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Vol.15 No.4 • 7-8/2010ISSN 1939-4470P R E M I E R N E W S S O U R C E F O R L I F E S C I E N C E R E S E A R C H E R S W O R L D W I D E

I N T E R N A T I O N A L

Clues into How CellsAchieve Immortality

SSwedish investigators can nowshow that cells that grow forev-

er, becoming immortal, obtain thiscapacity through gradual changesin the expression of genes thatcontrol the repair of DNA damageand regulate growth and celldeath. Their research also showsthat activation of the enzyme com-plex telomerase, which is essentialfor unlimited growth, occurs latein this process.

Neutrophil Enzyme DigestsCarbon Nanotubes

RResearchers have found that thehuman neutrophil enzyme

myeloperoxidase (hMPO) is able tobreakdown and detoxify carbonnanotubes, a finding that paves theway for their use as a drug deliverymechanism.

Investigators at the University ofPittsburgh (PA, USA; www.pitt.edu) and colleagues from severalother institutions exposed carbonnanotubes to myeloperoxidase in

New Tool Developedfor DNA Research

LLuminescent markers are anessential tool for researchers

working with DNA. However, themarkers are troublesome; sometend to destroy the function andstructure of DNA when inserted.Others emit so little light, thatthey can barely be detected in thehereditary material. Therefore,

RResearchers in genomics andrelated molecular biology fields

will benefit from the introductioninto the market of a panel of keybiomarkers associated with drugabsorption, distribution, metabo-lism, and excretion (ADME). TheVeraCode ADME Core Panel pro-duced by Illumina, Inc. (San Diego,

CA, USA; www.illumina.com) hasbeen designed to help researchersstudy genetic predispositions fordifferential drug response andadverse events. To this end, itspanel of biomarkers has been basedon those established by pharma-ceutical industry experts in thePharmADME Core List.

Biomarker Panel Now Available for Genome Research

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Genomics ProteomicsDrug DiscoveryBiochemistryTherapeuticsDiagnosticsLab TechniquesIndustry NewsProduct News . . . . . . 16-28Technical Literature . . . . 30International Calendar . . 34

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New Mapping Technique Finds Genes FasterNew Mapping Technique Finds Genes Faster

Image: Researcher holding petri dishes with specimens

used as a model organism in genetics research

Image: Researcher holding petri dishes with specimens

used as a model organism in genetics researchCont’d on page 6

Cont’d on page 4 Cont’d on page 8

GLOBETECH MEDIA>>> <<<

Potential Anticancer DrugActs via Energy Restriction

AArecently developed thiazolidine-dione derivative has demon-

strated potential as an anticancerdrug in tests conducted on culturesof breast and prostate cancer cells.

Thiazolidinediones (TZDs) act bybinding to PPARs (peroxisome pro-liferator-activated receptors), a

Cont’d on page 6

Therapeutic Target Foundto Stop Cancer Metastases

SScientists have uncovered whatcould be a very important lead in

answering one of the most mystify-ing questions about cancer: whydoes it spread to the liver more thanany other organ? In new research,scientists revealed experimentalresults suggesting that the immune

Cont’d on page 4

Handheld Device OffersAdvances in Cell Counting

Cont’d on page 6

Anovel handheld cell counter and analyzer isnow commercially available and is being

shipped to researchers worldwide.Before-sale information regarding the Millipore

(Billerica, MA, USA; www.millipore.com) “ScepterHandheld Automated Cell Counter” generated inter-est in the community of researchers working withcell cultures.

A global team of in-vestigators has de-

signed a specializedmapping method thatcould speed researchin genomic fields byrapidly finding geneticassociations that shapean organism’s observ-able characteristics.

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The study’s findings, published in the April2010 issue of the journal Aging Cell, was per-formed by a research team from Umeå University(Sweden; www.umu.se) and directed by Prof.Göran Roos at the department of medical bio-science, pathology. The study’s findings providemore insights into how cells’ telomeres are regu-lated during the process that leads to perpetuatingthe life of cells.

One type of blood cells, lymphocytes, wereanalyzed on repeated occasions during theircultivation in an incubator until they achievedthe ability to grow an unlimited number of cell

divisions, a process that is termed immortaliza-tion. In experiments, immortalization can beachieved following genetic manipulation ofcells in various ways, but in the lymphocytesunder study, this occurred spontaneously. Thisis an atypical phenomenon that can be com-pared to the development of leukemia inhumans, for example.

The ends of chromosomes, the telomeres, areimportant for the genetic stability of organisms’cells. In normal cells, telomeres are shortenedwith every cell division, and at a specific shorttelomere length, they stop dividing. With theoccurrence of genetic mutations, the cells can

continue to grow even though theirtelomeres continue to be shortened. Ata critically short telomere length, how-ever, a so-called crisis occurs, withimbalance in the genes and massive celldeath. In rare cases, the cells survivethis crisis and become immortalized. Inearlier research, this transition from cri-sis to eternal life has been associatedwith the activation of telomerase, anenzyme complex that can lengthencells’ telomeres and help stabilize thegenes. A typical finding is that cancercells have active telomerase.

The current study demonstratedthat cells initially lose telomere lengthwith each cell division, as expected,and after a while enter a crisis stagewith massive cell death. Those cellsthat survive the crisis and becomeimmortalized evince no activation oftelomerase; instead, this happens laterin the process. The Umeå researchersdiscovered that the expression of genesinhibiting telomerase is reduced in cellsthat get through the crisis, but telom-erase was not activated until positivelyregulating factors were activated, thusallowing the telomeres to become stabi-lized through lengthening. By analyz-ing the genetic expressions, the scien-tists were able to show that the cellsthat survived the crisis stage had muta-tions in genes that are crucial to therepair of DNA damage and the regula-tion of growth and cell death. This dis-covery provides new insights into theseries of events that needs to occur forcells to become immortalized, and itwill have an impact on future studies ofleukemia, for example.

The studies were performed in col-laboration with the Center forOncology and Applied Pharmacology,University of Glasgow (UK) and theMaria Skodowska-Curie MemorialCancer Center and Institute ofOncology (Warsaw, Poland).

Image: FISH light micrograph of humanchromosomes (blue) showing telomeres(pink) (Photo courtesy of Arturo Londono,ISM).

Clues into How Cells Achieve Immortality

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system may be the explanation. “Our work mayopen a new field of experimental therapeutics ascombating the eventual development of livermetastases by targeting immune suppressive cellsin the livers, in patients with early cancer canhave great benefit,” said Dr. George Miller, a sci-entist involved in the work from the departmentsof surgery and cell biology at the New YorkUniversity School of Medicine (New York, NY,USA; www.med.nyu.edu).

Dr. Miller and colleagues reached this con-clusion after conducting experiments in labmice. In the experiments, the investigators usedmice that spontaneously developed pancreaticcancer because of a mutation (Kras-mutation) inthe progenitor cells of the pancreas, as well asmice with advanced colon cancers that spreadto the abdomen. They then studied the expan-sion of immune suppressive cells in the liverfrom a very early stage in the cancer develop-ment to determine the immune phenotype,stimulus for recruitment, inhibitory effects, andtumor-enabling function of these cells. Thestudy’s results suggest that fighting immune sup-pressive cells in the liver early after cancerdevelopment may prevent the metastasis of can-cer to this vital organ.

The study’s findings were published in theApril 2010 issue of Journal of Leukocyte Biology(JLB). “This study could represent one of those ‘a-

ha’ moments in science where one idea or exper-iment opens up entirely new ways of approachingand understanding a problem,” said LuisMontaner, editor-in-chief of JLB. “Physicians haveknown that the spread of cancer to the liver is fartoo common to occur by chance. Now we knowthat the immune system likely plays a role infacilitating this process. The next step, obviously,is to learn more so we can prevent it from hap-pening.”

Image: Polarized light micrograph of normal andcancerous liver cells (Photo courtesy of J.W.Shuler / SPL).

Therapeutic Target Found to Stop Cancer Metastases


Bio Research InternationalBio Research International

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researchers have been asking for alternative mark-ers. Now a Danish Ph.D. student has developed atool that could solve both problems: a tool onemight call a molecular gauge.

Ph.D. student Soren Preus from the departmentof chemistry at the University of Copenhagen(Denmark; www.ku.dk) in collaboration withresearchers at Chalmers Technical University(Gothenburg, Sweden; www.chalmers.se) investi-gated the properties of the two luminescent so-called DNA base analogues of the tricyclic cytosine(tC) family, tCO and tCnitro. They tried to deter-mine whether they could measure the structure ofDNA without disrupting it. The research showedthat the function of DNA is unimpeded by the inser-tion of the molecular gauge. Moreover, one baseanalogue is very efficient at emitting light, and theother very good at receiving it. Therefore, becauseone can provoke transport of light energy betweenthe two luminescent markers, they are usable for ameasuring technique known as fluorescence reso-nance energy transfer (FRET).

In brief FRET, measurements are performed byforcing two luminescent markers to transfer lightenergy from one to the other, and then measuringthe efficiency of the transfer. The two differentmarkers are placed in the DNA helix. When theyare subjected to a light pulse, one marker (tCO)emits part of the energy to the other (tCnitro). Thisenergy transfer can be measured. Therefore, by cal-

culating backwards it is possible obtain very exactinformation about the distance and angle that thetwo have relative to one another.

Knowing distance and angle of the markersallows for calculations of distance and angle of allthe natural base pairs in the DNA structure. Thus,with this information the researcher can put togeth-er a picture showing every twist and turn of thestructure. Because structure and function are close-ly related in DNA, the technique holds the potentialto reveal new insights into the workings of DNA.

FRET measurements are not a new phenome-non. However, Mr. Preus has developed one of thebase analogues tCnitro in collaboration withSwedish research institution Chalmers University ofTechnology. Mr. Preus has used the facilities of theMolecular Engineering Group at University ofCopenhagen to analyze every aspect of the energytransfer between the two markers, because thisallows future DNA researchers to translate meas-urements to structure. Mr. Preus hopes that thenew tool might find its use in characterizing thestructural changes that take place when a proteinbinds to DNA or RNA as that could explain funda-mental cellular mechanisms. Equally important isthat the molecular gauge can be used to examineprecisely how new drugs work and when they bindto DNA or RNA. The results have been published inthe January 21, 2010, issue of the Journal ofPhysical Chemistry and the March 9, 2009, issue ofthe Journal of the American Chemical Society.

New Tool Developed for DNA Research


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group of receptor molecules inside the cell nucle-us, specifically PPAR-gamma. The ligands forthese receptors are free fatty acids (FFAs) andeicosanoids. When activated, the receptormigrates to the DNA, activating transcription of anumber of specific genes. Following activation ofPPAR-gamma, insulin resistance is decreased,adipocyte differentiation is modified, VEGF-induced angiogenesis is inhibited, leptin levelsdecrease (leading to an increased appetite), levelsof certain interleukins (e.g. IL-6) fall, andadiponectin levels rise.

While TZDs have been approved for use intreating type II diabetes, some data has indicatedthat they possess weak anticancer activity. Thesecompounds destroy cancer cells through dietarycaloric restriction in a manner similar to the natu-ral product-based energy restriction-mimeticagents (ERMAs) such as resveratrol and 2-deoxyglucose. In the current study, investigatorsat Ohio State University (Columbus, USA;www.osu.edu) sought to increase the anticanceractivity of the TZDs, and to this end prepared thecompound OSU-CG12, a derivative of the TZDciglitazone.

They reported in theMarch 26, 2010, issue ofthe Journal of BiologicalChemistry that when testedon cultures of breast orprostate cancer cells, OSU-CG12 was more than tentimes more effective atkilling cancer cells thaneither ciglitazone or resvera-trol. Energy restrictions trig-gered by the drug resultedin the cancer cells dyingfrom a combination ofautophagy and apoptosis.

“Our study proves thatthis new agent kills cancercells through energy restric-tion, said senior author Dr.Ching-Shih Chen, professor of medicinal chem-istry, internal medicine and urology at Ohio StateUniversity. “This is important because it showsthat it is possible to design drugs that target ener-gy restriction, and it is exciting because energy-restricting mimetic agents may also be useful forother diseases, including metabolic syndromes,

diabetes, cardiovascular disease, and obesity.Energy restriction may offer a powerful new strat-egy for treating cancer because it targets a survivalmechanism used by many types of cancer.”

Image: Colored scanning electron micrograph (SEM)of prostate cancer cells (Photo courtesy of DavidMcCarthy / SPL).

Potential Anticancer Drug Acts via Energy Restriction


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Using plants from 93 different Arabidopsisthaliana populations, a team led by the GregorMendel Institute of Plant Biology (Vienna, Austria;www.gmi.oeaw.ac.at) was able to find genetic linksamong multiple phenotypes, or traits, suggestingthat the same genes or closely related genes con-trolled those traits. Dr. David E. Salt, a PurdueUniversity (West Lafayette, IN, USA; www.purdue.edu), a professor of plant biology and coau-thor of the study released March 24, 2010, in thejournal Nature, reported that the ability to findthese types of genetic associations could speed sci-entists’ ability to find and isolate genes and under-stand their function. “This may show that multiplephenotypes are being controlled by a specific regionof the genome,” Dr. Salt said. “It helps us under-stand the mechanisms.”

A conventional search for a gene responsiblefor a particular characteristic requires usingplants that have been phenotyped, or identified

by characteristics. They are then crossed withothers, and the offspring are phenotyped.Scientists then look for similarities in offspring’sgenes with the desired trait. The process can bepainstaking and time-consuming because manythousands of individuals may need to bechecked, according to Dr. Salt.

Genome-wide association mapping comparesthe sequence of DNA in genomes of many individ-ual plants or animals to find similarities that nar-row the scope of the search for a particular gene.“We can look for a region in the genome that is incommon among the individuals,” Dr. Salt noted.“For plant biologists, it’s a much more efficientway of getting to genes. And for animal biologists,where making test crosses is more difficult, this iscritical.”

In this study, specific differences in DNA, calledsingle nucleotide polymorphisms (SNPs), werecompared at 250,000 sites across the genomes ofmany individuals. The genomes were matched up

against specific traits for each individual in order tofind SNPs that are associated with the trait of inter-est. If scientists were looking for plants that pro-duce high seed yields, for example, they wouldcompare the genomes of plants that have a range ofseed yields. The sites where the genomes match inindividuals with high seed yields are possible loca-tions of sought-after genes.

Genome-wide association mapping is a fasterprocess because fewer plants – typically in the hun-dreds – need to be grown and phenotyped. Findinggenetic associations among multiple phenotypescould reveal more information about how thosecharacteristics might be connected.

Of the 107 phenotypes used in the research, Dr.Salt was responsible for phenotyping the plants for18 characteristics, which focused on nutrient andmicronutrient content. He reported that the nextphase in the research would be to test those associ-ations to determine the genes responsible for partic-ular plant characteristics.

New Mapping Technique Finds Genes Faster

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The instrument, which looks and feels muchlike an electronic pipette, reports the cell count andaverage cell volume within 20 seconds of insertingthe sensor into a cell culture sample.

The Scepter tip draws precisely 50 µL of sampleinto its liquid handling microchannel. By drawing aprecise volume every time, the Scepter cytometerensures reproducible counts. By sampling accuratevolumes, the Scepter cytometer eliminates pipet-ting errors and uneven sample loading that canoccur with other devices. The tip has a precisiondrilled orifice through which cells pass, one by one,

and are counted based on the Coulter principle ofimpedance changes across a steady current, whichis established by the electrodes in the tip. The con-sistent size of the orifice ensures accurate cell sizeand volume data. In addition to a raw count andcell concentration, the Scepter screen displays a his-togram showing the population distribution of theculture. The real-time histogram monitors changesin the health and quality of the cell culture fromone cell preparation to the next.

The Scepter can be connected to a personalcomputer with the included USB cable. Uploadeddata may be manipulated through the Scepter soft-

ware to view histograms on the computer screen.Histograms can be saved as raw files or can beimported into Microsoft Excel to merge counts,overlay histograms for comparison, or perform sta-tistical analyses of the data.

“We continue to move aggressively to bringinnovation and productivity enhancements to thelife 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 scien-tists simplify tedious, repetitive tasks and improvethe reproducibility of their experiments.”

Handheld Device Offers Advances in Cell Counting


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Biomarker Panel Now Available for Genome Research

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The VeraCode ADME Core Panel allows for theidentification of 184 biomarkers in 34 genes. Thededicated system employs highly specific andstreamlined chemistry so that DNA can be geno-typed within eight hours with less than two-and-a-half hours of hands-on time. The supporting soft-ware offers a convenient user interface that man-ages user authentication, logs system activity, andautomatically translates genotype data into the starnomenclature used by researchers to analyze phar-macogenetic data.

“Understanding genetic variability associatedwith drug response and disposition is a key steptoward the realization of personalized medicine,and the VeraCode ADME Core Panel will helpenable this exciting transformation,” said JayFlatley, president and CEO of Illumina. “With thecost of bringing a new medicine to market nowexceeding US$1 billion and over $220 billion spentannually on medications in the U.S., it is criticalthat we look for savings in all stages of drug devel-opment. With its emphasis on rapid operation andhigh-quality data, the VeraCode ADME Core Panelcan help bring safe and effective therapies topatients as quickly as possible.”

Neutrophil Enzyme DigestsCarbon Nanotubes

cont’d from cover

vitro, in neutrophil cultures, and in macrophage cul-tures. To increase the uptake of the nanotubes byneutrophils they were first coated withimmunoglobulins. Results reported in the April 4,2010, online edition of the journal NatureNanotechnology showed that incubation of single-walled nanotubes with hMPO and hydrogen perox-ide resulted in degeneration of the nanotubes with-in 24 hours. This process could be accelerated bythe addition of sodium chloride, which generatedhypochlorite, a strong oxidizing compound knownto break down nanotubes.

Native or immunoglobulin-coated nanotubeswere introduced into neutrophil or macrophage cellcultures. After 12 hours in the neutrophil culture,essentially all the coated nanotubes were degradedas compared to only about 30% of the native nan-otubes. In contrast, after two days in themacrophage culture only about 50% percent of thecoated nanotubes had degenerated. The biodegrad-ed nanotubes did not generate an inflammatoryresponse when aspirated into the lungs of mice.

“The successful medical application of carbonnanotubes relies on their effective breakdown in thebody, but carbon nanotubes also are notoriouslydurable,” said first author Dr. Valerian Kagan, profes-sor of environmental and occupational health at theUniversity of Pittsburgh. “The ability of hMPO tobiodegrade carbon nanotubes reveals that this break-down is part of a natural inflammatory response. Thenext step is to develop methods for stimulating thatinflammatory response and reproducing thebiodegradation process inside a living organism.”

Bio Research InternationalBio Research International to view this issue in interactive digital magazine format visit www.LinkXpress.comto view this issue in interactive digital magazine format visit www.LinkXpress.comBio Research InternationalBio Research International for latest news updates visit www.BiotechDaily.comfor latest news updates visit www.BiotechDaily.com


AA new method of growing arteries could leadto a “biologic bypass” – or a noninvasive

way to treat coronary artery disease. Yale Schoolof Medicine (New Haven, CT, USA; http://medicine.yale.edu) researchers and their col-leagues reported their findings in the April 2010issue of Journal of Clinical Investigation.

Coronary arteries can become blocked withplaque, leading to a decrease in the supply ofblood and oxygen to the heart. Over time, thisblockage can lead to incapacitating chest pain orheart attack. Severe blockages in multiple majorvessels may require coronary artery bypass graftsurgery, a major invasive surgery.

“Successfully growing new arteries could pro-vide a biological option for patients facing bypasssurgery,” said lead author of the study MichaelSimons, M.D., chief of the section of cardiology at

Yale School of Medicine. In the past, researchers used

growth factors – proteins that stimu-late the growth of cells – to grownew arteries, but this method wasunsuccessful. Simons and his teamstudied mice and zebrafish to see ifthey could simulate arterial formationby turning on and off two signalingpathways – ERK1/2 and P13K.

“We found that there is a cross-talk betweenthe two signaling pathways. One-half of the sig-naling pathway inhibits the other. When we inhib-it this mechanism, we are able to grow arteries,”said Dr. Simons. “Instead of using growth factors,we stopped the inhibitor mechanism by using adrug that targets a particular enzyme called P13-kinase inhibitor. Because we’ve located this

inhibitory pathway, it opens the possibility ofdeveloping a new class of medication to grownew arteries. The next step is to test this findingin a human clinical trial.”

Image: Colored light micrograph of a sectionthrough a coronary artery that is partially blockedby a large atheroma (orange) (Photo courtesy ofAlain Pol, ISM).

Technique Devised to Grow ArteriesMay Lead to Biologic Bypass

The strange world of quantum mechanicsdescribes the bizarre, often contradictory, behaviorof small inanimate objects such as atoms.Researchers have now started looking for ways todetect quantum properties in more complex andlarger entities, possibly even living organisms.

A German-Spanish research group, splitbetween the Max Planck Institute for QuantumOptics (Garching, Germany; www.mpg.de) andthe Institute of Photonic Sciences (ICFO;Barcelona, Spain; www.icfo.es), is utilizing theprinciples of an iconic quantum mechanicsthought experiment – Schrödinger’s superposi-tioned cat – to test for quantum properties inobjects composed of as many as one billion atoms,possibly including the flu virus.

New research published on March 11, 2010, inNew Journal of Physics describes the constructionof an experiment to test for superposition states in

these larger objects. Quantum optics is a field wellrehearsed in the process of detecting quantumproperties in single atoms and some small mole-cules but the level that these researchers wish towork at is unprecedented.

When physicists try to figure out precisely howthe tiniest constituents of matter and energybehave, confusing patterns of their ability to do twothings at once (referred to as being in a superposi-tion state), and of their ‘spooky’ connection(referred to as entanglement) to their physically dis-tant subatomic brethren, emerge.

It is the ability of these objects to do two thingsat once that Dr. Oriol Romero-Isart and his cowork-ers are preparing to investigate. With this new tech-nique, the researchers suggest that viruses are onetype of object that could be probed. Albeit specula-tively, the researchers hope that their techniquemight offer a way to address experimentally ques-

tions such as the role of life and consciousness inquantum mechanics.

In order to test for superposition states, theexperiment involves finely tuning lasers to capturelarger objects such as viruses in an “optical cavity”(a very tiny space), another laser to slow the objectdown (and put it into what quantum mechanicscall a “ground state”) and then adding a photon ina specific quantum state to the laser to provoke itinto a superposition

The researchers concluded, “We hope that thissystem, apart from providing new quantum tech-nology, will allow us to test quantum mechanics atlarger scales, by preparing macroscopic superposi-tions of objects at the nano- and microscale. Thiscould then enable us to use more complex microor-ganisms, and thus test the quantum superpositionprinciple with living organisms by performing quan-tum optics experiments with them.”

Detecting Quantum Behavior in Viruses

AA recent paper pointed out the danger of overes-timating the amount of nucleic acids or pro-

tein in samples analyzed by UV spectrophotometrydue to contaminants that leach from plastic micro-tubes into the sample solution.

Plastic containers such as “microfuge” tubesused for the storage and manipulation of biologicalsamples comprise complex polymer materials con-taining several chemical additives. These additivesinclude supplements such as chemical antioxi-dants, antimold release agents, biocides, and UV-light stabilizers. Plastic materials may also containother low–molecular weight chemicals such asresidual unreacted monomers and polymer degra-dation products. Microfuge tubes are produced bynumerous manufacturers and are among the mostcommonly used pieces of laboratory ware inmolecular biology laboratories.

Since previous studies have demonstrated thatadditives and other chemicals can leach from plas-tics into the environment, investigators at Texas

State University (San Marcos, USA; www.txstate.edu) examined the effect of such contami-nants on spectrophotometric measurements car-ried out on samples stored in plastic microtubes.

They reported in the April 2010 issue of thejournal BioTechniques that normal handling of lab-oratory microtubes caused leaching of light-absorb-ing chemicals into biological samples that inter-fered with spectrophotometric measurements. Theleached chromophores absorbed UV light stronglybetween 220 nm and 280 nm, which are thewavelengths normally used to detect and quanti-tate proteins and DNA. Some common laboratorytechniques, including sonication and PCR, wereparticularly effective inducers of leaching. Themagnitude of the increase in absorbance wasdependent upon both exposure time and heat his-tory, with greatest induction after tubes werewarmed to temperatures at or above 37 °C. Massspectrometry revealed that aqueous solutionsstored in plastic microtubes accumulated a com-

plex mixture of leached chemicals with molecularmasses between 200 Da and 1,400 Da. Leachingwas a common attribute of all commercially avail-able brands of microtubes, indicating a persistentsource of error in biomolecule detection and con-centration measurements.

“It was quite surprising that leaching of chemi-cal additives, which absorb light at the same wave-lengths as DNA and proteins had not beendescribed before because it is so ubiquitous amongcommercially available plastic tubes, and bio-chemists have been using these small plastic tubesfor many decades,” said first author Dr. KevinLewis, associate professor of chemistry and bio-chemistry at Texas State University.

“Some manufacturers have recently begunoffering tubes that contain a reduced number ofadditives,” said Dr. Lewis. “At the moment the useof polypropylene tubes with fewer additivesappears to be the best way to reduce measurementerrors due to leaching.”

Contaminants from Plastic Microtubes Distort Results of UV Measurements


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AAPhase 1-2 clinical trial has established themaximum tolerated dose of the compound

MDV3100, a promising drug candidate for thetreatment of castration-resistant prostate cancer(CRPC) – once known as or androgen-independ-ent (androgen-resistant) prostate cancer.

MDV3100 is an androgen-receptor antagonistthat blocks androgens from binding to the androgenreceptor and prevents nuclear translocation andcoactivator recruitment of the ligand-receptor com-plex. It also induces tumor cell apoptosis and has noagonist activity. Since growth of CRPC is dependenton continued androgen-receptor signaling, investi-gators at Memorial Sloan-Kettering Cancer Center(New York, NY, USA; www.mskcc.org) assessed theantitumor activity and safety of MDV3100 in menwith this disease.

They reported in the April 24, 2010, issue ofthe journal the Lancet that all the 140 patientswho were treated with doses of MDV3100 rang-ing from 30 mg to 600 mg daily showed someantitumor 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% inmore than half of the patients and tumor regres-sions in 22% of the patients. Overall, two-thirds ofpatients had partial remissions or stable disease intumors that had spread to soft tissue or bone. Atthe maximum tolerated dose for sustained treat-ment (240 mg per day for 28 days), the numberof circulating tumor cells fell in 49% of patientsand 91% of patients who initiated therapy withfavorable counts retained favorable counts duringtreatment. The drug was generally well tolerated,with nausea, constipation, diarrhea, and anorexiabeing the most common mild side effects report-ed. The most frequently reported serious sideeffect at higher doses was fatigue, which general-ly resolved after dose reduction.

“We were encouraged to see antitumor activi-ty in men whose disease had spread to other partsof the body after either becoming resistant to pre-vious hormone treatments or progressing follow-ing chemotherapy,” said first author Dr. HowardScher, professor of oncology at Memorial Sloan-Kettering Cancer Center. “These findingsstrengthen the drug’s potential to change the out-

look for a group of patients who currently havelimited effective treatment options from which tochoose.”

Due to the positive outcome of the Phase 1-2study, a multinational randomized Phase 3 clinicaltrial has begun to examine MDV3100 versus aplacebo for the treatment of men with advancedprostate cancer who were previously treated withchemotherapy.

Image: Colored scanning electron micrograph (SEM)of tissue from the prostate gland of a patient suffer-ing from prostate cancer (Photo courtesy of SteveGschmeissner / SPL).

MDV3100 Shown to Be Safe and Effective Against Prostate Cancer

AAn advanced genotyping system isthe basis for a new genealogic

testing service that can match a widerange of family relationships within

five generations. Family Tree DNA (Houston, TX,

USA; www.familytreedna.com), thefirst company to develop the commer-

cial application of DNA testing forgenealogical purposes, has launched anew genotyping service (The FamilyFinder) that will allow individuals,regardless of gender, to explore link-ages to grandparents, aunts anduncles, half siblings, and first, second,third, and fourth cousins.

The test is based on Affymetrix(Santa Clara, CA, USA; www.affymetrix.com) Axiom genotypingtechnology and the associatedGeneTitan analytical system. Withthe Axiom test, total genomic DNA(200 ng) is amplified and randomlyfragmented into 25 to 125 base pairfragments. These fragments are puri-fied, resuspended, and hybridized toAxiom Genome-wide human arrayplates. Following hybridization, thebound target is washed under strin-gent conditions to remove nonspe-cific background to minimize back-ground noise caused by random liga-tion events. Each polymorphicnucleotide is queried via a multicol-or ligation event carried out on thearray surface. After ligation, thearrays are stained and imaged on theGeneTitan Instrument. The imagingdevice in the GeneTitan Instrumentuses an external, high-intensityxenon lamp and dual excitation andemission filters to capture imagesfrom array plates.

The Family Finder test analyzesthe DNA of two individuals usingAxiom array plates containing nearly

570,000 genetic markers, includingmany that are relevant to genealogy.The assay system utilizes the com-plete Axiom genotyping solution,which includes array plates, completereagent kits, and an automated work-flow that enables scientists to processmore than 760 samples per week.Family Tree DNA then analyzes theresulting data with internally devel-oped algorithms to determine thecloseness of the relationship.

“This is the most exciting geneticgenealogy breakthrough since 2000,when Family Tree DNA launched itsY-DNA test to uncover relatives inthe direct paternal line,” saidBennett Greenspan, CEO of FamilyTree DNA. “The comprehensive,genome-wide coverage of AxiomArrays enables us to offer consumersthe most advanced genealogical testavailable at a price that is attractiveto our customers. In addition, theautomated GeneTitan system allowsus to process hundreds of samples ata time with minimal hands-on timefor maximum efficiency.”

“The Family Finder test representsa huge step forward for the direct-to-consumer genetic genealogy marketand the application of microarraytechnology,” said Kevin King, CEO ofAffymetrix. “Now anyone can utilizethe power of the Axiom genotypingsolution and the GeneTitan System tofind and connect with a broader rangeof family members than ever before.”

Genealogy Testing Service Relies on High-Throughput Microarray Technology




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IIn an ongoing effort to mimic the ability of biologicaltissues to respond quickly and appropriately to

changing environments, researchers have synthesizeda single, multifunctional polymer material that candecontaminate both biological and chemical toxins.

Investigators from the University of PittsburghMcGowan Institute for Regenerative Medicine(Pittsburgh, PA, USA; www.mirm.pitt.edu) describedthe findings online March 2, 2010, in the journalBiomaterials. “Our lab applies biological principles tocreate materials that can do many things, just like ourskin protects us from both rain and sun,” said senior

investigator Alan Russell, Ph.D., university professorof surgery, University of Pittsburgh School ofMedicine (UPMC), and director, McGowan Institute,a joint effort of the university and UPMC. “Typically,labs engineer products that are designed to serve onlyone narrow function.”

Those traditional approaches might not providethe best responses for weapons of mass destruction,which could be biological, such as smallpox virus, orchemical, such as the nerve agent sarin, Dr. Russellnoted. Terrorists are not going to announce whatkind of threat they unleash in an attack. “That

uncertainty calls for a single broad-spectrum decon-tamination material that can rapidly neutralize bothkinds of threats and is easily delivered or adminis-tered, and it must not damage the environmentwhere it is applied,” he said. “Much work has goneinto developing ways to thwart either germ orchemical weapons, and now we’re combining someof them into one countermeasure.”

Dr. Russell and his team have devised apolyurethane fiber mesh containing enzymes thatlead to the production of bromine or iodine, whichkill bacteria, as well as chemicals that generate com-pounds that detoxify organophosphate nerve agents.

“This mesh could be developed into sponges,coatings or liquid sprays, and it could be used inter-nally or as a wound dressing that is capable of killingbacteria, viruses, and spores,” said lead investigatorGabi Amitai, Ph.D., of the McGowan Institute andthe Israel Institute for Biological Research (IIBR;Ness-Ziona; www.iibr.gov.il). “The antibacterial andantitoxin activities do not interfere with each other,and actually can work synergistically.”

In their experiments, the material fended offStaphylococcus aureus and Escherichia coli, whichrepresent different classes of bacteria. After 24hours, it restored 70% of the activity of acetyl-cholinesterase, an enzyme that is inhibited by nerveagents leading to fatal dysfunction of an essentialneurotransmitter.

The researchers reported that they are continu-ing to develop alternate decontamination strategiesto address chemical and biologic weapons.

The McGowan Institute for RegenerativeMedicine was established by the University ofPittsburgh School of Medicine and its clinical part-ner, UPMC, to realize the vast potential of tissueengineering and other techniques aimed at repairingdamaged or diseased tissues and organs. TheMcGowan Institute serves as a single base of opera-tions for the university’s leading scientists and clini-cal faculty working to develop tissue engineering,cellular therapies, biosurgery and artificial and bio-hybrid organ devices.

IInterrupting the biochemical pathway leading toalpha glucan synthesis in Mycobacterium

tuberculosis causes the buildup of a toxic precur-sor that quickly kills the microorganism.

Investigators at the Albert Einstein College ofMedicine (New York, NY, USA; www.einstein.yu.edu) traced a heretofore unrecognizedmolecular pathway from trehalose to alpha-glu-can in M. tuberculosis that comprised four dis-tinct steps mediated in turn by the enzymesTreS, Pep2, GlgE (which was identified as a mal-tosyltransferase that used maltose 1-phosphate),and GlgB. Alpha glucans are essential for main-taining the structure of the bacterial cell wall,and for generating new microbes through celldivision.

The investigators focused their attention onthe enzyme GlgE, since there are no enzymessimilar to it in humans or in the bacteria of thehuman gut. As described in their paper pub-

lished in the March 21, 2010, online issue ofthe journal Nature Chemical Biology, they usedtraditional and chemical reverse genetics toshow that GlgE inactivation caused rapid deathof M. tuberculosis both in vitro and in micethrough a self-poisoning accumulation of theprecursor maltose 1-phosphate, which damagedbacterial DNA.

“We were amazed when we knocked out GlgEthat we saw this DNA damage response,” saidsenior author Dr. William R. Jacobs, Jr., professorof microbiology, immunology, and genetics atAlbert Einstein College of Medicine. “That is usu-ally a very effective way to kill bacteria, when youstart damaging the DNA. This approach is totallydifferent from the way any other anti-TB drugworks. In the past few years, extremely drugresistant strains of TB have arisen that cannot beeliminated by any drugs, so new strategies forattacking TB are urgently needed.”

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

Multifunctional Polymer Neutralizes Biological and Chemical Weapons

Toxic Sugar Buildup Kills Tuberculosis Bacteria

Bio Research InternationalBio Research Internationalto view this issue in interactive digital magazine format visit www.LinkXpress.comto view this issue in interactive digital magazine format visit www.LinkXpress.com

AAdrug already approved for treat-ment of some types of cancer has

been shown to be an effective adjuncttherapy for visceral leishmaniasis byhelping to restore immunocompe-tence by stimulating the remodelingof the microarchitecture of the infect-ed spleen.

Visceral leishmaniasis (VL), causedby the protozoan parasites Leish-mania donovani and L. infantum, isone of the most important of the neg-lected tropical diseases, with approxi-mately 500,000 new cases and70,000 deaths reported per annum.Pentavalent antimonial drugs remainthe first-line therapy for VL in mostparts of the world, although increas-ing drug resistance now limits theiruse in India. Drug toxicity, increasingdrug resistance, and a paucity of new

drugs on the horizon have focusedattention on the need to develop newcombined approaches to therapy,including therapeutic vaccination,and on the development of dose-spar-ing regimens.

Investigators at York University(United Kingdom; www.york.ac.uk)evaluated the drug sunitinib maleate(SM) for its potential to reduce thedosages of antimonial agents used totreat VL. SM is a small-moleculeinhibitor of multiple receptor tyrosinekinases involved in cancer, includingvascular endothelial growth factorreceptors, platelet-derived growth fac-tor receptors and the KIT receptor. Itwas approved by the U.S. FDA for thetreatment of gastrointestinal stromaltumors and advanced renal-cell carci-noma in January 2006.

The investigators re-ported in the April 1,2010, issue of the Journalof Clinical Investigationthat SM both blocked thevascular remodeling andprogressive splenomegalyassociated with experi-mental visceral leishmania-sis and restored the integri-ty of the splenic microar-chitecture. Similar alter-ations to splenic architec-ture are also observed in other infec-tious causes of splenomegaly, includ-ing experimental malaria, trypanoso-miasis, and following infection withLymphocytic choriomeningitis virus(LCMV).

Although restoration of splenicarchitecture was accompanied by anincrease in the frequency of interfer-on producing cells, SM treatmentalone did not cause a reduction in tis-sue parasite burden. However, pre-conditioning with SM was shown tobe successful as a dose-sparing strate-gy for use with conventional antimo-nial drugs that are known to be

immune dependent for their efficacyin vivo. Senior author Dr. Paul Kaye,professor of immunology at YorkUniversity, said, “It is particularlyexciting that this potential has beendiscovered in a class of drugs that arealready well-established in clinicalpractice. While our research hasfocused on leishmaniasis, the findingscould have implications for a range ofglobally important diseases.”

Image: Light micrograph of a sectionthrough spleen tissue from a patientsuffering from visceral leishmaniasis(Photo courtesy of Sinclair Stammers/ SPL).

Cancer Drug Improves Immune Picture in Visceral Leishmaniasis

AApartnership has been announcedthat will unite the manufacturer

of a line of moderately priced bench-top flow cytometer systems with amajor producer of flow cytometryresearch reagents.

Accuri Cytometers (Ann Arbor, MI,USA; www.accuricytometers.com)makes a full-featured bench top cell-analysis system that provides powerfulcapabilities similar to industry-leadingflow cytometers in a user-friendly for-mat and at a fraction of the cost. The“C6 System” includes blue and redlasers, four color detectors and bothforward and side scatter detectors plussoftware that the manufacturer says isso intuitive that customers typicallyhave the instrument up and runningwithin an hour of receiving it.

The other half of the partnership iseBioscience (San Diego, CA, USA;www.ebioscience.com), a privatelyheld company that makes more than11,000 innovative high quality cellanalysis reagents. Their product listcomprises an array of high performingsolutions, such as fluorescent dyes andbead assay reagents that enable com-prehensive analysis of cells and solublefactors in the areas of immunologyand cell biology research.

The partnership is designed to offerresearchers a better and more compre-hensive solution for their flow cytom-etry needs, harnessing the cost-effec-tiveness, ease-of-use, performancecapabilities, and accessibility of theAccuri C6 Flow Cytometer Systemwith the market leading extensive line

of high quality cytometer researchreagents offered by eBioscience.

“We are pleased to partner withreagent leader eBioscience to offerour growing customer base a widerange of quality reagents optimizedfor their varied research needs,” saidJack Ball, chief commercial officer ofAccuri. “The adoption of the AccuriC6 Flow Cytometer System by over500 research labs for an increasingrange of applications has brought theneed for high quality reagents thatwork seamlessly with our systems tothe fore. This marketing partnershipallows Accuri to further deliver onour promise to our customers to offeran affordable, easy-to-use flowcytometer solution – now made evenmore accessible with the easy avail-ability of a full range of qualityresearch reagents.”

“We are delighted to partner withAccuri, the fastest growing supplier offlow cytometers, and welcome theopportunity to educate our customersabout the advantages of having a flowcytometer in their research labs, alongwith the outstanding performanceattributes and surprising accessibilityof the Accuri C6 Flow Cytometer sys-tem,” said Tony Ward, vice presidentof commercial operations ofeBioscience. “As part of our sharedgoal to make high performance cellanalysis more accessible to researchersworldwide, this agreement will pro-vide customers with an effective andcomprehensive solution right out ofthe box.”

Partnership Links Flow CytometryInstruments and Reagents

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SS ulforaphane, a compound found in abun-dance in broccoli destroys breast cancer stem

cells, the extremely drug-resistant cells thatoften stimulate regrowth of tumors followingchemotherapy.

Sulforaphane is an organosulfur compoundthat exhibits anticancer, antidiabetic, and antimi-crobial properties. It is obtained from cruciferousvegetables such as broccoli. In the plant theenzyme myrosinase transforms glucoraphanin, aglucosinolate, into sulforaphane upon damage tothe plant (such as from chewing). Young sproutsof broccoli and cauliflower are particularly rich inglucoraphanin.

Investigators from the University of Michigan(Ann Arbor, USA; www.umich.edu) recently evalu-ated the anticancer potential of sulforaphane onbreast cancer cells growing in culture and in axenograft mouse model. They reported in the April13, 2010, online edition of the journal ClinicalCancer Research that cultures treated with the

compound showed a markeddecrease in the cancer stem cell pop-ulation with little effect on neighbor-ing normal cells. Tumor cells takenfrom mice that had been treated withsulforaphane were unable to gener-ate new tumors after having beentransplanted into naive animals.

“Sulforaphane has been studiedpreviously for its effects on cancer,but this study shows that its benefitis in inhibiting the breast cancerstem cells. This new insight suggeststhe potential of sulforaphane orbroccoli extract to prevent or treatcancer by targeting the critical can-cer stem cells,” said senior author Dr. Duxin Sun,associate professor of pharmaceutical sciences atthe University of Michigan.

The positive findings reported in this studysupport the use of sulforaphane for the chemopre-

vention of breast cancer stem cells, and empha-size the need for further clinical evaluation.

Image: Colored scanning electron micrograph (SEM)of breast cancer cells (Photo courtesy of SteveGschmeissner / SPL).

Compound Found in Broccoli Eliminates Breast Cancer Stem Cells

AAnew line of dedicated software packagesdesigned to enhance the use of photomicroscopy

in the life sciences in an easy-to-use, user-friendly fash-ion is now available.

The camera and microscope manufacturerOlympus (Hamburg, Germany; www.microscopy.olympus.eu) has released a series of three differentsoftware packages called ”cellSens Entry,” “cellSensStandard,” and “cellSens Dimension.” The threepackages are interrelated and lead from basic to verycomplex applications.

The basic package, “cellSens Entry,” gives theuser the ability to perform simple image acquisitionand documentation. The customizable interfaceprovides complete control over a range of Olympusdigital cameras to obtain live images in a number offormats, including AVI movies. This software pack-age can perform straightforward postcapture pro-

cessing such as light intensity and white balanceadjustments, and its layers file format enables theaddition of arrows and annotation text withoutaffecting the original image channels.

The intermediate package, “cellSens Standard,”enables more advanced image capture, includingtime-lapse and TWAIN acquisition. The programsupports advanced hardware control for processessuch as objective and filter changes, focusing, andinternal shutter control. It also boasts extendedgeometry functions that allow images to be easilymanipulated via mirroring, rotation, resizing, crop-ping, and channel shifting. The “cellSens Standard”program can also convert bit-depth and color-spacesettings to meet the capabilities of the computersystem as well as the requirements of the applica-tion. Further image processing tools are availablefor 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 featuresas well as specialized, optional solution modulesthat support complex procedures such as extendedfocal imaging, multiple image alignment, and multi-position imaging. In addition, live images can betransferred directly to colleagues via the Internetusing the program’s “netcam” capability.

Within the images, interactive measurementfunctions can be executed on a separate imagelayer. Extracted numerical values such as size, dis-tance, or area can subsequently be exported toMicrosoft Excel for in-depth statistical analysis.Once data has been obtained, a unique report com-poser uses Microsoft Word templates to generateuser-defined reports that retrieve images and datadirectly from the cellSens database.

Packages Enhance Photomicroscopy Applications

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The CIL91000TN range of self-lami-nating labels features a clear, wrap-around tail to protect computer-print-ed data, and provide reliable identifi-cation. The labels are waterproof,and can withstand multiple freeze-thaw cycles, water baths, solvents,abrasion, and long-term storage.

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The Integrity single-use BPVs aredesigned for use in the storage andtransfer of clean or sterile liquids thatare critical to biotechnology process-es. The BPVs are available in both 2-D and 3-D, range in size up to 3,000liters, and are configurable to a broadrange of end user processes.

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17 Bio Research InternationalJuly-August/2010



AA low molecular weight inhibitor of the tumorpromoting protein MDMX has been isolated

that shows promise for treatment of the pediatriccancer retinoblastoma.

MDMX and a similar molecule MDM2 pro-mote cancer development by inhibiting the actionof the tumor suppressing protein p53. The twoinhibitors work differently, so it is necessary toprevent the activity of both of them to restore p53functionality. The p53 pathway is disrupted in vir-tually every human tumor. In about half of humancancers, the p53 gene is mutated, and in theremaining cancers, the pathway is dysregulatedby genetic lesions in other genes that modulatethe p53 pathway.

Investigators at St. Jude Children’s ResearchHospital (Memphis, TN, USA; www.stjude.org)developed biochemical and cell-based assays forhigh throughput screening of chemical libraries toidentify MDMX inhibitors. They reported in theApril 2, 2010, issue of the Journal of Biological

Chemistry that after screening nearly 300,000compounds they had identified one, SJ-172550.This compound was shown to attach to the p53-binding pocket of MDMX, thereby displacing p53and allowing p53 to direct potential cancer cellstowards the pathway to apoptosis.

When tested in conjunction with an MDM2inhibitor, it was found that SJ-172550 effectivelykilled retinoblastoma cells growing in culture.Since about 65% of retinoblastoma tumors featureextra 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 theactivity of this molecule.

“We went from a discovery in childhood can-cer, MDMX amplification, to characterizing thisfirst inhibitor in about three-and one-half years,”said senior author Dr. Michael Dyer, professor ofdevelopmental neurobiology at St. Jude Children’sResearch Hospital.

“It may also be useful for any tumor that has

normal p53,” Dr. Dyer said. “The idea is that ifyou have normal p53 and you need to turn it on,maybe by giving a drug that hits MDM2 andanother that hits MDMX; you free p53 up to killthe cell.”

Image: Funduscopic finding of a retinoblastoma(Photo courtesy of Meilahti Hospital, Department ofOphthalmology).

Candidate Drug Kills PediatricRetinoblastoma Cells

DDevelopment of a Universal Influenza Vaccineadvanced another step with the successful com-

pletion of the clinical phase of its second Phase I/IIclinical trial. The Multimeric-001 Universal FluVaccine, under development by BiondVax Pharma-ceuticals (Rehovot, Israel; www.biondvax.com), wastested in a randomized, single-blind, placebo-con-trolled, escalating double-dose safety study on a total60 participants aged 55-75, who received two injec-tions, either with or without adjuvant, at two differ-ent doses and in accordance with the approved clini-cal trial design. This phase of the study was directedat an older population group, which is consideredmost at-risk for influenza infections.

Results of the study showed that the vaccinewas safe to use at all doses tested, both with andwithout adjuvant. All participants who received the

vaccine developed a high level of antibodies againstthe Multimeric-001 Universal Flu Vaccine. Theseantibodies also specifically identified a number ofdifferent strains of influenza, including the swineflu strain (A/H1N1). Furthermore, those receivingthe vaccine showed a meaningful increase in whiteblood cells inducing the secretion of interferongamma and Interleukin-2. Thus, the vaccine acti-vated both the humoral (antibody) and the innate(cellular) arms of the human immune system.

The Multimeric-001 Universal Vaccine is a singleformulation consisting of nine conserved linear epi-topes in triplicate. The epitopes selected were takenfrom hemagglutinin (HA), nucleoprotein (NP), andmatrix (M) proteins, therefore ensuring high antigencontent. These epitopes are common to practicallyall existing and future flu virus strains, including both

seasonal and pandemic flu strains such as the avianand swine flu, regardless of their antigenic drift andshifts. This trial was the second of two Phase I/IIclinical trials of the Multimeric-001.

Dr. Ron Babecoff, CEO of BiondVax, said, “Theselatest excellent safety results are further evidence ofthe positive safety profile of our Multimeric-001 vac-cine. We are especially pleased to have been able toshow the safety of the vaccine in the elderly popula-tion, which is one of the most at-risk and vulnerablesectors of the population to flu infections. Followingthe recent success of the first Phase I/II study inwhich we showed proof of the safety and immuno-genicity of our vaccine in younger participants, theseadditional safety results represent yet another suc-cessful achievement in our path towards the devel-opment of the Universal Flu Vaccine.”

Universal Influenza Vaccine Passes Clinical Trial in Elderly Population




RR esveratrol, a bioactive compound in redwine, 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 skinsvaries with the grape cultivar, its geographic ori-gin, and exposure to fungal infection. Theamount of fermentation time a wine spends incontact with grape skins is an important determi-nant of its resveratrol content. Red wine con-tains between 0.2 mg/L and 5.8 mg/L, depend-ing on the grape variety, while white wine hasmuch less – the reason being that red wine is fer-mented with the skins, allowing the wine toabsorb the resveratrol, whereas white wine isfermented after the skin has been removed.

Epidemiological and experimental reportshave linked mild-to-moderate wine and/or grape

consumption to a lowered risk of cardiovascular,cerebrovascular, and peripheral vascular dis-eases. Based on these findings, investigators atJohns Hopkins University (Baltimore, MD, USA;www.jhu.edu) used a mouse stroke model toassess whether resveratrol could significantlyprotect the animals’ brains from damage causedby lack of oxygen.

The investigators reported in the April 8,2010, online edition of the journal ExperimentalNeurology that mice that received a single mod-est dose of resveratrol before induction ofischemic stroke suffered significantly less braindamage than the ones that had not been giventhe compound. At the molecular level, it wasfound that resveratrol increased levels of theenzyme heme oxygenase, which was alreadyknown to protect nerve cells from stroke dam-

age. Thus, mice from a strain lacking heme oxy-genase received no protective benefit fromresveratrol.

“Our study adds to evidence that resveratrolcan potentially build brain resistance to ischemicstroke,” said senior author Dr. Sylvain Doré,associate professor of anesthesiology, critical caremedicine, pharmacology, and molecular sciencesat Johns Hopkins University. “Resveratrol itselfmay not be shielding brain cells from free radicaldamage directly, but instead, resveratrol and itsmetabolites may be prompting the cells todefend themselves. It is not likely that brain cellscan have high enough local levels of resveratrolto be protective. Rather, the resveratrol is need-ed to jump-start this protective enzymatic systemthat is already present within the cells. Even asmall amount may be sufficient.”

Resveratrol Protects Brain Cells from Stroke Damage in Mouse Model

AA n international team of researchers hassequenced ancient mitochondrial DNA from

a finger bone of a female found in southernSiberia. She comes from a previously unknown

human species, which lived approximately48,000 to 30,000 years ago in the AltaiMountains in Central Asia.

The mitochondrial genome that was inheritedfrom the mother and passed on to the descendantsis an indication of a new wave of emigration fromAfrica. It differs from the Homo erectus ancestorsof Neanderthals and Homo sapiens, according to astudy published in the March 25, 2010, issue of thejournal Nature.

The first group of hominins, which left Africaabout 1.9 million years ago, was Homo erectus.Archaeological findings and genetic data suggestthat at least two other groups then left Africa: First,about 500,000 to 300,000 years ago, the ancestorsof Neanderthals, and after that, 50,000 years ago,anatomically modern humans. Direct descendantsof Homo erectus could have survived until lessthan 100,000 years ago in Indonesia. Earlier repre-sentatives of Homo erectus and Homo heidelber-gensis lived in northern latitudes – for example,more than 125,000 years in the Altai Mountains in

southern Siberia. Neanderthals also lived at thattime in Siberia.

Dr. Johannes Krause, Dr. Svante Pääbo and col-leagues from the Max Planck Institute forEvolutionary Anthropology (Leipzig, Germany;www.eva.mpg.de) have now sequenced mitochondr-ial DNA from a tiny piece of a finger bone. The bonewas found 2008 in the Denisova Cave in the AltaiMountains in southern Siberia. They compared theancient DNA from the mitochondria, with the mito-chondrial DNA of Neanderthals and living humans. Itwas revealed that the mitochondrial DNA of thehominins from South Siberia differs noticeably fromthat of all previously known hominins.

As demonstrated by a detailed examination of themitochondrial genome, these hominins shared a com-mon ancestor with modern humans andNeanderthals approximately 1.0 million years ago.Moreover, the age of the fossil suggests that theseunknown people in Southern Siberia lived close intime and space with Neanderthals as well as withmodern humans.

Mitochondrial Genome of Previously Unknown Human Species Decoded

SAMPLE PREPARATION COLUMNS

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CressetThe FieldView is a molecular viewerdesigned to create, modify, view, andcompare molecules with their associ-ated Field patterns and physico-chemical properties. The FieldViewis intended for drug discovery andchemistry-based research projects.

IN-LINE CONNECTOR SYSTEM

DolomiteThe Mitos system provides a reliablemultiway connection for sealing andalignment between tubes, enablinguninterrupted liquid flow. The con-nector is available in three standardsizes, and operates over a wide tem-perature and pressure range.


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AAnew study describes the development of arti-ficial human skin with biomechanical proper-

ties, based on an agarose-fibrin biomaterial.Researchers at the University of Granada

(UGR; Spain; www.ugr.es) first obtained humanskin samples from biopsies of patients whounderwent plastic surgery at the UniversityHospital Virgen de las Nieves (Granada, Spain;www.hvn.es). To create the artificial humanskin, tranexamic acid (to prevent fibrinolysis),calcium chloride (to precipitate fibrin coagula-tion), and 0.1% agarose was added to humanfibrin from plasma of healthy donors. The artifi-cial-skin substitutes were then grafted on theback of the nude mice, with the purpose ofobserving its optimal development, maturation,and functionality in vivo. To do so, theresearchers analyzed the samples by transmis-sion and scanning light, electron microscopy,and inmunofluorescence to evaluate factorssuch as cell proliferation, the presence of differ-entiating morphological markers, the expressionof cytokeratin, involucrine, filaggrin, and angio-genesis of the artificial skin into the recipientorganism.

The researchers found that the artificial humanskin created in the laboratory showed adequatebiocompatibility rates with the recipient, and no

rejection, dehiscence, or infection was registered.Additionally, the skin of all animals used in thestudy started to show granulation after six daysfrom implantation. Within the following 20 days,cicatrization was complete. Details on theresearch were released by the department of his-tology at UGR on April 20, 2010.

“These biomaterials added resistance, firm-ness, and elasticity to the skin. Definitively, wehave created a more stable skin with similar func-tionality to normal human skin,” said lead authorJosé María Jiménez Rodríguez, of the tissular engi-neering research group at UGR. ”This pioneeringfinding will allow the clinical use of human skinand its use in many laboratory tests on biologicaltissues. Further, this finding could be useful indeveloping new treatment approaches for derma-tological pathologies.”

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

Artificial Human Skin Created Using Tissue Engineering

Bio Research DemandsHighly Purified Water

OO ften overlooked, highly purified water is anabsolute requirement for successful biotechnol-

ogy research, and now a new and sophisticatedwater purification system has become available.

The new purification system, the ELGALabWater Purelab Pulse, (Marlow, United Kingdom;www.elgalabwater.com) has been developed to pro-duce consistently highly pure type II level water ateconomical running costs for a wide range of appli-cations including cell culture and media prepara-tion. Type II water is basic for general laboratoryapplications requiring higher inorganic purity aswell as being suitable for clinical analyzers, electro-chemistry, sample dilution, media preparation, andradioimmunoassay.

ELGA’s Pulse technology integrates EDI (elec-trodeionization), which combines ion exchangeresins and ion-selective membranes, with directcurrent to remove ionized impurities from waterefficiently. It is complemented by pretreatment,reverse osmosis, and a 254 nm UV lamp to producetype II pure water that the manufacturer saysmeets and exceeds European, U.S., and Japanesepharmacopeia standards. In addition, the PURE-LAB Pulse can be fitted with a point-of-use biofilterto reduce bacteria levels to less than one colony-forming unit per 10 mL.

The purification system has been designed to fitinto any laboratory environment and is easy to oper-ate and maintain. It can be wall or bench mountedfor convenient access and can be fitted with ELGA’sunique wrap-around reservoir to save valuable space.







AApreclinical photoacoustic com-puted tomography (CT) scan-

ner has been designed for small ani-mal imaging. The system is used forsimple, fast, noninvasive quantifica-tion of tumor vasculature and otherphysiologic parameters for preclini-cal research.

The Nexus 128, developed byEndra Life Sciences, makes in vivoquantification of tumor vasculaturepossible without the need for con-trast agents and helps preclinicalresearchers gain deeper insight intoareas such as how drugs treat dis-ease and cancer progression, with-out ionizing radiation or complicat-ed equipment.

Endra Life Sciences was foundedby Enlight Biosciences (Boston MA,USA: www.enlightbio.com), a fund-ing syndicate of six of the world’sleading pharmaceutical companiesfocused on commercializing trans-formational technologies. “Photo-acoustic imaging combines ultra-sound with the rich contrast of opti-cal imaging, based on the same prin-ciples that give cells, organs, and tis-sues their unique colors,” saidMichael Thornton, Endra’s presi-dent and chief operating officer. “Itprovides high spatial resolution atdepth far exceeding that of conven-tional optical imaging techniquessuch as fluorescence and biolumi-nescence. We are excited to makethis technology widely available tocancer biology researchers for thefirst time.”

“Mouse models of cancer are used

extensively to study tumor develop-ment and the effects of new thera-pies, but until now the tools to meas-ure this effect have had depth limita-tions,” said Dr. Rakesh Jain, director,Edwin L. Steele Laboratory for TumorBiology at Harvard Medical School(Boston, MA, USA), and EnlightBiosciences advisor. “The ability totrack abnormal vessel growth andnormalization in vivo with high reso-lution throughout a tumor mass dur-ing therapeutic intervention is a pow-erful new capability that will be wide-ly used in cancer research.”

The name Nexus 128 representsthe convergence of light and soundin a powerful new imaging approach.It employs a detector array consistingof 128 individual acoustic receiverelements arranged in a patentedgeometry. The system generates mul-tispectral, quantitative, three-dimen-sional (3D) images of tumor vascula-ture and hemoglobin concentrationin under two minutes, and completesvolumetric anatomic scans in as littleas 12 seconds. “For the past severalyears, our research group has devel-oped quantitative photoacousticspectroscopy imaging techniques andapplied them to mouse models ofcancer,” said Dr. Keith Stantz, facultymember of Purdue University. “Wehave been using Endra’s photoa-coustic tomography prototype systemregularly for the past year. The simpli-fied animal handling and highthroughput allow us to image entirestudy groups within a couple ofhours.”

Endra Life Sciences launched theproduct at the American Associationfor Cancer Research (AACR) 101stannual meeting 2010 in Washing-ton, DC, USA, April 17-21, 2010.The Nexus 128 system was featuredin a poster by Dr. Stantz and his col-leagues from Purdue University(West Lafayette, IN, USA).

Short pulses of light absorbeddeep within tissue create soundwaves that are detected by ultra-sound receivers to create an image.This noninvasive approach provideshigh contrast imaging at depths, andspatial resolution far exceedingexisting optical techniques. The

photoacoustic effect, a precursor tophotoacoustic imaging, revealedthat energy from sunlight could betransformed into a sound wave.Recent advances in pulsed lasersources, ultrasound devices, andimage reconstruction algorithmshave enabled the photoacousticeffect to be applied to biologic imag-ing. Endra’s Nexus 128 is the firstcommercial photoacoustic-imagingdevice designed specifically for highthroughput, quantitative, in vivosmall animal imaging.

Image: Preclinical Photoacoustic CTImaging of a mouse (Photo courtesyof Endra Life Sciences).

Photoacoustic 3D Tomographic Imaging Developed for Cancer Research

CHROMATOGRAPHY SYSTEMDorton Analytical

The Octave system is an automatedchromatography platform designedfor preparative-scale purification ofchemical and biological compounds.The system carries eight columnpositions, arranged in a series andconnected through a pneumaticvalve array.

QUARTZ REACTION TUBESExeter Analytical

The reaction tubes are designed toenable laboratories to achieve con-sistent low-level blanks to improvethe precision and accuracy of CHNmicroanalysis results. The tubes aremanufactured from high quality, lowhydroxyl materials, and can be sup-plied within 24 hours of order.

THERMAL CYCLERFluidigm

The FC1 Cycler is designed toreduce the thermal cycling time by afactor of three when compared withcurrent products. When added to anexisting Fluidigm system, the FC1provides the capability to double thenumber of microfluidic chips that canbe processed in a single day.

ARC SENSORHamilton

The pHeasy is intended for accurateprocess pH measurement withoutrecalibration. The sensor features adevice that provides feedback on theaccuracy of the measurement, deliv-ers alerts for electrode replacement,monitors chloride loss, and detectsreference poisons.

QQ uietly at work in the background of thelaboratory, the importance of a good incu-

bator to the success of biomedical research isoften overlooked. However, a new line of incu-bators, launched at PITTCON 2010 conferenceand expo in Orlando (FL, USA) requires anotherlook.

The line of CelCulture CO2 incubators by Esco(Hatboro, PA, USA; www.escoglobal.com) pro-vides the carefully monitored and consistent cellculture environment required by the contempo-rary biomedical researcher. Temperature, CO2level, and humidity in the CelCulture CO2 incu-bator is controlled by a set of proprietary algo-rithms that guarantee stable conditions as well asensuring fast recovery of the parameter values fol-lowing door openings. Cultures growing insidethe incubator are protected by an "all inclusive"contamination control system, which comprisesfiltration technology that maintains the culturechamber at a level of ISO class five.

If necessary, the incubators can be decontami-nated by a built-in moist heat 90 ºC decontamina-tion cycle that operates overnight. At the end ofthe cycle, the chamber is dry and ready to use. All

input gases are filtered by inline filters before theyenter the chamber to remove impurities and con-taminants.

The incubator's main body is made from elec-tro-galvanized steel with Esco's unique ISOCIDEantimicrobial coating. The interior of the 170-literchamber is made from stainless steel. A computer-ized reminder alarm system prompts the user toreplace the CO2 tank and bacteriological filterautomatically to prevent the incubator systemfrom being compromised. An intelligent data andevent logger records all incubator parameters foron-screen recalls, and a diagnostic interface withquick on-screen help provides comprehensivesolutions to frequently encountered problems.

Image: The CelCulture CO2 incubator, designed tocreate a consistent cell culture environment (Photocourtesy of Esco).

Maintenance of Cell Culture ConditionsEssential for Biomedical Research

Vitamin D InsufficiencyLinked to Development of

Crohn's Disease

RResults published in a recent paper suggest thatsupplementing the diet with vitamin D can pro-

tect against development of Crohn's disease, a chron-ic incurable inflammatory bowel condition.

Vitamin D signaling through the vitamin D recep-tor has emerged as a key regulator of innate immuni-ty in humans. Investigators at McGill University(Montreal, Canada; www.mcgill.ca) extended thisobservation to the serious autoimmune syndromeknown as Crohn's disease.

They reported in the January 22, 2010, edition ofthe Journal of Biological Chemistry that vitamin Dacted directly to stimulate two genes that could berelated to the development of Crohn's disease. Thefirst, the beta defensin 2 gene, encodes an antimicro-bial peptide that interacts with intestinal bacteria. Thesecond, the NOD2 gene, alerts immune cells to thepresence of invading microbes. When vitamin D lev-els were insufficient, these two genes malfunctioned,which induced the type of inflammatory responsefound in Crohn's disease.

"Our data suggests, for the first time, that vitaminD deficiency can contribute to Crohn's disease," saidDr. John White, professor of physiology at McGillUniversity. "It is a defect in innate immune handlingof intestinal bacteria that leads to an inflammatoryresponse that may lead to an autoimmune condition."

"Siblings of patients with Crohn's disease that havenot yet developed the disease might be well advisedto make sure they are vitamin D sufficient," said Dr.White. "It is something that is easy to do, becausethey can simply go to a pharmacy and buy vitamin Dsupplements. The vast majority of people would becandidates for vitamin D treatment."


Bio Research InternationalBio Research Internationalfor latest news updates visit www.BiotechDaily.comfor latest news updates visit www.BiotechDaily.com





AAnew range of recombinant proteins has beendeveloped that can substitute extracellular

matrix proteins that are currently extracted frommouse sarcoma.

The mussel adhesive protein-based matrix(MAPTrix) ECM line of products are coatingreagents with genetically incorporated bioactivepeptides that mimic the extracellular matrix(ECM) activity of collagen, fibronectin, laminin,and vitronectin proteins. These bioactive peptidesmimic ECM proteins and provide for cell attach-ment, spreading, and growth. A MAPTrix surfacecoating offers an animal-free, chemically definedattachment and growth surface that provides ahighly controlled environment for cell culture andtissue engineering applications.

Cell adhesion to the extracellular matrix isessential for the development and maintenance ofcells. Cell adhesion to ECM ligands is principallymediated by integrins. The Arg-Gly-Asp (RGD)recognition motif is present in many ECM pro-

teins including fibronectin, laminin, and osteo-pontin. Many biomimetic approaches have soughtto convey biofunctionality to synthetic materialsby presenting a cell adhesion motif such as theRGD recognition motif. The immobilization ofshort peptides such as RGD on synthetic or natu-ral materials may produce biofunctional surfacesthat bind adhesion receptors and promote celladhesion; however, this traditional chemistryapproach is time-consuming, inconvenient, andlacks reproducibility.

The MAPTrix ECM line of products, devel-oped by Amsbio (Abingdon, UK; www.amsbio.com), provide a better alternative to the conven-tional chemistry approach. In addition to RGDmotifs – MAPTrix includes a wide variety of alter-native motifs that mimic the extracellular matrix(ECM) activity of collagens, fibronectin, laminin,vitronectin and other matrix proteins. The use ofMAPTrix ECM-based coatings is simple, conven-ient, and highly reproducible. The MAPTrix ECM

line of flexible products can be used in a cell cul-ture application alone or in combination withother products. All MAPTrix products are solublein a variety of buffers including water under awide range of pH (pH = 2.0 to 9.5). Available forbasic research or drug discovery applications inserum-free or serum-reduced conditions –MAPTrix products are provided as ready-to-useaqueous coating formulations in 1.0 mg, 2.5 mg,5.0 mg, and 10.0 mg sizes (vials).

AMS Biotechnology (AMSBIO) is an interna-tional provider of products and custom servicesfor life sciences research. The company’s rangeincludes over 23,000 polyclonal and monoclonalantibodies, peptides, recombinant proteins, extra-cellular matrix, molecular detection reagents, tis-sue DNA, RNA, protein, and microarray products.Key research areas include apoptosis, cell invasionand migration, cell signaling, DNA damage, elec-trophoresis, glycobiology, posttranslational modifi-cation, and stem cell biology.

Nonanimal Recombinant Proteins Developed for Cell Culture and Tissue Engineering Applications

AA siRNA generation kit enables easy and cost-effective generation of a large number of

small interfering RNAs (siRNAs) from full-lengthtarget genes.

siRNAs are 21-23-nucleotide RNA moleculesthat can cause targeted gene silencing in mam-malian cells through a process known as RNAinterference. In nature, siRNAs are generated byribonuclease III cleavage of longer double-strand-ed RNAs (dsRNAs). When dsRNAs are transfect-ed directly into mammalian cells, they activatethe interferon system and provoke nonspecificgene suppression and cytotoxic response. siRNAshave proven to be effective at specifically silenc-ing gene expression without causing any interfer-on response.

Using an ultra-active form of human recombi-

nant dicer enzyme, a double-stranded RNA-spe-cific endonuclease, it is possible using the kit tocleave more than 95% of dsRNA template into 22bp [base pair] siRNAs within two hours underoptimized reaction conditions. In contrast to indi-vidual synthetic siRNAs, the Turbo Dicer kitallows the user to quickly produce multiplesiRNA species against the target mitochondrialRNA (mtRNA), and thereby achieve effectivegene silencing with minimal guesswork.Moreover, due to the minimal concentration ofany individual siRNA species generated with theTurbo Dicer enzyme, off-target effects are not aproblem.

For maximum convenience, the Turbo DicersiRNA generation kit, developed by from Amsbio(Abingdon, UK; www.amsbio.com), contains

everything that is required for preparing double-stranded RNA from the user’s target gene(s),dsRNA cleavage, siRNA cleanup, and transfec-tion. Both the Recombinant Turbo Dicer enzymeand the RNA purification columns are also avail-able separately.

AMS Biotechnology (Amsbio) is a leadinginternational provider of products and customservices for life sciences research. The company’srange includes over 23,000 polyclonal and mon-oclonal antibodies, peptides, recombinant pro-teins, extracellular matrix, molecular detectionreagents, tissue DNA, RNA, protein, and microar-ray products. Key research areas include apopto-sis, cell invasion and migration, cell signaling,DNA damage, electrophoresis, glycobiology, post-translational modification, and stem cell

Easy and Cost-Effective Production of Functional siRNA Achieved with Generation Kit

PIPETTE TIPSIntegra Biosciences

The VIAFLO GripTips deliver lowattachment and ejection forces,enabling comfortable, stress-freepipetting even over extended peri-ods of use. The GripTips feature aprecise and consistent tip seal,ensuring all tips on a multichannelpipette are at the same exact height.

MICROSCOPY ILLUMINATIONLeica Microsystems

The Intelligent Structured IlluminationMicroscopy uses the OptiGrid tech-nique to help keep the grid structurein focus, from UV to IR light. TheOptiGrid module can be used for bothupright and for inverted researchmicroscopes.

DETECTION SYSTEMMalvern Instruments

The Viscotek TDAmax GPC/SECtriple detection system with Omnisecsoftware allows users to character-ize heterogeneous mixtures of mate-rials. The system is designed for awide range of biomaterials andbiotechnology applications.

STORAGE PRODUCTSMicronic

Products available include biologicaland cryogenic sample storagetubes, sealing arrangements, tuberacks and sorters. Additional prod-ucts include the Track-IT samplemanagement system, and the MX4,a semi-automated sample handlingand verification system.

AAnew US$126 million, 13,536-m2

biomedical research “collaborato-ry” will pursue joint projects by itsmembers and collaboration partners toinvent tools and technologies intend-ed to advance research into stem cells,and to discover and develop innova-tive diagnostics and therapies.

The Sanford Consortium forRegenerative Medicine (www.sanfordconsortium.org), a consortium of fourworld leaders in life sciences research(the Salk Institute for BiologicalStudies, The Scripps Research Institute(La Jolla, CA, USA), Sanford-BurnhamMedical Research Institute (La Jolla),and the University of California, SanDiego, hosted an official groundbreak-ing ceremony on March 26, 2010, inLa Jolla, CA, USA.

The consortium, formed in 2006to build and operate the biomedicalresearch laboratory, consists of thesefour leading medical institutions – allinternationally known for their excep-tional contributions to medicalresearch and treatments.

The Sanford Consortium forRegenerative Medicine will be a pre-eminent research center to developthe next generation of breakthroughcures, therapies, diagnostics, researchtools, and technologies in stem cellresearch. The consortium’s keyresearch focuses on stem cell growthand differentiation, neuroscience, car-diovascular biology, blood cell devel-opment, and vision science.

The Sanford Consortium forRegenerative Medicine is designed asone of the most forward-thinking lab-oratories, effectively fostering infor-mal collaboration and communica-tion among researchers in a synergis-tic environment. Shared two-storybreak rooms interconnect all levelsand encourage interaction amongresearchers. Approximately 330investigators and associated staff willoccupy the open labs, offices, andspecialized core labs. Conferencefacilities include a 150-seat auditori-um, large divisible conference roomand a café.

BB itter melon (Momordica charan-tia) extract, a common dietary

supplement, has been show to exert asignificant effect against breast cancercell growth and may ultimatelybecome a chemopreventive agentagainst this form of cancer.

“Our findings suggest that bittermelon extract modulates several sig-nal transduction pathways, whichinduces breast cancer cell death,”said lead researcher Ratna B. Ray,Ph.D., a professor in the departmentof pathology at Saint Louis University(MO, USA; www.slu.edu). “Thisextract can be utilized as a dietarysupplement for the prevention ofbreast cancer.”

Results of this study were pub-lished in February 15, 2010, issue ofCancer Research, a journal of theAmerican Association for CancerResearch. Previous research hasshown bitter melon, to have hypo-glycemic and hypolipidemic effects,according to Dr. Ray. Because of theseeffects, the extract is typically used infolk medicine as a remedy for dia-betes, in regions such as India, China,and Central America, according tothe researchers.

Using human breast cancer cellsand primary human mammaryepithelial cells in vitro, Dr. Ray andcolleagues found the mechanism ofbitter melon extract significantly

decreased proliferation in cell growthand division, and induced death inbreast cancer cells. These early resultsoffer an encouraging path for researchinto breast cancer.

“Breast cancer is a major killeramong women around the world,and in that perspective, results fromthis study are quite significant,” saidRajesh Agarwal, Ph.D., professor inthe department of pharmaceuticalSciences at the University ofColorado, Denver School of Phar-macy (USA; www.uchsc.edu/sop).“This study may provide us with onemore agent as an extract that couldbe used against breast cancer if addi-tional studies hold true.”

According to Dr. Agarwal, theCancer Research associate editor forthis study, the simple study design,clear-cut results, and the overallimportance of these findings in breastcancer prevention makes thisresearch different from earlierresearch. However, he stressed, “Thisstudy is only a step towards establish-ing the cancer preventive efficacy ofbitter melon against breast cancer.”Additional research is needed tounderstand better the molecular tar-gets of bitter melon extract in cancercells, as well as for establishing its invivo efficacy. Dr. Agarwal gave a noteof caution, stating that while theseresults do provide hope as an anti-

cancer agent, it is important to estab-lish the validity of these results in ani-mal models before adding them toone’s diet to inhibit breast-cancer cellgrowth. Dr. Ray and colleagues arecurrently conducting follow-up stud-ies using a number of cancer cell linesto examine the antiproliferative effectof the extract. They are also planninga preclinical trial to assess its chemo-preventive efficacy by oral administra-tion. Bitter melon extract is cultivatedin Asia, Africa, and South America.Extract of this vegetable is being pop-ularized as a dietary supplement inWestern Countries, since it is knownto contain additional glycosides suchas mormordin, vitamin C, caro-tenoids, flavanoids, and polyphenols.

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

Bitter Melon Extract Inhibits Breast Cancer Cell Growth

Biomedical Research Consortium forRegenerative Medicine Under Construction




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BBy utilizing an advanced DNA capture technique,genomic researchers have succeeding in map-

ping a portion of the Neanderthal genome and com-paring it to that of modern humans.

Investigators at the Max Planck Institute(Munich, Germany; www.mpg.de), Cold SpringHarbor Laboratory (Cold Spring Harbor, NY, USA;www.cshl.edu), and Agilent Technologies, Inc.(Santa Clara, CA, USA; www.agilent.com) usedAgilent’s microarray system to sequence nearly14,000 protein-coding positions inferred to havechanged on the human lineage since the last com-mon ancestor shared with chimpanzees.

Generally, it has been extremely difficult to workwith ancient DNA due in part to chemical aging ofthe DNA molecules but even more so due to severebacterial contamination of the samples. Now, in astudy published in the May 7, 2010, issue of thejournal Science, investigators from the three institu-tions described the use of array-hybridization capture

technology, a process that enriched NeanderthalDNA sequences while depleting contaminant DNA.Thus, they were able to enrich Neanderthal protein-coding regions where differences occurred on thehuman evolutionary lineage up to 190,000-fold. Bygenerating the sequence of one Neanderthal and 50present-day humans, the investigators identified 88amino acid substitutions that have become fixed inhumans since our divergence from the Neanderthals.

“Attaining good coverage of the Neanderthalgenome had been a problem due to DNA contami-nation from microbes over the years,” said seniorinvestigator Dr. Svante Paabo, professor of evolu-tionary genetics at the Max Planck Institute.“Simply sequencing, without first enriching for thegenome, often did not work, especially where thecontamination levels were high. Array-hybridizationcapture technology was originally reported by theCold Spring Harbor Laboratory group and is the sub-ject of a longstanding collaboration with Agilent.

The team recognized this as a promising method forrecovering large regions of targeted sequence fromNeanderthal samples. The method can also be usedmore widely with many other kinds of humanremains.”

In a second article in the same issue of Science,the investigators presented their first detailed analy-sis of the draft sequence of the Neanderthalgenome, which now includes more than three bil-lion nucleotides collected from the bones of threefemale Neanderthals who lived in Croatia morethan 38,000 years ago. By comparing this compos-ite Neanderthal genome with the completegenomes of five living humans from different partsof the world, the investigators found that bothEuropeans and Asians share 1% - 4% of their nuclearDNA with Neanderthals, but that Africans do not.This suggests that early modern humans interbredwith Neanderthals after moderns left Africa, butbefore they spread into Asia and Europe.

New Microarray Technology Enables Sequencing of Neanderthal DNA

CCancer researchers have designed a lowmolecular weight drug that blocks the activi-

ty of BCL6, the protein product of the oncogenethat is the most commonly involved in B cell lym-phomas.

BCL6 is the most commonly involved onco-gene in B cell lymphomas. Depletion or blockadeof BCL6 potently kills lymphoma cells in tissueculture, and BCL6 is thus a critical therapeutictarget. Like many oncogenes and tumor suppres-sors, BCL6 is a transcription factor.

Investigators at the Weill Cornell MedicalCollege (New York, NY, USA; www.med.cornell.edu) used an integrated biochemical and compu-tational approach to identify small molecules thatcould specifically disrupt the activity of BCL6 byblocking its interaction with its corepressorsBCOR, N-CoR, and SMRT.

The investigators reported in the April 13, 2010,

issue of the journal Cancer Cell that they had iden-tified a low-molecular-weight drug that bound to thecorepressor binding groove of the BCL6 BTBdomain. This compound disrupted BCL6/corepres-sor complexes in vitro and in vivo, and it wasobserved by X-ray crystallography and NMR to bindto the critical site within the BTB groove. This com-pound could induce expression of BCL6 targetgenes and kill BCL6-positive lymphoma cell lines. Inxenotransplantation experiments, the compoundwas nontoxic and potently suppressed lymphomatumors in vivo. The compound also killed primarylymphomas from human patients.

“Our results show that given the right scientif-ic approach it is quite possible to design drugsagainst key protein regulatory factors like BCL6,”said Dr. Melnick. “The BCL6 inhibitor was specif-ic for BCL6 and did not block other master regu-lators. This means that if given as a therapeutic

agent, the compound would be unlikely to have illeffects on healthy normal cells, and thereforewould not be expected to have significant sideeffects. Since emerging data implicates BCL6 inother tumor types in addition to non-Hodgkin'slymphoma, it is possible that BCL6-targeted ther-apy could benefit many other cancer patients.”

Image: Light micrograph of a section through a lymphnode of a patient with diffuse B-cell non-Hodgkin’slymphoma (Photo courtesy of Kemeny, ISM).

Low Molecular Weight Drug Blocks Action of Lymphoma Oncogene

ALUMINUM HEAT SEALSPorvair Sciences

The range of aluminum heat seals isdesigned for PCR, storage, and lifescience applications. The four newfoils are color-coded and marked toensure proper use, and offer veryeasy piercing by robotic liquid han-dling equipment or pipette tips.

ULTRAFILTERSSartorius Stedim Biotech

The Sartocon ECO series of ultrafil-ters features high stability underalkaline conditions and over widetemperature ranges. The reusablefilters are intended for use in purifi-cation processes for the manufac-ture of vaccines and monoclonalantibodies.

PIPETTE ALTERNATIVESeward

The Simplette Straws feature univer-sal fit and are designed for use withfixed- or variable-volume pipettehandsets. The Straws offer an inex-pensive alternative to graduatedpipettes for various sample-handlingapplications.

MALDI MASSSPECTROMETER

Shimadzu Scientific InstrumentsThe MegaTOF is the integration of ahigh-performance Shimadzu linearMALDI TOF mass spectrometer witha CovalX high-mass system. Theunit allows for the detection ofmacromolecules up to 1,500 kDa.

AA large team of French researchershas discovered two low molecu-

lar weight compounds that block theaction of ricin, a highly toxic proteinoften mentioned as a possible bioter-ror weapon.

Ricin comprises two subunits, theA-chain and the B-chain, which arelinked by a disulphide bond. The B-chain facilitates cell entry and intra-cellular transport, and it is reductive-ly cleaved to free the A-chain, whichinactivates ribosomes and shutsdown protein synthesis.

A French team, headed by investi-gators at the Centre National de laRecherche Scientifique (Paris,France; www.cnrs.fr) used a cell-based assay system to screen over16,000 compounds for the ability toblock the intracellular transport of

ricin toxins. They reported in the April 16,

2010, online edition of the journalCell that they had identified twocompounds, Retro-1 and Retro-2 thatwere able to inhibit the retrogradetransport route of ricin from the plas-ma membrane to the endoplasmicreticulum. Unlike other compoundsthat are known to block retrogradetransport, Retro-1 and Retro-2 didnot affect other intracellular traffick-ing and did not show any toxicity.

In experiments in mice, Retro-2was shown to block the activity ofricin, if it were given prior to thetoxin. It is expected that these com-pounds should also inhibit othertoxic proteins such as the Shiga-liketoxins produced by pathogens suchas E. coli, Shigella, and V. cholerae.

French Team IdentifiesAntidote for Ricin Toxin

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

AAcontract high-content cell screen-ing service has been launched

that will benefit researchers investigat-ing various biological phenomena –including the cell cycle, RNAi profiling,angiogenesis, and signal pathway pro-filing.

High-content screening is the analy-sis of fluorescent cellular markers tomeasure multiple responses to biologi-cal stimuli or drug treatment. It haswide applications in drug discoverycovering everything from target identi-fication through to preclinical toxicolo-gy. To provide this type of screening forthe general research community TTPLabTech (Melbourn, United Kingdom;www.ttplabtech.com) is now makingits Acumen microplate cytometer avail-able on a contract basis.

The Acumen is a unique laser scan-ning cytometer containing three lasers,405 nm, 488 nm, and 633 nm, whichensure compatibility with a wide vari-ety of fluorescent probes. The instru-ment operates by scanning a laserthrough a wide field of view lensacross the bottom of a microplate orslide. The speed of data acquisition isnot affected by plate density andmicroplate types ranging from 24-wellup to 3456-well (or four microscopeslides) can all be rapidly analyzed.Scanning resolutions may be set to aslow as 0.5 µ where very detailed, orsmall object analysis is required. Thelasers fire sequentially to reducecrosstalk and give simultaneous detec-tion in four photomultiplier tube(PMT) detectors, providing a maxi-

mum of 12 channels of content-richdata for true multiplexing at highthroughputs. Acumen's maximumscanning resolution is equivalent tothat achieved using a 20x microscopeobjective.

Acumen’s patented approach todata analysis employs cytometric prin-ciples, rather than image analysis. Thelasers scan the entire field of view col-lecting intensity readings at regularintervals using the four PMTs.Thresholding algorithms identify allfluorescent intensities above the solu-tion background for automatic objectidentification. Laser scanning data col-lection combined with cytometric dataanalysis generates extremely fast androbust results.

TTP LabTech is now offering con-tract screening that will allow itsclients to apply this expertise to newand demanding applications to supportthe drug discovery process.

“As the inventors of the Acumen,we have extensive experience in theuse of this instrument for high-contentscreening and so we are well placed toapply its capabilities on behalf of ourclients,” said Dr. Philip Blenkinsop,managing director of TTP LabTech. “Inthe past, prospective clients seekingdirect access to high-content data haveoften asked us whether we can com-bine our in-house biology expertisewith the latest lab tools to provide acomplete package. We now feel thatthe time is right to introduce such aservice to augment our existing prod-uct business.”

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

AA low molecular weight drug that inhibits thecyclin-dependent kinases 4 and 6 (cdk4/6)

has been shown to prevent the growth of glioblas-toma brain cancer cells both in vitro and in amouse model. While the drug, PD-0332991, iscurrently being evaluated in clinical trials for oth-erwise untreatable teratomas as well as multiplemyeloma and breast cancer, the current report isthe first on its potential effectiveness againstglioblastoma.

Investigators at the University of California, SanFrancisco (USA; www.ucsf.edu) and GeorgetownUniversity (Washington, DC, USA; www.georgetown.edu) tested the drug on 21 differentcell cultures derived from the tumors of patientswith glioblastoma. They reported in the March 30,2010, online edition of the journal CancerResearch, that 16 of the cultures stopped growing.The remaining five, all of which lacked the genefor the tumor-suppressor protein retinoblastoma(Rb), were not affected by the drug.

In the animal experiment, the investigators

implanted three different strains of human glioblas-toma directly into the brains of mice, which werethen treated with PD-0332991. Results indicatedthat the drug effectively reached the intracranialtumors, and that the tumors did not grow as longas the mice continued to receive the drug.However, the animals quickly succumbed to thecancer if drug treatment was stopped.

“What is especially encouraging about thisagent is that we found it can easily pass throughthe blood-brain barrier and access glioblastoma,and that there is already a simple test availablefor screening glioblastoma patients in advanceto see whether or not they should be responsiveto this therapy,” said contributing author Dr. C.David James, professor of neurological surgeryat the University of California, San Francisco.“We do not know how well this agent will per-form in patients with glioblastoma, but in themice we studied, we saw very impressive,durable effect that was sustained as long as ther-apy was administered.”

Glioblastoma Growth Inhibitor Readily Passes Blood-Brain Barrier

CCancer researchers have synthesized a potentanalogue of a naturally occurring compound

that prevents most tumor metastasis in a mousemodel.

Investigators at Weill Cornell Medical College(New York, NY, USA; www.med.cornell.edu) havebeen working for several years with migrastatin, anatural product secreted by Streptomyces bacteria.While migrastatin has only weak antimetastasisactivity, synthetic analogues of this compound suchas macroketone are much more effective inhibitorsof tumor cell migration, invasion, and metastasis.

Results published in the April 15, 2010, onlineedition of the journal Nature revealed that miceimplanted with tumor cells and then treated withmacroketone did not die of metastatic cancer, while

untreated animals did. In experiments where ani-mals were treated a week following tumor trans-plantation, 80% of the treated animals survived.

Macroketone did not prevent implanted cancercells from forming tumors or from growing, but itdid stop tumor cells from spreading. This was trueeven when macroketone was given after tumorshad already formed. At the molecular level, theaction of macroketone was shown to be through itsspecific binding to the actin-binding site on thecytoskeleton protein fascin. This binding disruptedthe mechanism used by the cancer cells to move.

“This suggests to us that an agent like macroke-tone could be used to both prevent cancer spreadand to treat it as well,” said senior author Dr. Xin-Yun Huang, professor of physiology and biophysics

at Weill Cornell Medical College. “Of course,because it has no effect on the growth of a primarytumor, such a drug would have to be combinedwith other anticancer therapies acting on tumorcell growth. The beauty of this approach is thatfascin is overexpressed in metastatic tumor cells butis only expressed at a very low level in normalepithelial cells, so a treatment that attacks fascinwill have comparatively little effect on normal cells– unlike traditional chemotherapy which attacks alldividing cells.”

“More than 90% of cancer patients die becausetheir cancer has spread, so we desperately need away to stop this metastasis,” said Dr. Huang. “Thisstudy offers a paradigm shift in thinking and, poten-tially, a new direction in treatment.”

Macroketone Blocks Metastasis in Mouse Model

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Internet Tool PredictsRelationship BetweenMutation and Disease

GGenomic researchers have established a broad data-base that relates amino acid substitutions (AAS) in

proteins caused by mutations with the developmentand severity of diseases and disease syndromes.

Investigators at the Buck Institute for Age Research(Novato, CA, USA; www.buckinstitute.org) analyzednearly 40,000 AAS in what grew to become one of themost comprehensive studies of mutations. With thisdata, they compiled datasets of human disease-associat-ed AAS in the contexts of inherited monogenic disease,complex disease, functional polymorphisms with noknown disease association, and somatic mutations incancer, and compared them with respect to predictedfunctional sites in proteins. A detailed description ofthe research was published in the January 5, 2010,online edition of the journal Human Mutation.

"We now have a quantitative model of functionusing bioinformatic methods that can predict thingslike the stability of the protein and how its stability isdisrupted when a mutation occurs," said senior authorDr. Sean Mooney, associate professor bioinformatics atthe Buck Institute for Age Research. "Traditionally peo-ple have used a very time consuming process based onevolutionary information about protein structure topredict molecular activity. I think we are the first groupto really quantitatively describe the universe of molec-ular functions that cause human genetic disease."

To facilitate such collaboration the investigatorshave made public on the Internet a tool designed toenhance the functional profiling of novel AAS. The toolcan be accessed at www.mutdb.org/profile.

Label-Free Screening Available for Standard

Microtiter Plate Readers

AAhigh performance set of label-free screening toolsbased on surface plasmon resonance (SPR) tech-

nology that does not require expensive special equip-ment is now available to researchers and drug develop-ers.

The technology, represented by the Pharma-Diagnostics (Zellik, Belgium; www.pharmadiagnostics.com) SoPRano line of reagents, is based on ligand-coat-ed colloidal gold nanoparticles. A major advance is thatthese reagents can be used in standard 96-wellmicrotiter plates and read on the plate readers alreadyfound in most biotechnology laboratories. The reagentsare complemented by easy-to-use protocols and areapplicable to a wide range of assays for both small mol-ecule and antibody screening and characterization.

“With SoPRano, PharmaDiagnostics is providinglabel-free screening for a much broader range ofresearchers,” said Dr. David Ricketts, CEO ofPharmaDiagnostics. “Early customer feedback hasbeen extremely positive. This product launch and ournew corporate website and online SoPRano facilitydemonstrate PharmaDiagnostics' commitment todevelop and enhance SoPRano and bring our cus-tomers real value. After our recent USD 3.5 millionfundraising, the launch of SoPRano is another signifi-cant step forward in the development of Pharma-Diagnostics' business.”




SScientists have discovered that study of a genecalled DAF-16, which is found in many ani-

mals, including humans, could provide new waysfor altering aging, immunity, and resistance inhumans. DAF-16 is strongly involved in determin-ing the rate of aging and average lifespan of thenematode (roundworm) Caenorhabditis elegansand its close evolutionary cousins.

Dr. Robin May, from the University ofBirmingham (UK; www.bham.ac.uk), and thelead researcher of the study, said, “Aging is aprocess that all organisms experience, but at verydifferent rates. We know that, even betweenclosely related species, average life spans can varyenormously. We wanted to find out how normalaging is being governed by genes and what effectthese genes have on other traits, such as immuni-ty. We looked at a gene that we already knew tobe involved in the aging process, called DAF-16,to see how it may determine the different rates ofaging in different species.”

Dr. May and colleagues comparedlongevity, stress resistance, and immu-nity in four related species of the nem-atode. They also looked for differencesin the activity of DAF-16 in each of thefour species and discovered that theywere all quite distinct in this respect.Moreover, importantly, the differencesin DAF-16 corresponded to differencesin longevity, stress resistance, andimmunity between the four species-in generalhigher levels of DAF-16 activity correlated withlonger life, increased stress resistance, and betterimmunity against some infections.

Dr. May continued, “DAF-16 is part of a groupof genes that drive the biologic processes involvedin aging, immunity and responses to physical orenvironmental stresses. The fact that subtle differ-ences in DAF-16 between species seem to havesuch an impact on aging and health is very inter-esting 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 ofgenes in order to balance the differing needs of anindividual’s immune system over time.

The research was published the April 2010issue of the journal PLoS ONE.

Image: Light micrograph of Caenorhabditis elegans,a millimeter long, soil-dwelling nematode wormwhich feeds on bacteria (Photo courtesy of SinclairStammers / SPL).

Aging Gene Could Help Modify Immunity in Humans

DD rug developers will benefit from a newly avail-able highly predictive, relatively simple, and

cost-effective way to monitor the toxicity profile ofa test compound.

The objective of a drug developer is to assesstoxicology early in the preclinical discovery process,and generate optimized structures with a risk pro-file that can be advanced into in vivo safety assess-ment with a reasonable expectation of success.

The Scottish company Sistemic (Glasgow,United Kingdom; www.sistemic.co.uk) offers ahighly predictive, relatively simple, and cost-effective way to monitor the toxicity profile of atest compound. Sistemic’s “SystemRNA” kits aredirected at key therapeutic areas including oncol-ogy and inflammation where results they producewill enable better strategic decision making at

critical stages of the drug discovery and develop-ment process.

The “SistemRNA” platform uses human cellsand it is based on changes in the level ofmicroRNA expression upon exposure of the cellsto candidate drug compounds. There are only sev-eral hundred microRNAs expressed in a cell,whose expression pattern may change after expo-sure to a bioactive compound. The microRNAresponse is reproducible, characteristic of com-pound type, and is a robust early sentinel markerdefining the biological interaction between com-pound and cell. The benefit of “SistemRNA” is thatwith microRNA profiling, pathway control of theentire biological system of the cell can be analyzedin one assay. Data is kept to a minimum whereasknowledge is greatly enhanced allowing more

appropriate decisions to be taken on compounddevelopment.

“The validity of our use of microRNA profilingas a sentinel marker of phenotypic effects in modelsystems is overwhelming, and we are seeing timeand time again very strong correlations betweenmicroRNA changes and drug effects,” said Dr.Vincent O'Brien, chief scientific officer at Sistemic.

Dr. Chris Hillier, CEO of Sistemic, said, “Thestrength of Sistemic’s approach is that we providean extremely reliable way to make key decisionson safety and efficacy based on very strong biolog-ical information about the properties of your com-pound without reference to the expected target.This lack of bias produces valuable evidence tosupport drug development and has the power tocreate some very exciting opportunities.”

MicroRNA Profiling Kits Facilitate Drug Toxicity Studies

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AAnew technique that uses genetherapy to help repair damaged

lungs previously found unsuitablefor transplant shows promise foraddressing the significant shortageof healthy donor organs.

Recent research on interleukin-10 (IL-10) gene therapy was pre-sented April 21, 2010, during theInternational Society for Heart andLung Transplantation's (ISHLT) 30thannual meeting and ScientificSessions in Chicago, IL, USA.

More than 80% of potentialdonor lungs cannot be used fortransplantation because the organsare damaged either before or dur-ing the transplant process. The IL-10 gene therapy could potentiallyincrease the viability of thosedonor lungs. IL-10 is an anti-inflammatory cytokine. This pro-tein down-regulates, or decreases,the inflammatory potential ofinjured cells. It also has the capac-ity to inhibit the recipient’simmune system that rejects thetransplanted organ. The IL-10 geneis found normally in animal andhuman cells, and plays a role insuppressing the immune responseto infection and the rejectionresponse to foreign materials suchas transplanted organs.

“This type of therapy could ulti-mately have a great impact on lung

transplantation around the world,”said Shaf Keshavjee, M.D., from theUniversity of Toronto (Canada;www.utoronto.ca), who presentedthe findings at the ISHLT sympo-sium. Dr. Keshavjee and his team ofresearchers have focused on IL-10because the protein protects againstinflammatory injury as well asimmune therapy. This newapproach has successfully reducedinflammation and improved func-tion in pig lungs that were treatedoutside the body and transplantedinto recipient pigs. The sameapproach has brought about a simi-lar improvement in human donorlungs deemed unsuitable for trans-plantation.

This genetic technique couldalso be used to deliver other geneproducts to the lungs and mighteventually be used to repair dam-aged lungs in a living patient. TheInternational Society for Heart andLung Transplantation (ISHLT) is anot-for-profit organization dedicat-ed to the advancement of the sci-ence and treatment of end-stageheart and lung diseases. TheSociety now includes more than2,200 members from 45-plus coun-tries, representing a variety of disci-plines involved in the managementand treatment of end-stage heartand lung disease.

Technique May ImproveAvailability of Donor Organs

NNanoparticles coated with specificimmune markers have been used

to prevent and cure diabetes in a mousemodel of the disease. Investigators atthe University of Calgary (Alberta,Canada; www.ucalgary.ca) created anovel class of nanoparticles coated witha complex of diabetes-related peptideantigens bound to major histocompati-bility complexes (pMHC-NP). Thisnanoparticle vaccine was designed tostimulate a specific immune responsethat would inhibit autoimmune T cellsthat in diabetes attack and destroyinsulin-producing pancreatic beta cells.The stimulation was specific to theextent that only these T cells wereaffected while the integrity of theremainder of the immune response sys-tem was not.

Results published in the April 8,2010, online edition of the journalImmunity revealed that treatment ofNOD mice with the nanoparticlessuppressed the recruitment of anti-

beta T cells, prevented the disease inprediabetic mice, and restored nor-mal blood sugar levels in diabeticanimals.

“Essentially there is an internal tug-of-war between aggressive T cells thatwant to cause the disease and weaker Tcells that want to stop it from occur-ring," said senior author Dr. PereSantamaria, professor of microbiologyand infectious diseases at the Universityof Calgary. “If the paradigm on whichthis nanovaccine is based holds true inother chronic autoimmune diseases,such as multiple sclerosis, rheumatoidarthritis, and others, nanovaccinesmight find general applicability inautoimmunity.” The nanoparticle vac-cine technology used in this study hasbeen licensed by Parvus Therapeutics,Inc. (Calgary, Alberta, Canada; www.parvustherapeutics.com) a biotechnol-ogy transfer and commercializationcompany belonging to the Universityof Calgary.

Nanovaccine Suppresses AutoimmuneResponse in Diabetic Mouse Model

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

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SS tudies on breast cancer in amouse model have shown that

despite lacking estrogen and proges-terone receptors mammary stemcells are highly responsive to steroidhormone signaling, a finding thatopens the way for the developmentof new preventions and treatmentsfor the disease.

Previous studies have estab-lished a strong linkage betweenfemale hormone levels and breastcancer, with mutations in mamma-ry stem cells being the likely sourceof breast cancer cells. In the currentstudy, published in the April 11,2010, online edition of the journalNature, investigators at the Walterand Eliza Hall Institute (Parkville,Victoria, Australia; www.wehi.edu.au) showed in a mouse model

that removal of the ovaries or treat-ment with hormone inhibitorsreduced breast stem cell numbersand induced a state of dormancy inthese cells.

In contrast, pregnancy led to atransient 11-fold increase in breaststem cell numbers, probably medi-ated through signaling via theRANK ligand pathway. The aug-mented breast stem cell pool indi-cated a cellular basis for the short-term increase in breast cancer inci-dence that accompanies pregnancy.

“There is clear evidence that themore menstrual cycles a womanhas the greater her breast cancerrisk,” said senior author Dr. JaneVisvader, associate professor ofmolecular genetics at the Walterand Eliza Hall Institute. “There is

even an increase in breast cancerrisk in the short-term followingpregnancy. However the cellularbasis for these observations hasbeen poorly understood.”

Overall, the findings generatedin this study suggest that successfulchemical treatment to prevent

development of breast cancer maybe achieved, in part, through sup-pression of stem breast-cell func-tion.

Image: Colored scanning electronmicrograph (SEM) of breast cancercells (Photo courtesy of SteveGschmeissner / SPL).

Effect of Estrogen on Mammary Stem Cells Directly Linked to Breast Cancer Risk

TThe use of nanotubes coated with specific T cellantigens reduced by nearly one-third the time

required to enrich the blood culture of patientsundergoing adoptive immunotherapy with cancer-fighting antitumor specific T cells.

Adoptive immunotherapy is a cancer treatmentprotocol based on extracting a patient's blood inorder to increase the number of anticancer T cells,the growth of which is often suppressed by thetumor so that they are too few to be effective.Different growth factors are used to boost the pro-duction of T cells outside the body. Once enoughT cells have been produced, the blood is trans-ferred back into the patient's body.

In this regard, investigators at Yale University

(New Haven, CT, USA; www.yale.edu) used atype of carbon nanotube to stimulate in vitro Tcell production. They reported in the April 20,2010, issue of the journal Langmuir that function-alized single-walled carbon nanotube bundles (f-bSWNT) coated with T cell-stimulating antibodiesenhanced both the kinetics and magnitude of Tcell stimulation as compared to the same concen-tration of free antibodies in solution. Thisenhancement was unique to f-bSWNT comparedto other artificial substrates with high surface areaand similar chemistry.

The investigators used FRET (FluorescenceResonance Energy Transfer) microscopy to showthat enhanced T cell production was the result of

the preferential formation of large antibody stimuliclusters on the surface of functionalized versusuntreated nanotubes.

“Carbon nanotube bundles resemble a lymphnode microenvironment, which has a labyrinthsort of geometry,” explained senior author Dr.Tarek Fahmy, associate professor of chemical engi-neering and biomedical engineering at YaleUniversity. “The nanotube bundles seem to mimicthe physiology and adsorb more antigens, promot-ing a greater immunological response.”

“We think this is a really interesting use of car-bon nanotubes,” said Dr. Fahmy. “It is a way toexploit the unique properties of this material forbiological application in a safe way.

Clustered T Cell Antigens on Carbon Nanotubes Enhance Adoptive Immunotherapy

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AAprotein involved in tissue growth in animalssuch as salamanders, zebrafish, and mice can

also stimulate the regeneration of damagedhuman bone, according to a new study.

Researchers at the Stanford University Schoolof Medicine (CT, USA; med.stanford.edu) stimu-lated the rapid bone growth in laboratory mice byinjecting them with a protein called Wnt, pack-aged in a form that could be used in humans,opening the door to additional experiments toheal skin, muscle, brain, and other tissue injuries.It may also eventually provide a much-neededalternative to currently available drugs based onbone morphogenetic proteins (BMPs), which areapproved for use in humans to speed bone growthin spinal fusions and long bone fractures, but havebecome increasingly associated with a number ofadverse side effects.

Wnt, a key player in tissue regeneration inmany organisms, was exceedingly difficult topurify in an active form and, once isolated, wasfound to be both insoluble and hydrophobic. Theresearchers at Stanford succeeded in overcomingthis problem by using liposomes – tiny,hydrophilic molecular bubbles. The researchersplanted laboratory-made Wnt on the liposomesbubble’s outer surface, thus allowing it to be sus-pended in liquid for delivery into the body. Totest the delivery method, the researchers drilledone-millimeter holes into the leg bones of themice with a high-speed dental drill. They theninjected the Wnt-covered liposomes at the site ofthe damage and compared the rate and pattern ofbone formation with that of control animals, andwith that of animals injected with Wnt without aliposomal escort.

The researchers found that within threedays, the animals who had received Wnt had3.5 times more new bone than the other twogroups; and after 28 days, the newly formedbone had completely healed, while the controlanimals were still in the process of repairing theinjury.

Further investigation showed that Wntworks by increasing the proliferation of boneprogenitor cells, which then became new bone,mimicking the way Wnt-activated healingoccurs naturally. Laboratory mice that had beengenetically modified to have a more prolongedWnt signal also healed more quickly than didcontrol mice, and as in other animals, the Wntpathway was found to be activated in responseto injury and required for normal healing. Thestudy was published in the April 28, 2010,online issue of the journal Science TranslationalMedicine.

“We believe our strategy has the therapeuticpotential to accelerate and improve tissue heal-ing in a variety of contexts,” said lead authorprofessor of surgery Jill Helms, D.D.S., Ph.D.“After stroke and heart attack we heal theinjuries slowly and imperfectly, and the result-ing scar tissue lacks functionality. Using Wntmay one day allow us to regenerate tissue with-out scarring.”

Wnt proteins form afamily of highly conservedsecreted signaling mole-cules that regulate cell-to-cell interactions duringembryogenesis. Insightsinto the mechanisms ofWnt action have emergedfrom several systems:genetics in Drosophilaand Caenorhabditis ele-gans, ectopic gene expres-sion in Xenopus embryos,and biochemistry in cellcultures. Mutations in Wnt genes or Wnt pathwaycomponents lead to specific developmentaldefects, while various human diseases, includingcancer, are caused by abnormal Wnt signaling.

Image: Light micrograph of a section through agrowing bone, showing cartilage cells (blue)being replaced by bone (purple) formed fromosteoblast cells (Photo courtesy of SteveGschmeissner / SPL).

Novel Protein Technology Triggers Rapid Bone Growth



Bio Research InternationalBio Research International

DD rug developers now have accessto analytical systems that allow

for real time determinations of theeffects of candidate drugs on cell via-bility. An important facet of drugdevelopment is to understand how acandidate drug compound affects themolecular and biochemical pathwaysthat regulate cell viability. The otherside of the same coin is the need toidentify potential cytotoxic sideeffects of potential therapeutic agents.

To provide a means for collectingcritical information on drug cytotoxic-ity, one of the world’s largest biotechcompanies Roche (Basel, Switzerland;www.roche.com), has introduced itsxCELLigence System real time cellviability monitoring system. Roche isa world leader in in-vitro diagnostics,tissue-based cancer diagnostics, and apioneer in diabetes management witha catalogue of differentiated medi-cines in oncology, virology, inflamma-tion, metabolism, and central nervoussystem disorders.

The xCELLigence System allowsfor real-time, label-free dynamic mon-itoring of cellular phenotypic changesby measuring electrical impedance.The system measures impedanceusing interdigitated microelectrodesintegrated into the bottom of eachwell of the tissue culture E-Plates 96.Impedance measurements are dis-played as Cell Index (CI) values, pro-viding quantitative information aboutthe biological status of the cells,including cell number, cell viabilityand cell morphology.

Electronic impedance of the micro-electrodes is mainly determined bythe ionic environment in the regions

around the electrodes and can bemonitored as baseline impedance byapplying an electrical field to the elec-trodes. The presence of the cells willaffect the local ionic environment atthe electrode/solution interface, lead-ing to an increase in the electrodeimpedance. The more cells there areon the electrodes, the larger theincreases in electrode impedance. Inaddition, the impedance changedepends on the quality of the cellinteraction with the electrodes. Forexample, increased cell adhesion orspreading will lead to a larger changein electrode impedance. Thus, elec-trode impedance, which is displayedas cell index (CI) values, can be usedto monitor cell viability, number, mor-phology, and adhesion degree in anumber of cell-based assays.

CI was derived as a relativechange in measured electrical imped-ance to represent cell status. Thismeans that when cells are not pres-ent or are not well adhered on theelectrodes then the CI is zero.

Under the same physiological con-ditions, when more cells are attachedon the electrodes, then the CI valuesare larger. Thus, CI is a quantitativemeasure of cell number present in awell of the microplate. Additionally,change in a cell status, such as cellmorphology, cell adhesion, or cell via-bility will lead to a change in CI.

In addition to monitoring cell via-bility, the xCELLigence System is ableto identify culture wells with inappro-priate cell numbers at the beginning ofthe assay, thus minimizing the role ofcell seeding and culture-plate edgeartifacts during data analysis.

Real-Time Cell Analysis System Provides Data on Drug Cytotoxicity

ZyGEM to CommercializeDNA Detection and Testing

Platform

ZZyGEM Corp. Ltd. (Hamilton, New Zealand; andSolana Beach, CA, USA; www.zygem.com) has

acquired MicroLab Diagnostics Inc. (http://microlabdiagnostics.com), a private company develop-ing microfluidic devices for rapid DNA testing. ZyGEMwill market products integrating its DNA extraction,reagents, and detection assays with microfluidic chiptechnology developed by MicroLab, which will operateas a business unit of the new company.

MicroLab's miniaturization of the entire DNAtesting process within a single closed system signif-icantly reduces the amount of sample and reagentsthat are needed, while virtually eliminating thechances for handling error or contamination. Theintegrated new products will dramatically decreasethe time, complexity, and cost of conducting DNAtesting and have transformational potential in abroad range of applications.

The ZyGEM/MicroLab system is compact, easy-to-use, and cost-effective, making it suitable for useboth in the laboratory and out in the field. It canperform multiplexed analyses, and it can also beconfigured for specific applications. Portable hand-held versions are in development.

Partnership to Research Novel Image-Guided Therapy

Concepts based on RNAi

PPhilips Healthcare (Best, The Netherlands;www.medical.philips.com) and RXi Pharma-

ceuticals Corp. (Worcester, MA, USA; www.rxipharma.com), a biopharmaceutical company,announced that they have entered into a jointresearch agreement to study the benefits of combin-ing proprietary technologies from both companiesfor the targeted delivery of experimental therapeu-tics based on RNA interference (RNAi).

Compounds based on RNAi represent a promisingnew class of drugs for the targeted treatment of anumber of diseases including cancer and cardiovas-cular disease. Currently, however, one of the greatestchallenges in developing RNAi-based therapeutics isfinding ways to deliver them to their target whilekeeping them fully active. The joint research pro-gram between Philips and RXi will address this chal-lenge by examining, in preclinical studies, the possi-bility of using RXi’s sd-rxRNA (self-delivering rxRNA)in conjunction with Philips’ ultrasound technologyto achieve the targeted delivery and monitoring ofRNAi-based compounds in cells.

Each company will contribute proprietary tech-nologies, resources, and expertise to evaluate inno-vative approaches for the targeted delivery of RXi’ssd-rxRNA compounds in appropriate preclinicalmodels using ultrasound-mediated drug deliveryunder image guidance. The preparation andresearch will be conducted at Philips’ Life Techresearch facilities at the High Tech Campus inEindhoven (The Netherlands), which are focusedon R&D at the interface of life sciences and medicaltechnologies, and at RXi’s research and develop-ment facilities in Worcester.

MMerge Healthcare (Milwaukee, WI, USA;www.merge.com), a health information tech-

nology (IT) solutions provider, reported that it wasselected by Cato Research, Ltd. (Durham, NC, USA;www.cato.com) to provide the proprietary etrialsEDC solution through Merge’s technology transferprogram. This new agreement expands Merge’spartnership with Cato to provide additional technol-ogy for clinical trials management, as well as extend-ing the relationship for an additional five years.

“We have enjoyed a long-standing partnershipwith Merge Healthcare for their clinical trial solu-tions,” noted Allen Cato, M.D., Ph.D., and CEO ofCato Research, Ltd. “The etrials technology hasbeen consistent and intuitive, and the Merge teamhas been quick to help us use it successfully. Addingthe etrials EDC platform in a technology transfermodel will enable our company to efficiently buildand deliver solutions to help our customers runcost-effective clinical studies.”

The technology transfer program allows Cato touse the etrials EDC system to build and deploy cus-tom clinical trial studies that leverage the powerfulreporting capabilities of Merge’s technology.Because the etrials EDC solution is built on a SaaSplatform, it can be licensed on a subscription orstudy basis. Moreover, Merge’s etrials IVR andePRO solutions can be integrated with the EDC sys-tem to provide comprehensive eClinical solutions.Merge’s team of clinical trial experts will also pro-vide training and support to Cato.

“We are thrilled to partner with Cato to bring etri-als 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 todeliver an easy-to-use solution to their clients. It isour goal to understand how our customers’ conductbusiness in order to deliver robust solutions thatmeet their long-term needs and allow for mutuallybeneficial partnerships like this one.”


Merge Healthcare Selected as e-Trials Technology Transfer Service Provider

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