Archive for August, 2011

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

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Genetic Link Predisposes to Mesothelioma

Last Updated on Monday, 29 August 2011 11:34 Written by admin Monday, 29 August 2011 11:34

An investigation led by scientists at the University of Hawaii Cancer Center, Honolulu, and Fox Chase Cancer Center, Philadelphia has identified germline mutations in the BAP1 gene that predispose individuals to malignant mesothelioma. The research, published online yesterday in Nature Genetics, describes two U.S. families with a high incidence of mesothelioma, as well as other cancers, associated with mutations of the gene BAP1 [1].

Scientists have discovered that individuals who carry a mutation in a gene called BRCA1-associated protein 1 (BAP1) are susceptible to developing two forms of cancer — mesothelioma and melanoma of the eye. When these individuals are exposed to asbestos or similar mineral fibers, their risk of developing mesothelioma, an aggressive cancer of the lining of the chest and abdomen, may be markedly increased.

Mesothelioma tumors are typically associated with asbestos and erionite exposure. Erionite is a naturally occurring mineral fiber similar to asbestos that is found in rock formations and volcanic ash. Deposits have been located in at least 12 states. However, unlike asbestos, erionite is not currently regulated by the U.S. Environmental Protection Agency as one of the six asbestos fibers [2]. Only a small percentage of people exposed to asbestos or erionite actually develop mesothelioma.

Mesothelioma is one of the deadliest forms of cancer, killing approximately 3,000 people each year in the United States, with half of those diagnosed dying within one year. Moreover, rates of new cases of mesothelioma in parts of the world, including Europe and China, have risen steadily over the past decade.

Michele Carbone, M.D., Ph.D., study co-leader and director of the University of Hawaii Cancer Center, said [3]:

This discovery is a first step in understanding the role of the BAP1 gene and its potential utility when screening for mutations in those at high risk. Identifying people at greatest risk for developing mesothelioma, especially those exposed to dangerous levels of asbestos and erionite worldwide, is a task made easier by virtue of this discovery.

Joseph R. Testa, Ph.D., study co-leader and Carol and Kenneth E. Weg chair in Human Genetics at Fox Chase Cancer Center, added [3]:

This is the first study to demonstrate that individual genetic makeup can greatly influence susceptibility to mesothelioma. People exposed to dangerous levels of asbestos or erionite, those with a strong family history of mesothelioma, or those who have been previously diagnosed with a rare tumor of the eye known as uveal melanoma, may benefit from this new discovery.

The researchers focused on two US mesothelioma families — one in Wisconsin and one in Louisiana — in which members were not exposed to asbestos or erionite. Family members developed a number of malignancies, including breast, ovarian, pancreatic and renal cancers, although mesothelioma predominated.

The scientists suspected that mutations in the BAP1 gene might underlie mesothelioma in people with a strong family history of the disease after noticing genetic changes in or near other stretches of DNA where the BAP1 gene is located. Looking more closely at two families with unusually high rates of mesothelioma, they saw that every person who had provided a sample and had developed mesothelioma or melanoma of the eye also carried mutations in the BAP1 gene. Further study led to sequencing the gene in 26 individuals who had developed mesothelioma but did not have a family history of the disease. Tumors from about 25 percent of this group carried mutations in the BAP1 gene, and in two cases the mutations were inherited. Both of the individuals with inherited mutations had previously developed melanoma of the eye.

The researchers hypothesize that when individuals with BAP1 mutations are exposed to asbestos, mesothelioma predominates over melanoma of the eye. Alternatively, the BAP1 mutation alone may be sufficient to cause mesothelioma, providing a cause for tumors that arise spontaneously without previous environmental exposure.

Source: http://www.highlighthealth.com/research/genetic-link-predisposes-to-mesothelioma/

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Critical Protein Discovery Could Help Prevent Lethal Ebola Virus

Last Updated on Thursday, 25 August 2011 11:25 Written by admin Thursday, 25 August 2011 11:25

An international team of scientists has discovered a biochemical route used by the deadly Ebola virus to infect human cells. Scientists say the discovery points the way to new drugs that could prevent or treat one of the world’s most lethal viral diseases.

The Ebola hemorrhagic virus, which got its name from the central African river near where the disease first emerged in 1976, kills an estimated 90 percent of the people and non-human primates it infects.

The disease causes very high fever, both internal and external bleeding, and has led to thousands of deaths in many sub-Saharan African countries, including Gabon, Sudan, the Ivory Coast and Uganda, since the first reported outbreak 35 years ago.

Although considered a rare disease, Ebola causes panic whenever there is an outbreak, in part because little is known about where the illness comes from or how it spreads.

Experts believe infected bats may be one source of these sporadic occurrences of Ebola, and the disease is then spread from person to person through tainted body fluids or blood.

To better understand the biology of Ebola, a team of researchers at Albert Einstein College of Medicine, Harvard Medical School, the Whitehead Institute at MIT and the U.S. Army Medical Research Institute of Infectious Diseases studied how the virus actually infects cells.

Kartik Chandran, a professor of microbiology and immunology at Albert Einstein, is a senior author of the study.

“The critical step that we were studying is what we call viral entry,” Chandran explained. “And it’s basically the step that results in the virus getting into the cytoplasm where the [genetic] goodies are for making copies of itself.”

Researchers looked at normal cell proteins that the Ebola virus might be hijacking, in effect, to get inside and infect mammalian cells. Investigators focused on one protein in particular – called Neimann-Pick C1 or NPC1.

Chandran says that in experiments with both human cells and in mice, the Ebola virus was unable to gain a toehold in cells that were missing the NPC1 protein.

“You couldn’t infect the cells with Ebola. And there are also mice that, like the human[s], don’t have the protein and develop Neimann-Pick disease,” Chandran said.

The Neimann-Pick protein, which is embedded naturally in cell membranes, helps transport cholesterol throughout cells. People who are born with a rare genetic defect and don’t make the protein eventually die of Neimann-Pick disease, in which fatty substances called lipids collect and clog various internal organs.

Chandran says the disease progresses over time. But to prevent or treat an Ebola infection, he thinks it might be possible to design a small molecule that interferes with production of the Neimann-Pick protein in cells temporarily — too briefly to cause problems with elevated cholesterol.

Chandran says such a compound would not have to totally block production of the NPC1 protein.

“You know the [Ebola] virus, it’s like ‘shock and awe.’ It’s like over within a week,” noted Chandran. “I mean the virus grows very quickly and it kills off the very cells you need to mount your immune response. If we could stop that from happening or slow it down enough, we might give the person a chance.”

Chandran says scientists have developed a candidate drug that could be used to treat or prevent an Ebola outbreak. He says another hemorrhagic virus called Marburg uses a similar mechanism to infect cells and should also respond to a drug that blocks the Neimann-Pick protein.

Two articles by Chandran and colleagues on the biochemical keys involved in Ebola virus infections are published in the journal Nature.

Source: http://www.voanews.com/english/news/science-technology/Critical-Protein-Discovery-Could-Help-Prevent-Lethal-Ebola-Virus-128374013.html

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Combining Gene and Cell Therapy Is Arming Researchers with More Options for Cancer

Last Updated on Monday, 22 August 2011 10:46 Written by admin Monday, 22 August 2011 10:46

A few years ago most pharma and biotech companies ran away from autologous therapies, especially complex cell-based treatments. Following Dendreon’s introduction of its autologous dendritic cell therapy to treat prostate cancer, however, researchers are venturing into one-off treatments for difficult to treat diseases.

In a huge scientific boost to the entire field of cell-based adoptive immunotherapy, scientists from the University of Pennsylvania announced on August 10 that they had used autologous, genetically engineered T cells to rid three patients of chronic lymphoid leukemia (CLL). The researchers said that it took them 20 years to achieve this breakthrough and that their work may provide a roadmap for treating other cancers.

Additionally, researchers from Memorial Sloan-Kettering Cancer Center are reporting positive results in leukemia and ovarian cancer. Their treatment approach is similar to the Penn study but uses a different target.

Finally, Genesis Biopharma is also in the adoptive cell immunotherapy game. It signed a CRADA with NCI to develop treatments to destroy metastatic melanoma cells using a patient’s tumor infiltrating lymphocytes (TILs).

Leveraging TILS

Under the terms of Genesis’ five-year agreement, the company will work with Steven A. Rosenberg, M.D., Ph.D., chief of the NCI’s Surgery Branch. It has been independently developing its Contego™ autologous cell therapy product candidate for the treatment of stage IV metastatic melanoma.

This June, the company reported entering into a process development and scale-up agreement with Lonza. Genesis Biopharma will develop Contego as a ready-to-infuse autologous cell therapy product containing TILs obtained from an individual patient’s metastatic melanoma tumors.

Contego is made by isolating TILs from an individual patient’s resected tumor, then expanded in vitro to several hundred million cells. The expanded TILs are then infused into the patient, where they subsequently attack melanoma tumors throughout the body. Contego is based on the TIL adoptive cell therapy being used at the NCI, MD Anderson Cancer Center, and the H. Lee Moffitt Cancer & Research Institute.

In 2006, Dr. Rosenberg reported on studies using genetically engineered autologous T lymphocytes from melanoma patients. The authors commented that although objective cancer regression could be achieved in metastatic melanoma patients with TILs following patient immunodepletion, generation of tumor-specific T cells in this mode of immunotherapy often proved limiting.

The authors reported that they could specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encoded a T-cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least two months after the infusion.

The authors said that although the response rate (2 out of 15 patients, or 13%) is lower than that achieved by the infusion of unmodified autologous TILs (50%), the injected cells thrived and made up at least 10% of the patients’ total T cells weeks later. Two men who had even higher levels of the modified T cells experienced a dramatic recovery, remaining healthy 18 months following treatment.

While Dr. Rosenberg said the success rate was low, he noted that “this is just a start.” Dr. Rosenberg’s group is working on improving the treatment including engineering other molecules into the cells to improve their tumor-finding capabilities and long-term persistence in patients.

Souped-Up T Cells

The University of Pennsylvania team that reported the stunning results in leukemia this month seem to have overcome some of the challenges previous TIL therapies faced, such as persistence in patients as Dr. Rosenberg pointed out. The Penn investigators reported that in their trial, which included three advanced chronic lymphocytic leukemia (CLL) patients, genetically modified versions of their own T cells behaved like “serial killers” and hunted down and obliterated tumors, resulting in sustained remissions of up to a year.

“Within three weeks the tumors had been blown away in a way that was much more violent that we expected,” said senior author Carl June, M.D., director of Translation Research and a professor at Penn’s Abramson Cancer Center. His team published their results in simultaneously in The New England Journal of Medicine and Science Translational Medicine.

The treatment protocol involved removing patients’ cells, genetically modifying them in Penn’s vaccine production facility, and then infusing the new cells back into the patient’s body following chemotherapy. T cells extracted from patients were genetically customized to trigger an attack on cancer cells. Of the three patients treated with the T cells, two remained free of leukemia for more than a year, and the third patient remained in remission for seven months.

Investigators said that the treatment may potentially offer a replacement for risky bone marrow transplants as well as allow a personalized approach useful in other cancers. For the three patients in the study, the only potential curative therapy would have involved a bone marrow transplant. The procedure carries at least a 20% mortality risk and has only about a 50% chance of a cure.

Key hurdles that had to be overcome, according to the Penn scientists, included robust expansion of the cells after delivery to the patient, prolonged persistence of the cells in the patient, and ongoing functional expression of the chimeric antigen receptors (CARs) post-infusion.

Their technique for producing the CAR cells and the combination of genetic elements introduced into the cells overcame these problems. The scientists genetically modified patient T cells to express desired proteins, introducing genes into the cells via a nonreplicating lentivirus. The T cells were engineered to express CARs on their surfaces, recognizing a protein, CD19, expressed on the surface of normal and cancerous B cells.

Particularly ingenious was engineering cells that could provoke a T-cell response to CD19 antigen in the absence of a major histocompatibility (MHC) restriction, allowing for much broader cellular targeting than can be obtained with normal T cells. The CAR T cells also expanded over 1,000-fold in the patients and persisted for over six months.

It takes between 10 and 12 days to produce the genetically engineered T cells, including isolation of cells from the patient, selection of the appropriate cells, transfection with the lentiviral construct, and expansion in culture. Each infused CAR-expressing T cell, the investigators said, eradicates about 1,000 CLL cells and, they said, some of the infused cells persist as memory CAR T cells, retaining anti-CD19 functionality.

Also reporting encouraging results with TIL therapy, Alena Chekmasova, Ph.D., and Renier Brentjens, M.D., Ph.D., investigators at the Department of Medicine at Memorial Sloan-Kettering Cancer Center, reported the generation of several CARs targeted to the retained extracellular domain of MUC16, termed MUC-CD, an antigen expressed on most ovarian carcinomas.

“Our approach doesn’t differ particularly from the Penn group’s approach. Only the target is different,” Dr. Brentjens told GEN. “However, the dynamics of how a therapy works in a liquid tumor like leukemia may differ from how it works against a solid tumor.” He explained that his laboratory is using “mouse models to study how the cells will function when we translate the therapy to a clinical setting.” Dr. Brentjens noted that his group’s research with engineering T cells from leukemia patients will appear online in the journal Blood later this month.

In his ovarian cancer work, Dr. Brentjens’ team studied the in vitro biology of human T cells retrovirally transduced to express CARs by co-culture assays on artificial antigen-presenting cells as well as by cytotoxicity and cytokine-release assays using human MUC-CD(+) ovarian tumor cell lines and primary patient tumor cells. They also assessed the in vivo antitumor efficacy of MUC-CD-targeted T cells in SCID-Beige mice bearing peritoneal human MUC-CD(+) tumor cell lines.

They reported that the CAR-modified, MUC-CD-targeted T cells showed efficient MUC-CD-specific antitumor cell activity against both human ovarian cell lines and primary ovarian carcinoma cells in vitro. In mice bearing human MUC-CD(+) tumors, infusion of the engineered cells either delayed progression or eradicated the disease. The authors concluded that the preclinical study results justify further clinical investigation in patients with high-risk, MC16-bearing ovarian cancers.

Dr. Brentjens said that his laboratory collaborates with Dr. June’s group at Penn and also runs CD19 trials. “Going forward we have a collaboration with Carl June at Penn wherein we will treat patients with a 50-50 mix of T cells modified to express either our receptor or their receptor. While both receptors target CD19, we use a different co-signaling domain, CD28, and they use 4-1BB. The question, he says, for the field in general, centers on which type of receptor design works best so we can move forward on how to further optimize this technology.”

GEN asked Dr. Brentjens whether and how this cell-based therapy will be marketed. “It depends on what the product is,” he said. “Will it be the virus that contains the artificial receptor gene or will the modified T cells themselves be the product?” If the cells are the product, it requires GMP facilities where they can generate the cells. Each patient will be an individual customer, similar to the Dendreon model.

Tumors have evolved many different multiple strategies to evade the immune system, including reduced antigen presentation and inhibition of effector lymphocyte function as well as the maintenance of tumor microenvironments hostile to immune function.

Scientists however continue to hope that genetic modifications of adoptively transferred cells may eventually overcome these challenges and improve clinical outcomes for intractable cancers. As researchers translate basic research into clinical results, all eyes are on proving safety and efficacy in patients in Phase II and III studies.

Source: http://genengnews.com/analysis-and-insight/combining-gene-and-cell-therapy-is-arming-researchers-with-more-options-for-cancer/77899448/

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Scientists Claim Differentiated Cancer Cells Can Convert to Stem-Like Cells to Maintain Equilibrium

Last Updated on Friday, 19 August 2011 04:42 Written by admin Friday, 19 August 2011 04:42

Cells in individual tumors can interconvert into different cell types including reverting into cancer stem cells in order to maintain equilibria in terms of the proportion of cells existing in different states within the cancer, researchers claim.They found that rather than existing as a hierarchical society in which all cells are derived from cancer stem cells, cancers exist as a decentralized society of different cell types that can sense when one type of cell has been depleted and generate new cells of the relevant type to take their place.

The group included scientists at the Massachusetts of Institute of Technology Broad Institute, Tufts University, and Harvard Medical School. Details are published in Cell in a paper titled “Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells.” Results could have significant implications for cancer cell therapy, claim lead researchers Eric S. Lander, Ph.D., and Piyush B. Gupta, Ph.D., because removing cancer stem cells will just prompt other cell types in the tumor to convert into stem cells to top up the population.

One of the puzzling features of cancer cell populations is their ability to retain phenotypic equilibrium over extended periods of time, the team writes. Populations of cancer cells often harbor subpopulations with specific cell-surface marker profiles, which are stably maintained across many cell divisions in culture.

To investigate the basis of this equilibrium-maintaining phenomenon further, the researchers isolated and separately cultured three cell types—stem-like, basal, and luminal—from two different human breast cancer lines derived from primary tumors. Each of the three cell types was confirmed to display specific morphological and cell surface marker characteristics.

These relatively pure subpopulations of cells, which each represented a given differentiation state, were then allowed to expand in culture, and relevant population dynamics monitored over time. Surprising, the researchers found that when they assessed the relative proportions of stem-like, basal, and luminal cells in each originally ‘pure’ population after expansion, there had been an evident rapid progression back to equilibrium proportions.

Two lines of evidence indicated that this progression was due to interconversion between states, rather than as a result of differential growth rates of cells in the basal, stem-like, or luminal states, they claim. Firstly, there was no difference in the proliferation rates of the stem-like, basal, or luminal subpopulations sorted from either of the two stem cell lines: they all replicated at about the same rate.

Secondly, given the purity of the original sorted populations and the rapid rate of return to equilibrium proportions, some minority subpopulations would need to have been dividing at more than three times per day to achieve the observed proportions through differential growth rate alone. “Such a high proliferation rate is implausible because even the most rapidly dividing human cells— embryonic stem cells—require at least 24 hours to complete a proliferation cycle,” they claim.

Based on the notion that interconversion between cell states was therefore occurring, the team used data from their expanded breast cancer cell populations to developed a Markov model, in which the cell type transition probabilities depend only on a cell’s current state, not on its prior state. The inferred Markov transition probabilities thus make it possible to quantitatively predict how a population of cells evolves over time, given the initial proportions of cells in different states.

The resulting model made several predictions about how the cell populations would develop, and these were confirmed in the cultured breast cancer populations, the researchers note. However, a number of unexpected predictions also emerged. One of these was that basal and luminal cells can transition back into a stem-like state: “that is, cancer stem-like cells can arise from non-stem-like cells.” This essentially contradicts current concepts relating to normal tissues, which assume a rigid lineage-hierarchy in which stem cells can give rise to nonstem cells, but not vice versa, they write.

They tested this particular prediction by implanting either freshly sorted, or sorted and then cultured subpopulations of tumor cells in mice. As expected according to traditional dogma, only the stem-like fraction could efficiently seed tumors, and neither the luminal nor basal fraction was capable of doing so.

However, because the lack of tumor-seeding ability displayed by the basal and luminals could have been due to their inability to survive after transplantation, the researchers repeated the exercise by co-inoculating the cells with GFP-labeled, irradiated parental carrier cells from one of the breast cancer lines. Under these conditions, all three fractions (stem-like, basal, and luminal) were equally capable of efficiently seeding tumors.

Moreover, examination of the tumors arising from basal and luminal subpopulations mixed with irradiated carrier cells revealed the presence of significant numbers of stem-like cells. The proportions of basal, stem-like, and luminal cells contained in the resulting tumors were comparable irrespective of the sorted subpopulation initially used to seed the tumor.

“Collectively, these results demonstrated that the luminal and basal fractions can indeed regenerate functional stem-like cells in vivo and suggested that convergence toward equilibrium cell-state proportions could be occurring due to cell-state interconversion within tumors,” the authors write. “A specific prediction of this quantitative model is that any subpopulation of cancer cells will return to a fixed equilibrium of cell-state proportions over time, provided that it is possible through one or more interconversions to transition between any two states.”

The de novo generation of cancer stem cells has implications for the effectiveness of anticancer therapies focused on killing this cell type, because of the ability of other cancer cell types to regenerate cancer stem cells after cessation of therapy and lead to renewed tumor growth, they add. “Therefore, in order to be effective, cancer therapies will need to combine agents that are selectively toxic to cancer stem cells with agents that either target the bulk noncancer stem cell populations within tumors or inhibit transitions from noncancer stem cell to cancer stem cell states.”

The team claims their model could also be extended to other biological settings in which stochastic state transitions occur, either in normal or diseased contexts.

Source: http://www.genengnews.com/gen-news-highlights/scientists-claim-differentiated-cancer-cells-can-convert-to-stem-like-cells-to-maintain-equilibrium/81245572/

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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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Blood Antibody May Signal Start of Ovarian Cancer

Last Updated on Wednesday, 17 August 2011 02:49 Written by admin Wednesday, 17 August 2011 02:49

WEDNESDAY, Aug. 17 (HealthDay News) — Researchers have found an antibody that might someday be useful in identifying women who have a higher risk of ovarian cancer, or possibly diagnosing early ovarian cancer.

This particular antibody, which was detected in blood, develops as an immune system response to a protein called mesothelin. This protein is present in advanced ovarian cancer. Although mesothelin is found in normal tissue, it’s found in abundance in ovarian cancer cells.

The current study found that infertile women, who are known to have an increased risk of ovarian cancer, were more likely to have the mesothelin antibody. The researchers also found that women with ovarian cancer were more likely to have this antibody.

“We’re taking a novel approach to try to identify earlier biomarkers of ovarian cancer by looking at high-risk women,” said study author Judith Luborsky, a professor of pharmacology, obstetrics and gynecology, and preventive medicine at Rush University Medical Center in Chicago.

“This study found that there are antibodies to mesothelin circulating in women that have infertility,” noted Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society. Exactly what these findings mean isn’t yet clear, however. “Are these women who will develop ovarian cancer? Are these antibodies related to infertility? This research gives us some clues, and leads to many more questions,” he said.

As for an individual woman who’s currently concerned about ovarian cancer, Lichtenfeld said, “I would be very cautious about drawing any conclusion about the meaning of an elevated antibody level in an individual woman.”

Results of the study will be published Aug. 17 in the online version of the journal Cancer Epidemiology, Biomarkers & Prevention.

Almost 22,000 American women are diagnosed with ovarian cancer each year, and more than 15,000 women die each year as a result of this disease, reports the American Cancer Society.

Most women who develop ovarian cancer aren’t diagnosed until the disease is advanced. If it’s found early, ovarian cancer has a five-year survival rate of 94 percent, according to the cancer society. Two tests that experts hoped would help change that — a combination of transvaginal ultrasound and a blood test for CA-125, a marker associated with ovarian cancer — haven’t reduced a woman’s risk of dying from ovarian cancer, according to a recent study in the Journal of the American Medical Association.

Luborsky and her colleagues wanted to try to find a way to detect early cancer or a screening test for who’s at high risk for ovarian cancer before the cancer develops. Testing for mesothelin wouldn’t work, because it isn’t found at high levels until the cancer is advanced.

So, instead of looking for mesothelin, the researchers looked at a group of 109 infertile women, 28 women with ovarian cancer, and 24 women with benign ovarian cysts or tumors to see if these groups had antibodies to mesothelin. They also compared the three groups of women to healthy women to see if mesothelin antibodies were present.

Significant levels of mesothelin antibodies were found in women with ovarian cancer and in women with unexplained infertility or women who were infertile due to premature ovarian failure or ovulation problems. Women who were infertile due to endometriosis didn’t have significant levels of mesothelin antibodies, according to the study. Healthy women, and women with benign ovarian growths also didn’t have significant levels of mesothelin antibodies, the investigators found.

“There’s a lot more we have to learn, but our aim would be for a screening test that could improve detection,” said Luborsky.

Source: http://health.usnews.com/health-news/family-health/cancer/articles/2011/08/17/blood-antibody-may-signal-start-of-ovarian-cancer

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Five Genes May Be Tied to Lethal Prostate Cancer

Last Updated on Tuesday, 16 August 2011 02:42 Written by admin Tuesday, 16 August 2011 02:42

TUESDAY, Aug. 16 (HealthDay News) — In what may be a diagnostic advance, U.S. and Swedish researchers have linked five inherited genetic mutations to the development of a particularly aggressive and deadly form of prostate cancer.

The findings could someday lead to development of an easy-to-administer blood test to screen for such mutations to help physicians assess the long-term risk faced by newly diagnosed prostate cancer patients, the researchers suggested.

“The ability to distinguish patients at elevated risk for having aggressive, life-threatening prostate cancer at the time of diagnosis could improve care for the subset of cases most likely to benefit from aggressive therapy and help avoid over-treatment of patients whose tumors are likely to remain indolent,” the study team, led by Janet L. Stanford, co-director of the Fred Hutchinson Cancer Research Center’s program in prostate cancer research, reported in the Aug. 16 online edition of Cancer Epidemiology, Biomarkers and Prevention.

At issue are longstanding concerns about unnecessary over-treatment of many prostate cancer patients who actually face a relatively low risk for fast disease progression and death. Because treatment can bring about undesirable side effects, such as sexual impotence and urinary incontinence, an effort has been under way to achieve a more personalized assessment of a patient’s particular prognosis after diagnosis.

“Biomarkers that could distinguish between patients with indolent vs. more aggressive tumors are urgently needed,” Stanford said in a journal news release. “The panel of markers we’ve identified provides the first validated evidence that inherited genetic variants play a role in prostate cancer progression and mortality. Ultimately these markers could be used in the clinic, along with other known predictors that are used to assess tumor aggressiveness, such as a high Gleason score, to identify men with a high-risk profile.”

The authors, looking for genetic differences that could highlight risk differences, gathered blood samples from more than 1,300 prostate cancer patients living in the Seattle region. All were between the ages of 35 and 74 when diagnosed.

DNA analyses of the samples were compiled with those of nearly 2,900 Swedish prostate cancer patients.

The result: Five single-letter mutations (or SNPs) were isolated among the patients’ “DNA alphabet” as having a significant bearing on prostate cancer progression in terms of affecting cell death, tumor growth, inflammation, androgen hormone levels, blood-vessel development and bone density.

Patients found to have at least four out of the five cited SNP mutations appeared to face a 50 percent higher risk for dying from their disease compared with those who carried two or fewer of the mutations.

William Phelps, program director of translational and preclinical cancer research at the American Cancer Society, said the push to develop more revealing diagnostic tools is driven by an acknowledgement that current treatment options can debilitate patients.

“If the treatments we had for prostate cancer were very tolerable or very safe you would probably treat everybody,” he explained. “But the treatments we have available today are less than ideal.”

“So certainly we can try to improve treatment,” Phelps noted. “But at the same time we can also try to improve ways to identify patients who are more likely to progress rapidly from those likely to be very slow going, so we can reserve treatment for only those instances when it’s really necessary.”

If there are markers that better define the men whose cancer is most likely to progress, “that would certainly prove very useful in the current climate,” he said.

Source: http://health.usnews.com/health-news/family-health/cancer/articles/2011/08/16/five-genes-may-be-tied-to-lethal-prostate-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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New tests screen for gum disease, oral cancer

Last Updated on Wednesday, 10 August 2011 11:10 Written by admin Wednesday, 10 August 2011 11:10

Future dental visits may involve more than a simple cleaning. Oral DNA testing may also help screen patients for gum disease or oral cancer.

Dr. Jessica Lawson of Urbandale Family Dentistry began offering the tests last spring. Two tests involve gum disease and a third for oral human papillomavirus, or HPV, assesses risks for oral cancer.

Researchers anticipate salivary testing may become the diagnostic tool of the future, in some instances even replacing blood work, said Lawson, one of the few dentists in the metro area offering the tests.

“It really supports what we’re doing with our patients. They know we have their best interest at heart. We’re looking to prevent, rather than treat and fix,” she said.

According to the manufacturer, OralDNA Labs, the periodontal tests have been available for nearly two years and the HPV test since January 2010.

Lawson’s staff educates all patients about testing, especially existing gum disease patients who don’t respond to frequent cleanings. Tests cost $150 each.

So far, 24 of her patients have undergone one of the gum disease tests. A handful had the HPV test, which can be a more difficult discussion since transmission is associated with sexual contact.

Testing is simple. Patients swish saline in their mouths for 30 seconds and spit it into a collection tube. The HPV test requires that patients gargle since the virus typically lives in the soft palate, esophagus and throat — similar to tissue in the cervix, where HPV is also present. Results are returned in seven to 10 days.

An estimated 50 to 60 percent of Americans have gum disease — some undiagnosed. Those patients usually have cleanings every three months. One test shows a patient’s genetic susceptibility to gum disease. It’s also a good test for new patients, Lawson said.

The other periodontal test shows what concentration of bacteria are present in the saliva and what antibiotic best treats it. The manufacturer recommends re-testing in six weeks.

Patient Amanda Rynning, 31, took that test a month ago to pinpoint the cause of tender, bleeding gums during flossing.

“I kind of questioned it a bit, but the more she talked about it and explained things, the more I felt comfortable taking the test,” she said.

The results allowed Lawson to customize Rynning’s antibiotic treatment and schedule a follow-up in a few weeks.

The test is also recommended for pregnant women to identify the presence of a specific oral bacteria associated with a higher rate of pre-term, low birth weight babies.

The HPV test targets two strains associated with squamous cell carcinoma of the head and neck, which affects 40,000 Americans every year.

As sexual activity is beginning at younger ages, the virus has become a hot topic, Lawson said.

“The prototype has changed for oral cancer. It used to be middle-aged to older men who were heavy tobacco users, abused alcohol and had other risk factors. Eighteen to 40-year-olds are now the high risk population for oral cancer due to increased sexual activity and skin-to-skin or mucous membrane transmission.”

Because there is no evidence Gardisil, an HPV vaccine, will protect against oral cancer, dentists may recommend exams every three months if needed. Lawson also can monitor with a VELscope, a fluorescent light that reflects light back at different wavelengths if tissue is damaged.

Caught early, the prognosis for oral cancer is good, Lawson said, adding that actor Michael Douglas was treated for the same condition. Initial symptoms include:

Earaches

Sore throat

Changes in voice box

Swollen, hard lymph nodes.

“We’re hoping with this test we’re monitoring things so at the first sign of symptoms we get them referred to the appropriate physicians,” she said.

Source: http://www.desmoinesregister.com/article/20110810/LIFE/308100026/-1/GALLERY_ARRAY/New-tests-screen-gum-disease-oral-cancer

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

Genetic mutations cause schizophrenia

Last Updated on Monday, 8 August 2011 11:28 Written by admin Monday, 8 August 2011 11:28

More than 50 per cent of sporadic cases of schizophrenia are caused by new, or “de novo,” protein-altering mutations-genetic errors that are present in patients but not in their parents, a new research has shown.

A group led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD, PhD, examined the genomes of patients with schizophrenia and their families, as well as healthy control groups. All were from the genetically isolated, European-descent Afrikaner population of South Africa.

They found 40 mutations, all from different genes and most of them protein-altering.

The results point the way to finding more, perhaps even hundreds, of mutations that contribute to the genetics of schizophrenia-a necessary step toward understanding how the disease develops, the researchers said.

“Identification of these damaging de novo mutations has fundamentally transformed our understanding of the genetic basis of schizophrenia,” says Bin Xu, PhD, assistant professor of clinical neurobiology at Columbia University Medical Center and first author of the study.

“The fact that the mutations are all from different genes,” says Karayiorgou, “is particularly fascinating. It suggests that many more mutations than we suspected may contribute to schizophrenia. This is probably because of the complexity of the neural circuits that are affected by the disease; many genes are needed for their development and function,” she added.

The study was recently published online in Nature Genetics.

Source: http://timesofindia.indiatimes.com/life-style/health-fitness/health/Genetic-mutations-cause-schizophrenia/articleshow/9527010.cms

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Urine Test May Help Detect, Stratify Prostate Cancer

Last Updated on Thursday, 4 August 2011 11:07 Written by admin Thursday, 4 August 2011 11:07

In men with elevated prostate specific antigen (PSA), an investigational urine test can detect and stratify prostate cancer, researchers reported.

The test is based on the detection of a gene fusion that is specific to prostate cancer, combined with another marker, according to Arul Chinnaiyan, MD, PhD, of the University of Michigan Medical School in Ann Arbor, and colleagues.

Stratifying patients by the combined marker identified groups with markedly different risks of cancer, high-grade cancer, and clinically significant cancer on biopsy, Chinnaiyan and colleagues reported online in Science Translational Medicine.

The noninvasive test could allow some men with elevated PSA to avoid a needle biopsy, the researchers noted.

“Many more men have elevated PSA than actually have cancer but it can be difficult to determine this without biopsy,” Chinnaiyan said in a statement. “The hope is that this test could be an intermediate step before getting a biopsy.”

The fusion at the heart of the test involves the genes transmembrane protease, serine 2 (TMPRSS2), and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG).

The fusion appears in about half of all prostate cancers, Chinnaiyan and colleagues noted, but when it appears it is almost 100% specific for malignancy.

In a series of experiments, the researchers showed that the fusion gene was associated with indicators of clinically significant cancer at biopsy and prostatectomy.

The indicators included tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy, they reported.

But because the fusion gene is not universally present, the researchers created a model that combined it and the prostate cancer antigen 3 (PCA3) gene.

In 1,065 men who underwent biopsy, the researchers used the model to stratify men into three groups – lowest, intermediate, and highest levels of the combined genes.

They found that the groups had distinctly different patterns of risk. Specifically:

363, 346, and 356 men were in the lowest, intermediate, and highest score groups, respectively – or 34%, 32% and 33%.
Biopsy resulted in a cancer diagnosis in 21%, 43%, and 69% of men in the lowest, intermediate, and highest groups, respectively. The difference between the low and high groups was significant at P<0.001.
7%, 20%, and 40% of men in the lowest, intermediate, and highest groups were diagnosed with cancer that had a Gleason score of greater than 6. The difference between the low and high groups was again significant at P<0.001.
Of the 966 men with enough information to determine the Epstein criteria for significance of cancer on biopsy, 15%, 33%, and 61% of men in the three groups, respectively, had Epstein-criteria-defined significant cancer.

The researchers cautioned that the test remains investigational. As well, they noted, most of the men studied so far have been Caucasian, so that additional study is needed to see if the results apply more broadly.

Source: http://www.medpagetoday.com/HematologyOncology/ProstateCancer/27884?pfc=101&spc=224

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

Sanofi Pasteur to Evaluate Leukocare’s Stabilization Technology for Vaccines

Last Updated on Wednesday, 3 August 2011 02:51 Written by admin Wednesday, 3 August 2011 02:51

Sanofi Pasteur and Leukocare biotechnology inked a cooperation agreement through which Sanofi’s vaccines division will evaluate Leukocare’s Stabilizing and Protecting Solutions (SPS) platform for improving the shelf-life of certain vaccine formulations.

Leukocare’s postcoating technology is designed to both stabilize biotherapeutic and diagnostic products and protect them against the otherwise damaging effects of terminal sterilization by irradiation or ethylene oxide. The firm says the platform can be used to help preserve the activity of biologics during processing for dry storage, and is applicable to lyophilization, air drying, spray drying or microcrystal powders.

Leukocare specializes in technologies for biological functionalization of surfaces and for product stabilization. The firm offers collaborative research and development services that exploit its core technologies in the fields of biofunctional surface engineering, biopharmaceuticals, development and co-development of combination products, as well as related preclinical and clinical studies.

The SPS technology has been tailored to specific product types. SPS-CP is designed for stabilizing and protecting combination products. SPS-BP is adapted specifically for the stabilization and protection of biopharmaceutical formulations and galenics. SPS-LT is designed to stabilize and protect diagnostic surface coating.

In November 2010 Leukocare teamed up with sterilization services firm Sterigenics, for a collaboration that aims to combine the SPS platform with Sterigenics irradiation technologies and establish new sterilization procedures for biotherapeutics, including therapeutic antibodies.

Source: http://genengnews.com/gen-news-highlights/sanofi-pasteur-to-evaluate-leukocare-s-stabilization-technology-for-vaccines/81245462/

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Positive agreement received for approval of AXANUM (low-dose ASA/esomeprazole) in Europe

Last Updated on Tuesday, 2 August 2011 01:50 Written by admin Tuesday, 2 August 2011 01:50

AstraZeneca today announced that AXANUM, a fixed dose combination of 81 mg low-dose ASA (acetylsalicylic acid) and 20 mg esomeprazole, has received positive agreement for approval in 23 European Union member countries and in Norway. AXANUM is indicated for prevention of cardiovascular (CV) events such as heart attack or stroke, in high-risk CV patients in need of daily low-dose ASA treatment and who are at risk of gastric ulcers.

Low-dose ASA (commonly known as aspirin) is recommended mainstay therapy for patients with high-risk for cardiovascular events. About one third of these patients are also at increased risk of stomach ulcer. Low-dose ASA further increases the risk for gastric ulcers and gastrointestinal bleeding. In fact, the most common reason for stopping low-dose ASA treatment is upper gastrointestinal problems. The consequences of interrupting low-dose ASA treatment can be severe, increasing the risk of a heart attack or stroke as early as eight to 10 days later.

AXANUM is the only medicine that ensures every single pill of low-dose ASA comes with built-in protection against gastric ulcers. That means AXANUM has the potential to provide continuous CV protection in this patient population.

The EU decision took place under the decentralised procedure (DCP), with Germany acting as reference member state. This process is now followed by national approvals and local pricing and reimbursement discussions.

Tony Zook, Executive Vice President of AstraZeneca’s Global Commercial Organisation said: “AstraZeneca has had some significant regulatory approvals this year, and we’re pleased with this positive agreement for AXANUM in Europe. We will now work with relevant health authorities to secure reimbursement decisions and get onto formularies to bring this medicine to patients as soon as possible.”

Source: http://www.europeanpharmaceuticalreview.com/8417/news/industry-news/positive-agreement-received-for-approval-of-axanum-low-dose-asaesomeprazole-in-europe/?utm_medium=email&utm_campaign=EPR+-+Newsletter+16+2011&utm_content=EPR+-+Newsletter+16+2011+CID_0d42f174df14efdb3a6804bfbf1f416a&utm_source=Email+marketing&utm_term=Positive+agreement+received+for+approval+of+AXANUM+low-dose+ASAesomeprazole+in+Europe

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BioFocus to Offer IMD’s Natural Product Libraries through Drug Discovery Services

Last Updated on Tuesday, 2 August 2011 12:44 Written by admin Tuesday, 2 August 2011 12:44

BioFocus and InterMed Discovery (IMD) inked a marketing collaboration that will allow BioFocus to offer IMD’s natural product screening libraries through its drug discovery services. IMD will in addition provide follow-on services to BioFocus.

“We have been impressed with the scale of IMD’s natural product discovery capabilities, and we believe that when InterMed’s natural product libraries and services are combined with our screening services, our engine for drug discovery will be substantially enhanced and more cost-effective for our clients,” comments Chris Newton, Ph.D., BioFocus MD.

IMD was established as a management buyout from Bayer HealthCare in Germany. The firm’s expertise is based on its natural compound libraries and related databases, which are being exploited to offer compound discovery and consultancy to the pharmaceutical, crop science, and food industries. IMD claims to offer the largest collections of pure compounds, sample fractions, and mixtures as its source for potential natural product leads.

The firm is in addition generating a pipeline of early-stage pharmaceuticals and functional ingredients based on compounds it says have shown interesting in vitro or in vivo potential. Biologically characterized product leads are identified using the IMD Bioprofiling and Npsilico technologies, which together comprise a bioinformatics platform that draws on years worth of screening results, complemented by primary biological and chemical research on natural products.

The Npsilico platform is composed of literature and proprietary information about bioactive natural products. IMD claims that this enables the identification of lead structures without de novo wet lab identification, through systematic, focused, and structure-driven research.

Source: http://genengnews.com/gen-news-highlights/biofocus-to-offer-imd-s-natural-product-libraries-through-drug-discovery-services/81245443/

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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

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