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Four anti-cancer compounds identified

Last Updated on Friday, 2 December 2011 12:38 Written by admin Friday, 2 December 2011 12:38

Sydney: Four new anti-cancer compounds have shown promise in inhibiting the growth of tumours, according to a new approach.

Jason Smith, doing his M.Phil. in biomolecular sciences from Macquarie University, combined existing knowledge of an enzyme with computational chemistry approach to identify novel (cancer) inhibitors.

The enzyme (indoleamine 2,3-dioxygenase) has generated excitement amongst researchers due to its increasingly recognised role as a drug target, particularly in cancer.

Over the past 10 years, scientists have learnt that compounds inhibiting this enzyme allow the immune systemto attack cancer cells, the journal Bio-organic and Medicinal Chemistry reported.

“They have found that if you use these inhibitors alone, they slow tumour growth. Even more exciting is that in combination with chemotherapy, these inhibitors have the potential to destroy a tumour entirely,” explains Smith, a university statement said.

After conducting virtual screening of a database of almost 60,000 compounds, Smith found 18 compounds that could potentially act as inhibitors of this enzyme.

He then tested them and found four compounds with particularly exciting prospects.

“Computational chemistry means we don`t have to spend years testing thousands of compounds in the lab,” he said.

“We can analyse all the potential compounds and narrow them down in a matter of six month`s preparation and virtual screening, instead of years. In fact, after all the preparation and groundwork, the screening itself takes around 100 hours,” he further added.

Source: http://zeenews.india.com/news/health/diseases/four-anti-cancer-compounds-identified_14748.html

Posted under Cancer Research, Cell Analysis, Discoveries, Innovations and Patents, Oncology Research, R & D, Research Projects  |  Comments Off

NMR Fine-Tuned for High-Content Metabolomics Screening

Last Updated on Monday, 28 November 2011 01:48 Written by admin Monday, 28 November 2011 01:48

Scientists report on the development of a nuclear magnetic resonance (NMR)-based method forscreening the metabolomic response of drug-treated mammalian cells to drug therapy. TheSanford-Burnham Medical Research Institute, and Rady Children’s Hospital investigators, say the highly sensitive, fast, and simple method is carried out in 96-well format, and could have particular utility as a method for high-throughput primary screens. The preparation technique takes just five minutes to metabolically inactivate and lyse hundreds of drug-treated samples, and a metabolomic screening of around 100 samples can be carried out in 24 hours.

Giovanni Paternostro, M.D., and colleagues describe their approach, analyze the results of validation studies on drug-treated cancer cell lines, and evaluate the technique for screening a kinase inhibitor library. Their work is described in Nature Communications in a paper titled “Metabolomic high-content nuclear magnetic resonance-based drug screening of a kinase inhibitor library.”

High-throughput screening (HTS) is widely used as a tool in drug discovery, but most screens monitor a single variable, which is often related to activity on a single target, the researchers explain. Although high-content screening (HCS) approaches that provide multivariate readouts are gaining ground, these techniques generally rely on automated digital microscopy.

The technique developed by the Sanford-Burnham researchers involves seeding cells into a 96-well plate and treating them with several drugs. The cells’ metabolism is then quenched using sodium dodecyl sulphate (SDS), and the cells lysed using ultrasonication, in an overall process that takes just five minutes. The entire content of the well, including endo- and exo-metabolome, is then transferred into an NMR tube for analysis.

The team needed to address the relative contribution of the intracellular metabolome to the NMR spectrum acquired on the well content, including both medium and the lysed cell metabolomes. To answer this they generated NMR spectra on the entire content of the well (i.e., both endo- and exo-metabolomes), and also on the exometabolome, the endometabolome, and the medium. They found that major NMR signals arose from the extracellular metabolites, but several signals arising from the intracellular metabolites were also detected, for example glutamate, choline, and phosphocholine. Importantly, they found that spectra acquired on samples containing both endo- and extracellular metabolomes included signals resulting exclusively from the endometabolome—such as phosphocholine and glycerophosphocholine—which didn’t overlap with other extracellular resonances.

The researchers evaluated the sensitivity of the approach for monitoring metabolic changes induced by 24 hours of drug treatment, on both suspension (CCRF-CEM human leukemia cells) and adherent mammalian carcinoma cell lines (human SKOV-3 ovarian cancer cells). The cell lines were treated using either dexamethasone (Dex), rapamycin (Rap) dichloroacetate (DCA), vincristine (Vin), and different doses of L-asparaginase. The resulting spectra, generated using three different 1H NMR pulse sequences, showed that, as expected, the response to drug treatment by the more resistant SKOV-3 cells was far less pronounced compared with the CCRF-CEM cells. Encouragingly, the NMR screening approach could also be applied to detecting metabolic changes in response to forms of intervention, such as the transfection of HeLa cells the microRNAs mir-121 and mir-16. These results indicated that mir-16 induced a greater degree of metabolomic change than mir-121.

Because the developed technique requires just a small amount of cells, the investigators suggest in might have utility in studying drug response directly in primary cells, and so avoid phenotypic changes that can be induced by growth in culture. They evaluated metabolomic changes in cells isolated from bone marrow specimens of an untreated AML patient, in response to treatment with Rap and L-asparaginase, at different doses. In order to specifically highlight metabolic changes in the cells themselves, the NRM spectra acquired on unconditioned medium were compared to those acquired on AML primary cells with and without drug administraton. The resulting spectra clearly showed distinct changes in the metabolome of the primary cells as a result of drug treatment. Further analyses indicated these changes were more pronounced in response to L-asparaginase than for Rap therapy.

The team then moved on to use the approach for carrying out screening of metabolomic response to a kinase inhibitor (KI) library. Multiple rounds of screening on KIs with well-characterized and less well-characterized effects on the metabolome confirmed the utility of the technique for identifying metabolic alterations resulting from inhibitor treatment. More specifically, four hits were validated from their action on the well-characterized lactate to pyruvate ratio parameter.

“We believe that this NMR-based assay might find an immedi­ate relevant application for screening a large number of individual or combinatorial drug interventions, reducing the number of pos­sible drugs to be studied in more detail,” the authors state. “In addition, it might find an immediate relevant application into clinical studies.”

They admit that the main drawback of NMR is the relatively limited number of compounds that can be detected. However, they stress, “although not comprehensive of all metabolites, the wealth of information obtained from the multivariate metabolic readout is of great advantage for drug screening purposes.” The method could therefore represent a valuable high-throughput primary screen, which could then be followed by secondary assays to analyze the exo- and endo-metabolomes of selected hits using combinations of different anaytical platforms.

“There are many other possible applications of this method, for example lactate production and substrate utilization in cancer versus noncancer cells, or gluconeogenesis from different sub­strates in hepatocytes, relevant to diabetes. Importantly, because the measurements are performed within a global metabolic profile, they can also provide a series of compounds with partially different mechanisms of actions, which can be explored for potential syner­gies.”

Source: http://www.genengnews.com/gen-news-highlights/nmr-fine-tuned-for-high-content-metabolomics-screening/81245988/

Posted under Compound Screening, HT Screening, North America, Press Releases, Research Projects, USA and Canada  |  Comments Off

Research at A&M and Scripps finds HIV-killing compound

Last Updated on Monday, 28 November 2011 01:35 Written by admin Monday, 28 November 2011 01:35

COLLEGE STATION - A powerful topical preventative for HIV, the virus that causes AIDS, could be a step closer to clinical trials, thanks to a newly discovered molecular compound that research at Texas A&M University and the Scripps Research Institute shows dissolves the virus on contact.

The ability of the synthetic compound known as “PD 404,182″ to break apart the AIDS-causing virus before it can infect cells was discovered by Zhilei Chen, assistant professor in the university’s Artie McFerrin Department of Chemical Engineering, and her team of researchers. Their findings appear in the November online edition of “Antimicrobial Agents and Chemotherapy,” a journal of the American Society for Microbiology.

“This is a virucidal small-molecule compound, meaning that it has the ability to kill a virus; in this case that virus is HIV,” Chen says.

“Basically, it acts by breaking the virus open. We found that when HIV comes in contact with this compound, it breaks open and loses its genetic material. In a sense, the virus ‘dissolves,’ and its RNA becomes exposed.

Since RNA is pretty unstable, once it is exposed it’s gone very quickly and the virus is rendered non-infectious.”

In other words, the compound works by quickly ripping open the virus before it can inject its genetic material into a human cell. What’s more – and perhaps even more important – the compound, Chen explains, achieves this by acting on something within the virus other than its viral envelope protein, meaning that the virus can’t alter its proteins to bolster its resistance – something that’s made HIV notoriously difficult to treat.

“We believe this compound is not working on the viral protein of the viruses but on something else common in all the viruses on which we tested it – some cellular material common in these viruses,” Chen notes. “Because this compound is acting on a component that is not encoded by the virus, it will be difficult for the virus to evolve resistance against this compound.”

While not a cure for HIV, the compound demonstrates significant potential for use as a preventative, specifically in the form of a topical gel that could be applied in the vaginal canal, Chen explains.

“We conducted a number of tests to demonstrate that this compound remains active in vaginal fluid and is not rendered ineffective,” Chen says. “In the form of a vaginal gel, the compound would serve as a barrier, acting almost instantaneously to destroy the virus before it could infect a cell, thereby preventing HIV transmission from one person to another.”

Surprisingly, Chen and her team did not set out to discover an HIV preventative. Instead, they were conducting screenings of molecules for use in potential drug therapies targeting hepatitis C virus, which causes the dangerous and often fatal disease of the liver. Employing a screening system developed by Chen, the team screened thousands of molecular compounds, in search of those that could block aspects of the HCV life cycle.

During the course of the screenings, the team made an interesting discovery

- not only was PD 404,182 an HCV inhibitor, it also worked on lentiviruses (the group’s negative control in its experimental procedures). Intrigued by that finding, Chen then tested PD 404,182 on HIV, which itself is a lentivirus and found the compound to be even more effective on HIV than on HCV.

“We believe PD 404,182 acts through a unique and important mechanism,” Chen notes. “Most of the known virucidal compounds interact with the virus membrane, but our compound does not appear to interact with the virus membrane. Instead, it bypasses interaction with the membrane and still compromises the structural integrity of the virus.”

The ability of the compound to avoid interaction with the virus membrane is important because human cells have similar membranes, Chen notes. If the compound were to disrupt the structure of the virus membrane, it could also disrupt and ultimately kill human cells. PD 404,182 doesn’t interact with these membranes and is therefore a more attractive option for clinical treatment, Chen says.

As is the case with any potential pharmaceutical, several key steps are still needed before it winds up on drug store shelves. In addition to several rounds of animal studies to ensure the compound is safe for humans, further collaborations with chemists are needed to continue to improve the efficiency of the compound. Chen says. What’s more, Chen also plans to further explore the mechanism by which PD 404,182 breaks apart HIV.

This work is collaboration between Chen’s team, consisting of graduate students Ana Maria Chamoun and Rudo Simeon, postdoctoral associate Karuppiah Chockalingam, and Professor Philippe Gallay’s team at the Scripps Research Institute.

Source: http://www.kxxv.com/story/16095021/research-at-am-and-scripps-finds-hiv-killing-compound

Posted under Cell Analysis, Discoveries, Innovations and Patents, DNA Reasearch, HIV Research, New Drugs, North America, R & D, Reports, Research Projects, USA and Canada  |  Comments Off

First Clinical Trial of Autologous Cardiac Stem Cells Shows Positive Results

Last Updated on Tuesday, 22 November 2011 03:13 Written by admin Tuesday, 22 November 2011 03:13

Initial data from the first ever trial to evaluate autologous cardiac stem cell (CSC) transplants in humans suggests that the treatment improves left ventricular (LV) systolic function by an average of 12% over one year, and reduces infarct size in patients with severe heart failure due to ischemic heart disease. The trial investigators say the results triple the 4% average improvement that they had projected and calls for the start of larger Phase II trials.

Stage A of the ongoing open-label Phase I SCIPIO (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy) study, by investigators at the University of Louisville and Brigham and Women’s Hospital, is evaluating CSC transplantation in patients with severe heart failure secondary to ischemic cardiomyopathy. The target population includes patients who underwent coronary artery bypass grafting (CABG), had LV ejection fraction (EF) of less than or equal to 40%, and a previous myocardial infarction.

Treated patients were administered with about a million autologous CSCs by intracoronary infusion, at a mean of 113 days after CABG. To generate the cardiac stem cells, tissue from the right atrial appendage was harvested from the patients at the time of CABG, and CSCs were isolated and expanded at the Brigham and Women’s Hospital.

Data from 14 of 16 patients assigned to the treatment group, and seven from the control group (best supportive care), have now been published in The Lancet to coincide with data presentation at the American Heart Association’s Scientific Sessions meeting in Orlando, FL. The reported data showed that autologous CSC transplantation led to an increase in LVEF from 30.3% before CSC infusion to 38.5% at four months after infusion. In contrast, the LVEF of seven control patients didn’t change over eight months. The benefits of CSC transplantation was even more pronounced at one year in eight evaluated patients, for whom LVEF increased by 12.3 ejection fraction units compared with baseline. In the seven treated patients evaluated using MRI, infarct size was also shown to have decreased by 24% at 4 months, and 30% at one year.

The trial has been led by Roberto Bolli, M.D., at the University of Louisville and Piero Anversa, Ph.D., at Brigham and Women’s Hospital/Harvard Medical School in Boston. “The results are striking,” Dr. Bolli states. “While we do not yet know why the improvement occurs, we have no doubt now that ejection fraction increased and scarring decreased. If these results hold up in future studies, I believe this could be the biggest revolution in cardiovascular medicine in my lifetime.”

The published paper in The Lancet is titled “Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised Phase I trial.”

Source: http://www.genengnews.com/gen-news-highlights/first-clinical-trial-of-autologous-cardiac-stem-cells-shows-positive-results/81245949/

Posted under Cell Analysis, Discoveries, Innovations and Patents, Genetics & Pharmacogenetics, New Drugs, R & D, Reports, Research Projects, Stem Cell Research  |  Comments Off

Coffee Drinking Linked To Lower Risk Of Common Skin Cancer

Last Updated on Tuesday, 25 October 2011 11:19 Written by admin Tuesday, 25 October 2011 11:19

New research presented at a conference in the US on Monday finds that drinking coffee is linked to a lower risk of a common form of skin cancer known as basal cell carcinoma (BCC). Results of a prospective study that followed over 25,000 cases of skin cancer suggest coffee may be an important dietary option to prevent BCC.

The research is the work of Dr Fengju Song and colleagues. Song is a postdoctoral fellow in the department of dermatology at Brigham and Women’s Hospital and Harvard Medical School.

For the study, the researchers used data from the Nurses’ Health Study, covering 72,921 participants followed from June 1984 to June 2008, and the Health Professionals Follow-Up Study, covering 39,976 participants from June 1986 to June 2008. These studies gathered detailed information about diet and health, including consumption of beverages such as coffee.

From those cohorts, the researchers identified 25,480 cases of skin cancer, comprising 22,786 BCC cases, 1,953 squamous cell carcinoma (SCC) cases, and 741 cases of melanoma.

Song and colleagues found a 20% reduction in risk for BCC among women who drank more than three cups of coffee per day, while for men who drank more than three cups per day the risk was 9% lower. These reductions were in comparison to counterparts who only drank less than 1 cup of coffee a month.

The relationship between amount of coffee consumed and BCC was inverse: that is more coffee was linked to lower risk, so that when participants were ranked according to how much coffee they drank, those in the top 20% of consumption (upper quintile) had the lowest risk, with 18% reduction for women and 13% reduction for men, compared to those in the lowest 20% of consumption (bottom quintile).

Song told the press:

“Given the nearly 1 million new cases of BCC diagnosed each year in the United States, daily dietary factors with even small protective effects may have great public health impact. Our study indicates that coffee consumption may be an important option to help prevent BCC.”

The researchers were quite surprised at the finding, and that it only applied to BCC and not the other types of skin cancer.

Animal studies have pointed to links between skin cancer risk and coffee consumption, but epidemiological studies in human populations have not arrived at the same conclusions, they said.

Song explained that tests on mice have shown that consuming caffeine or applying it to the skin reduces the number of UV-damaged keratinocytes (the most common cell type in the outer skin layer or epidermis) via programmed cell death or apoptosis, and that this also markedly reduces the subsequent development of SCC.

“However, in our cohort analysis, we did not find any inverse association between coffee consumption and the risk for SCC,” said Song, who suggests there is a need for further research that specifically addresses the link between coffee intake and BCC and also explores the underlying biological mechanism.

Written by Catharine Paddock PhD
Copyright: Medical News Today

Source: http://www.medicalnewstoday.com/articles/236557.php

Posted under Cancer Research, Discoveries, Innovations and Patents, Oncology Research, R & D, Reports, Research Projects  |  Comments Off

X-Body BioSciences and Tanabe Research Labs Team Up to Develop mAbs for Autoimmune Diseases

Last Updated on Tuesday, 4 October 2011 12:18 Written by admin Tuesday, 4 October 2011 12:18

X-Body Biosciences entered a partnership with Tanabe Research Laboratories (TRL) to identify therapeutic target epitopes and develop monospecific and/or bispecific antibodies against those targets. TRL is focussed on discovery and development of biologicals for autoimmune diseases.

Under terms of the deal, X-Body will be responsible for screening, and TRL will fund the work. TRL has the option to negotiate rights to the antibodies discovered in the collaboration for further preclinical research, clinical development, and commercialization.

X-Body will leverage its human antibody library and Protein Chain Reaction™ screening technology. The platform reportedly allows for screening against cell surface targets in their native state on live cells or purified target proteins.

This selection system employs next-generation sequencing to analyze thousands of hits to obtain high-quality leads. The modular leads generated can be incorporated into V(H) domain, scFv, IgG, and bispecific antibody formats.

“X-Body’s technology represents a major step forward in the ability to rapidly generate thousands of human antibodies against functionally relevant targets,” according to Roland Newman, Ph.D., CSO of TRL. “The power and versatility of X-Body’s platform in generating antibodies against targets that are inaccessible by conventional techniques offers new and exciting prospects.”

Source: http://www.genengnews.com/gen-news-highlights/x-body-biosciences-and-tanabe-research-labs-team-up-to-develop-mabs-for-autoimmune-diseases/81245774/

Posted under Cell Analysis, Clinical Trials, Discoveries, Innovations and Patents, Medicinal Chemistry, R & D, Reports, Research Projects  |  Comments Off

Scientists Use Mutant Protein to Inhibit Cancer Stem Cells and Resensitize Tumors to Lapatinib

Last Updated on Wednesday, 14 September 2011 01:56 Written by admin Wednesday, 14 September 2011 01:56

    Blocking a cancer cell protein from binding to three other proteins may provide a new approach to cancer therapy that both reduces populations of breast cancer initiating cells (BCICs) in breast tumors and sensitizes the tumors to existing treatments such as lapatinib or paclitaxel, scientists claim. The technique uses a specially designed lipid-based vector to make cancer cells, including BCICs, express a mutant form of the BH3-only proapoptotic protein (Bik).

    The mutant protein, called BikDD, essentially competes with Bik for binding to the three antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1. This results in significant antitumor and apoptotic effects and, importantly, improves the anticancer effects of lapatinib or paclitaxel in relevant tumor types, claim the University of Texas M.D. Anderson Cancer Center researchers.

    Reporting on their in vitro and in vivo studies in Cancer Cell, Mien-Chie Hung, Ph.D., and colleagues, claim that their results in addition highlight an important role for the antiapoptotic Bcl-2 proteins in the survival of BCICs. Their paper is titled “BikDD Eliminates Breast Cancer Initiating Cells and Synergizes with Lapatinib for Breast Cancer Treatment.”

    There are currently no drugs that can effectively reduce BCICs in patients, and resistance of these cells to chemo- and radiotherapies means that following therapy, the relative proportions of these cells in the tumors increase, and eventually lead to relapse, the researchers report.

    One of the key mechanisms accounting for chemoresistance in cancer-initiating cells is their low susceptibility to apoptosis, and previous lines of research have implicated the Bcl-2 family of proteins in the ability of cancer cells to escape apoptosis in response to cancer therapy. For example, studies have shown that overexpression of the antiapoptosis proteins Bcl-2, Bcl-xL, and Mcl-1 correlates with high tumor grade, poor patient prognosis, and the development of resistance to chemotherapy.

    More specifically, the acquired resistance of breast cancer cells to lapatinib has been linked with overexpression of Bcl-2 and Mcl-1, suggesting that lapatinib-induced apoptosis requires inactivation of antiapoptotic Bcl-2 family proteins.

    The Anderson team hypothesized that because the overall expression pattern of Bcl-2, Bcl-xL, and Mcl-1 appears to correlate inversely with apoptotic response following drug treatment, an antagonist that targets all of these antiapoptotic proteins might stand a good chance of acting to reinstate apoptotic pathways in breast cancer cells.

    The researchers’ approach to achieving this involved introducing into cancer cells a competitive inhibitor, a mutant form of the Bik protein that normally binds to  to Bcl-2, Bcl-xL, and Mcl-1. To test whether this approach might work, they delivered a lentivirus carrying the BIKDD gene into cells from the human breast cancer line MDA-MB-468. These tests provided confirmation that expression of BikDD significantly inhibited cell growth and resulted in large numbers of apoptotic bodies.

    Interestingly, expression of BikDD also reduced the population of CD44+/CD24- cells (which have previously been identified as breast cancer stem-type cells) and reduced mamosphere formation in vitro. These results were recapitulated in a different cell line: Infecting BT474 human breast cancer cells with the BikDD vector also led to a reduction in the CD44+/CD24- population and of mammosphere formation. Importantly, introducing BikDD into human primary breast tumor samples that had undergone radiation therapy similarly led to significant reductions in the CD44+/CD24- cell population, and mammosphere formation. Equivalent results were obtained using primary mouse tumor cells: administration of BikDD led to marked reductions in populations of mouse breast stem cells, and again blocked mammosphere formation.

    The team went on to investigate whether BikDD could also inhibit cancer initiation. They infected mamospheres from MDA-MB-468 parental cells using the BikDD vector, and then injected surviving cells into NOD/SCID mice. Compared with untreated MDA-MB-468 cells, which readily formed tumors, the BikDD-infected cells demonstrated much lower cancer-forming capacity in vivo, and virtually no tumors developed in the recipient animals, suggesting that BikDD treatment reduced the BCIC population, the researchers remark.

    They then adopted a gene therapy protocol that allows for the assay of cancer initiation activity in tumor xenografts growing in mice after BikDD treatment. This approach exploits a cancer cell-targeting platform developed at the MD Anderson Center, called VISA, VISA’ (VP16-GAL4-WPRE integrated systemic amplifier), which is based on an engineered, promotor-driven expression vector designed to enhance cancer-specific promoter activity by several hundred-fold, and prolong duration of gene expression without loss of cancer specificity.

    Mice bearing MDA-MB-468 tumor xenografts were treated using either a control vector-liposome or with VISA-claudin4-BikDD-liposome complexes, and resulting tumor tissues removed and subsequently passaged into new animals. The results showed that transplanted cells taken from mice that had been treated with VISAclaudin4-BikDD-liposome complexes were far less tumorigenic in new animals than those from mice treated with vector-control-liposome complexes. In fact, none of the animals given tumor cells from the VISA-claudin4-BikDD-treated mice developed cancers. These animals also demonstrated lower numbers of CD44+/CD24- cells, and fewer mammospheres formed after VISAclaudin4-BikDD treatment.

    Because the team’s previous work had suggested that in comparison with wild-type Bik, BikDD demonstrates enhanced binding affinity to Bcl-2 antiapoptotic proteins, they looked more specifically at the effect of its major binding partners Bcl-2, Bcl-xL, and Mcl-1, in BCICs. Using combinations of shRNAs to silence the three Bcl-2, Bcl-xL, and Mcl-1 either individually or in combinations in cultured cells, the researchers found that while knocking down any of the proteins individually had no effect on the numbers of BCIC cells, silencing all three simultaneously reduced the CD44+/CD24- population to 25% of that in control MDA-MB-468 cells, and consequently decreased mammosphere formation. Similar results were obtained using different shRNAs (to verify that the effects weren’t due to off-target activity), and in a different cell line.

    “Taken together, we determined that efficient induction of apoptosis in BCICs requires silencing of all three antiapoptotic Bcl-2 proteins, which suggests that co-antagonism of multiple Bcl-2 antiapoptotic proteins by BikDD may have a better killing effect against BCICs than targeting individual antiapoptotic proteins, which is likely due to their functional redundancy in the survival of BCICs,” the authors state.

    They then exploited the cancer cell-targeting VISA technology to test the therapeutic effects of BikDD gene therapy both in vitro and in vivo. To this end, they engineered a VISA vector that would express BikDD under the claudin-4 promoter that is selectively expressed in breast cancer cells. Testing the resulting VISA-claudin4–BikDD vector in a panel of breast cancer and normal cell lines confirmed that it strongly inhibited the growth of different breast cancer cell lines, but had little or no effect on the growth of normal human cells. The tumor inhibitory effects of the vector were subsequently confirmed in vivo, in one syngeneic mouse breast tumor and multiple human breast tumor orthotopic xenograft models.

    Prior studies had demonstrated that the clinical efficacy of anti-Her2 drugs such as lapatinib and trastuzumab are greatly limited by either inoperative apoptosis machinery or overexpression of Bcl-2 antiapoptotic proteins, the researchers add. With this in mind they moved on to examine whether either the administration of BikDD, or the inhibition of antiapoptotic Bcl-2 proteins could enhance the therapeutic effect of lapatinib in breast cancer cells. They found that VISA-claudin4-BikDD effectively sensitized BT474 and MDA-MB-453 (Her2+), and MDA-MB-468 and BT20 (EGFR+) cells to lapatinib. Similarly, inhibiting Bcl-2, Bcl-xL, and Mcl-1 using shRNAs also sensitized EGFR+/Her2+ breast cancer cells to lapatinib, to about the same degree as BikDD vector therapy. Significantly, VISA-claudin4-BikDD therapy in addition sensitized multiple breast cancer cell lines to paclitaxel in vitro.

    To further examine the therapeutic efficacy of VISA-claudin4-BikDD plus lapatinib combination in vivo, the researchers then treated mice bearing Her2+ BT474 human breast cancer xenografts, with VISA-claudin4-BikDD and/or lapatinib. While VISA-claudin4-BikDD or lapatinib alone had significant tumor inhibitory effects, combining the two treatments demonstrated even better therapeutic efficacy. These results were confirmed in mice carrying tumors derived from different breast cancer cell lines.

    To evaluate therapy on BCIC cells in vivo, VISA-claudin4-BikDD, lapatinib, or paclitaxel were either alone or in combination, to treat a MDA-MB-468 tumor orthotopic xenograft mouse model. Consistent with the in vitro data, BikDD treatment significantly reduced the percentage of CD44+/CD24- cells, whereas, as expected, paclitaxel therapy on its own increased this population by about threefold. In fact, combining the two treatments was better at suppressing tumor growth than VISA-claudin3-BikDD therapy alone, even after therapy was withdrawn, the authors note. Similar results were observed as a result of combination therapy with VISAclaudin4-BikDD and lapatinib.

    Collectively, these results indicate that BikDD driven by VISA-claudin4 vector potently reduced the CD44+/CD24- population in vivo even after chemotherapy, and efficiently attenuated tumor growth after cessation of drug treatment, suggesting that VISA-claudin4-BikDD treatment may serve as a potential therapeutic approach to kill BCICs, which is considered as a major barrier for breast cancer treatment,” the authors write. “By using our newly developed VISA-claudin4-BikDD for treating breast cancer, it is likely that therapeutic efficacy will be enhanced and potential side effects prevented as we have shown that BikDD targets both non-BCICs and BCICs and demonstrates virtually no toxicity in normal cells…Therefore, it is worthy of moving VISA-claudin4-BikDD into a clinical trial.”

    Source: http://www.genengnews.com/gen-news-highlights/scientists-use-mutant-protein-to-inhibit-cancer-stem-cells-and-resensitize-tumors-to-lapatinib/81245670/

Posted under Cell Analysis, Clinical Trials, Discoveries, Innovations and Patents, R & D, Research Projects, Stem Cell Research  |  Comments Off

Insulin May Help Treat Alzheimer’s

Last Updated on Wednesday, 14 September 2011 01:54 Written by admin Wednesday, 14 September 2011 01:54

Researchers are investigating insulin as a possible treatment for Alzheimer’s disease, and in a preliminary study, the results look promising.A study in the journal Archives of Neurology suggests that intranasal insulin – that is, delivered through the nose – may help with cognition and functioning in patients who have both mild and more severe dementia.It’s premature to think of this as a treatment; the study only looked at 104 people, and needs to be repeated in much larger groups before it can be deemed effective. But it sets the stage for broader clinical trials.Recent research has suggested that insulin plays an important role in a number of brain functions, in addition to regulating blood sugar. Insulin promotes cell repair and cell genesis, so the thinking is that it could actually modify the course of Alzheimer’s disease, says lead study author Suzanne Craft, professor of psychiatry at VA Puget Sound and University of Washington.It also appears to protect against the toxic effects of beta-amyloid, the protein involved in the brain plaques associated with dementia. Insulin also prevents the formation of the toxic form of tau, a biomarker found in the cerebrospinal fluid of Alzheimers’ patients, Craft said.”What we saw was that for the insulin-treated patients, the ones who had improvement in memory and function had improvement in spinal fluid biomarkers,” she said.The goal of this study was to supplement and normalize the insulin levels in the brain without affecting levels in the rest of the body. This was done with a device that was designed to deliver insulin through the nose to the brain without getting too much into the blood.Researchers tested patients who had either early Alzheimer’s or mild cognitive impairment, a team for the early stages of dementia.Patients treated with insulin were able to remember information over a period of time better than those who got placebo; in fact, performance improved 20%. They also showed an enhancement in brain glucose metabolism in some areas; those who received placebo tended to show a decline.Alzheimer’s patients in the insulin group benefited more in terms of daily function than those with mild cognitive impairment, but by definition mild cognitive impairment does not greatly impair daily functioning.The treatment had the mild side effects of occasional mild headache and runny nose, but had a good safety profile generally, Craft said.In patients with mild cognitive impairment, researchers observed improvement in daily function and general cognitive abilities.But researchers don’t know what would be the optimal dosing and schedule of intranasal insulin for treating dementia; that is still an open question.So what does this mean for diabetics who already give themselves daily injections of insulin to manage their condition? Researchers don’t yet understand how much of that insulin is actually getting into the brain, Craft said; and if you’re not diabetic, having high levels of insulin in the blood is probably not good in the long run, so no one should experiment with this at home. Diabetes is a known risk factor for Alzheimer’s, but there are a lot of unanswered questions about that connection.

Source: http://www.kxly.com/health/29172695/detail.html

Posted under Alzheimer's disease, Cell Analysis, Discoveries, Innovations and Patents, Genetics & Pharmacogenetics, Press Releases, R & D, Reports, Research Projects  |  Comments Off

Ark to Manufacture PsiOxus’ IV-Administered Oncolytic Virus for Clinical Trials

Last Updated on Monday, 12 September 2011 04:06 Written by admin Monday, 12 September 2011 04:06

    Ark Therapeutics negotiated a manufacturing partnership with PsiOxus Therapeutics for the latter’s ColoAd1 candidate for the treatment of colorectal cancer. Under terms of the agreement Ark will work with PsiOxus to generate an IV formulation of the adenovirus-based oncolytic product using its suspension-based single-use system (ATOSUS) for toxicological and Phase I/II clinical studies.

    ColoAd1 is an Ad3/Ad11p hybrid, designed as a broad-spectrum anticancer therapeutic capable of destroying tumor cells at minute concentrations, but with minimal damage to healthy tissue. The oncolytic virus has been generated using the evolutionary principle of natural selection, to generate a candidate that PsiOxus claims demonstrates anticancer potency at 0.1–10 femtomolar concentration, including activity against drug-resistant cancers. The initial target indications for ColoAd1 will be metastatic colorectal cancer and primary hepatic cellular carcinoma.

    The evolutionary approach used to generate ColoAd1 involves generating a chimeric adenovirus library by homologous recombination under atypical conditions of super-infection, PsiOxus explains. Multiple rounds of selection are subsequently carried out to identify strains with a tumor-dependent phenotype that also rapidly killed tumor cells. Candidate oncolytic viruses are then screened on normal cells to select a candidate with optimal therapeutic index.

    PsiOxus was established in December 2010 through the merger of Myotec Therapeutics and Hybrid BioSystems. The ColoAd1 candidate originated at Hybrid Biosystems, a firm initially established to exploit viruses as therapeutics. The candidate was developed by Hybrid in collaboration with Bayer Schering. Hybrid Biosystems also developed the PolyStar vaccine vector system, and PolyMap adjuvant/immunotherapeutics platform, both of which PsiOxus inherited when it was formed last year.

    PsiOxus’ lead clinical-stage compound, MT-102, is a small-molecule anabolic catabolic transforming agent, which is currently undergoing a placebo-controlled Phase II trial as a treatment for disease-related cachexia. MT-102 was originally developed by Myotec, itself an Imperial College London spin-out established to progress work by university scientists on the underlying mechanisms of cachexia. PsiOxus says promising preclinical results from in vivo studies evaluating MT-102 against age-related sarcopenia will also be followed up through future clinical studies.

    Source: http://www.genengnews.com/gen-news-highlights/ark-to-manufacture-psioxus-iv-administered-oncolytic-virus-for-clinical-trials/81245663/

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Clinical Successes and New Technologies Revive Gene Therapy

Last Updated on Friday, 9 September 2011 12:48 Written by admin Friday, 9 September 2011 12:48

    The prospect of curing human diseases by replacing a disease-related gene with a normal version remains the ultimate goal of gene therapy. But in its early days, attempts at gene therapy met with unpredictable and occasionally fatal outcomes. The field sustained a serious setback in 2000 following the death of 18-year old Jesse Gelsinger after receiving gene therapy to treat orinthine trascarbamlase deficiency (OTCD), a rare metabolic disorder that prevents the body from breaking down ammonia.

    Gene therapy took another blow in September 2003, when the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells. The agency was responding to the development of a leukemia-like disorder that developed in a three-year-old boy following successful gene therapy for to X-linked severe combined immunodeficiency disease (X-SCID). Subsequently, the disease developed in three children, one of whom died from it.

    Now, bolstered by the development of enabling technologies and recent clinical successes, gene therapy is making a significant comeback. Effective gene delivery has been established in multiple formats including direct DNA delivery, genetically engineered autologous cells, and specifically targeted gene modification or insertion.

    Adrenoleukodystrophy

    In 2009, international teams of researchers reported the successful treatment of two children suffering from adrenoleukodystrophy (ALD). ALD is a severe hereditary condition caused by mutations in ABCD1 gene, which encodes the adrenoleukodystrophy protein (ALDP), a protein involved in fatty acid degradation.

    Over the course of the disease, afflicted individuals steadily lose the myelin sheath that surrounds nerve cells. Myelin loss results in loss of nerve function, leading to increasing physical and mental disability. X-linked ALD, the most common form of the disease, affects boys as early as age six, with death usually occurring before the patients reach adolescence.

    While ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT), finding correctly matched donors and the inherent dangers in the procedure present problems.

    Investigators in France reported successful treatment of two ALD patients for whom there were no matched donors. They first removed CD34+ cells, then transfected the cells ex vivo with a lentiviral vector encoding the wild-type correct form of the gene encoding ALDP, and finally re-infusing them into the patients after they had received myeloablative treatment.

    Over a span of 24 to 30 months of follow-up, the authors said, they could detect polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein.

    Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, the authors said, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.

    Leber Congenital Amaurosis

    Another successful area for gene therapy has been Leber congenital amaurosis (LCA), a heritable form of progressive blindness. LCA, the result of a mutation in the RPE65 gene, may be treatable by introducing a normal copy of the mutated gene directly into the retinas of affected individuals.

    Normally, the RPE65 protein converts dietary vitamin A into a retina-specific form of vitamin A needed for rhodopsin formation. Rhodopsin is a visual pigment that absorbs light after it enters the eye, and it requires the RPE65 protein to regenerate after light exposure. Therefore, mutations in the RPE65 gene seen in LCA disrupt the visual cycle and prevent normal vision.

    Several groups have reported progress in treating the disease in individuals with the specific mutation. In 2008, these researchers administered subretinal injections of recombinant adeno-associated virus (AAV) vector expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter.

    Investigators concluded that the safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.

    HIV/AIDS

    Apart from advancements in DNA delivery and in vectors for gene delivery into patients’ cells, zinc finger nuclease technology may prove truly transformative to gene therapy in general. Zinc finger nucleases (ZFNs) are synthetic proteins consisting of an engineered zinc finger DNA-binding domain fused to the cleavage domain of a restriction endonuclease. These engineered molecules allow cellular DNA to be cut at specific points, with gene modification then occurring via the cell’s own natural repair mechanisms. They may also allow the insertion of entire genes at desired cleavage sites to replace missing or mutated genes.

    Sangamo and colleagues from the University of Pennsylvania announced positive preliminary data from their Phase I trial being conducted in HIV-infected immunologic nonresponders. The patients enrolled in this study were HIV-infected individuals on highly active antiretroviral therapy with undetectable levels of virus but low T-cell counts.

    The investigators used zinc fingers custom-designed to bind to specific DNA sequences in the CCR5 gene in HIV-infected patients’ T cells. The zinc finger proteins act as molecular scissors, bringing a DNA enzyme to the CCR5 gene to cut its sequence. During the repair process, a new mutation arises in the CCR5 protein, rendering it nonfunctional. Since the HIV virus uses the normal, unmodified version of CCR5 to gain access to T cells, the engineered cells became completely resistant to infection.

    The data showed that a single infusion of the engineered cells was well tolerated, and the CCR5-modified cells successfully engrafted in all of the patients. The treatment also resulted in a durable improvement in total CD4+ T-cell counts in five of six patients analyzed.

    The ZFN-CCR5-modified cells also exhibited normal T-cell growth kinetics and trafficking and underwent selective expansion in the gut mucosa, a major reservoir of virus in the body, suggesting, as predicted, that the cells were resistant to HIV infection.

    Sangamo’s Philip Gregory, CSO and vp, research, told GEN that the goal of developing the company’s zinc finger nuclease program “has been to give investigators the ability to perform precision engineering directly on the genome itself.”

    In the HIV application, he pointed out, no new DNA is being introduced. “We are really introducing a mutation ourselves just with the nucleases. We were able to do this because DNA repair mechanisms themselves are error prone. When the cells repair the break generated by the ZFN, the process occurs without error checking and mutations are introduced specifically at the site of the break. We can use this to achieve one desired outcome, knockout of the gene that’s been cleaved by the nuclease—in this case, the CCR5 gene. When the cell repairs it, it will create mutations.”

    In explaining the production process for the autologous cells carrying the mutated CCR5 gene, Gregory said that the cells are collected from patients and sent to a processing facility, where they are exposed to the ZFN. The cells are expanded, and then re-infused into the patient, where they engraft, expand in the patients, and get trafficked to the normal place in the body.

    “These cells are noninfectable by HIV,” Gregory said. He further explained that “just by protecting T cells, we aimed to create a reservoir of these cells that couldn’t be infected. These cells protect against loss of cells in HIV-infected patients.”

    Gregory emphasized that CCR5 itself as a target “is one of the few situations in which we know the biology of the protein from the situation that exists in the natural population of patients. Patients with the Delta 32 CCR5 mutation don’t have the receptor on their cells and are completely normal but are resistant to infection.

    “It turns out,” he said, “that an important feature of that mutation is that it eliminates CCR5 completely, giving rise to cells with no receptor on their surfaces.”

    Sangamo says it is testing its product across a full range of HIV patients including those for whom current drug regimens are failing. “We are making good progress and are letting the data tell us where to focus our further clinical trials.”

    All this progress, investigators point out, represents the culmination of years of experience, encompassing multiple disciplines from molecular biology through clinical science. And hopefully as positive clinical results continue to emerge, effective gene therapy, in whatever format, will become a real therapeutic option for intractable human diseases.

    Source: http://www.genengnews.com/analysis-and-insight/clinical-successes-and-new-technologies-revive-gene-therapy/77899451/

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Canadian-made virus shows promise as cancer treatment

Last Updated on Wednesday, 31 August 2011 04:32 Written by admin Wednesday, 31 August 2011 04:32

An Ottawa-based research team has developed a virus that is showing promise as a new way of attacking and shrinking cancer tumours while leaving healthy tissue alone.

It’s early days in the still-experimental field of therapeutic cancer viruses, called oncolytic viruses. But this new study from researchers from the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa advances the field a little further by showing that the virus is safe in most patients.

For the study, researchers recruited 23 advanced cancer patients whose cancer had spread to multiple organs. All had failed to respond to the usual treatments and all were in the final stages of the disease.

The patients agreed to receive a single infusion of an experimental virus into their blood, called JX-594.

JX-594 is a form of vaccinia virus that’s been used as a live vaccine against smallpox. The JX-594 virus has been genetically engineered to enhance its natural anti-cancer properties.

The doctors tried out five doses of the virus, and then took biopsies of the tumours eight to 10 days later.

The researchers found that seven of the eight patients in the highest dose groups had evidence that the virus was in place and replicating in their tumours — and not in normal tissues.

What’s more, six of eight patients in the two highest dose groups experienced a shrinking or stabilization of their tumours, while those in lower dose groups saw less of this effect.

None of the 23 patients experienced significant side effects from the virus injection, with the most common side effect being mild to moderate flu-like symptoms that lasted less than one day.

The study, which is published in the journal Nature, was designed primarily to test the safety of the virus, not to cure the patients. In fact, some of the patients later died of their disease.

But the observation that some patients saw their tumours shrink was a welcome discovery.

Dr. John Bell, one of the study’s co-authors and a researcher at OHRI says it’s exciting that the virus led to results after just one dose.

“Of course, we will need to do more trials to know if this virus can truly make a difference for patients,” he said in a statement.

Bell says the advantage of therapeutic viruses is that they can be sent through the blood, infect the cancer tumours and leave the healthy tissue alone. It’s possible that oncolytic viruses could one day offer an alternative to conventional chemotherapy and radiation treatment, which tend to destroy healthy cells as well as cancer cells.

“Oncolytic viruses are unique because they can attack tumours in multiple ways, they have very mild side effects compared to other treatments, and they can be easily customized for different kinds of cancer,” Bell said.

“We’re still in the early stages of testing these viruses in patients, but I believe that someday, viruses and other biological therapies could truly transform our approach for treating cancer.”

JX-594 was developed with Jennerex Inc., a biotherapeutics company co-founded by Dr. Bell in Ottawa and Dr. David Kirn in San Francisco.

The study was funded in part by Jennerex, as well as the Terry Fox Foundation, the Canadian Institutes of Health Research and the Ontario Institute for Cancer Research, and others.

Bell and his research team plan to do further tests on many more patients to show the treatment actually works and that the body doesn’t learn to resist the virus over time.

A Phase 2 trial is to start soon aimed at patients with end-stage liver cancer or colon cancer.

Dr. Don Morris, a professor of Medicine and Oncology at the University of Calgary says even if this treatment is shown to be effective in cancer patients, it would be years before it would be widely available.

“Truly, this is not a treatment that could be applied to community cancer patients out of a trial. We may be three, five or seven years away before this is mainstream. The caution is that this is new hope, but tempered hope,” he told CTV News.

Source: http://calgary.ctv.ca/servlet/an/local/CTVNews/20110831/cancer-tumour-virus-ottawa-110831/20110831/?hub=CalgaryHome

Posted under Cancer Research, Cell Analysis, Discoveries, Innovations and Patents, Medicinal Chemistry, North America, Oncology Research, Press Releases, R & D, Research Projects, USA and Canada  |  Comments Off

Adding caffeine to sunscreen could guard against skin cancer

Last Updated on Thursday, 18 August 2011 12:18 Written by admin Thursday, 18 August 2011 12:18

Scientists have worked out how caffeine might protect against certain skin cancers – a finding that could lead to better sunscreens.

The research, conducted in mice, suggests that caffeine changes the activity of a gene involved in the destruction of cells that have DNA damage and are therefore more likely to become cancerous. The scientists said this may lead to new ways of preventing skin cancer, though other experts cautioned that it did not mean coffee lovers were better protected against the disease.

Skin cancer is a common disease. According to Cancer Research UK, around 100,000 cases of non-melanoma were registered in the UK in 2008, and just under 12,000 cases of the more dangerous malignant melanoma. These cancers can be caused by over-exposure to ultraviolet light from the sun, which can damage the DNA of skin cells, leading to errors when the cells divide.

The overall protective role of caffeine against cancers has been noted in previous studies, but Allan Conney of the department of chemical biology at Rutgers University in New Jersey wanted to find the specific molecular mechanisms behind it. He suspected that the response might involve a gene called ATR, which is suppressed when caffeine molecules are around. This suppression encourages the death of DNA-damaged cells.

Conney tested the idea by creating genetically modified mice whose ATR genes were deficient and exposing them to ultraviolet light until they developed skin cancer. After 19 weeks of UV exposure, he found that these mice developed 69% fewer tumours than those that had fully functioning ATR genes. In addition, tumours in the GM mice developed three weeks later than in standard mice.

After 34 weeks of UV exposure, all the mice had developed tumours, mainly a type of non-melanoma cancer called squamous cell carcinoma (SCC). The results were published on Monday in the Proceedings of the National Academy of Sciences.

“All of this suggests the possibility that caffeine, possibly [applied to the skin], would have an inhibitory effect on sunlight-induced skin cancer,” said Conney. “In addition to the effects on the ATR pathway, caffeine also has sunscreening properties.”

SCCs are less common than the other type of non-melanoma cancer, called basal cell carcinomas, but it’s the former that are more dangerous. “People rarely die from basal cell carcinomas, but you need more invasive cutting to get it out,” said Conney. “There’s more disfiguration with basal cell than squamous cell. It’s the squamous cell cancers that can metastasise and are more dangerous.”

Jessica Harris, a health information manager at Cancer Research UK, pointed out that Conney’s study examined how caffeine affected genes when it was directly applied to the skin, rather than ingested. “It didn’t look at the effects of drinking coffee, so doesn’t tell us whether or not this could reduce the risk of skin cancer,” she said.

Studies looking at coffee consumption and cancer in large groups of people have provided mixed results, she added. “Some have found that coffee drinking may slightly reduce the risk of certain types of cancer, but the evidence is not yet strong enough to be certain, and these effects tend to be seen among people who drink very large amounts.”

The best way to reduce the risk of skin cancer, said Harris, “is to enjoy the sun safely, taking care not to burn by using a combination of shade, clothing and sunscreen.”

Dot Bennett, a professor of cell biology at St George’s, University of London, said that any move to add caffeine or related molecules to sunscreens should be undertaken with care. “First one might want to check there is no adverse effect of caffeine on the incidence of other cancers, especially melanoma (pigmented skin cancer), which kills over four times as many people as [squamous cell carcinoma]. But caffeine lotion might promote tanning a little, since this family of molecules stimulates pigment cells to make more pigment.”

Source: http://www.guardian.co.uk/science/2011/aug/15/adding-caffeine-sunscreen-skin-cancer

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Suicide-Bombing Bacteria Could Fight Infections

Last Updated on Tuesday, 16 August 2011 02:38 Written by admin Tuesday, 16 August 2011 02:38

Like any good military unit, infectious bacteria have access to numerous weapons and efficient communication systems. But like soldiers in the field, they’re also susceptible to suicide bombers. Researchers have used the tools of synthetic biology to create an Escherichia coli cell that can infiltrate foreign bacteria and explode, killing off the pathogens along with itself.

The project, says bioengineer Chueh Loo Poh of Nanyang Technological University in Singapore, was “inspired by nature,” particularly by quorum sensing, the ability of some bacteria to detect the number of microorganisms—either of their own species or others—in their environment. When pathogenic Pseudomonas aeruginosa sense other species impeding on their space and nutrients, they communicate with members of their own species using chemical signals and collectively start releasing a bacterial toxin called pyocin that kills off the competition. Together, these communication and defense capabilities allow P. aeruginosa to form tightly packed layers called biofilms, which can cause respiratory tract infections in humans and are particularly dangerous to cystic fibrosis patients.

Poh and chemical engineer Matthew Wook Chang, also at Nanyang Technological University, decided to turn P. aeruginosa‘s weapon system against itself, using E. coli as the carrier. The researchers tweaked the genes that allow P. aeruginosa to detect other members of its species and put this synthetic genetic code into E. coli‘s genome. They also gave E. coli a gene for making a modified pyocin that is toxic to P. aeruginosa. By linking the pyocin gene to the sensing genes, the researchers ensured that when the E. coli detected P. aeruginosa in the vicinity, it would fill itself with large amounts of pyocin and become a biological time bomb.

The researchers gave E. coli one last synthetic component: a “suicide gene” that is activated once the pyocin has had some time to build up, causing the cells to burst open and release their toxin. When Chang and Poh grew these synthetic E. coli in a dish with P. aeruginosa, the suicide bomber was able to kill 99% of the P. aeruginosa cells, the researchers report today in Molecular Systems Biology.

Justin Gallivan, a synthetic biologist at Emory University in Atlanta, says in an e-mail that the study “nicely illustrates” how synthetic bacteria can perform complex tasks. But he worries they may not be able to finish the job, because 1% of the infectious bacteria remained after the treatment—even when the researchers put four times as many E. coli as P. aeruginosa into the mix.

The system would also have to undergo a lot of work before it can be considered for use in humans—including, perhaps, replacing E. coli with another delivery system, says Richard Kitney, a synthetic biologist at Imperial College London. “Exposing people to E. coli is not a good thing,” Kitney says, as the bacteria are toxic outside the gut. He adds that the team would also have to show that pyocin is effective at killing P. aeruginosa that have already formed a biofilm.

For their part, Chang and Poh say that they plan to test the suicidal bacteria in mice infected with P. aeruginosa. It’s not clear, they say, whether pyocin is harmful to mammals, although some other natural bacterial toxins are currently approved for use as food preservatives. They also hope to tweak the synthetic system so that it can sense and respond to signaling molecules released by other species of pathogenic bacteria, such as those responsible for cholera.

Source: http://news.sciencemag.org/sciencenow/2011/08/suicide-bombing-bacteria-could-f.html

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MS genetic discovery casts doubt on vein theory

Last Updated on Thursday, 11 August 2011 01:01 Written by admin Thursday, 11 August 2011 01:01

Scientists have discovered 29 new genetic variations linked to multiple sclerosis, with many involving genes relevant to the immune system – a finding that they say bolsters the theory that MS is a primarily an autoimmune disease.

The new study, published Wednesday in the journal Nature, is the largest-ever study on the genetics of multiple sclerosis. More than 250 scientists collaborated on the work, and close to 10,000 MS patients were involved.

Many of the gene variations the team discovered are involved in the development of the immune system’s T-cells, which are the immune cells that protect against infections. When T-cells become “confused,” they trigger autoimmune diseases that mistake healthy body tissues as foreign and attack them.

The study authors say the findings reaffirm the long-held assertion that MS is primarily an autoimmune disorder and that changes in the immune system set off the disease.

“Our research settles a longstanding debate on what happens first in the complex sequence of events that leads to disability in multiple sclerosis,” Dr. Alastair Compston, a University of Cambridge neurology professor who was one of the leaders of the study, said in a statement.

“It is now clear that multiple sclerosis is primarily an immunological disease. This has important implications for future treatment strategies.”

The findings also cast doubt on the recent theory proposed by Italian vascular surgeon Dr. Paolo Zamboni that MS is related to blocked neck veins.

For this new study, researchers in Britain, Canada and a dozen other countries performed genome-wide scans on the DNA of 9,772 people with MS. They looked for genetic anomalies that didn’t appear in the DNA of 17,376 healthy people without MS.

They discovered the MS patients had 29 genetic variations that other patients didn’t have. They also confirmed 23 other genetic variations that had already been associated with MS. As well, the team identified five more associations that might be significant and that require further study.

One third of the genes identified have previously been implicated in playing a role in other autoimmune diseases such as Crohn’s Disease and Type 1 diabetes, indicating that the same processes occur in more than one type of autoimmune disease.

The findings cast doubt on the theory put forward by Dr. Zamboni. He suggests that blocked neck and chest veins stop blood from draining properly from the brain – a condition he calls CCSVI – which leads the blood to deposit iron in the brain. It’s the iron deposits that lead to the brain changes that mark MS, he contends.

To treat this, he proposes a vascular procedure to open blocked and twisted neck veins. Hundreds of Canadian patients have flown to overseas clinics for the so-called “libertion treatment,” spending upwards of $20,000 or more.

They’ve returned with various results. Some have reported the procedure helped relieve their fatigue; others said it allowed them to walk again, while still others say it offered no relief at all.

At least two patients have died after having the procedure, though it’s unclear what role it played in the deaths.

Zamboni has conducted studies that suggest that the majority of MS patients have CCSVI while few healthy patients so. But further studies have been unable to replicate his findings.

One study published this week in the Archives of Neurology found no significant difference in venous abnormalities between MS patients and healthy controls. But CCSVI proponents argue the studies were performed improperly.

The vein theory has not been embraced by many neurologists who specialize in MS. Many contend that patients have a genetic predisposition for MS and that one or more environmental factors trigger the condition.

Multiple sclerosis is marked by damage to nerve fibres in the brain and spinal cord and their protective insulation, called the myelin sheath. When the myelin is destroyed, it causes patients to struggle with everyday activities such as walking, feeling, thinking and controlling the bowel and bladder.

Even among those who believe MS is an autoimmune disease, it’s been unclear what sparks the immune changes. Previous research has suggested a vitamin D deficiency might be the trigger. Populations in northern hemispheres have higher rates of MS than populations with more year-round sunlight.

In this latest genetics study, researchers did identify two genetic variations that are involved in the metabolism of vitamin D.

Source: http://ottawa.ctv.ca/servlet/an/local/CTVNews/20110811/ms-gene-study-immune-system-110811/20110811/?hub=OttawaHome

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Scientists Claim Leukemia Stem Cell Signature Independently Predicts Poor Survival in AML

Last Updated on Friday, 2 September 2011 11:39 Written by admin Tuesday, 2 August 2011 11:27

    Research on samples from human acute myeloid leukemia (AML) patients has suggested that the a leukemia stem cell (LSC) gene expression profile can accurately be used to predict patient survival, even among AML patients with cytogenetically normal disease. An international team led by researchers at Ontario’s University Health Network and the University of Toronto’s Department of Molecular Genetics claim their findings support those from xenograft models suggesting that the disease is propagated by a population of rare LSCs.

    Describing their findings in Nature Medicine, John E. Dick, M.D., Kolja Eppert, M.D., and colleagues report that the LSC gene signature is similar to that of hematopoietic stem cells (HSCs), and that both gene signatures were significant and independent predictors of patient survival. Moreover, the LSC gene signature could accurately predict poor survival in about 50% of AML patients with cytogenetically normal disease who would otherwise be classified as low risk on the basis of mutations in specific individual genes. Importantly, the LSC signature could be identified even in unsorted AML cell populations in which LSCs were very rare, suggesting that LSC-derived AML-blasts retain at least part of their progenitors’ expression profiles.

    The researchers finally highlight the need to develop LSC biomarkers for use in patient evaluation, and claim that therapies targeting LSCs would improve survival outcomes. Their paper is titled “Stem cell gene expression programs influence clinical outcome in human leukemia.”

    Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs), the authors write. Although the clinical relevance of the CSC model in humans has, to date, remained uncertain, recent evidence from leukemia patients does support the notion that LSC properties may be prognostic: correlative studies have linked outcome with either the capacity for a sample to be xenografted or surface expression of LSC-linked markers.

    Moreover, they continue, if CSCs are more prognostic than non-CSCs, the molecular machinery underpinning the properties of such stem cells is likely to likely to influence clinical outcome. “Indeed, LSCs have the core set of biological functions common to all stem cells, including self-renewal and the ability to produce differentiated, non-stem cell progeny.”

    The University Health Network team set out to investigate the specific properties of CSCs in leukemia further by defining the gene expression signatures of both LSCs and hematopoietic stem cells (HSCs) from functionally validated, sorted fractions of primary human AML samples. Sixteen primary human AML samples were sorted into four cell populations on the basis of surface expression of the markers CD34 and CD38: previous studies have suggested LSCs are primarily CD34+CD38-. Each cell fraction was then assayed using an optimized xenotransplantation assay to identify LSC-enriched and LSC-depleted populations.

    As expected, LSCs were found in the CD34+CD38? fraction in all but one of the informative cases. However, the cells were also found in at least one other fraction in the majority of AML samples, and in 50% of cases the majority of LSCs were found in the CD34+CD38+ fraction, “establishing heterogeneity between cell surface marker expression and LSC activity among individual samples,” the authors state. Overall, LSCs ranged in frequency from 1 in 1.6 × 103 cells, to 1 in 1.1 × 106, but were generally found at the highest frequency in the CD34+CD38? fraction. Importantly, the researchers note, “LSC-containing fractions that initiated leukemia generated a xenograft that acquired the marker phenotype of non-LSC fractions, confirming earlier reports that AML is hierarchically organized.”

    Each functionally validated fraction was then subjected to global gene expression analysis to identify LSC-related (LSC-R) gene profiles. Bioinformatics analyses compared global gene expression patterns of 25 LSC-enriched fractions to 29 fractions without LSCs. The results threw up an initial LSC-R signature including 42 genes, which was validated by RT-PCR. This same gene signature was identified in AML samples with a variety of karyotypic alterations and French-American-British subtype.

    Then, because LSCs and HSCs both have canonical stem cell functions including self-renewal and the ability to make non-stem cell, mature progeny, the team also generated HSC gene-expression profiles to see whether human LSCs share molecular mechanisms and gene-expression programs with HSCs.

    A comparison of the resulting 121-gene HSC-related (HSC-R) profile with the LSC-R gene profile identified 44 leading-edge genes, termed the core enriched HSC-LSC genes (CE-HSC-LSC), which appeared to represent HSC genes that are also differentially expressed in LSCs. Of these, 18 are implicated in stem cell regulation, oncogenesis, or both, the authors note. However, protein interaction network analyses highlighted the enrichment of multiple pathways distinct from the progenitor network, including Notch and Jak-STAT signaling, which are implicated in stem cell regulation, “thereby supporting the stem cell nature of the HSC- and LSC-related gene profiles.”

    Significantly, when the researchers compared their data with previously generated gene datasets from stem, progenitor, and mature cell populations, and from embryonic stem cells, they found that LSC gene expression correlated positively with primitive cell gene sets and negatively with gene sets derived from more differentiated cells and from ES cells. “Collectively, our data establishes that an HSC expression program and not a common lineage-committed progenitor or ES cell-expression pattern is preferentially expressed in LSCs compared with more mature non-LSC leukemic cells,” they conclude.

    To test the clinical relevance of LSCs, the team then looked for a link between LSC-R and HSC-R gene signatures and clinical outcomes, in three large clinically annotated gene expression datasets derived from unsorted AML cells. They found that the LSC-R and HSC-R profiles were very similar among a cohort of 285 AML samples, and that the profiles were either positively or negatively correlated with cluster gene sets characterized by molecular markers indicative of poor prognosis or good prognosis.

    They then analyzed the LSC-R, HSC-R, and CE-HSC-LSC signatures in new gene expression data generated on about a third of the AML samples that had been stratified in terms of poor or good prognostic risk groups on the basis of cytogenetic alterations. In this case higher expression of all three signatures distinguished poor prognostic risk subjects. “These findings demonstrate that AML samples associated with worse prognosis express stem cell-related genes more highly than less aggressive AML samples,” they note.

    As a final test of clinical relevance, the researchers looked at a cohort of 160 cytogenetically normal AML subjects for whom gene expression and survival data were available. For this analysis they used the LSC-R or HSC-R gene signature to divide the subjects into two equal groups, based on the median expression of the respective signatures in bulk AML bone marrow cells.

    Both signatures negatively correlated with overall survival and event-free survival with a high degree of significance. Moreover, there was a significant negative correlation between the occurrence of complete remission and high expression of the LSC-R signature, and an almost significant negative correlation between complete remission occurrence and the HSC-R signature. “Our data demonstrate that high expression of stem cell expression signatures directly predicts patient survival in cytogenetically normal AML and, therefore, that variation in stem cell expression programs among subject samples is highly correlated with heterogeneity in disease outcome,” the team writes.

    Of particular interest, multivariate analyses showed that the LSC-R and HSC-R signatures predicted overall and event-free survival independently of known molecular prognostic factors in cytogenetically normal patients, such as molecular risk status and CEBPA mutation. In fact, after subdividing the AML samples that were informative for molecular risk status, they found that each stem cell signature identified subsets of subjects with poor survival in both high molecular risk (HMR) group and low molecular risk (LMR) groups. “Thus, the LSC-R and HSC-R signatures can be used to separate patients currently identified as low risk into groups who respond well to standard therapy and those who may benefit from more intensive therapy, including stem cell transplant.”

    The researchers state their studies provide evidence supporting the hierarchical organization of AML according to the CSC model, and support the notion that LSCs are not just artifacts of experimental xenograft models. Moreover, they suggest a similar investigative approach could be used to assess both the identity and clinical relevance of LSCs and CSCs from other leukemias and solid tumors.

    “Our findings warrant validation in a large cohort and a clinical trial to test the LSC-R signature in the LMR subgroup,” they continue. “If our results are confirmed, poor-risk patients might benefit from more aggressive therapy such as allogeneic transplant or alternative therapy.”

    The authors admit that they found it rather counterintuitive that a stem cell signature could be detected in unsorted samples containing a very small population of LSCs, and in which the vast majority of cells are differentiated non-LSC blasts. This, they remark, suggests that stem cell expression programs persist in these blasts at a population level, even though no individual blast retains the full repertoire or expression level of stem cell genes.

    Source: http://genengnews.com/gen-news-highlights/scientists-claim-leukemia-stem-cell-signature-independently-predicts-poor-survival-in-aml/81245599/

Posted under Cancer Research, Cell Analysis, Discoveries, Innovations and Patents, North America, Oncology Research, R & D, Reports, Research Projects, USA and Canada  |  Comments Off

Smelly socks tested in Tanzania as way to prevent malaria

Last Updated on Thursday, 14 July 2011 11:49 Written by admin Thursday, 14 July 2011 11:49

In global public health, disease-fighting tools that are cheap, available and sustainable are the Holy Grail. It might be hard to top the one being tested in Tanzania as a way to prevent malaria: smelly socks.

Experiments in three villages where people get about 350 bites a year from malaria-infected mosquitoes are using dirty socks to lure the insects into traps, where they become contaminated with poisons and ultimately die.

Researchers hope that if the strategy works, it will eventually complement insecticide-treated bed nets as a low-tech way to prevent malaria, which kills nearly 900,000 people a year worldwide, most of them children.

“It’s a bold idea. Who would have thought there was a life-saving technology working in your laundry basket?” said Peter A. Singer, a physician who heads Grand Challenges Canada, a development agency of the Canadian government that is helping fund the research.

Previous lab studies have shown that smelly socks work well in attracting mosquitoes. Field experiments have shown that synthetic bait is more attractive than people, at least until the insects get close enough to realize there’s no blood waiting for them.

The new experiments, however, are the first head-to-head field tests of footwear vs. chemistry. The researchers hope the footwear wins.

“It is simply a cost issue and an expediency issue,” said Fredros O. Okumu, the Tanzanian entomologist leading the research. “Socks are more readily available, and you don’t have to mix any chemicals. It is the sort of thing that could be set up in a cottage factory.”

The traps are square boxes that look a little like commercial beehives. Some will contain the human-odor bait, which consists of simple chemicals (including lactic acid, ammonia and propionic acid) that are exuded by people, especially from the legs and feet. Some will contain socks worn for a day by adults. Others will contain cotton pads that schoolchildren will put inside their socks for a day and then deliver to researchers.

The researchers will compare the number of mosquitoes caught with each method.

Earlier work by Okumu and his colleagues at the Ifakara Health Institute in Tanzania showed that the chemical bait attracted four times as many mosquitoes as live people and that dirty socks worked just as well, at least in the lab. If the sock pads prove adequate, they will be the preferred bait.

The inside surfaces of some traps are coated with an organophosphate pesticide. Mosquitoes that land there will die within 24 hours. Other traps contain a fungus that infects the insects and kills them in five days — roughly half the time needed for the complicated cycle that enables a newly infected mosquito to transmit the malaria parasite to a person.

The bait-and-kill strategy is a new one in malaria prevention efforts.

Normally, attempts to prevent malaria by controlling mosquitoes, known as vector control, have aimed at driving the insects away from people or killing them once natural attraction has brought them into proximity.

Insecticide-treated bed nets, millions of which have been sold or given away in Africa in the past decade, have a long-acting repellant, permethrin. In many malaria-endemic areas, people spray the inside walls of dwellings with insecticide that kills mosquitoes when they land.

Bed nets have cut childhood deaths by about 20 percent in malaria-endemic areas. Modeling suggests that traps could reduce malaria transmission about as much as bed nets do in villages where half the households use them.

Despite its low-tech appearance, the strategy Okumu is testing is far more complicated, and potentially fraught with hazard, than it seems.

A key question is where to place traps. They need to be close enough to dwellings to attract mosquitoes, but not so close that they will increase people’s exposure to the disease-carrying insects. Okumu’s research suggests that the traps should be at least 100 feet from houses.

Another question is how many traps a village might need. Okumu has calculated the minimum number at 20 per 1,000 people, although in places where malaria transmission is especially intense and in certain village configurations, 130 traps per 1,000 people might be needed.

Despite these challenges, Singer said, projects such as these are what Grand Challenges Canada is looking to support. It is providing $388,000 for the research, and the Bill and Melinda Gates Foundation is providing a similar amount. The Gates Foundation gave Okumu $100,000 for preliminary studies, as well.

“We are inspired by people like Fredros,” Singer said. “We strongly believe that innovators in low-income countries are best situated to solve their own problems. He is an African researcher with an African innovation for an African problem.”

Okumu, who is a doctoral candidate at the London School of Hygiene and Tropical Medicine, said he is “working on the premise that this is a global problem — a global problem in a flat world.”

He said he doubted that there might be an application for his strategy — should it prove successful — in non-malarious places such as the United States. A pair of socks from a recent 10K run at the corner of a patio will only briefly divert mosquitoes. They’ll soon find the bare legs under the picnic table.

“Mosquitoes are still fairly clever animals,” he said. “What they are looking for is blood. They might be attracted to the socks, but they will not spend much time there.”

Source: http://www.washingtonpost.com/national/health-science/smelly-socks-tested-in-tanzania-as-way-to-prevent-malaria/2011/07/12/gIQAshifBI_story.html

Posted under Discoveries, Innovations and Patents, DNA Reasearch, Medicinal Chemistry, R & D, Reports, Research Projects  |  Comments Off

Stem cell research and use in veterinary medicine

Last Updated on Thursday, 7 July 2011 01:09 Written by admin Thursday, 7 July 2011 01:09

Stem cells show so much promise in human medicine. Cells that have the ability to become anything that the body needs is nothing short of a miracle. What is the role of stem cells in veterinary medicine? Do stem cells have a place? Many say they very much do.

Stem cells are able to be harvested from animals and are primarily used in horses, dogs, and cats for arthritic conditions.

There is much less controversy in veterinary medicine over the use of stem cells (at least at the present time) because of where they are harvested, or obtained. Rather than take stem cells from an umbilical cord or from an unborn fetus, the cells are harvested from the host itself.

How is this possible? Right now we know there is a certain amount of stem cells that exists in adult animals in either fat or bone marrow. These stem cells are considered adult stem cells and are somewhat limited in there ability to become “any cell” as compared to embryonic stem cells. However, adult stem cells can become cells similar to themselves.

What does this mean? There are individual reports of stem cells being used in veterinary medicine for conditions like ligament and tendon injuries in horses, as well as to treat a condition called laminitis. Everyone knows what tendons and ligaments are but what is laminitis?

Laminitis is a condition in horses that affects the blood supply and connective tissue from the bone to the hoof. In mild cases of laminitis there is just pain and inflammation which can be treated with rest, anti-inflammatories and special shoes to fit on the hoof.

Unfortunately, many times mild cases can progress to severe cases. There are also specific causes of laminitis that skip the mild phase and go right to the severe phase. The more severe phase can permanently damage the blood supply and the hoof would actually start to separate from the bone. If this happens many times it is irreversible and the only option for this is humane euthanasia. Stem cell therapy has been used to help to regrow the blood supply and connective tissue.

There are also reports that injecting adult stem cells harvested from bone marrow or fat can be used to treat arthritis in dogs and cats. There is a thin layer of cartilage that covers the bone at the joint called synovial cartilage. Synovial cartilage cushions the bone at the joint, as well as produces joint fluid. Joint fluid not only acts as a lubricant allowing the bones to slide back and forth, but also contains natural antioxidants and immune defenses.

When arthritis occurs in dogs the thin layers of synovial cartilage begin to degrade, or break down. It doesn’t happen all at once but when the cartilage is lost it does not grow back naturally. This is when you will hear orthopedists talk about “bone-on-bone” contact, and bone-on-bone contact is intensely painful.

The injection of stem cells into the joint has shown promise in regrowing this thin layer of synovial cartilage. No controlled studies have been performed to substantiate this claim. However, there are reports from various veterinarians using stem cells for this purpose that they see an improvement in their patients after receiving a stem cell treatment.

Using stem cells in veterinary patients to regrow tissue of any organ in the body is a long way off and even the use of stem cells for specific conditions like arthritis and laminitis has not been completely proven successful but there is hope on the horizon.

Source: http://www.northshoreoflongisland.com/Articles-i-2011-07-07-88828.112114-sub-Stem-cell-research-and-use-in-veterinary-medicine.html

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Who wants to live forever? Scientist sees aging cured

Last Updated on Tuesday, 5 July 2011 11:56 Written by admin Tuesday, 5 July 2011 11:56

(Reuters) – If Aubrey de Grey’s predictions are right, the first person who will live to see their 150th birthday has already been born. And the first person to live for 1,000 years could be less than 20 years younger.

A biomedical gerontologist and chief scientist of a foundation dedicated to longevity research, de Grey reckons that within his own lifetime doctors could have all the tools they need to “cure” aging — banishing diseases that come with it and extending life indefinitely.

“I’d say we have a 50/50 chance of bringing aging under what I’d call a decisive level of medical control within the next 25 years or so,” de Grey said in an interview before delivering a lecture at Britain’s Royal Institution academy of science.

“And what I mean by decisive is the same sort of medical control that we have over most infectious diseases today.”

De Grey sees a time when people will go to their doctors for regular “maintenance,” which by then will include gene therapies, stem cell therapies, immune stimulation and a range of other advanced medical techniques to keep them in good shape.

De Grey lives near Cambridge University where he won his doctorate in 2000 and is chief scientific officer of the non-profit California-based SENS (Strategies for Engineered Negligible Senescence) Foundation, which he co-founded in 2009.

He describes aging as the lifelong accumulation of various types of molecular and cellular damage throughout the body.

“The idea is to engage in what you might call preventative geriatrics, where you go in to periodically repair that molecular and cellular damage before it gets to the level of abundance that is pathogenic,” he explained.

CHALLENGE

Exactly how far and how fast life expectancy will increase in the future is a subject of some debate, but the trend is clear. An average of three months is being added to life expectancy every year at the moment and experts estimate there could be a million centenarians across the world by 2030.

To date, the world’s longest-living person on record lived to 122 and in Japan alone there were more than 44,000 centenarians in 2010.

Some researchers say, however, that the trend toward longer lifespan may falter due to an epidemic of obesity now spilling over from rich nations into the developing world.

De Grey’s ideas may seem far-fetched, but $20,000 offered in 2005 by the Massachusetts Institute of Technology (MIT) Technology Review journal for any molecular biologist who showed that de Grey’s SENS theory was “so wrong that it was unworthy of learned debate” was never won.

The judges on that panel were prompted into action by an angry put-down of de Grey from a group of nine leading scientists who dismissed his work as “pseudo science.”

They concluded that this label was not fair, arguing instead that SENS “exists in a middle ground of yet-to-be-tested ideas that some people may find intriguing but which others are free to doubt.”

CELL THERAPY

For some, the prospect of living for hundreds of years is not particularly attractive, either, as it conjures up an image of generations of sick, weak old people and societies increasingly less able to cope.

But de Grey says that’s not what he’s working for. Keeping the killer diseases of old age at bay is the primary focus.

“This is absolutely not a matter of keeping people alive in a bad state of health,” he told Reuters. “This is about preventing people from getting sick as a result of old age. The particular therapies that we are working on will only deliver long life as a side effect of delivering better health.”

De Grey divides the damage caused by aging into seven main categories for which repair techniques need to be developed if his prediction for continual maintenance is to come true.

He notes that while for some categories, the science is still in its earliest stages, there are others where it’s already almost there.

“Stem cell therapy is a big part of this. It’s designed to reverse one type of damage, namely the loss of cells when cells die and are not automatically replaced, and it’s already in clinical trials (in humans),” he said.

Stem cell therapies are currently being trialed in people with spinal cord injuries, and de Grey and others say they may one day be used to find ways to repair disease-damaged brains and hearts.

NO AGE LIMIT

Cardiovascular diseases are the world’s biggest age-related killers and de Grey says there is a long way to go on these though researchers have figured out the path to follow.

Heart diseases that cause heart failure, heart attacks and strokes are brought about by the accumulation of certain types of what de Grey calls “molecular garbage” — byproducts of the body’s metabolic processes — which our bodies are not able to break down or excrete.

“The garbage accumulates inside the cell, and eventually it gets in the way of the cell’s workings,” he said.

De Grey is working with colleagues in the United States to identify enzymes in other species that can break down the garbage and clean out the cells — and the aim then is to devise genetic therapies to give this capability to humans.

“If we could do that in the case of certain modified forms of cholesterol which accumulate in cells of the artery wall, then we simply would not get cardiovascular disease,” he said.

De Grey is reluctant to make firm predictions about how long people will be able to live in future, but he does say that with each major advance in longevity, scientists will buy more time to make yet more scientific progress.

In his view, this means that the first person who will live to 1,000 is likely to be born less than 20 years after the first person to reach 150.

“I call it longevity escape velocity — where we have a sufficiently comprehensive panel of therapies to enable us to push back the ill health of old age faster than time is passing. And that way, we buy ourselves enough time to develop more therapies further as time goes on,” he said.

“What we can actually predict in terms of how long people will live is absolutely nothing, because it will be determined by the risk of death from other causes like accidents,” he said.

“But there really shouldn’t be any limit imposed by how long ago you were born. The whole point of maintenance is that it works indefinitely.”

Source: http://www.reuters.com/article/2011/07/04/us-ageing-cure-idUSTRE7632ID20110704

Posted under Cell Analysis, Discoveries, Innovations and Patents, DNA Reasearch, Medicinal Chemistry, Research Projects, Stem Cell Research  |  Comments Off

Coffee buzz protects brain from Alzheimer’s

Last Updated on Thursday, 30 June 2011 11:00 Written by admin Thursday, 30 June 2011 11:00

For years we’ve been told that caffeinated coffee was bad for us. It’s unhealthy and addictive, doctors warned. But as vindication for all who stuck by their energizing elixir, a new study shows that guzzling caffeinated coffee may actually be good for our brains. In fact, it may help keep Alzheimer’s at bay.

The study, which was published early online in the Journal of Alzheimer’s Disease, was in mice whose DNA had been tweaked to contain a human Alzheimer’s gene. Just like humans with familial Alzheimer’s, these mice become increasingly forgetful as they age.

Amazingly, the equivalent of four to five cups of caffeinated coffee every few days led to much improved memories in the Alzheimer’s mice, says study co-author Gary Arendash, a scientist at the Florida Alzheimer’s Disease Research Center in Tampa.

Earlier research by Arendash and his colleagues showed that caffeine could at least partially block the production of beta amyloid, the sticky protein that clogs the brains of Alzheimer’s patients. They also found that a substance called granulocyte-colony stimulating factor, or GCSF, sparked the production of new axons, the communication cables that link nerve cells together, as well as new nerve cells themselves.

What’s really interesting is that caffeinated coffee — but not decaf — boosted the production of GCSF.

For the new study, Arendash and his colleagues “treated” healthy mice and Alzheimer’s mice with either caffeinated or decaffeinated coffee. Then the researchers ran a test to see if either beverage led to better memories.

The test they used mimics one that is given to humans to diagnose Alzheimer’s. In that test, people are given a bag of objects to look through (we’ll call that Bag A). And then they’re shown another bag of objects (Bag B). Later on, they’re asked to remember what was in Bag A.

Studies have shown that people with Alzheimer’s have a tough time remembering what was in Bag A because the distraction of looking through the objects from Bag B gets in the way of storing the contents of A in their long term memories. That’s generally not a problem for people with healthy brains.

The two part mouse test involved water mazes. The mice has to find — and remember — the location of a submerged platform in a tub of water that is deep enough that they need to swim till they find the platform.

After they find the platform in one tub, they’re moved to another tub where they have to find yet another platform. Mice with Alzheimer’s generally have a tough time remembering the location of the first platform when they’re placed in the original tub. But in Arendash’s study, Alzheimer’s mice that got caffeinated coffee had memories that were just as good as those of normal mice.

Lest you dismiss this study because it’s just in rodents, Arendash says he’s got new data in humans. That data is still being analyzed, he says, but so far it looks like caffeinated coffee has the same impact in people as it does in mice.

Source: http://bodyodd.msnbc.msn.com/_news/2011/06/28/6968218-coffee-buzz-protects-brain-from-alzheimers

Posted under Alzheimer's disease, Cell Analysis, Discoveries, Innovations and Patents, North America, R & D, Reports, Research Projects, USA and Canada  |  Comments Off

Hemophilia Is Target of Therapy on Genome

Last Updated on Monday, 27 June 2011 11:13 Written by admin Monday, 27 June 2011 11:13

Researchers using a new technique for editing the genome of living cells have shown that they can cure hemophilia in mice, at least in principle, with a couple of injections that carry out the “cut” and “paste” operations needed to insert a corrective gene.

This is the first time this genome-editing technique has succeeded in a live animal. Along with other applications, like two AIDS treatments in preliminary stages, the new technique could be the decisive improvement that gives credibility to the long-struggling field of gene therapy.

“This may well revolutionize the field, but it won’t do so overnight,” said Dr. Katherine A. High of the Children’s Hospital of Philadelphia, the research team leader. “Any novel kind of therapeutic takes time to develop.”

The essence of the technique is the molecular scissors custom-designed to cut the genome at a unique site. This allows the corrective gene to be inserted at the right place in a chromosome.

In previous forms of gene therapy, corrective genes have been inserted into the genome at random sites, for lack of the ability to control where they go. This approach means they are not under their natural control systems and, worse, may be inserted in the middle of some other gene that they disrupt.

“There’s a huge interest in this,” said Dr. Mark A. Kay, a gene therapist at the Stanford University School of Medicine. The genome editing approach “could be game-changing in some applications,” he said.

The technique depends on natural agents called zinc finger proteins whose role is to bind to specific sites on the genome and control adjacent genes. By mixing and matching the DNA of different natural zinc finger proteins, researchers can create artificial zinc fingers for any chosen target site on the genome.

In their genome-editing role, the zinc fingers are attached to a DNA-cutting enzyme derived from a bacterium. When a pair of zinc finger proteins line up on opposing strands of DNA, their DNA cutters face each other and scissor the DNA apart.

The zinc finger technique has been developed by Sangamo BioSciences and by academic researchers who belong to the Zinc Finger Consortium. “We are fairly inundated with requests,” said Philip D. Gregory, Sangamo’s chief scientific officer.

Sangamo designed the zinc finger pairs for Dr. High’s hemophilia project. But the fingers are designed to cut the human Factor 9 gene, not the mouse version, which has a different sequence of DNA units. So Dr. High genetically engineered a strain of hemophiliac mice that carry a mutated version of the human Factor 9 gene in place of their own.

After the cut-and-paste operation, the mice possessed a good working copy of human Factor 9, producing enough to make their blood clot much faster, and well enough to prevent hemophilia, Dr. High and her colleagues report in the journal Nature. To show that the new gene was stably incorporated into cells, they then cut out part of the mice’s livers. The liver regenerated from existing cells, retaining their ability to produce good copies of Factor 9.

Dr. High said it was too soon to try the technique in people, given that an adequate treatment for hemophilia already exists. She plans to test it next in dogs, which are a standard model for new hemophilia treatments. One of the possible problems with the technique is that the zinc fingers sometimes cut at sites other than the intended target site.

Dr. High said that besides hemophilia, the zinc finger technique could address many other liver-based genetic diseases.

Zinc fingers are being used in a different way in a treatment for AIDS, at present in early clinical trials. The fingers are used to disrupt a gene called CCR5, which makes the receptor used by the AIDS virus to gain access to cells. People with no CCR5 receptor are naturally immune to AIDS.

The hope is that patients will acquire the same immunity after their T cells are treated with zinc fingers and returned to the body.

“We are very hopeful that zinc finger technologies will have a spectacular impact on gene therapy and genetic medicine in general,” Dr. Gregory said.

Source: http://www.nytimes.com/2011/06/27/us/27therapy.html

Posted under Cell Analysis, Discoveries, Innovations and Patents, DNA Reasearch, HIV Research, North America, Research Projects, USA and Canada  |  Comments Off

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