New research from Rhode Island Hospital may help predict outcomes for stomach cancer patients

Study identifies possible markers for cancer prognosis

PROVIDENCE, R.I. – Researchers at Rhode Island Hospital have identified two potential molecular markers that may predict outcomes for patients with stomach cancer, one of the most common and fatal cancers worldwide.

According to the study, published in the July 1 issue of Clinical Cancer Research, patients who had poor outcomes following surgery for stomach cancer also had extremely low amounts of two proteins, known as gastrokine 1 and 2 (GKN1 and GKN2), which are produced by normal stomach cells.

The study's findings confirm previous research showing that once stomach cells become cancerous, they manufacture very low amounts of GKN1 and GKN2. However, this is the first known study to link these low protein levels with outcomes following stomach cancer surgery. Researchers say this discovery could eventually help physicians better determine and individualize therapy for stomach cancer, including which patients should be offered chemotherapy and other treatments in addition to surgery.

"Unfortunately, stomach cancer is difficult to cure unless it's discovered early, but because the early stage of the disease has very few symptoms, the cancer is usually advanced by the time it's diagnosed," says lead author Steven Moss, MD, a gastroenterologist with Rhode Island Hospital and an associate professor of medicine at The Warren Alpert Medical School of Brown University.

"That's what makes our findings so significant, because if the potential markers identified in our study can help predict a patient's prognosis, we can decide right away which course of action to take and hopefully help patients live longer and more comfortably," he adds.

According to the National Cancer Institute, approximately 760,000 cases of stomach cancer are diagnosed worldwide each year. Microscopically, stomach cancers can be subdivided into those which appear "diffuse" (a more aggressive form of cancer that can occur throughout the stomach and is more likely to spread) or "intestinal" (resembling the cells normally found only in the small or large intestines). Stomach cancers of both types are often triggered by a chronic infection brought on by Helicobacter pylori (H. pylori), a common bacterium that causes stomach inflammation and ulcers. Surgery is the most common treatment for stomach cancer and can include partial or full removal of the stomach. The five-year relative survival rate of patients with stomach cancer is 24 percent.

Moss, an expert on H.pylori, and colleagues initially set out to learn more about what the bacterium does to normal stomach cells. They focused on GKN1 and GKN2 because these proteins are also suppressed by stomach infections caused by H. pylori.

After looking at tissue samples from more than 150 stomach cancer patients who underwent surgery, the researchers discovered a near total suppression of GKN1 and GKN2 in the majority of patients. This was particularly evident in those patients with the diffuse variant of stomach cancer. More than three-quarters of these patients had extremely low levels of GKN1 and 85 percent had nearly nonexistent levels of GKN2.

Furthermore, in those patients with the intestinal variant of stomach cancer, very low levels of GKN 1 or GKN 2 at the time of surgery were associated with a significantly worse outcome. The median survival was about two years in these patients compared to a survival of more than 10 years for patients with normal levels of GKN1 or GKN2.

Researchers do not yet know the exact function of GKN1 and GKN2. They say further studies are needed to demonstrate the mechanisms responsible for the loss of GKN1 and GKN2 in this patient popoulation as well as the clinical biomarker potential of these two proteins.

The study included tissue samples from 155 patients with stomach cancer (81 men and 74 women) who underwent surgery at Rhode Island Hospital and The Miriam Hospital, both in Providence, R.I. The average age at surgery was 72 years. All four stages of cancer were represented in the study, including 37 patients with Stage I, 44 patients with Stage II, 34 patients with Stage III, and 40 patients with Stage IV. More than 61 patients were being treated for the intestinal variant of stomach cancer while 90 patients had the diffuse variant.

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The study was funded by research grants from the National Institutes of Health.

Study co-authors were Murray Resnick, Edmond Sabo, John Gao, Patricia A. Meitner, and Rose Tavares from Rhode Island Hospital and Alpert Medical School; John Rommel and Anna Rubin from Alpert Medical School; Jin-Woo Lee from Inha University Hospital, South Korea; and Bruce R. Westley and Felicity E.B. May from the Northern Institute for Cancer Research at University of Newscastle upon Tyne, United Kingdom.

Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org) is a private, not-for-profit hospital and is the largest teaching hospital of The Warren Alpert Medical School of Brown University. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Rhode Island Hospital ranks among the country's leading independent hospitals that receive funding from the National Institutes of Health, with research awards of nearly $27 million annually. Many of its physicians are recognized as leaders in their respective fields of cancer, cardiology, diabetes, orthopedics, neurology and minimally invasive surgery. The hospital's pediatrics division, Hasbro Children's Hospital, has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery. Rhode Island Hospital is a founding member of the Lifespan health system.

Genetic cause of innate resistance to HIV/AIDS

MUHC and CHUM researchers demonstrate how 2 specific genes are involved in an innate resistance to HIV infection

Montreal, 16 July 2008 - Some people may be naturally resistant to infection with HIV, the virus that causes AIDS. The results of a study conducted by Dr. Nicole Bernard of the Research Institute of the McGill University Health Centre (MUHC) bring us closer to a genetic explanation. Her study findings were published on July 16 in the journal AIDS.

The simultaneous expression of certain versions of two specific genes called KIR3DL1 and HLA-B*57 is thought to be at the root of some cases of this innate resistance to HIV infection. Depending on which versions of these two genes the patient has, he or she will resist HIV infection or develop AIDS at a slower rate.

These results were obtained by comparing the genetic profiles of people undergoing primary HIV infection ( in their first year of infection) to those repeatedly exposed to HIV but non-infected. The group of exposed but non-infected patients came from a cohort studied by Dr. Julie Bruneau of the Centre hospitalier de l'Université de Montréal. The cohort of primary HIV infected patients is studied by Dr. Jean-Pierre Routy, from the MUHC. Analyses show that the "good" versions of both genes were present in 12.2% of exposed but non-infected subjects versus only 2.7% in patients in primary HIV infection.

As of yet, no study has clearly described the mechanism of this protection. The KIR3DL1 gene codes for a receptor on the surface of the immune system's natural killer (NK) cells, which when activated destroy infected cells in the body. The HLA-B*57 gene codes for a protein normally found on the surface of all body cells that binds the KIR3DL1 and dampens NK cell activity. The most likely hypothesis is that HIV prevents the HLA-B*57-encoded protein from being expressed on the surface of the infected cells, making it unavailable to bind KIR3DL1. As a consequence, the NK cells retain their activity and destroy the virus-infected cells.

As this mechanism can occur very soon after the virus has started to infect the body cells, people carrying those versions of the 2 genes may be able to destroy more efficiently the infected cells following exposure to HIV, thus lowering their chances of developing AIDS.

"More research is needed to determine the exact mechanism behind the protection we have observed, but these findings have revealed a promising avenue," according to Dr. Bernard.

This study opens the way for new ideas in the fight against HIV infection. "In the future, our findings could be used to somehow 'boost' the innate immune system and thus fight the virus as soon as it enters the body," said Dr. Bernard.

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Dr. Nicole Bernard is a researcher in the Infection and Immunity Axis of the Research Institute of the McGill University Health Centre (RI MUHC) and a member of the McGill AIDS Centre. She is also an Associate Professor of Medicine at the Faculty of Medicine of McGill University.

Dr. Julie Bruneau is a practitioner at the Service de médecine des toxicomanies of the Centre hospitalier de l'Université de Montréal (CHUM) and Assistant Scientific Director of Clinical Research of the Centre de recherche du CHUM. She is also Associate professor at the department of family medicine, Université de Montréal

Dr Jean-Pierre Routy is an investigator in the Infection and Immunity Axis of the RI MUHC, and an Associate Professor of haematology at the Faculty of Medicine of McGill University.

This study was funded by the Canadian Institutes for Health Research (CIHR) and the Fonds de la recherche en santé du Québec (FRSQ).

The McGill University Health Centre

The McGill University Health Centre (MUHC) is a comprehensive academic health institution with an international reputation for excellence in clinical programs, research and teaching. Its partner hospitals are the Montreal Children's Hospital, the Montreal General Hospital, the Royal Victoria Hospital, the Montreal Neurological Hospital, the Montreal Chest Institute and the Lachine Hospital. The goal of the MUHC is to provide patient care based on the most advanced knowledge in the health care field and to contribute to the development of new knowledge. www.muhc.ca

The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.

The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santé du Québec.

For further details visit: www.muhc.ca/research.

About CHUM

The Centre hospitalier de l'Université de Montréal (CHUM) provides specialized and ultra-specialized services to a regional and supra-regional clientele. Within its more immediate coverage area, the CHUM also provides general and specialized hospital care and services. The CHUM uses an integrated network model to carry out its five-part mandate of care, teaching, research, the assessment of technologies and health care methodologies, and the promotion of health care. Through its determined efforts to continuously improve quality of care and patient safety, the CHUM has again received accreditation from the Canadian Council on Health Services Accreditation, for the 2007-2010 period. Hôtel-Dieu, Hôpital Notre-Dame, and Hôpital Saint-Luc make up the CHUM, with approximately 10,000 employees, 900 physicians, 270 researchers, 6,000 students and trainees and 700 volunteers providing services to over a million patients each year. www.chumontreal.qc.ca.

For more information please contact:

Isabelle Kling
Communications Coordinator (research)
MUHC Public Relations and Communications
(514) 843 1560
isabelle.kling@muhc.mcgill.ca

Nathalie Forgue
Communications Advisor
CHUM
514 890-8000, ext. 14342
Pager : 514 801-5762

Genetic variation increases HIV risk in Africans

A genetic variation which evolved to protect people of African descent against malaria has now been shown to increase their susceptibility to HIV infection by up to 40 per cent, according to new research. Conversely, the same variation also appears to prolong survival of those infected with HIV by approximately two years.

The discovery marks the first genetic risk factor for HIV found only in people of African descent, and sheds light on the differences in genetic makeup that play a crucial role in susceptibility to HIV and AIDS.

The research, published today in Cell Host & Microbe, was co-authored by Professor Robin Weiss, UCL Infection and Immunity, who worked with colleagues in the US to analyse data from a 25-year study of thousands of Americans of different ethnic backgrounds.

The gene that the research focused on encodes a binding protein found on the surface of cells, called Duffy Antigen Receptor for Chemokines (DARC). The variation of this gene, which is common in people of African descent, means that they do not express DARC on red blood cells. DARC influences the levels of inflammatory and anti-HIV blood factors called chemokines.

Discussing the findings, Professor Weiss said: "The big message here is that something that protected against malaria in the past is now leaving the host more susceptible to HIV.

"In sub-Saharan Africa, the vast majority of people do not express DARC on their red blood cells and previous research has shown that this variation seems to have evolved to protect against a particular form of malaria. However, this protective effect actually leaves those with the variation more susceptible to HIV."

Lead author of the study, Professor Sunil K. Ahuja, from The University of Texas Health Science Center at San Antonio, added: "It turns out that having this variation is a double-edged sword. The finding is another valuable piece in the puzzle of HIV-AIDS genetics."

HIV affects 25 million people in sub-Saharan Africa today, an HIV burden greater than any other region of the world. Around 90 per cent of people in Africa carry the genetic variation, meaning that it may be responsible for an estimated 11 per cent of the HIV burden there. The authors observe that sexual behaviour and other social factors do not fully explain the large discrepancy in HIV prevalence in populations around the world, which is why genetic factors are a vital field of study.

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Notes for Editors

1. Journalists seeking more information, or to interview Professor Robin Weiss, can contact Ruth Metcalfe in the UCL Media Relations Office on tel: +44 (0)20 7679 9739, mobile: +44 (0)7990 675 947, out of hours: +44 (0)7917 271 364, e-mail: r.metcalfe@ucl.ac.uk

2. The paper 'Duffy Antigen Receptor for Chemokines (DARC) Mediates Trans-infection of HIV-1 from Red Blood Cells to Target cells and Affects HIV-AIDS Susceptibility' is published in the journal Cell Host & Microbe, published by Cell Press. This is not an open-access journal but copies of the paper can be obtained from Ruth Metcalfe, UCL Media Relations, using the above contact details.

3. The authors of this paper are from: South Texas Veterans Health Care System, Texas, US; The University of Texas Health Science Center in San Antonio, US; UCL; Uniformed Services University, Maryland, US; Wilford Hall United States Air Force Medical Center, US and the San Antonio Military Medical Center.

4. In the UK, this work was supported by a grant to Professor Weiss from the Medical Research Council.

About UCL

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. In the government's most recent Research Assessment Exercise, 59 UCL departments achieved top ratings of 5* and 5, indicating research quality of international excellence.

UCL is in the top ten world universities in the 2007 THES-QS World University Rankings, and the fourth-ranked UK university in the 2007 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. www.ucl.ac.uk

After ER visit, many patients in a fog, U-M study finds

3/4 don't understand either what's wrong, what was done, or what they should do after leaving emergency room

ANN ARBOR, Mich. — Every year, more than 115 million patients enter emergency rooms at hospitals around the nation. And more than three-quarters of them leave with an impression of what happened – or what should happen next – that doesn't match what their emergency care team would want.

That's the finding of a new study led by University of Michigan Health System researchers, and published early online in the Annals of Emergency Medicine. The results suggest that emergency room teams need to do a better job of making sure patients go home with clear information and instructions – and that patients and their loved ones shouldn't leave until they fully comprehend their situation.

The researchers carried out detailed interviews with 140 English-speaking patients who visited one of two emergency departments, and were released to go home. They compared those interviews with the patients' medical records, and found a serious mismatch between what doctors and nurses found or advised, and what patients comprehended.

What's worse, patients were pretty sure of what they "knew" 80 percent of the time – even if what they knew wasn't quite right.

"It is critical that emergency patients understand their diagnosis, their care, and perhaps most important, their discharge instructions," says lead author Kirsten Engel, M.D., a former U-M emergency medicine fellow and Robert Wood Johnson Clinical Scholar who is now at Northwestern University. "It is disturbing that so many patients do not understand their post-emergency department care, and that they do not even recognize where the gaps in understanding are. Patients who fail to follow discharge instructions may have a greater likelihood of complications after leaving the emergency department."

The study's senior author agrees. "As a physician, I would like to think I could look someone in the eye and ask: 'Do you have any questions?,' and those who were confused or overwhelmed would ask for more help," says Peter Ubel, M.D., a professor of internal medicine at the U-M Medical School. "This study shows that many patients walk away from important clinical encounters confident that they know what happened and why, but with little reason to be so confident."

The researchers measured the extent to which patients' reports agreed with their doctors' records in four areas: diagnosis, emergency care that was given, post-ER care needs and what kinds of symptoms or signs would require the patient to return to the ER or seek immediate care.

Only 22 percent of patients' reports were in complete harmony with what their care teams reported on all four counts.

Fifty-eight percent of patients understood at least two of the four areas, but 20 percent were off on three or four areas of their care and follow-up needs.

After asking patients about their diagnosis, care and post-ER instructions, the team also asked them if they were not sure about any of the four areas. Interestingly, patients whose understanding perfectly matched their doctors' records were just as likely to report being unsure as patients whose understanding was lacking.

"Doctors need to not only ask patients if they have questions, but ask them to explain, in their own words, what they think is wrong with their health and what they can do about it," says Ubel. "And patients need to ask their doctors more questions, and even need to explain, to their doctors, what they think is going on."

The biggest area of misunderstanding or lack of comprehension was post-emergency care – that is, what steps the patient needs to take to be seen by their regular doctor or a specialist, how soon to see a doctor, or what medicines or self-care steps they need to take, how to take them, and when.

Ubel, Engel and their colleagues found that 34 percent of the deficiencies in patient comprehension reflected a less-than-complete understanding of what their ER team recommended they do after they left the ER. Meanwhile, 22 percent of the deficiencies in the study had to do with patients' understanding of what symptoms or changes in their condition should spur them to return to the ER.

Recently, the U-M Health System introduced a program that aims directly at this problem: the Emergency Medicine Consult/Referral Service, run by the Department of Emergency Medicine and the Physician and Consumer Communications division of Public Relations & Marketing Communications.

It is staffed by referral coordinators who follow up with ER patients by phone within 24 hours of their ER visit, to help schedule appointments with U-M physicians for specialty care if the patients' insurance allows it or make sure they know that they need to schedule an appointment elsewhere.

More than 12,000 follow-up appointments have been scheduled for recent U-M ER patients since the program began in February 2007, and 81 percent of those patients have arrived for their scheduled appointments, up from 59 percent before the program began. Appointment cancellations are also down.

Before the program began, 24 percent of U-M ER patients who needed a follow-up appointment never scheduled one. And many patients and clinicians who did try to arrange follow-up care went through a frustrating and confusing process that is repeated every day in hospitals around the country. The new call center offers a standardized, centralized way to make sure patients get scheduled to see the provider they need soon after their ER visit.

The new study involved patients from ages 18 to 83 years, 59 percent of whom were women. Nineteen percent of patients were African-American, and 68 percent were white, with the remaining percentage being other races or without a race recorded on their record. Thirty-five percent had a high school education or less. Patients were given a brief cognition test before being interviewed, to make sure their thinking and understanding abilities were normal. In some cases, caretakers were also interviewed.

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In addition to Engel and Ubel, who directs the Program for Behavioral and Decision Sciences in Medicine, the new study's authors include Michele Heisler, M.D., MPA, Dylan Smith, Ph.D., Claire Robinson, MPH, and Jane Forman, M.D. The study was funded by the Robert Wood Johnson Foundation and the U-M Clinical Scholars Program.

Reference: Annals of Emergency Medicine, doi:10.1016/j.annemergmed.2008.05.016

In two complementary studies

Weizmann Institute scientists have developed a new method for reconstructing a cell’s 'family tree,' and have applied this technique to trace the history of the development of cancer. So far, the scientists have been able to calculate the age of the tumor and characterize its growth pattern. The scientists believe cell lineage studies of cancer can eventually lead us to the root of cancer.

Weizmann Institute Scientists’ New Technique Gets to the Root of Cancer

In two complementary studies, Weizmann Institute scientists have developed a new method for reconstructing a cell’s 'family tree,' and have applied this technique to trace the history of the development of cancer.

The quest to understand a cell’s path of descent, called a cell lineage tree, is shared by many branches of biology and medicine as gleaning such knowledge is key to answering many fundamental questions, such as whether neurons in our brain can regenerate, or whether new eggs are created in adult females.

So far, only tree lineages of tiny organisms, such as worms, which possess only a thousand cells, or 'branches,' have been determined. Now, Prof. Ehud Shapiro of the Institute’s Biological Chemistry, and Computer Science and Applied Mathematics Departments, together with Doctoral students Dan Frumkin and Adam Wasserstrom have developed a novel way to reconstruct, in principle, trees for larger organisms, including humans.

The human body is made of about 100 trillion cells, all of which are descendants of a single cell – the fertilized egg (zygote). Cells that have undergone a small number of cell divisions are relatively close descendants (akin to branches representing children and grandchildren etc., on a family tree), while some cells may have undergone hundreds or even thousands of divisions ('distant cell generations'). Knowing the number of cell divisions since the zygote, known as the depth of cells, would enable scientists to address questions about the behavior of the body under physiological and pathological conditions.

Until now, estimates of cell depth were based on theoretical calculations and assumptions, but Shapiro provides a practical way of determining cell depth precisely. The concept behind their new method is simple: Previous research indicated that each time a cell divides, harmless mutations are introduced, and that 'cell relatives' of distant generations tend to acquire more mutations, drifting away from the original DNA sequence of the zygote. Inspired by this, the team developed a non-invasive, accurate and systematic way, involving DNA amplification and computer simulations, to quantitatively estimate cell depth on the basis of the number of mutations in microsatellites (repetitive DNA sequences), and has applied it to several cell lineages in mice.

According to the team’s estimates, as reported in PLoS Computational Biology, the average depth of B cells – a type of immune cell – is related to mouse age, suggesting a rate of one cell division per day. In contrast, various types of adult stem cells underwent fewer divisions, supporting the notion that they are relatively quiescent.

Shapiro and Frumkin, in collaboration with Prof. Gideon Rechavi from the Sheba Medical Center and others then decided to apply this method to reconstruct, for the first time, the family tree of a cancer cell. 'Despite several decades of scientific research, basic properties of the growth and spread of tumor cells remain controversial. This is surprising, since cancer is primarily a disturbance of cell growth and survival, and an aberrant growth pattern is perhaps the only property that is shared by all cancers. However, because the initiation and much of the subsequent development of tumors occurs prior to diagnosis, studying the growth and spread of tumors seems to require retrospective techniques and these have not been forthcoming,' explains Shapiro.

Therefore, by reconstructing a cancer cell lineage tree and performing an analysis of mutations accumulated in the cells, scientists would be able to trace back and reveal several aspects of the tumor’s developmental history. Shapiro: 'We intend to apply this method to study key questions in human cancers, including when and where does a tumor initiate? The progression from pre-malignant to malignant states. At what stage does metastasis occur? Can the depth of tumor cells serve as a prognostic marker for cancer severity? And does chemotherapy target a subset of cells characterized by distinct lineage features (e.g. greater depth)?'

So far, their findings, featuring on the cover of the July 15th issue of Cancer Research, show that cancer cells (extracted from tissue sections of a mouse lymphoma by laser micro-dissection) had almost double the number of branched generations (i.e., had divided almost twice as many times) compared to adjacent normal lung cells in the same amount of time. They were also able to calculate the age of the tumor and characterize its growth pattern. Further analysis was sufficient to corroborate the long-standing hypothesis on the single-cell origin of cancer.

The scientists believe cell lineage studies of cancer can greatly enhance our understanding of, and eventually lead us to the root of cancer.

Prof. Ehud Shapiro's research is supported by the Clore Center for Biological Physics; the Arie and Ida Crown Memorial Charitable Fund; the Cymerman - Jakubskind Prize; the Fusfeld Research Fund; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; the Henry Gutwirth Fund for Research; Ms. Sally Leafman Appelbaum, Scottsdale, AZ; the Carolito Stiftung, Switzerland; the Louis Chor Memorial Trust Fund; and the estate of Fannie Sherr, New York, NY.
Prof. Shapiro is the incumbent of the Harry Weinrebe Chair of Computer Science and Biology

The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.

Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il, and are also available at http://www.eurekalert.org.

Researchers discover link between organ transplantation and increased cancer risk

Researchers have determined a novel mechanism through which organ transplantation often leads to cancer, and their findings suggest that targeted therapies may reduce or prevent that risk.

In the July 15, 2008, issue of Cancer Research, researchers at Harvard Medical School found in animal and laboratory experiments that the anti-rejection, immunosuppressive drug cyclosporine ramps up expression of vascular endothelial growth factor (VEGF), which signals the growth of new blood vessels that can feed tumors.

They also found that simultaneously administering an anti-VEGF therapy with cyclosporine in mice repressed this tumor growth. Several inhibitors of VEGF are already in use in human cancer therapy.

The findings could offer some good news for the 15 to 20 percent of transplant patients who develop cancer within a decade of receiving new organs, according to the study's senior investigator, Soumitro Pal, Ph.D., an assistant professor at Harvard Medical School's Transplantation Research Center at Children's Hospital in Boston.

"It may be that anti-VEGF agents given judiciously after transplantation can reduce future cancer occurrence," he said.

VEGF expression is markedly increased in patients post-transplantation, and this can aid in the development of a blood supply to a transplanted organ, helping it survive and thrive. "But once the organ has stabilized, it may be possible to lower the level of VEGF expression to prevent tumor growth," he said. "We would need to figure out how to balance benefit and risk to keep cancer at bay."

Tumors that develop after transplantation may have three potential sources: they may have pre-existed or could have been a recurrence of previous cancer – and in both of these cases, a patient's pre-transplant immune system might have kept these cancers in check – or cancer-causing viruses could have come from the donor organ. Physicians have long observed that immunosuppressive agents, such as the class of calcineurin inhibitors that includes cyclosporine, appear to promote cancer development, often in organs that are not transplanted, but the cause of this was unclear. The Harvard team tested the ability of cyclosporine to promote growth of pre-existing tumors in mice implanted with human renal (kidney) cancer cells. Mice treated with the agent formed tumors faster than untreated mice, but anti-VEGF therapy substantially reduced that excessive growth.

Digging deeper into the biological pathway of VEGF activation, the scientists found that cyclosporine activates two of the three forms of the common protein catalyst, protein kinase C, which leads to increased expression of VEGF.

"We think PKC-mediated VEGF transcriptional activation is a key component in the progression of cyclosporine-induced post-transplantation cancer," Pal said. "It is likely not the whole story, but this gives us a clue that we might be able to use existing or novel therapies to reduce cancer risk in transplanted patients."

Gene variant found in those with African ancestry increases odds of HIV infection

A variant of a gene found only in people of African ancestry increases the odds of becoming infected with the human immunodeficiency virus (HIV-1) by 40 percent, according to a long-term study of African Americans reported in the [date] issue of the journal Cell Host & Microbe, a publication of Cell Press. However, once people are infected, the same variant seems to protect against progression of the disease, allowing those who carry it to live about two years longer.

" It's well-known that individuals vary in their susceptibility to HIV and that after infection occurs, the disease progresses at variable rates," said Sunil Ahuja of South Texas Veterans Health Care System and University of Texas Health Science Center at San Antonio. "The mystery of variable infection and progression was originally thought to be mainly the result of viral characteristics, but in recent years it has become evident that there is a strong host genetic component."

The new discovery is one of few genetic risk factors for HIV found only in people of African descent, the researchers added. If the new findings can be extrapolated to Africa, where about 90 percent of all people carry the variant, it may be responsible for 11 percent of the HIV burden there, they estimate.

The gene in question encodes a protein found mainly at the surface of red blood cells, which is called Duffy Antigen Receptor for Chemokines (DARC). The DARC variant found commonly in people of African ancestry leaves them without this particular red blood cell receptor. That so-called "DARC-negative" condition has been well studied because it also confers protection against infection by a malaria parasite known as Plasmodium vivax. (P. vivax is unfortunately not the parasite responsible for millions of malaria deaths each year in Africa today. The researchers speculate that this DARC gene variant may have risen to such high frequency as protection against some other, more lethal strain of malaria that existed at some time in the past.)

" The big message of this paper is that something that protected people against malaria in the past is now leaving them more susceptible to HIV," said Robin Weiss of University College London. "After thousands of years of adaptation, this Duffy variant rose to high frequency because it helped protect against malaria," added Matthew Dolan of the Wilford Hall United States Air Force Medical Center and San Antonio Military Medical Center. "Now, with another global pandemic on the scene, this same variant renders people more susceptible to HIV. It shows the complex interplay between historically important diseases and susceptibility in contemporary times."

Earlier studies had suggested that HIV can bind to red blood cells via DARC. In accord with its name, DARC also binds a wide array of inflammatory molecules known as chemokines, including one called CCL5, which is highly effective in suppressing replication of HIV-1.

Those hints led the researchers to wonder just what the impact of DARC on HIV-AIDS might be. In cell culture, they found further evidence that HIV binds to DARC on red cells. "We started looking at red cells together with HIV and, sure enough, the virus attached," Weiss said. "The DARC molecule on red cells in cell culture then transferred the virus to lymphocytes to get infected." CD4+ T lymphocytes are white blood cells that are a primary target of HIV infection.

When chemokines that also bind DARC were added to the mix, less HIV-1 bound to the red cells, confirming that the virus and chemokines were in competition for the DARC receptor. "Duffy acts somewhat like a sponge," Ahuja said. "It binds all these chemokine molecules and that binding also extends to HIV, setting up a triumvirate of interactions between DARC, chemokines and virus."

The researchers next looked to a large cohort of people in the U.S. Air Force, including more than 1,200 who are HIV positive, who have been followed for nearly 22 years. This group is ideal for evaluating the role of such a gene because this cohort is ethnically balanced and without many of the factors, including differences in economic status and access to health care, that would generally confound any genetic effect, Dolan explained.

Those studies showed that the prevalence of the "DARC-negative" variant in African Americans was greater amongst those with HIV than in those without. Although the DARC-negative genotype was associated with an increased risk of acquiring HIV infection, within the context of established infection a contrary result was observed: people with that variant had a slower disease course, they report.

" The parts of a car that get it into gear are separate from those that get it moving once in gear," Ahuja said. "A similar analogy applies to HIV; the factors that influence its transmission are not necessarily the same as those that influence disease progression."

Although it isn't yet entirely clear how exactly DARC mediates opposing effects during HIV acquisition and disease, the researchers suspect those with the DARC receptor are initially protected because they also have more HIV suppressive chemokines in their system. Once infected, however, the balance turns in favor of those without DARC as increased chemokine levels may promote inflammation in those with DARC. Also, once the virus reaches higher levels, it is more likely to displace chemokines bound to DARC on red cells, further exacerbating inflammation. And during established infection, HIV bound to DARC on red cells is poised for delivery to CD4+ T cells, the researchers said.

The findings help answer an earlier conundrum: the researchers had previously shown that people with a particular variant of the chemokine CCL5 have a faster rate of HIV progression. But, that pattern only held in European Americans, not in African Americans. They now show that the disease-accelerating effect of the CCL5 variant is evident only in DARC-expressing and not in DARC-negative HIV-positive individuals. In other words, the unmeasured effects of DARC amongst African Americans in the earlier study "masked" the influence of CCL5, exemplifying the importance of accounting for such complex gene-gene interactions in genetic studies.

" The results underscore that genetic variants that influence transmission and disease progression can differ in their frequency among different populations, with possible impacts on the heterogeneity of HIV disease burden--not just at the level of individuals but also populations," they concluded. They may also have implications for evaluating the efficacy of HIV vaccines.