Sutureless Method for Joining Blood Vessels Invented

Reconnecting severed blood vessels is mostly done the same way today -- with sutures -- as it was 100 years ago, when the French surgeon Alexis Carrel won a Nobel Prize for advancing the technique. Now, a team of researchers at the Stanford University School of Medicine has developed a sutureless method that appears to be a faster, safer and easier alternative.

In animal studies, a team led by Stanford microsurgeon Geoffrey Gurtner, MD, used a poloxamer gel and bioadhesive rather than a needle and thread to join together blood vessels, a procedure called vascular anastomosis. Results of the research are published online Aug. 28 in Nature Medicine. Lead authors of the study were Stanford postdoctoral scholar Edward Chang, MD, and surgery resident Michael Galvez, MD.

The big drawback of sutures is that they are difficult to use on blood vessels less than 1 millimeter wide. Gurtner began thinking about alternatives to sutures about a decade ago. "Back in 2002, I was chief of microsurgery at Bellevue in New York City, and we had an infant -- 10 to 12 months old -- who had a finger amputated by the spinning wheel of an indoor exercise bike," said Gurtner, senior author of the study and professor of surgery. "We struggled with reattaching the digit because the blood vessels were so small -- maybe half a millimeter. The surgery took more than five hours, and at the end we were only able to get in three sutures.

"Everything turned out OK in that case," he continued. "But what struck me was how the whole paradigm of sewing with a needle and thread kind of falls apart at that level of smallness."

Sutures are troublesome in other ways, too. They can lead to complications, such as intimal hyperplasia, in which cells respond to the trauma of the needle and thread by proliferating on the inside wall of the blood vessel, causing it to narrow at that point. This increases the risk of a blood clot getting stuck and obstructing blood flow. In addition, sutures may trigger an immune response, leading to inflamed tissue that also increases the risk of a blockage.

The new method could sidestep these problems. "Ultimately, this has the potential to improve patient care by decreasing amputations, strokes and heart attacks while reducing health-care costs," the authors write in the study.

Earlier in his career, as Gurtner contemplated a better way of joining together blood vessels, he considered whether ice could be used to fill the lumen, the inner space of the blood vessel, to keep both ends open to their full diameter long enough to glue them together. Not feasible, he concluded. "Water turns to ice quite slowly and you would have to drop the temperature of the surgical site a lot -- from 98.6 degrees to 32 degrees Fahrenheit," he said.

Shortly after arriving at Stanford in 2005, Gurtner approached fellow faculty member Gerald Fuller, PhD, professor of chemical engineering and the Fletcher Jones II Professor in the School of Engineering, about whether he knew of a substance that could be turned easily from a liquid to a solid and back to a liquid again, and that would also be safe to use in vascular surgery. Fuller immediately suggested a Food and Drug Administration-approved thermoreversible poloxamer called Poloxamer 407. It is constructed of polymer blocks whose properties can be reversed by heating.

Fuller teamed up with Jayakumar Rajadas, PhD, director of the Stanford Biomaterials and Advanced Drug Delivery Laboratory, to modify the poloxamer so that it would become solid and elastic when heated above body temperature but dissolve harmlessly into the bloodstream when cooled. The poloxamer then was used to distend both openings of a severed blood vessel, allowing researchers to glue them together precisely.

The researchers used a simple halogen lamp to heat the gel. In tests on animals, the technique was found to be five times faster than the traditional hand-sewn method, according to the study. It also resulted in considerably less inflammation and scarring after two years. The method even worked on extremely slim blood vessels -- those only 0.2 mm wide -- which would have been too tiny and delicate for sutures. "That's where it really shines," Gurtner said.

Dermabond, a surgical sealant, was used to attach the ends of the blood vessels together.

Poloxamers have been used before as a vehicle for delivering drugs, including chemotherapeutics, vaccines and anti-viral therapies. Researchers have used Poloxamer 407 to occlude blood vessels in experimental animals for the purpose of evaluating the gel's safety and efficacy in so-called "beating heart surgery," in which certain vessels need to be temporarily blocked to improve visibility for the surgeons performing a coronary artery bypass.

Although other sutureless methods have been developed, they generally have not produced better outcomes, the authors said. "Often, the use of microclips, staples or magnets is itself traumatic to blood vessels leading to failure rates comparable to or higher than sutured anastomoses," they wrote.

"This is a novel approach to anastomosis that could play a valuable role in microvascular surgery," said Frank Sellke, MD, chief of cardiothoracic surgery at Brown University Medical Center and associate editor of the Journal of Thoracic and Cardiovascular Surgery, who was not involved in the study. "But it really needs to show that it holds up in clinical trials."

The authors say further testing on large animals is needed before human trials can begin, but they note that all of the components used in the technique are already approved by the FDA. "This technology has the potential to progress rapidly from the 'bench to bedside,'" they write.

Gurtner said he believes the new technique could satisfy a huge unmet need and prove especially useful in minimally invasive surgeries, in which manipulating sutures takes on a whole new level of difficulty.

Michael Longaker, MD, the Deane P. and Louise Mitchell Professor in the School of Medicine and a co-author of the study, called the technique a "potential game-changer."

"When you're bringing together hollow tubes, whether they're large structures, like the colon or the aorta, or a small structure, like a vein in the finger of a child, you're always worried about lining them up directly and effectively sealing them," Longaker said. "The technique that Dr. Gurtner has pioneered could allow surgeons to perform anastomosis more quickly and with improved precision."

He continued: "Coming up with this solution was the result of the classic Stanford model of bringing together researchers from a variety of disciplines."

Other Stanford co-authors of the study were postdoctoral scholars Jason Glotzbach, MD, Kristin-Maria Sommer, PhD, Oscar Abilez, MD, PhD, and Cynthia Hamou, MD; medical student Samyra El-ftesi; and technician Travis Rappleye.

The work was supported by a Stanford Bio-X Interdisciplinary Initiatives Research Award and the Oak Foundation. Stanford University has patented the technology.

Gurtner and Longaker are also members of the Stanford Cancer Institute.

In animal studies, a team led by Stanford microsurgeon Geoffrey Gurtner, MD, used a poloxamer gel and bioadhesive rather than a needle and thread to join together blood vessels, a procedure called vascular anastomosis. Results of the research are published online Aug. 28 in Nature Medicine. Lead authors of the study were Stanford postdoctoral scholar Edward Chang, MD, and surgery resident Michael Galvez, MD.

The big drawback of sutures is that they are difficult to use on blood vessels less than 1 millimeter wide. Gurtner began thinking about alternatives to sutures about a decade ago. "Back in 2002, I was chief of microsurgery at Bellevue in New York City, and we had an infant -- 10 to 12 months old -- who had a finger amputated by the spinning wheel of an indoor exercise bike," said Gurtner, senior author of the study and professor of surgery. "We struggled with reattaching the digit because the blood vessels were so small -- maybe half a millimeter. The surgery took more than five hours, and at the end we were only able to get in three sutures.

"Everything turned out OK in that case," he continued. "But what struck me was how the whole paradigm of sewing with a needle and thread kind of falls apart at that level of smallness."

Sutures are troublesome in other ways, too. They can lead to complications, such as intimal hyperplasia, in which cells respond to the trauma of the needle and thread by proliferating on the inside wall of the blood vessel, causing it to narrow at that point. This increases the risk of a blood clot getting stuck and obstructing blood flow. In addition, sutures may trigger an immune response, leading to inflamed tissue that also increases the risk of a blockage.

The new method could sidestep these problems. "Ultimately, this has the potential to improve patient care by decreasing amputations, strokes and heart attacks while reducing health-care costs," the authors write in the study.

Earlier in his career, as Gurtner contemplated a better way of joining together blood vessels, he considered whether ice could be used to fill the lumen, the inner space of the blood vessel, to keep both ends open to their full diameter long enough to glue them together. Not feasible, he concluded. "Water turns to ice quite slowly and you would have to drop the temperature of the surgical site a lot -- from 98.6 degrees to 32 degrees Fahrenheit," he said.

Shortly after arriving at Stanford in 2005, Gurtner approached fellow faculty member Gerald Fuller, PhD, professor of chemical engineering and the Fletcher Jones II Professor in the School of Engineering, about whether he knew of a substance that could be turned easily from a liquid to a solid and back to a liquid again, and that would also be safe to use in vascular surgery. Fuller immediately suggested a Food and Drug Administration-approved thermoreversible poloxamer called Poloxamer 407. It is constructed of polymer blocks whose properties can be reversed by heating.

Fuller teamed up with Jayakumar Rajadas, PhD, director of the Stanford Biomaterials and Advanced Drug Delivery Laboratory, to modify the poloxamer so that it would become solid and elastic when heated above body temperature but dissolve harmlessly into the bloodstream when cooled. The poloxamer then was used to distend both openings of a severed blood vessel, allowing researchers to glue them together precisely.

The researchers used a simple halogen lamp to heat the gel. In tests on animals, the technique was found to be five times faster than the traditional hand-sewn method, according to the study. It also resulted in considerably less inflammation and scarring after two years. The method even worked on extremely slim blood vessels -- those only 0.2 mm wide -- which would have been too tiny and delicate for sutures. "That's where it really shines," Gurtner said.

Dermabond, a surgical sealant, was used to attach the ends of the blood vessels together.

Poloxamers have been used before as a vehicle for delivering drugs, including chemotherapeutics, vaccines and anti-viral therapies. Researchers have used Poloxamer 407 to occlude blood vessels in experimental animals for the purpose of evaluating the gel's safety and efficacy in so-called "beating heart surgery," in which certain vessels need to be temporarily blocked to improve visibility for the surgeons performing a coronary artery bypass.

Although other sutureless methods have been developed, they generally have not produced better outcomes, the authors said. "Often, the use of microclips, staples or magnets is itself traumatic to blood vessels leading to failure rates comparable to or higher than sutured anastomoses," they wrote.

"This is a novel approach to anastomosis that could play a valuable role in microvascular surgery," said Frank Sellke, MD, chief of cardiothoracic surgery at Brown University Medical Center and associate editor of the Journal of Thoracic and Cardiovascular Surgery, who was not involved in the study. "But it really needs to show that it holds up in clinical trials."

The authors say further testing on large animals is needed before human trials can begin, but they note that all of the components used in the technique are already approved by the FDA. "This technology has the potential to progress rapidly from the 'bench to bedside,'" they write.

Gurtner said he believes the new technique could satisfy a huge unmet need and prove especially useful in minimally invasive surgeries, in which manipulating sutures takes on a whole new level of difficulty.

Michael Longaker, MD, the Deane P. and Louise Mitchell Professor in the School of Medicine and a co-author of the study, called the technique a "potential game-changer."

"When you're bringing together hollow tubes, whether they're large structures, like the colon or the aorta, or a small structure, like a vein in the finger of a child, you're always worried about lining them up directly and effectively sealing them," Longaker said. "The technique that Dr. Gurtner has pioneered could allow surgeons to perform anastomosis more quickly and with improved precision."

He continued: "Coming up with this solution was the result of the classic Stanford model of bringing together researchers from a variety of disciplines."

Other Stanford co-authors of the study were postdoctoral scholars Jason Glotzbach, MD, Kristin-Maria Sommer, PhD, Oscar Abilez, MD, PhD, and Cynthia Hamou, MD; medical student Samyra El-ftesi; and technician Travis Rappleye.

The work was supported by a Stanford Bio-X Interdisciplinary Initiatives Research Award and the Oak Foundation. Stanford University has patented the technology.

Gurtner and Longaker are also members of the Stanford Cancer Institute.

Journal Reference:

1. Edward I Chang, Michael G Galvez, Jason P Glotzbach, Cynthia D Hamou, Samyra El-ftesi, C Travis Rappleye, Kristin-Maria Sommer, Jayakumar Rajadas, Oscar J Abilez, Gerald G Fuller, Michael T Longaker, Geoffrey C Gurtner. Vascular anastomosis using controlled phase transitions in poloxamer gels. Nature Medicine, 2011; DOI: 10.1038/nm.2424

Courtesy: ScienceDaily

Deaths from Strong Prescription Painkillers Are On the Increase, Experts Say

Action is needed to tackle the increasing number of deaths in the United States and Canada from prescription painkillers known as opioids, say experts in an article published online in the British Medical Journal.

Opioids are prescription painkillers that contain compounds derived from the opium poppy.

While they have long been used to control the symptoms of cancer and acute medical conditions, they are increasingly being used to control chronic pain, for example in patients suffering from osteoarthritis, say Dr Irfan Dhalla and colleagues at the University of Toronto.

They describe how in the US, deaths involving opioid painkillers increased from 4,041 in 1999 to 14,459 in 2007 and are now more common than deaths from skin cancer, HIV and alcoholic liver disease. They add that between 1.4 million and 1.9 million Germans are addicted to prescription drugs and that some authorities have suggested that the UK may face a similar epidemic to that of North America in five to ten years time. Indeed, the use of strong opioids for chronic non-cancer pain in the UK has been described as a "disaster in the making" by Dr. Des Spence previously on bmj.com.

Dr. Dhalla and colleagues add that "deaths involving methadone and codeine roughly doubled in England and Wales between 2005 and 2009, while deaths involving heroin or morphine remained unchanged."

In order to tackle the crisis in the US and Canada, the authors put forward several strategies.

They say staff working for drug companies should not get commission for marketing prescription opioid drugs and that regulators should evaluate adverts for them before they are disseminated. Another initiative would be to introduce real-time electronic databases to reduce the frequency with which opioids are obtained from multiple doctors or pharmacies.

Dhalla and colleagues also call for educational outreach programmes for doctors to improve opioid prescribing, as well as more research to guide practice. They note that the evidence for the use of opioids to control chronic pain is very limited and the risks may outweigh the benefits.

In conclusion, they say that maintaining access to opioids for appropriately selected patients while striving for major reductions in overdose deaths must be a major priority for physicians and policymakers.

Journal Reference:

1. I. A. Dhalla, N. Persaud, D. N. Juurlink. Facing up to the prescription opioid crisis. BMJ, 2011; 343 (aug23 1): d5142 DOI: 10.1136/bmj.d5142

Courtesy: ScienceDaily

Blood Vessels Participate in the Eradication of Tumors

Breast cancer: for the first time, very specific blood vessels have been discovered in tumors. These vessels facilitate the access of certain white blood cells, known as "killer lymphocytes," into tumor tissues and thus lead to the efficient destruction of tumors. This work, led by Jean-Philippe Girard, Inserm senior researcher at the Institut de Pharmacologie et de Biologie Structurale (CNRS/Université Toulouse III -- Paul Sabatier), in collaboration with the Institut Claudius Regaud, is published in the journal Cancer Research.

A category of white blood cells, called "killer lymphocytes," has the function of recognizing and destroying cancerous cells in the body. However, the eradication of the disease requires the presence of a large number of killer cells in contact with the tumors. How do these lymphocytes manage to penetrate the tumors in order to destroy them?

Although the mechanism has been shrouded in mystery until now, Girard's team at the Institut de Pharmacologie et de Biologie Structurale (CNRS / Université Toulouse III -- Paul Sabatier), in collaboration with researchers from the Institut Claudius Regaud (Centre de Lutte Contre le Cancer de Toulouse)[1], has lifted the veil on how lymphocytes infiltrate into tumors. By carrying out a study involving nearly 150 patients suffering from breast cancer, the scientists discovered the presence of a particular type of blood vessel, known as HEVs (High Endothelial Venules), in tumors. Normally, these HEV vessels are present in the lymph nodes[2] where they serve as port of entry for lymphocytes from the blood. The cells lining the walls of these HEV vessels are bulging and rounded and this very characteristic morphology facilitates the passage of lymphocytes from the blood into the tissue.

The Toulouse-based team discovered that the presence of a large number of killer lymphocytes in breast tumors was linked to the presence of a large number of HEV vessels in these tumors. This suggests that, as in lymph nodes, HEVs constitute the port of entry for lymphocytes into tumors. In addition, the researchers observed that when a tumor contains many HEV vessels, the patients are more likely to recover. The presence of these HEV vessels in a tumor could thus be a favorable prognosis factor.

The next steps for the researchers will be to confirm these results on larger groups of patients and to study the influence of HEV vessels on the response to therapeutics (chemo- and radiotherapy) widely used in breast cancer treatment. Studies are also underway to examine the role of HEV vessels in melanoma and cancer of the ovaries and the colon. The longer-term objective is to increase the quantity of HEVs in tumors and/or to make them form in tumors that do not have them, so as to enable a massive recruitment of killer lymphocytes for eradicating cancerous cells.

[1] This work benefited from financial support from the Ligue Nationale Contre le Cancer (Equipe Labellisée Ligue 2009), of the Fondation RITC (Recherche et Innovation Thérapeutique en Cancérologie) and the Région Midi-Pyrénées.

[2] Lymph nodes are where immune cells proliferate and differentiate. The lymphatic vessels bring an antigen (often from a pathogen) from the tissue to the ganglions, thus making it possible to bring about a specific immune response by activating the T and B lymphocytes.

Journal Reference:

1. Ludovic Martinet, Ignacio Garrido, Thomas Filleron, Sophie Le Guellec, Elisabeth Bellard, Jean-Jacques Fournie, Philippe Rochaix and Jean-Philippe Girard. Human solid tumors contain high endothelial venules (HEVs): association with T and B lymphocyte infiltration and favourable prognosis in breast cancer. Cancer Research, 16 August 2011 DOI: 10.1158/0008-5472.CAN-11-0431

Courtesy: ScienceDaily

New Target for Treatment of Type 2 Diabetes and Prediabetes Identified

Researchers at the Joslin Diabetes Center have shown that an enzyme found in the mitochondria of cells is decreased in the skeletal muscle of those with diabetes, a finding that could lead to the development of drugs to boost the activity of this enzyme in an effort to fight the disease.

A paper in published online in the Proceedings of the National Academy of Sciences, showed that the enzyme, Sirt3, is decreased in the skeletal muscle of humans and animals with diabetes by at least half, compared to those without diabetes and that this may contribute to development of insulin resistance, one of the earliest manifestations of the disease. Sirt3 is found in the mitochondria, the power producers of cells that convert energy into usable forms.

"Ours is perhaps the first study to understand what is going wrong in the mitochondria of those with diabetes," said senior author C. Ronald Kahn, M.D., Head of the Joslin Section on Integrative Physiology and Metabolism and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. "Many studies have shown that the mitochondria don't work well in those with diabetes. This points to a cause of why they don't work well."

Dr. Kahn said the study sought to look at how decreased Sirt3 levels might affect the metabolism of cells, particularly how it could affect insulin action in cells. "We know that one of the hallmarks of early diabetes is insulin resistance in muscle, but we didn't know what caused it," he said.

He said the study showed that when Sirt3 levels are low, as they are in the case of diabetes, the mitochondria of the cells are not as efficient in energy metabolism as they should be.

When the mitochondria become inefficient, they generate what are known as reactive oxygen species (ROS), chemically reactive molecules containing oxygen, which create insulin resistance in the muscles, he said.

"This is the first time this has been shown," Dr. Kahn said.

The goal for the future will be to find ways to restore levels of Sirt3 or increase the activity of the existing Sirt3, perhaps with a drug, in a bid to improve insulin resistance in the muscle and improve muscle metabolism, he said.

"It is a new target," he said.

Dr. Kahn noted that this study is one of the first demonstrations of a single defect that could affect mitochondrial metabolism and insulin signaling in the muscle.

"In further studies we will try to understand what proteins Sirt3 acts on," he said.

He noted that one of the earliest hallmarks of diabetes is insulin resistance in the skeletal muscle. As a result, a drug to boost Sirt3 levels could be useful in the treatment of prediabetes or in those newly diagnosed with the disease, he said.

"Agents which increase Sirt3 activity could, therefore, potentially reverse at least some of the adverse effects of type 2 diabetes," the paper concludes.

Co-authors included Enxuan Jing, lead author, as well as Brice Emanuelli, Jeremie Boucher and Kevin Lee, all of Joslin; Matthew D. Hirschey and Eric M. Verdin, both of Gladstone Institute of Virology and Immunology and the University of California, San Francisco; and David Lombard, formerly of the Department of Genetics at Harvard Medical School and currently at the Department of Pathology and Institute of Gerontology at the University of Michigan.

Dr. Verdin noted that by "uncovering the multi-faceted role of SIRT3, we are laying important groundwork to better combat this widespread disease at the cellular level."

The study was supported by research grants to Kahn and Verdin as well as a grant from the Ellison Foundation and the Mary K. Iacocca Professorship. The study also received support from the Joslin DERC cores laboratories.

Journal Reference:

1. Enxuan Jing, Brice Emanuelli, Matthew D. Hirschey, Jeremie Boucher, Kevin Y. Lee, David Lombard, Eric M. Verdin, C. Ronald Kahn. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1111308108

Courtesy: ScienceDaily

Salmonella Stays Deadly With a 'Beta' Version of Cell Behavior

Salmonella cells have hijacked the protein-building process to maintain their ability to cause illness, new research suggests. Scientists say that these bacteria have modified what has long been considered typical cell behavior by using a beta form of an amino acid -- as opposed to an alpha form -- during the act of making proteins.

Beta versions of amino acids occur in nature under rare and specific circumstances, but have never been observed as part of protein synthesis. Before this finding, in fact, researchers had determined that virtually all proteins were constructed with the alpha forms of amino acids.

This work has shown that when researchers delete any one of three genes from the process that makes use of the beta form of the amino acid, or if they insert the alpha form in the beta version's place, Salmonella cells are no longer able to cause disease. The amino acid in question is lysine, one of 22 genetically encoded amino acids that are strung together in cells to make proteins.

"When these genes were knocked out, the cells became sensitive to antibiotics. And if we put beta lysine into the medium where cells were growing, they became resistant to antibiotics," said Michael Ibba, professor of microbiology at Ohio State University and a senior author of the study. "So we could see the beta amino acid being taken up and used. The cells really do need the beta amino acid to be resistant to antibiotics, and for other aspects of their virulence."

This finding suggests that the process using this specific beta amino acid could be an attractive antibiotic target for this common pathogen, the researchers say.

The Centers for Disease Control and Prevention estimates that about 1.4 million people in the United States are infected with Salmonella each year, though only 40,000 cases are reported. Most people infected with Salmonella develop diarrhea, fever and abdominal cramps. Though recovery can occur within a week without treatment, some severe cases require antibiotic treatment and hospitalization.

The study is published in the Aug. 14 online edition of the journal Nature Chemical Biology.

This work began when University of Toronto scientists exploring the origins of Salmonella's virulence identified three genes that were clear players in the process. These three genes -- called YjeK, PoxA and EF-P -- were unusual in this context.

Genes that confer virulence in bacteria typically have a specific job, such as producing toxins or transporters. But these three virulence genes all looked like they should have a role in the protein synthesis machinery -- which is Ibba's expertise.

Under normal circumstances in cells, an enzyme will select amino acids in the cell and place them on a molecule called transfer RNA, or tRNA, which leads to translation of the genetic code into proteins.

In Salmonella cells, these steps are similar, but with a few surprising twists, Ibba said. He and colleagues confirmed that the YjeK gene makes beta lysine, and showed that the PoxA gene takes that beta lysine and attaches it to EF-P -- a protein that partially mimics the shape and function of tRNA.

"It's a really unexpected pathway," said Ibba, also an investigator in Ohio State's Center for RNA Biology. "It is a mimic of what normally makes protein in a cell. Where a cell would normally be expected to use an alpha amino acid, Salmonella puts on a beta amino acid. And it ends up making molecules that lead to the cells being virulent."

The research team first reconstructed this unusual protein synthesis process in test tube experiments, and then followed with studies in cell cultures. Even before they took on studying the mechanism, however, they knew that the effects of these virulence genes were powerful: In earlier animal studies, deleting any one of the three genes and then infecting mice with these altered Salmonella cellshad no effect on the animals. When the genes were left intact and cells were injected into mice, the resulting Salmonella infection killed the animals.

In addition, when the researchers tricked Salmonella cells into using alpha lysine for this pathway instead of beta lysine, the cells lost their ability to cause illness.

"This tells us the cell is not going to be able to easily replace the beta amino acid," Ibba said. "It is essential for virulence in Salmonella."

And that, he said, is why that amino acid might be such an effective drug target, especially as humans don't seem to make beta amino acids at all. "You have to make an antibiotic look like something natural, only different. If you have something that's already different like a beta amino acid, you've potentially got a much better drug target because it involves chemistry that's comparatively rare in the cell. It's harder for the cell to try to alter its own chemistry to develop resistance," Ibba said.

From here, the researchers are observing cell behavior later in the protein-building process to figure out how this hijacked system actually gives Salmonella its virulence.

This work is supported by the National Institutes of Health, the Canada Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and Ohio State.

Co-authors include Hervé Roy, a former Ohio State research scientist now at the University of Central Florida; S. Betty Zou and William Navarre of the University of Toronto; Tammy Bullwinkle of Ohio State's Department of Microbiology; and Benjamin Wolfe and Craig Forsyth of Ohio State's Department of Chemistry.

Written by Emily Caldwell, (614) 292-8310; Caldwell.151@osu.edu

Journal Reference:

1. Hervé Roy, S Betty Zou, Tammy J Bullwinkle, Benjamin S Wolfe, Marla S Gilreath, Craig J Forsyth, William W Navarre & Michael Ibba. The tRNA synthetase paralog PoxA modifies elongation factor-P with (R)-β-lysine. Nature Chemical Biology, 14 August 2011 DOI: 10.1038/nchembio.632

Courtesy: ScienceDaily

Five Inherited Genetic Variants Linked to the Most Lethal Prostate Cancers

An international team of researchers led by Fred Hutchinson Cancer Research Center has identified five inherited genetic variants that are strongly associated with aggressive, lethal prostate cancer. The discovery ultimately could lead to the development of a simple blood test that could be given upon diagnosis to determine which men should receive aggressive treatment versus a more conservative "watchful waiting" approach.

The findings, by Janet L. Stanford, Ph.D., co-director of the Hutchinson Center's Program in Prostate Cancer Research and a member of its Public Health Sciences Division, are published online Aug. 16 ahead of the September issue of Cancer Epidemiology, Biomarkers and Prevention.

A substantial number of men with indolent tumors -- which have a low probability of progressing to clinically significant, lethal prostate cancer -- are overtreated and, as a result, suffer side effects such as sexual impotence and urinary incontinence. In addition to its personal toll, overtreatment of indolent prostate cancer also carries a substantial economic burden, with an average of $2 billion to $3 billion spent annually in the U.S. on initial therapy alone.

"Biomarkers that could distinguish between patients with indolent versus more-aggressive tumors are urgently needed," Stanford said. "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 Hutchinson Center has filed a patent on the panel of five single-nucleotide polymorphisms, or SNPs (pronounced "snips"), which are single-letter variations within the four-letter DNA alphabet that serve as markers of genetic variation across the genome which may play a role in the development or progression of disease. "We chose to study SNPs in genes that potentially play a key role in biological pathways that may contribute to prostate cancer progression such as inflammation, steroid-hormone production and metabolism, DNA repair, circadian rhythm and vitamin D activity," Stanford said.

For the study, the researchers analyzed DNA in blood samples taken from a population-based group of 1,309 Seattle-area prostate cancer patients who were age 35 to 74 at the time of diagnosis. They evaluated 937 SNPs in 156 candidate genes and, of these, 22 SNPs emerged as being significantly associated with prostate cancer-specific mortality.

A subsequent validation study of these 22 SNPs was conducted in another population-based group of 2,875 prostate cancer patients in Sweden who were age 35 to 74 at diagnosis. Upon genotyping DNA from their blood, five of the 22 SNPs emerged as being significantly associated with death from prostate cancer. A higher proportion of patients from Sweden (17.4 percent) had died of prostate cancer relative to those from Seattle (4.6 percent) during a median follow-up period of 6.5 years, which is consistent with the higher prostate cancer mortality rate in Sweden relative to the U.S.

The five SNPs were located in or tagged, one each, to five genes that may affect prostate cancer progression:

• LEPR -- The strongest marker associated with prostate cancer mortality in the study was the leptin receptor gene, which helps control tissue growth, inflammation, blood-vessel development and bone density. The latter effect makes LEPR an interesting candidate for understanding disease progression, since the primary metastatic site for prostate cancer is bone, and such metastases are predictive of fatal disease.
• RNASEL -- This gene is associated with hereditary prostate cancer and is associated with apoptosis (programmed cell death), inflammation and the ability of cells to proliferate and stick to each other (hallmarks of cancer growth).
• IL4 -- This Interleukin 4 gene is associated with tumor growth, blood vessel development and cancer cell migration.
• CRY1 -- Cytochrome 1 is a gene that impacts the circadian rhythm and thereby may affect androgen levels, which are known to be involved in prostate cancer progression.
• ARVCF -- This gene is a member of the catenin family of proteins, which help the inside and outside of cells "talk" to each other. Increased expression of ARVCF has been shown to disrupt cell adhesion, which may facilitate cancer progression.

Patients who carried four or all five of these genetic markers had a 50 percent higher risk of dying from their prostate cancer than patients who had two or fewer. The risk of dying from prostate cancer increased with the number of SNP genetic variants a patient carried.

"While previous studies have suggested that genetic background influences prostate cancer outcomes, this is the first study to validate genetic markers associated with lethal disease," Stanford said.

"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 overtreatment of patients whose tumors are likely to remain indolent," the authors wrote.

The potential usefulness of the panel of five SNPs in the clinic to stratify patients at higher risk for disease progression now needs to be evaluated in other patient populations. Stanford and colleagues are also planning additional studies of this set of genetic markers to predict adverse prostate cancer outcomes.

Journal Reference:

1. Daniel W. Lin, Liesel M. FitzGerald, Rong Fu, Erika M. Kwon, Siqun Lilly Zheng, Suzanne Kolb, Fredrik Wiklund, Pär Stattin, William B. Isaacs, Jianfeng Xu, Elaine A. Ostrander, Ziding Feng, Henrik Grönberg, and Janet L. Stanford. Genetic Variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF Genes Are Prognostic Markers of Prostate Cancer-Specific Mortality. Cancer Epidemiol Biomarkers Prev, August 16, 2011 DOI: 10.1158/1055-9965.EPI-11-0236

Courtesy: ScienceDaily

Antibody Discovered That May Help Detect Ovarian Cancer in Earliest Stages

Using a new approach to developing biomarkers for the very early detection of ovarian cancer, researchers at Rush University Medical Center have identified a molecule in the bloodstream of infertile women that could one day be used to screen for those at high risk for the disease -- or even those with early-stage ovarian cancer.

The molecule, an antibody that the human body manufactures, is an autoimmune response to mesothelin. This well-studied protein is found in abundance on the surface of ovarian cancer cells but present only in limited amounts in normal human tissue.

The study is published in the online version issue of Cancer Epidemiology, Biomarkers & Prevention, published by the American Society for Cancer Research.

"The finding is extremely important because at present medical tests are unable to detect ovarian cancer in its early stages, which is why death rates from this disease are so high," said Judith Luborsky, PhD, professor of pharmacology, obstetrics and gynecology and preventive medicine at Rush and lead author of the study.

"Our approach to discovering cancer biomarkers was unique in this study. Instead of investigating molecules specific to ovarian cancer alone, we asked what molecules women with a risk of ovarian cancer and those with ovarian cancer had in common," Luborsky said.

The study enabled the researchers to explain the link between infertility and ovarian cancer that has been established in numerous epidemiological surveys.

"More important, with the discovery of the mesothelin antibody, we now have what appears to be a biomarker that can potentially be used in screening tests to help us conquer ovarian cancer," Luborsky said.

According to the American Cancer Society's most recent estimates, there are expected to be about 21,900 new cases of ovarian cancer in the U.S. in 2011 and about 15,460 deaths from the disease. Ovarian cancer is the ninth most common cancer in women (not counting skin cancer) and ranks fifth as the cause of cancer death in women. The poor prognosis for women with ovarian cancer is due to the lack of both clinical symptoms when the cancer first develops and the absence of laboratory tests specific to the disease.

In the study at Rush, researchers tested for mesothelin antibodies in the bloodstream of 109 women who were infertile, 28 women diagnosed with ovarian cancer, 24 women with benign ovarian tumors or cysts, and 152 healthy women. Infertility was due to endometriosis, ovulatory dysfunction or premature ovarian failure or was unexplained.

Significant levels of mesothelin antibodies were found in women with premature ovarian failure, ovulatory dysfunction and unexplained infertility, as well as in women with ovarian cancer, although not in women with endometriosis and not in healthy women or women with benign disease. Endometriosis is generally associated with a different kind of ovarian carcinoma than other types of infertility, which may explain why mesothelin antibodies were not found in these cases.

Why the presence of mesothelin antibodies in the bloodstream should be linked with ovarian cancer is not clear.

"It has been hypothesized that an autoimmune response precedes or somehow contributes to the development and progression of malignant tumors," Luborsky said. "We think that antibodies may arise in response to very early abnormal changes in ovarian tissue that may or may not progress to malignancy, depending on additional triggering events. Or, alternatively, antibodies may bind to normal cells in the ovary, causing dysfunction and leading to infertility -- and, in a subpopulation of women, to the development of ovarian cancer."

Other researchers involved in the study were Yi Yu, MS, and Seby Edassery, MS, both from Rush, and a group led by Ingegerd Hellstrom, MD, PhD, and Karl Eric Hellstrom, MD, PhD, and including Yuan Yee Yip, BS, Jade Jaffar, BS, and Pu Liu, PhD, from Harborview Medical Center at the University of Washington.

The study was supported by funding from the National Institutes of Health and Fujirebio Diagnostics, Inc.

Journal Reference:

1. Judith L. Luborsky, Yi Yu, Seby L. Edassery, Jade Jaffar, Yuan Yee Yip, Pu Liu, Karl Eric Hellstrom, and Ingegerd Hellstrom. Autoantibodies to Mesothelin in Infertility. Cancer Epidemiol Biomarkers Prev, August 16, 2011 DOI: 10.1158/1055-9965.EPI-11-0139

Courtesy: ScienceDaily

Scientists Map Genes for Common Form of Brain Cancer; Findings Reveal Cause of the Tumors

Johns Hopkins Kimmel Cancer Center scientists have completed a comprehensive map of genetic mutations occurring in the second-most common form of brain cancer, oligodendroglioma. The findings, reported in the Aug. 4 issue of Science, also appear to reveal the biological cause of the tumors, they say.

To create the map, the scientists sequenced protein-coding genes in seven oligodendroglioma tissue samples, and focused attention on recurring mutations in two genes not previously associated with these tumors -- CIC and FUBP1. The investigators say that CIC and FUBP1 are known to regulate cell-signaling processes, and CIC mutations have been rarely linked to sarcoma, breast and prostate cancers.

More mutations in the two genes were found in an additional 27 oligodendroglioma samples. In all, two-thirds of the samples studied had CIC and FUBP1 mutations.

"Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor," says Nickolas Papadopoulos, Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

In brain cancer, the Hopkins investigators say CIC and FUBP1 mutations may be the "missing link" in what scientists describe as a "two-hit" theory of cancer development. The theory is based on the fact that each cell in the human body has two copies of 23 chromosomes containing thousands of protein-producing genes. If a gene on one chromosome is damaged or deleted, the other copy makes up for the loss of protein. But if the second copy fails as well, the cell cannot make the proper protein and may become cancerous.

In oligodendrogliomas, the "first hit" has long been known to occur in regions of chromosome 1 and 19, which fuse together resulting in a loss of many genes on both chromosomes. Up to 70 percent of oligodendroglioma patients have these DNA fusions, and most of them respond better to chemotherapy and radiation than those who lack the deletions in the chromosomes. For more than a decade, researchers have been looking for evidence of a "second hit" in specific mutated genes that allow oligodendrogliomas to develop.

In the current study, the Johns Hopkins investigators found mutations in the remaining copies of the CIC and FUBP1 genes on chromosomes 1 and 19, suggesting that these mutations represent the second hit needed to create cancer.

"Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer," says Kenneth Kinzler, Ph.D., professor and co-director of the Ludwig Center at Johns Hopkins. "Knowing the genetic roadmap of a cancer is the key to attacking it."

Oligodendrogliomas account for up to 20 percent of brain cancers and more commonly occur in younger people aged 30 to 45. The cancer forms most often in the frontal lobe of the brain in cells that coat neurons. Median survival of 10 years is considered far better than other brain cancers. Oligodendrogliomas are treated initially with surgery, followed by chemotherapy and radiation.

The research team says its next step will be to test whether patients with CIC and FUBP1 mutations have the same favorable prognosis as those who have the chromosome 1 and 19 fusion, says Chetan Bettegowda, M.D., Ph.D., chief resident in the Department of Neurosurgery at Johns Hopkins.

"We can focus now on when these mutations develop during tumor formation, whether they can guide prognosis, and how they might form targets for therapy," says Bettegowda.

Bettegowda says the gene map uncovered mutations in other genes, such as PIK3CA, which have been well-studied in cancer. It is possible, he says, that oligodendroglioma patients with mutations in PIK3CA or other genes could be enrolled in current clinical trials using experimental therapies that target these mutations.

Funding for the research was provided by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, the James S. McDonnell Foundation, state funding from Sao Paulo (FAPESP), the National Cancer Institute and National Institutes of Health.

Contributors to the research include Nishant Agrawal, Yuchen Jiao, Mark Sausen, Laura D. Wood, Ralph H. Hruban, Fausto J. Rodriguez, Daniel P. Cahill, Gregory Riggins, Victor Velculescu and Bert Vogelstein of Johns Hopkins; Roger McLendon, Darell Bigner and Hai Yan of Duke University; and Sueli Mieko Oba-Shinjo and Suely Kazue Nagahashi Marie of the University of Sao Paulo, Brazil.

Under agreements between the Johns Hopkins University, Genzyme, Exact Sciences, Inostics, Qiagen, Invitrogen and Personal Genome Diagnostics, Papadopoulos, Vogelstein, Kinzler and Velculescu are entitled to a share of the royalties received by the University on sales of products related to genes and technologies described in this manuscript. Papadopoulos, Vogelstein, Kinzler, and Velculescu are co-founders of Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy.

Journal Reference:

1. Chetan Bettegowda, Nishant Agrawal, Yuchen Jiao, Mark Sausen, Laura D. Wood, Ralph H. Hruban, Fausto J. Rodriguez, Daniel P. Cahill, Roger Mclendon, Gregory Riggins, Victor E. Velculescu, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie, Bert Vogelstein, Darell Bigner, Hai Yan, Nickolas Papadopoulos, Kenneth W. Kinzler. Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma. Science, 2011; DOI: 10.1126/science.1210557

Courtesy: ScienceDaily

Making Sperm from Stem Cells in a Dish

Researchers have found a way to turn mouse embryonic stem cells into sperm. This finding, reported in the journal Cell in a special online release on August 4th, opens up new avenues for infertility research and treatment. A Kyoto University team has coaxed mouse embryonic stem cells into sperm precursors, called primordial germ cells (PGCs), and shown that these cells can give rise to healthy sperm.

The researchers say that such in vitro reconstitution of germ cell development represents one of the most fundamental challenges in biology.

When transplanted into mice that were unable to produce sperm normally, the stem cell derived PGCs produced normal-looking sperm, which were then used to successfully fertilize eggs. These fertilized eggs, when transplanted into a recipient mother, produced healthy offspring that grew into fertile male and female adult mice. The same procedure could produce fertile offspring from induced pluripotent stem cells that are often derived from adult skin cells.

"Continued investigations aimed at in vitro reconstitution of germ cell development, including the induction of female PGCLCs and their descendants, will be crucial for a more comprehensive understanding of germ cell biology in general, as well as for the advancement of reproductive technology and medicine," the researchers wrote.

Journal Reference:

1. Katsuhiko Hayashi, Hiroshi Ohta, Kazuki Kurimoto, Shinya Aramaki, Mitinori Saitou. Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells. Cell, 04 August 2011 DOI: 10.1016/j.cell.2011.06.052

Courtesy: ScienceDaily

Why Plant 'Clones' Aren't Identical

A new study of plants that are reproduced by 'cloning' has shown why cloned plants are not identical.Scientists have known for some time that 'clonal' (regenerant) organisms are not always identical: their observable characteristics and traits can vary, and this variation can be passed on to the next generation. This is despite the fact that they are derived from genetically identical founder cells.

Now, a team from Oxford University, UK, and King Abdullah University of Science and Technology, Saudi Arabia, believe they have found out why this is the case in plants: the genomes of regenerant plants carry relatively high frequencies of new DNA sequence mutations that were not present in the genome of the donor plant.

The team report their findings in this week's Current Biology.

'Anyone who has ever taken a cutting from a parent plant and then grown a new plant from this tiny piece is actually harnessing the ability such organisms have to regenerate themselves,' said Professor Nicholas Harberd of Oxford University's Department of Plant Sciences, lead author of the paper. 'But sometimes regenerated plants are not identical, even if they come from the same parent. Our work reveals a cause of that visible variation.'

Using DNA sequencing techniques that can decode the complete genome of an organism in one go (so-called 'whole genome sequencing') the researchers analysed 'clones' of the small flowering plant 'thalecress' (Arabidopsis). They found that observable variations in regenerant plants are substantially due to high frequencies of mutations in the DNA sequence of these regenerants, mutations which are not contained in the genome of the parent plant.

'Where these new mutations actually come from is still a mystery,' said Professor Harberd. 'They may arise during the regeneration process itself or during the cell divisions in the donor plant that gave rise to the root cells from which the regenerant plants are created. We are planning further research to find out which of these two processes is responsible for these mutations. What we can say is that Nature has safely been employing what you might call a 'cloning' process in plants for millions of years, and that there must be good evolutionary reasons why these mutations are introduced.'

The new results suggest that variation in clones of plants may have different underlying causes from that of variation in clones of animals -- where it is believed that the effect of environmental factors on how animal genes are expressed is more important and no similar high frequencies of mutations have been observed.

Professor Harberd said: 'Whilst our results highlight that cloned plants and animals are very different they may give us insights into how both bacterial and cancer cells replicate themselves, and how mutations arise during these processes which, ultimately, have an impact on human health.'

Journal Reference:

1. Caifu Jiang, Aziz Mithani, Xiangchao Gan, Eric J. Belfield, John P. Klingler, Jian-Kang Zhu, Jiannis Ragoussis, Richard Mott, Nicholas P. Harberd. Regenerant Arabidopsis Lineages Display a Distinct Genome-Wide Spectrum of Mutations Conferring Variant Phenotypes. Current Biology, 2011; DOI: 10.1016/j.cub.2011.07.002

Courtesy: ScienceDaily

Increasing Potency of HIV-Battling Proteins

If one is good, two can sometimes be better. Researchers at the California Institute of Technology (Caltech) have certainly found this to be the case when it comes to a small HIV-fighting protein.

The protein, called cyanovirin-N (CV-N), is produced by a type of blue-green algae and has gained attention for its ability to ward off several diseases caused by viruses, including HIV and influenza. Now Caltech researchers have found that a relatively simple engineering technique can boost the protein's battling prowess.

"By linking two cyanovirins, we were able to make significantly more potent HIV-fighting molecules," says Jennifer Keeffe, a staff scientist at Caltech and first author of a new paper describing the study in the Proceedings of the National Academy of Sciences (PNAS). "One of our linked molecules was 18 times more effective at preventing infection than the naturally occurring, single protein."

The team's linked pairs, or dimers, were able to neutralize all 33 subtypes of HIV that they were tested against. The researchers also found the most successful dimer to be similar or more potent than seven well-studied anti-HIV antibodies that are known to be broadly neutralizing.

CV-N binds well to certain carbohydrates, such as the kind found in high quantities connected to the proteins on the envelope that surrounds the HIV virus. Once attached, CV-N prevents a virus from infecting cells, although the mechanism by which it accomplishes this is not well understood.

What is known is that each CV-N protein has two binding sites where it can bind to a carbohydrate and that both sites are needed to neutralize HIV.

Once the Caltech researchers had linked two CV-Ns together, they wanted to know if the enhanced ability of their engineered dimers to ward off HIV was related to the availability of additional binding sites. So they engineered another version of the dimers -- this time with one or more of the binding sites knocked out -- and tested their ability to neutralize HIV.

It turns out that the dimers' infection-fighting potency increased with each additional binding site -- three sites are better than two, and four are better than three. The advantages seemed to stop at four sites, however; the researchers did not see additional improvements when they linked three or four CV-N molecules together to create molecules with six to eight binding sites.

Although CV-N has a naturally occurring dimeric form, it isn't stable at physiological temperatures, and thus mainly exists in single-copy form. To create dimers that would be stable under such conditions, the researchers covalently bound together two CV-N molecules in a head-to-tail fashion, using flexible polypeptide linkers of varying lengths.

Interestingly, by stabilizing the dimers and locking them into a particular configuration, it seems that the group created proteins with distances between binding sites that are very similar to those between the carbohydrate binding sites in a broadly neutralizing anti-HIV antibody.

"It is possible that we have created a dimer that has its carbohydrate binding sites optimally positioned to block infection," says Stephen Mayo, Bren Professor of Biology and Chemistry, chair of the Division of Biology, and corresponding author of the new paper.

Because it is active against multiple disease-causing viruses, including multiple strains of HIV, CV-N holds unique promise for development as a drug therapy. Other research groups have already started investigating its potential application in prophylactic gels and suppositories.

"Our hope is that those who are working to make prophylactic treatments using cyanovirin will see our results and will use CVN2L0 instead of naturally occurring cyanovirin," Keeffe says. "It has higher potency and may be more protective."

The work was funded by the National Security Science and Engineering Faculty Fellowship program, the Defense Advanced Research Projects Agency Protein Design Processes program, and the Bill and Melinda Gates Foundation through the Grand Challenges in Global Health Initiative.

Journal Reference:

1. J. R. Keeffe, P. N. P. Gnanapragasam, S. K. Gillespie, J. Yong, P. J. Bjorkman, S. L. Mayo. Designed oligomers of cyanovirin-N show enhanced HIV neutralization. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1108777108

Courtesy: ScienceDaily

A Cellular Protein Can Reduce the Growth and Spread of Cancer Cells

According to the Canadian Cancer Society, one in four Canadians will die of cancer. This year alone, the disease will kill an estimated 75,000 people. With incidence rates on the rise, more cancer patients are facing grave prognoses. Fortunately, Lawson Health Research Institute's Dr. John Lewis, Dr. Ann Chambers, and colleagues have found new hope for survival. Their new study released July 28 in Laboratory Investigation shows that maspin, a cellular protein, can reduce the growth and spread of cancer cells -- but only when it is in the nucleus.

Maspin is believed to inhibit the formation, development, and spread of tumors in several aggressive cancers, including breast, ovarian, and head and neck cancers. Yet efforts to use this information to predict how cancer patients will fare have been challenging; the presence of maspin has been linked to both good and bad prognoses. Dr. Lewis, Dr. Chambers, and their team believed that this inconsistency was caused by the location of maspin in the cell, whether in the nucleus or in the cytoplasm, and sought to test this theory.

To assess the effects of maspin on tumor growth and development, they tested two aggressive cancers: a highly invasive head and neck cancer, and a breast cancer known to spread to the lymph nodes and the lungs. The team introduced two forms of maspin into the cancer cells, one that went into the nucleus and one that was blocked from the nucleus. Then they injected the cells into both chicken embryo and mouse models of cancer and asked the simple question: which one slowed the cancer down?

It turned out the answer was simple: when maspin was allowed to get into the nucleus of the cancer cells, the disease's ability to spread was significantly limited. In fact, the incidence of metastasis was lowered from 75% to 40%. When maspin was not established in the nucleus; however, this ability was reversed and cancer cells were far more likely to spread. These findings demonstrate that the location of maspin within the cell significantly influences cancer cells' behavior, determining how aggressive the disease will be and how positive patient outcomes will be.

"The difference is night and day," Dr. Lewis says. "Metastasis is the cause of 90% of cancer deaths. We can now clearly see that maspin is working in the nucleus to dramatically reduce both the extent and the size of distant metastases."

"This study resolves a mystery in which maspin was sometimes linked with poor patient prognosis and sometimes with good patient prognosis," Dr. Chambers explains. "Our new work suggests that when maspin is located in the nucleus it blocks cancer growth and spread. This study may help doctors to understand how aggressive a patient's cancer will be, and may also lead to new targets for drug development."

The study was funded through a Postdoctoral Fellowship Award from the Terry Fox Foundation, the Canadian Breast Cancer Research Alliance, the Canadian Cancer Society Research Institute, and the Canadian Institutes of Health Research.

Journal Reference:

1. Brigitte Goulet, Wendy Kennette, Amber Ablack, Carl O Postenka, M Nicole Hague, Joe S Mymryk, Alan B Tuck, Vincent Giguère, Ann F Chambers, John D Lewis. Nuclear localization of maspin is essential for its inhibition of tumor growth and metastasis. Laboratory Investigation, 2011; 91 (8): 1181 DOI: 10.1038/labinvest.2011.66

Courtesy: ScienceDaily

Bacterial Resistance to Antibiotics: The More They Resist, the More They Divide

The number of multiresistant strains of bacteria in hospitals is increasing. Bacteria acquire resistance to antibiotics through mutations in their chromosomes and by incorporating new genes, either from the surrounding environment or from other bacteria. Now, a research team at the Portuguese CBA research (University of Lisbon) and the Instituto Gulbenkian de Ciência has shown that, surprisingly, when both mechanisms of resistance are playing out in the bacterium Escherichia coli (E. coli), its ability to survive and reproduce is increased.

These results are now published in the open-access journal PLoS Genetics.

Usually, the acquisition of new genes, either through the insertion of pieces of DNA -- called plasmids -- or through mutations, comes at a cost to the bacteria, reflected in a reduction in its rate of cell division, for example. Francisco Dionísio, senior author of the paper, describes the process using the following analogy: "If you disassembled your computer and randomly changed connections and pieces, you wouldn't expect it to work better than before."

However, Francisco and his colleagues show that, when a mutation occurs in the chromosome of a bacterium that has already incorporated a resistance-carrying plasmid, the bacteria divide faster in 10% of the mutation-plasmid combinations tested. Similarly, bacteria that first acquire resistance to antibiotics through mutation of their chromosome and then gain further resistance by insertion of plasmids into their DNA show reproduction rate increases in 32% of combinations.

In 2009, the same research groups showed, for the first time, the importance of interactions between random genes in determining antibiotic resistance in bacteria. This latest study takes their initial findings a step further, by demonstrating that this is a general phenomenon, and thus may help to predict how a bacterial population will evolve after receiving a plasmid that confers resistance to a certain antibiotic.

Francisco Dionísio adds: "These results are, at least, unexpected in light of what we previously knew about genetic interactions, and may underlie the mechanism whereby rapid resistance to antibiotics appeared.

Journal Reference:

1. Rui F. Silva, Sílvia C. M. Mendonça, Luís M. Carvalho, Ana M. Reis, Isabel Gordo, Sandra Trindade, Francisco Dionisio. Pervasive Sign Epistasis between Conjugative Plasmids and Drug-Resistance Chromosomal Mutations. PLoS Genetics, 2011; 7 (7): e1002181 DOI: 10.1371/journal.pgen.1002181

Courtesy: ScienceDaily