash flow with Nycomed's more than EUR 2.8 billion in annual revenue, excluding the US Dermatology business, which is not included in the purchase. The transaction is expected to be completed within 90-120 days.
Nycomed enables Takeda to maximize the value of our portfolio and gives us an immediate strong presence in the high-growth emerging markets while doubling Takeda's European sales, said Yasuchika Hasegawa, president and CEO of Takeda. Nycomed's strength in a geographically wide range of markets and its diverse talent base will be a strong driver to helping us realize our important mission of striving toward better health for patients worldwide through leading innovation in medicine. The combination of Takeda's successful track record of innovation with Nycomed's efficient commercialization and manufacturing infrastructure will create a global player with a phenomenal ability to bring medicines to patients and healthcare providers around the world, said Hkan Bjrklund, CEO of Nycomed. Nycomed is a privately owned pharmaceutical company with a diversified product portfolio that includes both established prescription pharmaceutical products as a primary revenue driver, and over the counter (OTC) products. It has a strong European commercial network and it is aggressively growing in emerging markets, which account for more than 50% of global pharmaceutical growth.
Sdpack Medica AG has already been developing and manufacturing packaging solutions for medical product manufacturers for many years. Cooperation with Sartorius Stedim Biotech is now an important step into the new, promising markets of the future. We are proud that Sartorius Stedim Biotech, one of the market leaders in the biotechnology industry, has selected us as a partner to jointly develop innovative film laminates. This also tells me that we are on the right track with our strategy of continuously investing in new technologies and developments, said Johannes Remmele, managing director of Sdpack. Through the alliance with Sdpack, we have gained an excellent partner for the development and manufacture of complex multi-layer films that we process in the production of our single-use bags. By supplying innovative single-use products, we are striving to continue offering our customers real added value in the future as well. For this reason, the strategic partnership with Sdpack represents a key step for us, said Dr. Oscar-Werner Reif, executive vice president of research and development at Sartorius Stedim Biotech.
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PREMIER NEWS SOURCE FOR LIFE SCIENCE RESEARCHERS WORLDWIDE ISSN 1939-4470 Vol.16 No.

DNA Sequencing from Small or Degraded RNA Samples

Next-Generation Sequencers Essential Tools in Biomedical Research

New Insights into Protein Molecular Structure

Biosensor to Speed Up Drug Development T

Protein Regulator of Blood Vessel Formation Identified

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