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PREMIER NEWS SOURCE FOR LIFE SCIENCE RESEARCHERS WORLDWIDE ISSN 1939-4470 Vol.15 No. 4 • 7-8/2010

New Tool Developed for DNA Research

uminescent markers are an essential tool for researchers working with DNA. However, the markers are troublesome; some tend to destroy the function and structure of DNA when inserted. Others emit so little light, that they can barely be detected in the hereditary material. Therefore,

Biomarker Panel Now Available for Genome Research

esearchers in genomics and related molecular biology fields will benefit from the introduction into the market of a panel of key biomarkers associated with drug absorption, distribution, metabolism, and excretion (ADME). The VeraCode ADME Core Panel produced by Illumina, Inc. (San Diego,

CA, USA; www.illumina.com) has been designed to help researchers study genetic predispositions for differential drug response and adverse events. To this end, its panel of biomarkers has been based on those established by pharmaceutical industry experts in the PharmADME Core List.

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New Mapping Technique Finds Genes Faster

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Clues into How Cells Achieve Immortality

wedish investigators can now show that cells that grow forever, becoming immortal, obtain this capacity through gradual changes in the expression of genes that control the repair of DNA damage and regulate growth and cell death. Their research also shows that activation of the enzyme complex telomerase, which is essential for unlimited growth, occurs late in this process.

Image: Image: Researcher Researcher holding holding petri petri dishes dishes with with specimens specimens used used as as aa model model organism organism in in genetics genetics research research

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Neutrophil Enzyme Digests Carbon Nanotubes

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global team of investigators has designed a specialized mapping method that could speed research in genomic fields by rapidly finding genetic associations that shape an organism’s observable characteristics.

novel handheld cell counter and analyzer is now commercially available and is being shipped to researchers worldwide. Before-sale information regarding the Millipore (Billerica, MA, USA; www.millipore.com) “Scepter Handheld Automated Cell Counter” generated interest in the community of researchers working with cell cultures.

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Potential Anticancer Drug Acts via Energy Restriction

Therapeutic Target Found to Stop Cancer Metastases

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INSIDE Latest Advances & Applications in:

Handheld Device Offers Advances in Cell Counting

recently developed thiazolidinedione derivative has demonstrated potential as an anticancer drug in tests conducted on cultures of breast and prostate cancer cells. Thiazolidinediones (TZDs) act by binding to PPARs (peroxisome proliferator-activated receptors), a

esearchers have found that the human neutrophil enzyme myeloperoxidase (hMPO) is able to breakdown and detoxify carbon nanotubes, a finding that paves the way for their use as a drug delivery mechanism. Investigators at the University of Pittsburgh (PA, USA; www.pitt. edu) and colleagues from several other institutions exposed carbon nanotubes to myeloperoxidase in

cientists have uncovered what could be a very important lead in answering one of the most mystifying questions about cancer: why does it spread to the liver more than any other organ? In new research, scientists revealed experimental results suggesting that the immune Cont’d on page 4

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Clues into How Cells Achieve Immortality cont’d from cover

The study’s findings, published in the April 2010 issue of the journal Aging Cell, was performed by a research team from Umeå University (Sweden; www.umu.se) and directed by Prof. Göran Roos at the department of medical bioscience, pathology. The study’s findings provide more insights into how cells’ telomeres are regulated during the process that leads to perpetuating the life of cells. One type of blood cells, lymphocytes, were analyzed on repeated occasions during their cultivation in an incubator until they achieved the ability to grow an unlimited number of cell

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divisions, a process that is termed immortalization. In experiments, immortalization can be achieved following genetic manipulation of cells in various ways, but in the lymphocytes under study, this occurred spontaneously. This is an atypical phenomenon that can be compared to the development of leukemia in humans, for example. The ends of chromosomes, the telomeres, are important for the genetic stability of organisms’ cells. In normal cells, telomeres are shortened with every cell division, and at a specific short telomere length, they stop dividing. With the occurrence of genetic mutations, the cells can continue to grow even though their telomeres continue to be shortened. At a critically short telomere length, however, a so-called crisis occurs, with imbalance in the genes and massive cell death. In rare cases, the cells survive this crisis and become immortalized. In earlier research, this transition from crisis to eternal life has been associated with the activation of telomerase, an enzyme complex that can lengthen cells’ telomeres and help stabilize the genes. A typical finding is that cancer cells have active telomerase. The current study demonstrated that cells initially lose telomere length with each cell division, as expected, and after a while enter a crisis stage with massive cell death. Those cells that survive the crisis and become immortalized evince no activation of telomerase; instead, this happens later in the process. The Umeå researchers discovered that the expression of genes inhibiting telomerase is reduced in cells that get through the crisis, but telomerase was not activated until positively regulating factors were activated, thus allowing the telomeres to become stabilized through lengthening. By analyzing the genetic expressions, the scientists were able to show that the cells that survived the crisis stage had mutations in genes that are crucial to the repair of DNA damage and the regulation of growth and cell death. This discovery provides new insights into the series of events that needs to occur for cells to become immortalized, and it will have an impact on future studies of leukemia, for example. The studies were performed in collaboration with the Center for Oncology and Applied Pharmacology, University of Glasgow (UK) and the Maria Skodowska-Curie Memorial Cancer Center and Institute of Oncology (Warsaw, Poland). Image: FISH light micrograph of human chromosomes (blue) showing telomeres (pink) (Photo courtesy of Arturo Londono, ISM).

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Therapeutic Target Found to Stop Cancer Metastases cont’d from cover

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system may be the explanation. “Our work may open a new field of experimental therapeutics as combating the eventual development of liver metastases by targeting immune suppressive cells in the livers, in patients with early cancer can have great benefit,” said Dr. George Miller, a scientist involved in the work from the departments of surgery and cell biology at the New York University School of Medicine (New York, NY, USA; www.med.nyu.edu). Dr. Miller and colleagues reached this conclusion after conducting experiments in lab mice. In the experiments, the investigators used mice that spontaneously developed pancreatic cancer because of a mutation (Kras-mutation) in the progenitor cells of the pancreas, as well as mice with advanced colon cancers that spread to the abdomen. They then studied the expansion of immune suppressive cells in the liver from a very early stage in the cancer development to determine the immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of these cells. The study’s results suggest that fighting immune suppressive cells in the liver early after cancer development may prevent the metastasis of cancer to this vital organ. The study’s findings were published in the April 2010 issue of Journal of Leukocyte Biology (JLB). “This study could represent one of those ‘a-

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ha’ moments in science where one idea or experiment opens up entirely new ways of approaching and understanding a problem,” said Luis Montaner, editor-in-chief of JLB. “Physicians have known that the spread of cancer to the liver is far too common to occur by chance. Now we know that the immune system likely plays a role in facilitating this process. The next step, obviously, is to learn more so we can prevent it from happening.” Image: Polarized light micrograph of normal and cancerous liver cells (Photo courtesy of J.W. Shuler / SPL).

New Tool Developed for DNA Research cont’d from cover

researchers have been asking for alternative markers. Now a Danish Ph.D. student has developed a tool that could solve both problems: a tool one might call a molecular gauge. Ph.D. student Soren Preus from the department of chemistry at the University of Copenhagen (Denmark; www.ku.dk) in collaboration with researchers at Chalmers Technical University (Gothenburg, Sweden; www.chalmers.se) investigated the properties of the two luminescent socalled DNA base analogues of the tricyclic cytosine (tC) family, tCO and tCnitro. They tried to determine whether they could measure the structure of DNA without disrupting it. The research showed that the function of DNA is unimpeded by the insertion of the molecular gauge. Moreover, one base analogue is very efficient at emitting light, and the other very good at receiving it. Therefore, because one can provoke transport of light energy between the two luminescent markers, they are usable for a measuring technique known as fluorescence resonance energy transfer (FRET). In brief FRET, measurements are performed by forcing two luminescent markers to transfer light energy from one to the other, and then measuring the efficiency of the transfer. The two different markers are placed in the DNA helix. When they are subjected to a light pulse, one marker (tCO) emits part of the energy to the other (tCnitro). This energy transfer can be measured. Therefore, by cal-

culating backwards it is possible obtain very exact information about the distance and angle that the two have relative to one another. Knowing distance and angle of the markers allows for calculations of distance and angle of all the natural base pairs in the DNA structure. Thus, with this information the researcher can put together a picture showing every twist and turn of the structure. Because structure and function are closely related in DNA, the technique holds the potential to reveal new insights into the workings of DNA. FRET measurements are not a new phenomenon. However, Mr. Preus has developed one of the base analogues tCnitro in collaboration with Swedish research institution Chalmers University of Technology. Mr. Preus has used the facilities of the Molecular Engineering Group at University of Copenhagen to analyze every aspect of the energy transfer between the two markers, because this allows future DNA researchers to translate measurements to structure. Mr. Preus hopes that the new tool might find its use in characterizing the structural changes that take place when a protein binds to DNA or RNA as that could explain fundamental cellular mechanisms. Equally important is that the molecular gauge can be used to examine precisely how new drugs work and when they bind to DNA or RNA. The results have been published in the January 21, 2010, issue of the Journal of Physical Chemistry and the March 9, 2009, issue of the Journal of the American Chemical Society.

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ISSN 1939-4470 Vol.15 No.4. Published, under license, by Globetech Media LLC. Copyright © 2010. All rights reserved. Reproduction in any form is forbidden without express permission. Opinions expressed are solely those of the authors, and do not represent an endorsement, or lack thereof, by the Publisher of any products or services. Teknopress Yayıncılık ve Ticaret Ltd. S¸ti. adına Imtiyaz Sahibi: R.M. Geron • Yazı is¸leri Müdürü: Ersin Köklü Akıncıbayırı 10/4, 80300 Mecidiyeköy, Istanbul, Türkiye Faks: (212) 882-0613 • P. K. 1, AVPIM, 34001 Istanbul Baskı: Promat Web Ofset Tesisi • Örnek Mahallesi 1590. Sokak No: 32 • 34517 Esenyurt B. Çekmece • Istanbul, Türkiye Yerel süreli yayındır. Iki ayda bir yayınlanır, ücretsiz dag˘ıtılır.

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Potential Anticancer Drug Acts via Energy Restriction cont’d from cover

group of receptor molecules inside the cell nucleus, specifically PPAR-gamma. The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes. Following activation of PPAR-gamma, insulin resistance is decreased, adipocyte differentiation is modified, VEGFinduced angiogenesis is inhibited, leptin levels decrease (leading to an increased appetite), levels of certain interleukins (e.g. IL-6) fall, and adiponectin levels rise. While TZDs have been approved for use in treating type II diabetes, some data has indicated that they possess weak anticancer activity. These compounds destroy cancer cells through dietary caloric restriction in a manner similar to the natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2deoxyglucose. In the current study, investigators at Ohio State University (Columbus, USA; www.osu.edu) sought to increase the anticancer activity of the TZDs, and to this end prepared the compound OSU-CG12, a derivative of the TZD ciglitazone.

They reported in the March 26, 2010, issue of the Journal of Biological Chemistry that when tested on cultures of breast or prostate cancer cells, OSUCG12 was more than ten times more effective at killing cancer cells than either ciglitazone or resveratrol. Energy restrictions triggered by the drug resulted in the cancer cells dying from a combination of autophagy and apoptosis. “Our study proves that this new agent kills cancer cells through energy restriction, said senior author Dr. Ching-Shih Chen, professor of medicinal chemistry, internal medicine and urology at Ohio State University. “This is important because it shows that it is possible to design drugs that target energy restriction, and it is exciting because energyrestricting mimetic agents may also be useful for other diseases, including metabolic syndromes,

diabetes, cardiovascular disease, and obesity. Energy restriction may offer a powerful new strategy for treating cancer because it targets a survival mechanism used by many types of cancer.” Image: Colored scanning electron micrograph (SEM) of prostate cancer cells (Photo courtesy of David McCarthy / SPL).

New Mapping Technique Finds Genes Faster cont’d from cover

Using plants from 93 different Arabidopsis thaliana populations, a team led by the Gregor Mendel Institute of Plant Biology (Vienna, Austria; www.gmi.oeaw.ac.at) was able to find genetic links among multiple phenotypes, or traits, suggesting that the same genes or closely related genes controlled those traits. Dr. David E. Salt, a Purdue University (West Lafayette, IN, USA; www. purdue.edu), a professor of plant biology and coauthor of the study released March 24, 2010, in the journal Nature, reported that the ability to find these types of genetic associations could speed scientists’ ability to find and isolate genes and understand their function. “This may show that multiple phenotypes are being controlled by a specific region of the genome,” Dr. Salt said. “It helps us understand the mechanisms.” A conventional search for a gene responsible for a particular characteristic requires using plants that have been phenotyped, or identified

by characteristics. They are then crossed with others, and the offspring are phenotyped. Scientists then look for similarities in offspring’s genes with the desired trait. The process can be painstaking and time-consuming because many thousands of individuals may need to be checked, according to Dr. Salt. Genome-wide association mapping compares the sequence of DNA in genomes of many individual plants or animals to find similarities that narrow the scope of the search for a particular gene. “We can look for a region in the genome that is in common among the individuals,” Dr. Salt noted. “For plant biologists, it’s a much more efficient way of getting to genes. And for animal biologists, where making test crosses is more difficult, this is critical.” In this study, specific differences in DNA, called single nucleotide polymorphisms (SNPs), were compared at 250,000 sites across the genomes of many individuals. The genomes were matched up

against specific traits for each individual in order to find SNPs that are associated with the trait of interest. If scientists were looking for plants that produce high seed yields, for example, they would compare the genomes of plants that have a range of seed yields. The sites where the genomes match in individuals with high seed yields are possible locations of sought-after genes. Genome-wide association mapping is a faster process because fewer plants – typically in the hundreds – need to be grown and phenotyped. Finding genetic associations among multiple phenotypes could reveal more information about how those characteristics might be connected. Of the 107 phenotypes used in the research, Dr. Salt was responsible for phenotyping the plants for 18 characteristics, which focused on nutrient and micronutrient content. He reported that the next phase in the research would be to test those associations to determine the genes responsible for particular plant characteristics.

Handheld Device Offers Advances in Cell Counting cont’d from cover

The instrument, which looks and feels much like an electronic pipette, reports the cell count and average cell volume within 20 seconds of inserting the sensor into a cell culture sample. The Scepter tip draws precisely 50 µL of sample into its liquid handling microchannel. By drawing a precise volume every time, the Scepter cytometer ensures reproducible counts. By sampling accurate volumes, the Scepter cytometer eliminates pipetting errors and uneven sample loading that can occur with other devices. The tip has a precision drilled orifice through which cells pass, one by one,

and are counted based on the Coulter principle of impedance changes across a steady current, which is established by the electrodes in the tip. The consistent size of the orifice ensures accurate cell size and volume data. In addition to a raw count and cell concentration, the Scepter screen displays a histogram showing the population distribution of the culture. The real-time histogram monitors changes in the health and quality of the cell culture from one cell preparation to the next. The Scepter can be connected to a personal computer with the included USB cable. Uploaded data may be manipulated through the Scepter soft-

ware to view histograms on the computer screen. Histograms can be saved as raw files or can be imported into Microsoft Excel to merge counts, overlay histograms for comparison, or perform statistical analyses of the data. “We continue to move aggressively to bring innovation and productivity enhancements to the life science research market,” said John Sweeney, vice president of Millipore’s life science business. “With the introduction of the Scepter instrument, we now have a range of tools that help life scientists simplify tedious, repetitive tasks and improve the reproducibility of their experiments.” Bio Research International July-August/2010

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Biomarker Panel Now Available for Genome Research

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The VeraCode ADME Core Panel allows for the identification of 184 biomarkers in 34 genes. The dedicated system employs highly specific and streamlined chemistry so that DNA can be genotyped within eight hours with less than two-and-ahalf hours of hands-on time. The supporting software offers a convenient user interface that manages user authentication, logs system activity, and automatically translates genotype data into the star nomenclature used by researchers to analyze pharmacogenetic data. “Understanding genetic variability associated with drug response and disposition is a key step toward the realization of personalized medicine, and the VeraCode ADME Core Panel will help enable this exciting transformation,” said Jay Flatley, president and CEO of Illumina. “With the cost of bringing a new medicine to market now exceeding US$1 billion and over $220 billion spent annually on medications in the U.S., it is critical that we look for savings in all stages of drug development. With its emphasis on rapid operation and high-quality data, the VeraCode ADME Core Panel can help bring safe and effective therapies to patients as quickly as possible.”

Neutrophil Enzyme Digests Carbon Nanotubes cont’d from cover

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vitro, in neutrophil cultures, and in macrophage cultures. To increase the uptake of the nanotubes by neutrophils they were first coated with immunoglobulins. Results reported in the April 4, 2010, online edition of the journal Nature Nanotechnology showed that incubation of singlewalled nanotubes with hMPO and hydrogen peroxide resulted in degeneration of the nanotubes within 24 hours. This process could be accelerated by the addition of sodium chloride, which generated hypochlorite, a strong oxidizing compound known to break down nanotubes. Native or immunoglobulin-coated nanotubes were introduced into neutrophil or macrophage cell cultures. After 12 hours in the neutrophil culture, essentially all the coated nanotubes were degraded as compared to only about 30% of the native nanotubes. In contrast, after two days in the macrophage culture only about 50% percent of the coated nanotubes had degenerated. The biodegraded nanotubes did not generate an inflammatory response when aspirated into the lungs of mice. “The successful medical application of carbon nanotubes relies on their effective breakdown in the body, but carbon nanotubes also are notoriously durable,” said first author Dr. Valerian Kagan, professor of environmental and occupational health at the University of Pittsburgh. “The ability of hMPO to biodegrade carbon nanotubes reveals that this breakdown is part of a natural inflammatory response. The next step is to develop methods for stimulating that inflammatory response and reproducing the biodegradation process inside a living organism.” Bio Research International July-August/2010

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Technique Devised to Grow Arteries May Lead to Biologic Bypass new method of growing arteries could lead to a “biologic bypass” – or a noninvasive way to treat coronary artery disease. Yale School of Medicine (New Haven, CT, USA; http:// medicine.yale.edu) researchers and their colleagues reported their findings in the April 2010 issue of Journal of Clinical Investigation. Coronary arteries can become blocked with plaque, leading to a decrease in the supply of blood and oxygen to the heart. Over time, this blockage can lead to incapacitating chest pain or heart attack. Severe blockages in multiple major vessels may require coronary artery bypass graft surgery, a major invasive surgery. “Successfully growing new arteries could provide a biological option for patients facing bypass surgery,” said lead author of the study Michael Simons, M.D., chief of the section of cardiology at

Yale School of Medicine. In the past, researchers used growth factors – proteins that stimulate the growth of cells – to grow new arteries, but this method was unsuccessful. Simons and his team studied mice and zebrafish to see if they could simulate arterial formation by turning on and off two signaling pathways – ERK1/2 and P13K. “We found that there is a cross-talk between the two signaling pathways. One-half of the signaling pathway inhibits the other. When we inhibit this mechanism, we are able to grow arteries,” said Dr. Simons. “Instead of using growth factors, we stopped the inhibitor mechanism by using a drug that targets a particular enzyme called P13kinase inhibitor. Because we’ve located this

inhibitory pathway, it opens the possibility of developing a new class of medication to grow new arteries. The next step is to test this finding in a human clinical trial.” Image: Colored light micrograph of a section through a coronary artery that is partially blocked by a large atheroma (orange) (Photo courtesy of Alain Pol, ISM).

Contaminants from Plastic Microtubes Distort Results of UV Measurements recent paper pointed out the danger of overestimating the amount of nucleic acids or protein in samples analyzed by UV spectrophotometry due to contaminants that leach from plastic microtubes into the sample solution. Plastic containers such as “microfuge” tubes used for the storage and manipulation of biological samples comprise complex polymer materials containing several chemical additives. These additives include supplements such as chemical antioxidants, antimold release agents, biocides, and UVlight stabilizers. Plastic materials may also contain other low–molecular weight chemicals such as residual unreacted monomers and polymer degradation products. Microfuge tubes are produced by numerous manufacturers and are among the most commonly used pieces of laboratory ware in molecular biology laboratories. Since previous studies have demonstrated that additives and other chemicals can leach from plastics into the environment, investigators at Texas

State University (San Marcos, USA; www. txstate.edu) examined the effect of such contaminants on spectrophotometric measurements carried out on samples stored in plastic microtubes. They reported in the April 2010 issue of the journal BioTechniques that normal handling of laboratory microtubes caused leaching of light-absorbing chemicals into biological samples that interfered with spectrophotometric measurements. The leached chromophores absorbed UV light strongly between 220 nm and 280 nm, which are the wavelengths normally used to detect and quantitate proteins and DNA. Some common laboratory techniques, including sonication and PCR, were particularly effective inducers of leaching. The magnitude of the increase in absorbance was dependent upon both exposure time and heat history, with greatest induction after tubes were warmed to temperatures at or above 37 °C. Mass spectrometry revealed that aqueous solutions stored in plastic microtubes accumulated a com-

plex mixture of leached chemicals with molecular masses between 200 Da and 1,400 Da. Leaching was a common attribute of all commercially available brands of microtubes, indicating a persistent source of error in biomolecule detection and concentration measurements. “It was quite surprising that leaching of chemical additives, which absorb light at the same wavelengths as DNA and proteins had not been described before because it is so ubiquitous among commercially available plastic tubes, and biochemists have been using these small plastic tubes for many decades,” said first author Dr. Kevin Lewis, associate professor of chemistry and biochemistry at Texas State University. “Some manufacturers have recently begun offering tubes that contain a reduced number of additives,” said Dr. Lewis. “At the moment the use of polypropylene tubes with fewer additives appears to be the best way to reduce measurement errors due to leaching.”

Detecting Quantum Behavior in Viruses The strange world of quantum mechanics describes the bizarre, often contradictory, behavior of small inanimate objects such as atoms. Researchers have now started looking for ways to detect quantum properties in more complex and larger entities, possibly even living organisms. A German-Spanish research group, split between the Max Planck Institute for Quantum Optics (Garching, Germany; www.mpg.de) and the Institute of Photonic Sciences (ICFO; Barcelona, Spain; www.icfo.es), is utilizing the principles of an iconic quantum mechanics thought experiment – Schrödinger’s superpositioned cat – to test for quantum properties in objects composed of as many as one billion atoms, possibly including the flu virus. New research published on March 11, 2010, in New Journal of Physics describes the construction of an experiment to test for superposition states in

these larger objects. Quantum optics is a field well rehearsed in the process of detecting quantum properties in single atoms and some small molecules but the level that these researchers wish to work at is unprecedented. When physicists try to figure out precisely how the tiniest constituents of matter and energy behave, confusing patterns of their ability to do two things at once (referred to as being in a superposition state), and of their ‘spooky’ connection (referred to as entanglement) to their physically distant subatomic brethren, emerge. It is the ability of these objects to do two things at once that Dr. Oriol Romero-Isart and his coworkers are preparing to investigate. With this new technique, the researchers suggest that viruses are one type of object that could be probed. Albeit speculatively, the researchers hope that their technique might offer a way to address experimentally ques-

tions such as the role of life and consciousness in quantum mechanics. In order to test for superposition states, the experiment involves finely tuning lasers to capture larger objects such as viruses in an “optical cavity” (a very tiny space), another laser to slow the object down (and put it into what quantum mechanics call a “ground state”) and then adding a photon in a specific quantum state to the laser to provoke it into a superposition The researchers concluded, “We hope that this system, apart from providing new quantum technology, will allow us to test quantum mechanics at larger scales, by preparing macroscopic superpositions of objects at the nano- and microscale. This could then enable us to use more complex microorganisms, and thus test the quantum superposition principle with living organisms by performing quantum optics experiments with them.” Bio Research International July-August/2010

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MDV3100 Shown to Be Safe and Effective Against Prostate Cancer Phase 1-2 clinical trial has established the maximum tolerated dose of the compound MDV3100, a promising drug candidate for the treatment of castration-resistant prostate cancer (CRPC) – once known as or androgen-independent (androgen-resistant) prostate cancer. MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and coactivator recruitment of the ligand-receptor complex. It also induces tumor cell apoptosis and has no agonist activity. Since growth of CRPC is dependent on continued androgen-receptor signaling, investigators at Memorial Sloan-Kettering Cancer Center (New York, NY, USA; www.mskcc.org) assessed the antitumor activity and safety of MDV3100 in men with this disease. They reported in the April 24, 2010, issue of the journal the Lancet that all the 140 patients who were treated with doses of MDV3100 ranging from 30 mg to 600 mg daily showed some antitumor response as measured by PET imaging, bone scans, and blood tests. These positive responses included a decline in

PSA (prostate-specific antigen) of at least 50% in more than half of the patients and tumor regressions in 22% of the patients. Overall, two-thirds of patients had partial remissions or stable disease in tumors that had spread to soft tissue or bone. At the maximum tolerated dose for sustained treatment (240 mg per day for 28 days), the number of circulating tumor cells fell in 49% of patients and 91% of patients who initiated therapy with favorable counts retained favorable counts during treatment. The drug was generally well tolerated, with nausea, constipation, diarrhea, and anorexia being the most common mild side effects reported. The most frequently reported serious side effect at higher doses was fatigue, which generally resolved after dose reduction. “We were encouraged to see antitumor activity in men whose disease had spread to other parts of the body after either becoming resistant to previous hormone treatments or progressing following chemotherapy,” said first author Dr. Howard Scher, professor of oncology at Memorial SloanKettering Cancer Center. “These findings strengthen the drug’s potential to change the out-

look for a group of patients who currently have limited effective treatment options from which to choose.” Due to the positive outcome of the Phase 1-2 study, a multinational randomized Phase 3 clinical trial has begun to examine MDV3100 versus a placebo for the treatment of men with advanced prostate cancer who were previously treated with chemotherapy. Image: Colored scanning electron micrograph (SEM) of tissue from the prostate gland of a patient suffering from prostate cancer (Photo courtesy of Steve Gschmeissner / SPL).

Genealogy Testing Service Relies on High-Throughput Microarray Technology n advanced genotyping system is the basis for a new genealogic testing service that can match a wide range of family relationships within

five generations. Family Tree DNA (Houston, TX, USA; www.familytreedna.com), the first company to develop the commer-

cial application of DNA testing for genealogical purposes, has launched a new genotyping service (The Family Finder) that will allow individuals, regardless of gender, to explore linkages to grandparents, aunts and uncles, half siblings, and first, second, third, and fourth cousins. The test is based on Affymetrix (Santa Clara, CA, USA; www. affymetrix.com) Axiom genotyping technology and the associated GeneTitan analytical system. With the Axiom test, total genomic DNA (200 ng) is amplified and randomly fragmented into 25 to 125 base pair fragments. These fragments are purified, resuspended, and hybridized to Axiom Genome-wide human array plates. Following hybridization, the bound target is washed under stringent conditions to remove nonspecific background to minimize background noise caused by random ligation events. Each polymorphic nucleotide is queried via a multicolor ligation event carried out on the array surface. After ligation, the arrays are stained and imaged on the GeneTitan Instrument. The imaging device in the GeneTitan Instrument uses an external, high-intensity xenon lamp and dual excitation and emission filters to capture images from array plates. The Family Finder test analyzes the DNA of two individuals using Axiom array plates containing nearly

570,000 genetic markers, including many that are relevant to genealogy. The assay system utilizes the complete Axiom genotyping solution, which includes array plates, complete reagent kits, and an automated workflow that enables scientists to process more than 760 samples per week. Family Tree DNA then analyzes the resulting data with internally developed algorithms to determine the closeness of the relationship. “This is the most exciting genetic genealogy breakthrough since 2000, when Family Tree DNA launched its Y-DNA test to uncover relatives in the direct paternal line,” said Bennett Greenspan, CEO of Family Tree DNA. “The comprehensive, genome-wide coverage of Axiom Arrays enables us to offer consumers the most advanced genealogical test available at a price that is attractive to our customers. In addition, the automated GeneTitan system allows us to process hundreds of samples at a time with minimal hands-on time for maximum efficiency.” “The Family Finder test represents a huge step forward for the direct-toconsumer genetic genealogy market and the application of microarray technology,” said Kevin King, CEO of Affymetrix. “Now anyone can utilize the power of the Axiom genotyping solution and the GeneTitan System to find and connect with a broader range of family members than ever before.” Bio Research International July-August/2010

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Toxic Sugar Buildup Kills Tuberculosis Bacteria nterrupting the biochemical pathway leading to alpha glucan synthesis in Mycobacterium tuberculosis causes the buildup of a toxic precursor that quickly kills the microorganism. Investigators at the Albert Einstein College of Medicine (New York, NY, USA; www.einstein. yu.edu) traced a heretofore unrecognized molecular pathway from trehalose to alpha-glucan in M. tuberculosis that comprised four distinct steps mediated in turn by the enzymes TreS, Pep2, GlgE (which was identified as a maltosyltransferase that used maltose 1-phosphate), and GlgB. Alpha glucans are essential for maintaining the structure of the bacterial cell wall, and for generating new microbes through cell division. The investigators focused their attention on the enzyme GlgE, since there are no enzymes similar to it in humans or in the bacteria of the human gut. As described in their paper pub-

lished in the March 21, 2010, online issue of the journal Nature Chemical Biology, they used traditional and chemical reverse genetics to show that GlgE inactivation caused rapid death of M. tuberculosis both in vitro and in mice through a self-poisoning accumulation of the precursor maltose 1-phosphate, which damaged bacterial DNA. “We were amazed when we knocked out GlgE that we saw this DNA damage response,” said senior author Dr. William R. Jacobs, Jr., professor of microbiology, immunology, and genetics at Albert Einstein College of Medicine. “That is usually a very effective way to kill bacteria, when you start damaging the DNA. This approach is totally different from the way any other anti-TB drug works. In the past few years, extremely drug resistant strains of TB have arisen that cannot be eliminated by any drugs, so new strategies for attacking TB are urgently needed.”

Image: Colored scanning electron micrgraph (SEM) of Mycobacterium tuberculosis bacteria (Photo courtesy of A. Dowsett, Health Protection Agency).

Multifunctional Polymer Neutralizes Biological and Chemical Weapons n an ongoing effort to mimic the ability of biological tissues to respond quickly and appropriately to changing environments, researchers have synthesized a single, multifunctional polymer material that can decontaminate both biological and chemical toxins. Investigators from the University of Pittsburgh McGowan Institute for Regenerative Medicine (Pittsburgh, PA, USA; www.mirm.pitt.edu) described the findings online March 2, 2010, in the journal Biomaterials. “Our lab applies biological principles to create materials that can do many things, just like our skin protects us from both rain and sun,” said senior

investigator Alan Russell, Ph.D., university professor of surgery, University of Pittsburgh School of Medicine (UPMC), and director, McGowan Institute, a joint effort of the university and UPMC. “Typically, labs engineer products that are designed to serve only one narrow function.” Those traditional approaches might not provide the best responses for weapons of mass destruction, which could be biological, such as smallpox virus, or chemical, such as the nerve agent sarin, Dr. Russell noted. Terrorists are not going to announce what kind of threat they unleash in an attack. “That

uncertainty calls for a single broad-spectrum decontamination material that can rapidly neutralize both kinds of threats and is easily delivered or administered, and it must not damage the environment where it is applied,” he said. “Much work has gone into developing ways to thwart either germ or chemical weapons, and now we’re combining some of them into one countermeasure.” Dr. Russell and his team have devised a polyurethane fiber mesh containing enzymes that lead to the production of bromine or iodine, which kill bacteria, as well as chemicals that generate compounds that detoxify organophosphate nerve agents. “This mesh could be developed into sponges, coatings or liquid sprays, and it could be used internally or as a wound dressing that is capable of killing bacteria, viruses, and spores,” said lead investigator Gabi Amitai, Ph.D., of the McGowan Institute and the Israel Institute for Biological Research (IIBR; Ness-Ziona; www.iibr.gov.il). “The antibacterial and antitoxin activities do not interfere with each other, and actually can work synergistically.” In their experiments, the material fended off Staphylococcus aureus and Escherichia coli, which represent different classes of bacteria. After 24 hours, it restored 70% of the activity of acetylcholinesterase, an enzyme that is inhibited by nerve agents leading to fatal dysfunction of an essential neurotransmitter. The researchers reported that they are continuing to develop alternate decontamination strategies to address chemical and biologic weapons. The McGowan Institute for Regenerative Medicine was established by the University of Pittsburgh School of Medicine and its clinical partner, UPMC, to realize the vast potential of tissue engineering and other techniques aimed at repairing damaged or diseased tissues and organs. The McGowan Institute serves as a single base of operations for the university’s leading scientists and clinical faculty working to develop tissue engineering, cellular therapies, biosurgery and artificial and biohybrid organ devices. Bio Research International July-August/2010

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Bio Research International

Cancer Drug Improves Immune Picture in Visceral Leishmaniasis drug already approved for treatment of some types of cancer has been shown to be an effective adjunct therapy for visceral leishmaniasis by helping to restore immunocompetence by stimulating the remodeling of the microarchitecture of the infected spleen. Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L. infantum, is one of the most important of the neglected tropical diseases, with approximately 500,000 new cases and 70,000 deaths reported per annum. Pentavalent antimonial drugs remain the first-line therapy for VL in most parts of the world, although increasing drug resistance now limits their use in India. Drug toxicity, increasing drug resistance, and a paucity of new

drugs on the horizon have focused attention on the need to develop new combined approaches to therapy, including therapeutic vaccination, and on the development of dose-sparing regimens. Investigators at York University (United Kingdom; www.york.ac.uk) evaluated the drug sunitinib maleate (SM) for its potential to reduce the dosages of antimonial agents used to treat VL. SM is a small-molecule inhibitor of multiple receptor tyrosine kinases involved in cancer, including vascular endothelial growth factor receptors, platelet-derived growth factor receptors and the KIT receptor. It was approved by the U.S. FDA for the treatment of gastrointestinal stromal tumors and advanced renal-cell carcinoma in January 2006.

Partnership Links Flow Cytometry Instruments and Reagents partnership has been announced that will unite the manufacturer of a line of moderately priced benchtop flow cytometer systems with a major producer of flow cytometry research reagents. Accuri Cytometers (Ann Arbor, MI, USA; www.accuricytometers.com) makes a full-featured bench top cellanalysis system that provides powerful capabilities similar to industry-leading flow cytometers in a user-friendly format and at a fraction of the cost. The “C6 System” includes blue and red lasers, four color detectors and both forward and side scatter detectors plus software that the manufacturer says is so intuitive that customers typically have the instrument up and running within an hour of receiving it. The other half of the partnership is eBioscience (San Diego, CA, USA; www.ebioscience.com), a privately held company that makes more than 11,000 innovative high quality cell analysis reagents. Their product list comprises an array of high performing solutions, such as fluorescent dyes and bead assay reagents that enable comprehensive analysis of cells and soluble factors in the areas of immunology and cell biology research. The partnership is designed to offer researchers a better and more comprehensive solution for their flow cytometry needs, harnessing the cost-effectiveness, ease-of-use, performance capabilities, and accessibility of the Accuri C6 Flow Cytometer System with the market leading extensive line

Bio Research International July-August/2010

of high quality cytometer research reagents offered by eBioscience. “We are pleased to partner with reagent leader eBioscience to offer our growing customer base a wide range of quality reagents optimized for their varied research needs,” said Jack Ball, chief commercial officer of Accuri. “The adoption of the Accuri C6 Flow Cytometer System by over 500 research labs for an increasing range of applications has brought the need for high quality reagents that work seamlessly with our systems to the fore. This marketing partnership allows Accuri to further deliver on our promise to our customers to offer an affordable, easy-to-use flow cytometer solution – now made even more accessible with the easy availability of a full range of quality research reagents.” “We are delighted to partner with Accuri, the fastest growing supplier of flow cytometers, and welcome the opportunity to educate our customers about the advantages of having a flow cytometer in their research labs, along with the outstanding performance attributes and surprising accessibility of the Accuri C6 Flow Cytometer system,” said Tony Ward, vice president of commercial operations of eBioscience. “As part of our shared goal to make high performance cell analysis more accessible to researchers worldwide, this agreement will provide customers with an effective and comprehensive solution right out of the box.”

The investigators reported in the April 1, 2010, issue of the Journal of Clinical Investigation that SM both blocked the vascular remodeling and progressive splenomegaly associated with experimental visceral leishmaniasis and restored the integrity of the splenic microarchitecture. Similar alterations to splenic architecture are also observed in other infectious causes of splenomegaly, including experimental malaria, trypanosomiasis, and following infection with Lymphocytic choriomeningitis virus (LCMV). Although restoration of splenic architecture was accompanied by an increase in the frequency of interferon producing cells, SM treatment alone did not cause a reduction in tissue parasite burden. However, preconditioning with SM was shown to be successful as a dose-sparing strategy for use with conventional antimonial drugs that are known to be

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immune dependent for their efficacy in vivo. Senior author Dr. Paul Kaye, professor of immunology at York University, said, “It is particularly exciting that this potential has been discovered in a class of drugs that are already well-established in clinical practice. While our research has focused on leishmaniasis, the findings could have implications for a range of globally important diseases.” Image: Light micrograph of a section through spleen tissue from a patient suffering from visceral leishmaniasis (Photo courtesy of Sinclair Stammers / SPL).

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Compound Found in Broccoli Eliminates Breast Cancer Stem Cells ulforaphane, a compound found in abundance in broccoli destroys breast cancer stem cells, the extremely drug-resistant cells that often stimulate regrowth of tumors following chemotherapy. Sulforaphane is an organosulfur compound that exhibits anticancer, antidiabetic, and antimicrobial properties. It is obtained from cruciferous vegetables such as broccoli. In the plant the enzyme myrosinase transforms glucoraphanin, a glucosinolate, into sulforaphane upon damage to the plant (such as from chewing). Young sprouts of broccoli and cauliflower are particularly rich in glucoraphanin. Investigators from the University of Michigan (Ann Arbor, USA; www.umich.edu) recently evaluated the anticancer potential of sulforaphane on breast cancer cells growing in culture and in a xenograft mouse model. They reported in the April 13, 2010, online edition of the journal Clinical Cancer Research that cultures treated with the

compound showed a marked decrease in the cancer stem cell population with little effect on neighboring normal cells. Tumor cells taken from mice that had been treated with sulforaphane were unable to generate new tumors after having been transplanted into naive animals. “Sulforaphane has been studied previously for its effects on cancer, but this study shows that its benefit is in inhibiting the breast cancer stem cells. This new insight suggests the potential of sulforaphane or broccoli extract to prevent or treat cancer by targeting the critical cancer stem cells,” said senior author Dr. Duxin Sun, associate professor of pharmaceutical sciences at the University of Michigan. The positive findings reported in this study support the use of sulforaphane for the chemopre-

vention of breast cancer stem cells, and emphasize the need for further clinical evaluation. Image: Colored scanning electron micrograph (SEM) of breast cancer cells (Photo courtesy of Steve Gschmeissner / SPL).

Packages Enhance Photomicroscopy Applications new line of dedicated software packages designed to enhance the use of photomicroscopy in the life sciences in an easy-to-use, user-friendly fashion is now available. The camera and microscope manufacturer Olympus (Hamburg, Germany; www.microscopy. olympus.eu) has released a series of three different software packages called ”cellSens Entry,” “cellSens Standard,” and “cellSens Dimension.” The three packages are interrelated and lead from basic to very complex applications. The basic package, “cellSens Entry,” gives the user the ability to perform simple image acquisition and documentation. The customizable interface provides complete control over a range of Olympus digital cameras to obtain live images in a number of formats, including AVI movies. This software package can perform straightforward postcapture pro-

cessing such as light intensity and white balance adjustments, and its layers file format enables the addition of arrows and annotation text without affecting the original image channels. The intermediate package, “cellSens Standard,” enables more advanced image capture, including time-lapse and TWAIN acquisition. The program supports advanced hardware control for processes such as objective and filter changes, focusing, and internal shutter control. It also boasts extended geometry functions that allow images to be easily manipulated via mirroring, rotation, resizing, cropping, and channel shifting. The “cellSens Standard” program can also convert bit-depth and color-space settings to meet the capabilities of the computer system as well as the requirements of the application. Further image processing tools are available for contrast adjustment, smoothing, image sharpen-

ing, as well as noise and shading correction. The advanced “cellSens Dimensions” software package provides a broad range of advanced features as well as specialized, optional solution modules that support complex procedures such as extended focal imaging, multiple image alignment, and multiposition imaging. In addition, live images can be transferred directly to colleagues via the Internet using the program’s “netcam” capability. Within the images, interactive measurement functions can be executed on a separate image layer. Extracted numerical values such as size, distance, or area can subsequently be exported to Microsoft Excel for in-depth statistical analysis. Once data has been obtained, a unique report composer uses Microsoft Word templates to generate user-defined reports that retrieve images and data directly from the cellSens database. Bio Research International July-August/2010

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Bio Research International

Candidate Drug Kills Pediatric Retinoblastoma Cells low molecular weight inhibitor of the tumor promoting protein MDMX has been isolated that shows promise for treatment of the pediatric cancer retinoblastoma. MDMX and a similar molecule MDM2 promote cancer development by inhibiting the action of the tumor suppressing protein p53. The two inhibitors work differently, so it is necessary to prevent the activity of both of them to restore p53 functionality. The p53 pathway is disrupted in virtually every human tumor. In about half of human cancers, the p53 gene is mutated, and in the remaining cancers, the pathway is dysregulated by genetic lesions in other genes that modulate the p53 pathway. Investigators at St. Jude Children’s Research Hospital (Memphis, TN, USA; www.stjude.org) developed biochemical and cell-based assays for high throughput screening of chemical libraries to identify MDMX inhibitors. They reported in the April 2, 2010, issue of the Journal of Biological

Chemistry that after screening nearly 300,000 compounds they had identified one, SJ-172550. This compound was shown to attach to the p53binding pocket of MDMX, thereby displacing p53 and allowing p53 to direct potential cancer cells towards the pathway to apoptosis. When tested in conjunction with an MDM2 inhibitor, it was found that SJ-172550 effectively killed retinoblastoma cells growing in culture. Since about 65% of retinoblastoma tumors feature extra copies of the MDMX gene as do nearly 20% of patients with breast, colon, and lung cancer, there is an urgent need for a drug to reverse the activity of this molecule. “We went from a discovery in childhood cancer, MDMX amplification, to characterizing this first inhibitor in about three-and one-half years,” said senior author Dr. Michael Dyer, professor of developmental neurobiology at St. Jude Children’s Research Hospital. “It may also be useful for any tumor that has

normal p53,” Dr. Dyer said. “The idea is that if you have normal p53 and you need to turn it on, maybe by giving a drug that hits MDM2 and another that hits MDMX; you free p53 up to kill the cell.” Image: Funduscopic finding of a retinoblastoma (Photo courtesy of Meilahti Hospital, Department of Ophthalmology).

Universal Influenza Vaccine Passes Clinical Trial in Elderly Population evelopment of a Universal Influenza Vaccine advanced another step with the successful completion of the clinical phase of its second Phase I/II clinical trial. The Multimeric-001 Universal Flu Vaccine, under development by BiondVax Pharmaceuticals (Rehovot, Israel; www.biondvax.com), was tested in a randomized, single-blind, placebo-controlled, escalating double-dose safety study on a total 60 participants aged 55-75, who received two injections, either with or without adjuvant, at two different doses and in accordance with the approved clinical trial design. This phase of the study was directed at an older population group, which is considered most at-risk for influenza infections. Results of the study showed that the vaccine was safe to use at all doses tested, both with and without adjuvant. All participants who received the

Bio Research International July-August/2010

vaccine developed a high level of antibodies against the Multimeric-001 Universal Flu Vaccine. These antibodies also specifically identified a number of different strains of influenza, including the swine flu strain (A/H1N1). Furthermore, those receiving the vaccine showed a meaningful increase in white blood cells inducing the secretion of interferon gamma and Interleukin-2. Thus, the vaccine activated both the humoral (antibody) and the innate (cellular) arms of the human immune system. The Multimeric-001 Universal Vaccine is a single formulation consisting of nine conserved linear epitopes in triplicate. The epitopes selected were taken from hemagglutinin (HA), nucleoprotein (NP), and matrix (M) proteins, therefore ensuring high antigen content. These epitopes are common to practically all existing and future flu virus strains, including both

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seasonal and pandemic flu strains such as the avian and swine flu, regardless of their antigenic drift and shifts. This trial was the second of two Phase I/II clinical trials of the Multimeric-001. Dr. Ron Babecoff, CEO of BiondVax, said, “These latest excellent safety results are further evidence of the positive safety profile of our Multimeric-001 vaccine. We are especially pleased to have been able to show the safety of the vaccine in the elderly population, which is one of the most at-risk and vulnerable sectors of the population to flu infections. Following the recent success of the first Phase I/II study in which we showed proof of the safety and immunogenicity of our vaccine in younger participants, these additional safety results represent yet another successful achievement in our path towards the development of the Universal Flu Vaccine.”

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Resveratrol Protects Brain Cells from Stroke Damage in Mouse Model esveratrol, a bioactive compound in red wine, has been shown to protect against brain damage in a mouse stroke model. Resveratrol is found primarily in the skin and seeds of grapes. The amount found in grape skins varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content. Red wine contains between 0.2 mg/L and 5.8 mg/L, depending on the grape variety, while white wine has much less – the reason being that red wine is fermented with the skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Epidemiological and experimental reports have linked mild-to-moderate wine and/or grape

consumption to a lowered risk of cardiovascular, cerebrovascular, and peripheral vascular diseases. Based on these findings, investigators at Johns Hopkins University (Baltimore, MD, USA; www.jhu.edu) used a mouse stroke model to assess whether resveratrol could significantly protect the animals’ brains from damage caused by lack of oxygen. The investigators reported in the April 8, 2010, online edition of the journal Experimental Neurology that mice that received a single modest dose of resveratrol before induction of ischemic stroke suffered significantly less brain damage than the ones that had not been given the compound. At the molecular level, it was found that resveratrol increased levels of the enzyme heme oxygenase, which was already known to protect nerve cells from stroke dam-

age. Thus, mice from a strain lacking heme oxygenase received no protective benefit from resveratrol. “Our study adds to evidence that resveratrol can potentially build brain resistance to ischemic stroke,” said senior author Dr. Sylvain Doré, associate professor of anesthesiology, critical care medicine, pharmacology, and molecular sciences at Johns Hopkins University. “Resveratrol itself may not be shielding brain cells from free radical damage directly, but instead, resveratrol and its metabolites may be prompting the cells to defend themselves. It is not likely that brain cells can have high enough local levels of resveratrol to be protective. Rather, the resveratrol is needed to jump-start this protective enzymatic system that is already present within the cells. Even a small amount may be sufficient.”

Mitochondrial Genome of Previously Unknown Human Species Decoded n international team of researchers has sequenced ancient mitochondrial DNA from a finger bone of a female found in southern Siberia. She comes from a previously unknown

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human species, which lived approximately 48,000 to 30,000 years ago in the Altai Mountains in Central Asia. The mitochondrial genome that was inherited from the mother and passed on to the descendants is an indication of a new wave of emigration from Africa. It differs from the Homo erectus ancestors of Neanderthals and Homo sapiens, according to a study published in the March 25, 2010, issue of the journal Nature. The first group of hominins, which left Africa about 1.9 million years ago, was Homo erectus. Archaeological findings and genetic data suggest that at least two other groups then left Africa: First, about 500,000 to 300,000 years ago, the ancestors of Neanderthals, and after that, 50,000 years ago, anatomically modern humans. Direct descendants of Homo erectus could have survived until less than 100,000 years ago in Indonesia. Earlier representatives of Homo erectus and Homo heidelbergensis lived in northern latitudes – for example, more than 125,000 years in the Altai Mountains in

southern Siberia. Neanderthals also lived at that time in Siberia. Dr. Johannes Krause, Dr. Svante Pääbo and colleagues from the Max Planck Institute for Evolutionary Anthropology (Leipzig, Germany; www.eva.mpg.de) have now sequenced mitochondrial DNA from a tiny piece of a finger bone. The bone was found 2008 in the Denisova Cave in the Altai Mountains in southern Siberia. They compared the ancient DNA from the mitochondria, with the mitochondrial DNA of Neanderthals and living humans. It was revealed that the mitochondrial DNA of the hominins from South Siberia differs noticeably from that of all previously known hominins. As demonstrated by a detailed examination of the mitochondrial genome, these hominins shared a common ancestor with modern humans and Neanderthals approximately 1.0 million years ago. Moreover, the age of the fossil suggests that these unknown people in Southern Siberia lived close in time and space with Neanderthals as well as with modern humans. Bio Research International July-August/2010

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Bio Research International

Artificial Human Skin Created Using Tissue Engineering new study describes the development of artificial human skin with biomechanical properties, based on an agarose-fibrin biomaterial. Researchers at the University of Granada (UGR; Spain; www.ugr.es) first obtained human skin samples from biopsies of patients who underwent plastic surgery at the University Hospital Virgen de las Nieves (Granada, Spain; www.hvn.es). To create the artificial human skin, tranexamic acid (to prevent fibrinolysis), calcium chloride (to precipitate fibrin coagulation), and 0.1% agarose was added to human fibrin from plasma of healthy donors. The artificial-skin substitutes were then grafted on the back of the nude mice, with the purpose of observing its optimal development, maturation, and functionality in vivo. To do so, the researchers analyzed the samples by transmission and scanning light, electron microscopy, and inmunofluorescence to evaluate factors such as cell proliferation, the presence of differentiating morphological markers, the expression of cytokeratin, involucrine, filaggrin, and angiogenesis of the artificial skin into the recipient organism. The researchers found that the artificial human skin created in the laboratory showed adequate biocompatibility rates with the recipient, and no

rejection, dehiscence, or infection was registered. Additionally, the skin of all animals used in the study started to show granulation after six days from implantation. Within the following 20 days, cicatrization was complete. Details on the research were released by the department of histology at UGR on April 20, 2010. “These biomaterials added resistance, firmness, and elasticity to the skin. Definitively, we have created a more stable skin with similar functionality to normal human skin,” said lead author José María Jiménez Rodríguez, of the tissular engineering research group at UGR. ”This pioneering finding will allow the clinical use of human skin and its use in many laboratory tests on biological tissues. Further, this finding could be useful in developing new treatment approaches for dermatological pathologies.”

Image: Colored scanning electron micrograph (SEM) of the epidermis, the outermost layer of human skin (Photo courtesy of Susumu Nishinaga / SPL).

Bio Research Demands Highly Purified Water ften overlooked, highly purified water is an absolute requirement for successful biotechnology research, and now a new and sophisticated water purification system has become available. The new purification system, the ELGA LabWater Purelab Pulse, (Marlow, United Kingdom; www.elgalabwater.com) has been developed to produce consistently highly pure type II level water at economical running costs for a wide range of applications including cell culture and media preparation. Type II water is basic for general laboratory applications requiring higher inorganic purity as well as being suitable for clinical analyzers, electrochemistry, sample dilution, media preparation, and radioimmunoassay. ELGA’s Pulse technology integrates EDI (electrodeionization), which combines ion exchange resins and ion-selective membranes, with direct current to remove ionized impurities from water efficiently. It is complemented by pretreatment, reverse osmosis, and a 254 nm UV lamp to produce type II pure water that the manufacturer says meets and exceeds European, U.S., and Japanese pharmacopeia standards. In addition, the PURELAB Pulse can be fitted with a point-of-use biofilter to reduce bacteria levels to less than one colonyforming unit per 10 mL. The purification system has been designed to fit into any laboratory environment and is easy to operate and maintain. It can be wall or bench mounted for convenient access and can be fitted with ELGA’s unique wrap-around reservoir to save valuable space.

Bio Research International July-August/2010

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The reaction tubes are designed to enable laboratories to achieve consistent low-level blanks to improve the precision and accuracy of CHN microanalysis results. The tubes are manufactured from high quality, low hydroxyl materials, and can be supplied within 24 hours of order.

The FC1 Cycler is designed to reduce the thermal cycling time by a factor of three when compared with current products. When added to an existing Fluidigm system, the FC1 provides the capability to double the number of microfluidic chips that can be processed in a single day.

The pHeasy is intended for accurate process pH measurement without recalibration. The sensor features a device that provides feedback on the accuracy of the measurement, delivers alerts for electrode replacement, monitors chloride loss, and detects reference poisons.

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Photoacoustic 3D Tomographic Imaging Developed for Cancer Research preclinical photoacoustic computed tomography (CT) scanner has been designed for small animal imaging. The system is used for simple, fast, noninvasive quantification of tumor vasculature and other physiologic parameters for preclinical research. The Nexus 128, developed by Endra Life Sciences, makes in vivo quantification of tumor vasculature possible without the need for contrast agents and helps preclinical researchers gain deeper insight into areas such as how drugs treat disease and cancer progression, without ionizing radiation or complicated equipment. Endra Life Sciences was founded by Enlight Biosciences (Boston MA, USA: www.enlightbio.com), a funding syndicate of six of the world’s leading pharmaceutical companies focused on commercializing transformational technologies. “Photoacoustic imaging combines ultrasound with the rich contrast of optical imaging, based on the same principles that give cells, organs, and tissues their unique colors,” said Michael Thornton, Endra’s president and chief operating officer. “It provides high spatial resolution at depth far exceeding that of conventional optical imaging techniques such as fluorescence and bioluminescence. We are excited to make this technology widely available to cancer biology researchers for the first time.” “Mouse models of cancer are used

extensively to study tumor development and the effects of new therapies, but until now the tools to measure this effect have had depth limitations,” said Dr. Rakesh Jain, director, Edwin L. Steele Laboratory for Tumor Biology at Harvard Medical School (Boston, MA, USA), and Enlight Biosciences advisor. “The ability to track abnormal vessel growth and normalization in vivo with high resolution throughout a tumor mass during therapeutic intervention is a powerful new capability that will be widely used in cancer research.” The name Nexus 128 represents the convergence of light and sound in a powerful new imaging approach. It employs a detector array consisting of 128 individual acoustic receiver elements arranged in a patented geometry. The system generates multispectral, quantitative, three-dimensional (3D) images of tumor vasculature and hemoglobin concentration in under two minutes, and completes volumetric anatomic scans in as little as 12 seconds. “For the past several years, our research group has developed quantitative photoacoustic spectroscopy imaging techniques and applied them to mouse models of cancer,” said Dr. Keith Stantz, faculty member of Purdue University. “We have been using Endra’s photoacoustic tomography prototype system regularly for the past year. The simplified animal handling and high throughput allow us to image entire study groups within a couple of hours.”

Endra Life Sciences launched the product at the American Association for Cancer Research (AACR) 101st annual meeting 2010 in Washington, DC, USA, April 17-21, 2010. The Nexus 128 system was featured in a poster by Dr. Stantz and his colleagues from Purdue University (West Lafayette, IN, USA). Short pulses of light absorbed deep within tissue create sound waves that are detected by ultrasound receivers to create an image. This noninvasive approach provides high contrast imaging at depths, and spatial resolution far exceeding existing optical techniques. The

photoacoustic effect, a precursor to photoacoustic imaging, revealed that energy from sunlight could be transformed into a sound wave. Recent advances in pulsed laser sources, ultrasound devices, and image reconstruction algorithms have enabled the photoacoustic effect to be applied to biologic imaging. Endra’s Nexus 128 is the first commercial photoacoustic-imaging device designed specifically for high throughput, quantitative, in vivo small animal imaging. Image: Preclinical Photoacoustic CT Imaging of a mouse (Photo courtesy of Endra Life Sciences). Bio Research International July-August/2010

Bio Research International

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Maintenance of Cell Culture Conditions Essential for Biomedical Research uietly at work in the background of the laboratory, the importance of a good incubator to the success of biomedical research is often overlooked. However, a new line of incubators, launched at PITTCON 2010 conference and expo in Orlando (FL, USA) requires another look. The line of CelCulture CO2 incubators by Esco (Hatboro, PA, USA; www.escoglobal.com) provides the carefully monitored and consistent cell culture environment required by the contemporary biomedical researcher. Temperature, CO2 level, and humidity in the CelCulture CO2 incubator is controlled by a set of proprietary algorithms that guarantee stable conditions as well as ensuring fast recovery of the parameter values following door openings. Cultures growing inside the incubator are protected by an "all inclusive" contamination control system, which comprises filtration technology that maintains the culture chamber at a level of ISO class five. If necessary, the incubators can be decontaminated by a built-in moist heat 90 ยบC decontamination cycle that operates overnight. At the end of the cycle, the chamber is dry and ready to use. All

input gases are filtered by inline filters before they enter the chamber to remove impurities and contaminants. The incubator's main body is made from electro-galvanized steel with Esco's unique ISOCIDE antimicrobial coating. The interior of the 170-liter chamber is made from stainless steel. A computerized reminder alarm system prompts the user to replace the CO2 tank and bacteriological filter automatically to prevent the incubator system from being compromised. An intelligent data and event logger records all incubator parameters for on-screen recalls, and a diagnostic interface with quick on-screen help provides comprehensive solutions to frequently encountered problems. Image: The CelCulture CO2 incubator, designed to create a consistent cell culture environment (Photo courtesy of Esco).

Vitamin D Insufficiency Linked to Development of Crohn's Disease esults published in a recent paper suggest that supplementing the diet with vitamin D can protect against development of Crohn's disease, a chronic incurable inflammatory bowel condition. Vitamin D signaling through the vitamin D receptor has emerged as a key regulator of innate immunity in humans. Investigators at McGill University (Montreal, Canada; www.mcgill.ca) extended this observation to the serious autoimmune syndrome known as Crohn's disease. They reported in the January 22, 2010, edition of the Journal of Biological Chemistry that vitamin D acted directly to stimulate two genes that could be related to the development of Crohn's disease. The first, the beta defensin 2 gene, encodes an antimicrobial peptide that interacts with intestinal bacteria. The second, the NOD2 gene, alerts immune cells to the presence of invading microbes. When vitamin D levels were insufficient, these two genes malfunctioned, which induced the type of inflammatory response found in Crohn's disease. "Our data suggests, for the first time, that vitamin D deficiency can contribute to Crohn's disease," said Dr. John White, professor of physiology at McGill University. "It is a defect in innate immune handling of intestinal bacteria that leads to an inflammatory response that may lead to an autoimmune condition." "Siblings of patients with Crohn's disease that have not yet developed the disease might be well advised to make sure they are vitamin D sufficient," said Dr. White. "It is something that is easy to do, because they can simply go to a pharmacy and buy vitamin D supplements. The vast majority of people would be candidates for vitamin D treatment."

Bio Research International July-August/2010

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The Viscotek TDAmax GPC/SEC triple detection system with Omnisec software allows users to characterize heterogeneous mixtures of materials. The system is designed for a wide range of biomaterials and biotechnology applications.

Products available include biological and cryogenic sample storage tubes, sealing arrangements, tube racks and sorters. Additional products include the Track-IT sample management system, and the MX4, a semi-automated sample handling and verification system.

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Nonanimal Recombinant Proteins Developed for Cell Culture and Tissue Engineering Applications new range of recombinant proteins has been developed that can substitute extracellular matrix proteins that are currently extracted from mouse sarcoma. The mussel adhesive protein-based matrix (MAPTrix) ECM line of products are coating reagents with genetically incorporated bioactive peptides that mimic the extracellular matrix (ECM) activity of collagen, fibronectin, laminin, and vitronectin proteins. These bioactive peptides mimic ECM proteins and provide for cell attachment, spreading, and growth. A MAPTrix surface coating offers an animal-free, chemically defined attachment and growth surface that provides a highly controlled environment for cell culture and tissue engineering applications. Cell adhesion to the extracellular matrix is essential for the development and maintenance of cells. Cell adhesion to ECM ligands is principally mediated by integrins. The Arg-Gly-Asp (RGD) recognition motif is present in many ECM pro-

teins including fibronectin, laminin, and osteopontin. Many biomimetic approaches have sought to convey biofunctionality to synthetic materials by presenting a cell adhesion motif such as the RGD recognition motif. The immobilization of short peptides such as RGD on synthetic or natural materials may produce biofunctional surfaces that bind adhesion receptors and promote cell adhesion; however, this traditional chemistry approach is time-consuming, inconvenient, and lacks reproducibility. The MAPTrix ECM line of products, developed by Amsbio (Abingdon, UK; www.amsbio. com), provide a better alternative to the conventional chemistry approach. In addition to RGD motifs – MAPTrix includes a wide variety of alternative motifs that mimic the extracellular matrix (ECM) activity of collagens, fibronectin, laminin, vitronectin and other matrix proteins. The use of MAPTrix ECM-based coatings is simple, convenient, and highly reproducible. The MAPTrix ECM

line of flexible products can be used in a cell culture application alone or in combination with other products. All MAPTrix products are soluble in a variety of buffers including water under a wide range of pH (pH = 2.0 to 9.5). Available for basic research or drug discovery applications in serum-free or serum-reduced conditions – MAPTrix products are provided as ready-to-use aqueous coating formulations in 1.0 mg, 2.5 mg, 5.0 mg, and 10.0 mg sizes (vials). AMS Biotechnology (AMSBIO) is an international provider of products and custom services for life sciences research. The company’s range includes over 23,000 polyclonal and monoclonal antibodies, peptides, recombinant proteins, extracellular matrix, molecular detection reagents, tissue DNA, RNA, protein, and microarray products. Key research areas include apoptosis, cell invasion and migration, cell signaling, DNA damage, electrophoresis, glycobiology, posttranslational modification, and stem cell biology.

Easy and Cost-Effective Production of Functional siRNA Achieved with Generation Kit siRNA generation kit enables easy and costeffective generation of a large number of small interfering RNAs (siRNAs) from full-length target genes. siRNAs are 21-23-nucleotide RNA molecules that can cause targeted gene silencing in mammalian cells through a process known as RNA interference. In nature, siRNAs are generated by ribonuclease III cleavage of longer double-stranded RNAs (dsRNAs). When dsRNAs are transfected directly into mammalian cells, they activate the interferon system and provoke nonspecific gene suppression and cytotoxic response. siRNAs have proven to be effective at specifically silencing gene expression without causing any interferon response. Using an ultra-active form of human recombi-

nant dicer enzyme, a double-stranded RNA-specific endonuclease, it is possible using the kit to cleave more than 95% of dsRNA template into 22 bp [base pair] siRNAs within two hours under optimized reaction conditions. In contrast to individual synthetic siRNAs, the Turbo Dicer kit allows the user to quickly produce multiple siRNA species against the target mitochondrial RNA (mtRNA), and thereby achieve effective gene silencing with minimal guesswork. Moreover, due to the minimal concentration of any individual siRNA species generated with the Turbo Dicer enzyme, off-target effects are not a problem. For maximum convenience, the Turbo Dicer siRNA generation kit, developed by from Amsbio (Abingdon, UK; www.amsbio.com), contains

everything that is required for preparing doublestranded RNA from the user’s target gene(s), dsRNA cleavage, siRNA cleanup, and transfection. Both the Recombinant Turbo Dicer enzyme and the RNA purification columns are also available separately. AMS Biotechnology (Amsbio) is a leading international provider of products and custom services for life sciences research. The company’s range includes over 23,000 polyclonal and monoclonal antibodies, peptides, recombinant proteins, extracellular matrix, molecular detection reagents, tissue DNA, RNA, protein, and microarray products. Key research areas include apoptosis, cell invasion and migration, cell signaling, DNA damage, electrophoresis, glycobiology, posttranslational modification, and stem cell Bio Research International July-August/2010

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Bio Research International

Bitter Melon Extract Inhibits Breast Cancer Cell Growth itter melon (Momordica charantia) extract, a common dietary supplement, has been show to exert a significant effect against breast cancer cell growth and may ultimately become a chemopreventive agent against this form of cancer. “Our findings suggest that bitter melon extract modulates several signal transduction pathways, which induces breast cancer cell death,” said lead researcher Ratna B. Ray, Ph.D., a professor in the department of pathology at Saint Louis University (MO, USA; www.slu.edu). “This extract can be utilized as a dietary supplement for the prevention of breast cancer.” Results of this study were published in February 15, 2010, issue of Cancer Research, a journal of the American Association for Cancer Research. Previous research has shown bitter melon, to have hypoglycemic and hypolipidemic effects, according to Dr. Ray. Because of these effects, the extract is typically used in folk medicine as a remedy for diabetes, in regions such as India, China, and Central America, according to the researchers. Using human breast cancer cells and primary human mammary epithelial cells in vitro, Dr. Ray and colleagues found the mechanism of bitter melon extract significantly

decreased proliferation in cell growth and division, and induced death in breast cancer cells. These early results offer an encouraging path for research into breast cancer. “Breast cancer is a major killer among women around the world, and in that perspective, results from this study are quite significant,” said Rajesh Agarwal, Ph.D., professor in the department of pharmaceutical Sciences at the University of Colorado, Denver School of Pharmacy (USA; www.uchsc.edu/sop). “This study may provide us with one more agent as an extract that could be used against breast cancer if additional studies hold true.” According to Dr. Agarwal, the Cancer Research associate editor for this study, the simple study design, clear-cut results, and the overall importance of these findings in breast cancer prevention makes this research different from earlier research. However, he stressed, “This study is only a step towards establishing the cancer preventive efficacy of bitter melon against breast cancer.” Additional research is needed to understand better the molecular targets of bitter melon extract in cancer cells, as well as for establishing its in vivo efficacy. Dr. Agarwal gave a note of caution, stating that while these results do provide hope as an anti-

cancer agent, it is important to establish the validity of these results in animal models before adding them to one’s diet to inhibit breast-cancer cell growth. Dr. Ray and colleagues are currently conducting follow-up studies using a number of cancer cell lines to examine the antiproliferative effect of the extract. They are also planning a preclinical trial to assess its chemopreventive efficacy by oral administration. Bitter melon extract is cultivated in Asia, Africa, and South America. Extract of this vegetable is being popularized as a dietary supplement in Western Countries, since it is known to contain additional glycosides such as mormordin, vitamin C, carotenoids, flavanoids, and polyphenols.

Image: Close up of bitter melon (Momordica charantia) fruit on a tree (Photo courtesy of Adrian Thomas / SPL).

VISIT US AT

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ANNUAL MEETING Booth: 2338

Biomedical Research Consortium for Regenerative Medicine Under Construction new US$126 million, 13,536-m2 biomedical research “collaboratory” will pursue joint projects by its members and collaboration partners to invent tools and technologies intended to advance research into stem cells, and to discover and develop innovative diagnostics and therapies. The Sanford Consortium for Regenerative Medicine (www.sanford consortium.org), a consortium of four world leaders in life sciences research (the Salk Institute for Biological Studies, The Scripps Research Institute (La Jolla, CA, USA), Sanford-Burnham Medical Research Institute (La Jolla), and the University of California, San Diego, hosted an official groundbreaking ceremony on March 26, 2010, in La Jolla, CA, USA. The consortium, formed in 2006 to build and operate the biomedical research laboratory, consists of these four leading medical institutions – all internationally known for their exceptional contributions to medical research and treatments.

Bio Research International July-August/2010

The Sanford Consortium for Regenerative Medicine will be a preeminent research center to develop the next generation of breakthrough cures, therapies, diagnostics, research tools, and technologies in stem cell research. The consortium’s key research focuses on stem cell growth and differentiation, neuroscience, cardiovascular biology, blood cell development, and vision science. The Sanford Consortium for Regenerative Medicine is designed as one of the most forward-thinking laboratories, effectively fostering informal collaboration and communication among researchers in a synergistic environment. Shared two-story break rooms interconnect all levels and encourage interaction among researchers. Approximately 330 investigators and associated staff will occupy the open labs, offices, and specialized core labs. Conference facilities include a 150-seat auditorium, large divisible conference room and a café. LINKXPRESS COM

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ALUMINUM HEAT SEALS

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Porvair Sciences

Sartorius Stedim Biotech

Seward

MALDI MASS SPECTROMETER

The range of aluminum heat seals is designed for PCR, storage, and life science applications. The four new foils are color-coded and marked to ensure proper use, and offer very easy piercing by robotic liquid handling equipment or pipette tips.

The Sartocon ECO series of ultrafilters features high stability under alkaline conditions and over wide temperature ranges. The reusable filters are intended for use in purification processes for the manufacture of vaccines and monoclonal antibodies.

The Simplette Straws feature universal fit and are designed for use with fixed- or variable-volume pipette handsets. The Straws offer an inexpensive alternative to graduated pipettes for various sample-handling applications.

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Low Molecular Weight Drug Blocks Action of Lymphoma Oncogene ancer researchers have designed a low molecular weight drug that blocks the activity of BCL6, the protein product of the oncogene that is the most commonly involved in B cell lymphomas. BCL6 is the most commonly involved oncogene in B cell lymphomas. Depletion or blockade of BCL6 potently kills lymphoma cells in tissue culture, and BCL6 is thus a critical therapeutic target. Like many oncogenes and tumor suppressors, BCL6 is a transcription factor. Investigators at the Weill Cornell Medical College (New York, NY, USA; www.med.cornell. edu) used an integrated biochemical and computational approach to identify small molecules that could specifically disrupt the activity of BCL6 by blocking its interaction with its corepressors BCOR, N-CoR, and SMRT. The investigators reported in the April 13, 2010,

issue of the journal Cancer Cell that they had identified a low-molecular-weight drug that bound to the corepressor binding groove of the BCL6 BTB domain. This compound disrupted BCL6/corepressor complexes in vitro and in vivo, and it was observed by X-ray crystallography and NMR to bind to the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive lymphoma cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed lymphoma tumors in vivo. The compound also killed primary lymphomas from human patients. “Our results show that given the right scientific approach it is quite possible to design drugs against key protein regulatory factors like BCL6,” said Dr. Melnick. “The BCL6 inhibitor was specific for BCL6 and did not block other master regulators. This means that if given as a therapeutic

agent, the compound would be unlikely to have ill effects on healthy normal cells, and therefore would not be expected to have significant side effects. Since emerging data implicates BCL6 in other tumor types in addition to non-Hodgkin's lymphoma, it is possible that BCL6-targeted therapy could benefit many other cancer patients.” Image: Light micrograph of a section through a lymph node of a patient with diffuse B-cell non-Hodgkin’s lymphoma (Photo courtesy of Kemeny, ISM).

New Microarray Technology Enables Sequencing of Neanderthal DNA y utilizing an advanced DNA capture technique, genomic researchers have succeeding in mapping a portion of the Neanderthal genome and comparing it to that of modern humans. Investigators at the Max Planck Institute (Munich, Germany; www.mpg.de), Cold Spring Harbor Laboratory (Cold Spring Harbor, NY, USA; www.cshl.edu), and Agilent Technologies, Inc. (Santa Clara, CA, USA; www.agilent.com) used Agilent’s microarray system to sequence nearly 14,000 protein-coding positions inferred to have changed on the human lineage since the last common ancestor shared with chimpanzees. Generally, it has been extremely difficult to work with ancient DNA due in part to chemical aging of the DNA molecules but even more so due to severe bacterial contamination of the samples. Now, in a study published in the May 7, 2010, issue of the journal Science, investigators from the three institutions described the use of array-hybridization capture

technology, a process that enriched Neanderthal DNA sequences while depleting contaminant DNA. Thus, they were able to enrich Neanderthal proteincoding regions where differences occurred on the human evolutionary lineage up to 190,000-fold. By generating the sequence of one Neanderthal and 50 present-day humans, the investigators identified 88 amino acid substitutions that have become fixed in humans since our divergence from the Neanderthals. “Attaining good coverage of the Neanderthal genome had been a problem due to DNA contamination from microbes over the years,” said senior investigator Dr. Svante Paabo, professor of evolutionary genetics at the Max Planck Institute. “Simply sequencing, without first enriching for the genome, often did not work, especially where the contamination levels were high. Array-hybridization capture technology was originally reported by the Cold Spring Harbor Laboratory group and is the subject of a longstanding collaboration with Agilent.

The team recognized this as a promising method for recovering large regions of targeted sequence from Neanderthal samples. The method can also be used more widely with many other kinds of human remains.” In a second article in the same issue of Science, the investigators presented their first detailed analysis of the draft sequence of the Neanderthal genome, which now includes more than three billion nucleotides collected from the bones of three female Neanderthals who lived in Croatia more than 38,000 years ago. By comparing this composite Neanderthal genome with the complete genomes of five living humans from different parts of the world, the investigators found that both Europeans and Asians share 1% - 4% of their nuclear DNA with Neanderthals, but that Africans do not. This suggests that early modern humans interbred with Neanderthals after moderns left Africa, but before they spread into Asia and Europe. Bio Research International July-August/2010

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Bio Research International

French Team Identifies Antidote for Ricin Toxin large team of French researchers has discovered two low molecular weight compounds that block the action of ricin, a highly toxic protein often mentioned as a possible bioterror weapon. Ricin comprises two subunits, the A-chain and the B-chain, which are linked by a disulphide bond. The Bchain facilitates cell entry and intracellular transport, and it is reductively cleaved to free the A-chain, which inactivates ribosomes and shuts down protein synthesis. A French team, headed by investigators at the Centre National de la Recherche Scientifique (Paris, France; www.cnrs.fr) used a cellbased assay system to screen over 16,000 compounds for the ability to block the intracellular transport of

ricin toxins. They reported in the April 16, 2010, online edition of the journal Cell that they had identified two compounds, Retro-1 and Retro-2 that were able to inhibit the retrograde transport route of ricin from the plasma membrane to the endoplasmic reticulum. Unlike other compounds that are known to block retrograde transport, Retro-1 and Retro-2 did not affect other intracellular trafficking and did not show any toxicity. In experiments in mice, Retro-2 was shown to block the activity of ricin, if it were given prior to the toxin. It is expected that these compounds should also inhibit other toxic proteins such as the Shiga-like toxins produced by pathogens such as E. coli, Shigella, and V. cholerae.

Image: Molecular model of the secondary structure of interleukin-10, a small protein known as a cytokine that plays an important regulatory role in the body’s immune system (Photo courtesy of Dr. Mark J. Winter / SPL).

High-Content Cell Screening Service Now Available on a Contract Basis contract high-content cell screening service has been launched that will benefit researchers investigating various biological phenomena – including the cell cycle, RNAi profiling, angiogenesis, and signal pathway profiling. High-content screening is the analysis of fluorescent cellular markers to measure multiple responses to biological stimuli or drug treatment. It has wide applications in drug discovery covering everything from target identification through to preclinical toxicology. To provide this type of screening for the general research community TTP LabTech (Melbourn, United Kingdom; www.ttplabtech.com) is now making its Acumen microplate cytometer available on a contract basis. The Acumen is a unique laser scanning cytometer containing three lasers, 405 nm, 488 nm, and 633 nm, which ensure compatibility with a wide variety of fluorescent probes. The instrument operates by scanning a laser through a wide field of view lens across the bottom of a microplate or slide. The speed of data acquisition is not affected by plate density and microplate types ranging from 24-well up to 3456-well (or four microscope slides) can all be rapidly analyzed. Scanning resolutions may be set to as low as 0.5 µ where very detailed, or small object analysis is required. The lasers fire sequentially to reduce crosstalk and give simultaneous detection in four photomultiplier tube (PMT) detectors, providing a maxi-

Bio Research International July-August/2010

mum of 12 channels of content-rich data for true multiplexing at high throughputs. Acumen's maximum scanning resolution is equivalent to that achieved using a 20x microscope objective. Acumen’s patented approach to data analysis employs cytometric principles, rather than image analysis. The lasers scan the entire field of view collecting intensity readings at regular intervals using the four PMTs. Thresholding algorithms identify all fluorescent intensities above the solution background for automatic object identification. Laser scanning data collection combined with cytometric data analysis generates extremely fast and robust results. TTP LabTech is now offering contract screening that will allow its clients to apply this expertise to new and demanding applications to support the drug discovery process. “As the inventors of the Acumen, we have extensive experience in the use of this instrument for high-content screening and so we are well placed to apply its capabilities on behalf of our clients,” said Dr. Philip Blenkinsop, managing director of TTP LabTech. “In the past, prospective clients seeking direct access to high-content data have often asked us whether we can combine our in-house biology expertise with the latest lab tools to provide a complete package. We now feel that the time is right to introduce such a service to augment our existing product business.” LINKXPRESS COM

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Glioblastoma Growth Inhibitor Readily Passes Blood-Brain Barrier low molecular weight drug that inhibits the cyclin-dependent kinases 4 and 6 (cdk4/6) has been shown to prevent the growth of glioblastoma brain cancer cells both in vitro and in a mouse model. While the drug, PD-0332991, is currently being evaluated in clinical trials for otherwise untreatable teratomas as well as multiple myeloma and breast cancer, the current report is the first on its potential effectiveness against glioblastoma. Investigators at the University of California, San Francisco (USA; www.ucsf.edu) and Georgetown University (Washington, DC, USA; www. georgetown.edu) tested the drug on 21 different cell cultures derived from the tumors of patients with glioblastoma. They reported in the March 30, 2010, online edition of the journal Cancer Research, that 16 of the cultures stopped growing. The remaining five, all of which lacked the gene for the tumor-suppressor protein retinoblastoma (Rb), were not affected by the drug. In the animal experiment, the investigators

Image: Fluorescence deconvolution micrograph of cultured microglial cells from a glioblastoma in the brain, showing the typical large number of mitochondria (Photo R. Bick, B. Poindexter, UT Medical School).

implanted three different strains of human glioblastoma directly into the brains of mice, which were then treated with PD-0332991. Results indicated that the drug effectively reached the intracranial tumors, and that the tumors did not grow as long as the mice continued to receive the drug. However, the animals quickly succumbed to the cancer if drug treatment was stopped. “What is especially encouraging about this agent is that we found it can easily pass through the blood-brain barrier and access glioblastoma, and that there is already a simple test available for screening glioblastoma patients in advance to see whether or not they should be responsive to this therapy,” said contributing author Dr. C. David James, professor of neurological surgery at the University of California, San Francisco. “We do not know how well this agent will perform in patients with glioblastoma, but in the mice we studied, we saw very impressive, durable effect that was sustained as long as therapy was administered.”

Macroketone Blocks Metastasis in Mouse Model ancer researchers have synthesized a potent analogue of a naturally occurring compound that prevents most tumor metastasis in a mouse model. Investigators at Weill Cornell Medical College (New York, NY, USA; www.med.cornell.edu) have been working for several years with migrastatin, a natural product secreted by Streptomyces bacteria. While migrastatin has only weak antimetastasis activity, synthetic analogues of this compound such as macroketone are much more effective inhibitors of tumor cell migration, invasion, and metastasis. Results published in the April 15, 2010, online edition of the journal Nature revealed that mice implanted with tumor cells and then treated with macroketone did not die of metastatic cancer, while

untreated animals did. In experiments where animals were treated a week following tumor transplantation, 80% of the treated animals survived. Macroketone did not prevent implanted cancer cells from forming tumors or from growing, but it did stop tumor cells from spreading. This was true even when macroketone was given after tumors had already formed. At the molecular level, the action of macroketone was shown to be through its specific binding to the actin-binding site on the cytoskeleton protein fascin. This binding disrupted the mechanism used by the cancer cells to move. “This suggests to us that an agent like macroketone could be used to both prevent cancer spread and to treat it as well,” said senior author Dr. XinYun Huang, professor of physiology and biophysics

at Weill Cornell Medical College. “Of course, because it has no effect on the growth of a primary tumor, such a drug would have to be combined with other anticancer therapies acting on tumor cell growth. The beauty of this approach is that fascin is overexpressed in metastatic tumor cells but is only expressed at a very low level in normal epithelial cells, so a treatment that attacks fascin will have comparatively little effect on normal cells – unlike traditional chemotherapy which attacks all dividing cells.” “More than 90% of cancer patients die because their cancer has spread, so we desperately need a way to stop this metastasis,” said Dr. Huang. “This study offers a paradigm shift in thinking and, potentially, a new direction in treatment.” Bio Research International July-August/2010

Internet Tool Predicts Relationship Between Mutation and Disease enomic researchers have established a broad database that relates amino acid substitutions (AAS) in proteins caused by mutations with the development and severity of diseases and disease syndromes. Investigators at the Buck Institute for Age Research (Novato, CA, USA; www.buckinstitute.org) analyzed nearly 40,000 AAS in what grew to become one of the most comprehensive studies of mutations. With this data, they compiled datasets of human disease-associated AAS in the contexts of inherited monogenic disease, complex disease, functional polymorphisms with no known disease association, and somatic mutations in cancer, and compared them with respect to predicted functional sites in proteins. A detailed description of the research was published in the January 5, 2010, online edition of the journal Human Mutation. "We now have a quantitative model of function using bioinformatic methods that can predict things like the stability of the protein and how its stability is disrupted when a mutation occurs," said senior author Dr. Sean Mooney, associate professor bioinformatics at the Buck Institute for Age Research. "Traditionally people have used a very time consuming process based on evolutionary information about protein structure to predict molecular activity. I think we are the first group to really quantitatively describe the universe of molecular functions that cause human genetic disease." To facilitate such collaboration the investigators have made public on the Internet a tool designed to enhance the functional profiling of novel AAS. The tool can be accessed at www.mutdb.org/profile.

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Label-Free Screening Available for Standard Microtiter Plate Readers high performance set of label-free screening tools based on surface plasmon resonance (SPR) technology that does not require expensive special equipment is now available to researchers and drug developers. The technology, represented by the PharmaDiagnostics (Zellik, Belgium; www.pharmadiagnostics. com) SoPRano line of reagents, is based on ligand-coated colloidal gold nanoparticles. A major advance is that these reagents can be used in standard 96-well microtiter plates and read on the plate readers already found in most biotechnology laboratories. The reagents are complemented by easy-to-use protocols and are applicable to a wide range of assays for both small molecule and antibody screening and characterization. “With SoPRano, PharmaDiagnostics is providing label-free screening for a much broader range of researchers,” said Dr. David Ricketts, CEO of PharmaDiagnostics. “Early customer feedback has been extremely positive. This product launch and our new corporate website and online SoPRano facility demonstrate PharmaDiagnostics' commitment to develop and enhance SoPRano and bring our customers real value. After our recent USD 3.5 million fundraising, the launch of SoPRano is another significant step forward in the development of PharmaDiagnostics' business.”

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Aging Gene Could Help Modify Immunity in Humans cientists have discovered that study of a gene called DAF-16, which is found in many animals, including humans, could provide new ways for altering aging, immunity, and resistance in humans. DAF-16 is strongly involved in determining the rate of aging and average lifespan of the nematode (roundworm) Caenorhabditis elegans and its close evolutionary cousins. Dr. Robin May, from the University of Birmingham (UK; www.bham.ac.uk), and the lead researcher of the study, said, “Aging is a process that all organisms experience, but at very different rates. We know that, even between closely related species, average life spans can vary enormously. We wanted to find out how normal aging is being governed by genes and what effect these genes have on other traits, such as immunity. We looked at a gene that we already knew to be involved in the aging process, called DAF-16, to see how it may determine the different rates of aging in different species.”

Dr. May and colleagues compared longevity, stress resistance, and immunity in four related species of the nematode. They also looked for differences in the activity of DAF-16 in each of the four species and discovered that they were all quite distinct in this respect. Moreover, importantly, the differences in DAF-16 corresponded to differences in longevity, stress resistance, and immunity between the four species-in general higher levels of DAF-16 activity correlated with longer life, increased stress resistance, and better immunity against some infections. Dr. May continued, “DAF-16 is part of a group of genes that drive the biologic processes involved in aging, immunity and responses to physical or environmental stresses. The fact that subtle differences in DAF-16 between species seem to have such an impact on aging and health is very interesting and may explain how differences in lifespan

and related traits have arisen during evolution.” The researchers are now examining the way in which DAF-16 coordinates a complex network of genes in order to balance the differing needs of an individual’s immune system over time. The research was published the April 2010 issue of the journal PLoS ONE. Image: Light micrograph of Caenorhabditis elegans, a millimeter long, soil-dwelling nematode worm which feeds on bacteria (Photo courtesy of Sinclair Stammers / SPL).

MicroRNA Profiling Kits Facilitate Drug Toxicity Studies rug developers will benefit from a newly available highly predictive, relatively simple, and cost-effective way to monitor the toxicity profile of a test compound. The objective of a drug developer is to assess toxicology early in the preclinical discovery process, and generate optimized structures with a risk profile that can be advanced into in vivo safety assessment with a reasonable expectation of success. The Scottish company Sistemic (Glasgow, United Kingdom; www.sistemic.co.uk) offers a highly predictive, relatively simple, and costeffective way to monitor the toxicity profile of a test compound. Sistemic’s “SystemRNA” kits are directed at key therapeutic areas including oncology and inflammation where results they produce will enable better strategic decision making at

critical stages of the drug discovery and development process. The “SistemRNA” platform uses human cells and it is based on changes in the level of microRNA expression upon exposure of the cells to candidate drug compounds. There are only several hundred microRNAs expressed in a cell, whose expression pattern may change after exposure to a bioactive compound. The microRNA response is reproducible, characteristic of compound type, and is a robust early sentinel marker defining the biological interaction between compound and cell. The benefit of “SistemRNA” is that with microRNA profiling, pathway control of the entire biological system of the cell can be analyzed in one assay. Data is kept to a minimum whereas knowledge is greatly enhanced allowing more

appropriate decisions to be taken on compound development. “The validity of our use of microRNA profiling as a sentinel marker of phenotypic effects in model systems is overwhelming, and we are seeing time and time again very strong correlations between microRNA changes and drug effects,” said Dr. Vincent O'Brien, chief scientific officer at Sistemic. Dr. Chris Hillier, CEO of Sistemic, said, “The strength of Sistemic’s approach is that we provide an extremely reliable way to make key decisions on safety and efficacy based on very strong biological information about the properties of your compound without reference to the expected target. This lack of bias produces valuable evidence to support drug development and has the power to create some very exciting opportunities.” Bio Research International July-August/2010

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Technique May Improve Availability of Donor Organs new technique that uses gene therapy to help repair damaged lungs previously found unsuitable for transplant shows promise for addressing the significant shortage of healthy donor organs. Recent research on interleukin10 (IL-10) gene therapy was presented April 21, 2010, during the International Society for Heart and Lung Transplantation's (ISHLT) 30th annual meeting and Scientific Sessions in Chicago, IL, USA. More than 80% of potential donor lungs cannot be used for transplantation because the organs are damaged either before or during the transplant process. The IL10 gene therapy could potentially increase the viability of those donor lungs. IL-10 is an antiinflammatory cytokine. This protein down-regulates, or decreases, the inflammatory potential of injured cells. It also has the capacity to inhibit the recipient’s immune system that rejects the transplanted organ. The IL-10 gene is found normally in animal and human cells, and plays a role in suppressing the immune response to infection and the rejection response to foreign materials such as transplanted organs. “This type of therapy could ultimately have a great impact on lung

transplantation around the world,” said Shaf Keshavjee, M.D., from the University of Toronto (Canada; www.utoronto.ca), who presented the findings at the ISHLT symposium. Dr. Keshavjee and his team of researchers have focused on IL-10 because the protein protects against inflammatory injury as well as immune therapy. This new approach has successfully reduced inflammation and improved function in pig lungs that were treated outside the body and transplanted into recipient pigs. The same approach has brought about a similar improvement in human donor lungs deemed unsuitable for transplantation. This genetic technique could also be used to deliver other gene products to the lungs and might eventually be used to repair damaged lungs in a living patient. The International Society for Heart and Lung Transplantation (ISHLT) is a not-for-profit organization dedicated to the advancement of the science and treatment of end-stage heart and lung diseases. The Society now includes more than 2,200 members from 45-plus countries, representing a variety of disciplines involved in the management and treatment of end-stage heart and lung disease.

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Nanovaccine Suppresses Autoimmune Response in Diabetic Mouse Model anoparticles coated with specific immune markers have been used to prevent and cure diabetes in a mouse model of the disease. Investigators at the University of Calgary (Alberta, Canada; www.ucalgary.ca) created a novel class of nanoparticles coated with a complex of diabetes-related peptide antigens bound to major histocompatibility complexes (pMHC-NP). This nanoparticle vaccine was designed to stimulate a specific immune response that would inhibit autoimmune T cells that in diabetes attack and destroy insulin-producing pancreatic beta cells. The stimulation was specific to the extent that only these T cells were affected while the integrity of the remainder of the immune response system was not. Results published in the April 8, 2010, online edition of the journal Immunity revealed that treatment of NOD mice with the nanoparticles suppressed the recruitment of anti-

beta T cells, prevented the disease in prediabetic mice, and restored normal blood sugar levels in diabetic animals. “Essentially there is an internal tugof-war between aggressive T cells that want to cause the disease and weaker T cells that want to stop it from occurring," said senior author Dr. Pere Santamaria, professor of microbiology and infectious diseases at the University of Calgary. “If the paradigm on which this nanovaccine is based holds true in other chronic autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and others, nanovaccines might find general applicability in autoimmunity.” The nanoparticle vaccine technology used in this study has been licensed by Parvus Therapeutics, Inc. (Calgary, Alberta, Canada; www. parvustherapeutics.com) a biotechnology transfer and commercialization company belonging to the University of Calgary.

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Effect of Estrogen on Mammary Stem Cells Directly Linked to Breast Cancer Risk tudies on breast cancer in a mouse model have shown that despite lacking estrogen and progesterone receptors mammary stem cells are highly responsive to steroid hormone signaling, a finding that opens the way for the development of new preventions and treatments for the disease. Previous studies have established a strong linkage between female hormone levels and breast cancer, with mutations in mammary stem cells being the likely source of breast cancer cells. In the current study, published in the April 11, 2010, online edition of the journal Nature, investigators at the Walter and Eliza Hall Institute (Parkville, Victoria, Australia; www.wehi. edu.au) showed in a mouse model

that removal of the ovaries or treatment with hormone inhibitors reduced breast stem cell numbers and induced a state of dormancy in these cells. In contrast, pregnancy led to a transient 11-fold increase in breast stem cell numbers, probably mediated through signaling via the RANK ligand pathway. The augmented breast stem cell pool indicated a cellular basis for the shortterm increase in breast cancer incidence that accompanies pregnancy. “There is clear evidence that the more menstrual cycles a woman has the greater her breast cancer risk,” said senior author Dr. Jane Visvader, associate professor of molecular genetics at the Walter and Eliza Hall Institute. “There is

even an increase in breast cancer risk in the short-term following pregnancy. However the cellular basis for these observations has been poorly understood.” Overall, the findings generated in this study suggest that successful chemical treatment to prevent

development of breast cancer may be achieved, in part, through suppression of stem breast-cell function. Image: Colored scanning electron micrograph (SEM) of breast cancer cells (Photo courtesy of Steve Gschmeissner / SPL).

Clustered T Cell Antigens on Carbon Nanotubes Enhance Adoptive Immunotherapy he use of nanotubes coated with specific T cell antigens reduced by nearly one-third the time required to enrich the blood culture of patients undergoing adoptive immunotherapy with cancerfighting antitumor specific T cells. Adoptive immunotherapy is a cancer treatment protocol based on extracting a patient's blood in order to increase the number of anticancer T cells, the growth of which is often suppressed by the tumor so that they are too few to be effective. Different growth factors are used to boost the production of T cells outside the body. Once enough T cells have been produced, the blood is transferred back into the patient's body. In this regard, investigators at Yale University

(New Haven, CT, USA; www.yale.edu) used a type of carbon nanotube to stimulate in vitro T cell production. They reported in the April 20, 2010, issue of the journal Langmuir that functionalized single-walled carbon nanotube bundles (fbSWNT) coated with T cell-stimulating antibodies enhanced both the kinetics and magnitude of T cell stimulation as compared to the same concentration of free antibodies in solution. This enhancement was unique to f-bSWNT compared to other artificial substrates with high surface area and similar chemistry. The investigators used FRET (Fluorescence Resonance Energy Transfer) microscopy to show that enhanced T cell production was the result of

the preferential formation of large antibody stimuli clusters on the surface of functionalized versus untreated nanotubes. “Carbon nanotube bundles resemble a lymph node microenvironment, which has a labyrinth sort of geometry,” explained senior author Dr. Tarek Fahmy, associate professor of chemical engineering and biomedical engineering at Yale University. “The nanotube bundles seem to mimic the physiology and adsorb more antigens, promoting a greater immunological response.” “We think this is a really interesting use of carbon nanotubes,” said Dr. Fahmy. “It is a way to exploit the unique properties of this material for biological application in a safe way. Bio Research International July-August/2010

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Novel Protein Technology Triggers Rapid Bone Growth protein involved in tissue growth in animals such as salamanders, zebrafish, and mice can also stimulate the regeneration of damaged human bone, according to a new study. Researchers at the Stanford University School of Medicine (CT, USA; med.stanford.edu) stimulated the rapid bone growth in laboratory mice by injecting them with a protein called Wnt, packaged in a form that could be used in humans, opening the door to additional experiments to heal skin, muscle, brain, and other tissue injuries. It may also eventually provide a much-needed alternative to currently available drugs based on bone morphogenetic proteins (BMPs), which are approved for use in humans to speed bone growth in spinal fusions and long bone fractures, but have become increasingly associated with a number of adverse side effects. Wnt, a key player in tissue regeneration in many organisms, was exceedingly difficult to purify in an active form and, once isolated, was found to be both insoluble and hydrophobic. The researchers at Stanford succeeded in overcoming this problem by using liposomes – tiny, hydrophilic molecular bubbles. The researchers planted laboratory-made Wnt on the liposomes bubble’s outer surface, thus allowing it to be suspended in liquid for delivery into the body. To test the delivery method, the researchers drilled one-millimeter holes into the leg bones of the mice with a high-speed dental drill. They then injected the Wnt-covered liposomes at the site of the damage and compared the rate and pattern of bone formation with that of control animals, and with that of animals injected with Wnt without a liposomal escort. The researchers found that within three days, the animals who had received Wnt had 3.5 times more new bone than the other two groups; and after 28 days, the newly formed bone had completely healed, while the control animals were still in the process of repairing the injury. Further investigation showed that Wnt works by increasing the proliferation of bone progenitor cells, which then became new bone, mimicking the way Wnt-activated healing occurs naturally. Laboratory mice that had been genetically modified to have a more prolonged Wnt signal also healed more quickly than did control mice, and as in other animals, the Wnt pathway was found to be activated in response to injury and required for normal healing. The study was published in the April 28, 2010, online issue of the journal Science Translational Medicine. “We believe our strategy has the therapeutic potential to accelerate and improve tissue healing in a variety of contexts,” said lead author professor of surgery Jill Helms, D.D.S., Ph.D. “After stroke and heart attack we heal the injuries slowly and imperfectly, and the resulting scar tissue lacks functionality. Using Wnt may one day allow us to regenerate tissue without scarring.”

Bio Research International July-August/2010

Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-tocell interactions during embryogenesis. Insights into the mechanisms of Wnt action have emerged from several systems: genetics in Drosophila and Caenorhabditis elegans, ectopic gene expression in Xenopus embryos, and biochemistry in cell cultures. Mutations in Wnt genes or Wnt pathway components lead to specific developmental defects, while various human diseases, including cancer, are caused by abnormal Wnt signaling.

Image: Light micrograph of a section through a growing bone, showing cartilage cells (blue) being replaced by bone (purple) formed from osteoblast cells (Photo courtesy of Steve Gschmeissner / SPL).

Bio Research International

Real-Time Cell Analysis System Provides Data on Drug Cytotoxicity rug developers now have access to analytical systems that allow for real time determinations of the effects of candidate drugs on cell viability. An important facet of drug development is to understand how a candidate drug compound affects the molecular and biochemical pathways that regulate cell viability. The other side of the same coin is the need to identify potential cytotoxic side effects of potential therapeutic agents. To provide a means for collecting critical information on drug cytotoxicity, one of the worldâ&#x20AC;&#x2122;s largest biotech companies Roche (Basel, Switzerland; www.roche.com), has introduced its xCELLigence System real time cell viability monitoring system. Roche is a world leader in in-vitro diagnostics, tissue-based cancer diagnostics, and a pioneer in diabetes management with a catalogue of differentiated medicines in oncology, virology, inflammation, metabolism, and central nervous system disorders. The xCELLigence System allows for real-time, label-free dynamic monitoring of cellular phenotypic changes by measuring electrical impedance. The system measures impedance using interdigitated microelectrodes integrated into the bottom of each well of the tissue culture E-Plates 96. Impedance measurements are displayed as Cell Index (CI) values, providing quantitative information about the biological status of the cells, including cell number, cell viability and cell morphology. Electronic impedance of the microelectrodes is mainly determined by the ionic environment in the regions

around the electrodes and can be monitored as baseline impedance by applying an electrical field to the electrodes. The presence of the cells will affect the local ionic environment at the electrode/solution interface, leading to an increase in the electrode impedance. The more cells there are on the electrodes, the larger the increases in electrode impedance. In addition, the impedance change depends on the quality of the cell interaction with the electrodes. For example, increased cell adhesion or spreading will lead to a larger change in electrode impedance. Thus, electrode impedance, which is displayed as cell index (CI) values, can be used to monitor cell viability, number, morphology, and adhesion degree in a number of cell-based assays. CI was derived as a relative change in measured electrical impedance to represent cell status. This means that when cells are not present or are not well adhered on the electrodes then the CI is zero. Under the same physiological conditions, when more cells are attached on the electrodes, then the CI values are larger. Thus, CI is a quantitative measure of cell number present in a well of the microplate. Additionally, change in a cell status, such as cell morphology, cell adhesion, or cell viability will lead to a change in CI. In addition to monitoring cell viability, the xCELLigence System is able to identify culture wells with inappropriate cell numbers at the beginning of the assay, thus minimizing the role of cell seeding and culture-plate edge artifacts during data analysis.

INDUSTRY NEWS

ZyGEM to Commercialize DNA Detection and Testing Platform yGEM Corp. Ltd. (Hamilton, New Zealand; and Solana Beach, CA, USA; www.zygem.com) has acquired MicroLab Diagnostics Inc. (http:// microlabdiagnostics.com), a private company developing microfluidic devices for rapid DNA testing. ZyGEM will market products integrating its DNA extraction, reagents, and detection assays with microfluidic chip technology developed by MicroLab, which will operate as a business unit of the new company. MicroLab's miniaturization of the entire DNA testing process within a single closed system significantly reduces the amount of sample and reagents that are needed, while virtually eliminating the chances for handling error or contamination. The integrated new products will dramatically decrease the time, complexity, and cost of conducting DNA testing and have transformational potential in a broad range of applications. The ZyGEM/MicroLab system is compact, easyto-use, and cost-effective, making it suitable for use both in the laboratory and out in the field. It can perform multiplexed analyses, and it can also be configured for specific applications. Portable handheld versions are in development.

Partnership to Research Novel Image-Guided Therapy Concepts based on RNAi hilips Healthcare (Best, The Netherlands; www.medical.philips.com) and RXi Pharmaceuticals Corp. (Worcester, MA, USA; www. rxipharma.com), a biopharmaceutical company, announced that they have entered into a joint research agreement to study the benefits of combining proprietary technologies from both companies for the targeted delivery of experimental therapeutics based on RNA interference (RNAi). Compounds based on RNAi represent a promising new class of drugs for the targeted treatment of a number of diseases including cancer and cardiovascular disease. Currently, however, one of the greatest challenges in developing RNAi-based therapeutics is finding ways to deliver them to their target while keeping them fully active. The joint research program between Philips and RXi will address this challenge by examining, in preclinical studies, the possibility of using RXi’s sd-rxRNA (self-delivering rxRNA) in conjunction with Philips’ ultrasound technology to achieve the targeted delivery and monitoring of RNAi-based compounds in cells. Each company will contribute proprietary technologies, resources, and expertise to evaluate innovative approaches for the targeted delivery of RXi’s sd-rxRNA compounds in appropriate preclinical models using ultrasound-mediated drug delivery under image guidance. The preparation and research will be conducted at Philips’ Life Tech research facilities at the High Tech Campus in Eindhoven (The Netherlands), which are focused on R&D at the interface of life sciences and medical technologies, and at RXi’s research and development facilities in Worcester.

Bio Research International July-August/2010

Merge Healthcare Selected as e-Trials Technology Transfer Service Provider erge Healthcare (Milwaukee, WI, USA; www.merge.com), a health information technology (IT) solutions provider, reported that it was selected by Cato Research, Ltd. (Durham, NC, USA; www.cato.com) to provide the proprietary etrials EDC solution through Merge’s technology transfer program. This new agreement expands Merge’s partnership with Cato to provide additional technology for clinical trials management, as well as extending the relationship for an additional five years. “We have enjoyed a long-standing partnership with Merge Healthcare for their clinical trial solutions,” noted Allen Cato, M.D., Ph.D., and CEO of Cato Research, Ltd. “The etrials technology has been consistent and intuitive, and the Merge team has been quick to help us use it successfully. Adding the etrials EDC platform in a technology transfer model will enable our company to efficiently build and deliver solutions to help our customers run cost-effective clinical studies.”

The technology transfer program allows Cato to use the etrials EDC system to build and deploy custom clinical trial studies that leverage the powerful reporting capabilities of Merge’s technology. Because the etrials EDC solution is built on a SaaS platform, it can be licensed on a subscription or study basis. Moreover, Merge’s etrials IVR and ePRO solutions can be integrated with the EDC system to provide comprehensive eClinical solutions. Merge’s team of clinical trial experts will also provide training and support to Cato. “We are thrilled to partner with Cato to bring etrials EDC into their portfolio of clinical trial solutions,” said Justin Dearborn, Merge’s chief executive officer. “With our robust EDC offering, Cato will be able to deliver an easy-to-use solution to their clients. It is our goal to understand how our customers’ conduct business in order to deliver robust solutions that meet their long-term needs and allow for mutually beneficial partnerships like this one.”

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AUGUST 2010 The 24nd Annual Symposium of the Protein Society. August 1; San Diego, CA, USA; Web: www.proteinsociety.org Drug Discovery and Development Week. August 24. Burlingame, CA, USA; Web: www.drugdisc.com 9th Annual Mount Desert Island Stem Cell Symposium. August 6-7; Salisbury Cove, ME, USA; Web: www.mdibl.org ImVacs – CHI’s Immunotherapeutics & Vaccine Summit. August 17-19; Cambridge, MA, USA; Web: www.healthtech.com Mechanisms & Models of Cancer. August 17-21; Cold Spring Harbor, NY, USA; Web: http://meetings.cshl.edu World Biobanking Summit. August 24-25; Edinburgh, UK; Web: www.selectbiosciences.com Fall 2010 National Meeting and Exposition of the American Chemical Society. August 22-26; Boston, Massachusetts, USA; Web: www.acs.org Bioprocessing Summit. August 23-26; Boston, MA, USA; Web: www.healthtech.com Stem Cells Europe and Regenerative Medicine. August 24-25; Edinburgh, UK; Web: www.selectbiosciences.com CHI’s Next Generation Dx Summit. August 24-26; Washington DC, USA; Web: www.nextgenerationdx.com FIP 2010 - 70th World Congress of Pharmacy and Pharmaceutical Sciences 2010. August 28, September 2; Lisbon, Portugal; e-mail: congress@ fip.org; Web: www.fip.org BioProcess International China. August 30 – September 1; Beijing, China; Web: www.ibclifesciences.com

www.expressgenes.com 1st European Genomics - 2010 Meeting. September 20-21; Oxford, UK; Web: www.expressgenes.com German Conference on Bioinformatics 2010. September 20-22; Braunschweig, Germany; e-mail: contact@gcb2010.de ; Web: www.gcb2010.de MipTec 2010. September 20-24; Basel, Switzerland; e-mail: Sabine.Adam@congrex.com; Web: www. miptec.com Pharma CI Conference & Exhibtion. September 21-22; Parsippany, NJ, USA; e-mail: info@pharmaciconference.com; Web: www.pharmaciconference.com 2010 International Symposium on Drug Analysis. September 21-24; Antwerp, Belgium; Web: www.ldorganisation.com 36th Annual Symposium and Congress of the National Society for Histotechnology (NSH). September 24-29; Seattle, WA, USA; Web: www.nsh.org ASHI 36th Annual Meeting – American Scoiety for Histocompatibility & Immunogenetics. September 26-30; Hollywood, FL, USA; e-mail: info@ashi-hla.org; Web: www.ashi-hla.org 11th International Conference on Alzheimer’s Disease Drug Discovery. September 27-28; Jersey City, NJ, USA; Web: www.worldeventsforum.com Probe Discovery. September 28-29; Washington, DC, USA; Web: www.selectbiosciences.com Biotech Forum: Biotech & Medtech Partnering. September 28-30; Copenhagen, Denmark; Web: www.biotechforum.org BIOSPAIN 2010. September 29- October 1; Pamplona, Spain; Web: www.biospain2010.org

SEPTEMBER 2010 Drug Discovery 2010. September 1-2; Ricoh arena, Coventry, UK; Web: www.elrig.org 2010 European Molecular Biology Laboratory (EMBO) Meeting. September 4-7; Barcelona, Spain; Web: www.the-embo-meeting.org 9th International Society for the Study of Xenobiotics (ISSX) Meeting. September 4-8; Istanbul, Turkey; Web: www.issx.org EFMC-ISMC 2010 21st International Symposium on Medicinal Chemistry. September 5-9; Brussels, Belgium; Web:www.ldorganisation.com British Human Genetics Conference – The British Society for Human Genetics (BSHG). September 6-8; Warwick (Coventry), UK; Web: www.bshg.org.uk 14th Workshop of the International Study Group for Systems Biology. September 6-10; Vladimir, Russia; Web: http://isgsb2010.org ISEH 39th Annual Scientific Meeting – Society for Hematology and Stem Cells. September 9-12; Melbourne, Australia; Web: www.iseh.org 39th Annual Meeting of the American College of Clinical Pharmacology. September 12-14; Baltimore, MD, USA; Web: www.accp1.org ADAPT 2010 – Accelerating Development & Advancing Personalized Therapy. September 13-16; Arlington, VA, USA; Web: www. adaptcongress.com RNAi Europe. September 14-15. Dublin,Ireland; Web: www.selectbiosciences.com Epigenetics Europe. September 14-15; Dublin, Ireland; Web: www.selectbiosciences.com Advances in qPCR. September 14-15; Dublin, Ireland; web: www.selectbiosciences.com World Drug Safety Congress Europe 2010; September 14-17; London. UK; Web: www. terrapinn.com AMATA 2010 Conference: September 14-17; Hobart,Tazmania, Australia; Web: www.amata.org.au BioPharm America 2010. September 15-17; Boston, MA, USA; Web: www.ebdgroup.com Analytica – China. September 15-17; Shanghai, China; Web: www.analyticachina.com HUPO 2010 – 9th Human Proteome Organization World Congress. September 19-24; Sydney, NSW, Australia; Web: www.hupo2010.com 1st European Neurodegenerative Diseases - 2010 Meeting. September 20-21; Oxford, UK; Web:

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OCTOBER 2010 APCCB 2010 – 12th Asia-Pacific Congress of Clinical Biochemistry. October 3-7; Seoul, Korea; Web: www.apccb2010.org 2010 World Stem Cell Summit. October 4-6; Detroit, MI, USA; e-mail: rob@genpol.org; Web: www.worldstemcellsummit.com Cell Based Assays and Bioanalytical Method Development. October 4-6; San Francisco, CA, USA; Web: www.iirusa.com Biotechnica 2010. October 5-7; Hanover, Germany; Web: www.biotechnica.de Bio-IT World Europe Conference & Expo 2010. October 5-7; Hanover, Germany; Web: www.

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INTERNATIONAL CALENDAR International Federation of Adipose Therapeutics & Science (IFATS) 2010 Conference. October 2224; Dallas, TX, USA; e-mail: ifats@conmx.net; Web: http://dallas2010.ifats.org BIT’s 8th Annual Congress of International Drug Discovery Science and Technology. October 23-26; Beijing, China; Web: www.iddst.com The 3rd Congress of the European Academy of Paediatric Societies (EAPS). October 23-26; Copenhagen, Denmark; Web: www2.kenes.com American Society for Matrix Biology (ASMB). October 24-27; Charleston, SC, USA; Web: www.asmb.net Windhover’s PharmAsia Summit. October 25-26; San Francisco, CA, USA; Web: www.windhover.com 22nd Annual National Congress of Turkish Biochemical Society. October 27-30; Eskisehir, Turkey; e-mail: ubk@kenes.com; Web: www. biyokimyakongresi.org HIV/AIDS Vaccine for Life. October 28-29; London, UK; Web: www.mondialresearchgroup.com Microarray World Congress.October 28-29; San Diego, CA, USA; Web: www.selectbiosciences.com Lab-on-a-Chip World Congress. October 28-29; San Diego, CA, USA; Web: www. selectbiosciences.com Fraunhofer Life Science Symposium 2010. October 29-30; Leipzig, Germany; e-mail: info@fs-leipzig. com; Web: www.fs-leipzig.com

NOVEMBER 2010 qPCR Symposium USA. November 1-4; San Francisco, CA, USA; Web: www.qpcrsymposium.com 6th Annual Cambridge Healthtech Institute Discovery on Target. November. 2-4; Boston, MA, USA; Web: www.discoveryontarget.com 60th Annual Meeting American Society of Human Genetics (ASHG). November 2-6; Washington, DC, USA; Web: www.ashg.org JIB 2010 – Journées Internationales de Biologie. November 3-5; Paris, France; Web: www.jib-sdbio.fr ISABEL 2010 – 3rd International Symposium on Applied Sciences in Biomedical and Communications Technologies. November 7-10; Rome, Italy; Web: www.isabelconference.com International Society of Pharmaceutical Engineering (ISPE) 2010 Annual Meeting. November 7-10; Orlando, FL, USA; Web: www.ispe.org EuroPLX 44 Barcelona. November 8-9; Barcelona, Spain; Web: www.europlx.com Stem Cells in Drug Discovery and Development. November 8-9; San Diego, CA, USA; Web: www.healthtech.com 5th Annual Post-Approval Drug Safety Strategies. November 8-9; Philadelphia, PA, USA; Web: www.healthtech.com Mass Spec Europe. November 9-10; Florence, Italy; Web: www.selectbiosciences.com European Biomarkers Summit. November 9-10; Florence, Italy; Web: www.selectbiosciences.com Advances in Metabolic Profiling. November 9-10; Florence, Italy; Web: www.selectbiosciences.com 20th Neuropharmaology Conference . November 10-12; San Diego, CA, USA; Web: www.neuropharmacology-conference.elsevier.com EMBO Conference Series: From Functional Genomics to Systems Biology. November 13-16; Heidelberg, Germany; Web: www.embl.de Neuroscience 2010. November 13-17; San Diego, CA, USA; Web: www.sfn.org FIP Pharmaceutical Sciences 2010 World Congress in Association with APPS Annual Meeting and Exposition. November 14-18; New Orleans, LA, USA; Web: www.pswc2010.org 2010 Eastern Analytical Symposium and Exposition. November 15-18; Somerset, NJ, USA; email: easinfo@aol.com; Web: www.eas.org RNAi Asia. November 15-16; Singapore; Web: www.selectbiosciences.com BIO-Europe 2010. November 15-17; Munich, Germany; Web: www.ebdgroup.com World Generic Medicines Congress Americas 2010. November 16-19; Washington DC, USA; Web: www.healthnetworkcommunications.com 9th Annual Partnerships in Clinical Trials. November 17-18;Vienna, Austria; Web: www.ct-partnerships.com Medica 2010. November 17-20; Dusseldorf, Germany; Web: www.medica.de Pharmtech 2010. November 23-26; Moscow, Russia; Web: www.pharmtech-expo.ru 8th Annual World Drug Manufacturing Summit. November 30/ December 1; Berlin, Germany; Web: www.dmsummit.com

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Geneva, Switzerland; Web: www.terrapinn.com 5th International Conference on Bio-Inspired Models of Network, Information and Computing Systems . December 1-3; Boton, MA, USA; Web:www.bionetics.org Drug Discovery India 2010. December 1-3; Mumbai, India; Web: www.terrapinn.com CPhI India 2010. December 1-3; Mumbai, India; Web: www.cphi-india.com 4rd Annual World Congress of Gene. December 14; Foshan, China; Web: www.bitlifesciences.com Antibody Engineering. December 5-9; San Diego, CA, USA; Web: www.ibclifesciences.com International Scientific Conference (WAO). Dec 58;Dubai, UAE; Web: www.worldallergy.org The Science of BioBanking. December 6-8; Rhode Island, USA; Web: www.healthtech.com/bnk Antibody Therapeutics. December 7-9; San Diego; CA; USA; Web: www.ibclifesciences.com 33rd Annual San Antonio Breast Cancer Symposium December 8-12; San Antonio, TX, USA; Web: www.aacr.org Science and Enterprise Group Annual General Meeting. December 09; London, UK; Web: www.soci.org 50th Annual American Society for Cell Biology (ASCB) Meeting. December 11-15; Philadelphia, PA, USA; Web: www.ascb.org BPS Winter Meeting 2010 – British Pharmacological Society. December 14-16; London, UK; Web: www.bps.ac.uk

JANUARY 2011 BioBusiness 2011. January 3; London, UK; Web: www.wbr.co.uk Biotech Showcase 2011. January 10-12; San Francisco, CA, USA; Web: www.ebdgroup.com 5th International Symposium on Separation and Characterization of Natural and Synthetic Macromolecules. January 25-27; Amsterdam, The Nederlands; Web: www.ordibo.be/scm Lab Automation 2011. January 29 – February 2; Palm Springs, CA, USA; Web: www.labautomation.org

MARCH 2011 Bio-Europe Spring 2011 – 5th Annual Partnering Conference. March 14-16; Milan, Italy; Web: www.ebdgroup.com

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