Feb. 5, 2013 — Tourists coming into contact with sea turtles at holiday attractions face a risk of health problems, according to research published February 5 by JRSM Short Reports. Encountering free-living sea turtles in nature is quite safe, but contact with wild-caught and captive-housed sea turtles, typically through handling turtles in confined pools or through consuming turtle products, carries the risk of exposure to toxic contaminants and to zoonotic (animal to human) pathogens such as bacteria, viruses, fungi and parasites. Symptoms, which may take some time to emerge, can resemble gastrointestinal disorders or flu but people more severely affected can suffer septicaemia, pneumonia, meningitis and acute renal failure.

The review included a case study of the Cayman Turtle Farm in Grand Cayman, which between 2007 and 2011 attracted approximately 1.2 million visitors. CTF sells farmed turtle meat to the public and local restaurants. One of the researchers, Clifford Warwick of the Emergent Disease Foundation, said: “The subsequent distribution of visitors exposed to turtle farm conditions may also involve opportunities for further dissemination of contaminants into established tourist hubs including cruise ship and airline carriers.”

Warwick added that awareness of potential threats may be modest among health-care professionals and low among the public. “To prevent and control the spreading of sea turtle-related disease, greater awareness is needed among health-care professionals regarding potential pathogens and toxic contaminants from sea turtles, as well as key signs and symptoms of typical illnesses.”

The study was funded by the World Society for the Protection of Animals. Warwick said: “Significantly, the captive farming of turtles arguably increases the threat to health, in particular from bacteria, due to the practice of housing many turtles in a relatively confined space and under intensive conditions.”

Warwick concluded: “People should avoid food derived from sea turtles and perhaps also other relatively long-lived species regardless of their role in the food chain as all these animals potentially have more time in which to accumulate hazardous organisms and toxins and present an increased risk of animal-linked human pathology.”

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The above story is reprinted from materials provided by SAGE Publications, via EurekAlert!, a service of AAAS.

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1. Clifford Warwick, Phillip C Arena and Catrina Steedman. Health implications associated with exposure to farmed and wild sea turtles. JRSM Short Reports, Feb 2013

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 31, 2013 — New research has shown the presence of a disease affecting small blood vessels, known as microangiopathy, in the bone marrow of diabetic patients. While it is well known that microangiopathy is the cause of renal damage, blindness and heart attacks in patients with diabetes, this is the first time that a reduction of the smallest blood vessels has been shown in bone marrow, the tissue contained inside the bones and the main source of stem cells.

These precious cells not only replace old blood cells but also exert an important reparative function after acute injuries and heart attacks. The starvation of bone marrow as a consequence of microangiopathy can lead to a less efficient healing in diabetic patients. Also, stem cells from a patient’s bone marrow are the most used in regenerative medicine trials to mend hearts damaged by heart attacks. Results from this study highlight an important deficit in stem cells and supporting microenvironment that can reduce stem cells’ therapeutic potential in diabetic patients.

The research team, led by Professor Paolo Madeddu, Chair of Experimental Cardiovascular Medicine in the School of Clinical Sciences and Bristol Heart Institute at the University of Bristol, investigated the effect of diabetes on bone marrow stem cells and the nurturing of small blood vessels in humans.

The new study, published in the American Heart Association journal Circulation Research, was funded by the British Heart Foundation (BHF).

The researchers have shown a profound remodelling of the marrow, which shows shortage of stem cells and surrounding vessels mainly replaced by fat, especially in patients with a critical lack of blood supply to a tissue (ischaemia). This means that, as peripheral vascular complications progress, more damage occurs in the marrow. In a vicious cycle, depletion of bone marrow stem cells worsens the consequences of peripheral ischaemia.

Investigation of underpinning mechanisms revealed that exposure of bone marrow stem cells to the high glucose level typical of diabetes mellitus impacts on “microRNAs,” which are tiny RNA molecules controlling gene expression and hence biological functions. In particular, microRNA-155, that normally controls the production of stem cells, becomes dramatically reduced in bone marrow cells exposed to high glucose. Diabetes-induced deficits are corrected by reintroducing microRNA-155 in human stem cells. The authors foresee that microRNAs could be used to regain proper stem cells number in diabetes and fix stem cells before reintroduction into a patient’s body.

Professor Paolo Madeddu said: “Our study draws attention to the bone marrow as a primary target of diabetes-induced damage. The research suggests that the severity of systemic vascular disease has an impact on bone marrow causing a precocious senescence of stem cells. More severe bone marrow pathologies can cause, or contribute to, cardiovascular disease and lead to worse outcomes after a heart attack, through the shortage of vascular regenerative cells. Clinical evidence indicates that achieving a good control of glucose levels is fundamental to prevent vascular complications, but is less effective in correcting microangiopathy. We need to work hard to find new therapies for mending damaged microvessels.”

Professor Costanza Emanueli, Chair of Vascular Pathology and Regeneration at the University of Bristol and co-author of the paper, added: “MicroRNAs represent an attractive means to repair the marrow damage and generate “better” stem cells for regenerative medicine applications. We are working at protocols using microRNA targeting for enhancing the therapeutic potential of stem cells before their transplantation to cure heart and limb ischaemia, which are often associated with diabetes mellitus. More work is, however, necessary before using this strategy in patients.”

The findings advance the current understanding of pathological mechanisms leading to collapse of the vascular niche and reduced availability of regenerative cells. The data provides a key for interpretation of diabetes-associated defect in stem cell mobilisation following a heart attack. In addition, the research reveals a new molecular mechanism that could in the future become the target of specific treatments to alleviate vascular complications in patients with diabetes.

Professor Jeremy Pearson, Associate Medical Director at the BHF said: “Professor Madeddu and his team have shown for the first time that the bone marrow in patients with diabetes can’t release stem cells which are important for the repair of blood vessel damage commonly found in people with the disease.

“If we could restore the ability of the marrow to release stem cells there is potential to reduce the effects of diabetes, and prevent the devastating consequences of the condition such as blindness and amputation. Understanding more about injured blood vessel repair will also aid in the fight to mend hearts damaged after a heart attack, a vital research area we fund through our Mending Broken Hearts Appeal.”

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The above story is reprinted from materials provided by University of Bristol.

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1. G. Spinetti, D. Cordella, O. Fortunato, E. Sangalli, S. P. Losa, A. Gotti, F. Carnelli, F. Rosa, S. Riboldi, F. Sessa, E. Avolio, A. P. Beltrami, C. Emanueli, P. R. Madeddu. Global Remodeling of the Vascular Stem Cell Niche in Bone Marrow of Diabetic Patients: Implication of the miR-155/FOXO3a Signaling Pathway. Circulation Research, 2012; DOI: 10.1161/CIRCRESAHA.112.300598

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 31, 2013 — Most ovarian cancer patients are diagnosed with late stage disease that is unresponsive to existing therapies. In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using patients’ own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in these type of patients. Four of the six patients treated in the trial responded to the therapy, the investigators report this month in OncoImmunology.

“What we proved in this study is that this is a safe treatment strategy,” says co-first author Lana Kandalaft, PharmD, MTR, PhD, research assistant professor of Obstetrics and Gynecology and director of clinical development in the Ovarian Cancer Research Center. “It is a walk in the park for patients, especially compared to standard chemotherapies and surgical treatments for ovarian cancer — literally, some patients left the clinic and went for a walk in a nearby park after their treatment.”

The findings follow research by the study’s senior author, George Coukos, MD, PhD, director of the Ovarian Cancer Research Center at Penn, who showed in 2003 that women whose ovarian tumors were infiltrated by healthy immune cells, called T cells, tended to live longer than women whose tumors were devoid of T cells. That observation and other subsequent ones suggest the patient’s immune system is trying to fight off the disease but can’t quite muster the strength to beat it. Therefore, investigators have been trying to find ways using patients’ own tumor cells to boost the immune system’s power.

In the current study, Coukos, Kandalaft, co-first author Daniel J. Powell Jr., PhD, research assistant professor of Pathology and Laboratory Medicine, and colleagues treated six women with advanced ovarian cancer in a two-staged immunotherapy protocol in which they utilized a dendritic cell vaccine created from tissue in the patients’ own tumor, which was stored at time of surgery. All of these women’s cancers had progressed on standard of care chemotherapy.

In the first segment of the study, the team prepared an individualized dendritic cell vaccine for each patient. They harvested dendritic cells from each patient using apheresis, the same process volunteers go through when they donate platelets or other blood products such as those collected for stem cell transplants. Kandalaft and colleagues then exposed each patient’s dendritic cells to tumor extract produced from the woman’s own tumor, which teaches the dendritic cells who the enemy is. After this priming, the investigators vaccinated each patient with her own dendritic cells and gave them a combination chemotherapy regimen of bevacizumab and cyclophosphamide. Because dendritic cells are like the generals of the immune system, they then induce other immune cells to take up the fight.

Of the six patients who received the dendritic cell vaccine, four developed an anti-tumor immune response, indicating that the approach was working. One of those patients had no measurable disease at study entry because all of it had been successfully removed during surgery. She remains in remission today, 42 months following vaccine treatment. The other three who had an immune response to the vaccine still had residual disease and went on to the second segment of treatment.

The team harvested T cells from each of these three women. Using a technique developed at Penn, they grew the cells in the laboratory, expanding their numbers exponentially, and then reintroduced them into each patient after she underwent a lymphodepleting chemotherapy regimen. Because the T cells had already been trained by the dendritic cell vaccine to attack the tumor cells, the adoptive T cell transfer amplifies the anti-tumor immune response.

Two of the women showed a restored immune response after the T cell transfer. One of the women continued to have stable disease, whereas the other had a complete response to the therapy.

The researchers say it is too early to say whether this type of therapy will be effective in a large number of ovarian cancer patients, but the early results are promising. First, and foremost, she notes, the two-step approach appears safe and well tolerated by the patients. Additionally, the team saw a correlation in both treatment steps between immune responses and clinical benefit, suggesting that it is, in fact, the immune response that is holding the disease in check.

With these encouraging results in hand, the team has opened a larger trial in which they have already enrolled about 25 women and aim for up to 30 more. The new protocol uses an improved vaccine platform and an optimized adoptive T cell transfer protocol. The PI of this study is Janos Tanyi, MD, PhD.

“Large clinical trials have shown that intensifying chemotherapy doesn’t improve outcomes for women with advanced ovarian cancer,” Coukos says. “So we need to explore other avenues. We think the combinatorial approach of both immune and chemotherapy is the way to go.”

Other co-authors from Penn include Cheryl L. Chiang, Janos Tanyi, Sarah Kim, Kathy Montone, Rosemarie Mick, Bruce L. Levine, Drew A. Torigian, and Carl H. June. Co-author Marnix Bosch is from Northwest Biotherapeutics in Bethesda, MD.

This study was supported by National Cancer Institute Ovarian SPORE grant P01-CA83638, National Institution of Health R01FD003520-02, and the Ovarian Cancer Immunotherapy Initiative.

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The above story is reprinted from materials provided by University of Pennsylvania School of Medicine.

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1. Lana E. Kandalaft, Daniel J. Powell, Cheryl L. Chiang, Janos Tanyi, Sarah Kim, Marnix Bosch, Kathy Montone, Rosemarie Mick, Bruce L. Levine, Drew A. Torigian, Carl H. June and George Coukos. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. OncoImmunology, 2013; 2: e22664 link

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 30, 2013 — Tuberculosis is a devastating disease that kills nearly 2 million people worldwide each year. Although antibiotics exist that can ameliorate the symptoms, the courses of therapy last for months and don’t completely eradicate the disease, which frequently recurs years or decades after the initial treatment.

Now, in a classic case of bench-to-bedside research, scientists at the Stanford University School of Medicine have discovered a possible reason for the disease’s resistance: The ability of the tuberculosis bacteria to infiltrate and settle down in a particular class of stem cell in the bone marrow. By doing so, the bacteria take advantage of the body’s own mechanisms of self-renewal.

“Cancer scientists have noted that self-renewing stem cells like these in the bone marrow have properties — such as natural drug resistance, infrequent division and a privileged immune status — that make them resistant to many types of treatment,” said Dean Felsher, MD, PhD, professor of oncology and of pathology. “Now it turns out that this ancient organism, Mycobacterium tuberculosis, figured out a long time ago that, for the same reasons, these cells are ideal hosts to invade and in which to hide.”

Not only did the scientists find genetic material from the bacteria inside the stem cells, they were also able to isolate active bacteria from the cells of human patients with tuberculosis who had undergone extensive treatment for the disease. The findings raise the possibility that other infectious agents may employ similar “wolf-in-stem-cell-clothing” tactics. And, although any new human treatments are likely to still be years away, they suggest a new possible target in the fight against tuberculosis, which infects nearly 2.2 billion people worldwide.

“We now need to learn how the bacteria find and infect this tiny population of stem cells, and what triggers it to reactivate years or decades after successful treatment of the disease,” said postdoctoral scholar Bikul Das, MBBS, PhD.

Felsher is a co-senior author of the study, which was published online Jan. 30 in Science Translational Medicine. Das is the lead author. The research was conducted in collaboration with scientists from the Forsyth Institute in Cambridge, Mass.; the Hospital for Sick Children in Toronto; and several research groups in India.

The research focuses on a subset of stem cells in the bone marrow called mesenchymal stem cells. These cells are multipotent, meaning they can become several different types of specialized cells, including bone, fat and cartilage. Although the mesenchymal stem cells are most often found in the bone marrow, they are known to be able to migrate to sites in the lungs, where the tuberculosis bacteria thrive.

“Hematopoeitic cells, especially macrophages, have long been thought of as the primary intracellular niche for M. tuberculosis, even when the infection is present at a very low levels and the individual is asymptomatic,” said Kevin Urdahl, MD, PhD, an assistant professor at Seattle Biomedical Research Institute, the country’s largest independent organization devoted to the study of infectious diseases. Urdahl was not involved in the research. “However, this study shows that the bacteria also has the capacity to reside within mesenchymal stem cells, and may even persist in these cells after drug treatment. Although further studies will be needed to establish the relative importance of this niche during latent infection, the immunoprivileged nature of the bone marrow and the ability of mesenchymal stem cells to express drug efflux pumps make this an intriguing possibility that could have important clinical implications.”

Although tuberculosis is most commonly known as a disease of the lungs, it can infect many parts of the body, including the abdomen, bone, skin and brain. The respiratory form of the disease is spread through infectious particles aerosolized when an infected person coughs or sneezes. Many cell types have been found to harbor tuberculosis bacteria, but the location of the bacteria’s primary (and highly successful dormant variant) hideout has remained unclear. However, Das noticed a clue during his years as a physician in India.

“Fifteen years ago, I was treating hundreds of tuberculosis cases,” said Das. “At the time, we noticed we were finding tuberculosis bacteria in bone marrow biopsies that had been obtained from some of these patients for other reasons. This was a totally unexpected and accidental finding, but it gave me the idea that the bacteria could be infiltrating these cells.”

To test his finding, Das, who came to Stanford as a postdoctoral scholar after completing a fellowship at the Hospital for Sick Children in Toronto, exposed bone marrow stem cells from healthy human donors to the tuberculosis bacteria. He found that not only did the bacteria infect the cells, but that they were also able to persist inside the cells for at least two weeks as they were maintained in culture. Upon closer investigation, he found that the bacteria preferentially infect mesenchymal stem cells expressing a cell surface marker called CD271 and that the viability of the bacteria in the cells decreased if the stem cells were stimulated to specialize, or differentiate, into other cell types.

Das next turned to a mouse model of dormant tuberculosis devised and created by his colleagues in Cambridge. This model relies on a genetically modified strain of tuberculosis bacteria that can replicate only in the presence of a compound called streptomycin. In the absence of streptomycin, the bacteria remain dormant in the animal in a manner similar to that seen in treated human tuberculosis patients.

Together the researchers exposed laboratory mice to aerosolized particles of the modified bacteria. The mice became infected, and dormant bacteria were found in the CD271-expressing mesenchymal stem cells in the bone marrow of the animals six months after streptomycin withdrawal. When Das and his colleagues injected other mice with these tuberculosis-carrying stem cells, those animals went on to develop characteristic symptoms of the disease, including lung lesions called granulomas.

“These mesenchymal stem cells have never been implicated as a host for tuberculosis,” said Felsher, “and they serve as a potential source for dormant disease. Moreover, these cells express drug-efflux pumps in their outer membranes that could make them resistant to anti-tuberculosis medications.”

Finally, Das turned to collaborators in India to determine whether what happened in the mice reflected what happens in infected people. The researchers conducted a small clinical study in which bone marrow biopsies were collected from nine people who had undergone the complete course of anti-tuberculosis treatment and whose sputum, a mucus-like substance secreted into the airways of the respiratory tract, contained no detectable bacteria. In eight of the nine people, the researchers were able to detect bacterial DNA in the mesenchymal stem cells obtained from bone marrow; in two of these eight, they were able to isolate living bacteria.

“Not only is this strong evidence that the tuberculosis can remain dormant in stem cells, but it shows that the living bacteria could be recovered from these cells after a long period of time,” said Das. “It’s also very suggestive of how the reactivation could be triggered: These stem cells are known to migrate to sites of injury or inflammation and begin dividing. So, migrating stem cells harboring dormant bacteria might reactivate the disease in the lung. Interestingly, I and other physicians treating patients with chronic obstructive pulmonary disease — which results in lung inflammation — have seen a strong correlation between COPD and tubercular relapse. It is possible that the tuberculosis relapse in COPD might involve the stem-cell mediated reactivation of a dormant tuberculosis infection.”

In the future the scientists plan to focus on investigating the cellular mechanisms used by the tuberculosis bacteria to infect and persist in the mesenchymal stem cells, and how reactivation occurs on a molecular level. They’re also interested in the possibility that tuberculosis might not be the only microbial bad boy that’s learned how to exploit the stem cells’ properties as a perfect hiding place.

“This could possibly be a more general paradigm,” said Felsher. “Other infectious agents might use stem cells in a similar manner. We’d like to further characterize whether and how these stem cells provide a protective niche for other infectious agents.”

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The above story is reprinted from materials provided by Stanford University Medical Center. The original article was written by Krista Conger.

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Jan. 25, 2013 — Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye, according to scientists at Washington University School of Medicine in St. Louis.

Working in mice with retinitis pigmentosa, a disease that causes gradual blindness, the researchers reprogrammed the cells in the eye that enable night vision. The change made the cells more similar to other cells that provide sight during daylight hours and prevented degeneration of the retina, the light-sensing structure in the back of the eye. The scientists now are conducting additional tests to confirm that the mice can still see.

“We think it may be significantly easier to preserve vision by modifying existing cells in the eye than it would be to introduce new stem cells,” says senior author Joseph Corbo, MD, PhD, assistant professor of pathology and immunology. “A diseased retina is not a hospitable environment for transplanting stem cells.”

The study is available in the early online edition of Proceedings of the National Academy of Sciences.

Mutations in more than 200 genes have been linked to various forms of blindness. Efforts are underway to develop gene therapies for some of these conditions.

Rather than seek treatments tailored to individual mutations, Corbo hopes to develop therapies that can alleviate many forms of visual impairment. To make that possible, he studies the genetic factors that allow cells in the developing eye to take on the specialized roles necessary for vision.

The retina has two types of light-sensing cells or photoreceptors. The rods provide night vision, and the cones sense light in the daytime and detect fine visual details.

In retinitis pigmentosa, the rods die first, leaving patients unable to see at night. Daytime vision often remains intact for some time until the cones also die.

Corbo and others have identified several genes that are active in rods or in cones but not in both types of photoreceptors. He wondered whether turning off a key gene that is activated only in rods could protect the cells from the loss of vision characteristic of retinitis pigmentosa.

‘”The question was, when retinitis pigmentosa is caused by a mutation in a protein only active in rods, can we reduce or stop vision loss by making the cells less rod-like?” he explains.

The new study focuses on a protein known as Nrl, which influences development of photoreceptors. Cells that make Nrl become rods, while cells that lack the protein become cones. Turning off the Nrl gene in developing mice leads to a retina packed with cone cells.

To see if this rod-to-cone change was possible in adult mice, Corbo created a mouse model of retinitis pigmentosa with an Nrl gene that could be switched on and off by scientists.

“In adult mice, switching off Nrl partially converts the rod cells into cone cells,” he says. “Several months later, when the mutant mice normally had very little vision left, we tested the function of their retina.”

The test showed a healthier level of electrical activity in the retinas of mice that lacked Nrl, suggesting that the mice could still see.

Corbo now is looking for other critical development factors that can help scientists more fully transform adult rods into cones. He notes that if complete conversion of rods to cones were possible, this therapy could also be helpful for conditions where cone cells die first, such as macular degeneration.

Montana CL, Kolesnikov AV, Shen SQ, Myers CA, Kefalov VJ, Corbo JC. Reprogramming of adult rod photoreceptors prevents retinal degeneration. Proceedings of the National Academy of Sciences, online January 14, 2013.

Funding from the National Eye Institute (EY018826 and EY019312), an Institutional Vision Science Training Grant (EY13360) and a grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences at Washington University supported this research.​

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The above story is reprinted from materials provided by Washington University in St. Louis. The original article was written by Michael C. Purdy.

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1. C. L. Montana, A. V. Kolesnikov, S. Q. Shen, C. A. Myers, V. J. Kefalov, J. C. Corbo. Reprogramming of adult rod photoreceptors prevents retinal degeneration. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1214387110

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 25, 2013 — Researchers at Hospital for Special Surgery have identified a potential new target for drugs to treat patients with rheumatoid arthritis (RA), a protein known as IRHOM2. The finding could provide an effective and potentially less toxic alternative therapy to tumor necrosis factor-alpha blockers (TNF-blockers), the mainstay of treatment for rheumatoid arthritis, and could help patients who do not respond to this treatment. Efforts to develop drugs that hone in on this new target are underway.

“This study is an elegant example of the capacity of basic science cell biologists to work with translational rheumatologists to address a clinically relevant question at a basic level,” said Jane Salmon, M.D., Collette Kean Research Chair and co-director, Mary Kirkland Center for Lupus Research at Hospital for Special Surgery (HSS) in New York City, and an author of the study. “We have identified a clinically relevant target that can be applied to patients in the near term.” The study will appear online, ahead of print, on January 25, in the Journal of Clinical Investigation and in the February 2013 print issue.

Rheumatoid arthritis, an autoimmune disease, is triggered, in large part, by TNF-alpha, a small signaling protein usually involved in launching protective systemic inflammatory responses. With excessive TNF production, however, immune cells can become activated inappropriately and cause tissue inflammation. This produces a number of diseases, including RA. While TNF-blockers help many RA patients, these treatments are very expensive, and some patients do not respond. For this reason, researchers have been searching for alternative targets in patients with inflammatory diseases against which drugs can be directed.

“TNF can be thought of as a balloon tethered to the surface of cells. To work, it must be cut loose by signaling scissors called TACE (TNF-alpha converting enzyme),” said Carl Blobel, M.D., Ph.D., program director of the Arthritis and Tissue Degeneration Program at HSS. While blocking TACE could be another way to treat rheumatoid arthritis, researchers know this strategy would likely have side effects since patients lacking TACE are prone to skin infections and intestinal lesions.

Earlier this year, HSS investigators demonstrated that the TACE scissors are regulated by molecules called IRHOM1 and IRHOM2, which are thought to wrap around TACE and help it mature into functional scissors. They also demonstrated that mice that are genetically engineered to lack IRHOM2 lack functional TACE on the surface of their immune cells and don’t release TNF. Surprisingly, these mice are healthy, and do not develop skin or intestinal defects.

In the current study, HSS researchers set out to investigate why this paradox exists. After examining tissues of IRHOM2-deficient mice, they found that IRHOM2 regulates TACE on immune cells, whereas IRHOM1 is responsible for helping TACE mature elsewhere in the body, such as in brain, heart, kidney, liver, lung and spleen cells. “IRHOM2 appears to have a more restrictive and exclusive function in immune cells,” said Dr. Blobel.

The researchers then set out to determine whether blocking IRHOM2 could be a strategy to treat RA. They used a mouse model that mimics human rheumatoid arthritis in mice genetically engineered to be deficient in IRHOM2. They found that these rodents did not develop inflammatory arthritis and were otherwise healthy.

“When we tested mice that don’t have IRHOM2 in a model for inflammatory arthritis, we found they were protected and they were protected as well as mice that didn’t have any TNF,” said Dr. Blobel. “Because TNF is the driver of rheumatoid arthritis in human disease, as evidenced by how well anti-TNF drugs work, we feel that this provides a completely new angle on blocking TNF release. It would be wonderful to be able to inactivate TACE in a tissue-specific manner and IRHOM2 provides a unique mechanism for us to do so.”

Using drugs that inactivate IRHOM2 in humans, clinicians will be able to block the function of TACE only in immune cells. “We can prevent the deleterious contribution of TACE to rheumatoid arthritis patients and preserve its protective function in skin and intestines,” said Dr. Blobel. “With IRHOM2, we have a unique and unprecedented opportunity to inactive TACE only in certain cell types, and not in others, and there is currently no other effective way of doing that.”

The researchers say the next step is to identify antibodies or pharmacological compounds that can be used to block the function of IRHOM2 and are safe in patients. These HSS investigators are currently working to identify and test such agents. “In theory, IRHOM2-targeted drugs will have less toxicity than TNF alpha blockers,” said Dr. Salmon. “They block TNF release only from specific cells, those known to contribute to joint inflammation and damage.”

Dr. Salmon and Dr. Blobel are co-senior authors of the study. Other investigators involved in the study are from Weill Cornell Medical College, New York City; Ontario Cancer Institute, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada; Heinrich-Heine University, Dusseldorf, Germany; TriInstitutional Laboratory of Comparative Pathology, New York City; and Keio University, Tokyo, Japan.

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1. Priya Darshinee A. Issuree, Thorsten Maretzky, David R. McIlwain, Sébastien Monette, Xiaoping Qing, Philipp A. Lang, Steven L. Swendeman, Kyung-Hyun Park-Min, Nikolaus Binder, George D. Kalliolias, Anna Yarilina, Keisuke Horiuchi, Lionel B. Ivashkiv, Tak W. Mak, Jane E. Salmon, Carl P. Blobel. iRHOM2 is a critical pathogenic mediator of inflammatory arthritis. Journal of Clinical Investigation, 2013; DOI: 10.1172/JCI66168

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 25, 2013 — In recent years, it has been thought that select sets of genes might reveal cancer patients’ prognoses. However, a study published last year examining breast cancer cases found that most of these “prognostic signatures” were no more accurate than random gene sets in determining cancer prognoses. While many saw this as a disappointment, investigators at Beth Israel Deaconess Medical Center (BIDMC), the Dana-Farber Cancer Institute, and the Institut de Recherches Cliniques de Montréal (IRCM) saw this as an opportunity to design a new method to identify gene sets that could yield more significant prognostic value.

Led by Andrew Beck, MD, Director of the Molecular Epidemiology Research Laboratory at BIDMC, the team has developed SAPS (Significance Analysis of Prognostic Signatures), a new algorithm that makes use of three specific criteria to more accurately identify prognostic signatures associated with patient survival.

Their results, the largest analysis of its kind ever performed, are reported in the January 24 on-line issue of the journal PLOS Computational Biology.

“SAPS makes use of three specific criteria,” explains Beck, who is also an Assistant Professor of Pathology at Harvard Medical School. “First, the gene set must be enriched for genes that are associated with survival. In addition, the gene set must separate patients into groups that show survival differences. Lastly, it must also perform significantly better than sets of random genes at these tasks.”

In the new study, the scientific team applied the SAPS algorithm to gene expression profiling data from the study’s senior author Benjamin Haibe-Kains, PhD, Director of the Bioinformatics and Computational Genomics Laboratory at IRCM and an Assistant Research Professor at the University of Montreal. The first collection of data was obtained from 19 published breast cancer studies (including approximately 3800 patients), and the second included 12 published gene expression profiling studies in ovarian cancer (including data from approximately 1700 patients).

When the investigators used SAPS to analyze these previously identified prognostic signatures in breast and ovarian cancer, they found that only a small subset of the signatures that were considered statistically significant by standard measurements also achieved statistical significance when evaluated by SAPS.

“Our work shows that when using prognostic associations to identify biological signatures that drive cancer progression, it is important to not rely solely on a gene set’s association with patient survival,” says Beck. “A gene set may appear to be important based on its survival association, when in reality it does not perform significantly better than random genes. This can be a serious problem, as it can lead to false conclusions regarding the biological and clinical significance of a gene set.”

By using SAPS, Beck and his colleagues found that they could overcome this problem. “The SAPS procedure ensures that a significant prognostic gene set is not only associated with patient survival but also performs significantly better than random gene sets,” says Beck. His team revealed new prognostic signatures in subtypes of breast cancer and ovarian cancer and demonstrated a striking similarity between signatures in estrogen receptor negative breast cancer and ovarian cancer, suggesting new shared therapeutic targets for these aggressive malignancies.

The findings also indicate that the prognostic signatures identified with SAPS will not only help predict patient outcomes but might also help in the development of new anti-cancer drugs. “We hope that markers identified in our analysis will provide new insights into the biological pathways driving cancer progression in breast and ovarian cancer subtypes, and will one day lead to improvements in targeted diagnostics and therapeutics,” says Beck. “We also hope the method proves widely useful to other researchers.” To that end, the team would like to create a web-accessible tool to enable investigators with little knowledge of statistical software and programming to identify gene sets significantly associated with patient outcomes in different diseases.

“We also plan to soon release a software package, which includes all the code and corresponding documentation of our analysis pipeline,” adds Haibe-Kains. “This will allow others to fully reproduce our results while enabling the bioinformatics and computational biology communities to take over and potentially adapt and improve our pipeline to address important new issues in biomedicine.”

Beck and his collaborators are currently working to further validate the prognostic signatures they identified in breast and ovarian cancers, with the hopes of bringing them closer to the clinic through the development of new diagnostics and treatments. “We are also extending our approach to other common cancers that lack robust prognostic signatures,” he notes.

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The above story is reprinted from materials provided by Beth Israel Deaconess Medical Center, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Andrew H. Beck, Nicholas W. Knoblauch, Marco M. Hefti, Jennifer Kaplan, Stuart J. Schnitt, Aedin C. Culhane, Markus S. Schroeder, Thomas Risch, John Quackenbush, Benjamin Haibe-Kains. Significance Analysis of Prognostic Signatures. PLoS Computational Biology, 2013; 9 (1): e1002875 DOI: 10.1371/journal.pcbi.1002875

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 24, 2013 — Researchers at the Paris Cardiovascular Research Center (PARCC) have shown how adhesion of Neisseria (N.) meningitidis to human microvessels in a humanized mouse model leads to the characteristic cutaneous lesions of meningococcal sepsis. This work, published on January 24 in the Open Access journal PLOS Pathogens, is an important demonstration of the direct role of adhesion, specifically Type IV pili mediated adhesion, plays in the development of the disease.

Meningococcal sepsis is a rapidly developing and often fatal infection. Cutaneous lesions, often presenting clinically as purpuric or petechial skin rashes, are a hallmark feature of the infection hence the term purpura fulminans to describe this severe form of sepsis. Understanding the mechanisms behind the development of these lesions is important to understand disease progression because it reveals the underlying mechanisms of the pathological process. From the experimental point of view the strict human specificity of N. meningitidis has long been a limiting factor in the development of relevant in vivo models of this infection and for understanding how the bacteria interact with the blood vessels. It was previously thought that that the large number of circulating bacteria was responsible for the vascular damage through the release of LPS in particular.

In this research, investigators utilized a humanized mouse model, where human skin, containing an abundance of human microvessels, was grafted onto immunocompromised mice. Grafted mice thus had a hybrid vasculature, part mouse, and part human. In this context, N. meningitidis associated exclusively, and in significant numbers, with the human vessels. Once associated with the human vessels the bacteria rapidly led to an endothelial inflammatory response with expression of the human pro-inflammatory cytokines IL-6 and IL-8 and the infiltration of inflammatory cells. Vascular events such as clotting, thrombosis, congestion and vascular leak were all observed in the infected human vessels, mimicking the clinical pathology. The combination of these factors led to the development of a purpuric rash in 30% of the infections. The association of the bacteria with the human vessels was shown to be dependent on the adhesive properties of the bacterial Type IV pili, filamentous structures found at the surface of many pathogenic bacteria. Importantly, bacterial mutants deficient for these adhesive structures do not lead to any distinctive pathology despite normal numbers of circulating bacteria.

This work thus leads to a change in the paradigm in our understanding of the disease mechanism, with local adhesion events now considered central to the disease process. Because it recapitulates key features of human infection, the described experimental model opens new avenues of research to further understand the mechanisms of disease and to design new prevention and treatment strategies.

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The above story is reprinted from materials provided by Public Library of Science.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Keira Melican, Paula Michea Veloso, Tiffany Martin, Patrick Bruneval, Guillaume Duménil. Adhesion of Neisseria meningitidis to Dermal Vessels Leads to Local Vascular Damage and Purpura in a Humanized Mouse Model. PLoS Pathogens, 2013; 9 (1): e1003139 DOI: 10.1371/journal.ppat.1003139

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 23, 2013 — Estrogen levels drop dramatically in menopause, a time when the risk of urinary tract infections increases significantly.

Researchers at Washington University School of Medicine in St. Louis have found new evidence in mice that the two phenomena are connected by more than just timing. If further research confirms these links, boosting estrogen levels may get a second look as an approach for reducing urinary infections in menopausal women.

“Scientists tested estrogen as a treatment for post-menopausal women with urinary tract infections in the 1990s, but the results were either ambiguous or negative,” says senior author Indira Mysorekar, PhD, assistant professor of obstetrics and gynecology and of pathology and immunology. “With the mouse model of menopause that we’ve created, we can more completely understand how estrogen levels affect infection susceptibility, bladder health and the inflammatory response to infection. That should point the way to better treatment strategies.”

The findings appear online in Infection and Immunity.

Urinary infections are a significant cause of illness in many women throughout their lives and are particularly prevalent after menopause. The bacteria that cause these infections can spread to the kidney and bloodstream, with the potential for serious complications.

To simulate menopause in mice, scientists surgically remove their ovaries. Like menopausal women, the mice no longer make estrogen.

To rule out the possibility that the stress of surgery affects the risk of urinary tract infections, the researchers conducted the same surgery in other mice but put the ovaries back in, maintaining their ability to make estrogen.

When researchers gave both groups of mice urinary tract infections, the menopausal mice had higher levels of infectious bacteria in their urine. Most of the bacteria came from barrier cells, which line the interior of the bladder. These cells are the first to be infected by the bacteria.

“When the barrier cells are lost, they need to be replaced immediately,” Mysorekar says. “In the menopausal mice, we found that this replacement process was stopping short of completion. That left cells under barrier cells exposed, and they are much more vulnerable to infection.”

The menopausal mice had more bacterial reservoirs, which are pockets of infection that may provide a place for the bacteria to hide during antibiotic treatment. After treatment stops, the reservoirs can reseed the infection.

In earlier research, Mysorekar had identified an important regulator of the barrier cell repair process. In the new study, she showed that low estrogen levels disable this regulator.

The bladders of the menopausal mice also had higher levels of immune inflammatory compounds known as cytokines.

“The cytokines caused inflammation that left the bladder in bad shape,” Mysorekar says. “It’s possible that damage caused by inflammation increases the bacteria’s ability to break into bladder tissue and create reservoirs of infection.”

In the control mice, which had normal estrogen levels, cytokine levels and inflammatory damage were both significantly lower. When researchers gave the menopausal mice estrogen, their cytokine levels and inflammatory damage also decreased significantly, as did reservoirs of infectious bacteria.

Mysorekar notes that earlier clinical trials of estrogen’s usefulness against urinary infection evaluated the treatment’s success by tracking levels of bacteria in the urine. The researchers say their new results suggest that bacteria levels alone may not provide a complete picture of estrogen’s effectiveness against the infections.

“If we can find ways to look at other aspects of the infectious process in humans, we may find that estrogen is more helpful than we previously realized,” Mysorekar says. “We need to look for other indicators, such as cytokines in the urine, to more fully assess estrogen’s potential role in treatment.”

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The above story is reprinted from materials provided by Washington University in St. Louis. The original article was written by Michael C. Purdy.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Wang C, Symington JW, Ma E, Cao B, Mysorekar IU. Escherichia coli pathogenesis in a murine menopause model. Infection and Immunity, March 2013

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Jan. 23, 2013 — Estrogen levels drop dramatically in menopause, a time when the risk of urinary tract infections increases significantly.

Researchers at Washington University School of Medicine in St. Louis have found new evidence in mice that the two phenomena are connected by more than just timing. If further research confirms these links, boosting estrogen levels may get a second look as an approach for reducing urinary infections in menopausal women.

“Scientists tested estrogen as a treatment for post-menopausal women with urinary tract infections in the 1990s, but the results were either ambiguous or negative,” says senior author Indira Mysorekar, PhD, assistant professor of obstetrics and gynecology and of pathology and immunology. “With the mouse model of menopause that we’ve created, we can more completely understand how estrogen levels affect infection susceptibility, bladder health and the inflammatory response to infection. That should point the way to better treatment strategies.”

The findings appear online in Infection and Immunity.

Urinary infections are a significant cause of illness in many women throughout their lives and are particularly prevalent after menopause. The bacteria that cause these infections can spread to the kidney and bloodstream, with the potential for serious complications.

To simulate menopause in mice, scientists surgically remove their ovaries. Like menopausal women, the mice no longer make estrogen.

To rule out the possibility that the stress of surgery affects the risk of urinary tract infections, the researchers conducted the same surgery in other mice but put the ovaries back in, maintaining their ability to make estrogen.

When researchers gave both groups of mice urinary tract infections, the menopausal mice had higher levels of infectious bacteria in their urine. Most of the bacteria came from barrier cells, which line the interior of the bladder. These cells are the first to be infected by the bacteria.

“When the barrier cells are lost, they need to be replaced immediately,” Mysorekar says. “In the menopausal mice, we found that this replacement process was stopping short of completion. That left cells under barrier cells exposed, and they are much more vulnerable to infection.”

The menopausal mice had more bacterial reservoirs, which are pockets of infection that may provide a place for the bacteria to hide during antibiotic treatment. After treatment stops, the reservoirs can reseed the infection.

In earlier research, Mysorekar had identified an important regulator of the barrier cell repair process. In the new study, she showed that low estrogen levels disable this regulator.

The bladders of the menopausal mice also had higher levels of immune inflammatory compounds known as cytokines.

“The cytokines caused inflammation that left the bladder in bad shape,” Mysorekar says. “It’s possible that damage caused by inflammation increases the bacteria’s ability to break into bladder tissue and create reservoirs of infection.”

In the control mice, which had normal estrogen levels, cytokine levels and inflammatory damage were both significantly lower. When researchers gave the menopausal mice estrogen, their cytokine levels and inflammatory damage also decreased significantly, as did reservoirs of infectious bacteria.

Mysorekar notes that earlier clinical trials of estrogen’s usefulness against urinary infection evaluated the treatment’s success by tracking levels of bacteria in the urine. The researchers say their new results suggest that bacteria levels alone may not provide a complete picture of estrogen’s effectiveness against the infections.

“If we can find ways to look at other aspects of the infectious process in humans, we may find that estrogen is more helpful than we previously realized,” Mysorekar says. “We need to look for other indicators, such as cytokines in the urine, to more fully assess estrogen’s potential role in treatment.”

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

---

Story Source:

The above story is reprinted from materials provided by Washington University in St. Louis. The original article was written by Michael C. Purdy.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

---

Journal Reference:

1. Wang C, Symington JW, Ma E, Cao B, Mysorekar IU. Escherichia coli pathogenesis in a murine menopause model. Infection and Immunity, March 2013

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.