Loss of cell’s ‘antenna’ linked to cancer’s development

Contact: Karen Mallet
Karen.Mallet@fccc.edu
215-728-2700
Fox Chase Cancer Center

Fox Chase Cancer Center researchers described dismantling proteins in journal Cell

Submarines have periscopes. Insects have antennae. And increasingly, biologists are finding that most normal vertebrate cells have cilia, small hair-like structures that protrude like antennae into the surrounding environment to detect signals that control cell growth. In a new study published in the June 29 issue of Cell, Fox Chase Cancer Center researchers describe the strong link between ciliary signaling and cancer and identify the rogue engineers responsible for dismantling the cell’s antenna.

Cilia-based sensing has important roles in sight, smell and motion detection and in helping an embryo develop into a normal baby. Defects in cilia can produce a range of disorders, including kidney cysts, infertility, respiratory problems, reversal of organs (for example, heart on the right) and a predisposition to obesity, diabetes and high blood pressure. In each case, cells fail to appropriately detect growth-controlling signals and develop abnormally. Now, researchers are adding cancer to this list.

“Many cancers arise from defects in cellular signaling systems, and we think we have just identified a really exciting signaling connection,” Fox Chase Cancer Center molecular biologist Erica A. Golemis, Ph.D., points out. In the new study, Golemis and her Fox Chase colleagues found that two proteins with important roles in cancer progression and metastasis, HEF1 and Aurora A, have an unexpected role in controlling the temporary disappearance of cilia during normal cell division, by turning on a third protein, HDAC6. This action causes the “antenna” to be dismantled in an untimely way.

Why cilia come and go on normal cells is not entirely understood, but scientists increasingly suspect that it may play a role in timing the cell division process. Commonly, cancer cells have entirely lost their cilia, and this absence may help explain why tumors fail to respond properly to environmental cues that cause normal cells to stop growing. Hence, the discovery that too much HEF1 and Aurora A cause cilia to disassemble provides important hints into what may be happening in cancers.

Defects in cilia have already been identified in one disease that represents a significant public health burden. Polycystic kidney disease, or PKD, arises from genetic mutations that cause flawed kidney-cell ciliary signaling. PKD is the most common serious hereditary disease, affecting more than 600,000 Americans and 12.5 million people worldwide.

In this incurable syndrome, patients develop numerous, fluid-filled cysts on the kidneys. For many patients, chronic pain is a common problem. PKD leads to kidney failure in about half of cases, requiring kidney dialysis or a kidney transplant.

The proteins involved in dismantling the cilia are no strangers to Golemis and her team. Golemis has been studying HEF1 for over a decade, since she first identified the gene. She first discovered that HEF1 has a role in controlling normal cell movement and tumor cell invasion. Golemis’ laboratory has also shown that Aurora A and HEF1 interact to initiate mitosis (chromosome separation) during cell division.

Suggestively, many cancers produce too much of the Aurora A protein, including breast and colorectal cancers and leukemia. In 2006, excessive production of HEF1 (also known as NEDD9) was found to drive metastasis in over a third of human melanomas, while HEF1 signaling also contributes to the aggressiveness of some brain cancers (glioblastomas).

“Now there’s a new activity for these proteins at cilia,” said co-author Elizabeth P. Henske, M.D., a medical oncologist and genetics researcher who studies the genetic basis of kidney tumors. This complex HEF1 and Aurora A function may mean the increased levels of these proteins in cancer affect cellular response to multiple signaling pathways, rather like a chain reaction highway accident.

Clinical Application

The research has significant implications for the understanding and treatment of cancer. The experiments leading to the new paper showed that “small-molecule inhibitors of Aurora A and HDAC6 selectively stabilize cilia,” the authors concluded, “suggesting a novel mode of action for these clinical agents.” Clinical trials of such inhibitors have already begun, so learning more about the mechanisms of their targets is important in understanding how these agents work and who might benefit from them.

“It is also tantalizing to consider that closer connections exist between dysplastic disorders leading to cysts and cancer than have previously been appreciated,” the authors wrote. “Overall, deregulated Aurora A/HEF1/HDAC6 signaling may have broad implications for studies of human development and disease.”

The authors are now investigating possible roles for HEF1 and Aurora A in PKD. They are intrigued by the fact that a study published last year showed that important gene, PKHD1, commonly mutated in PKD has also been found as a target of mutation in colorectal cancer.

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In addition to Golemis and Henske, co-authors include Elena N. Pugacheva, Ph.D., Tiffiney Hartman, Ph.D., and Sandra A. Jablonski, Ph.D., all of Fox Chase Cancer Center. Grants from the National Institutes of Health, Department of Defense, Pennsylvania Tobacco Settlement Funds and the Susan B. Komen Foundation supported this research, along with the Cancer Center support grant from NIH and an appropriation from the Commonwealth of Pennsylvania to Fox Chase Cancer Center.

Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation’s first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of cancer prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center’s web site at http://www.fccc.edu or call 1-888-FOX CHASE.

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Common hip condition may not always cause osteoarthritis in some racial groups

Contact: Amy Molnar
amolnar@wiley.com
John Wiley & Sons, Inc.

Osteoarthritis is the most common joint disorder worldwide, yet the cause of osteoarthritis of the hip is still unknown. One condition that may play a role is femoro-acetabular impingement (FAI), in which the femoral head of the thighbone causes damage by rubbing abnormally on the hip socket (acetabulum). FAI caused by an abnormality in the hip socket can lead to osteoarthritis, but it is not known if FAI that is not caused by a defect can also lead to the condition. Recognizing that the Asian lifestyle requires a larger range of hip motion than the Western lifestyle, a new study examined FAI in Japanese patients with normal hips. The study will publish online in the Journal of Orthopaedic Research (http://www.interscience.wiley.com/journal/jor), the official journal of the Orthopaedic Research Society.

Led by Mitsuyoshi Yamamura of Kyowakai Hospital in Osaka, Japan, researchers conducted a study on five healthy female volunteers between the ages of 18 and 26. They defined impingement using an open-configuration MRI, which allows imaging of the hip joint throughout the entire range of motion, by imaging subjects in the W-sitting position (in which the legs are bent behind the person) in two variations with the legs flexed to different degrees. Images were then obtained for 5 sitting positions, including sitting straight, bowing while sitting straight, sitting cross-legged, W-sitting, and squatting. Most of these positions are used in eating, socializing and in religious or traditional ceremonies and squatting is the position usually used for defecation in Asia and the Middle East.

The results showed that impingement occurred in all subjects in the W-sitting position and was also seen in 2 subjects in the squatting position. The largest hip internal rotation angle was seen in the W-sitting position. “No subjects complained of hip pain while maintaining any of the positions, even though the MR imaging process took from 10 to 14 minutes,” the authors note.

Populations in the Middle East and Asia have a low incidence of osteoarthritis in those with normal hips even though they regularly adopt positions that induce FAI, which suggests that FAI might not cause degenerative change in the hips. The researchers speculate that this may be related to soft tissue laxity around the hip, citing reports that joint laxity or range of motion differ by race. In addition, they note that impingement did not appear to be associated with pathology both in the present study and another study involving the shoulder area. Another reason FAI may not cause hip damage is that the positions in the study were static, as opposed to repetitive trauma, which the study did not evaluate.

The authors acknowledge that since the study was so small, the findings cannot necessarily be generalized to all Asian populations. Also, it is not known whether the subject in the study will develop osteoarthritis in the future. However, they note it is remarkable that FAI was seen in all 5 subjects. “This suggests that, depending on race, femoro-acetabular impingement might not always be a cause of osteoarthritis of the hip,” they conclude. “Further work in this area, including healthy males and patients with abnormalities, will confirm this conclusion.”

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Article: “An Open-Configuration MRI Study of Femoro-Acetabular Impingement,” Mitsuyoshi Yamamura, Hidenobu Miki, Nobuo Nakamura, Masakazu Murai, Hideki Yoshikawa, Nobuhiko Sugano, Journal of Orthopaedic Research, July 2007; (DOI: 10.1002/jor.20448).

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Autism theory put to the test with new technology

Contact: Don McSwiney
don.mcswiney@ucalgary.ca
403-220-7652
University of Calgary

University of Calgary researcher hopes to advance understanding of autism by studying ancient human searching behavior
Next time you lose your car keys and enlist the family to help you search, try a little experiment. After your spouse searches an area, go and look in the same place. It will likely feel strange, even irritating to both of you – and that’s because you may be fighting an ancient, hard-wired, human behaviour pattern.

The behavioural phenomenon is called ‘inhibition of return’ and for our ancient hunter-gatherer ancestors it made a lot of sense. As Dr. Tim Welsh explains, “This behaviour likely developed through evolution to increase search efficiency. Returning to search an area that someone else has already searched doesn’t make a lot of sense from a survival point of view because they’ve either found the food and eaten it, or there’s no food there.”

Inhibition of return has been well-documented over the years, but Welsh is interested in measuring exactly how the actions of another individual affect our own, and whether people with autism react differently than the rest of the population. To test this Welsh, a professor in the Faculties of Kinesiology and Medicine, came up with a unique and elegant experiment that uses some cutting-edge technology.

In Welsh’s set-up, two subjects sit across from each other wearing, liquid crystal goggles. They are told to reach for a lighted target in front of them.

Welsh’s previous work has shown that if we see someone else touching an area, we are much slower to move there, but Welsh wanted to see how much of another person’s actions we need to be aware of, to affect our own. Welsh’s crystal goggles become opaque allowing the subject to see only a fraction of the other person’s movement.

He discovered that as social beings, we are so sensitive to another’s actions that just the suggestion of a movement was enough to trigger the inhibition of return effect.

So what happens when the individual doesn’t really recognize, or can’t recognize the actions of another individual” Sadly this is often the case for people with autism, a complex neurological, developmental disability that affects over 50,000 Canadians. A current theory of autism is that individuals with the disorder have a problem with their mirror neuron system.

“In normal individuals if you see someone throwing a ball, your mind will ‘mirror’ those actions to make it seem as if you are throwing it yourself,” Welsh explains. “The theory is that a person with autism may not be able to mirror the actions of other individuals. So in our experimental set-up you would expect them to be unaffected by the actions of another person and this is exactly what we have found to this point.”

Welsh believes his research will advance our understanding of autism and the mirror neuron system – perhaps leading to more effective intervention and treatment of a condition that seems to be growing at an alarming rate. “What I think is very interesting,” says Welsh, “is that the same experimental set-up can effectively be used to test two theories, and in many ways the two groups we are working with – a typically-developing population and an autistic population – provide a control for the other group. I’m very excited about this research.”

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Dr. Welsh is currently looking for people between the ages of 14 and 25 to participate in his experiments. He is looking for with people autism and people from the typically-developing population.

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New genetic test developed at Emory advances detection and diagnosis of muscular dystrophy

Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University

A new genetic test targeting the most common types of muscular dystrophy–those caused by mutations in the dystrophin gene–is far quicker with greater accuracy and sensitivity than existing tests. It can be used to confirm clinical diagnoses, to test female family members who may be carriers, and to perform prenatal testing.

The test was developed by Michael Zwick, PhD, and Madhuri Hegde, PhD, assistant professors in the Department of Human Genetics and the Emory Genetics Laboratory in the Emory University School of Medicine.

Muscular dystrophy includes more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. Some forms are seen in infancy or childhood, while others may not appear until middle age or later. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy and primarily affects boys. It is caused by absence of dystrophin, an important muscle protein involved in maintaining the strength of muscle fibers.

According to the National Institute of Neurodegenerative Diseases and Stroke (NINDS), DMD onset is between 3 and 5 years, with rapid progression. Most boys are unable to walk by age 12 and later need a respirator to breathe. Girls in these families have a 50 percent chance of inheriting and passing the defective gene to their children. Becker muscular dystrophy, which is similar to Duchenne but less severe, results from faulty or not enough dystrophin.

As currently implemented the new test, called EmArray Dystrophin, detects 99 percent of mutations in the dystrophin gene including deletions, duplications and point mutations.

The EmArray Dystrophin test uses a new kind of microarray technology that contains the entire sequence of the dystrophin gene, the largest known gene in humans, on a chip the size of a microscope slide. The test initially detects deletions and duplications, then microarray-based resequencing is used to rapidly identify subtle genetic variations that may cause muscular dystrophy.

The EmArray Dystrophin test confirms clinical diagnosis of Duchenne and Becker muscular dystrophy in a male and characterizes the type and size of the mutation. Women with a family history of Duchenne or Becker who are at risk to be carriers can be tested, then, if found to be carriers, can have prenatal testing.

“Previously, access to prenatal testing was limited for some women when the affected male relative was not available for testing. The EmArray Dystrophin test greatly improves access to prenatal and carrier testing for women without the need to test a male relative, in a rapid timeframe,” according to Vanessa Rangel Miller, MS. In addition to improved testing, the Emory Genetics Laboratory, Parent Project Muscular Dystrophy, leading researchers and clinicians are working together to develop a database for mutations and clinical data.

“Our new genetic test, along with new therapies currently in clinical trials, is a very positive development for muscular dystrophy patients and their families,” says Dr. Hegde.

In the last five years DMD research has accelerated, resulting in more knowledge about the role of the dystrophin gene and an increased understanding about what happens to a muscle cell lacking the dystrophin protein. Researchers around the world are investigating a number of different treatment strategies, all with the goal of slowing or stopping muscle degeneration. Several clinical trials are underway and many others are in development, including testing of an oral medication intended to circumvent mutations in the dystrophin gene and increase normal gene expression.

According to Dr. Hegde, about 13 percent of mutations in the dystrophin gene are nonsense mutations–point mutations in a sequence of DNA that can result in mistakes in gene expression and nonfunctional proteins. New data published online in the current edition of the journal Nature show that PTC124, an investigational new drug designed to bypass dystrophin nonsense mutations and restore a functional protein, was effective in a preclinical (animal) model of Duchenne muscular dystrophy (DMD). (www.clinicaltrials.gov).

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Other treatment for symptoms associated with muscular dystrophy may include physical therapy, respiratory therapy, speech therapy, orthopedic appliances and corrective orthopedic surgery. Drug therapy may include corticosteroids, anticonvulsants, immunosuppressants and antibiotics.

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Place of death shifting for children with complex chronic conditions

Contact: Rachel Salis-Silverman
267-426-6063
JAMA and Archives Journals

It is becoming more common for children with complex chronic conditions to die in their home than in a hospital, although black and Hispanic children with these conditions are less likely to die in their home, according to a study in the June 27 issue of JAMA, a theme issue on chronic diseases of children.

Chris Feudtner, M.D., Ph.D., M.P.H., of Children’s Hospital of Philadelphia, presented the findings of the study at a JAMA media briefing in New York.

Many pediatric palliative care clinicians suggest that the preferred place of death, by the family, of an infant, child, or adolescent with a medically complex chronic condition is the home. Advances in home-based medical technology and changes in attitudes about pediatric palliative care and hospice services may be making this a more viable option, according to background information in the article.

Dr. Feudtner and colleagues conducted a study to determine if the proportion of complex chronic condition-related deaths occurring at home among children and adolescents increased between 1989 and 2003, and to assess if there were any race and ethnicity disparities in the location of death. The researchers analyzed data from the National Center for Health Statistics’ Multiple Cause of Death Files.

Among the 22.1 percent of deaths (198,160 of 896,509 total deaths) attributed to a complex chronic condition between 1989 and 2003, the percentage of deaths occurring at home increased significantly for all age groups (overall, from 10.1 percent in 1989 to 18.2 percent in 2003), but with larger increases for deaths beyond infancy. The odds of death occurring at home increased by 3.8 percent annually.

The percentage of individuals dying at home increased significantly over time for infants (4.9 percent home deaths in 1989 to 7.3 percent in 2003); 1 to 9-year-olds (17.9 percent to 30.7 percent), and 10 to 19-year-olds (18.4 percent to 32.2 percent). During this same period, there was a significant decline in the percentage of deaths occurring in the hospital for each of these three age categories.

The authors suggest that this gradual change in place of death may be occurring because of advances in medical technology in the home setting and broad shifts in attitudes and decision-making processes regarding palliative and end-of-life care in U.S. culture.

The child’s race, ethnicity, and region of home residence were significantly associated with death occurring at home. The odds of dying at home were reduced by 50 percent among black individuals, and reduced by 48 percent among Hispanic individuals, when compared with whites.

Concerning possible reasons for the observed racial and ethnic differences, “ … differential access to health care services or medical technology, divergent cultural attitudes or approaches to palliative and end-of-life care decision making, or differing levels of financial or other support within the patient’s or family’s social network may make dying at home more or less likely.”

“… as efforts to improve understanding of the sources and remedies of racial and ethnic disparities in pediatric end-of-life care are completed, medical and other concerned professionals need to ensure that all patients have access to necessary care and that all dialogue and interactions regarding decisions about care—whether curative, life-extending, or palliative—are built on mutual understanding, trust, and respect,” the authors conclude.

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(JAMA. 2007;297:2725-2732. Available pre-embargo to the media at http://www.jamamedia.org)

Editor’s Note: The conduct of this study was supported in part by grants from the Agency for Healthcare Research and Quality and the National Institute of Nursing Research of the National Institutes of Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

For More Information: Contact the JAMA/Archives Media Relations Department at 312-464-JAMA or email: mediarelations@jama-archives.org.

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Demonic possession and miraculous healing

PA110/07 — June 25 2007

Latest research into health in medieval Europe — taking in everything from demonic possession to miracles of healing — is to be revealed at The University of Nottingham.

Experts from all over the world are gathering at the University to exchange their latest findings on concepts of ‘Health and the Healthy Body’ in early medieval times, 400-1200AD.

Their research focuses on our ancestors’ view of sickness, spiritual healing, diet, disability, burial rituals, exorcism, divine intervention, Hebrew medical manuscripts and Christian concepts of the healthy body.

Scholars of the period are particularly interested in how attitudes and beliefs that originated centuries ago continue to resonate today. Until recently there was very little study of early medieval health and illness – but research findings are already suggesting that it may be time to re-think the way we regard this key aspect of life in the early Middle Ages.

The two-day conference, ‘Disease, Disability and Medicine in Early Medieval Europe’ brings together leading experts in the field from the USA, Norway, Germany, Israel and the UK on July 6-7, 2007.

Co-organiser Dr Christina Lee, of The University of Nottingham’s School of English Studies, said: “I am delighted to host the second workshop at The University of Nottingham. We are working closely with colleagues who look at modern attitudes towards disease and this event will once again be a forum for discussion between disciplines.

“We have to look towards the past to understand the ways in which attitudes towards diseases develop. The success of healing is linked to prevalent cultural views. Ethical codes played a major role in past approaches in dealing with the sick, but today we tend regard most of them as superstition.

“Our own reaction to disease and healing, such as for example the hotly-debated stem cell research, is also linked to contemporary views. By looking at past societies we may be able to understand more about our own attitudes. There is a question of what position the sick and impaired hold within a society or how much illness is accepted as part of life, which may differ from modern views where the prevalent idea is that afflictions should be cured and the expectation that bodies should ‘function’ normally.”

Lectures at the conference include:

· ‘Demon possession in Anglo-Saxon England’, Peter Dendle, Pennsylvania State University, USA. Part of an ongoing study of early medieval demonology and constructs of evil — how prevalent was demonic possession and exorcism and how often did it touch on the day-to-day lives of the Anglo-Saxons?

· ‘Healing from God: physically impaired people in miracle reports’, Klaus-Peter Horn, University of Bremen, Germany. Research focusing on pilgrimages by physically impaired people — and how much help they could receive from relatives, neighbours, servants on the long road to miraculous healing.

· ‘You are what you eat: Christian concepts of the healthy body in Old Norse Society’, Anne Irene Riisoy, University of Oslo, Norway. An overview of the dietary regulations introduced in church legislation in Norway and Iceland, with animals that had been a common feature of the pre-Christian menu — such as horses, cats and dogs — acquiring taboo status.

· ‘”This should not be shown to a gentile”: Medico-magical entries in medieval Franco-German Hebrew manuscripts and their social significance’, Ephraim Shoham-Steiner, Ben-Gurion University, Israel. Includes a discussion of texts detailing short potions, charms and medical remedies in the pages of Hebrew manuscripts.

· ‘Miraculous healing in Medieval Iceland’, Joel Anderson, University of Oslo, Norway. Includes a look at stories of saintly healing miracles and how they were viewed by contemporary Icelandic society, particularly miracles attributed to Bishop Guðmundr Arason ‘the Good’, 1161-1237.

Dr Lee will give a session with the title ‘In good company’, looking at burial patterns of people with disease in Anglo-Saxon England.

Dr Sara Goodacre, of The University of Nottingham, will give a lecture entitled ‘The history of modern Europeans: a genetic perspective’. She will present new data showing geographic trends in patterns of maternally and paternally inherited genetic variation with the British Isles, and what these findings suggest about likely patterns of male and female migration.

The meeting, sponsored by the Wellcome Trust, aims to be a forum for scholars working on the topic in a variety of disciplines and regions of Northern Europe, including all aspects of disease, disability and medicine.

Conference organisers are hoping to build bridges between experts in archaeology, palaeopathology — the study of ancient diseases — the history of medicine, as well as the history of religion, philosophy, linguistic and historical sciences.

The event takes place in the School of English Studies, at The University of Nottingham. It is a collaboration between Dr Lee at Nottingham and Dr Sally Crawford and Robert Arnott, of the University of Birmingham.

Academics wishing to attend should request a registration form from Rebecca Peck in the School of English Studies at The University of Nottingham, before June 30, on: Rebecca.peck@nottingham.ac.uk

— Ends —

Notes to editors: The University of Nottingham is Britain’s University of the Year (The Times Higher Awards 2006). It undertakes world-changing research, provides innovative teaching and a student experience of the highest quality. Ranked by Newsweek in the world’s Top 75 universities, its academics have won two Nobel Prizes since 2003. The University is an international institution with campuses in the United Kingdom, Malaysia and China.

More information is available from Dr Christina Lee, School of English Studies, University of Nottingham, on +44 (0)115 846 7194, christina.lee@nottingham.ac.uk; or Media Relations Manager Tim Utton in the University’s Media and Public Relations Office on +44 (0)115 846 8092, tim.utton@nottingham.ac.uk

The full programme and registration form can de downloaded from: http://www.nottingham.ac.uk/english/conference/ddme.htm

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Type 1 diabetes and heart disease — Heavier may mean healthier

Contact: Michele D. Baum
BaumMD@upmc.edu
412-647-3555
University of Pittsburgh Schools of the Health Sciences

Pittsburgh scientists find more fat equals less coronary artery calcification
CHICAGO, June 23 — Researchers at the University of Pittsburgh Schools of the Health Sciences studying links between an early sign of heart disease called coronary artery calcification and body fat have found that, paradoxically, more fat may have some advantages, at least for people – particularly women – who have type 1 diabetes. Cardiovascular complications, including heart disease, are a leading cause of death for people with diabetes, who tend to suffer cardiovascular disease decades earlier than non-diabetics.

“Gaining weight may reflect good or better treatment with insulin therapy, which may partly explain why participants who gained weight over time had lower mortality rates,” said Trevor Orchard, M.D., professor of epidemiology at the University of Pittsburgh Graduate School of Public Health (GSPH), who is presenting the findings during the 67th annual meeting of the American Diabetes Association. Scientific sessions take place June 22-26 at the McCormick Place Convention Center, Chicago.

For this particular report, Dr. Orchard and his colleagues focused on 315 patients with type 1 diabetes participating in the Pittsburgh Epidemiology of Diabetes Complications Study, an 18-year prospective study of childhood onset type 1 diabetes, which began in 1986. As part of the study, the patients recently received a special computed tomography scan (CT) to assess coronary artery calcification.

The participants’ mean age was 42, and mean duration of diabetes was 34 years. In addition to the CT scan, patients were evaluated for fat underneath the skin and in the abdominal region, body mass index (BMI) and waist circumference. Although investigators noted a positive association for all measures of fatness and having any coronary artery calcification, in the two-thirds of patients who had calcification, the relationship reversed so that people with more fat had less severe calcification.

This association also varied by gender. Women with less fat under the skin had more evidence of coronary artery calcification than those with more fat. Thinner men also had more evidence of coronary artery calcification than men with a higher BMI.

“What it comes down to is a kind of double-edged relationship,” said Baqiyyah Conway, M.P.H., lead author of the abstract, adding that these associations of less severe artery calcification with greater fat persisted even when controlling for standard cardiovascular disease risk factors such as increased levels of LDL, or bad cholesterol, triglycerides, high blood pressure and lower levels of HDL, or good cholesterol. Controlling for kidney disease, another common complication of diabetes, weakened the association in men but not in women.

“This is not a firm recommendation to people with type 1 diabetes to put on weight, but it does raise the possibility that weight recommendations in type 1 diabetes may be somewhat different than those for the general population, and emphasizes the complex relationship between body fat and cardiovascular risk in diabetes,” said Dr. Orchard, who also is professor of medicine and pediatrics at the University of Pittsburgh School of Medicine.

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CONTACT: Amy Dugas, DugasAK@upmc.edu
PHONE: (412) 647-3555

EMBARGOED FOR RELEASE UNTIL 5 P.M., EDT, SATURDAY, JUNE 23

In addition to Dr. Orchard and Ms. Conway, other authors are Rachel G. Miller, M.S.; Tina Costacou, Ph.D.; and Daniel Edmundowicz, M.D., all of the University of Pittsburgh Schools of the Health Sciences.

Founded in 1948 and fully accredited by the Council on Education for Public Health, GSPH is world-renowned for contributions that have influenced public health practices and medical care for millions of people. One of the top-ranked schools of public health in the United States, GSPH was the first fully-accredited school of public health in the Commonwealth of Pennsylvania, with alumni who are among the leaders in their fields of public health. A member of the Association of Schools of Public Health, GSPH currently ranks third among schools of public health in NIH funding received. The only school of public health in the nation with a chair in minority health, GSPH is a leader in research related to women’s health, HIV/AIDS and human genetics, among others. For more information about GSPH, visit the GSPH Web site at http://www.publichealth.pitt.edu.

Note to editors: This presentation is abstract No. 0129-OR, scheduled for 5 p.m., EDT, Saturday, June 23.

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Revealed — Mosquito genes that could be controlling the spread of killer viruses

Contact: Danielle Reeves
danielle.reeves@imperial.ac.uk
44-020-759-42198
Imperial College London

The genes that make up the immune system of the Aedes aegypti mosquito which transmits deadly viral diseases to humans have been identified in new research out today in Science.

The immune system of this mosquito is of great importance as scientists believe it plays a key role in controlling the transmission of viruses that cause yellow and dengue fevers – diseases that infect over 50 million people worldwide every year.

This study is the first of its kind on the newly-sequenced genome of the Aedes aegypti mosquito, which is also published in this week’s Science. The researchers identified over 350 genes which are involved in the Aedes mosquito’s immune system, and discovered that they evolve much faster than the rest of the genes in the genome. Identifying which of these key genes are implicated in the transmission of viral diseases is an area of future research that could lead to new ways of combating these diseases. One possibility would be to affect the activity of the genes and therefore help the mosquitoes fight off the viruses more effectively, preventing transmission to humans.

Imperial College scientists participating in this study established previously that other mosquitoes do have a robust immune system that can either allow or block transmission of malaria parasites. Further research will be needed to ascertain whether some of the newly discovered genes in Aedes may provide a similar defence mechanism that can fight the disease viruses.

Dr George Christophides of Imperial’s Division of Cell and Molecular Biology, senior author on the paper explains: “Our study has revealed the genetic ‘landscape’ made by parts of this mosquito’s newly-sequenced genome which are involved with immunity. By working to understand as much as possible about these genes, and the way they interact with specific pathogens, we hope to gain a more complete understanding of the mechanisms by which a pathogen either survives inside the insect body, or is killed by the insect’s defences.”

The international research team, led by Imperial PhD student Robert Waterhouse, focused on comparing the immunity genes of the Aedes mosquito with similar groups of genes in the harmless fruit fly and the Anopheles mosquito that transmits malaria. When comparing the two different mosquitoes, the scientists found some similarities in the genes controlling their respective immune systems, but also numerous differences. The team aims to discover which of these genetic differences could explain why one type of mosquito transmits dengue and yellow fevers, while the other transmits malaria. Beyond the present descriptive work, functional studies will be needed to clarify exactly how this happens.

“This study made us realise that the immune systems of insects are not static but evolve and differentiate rapidly, most likely in response to the different pathogens which each insect species encounters”, says Dr Christophides.

Professor Fotis Kafatos, senior researcher of Imperial’s immunogenomics lab and co-author of the paper, explains the significance of their study, saying: “Understanding the genetics behind pathogen/immune system interactions in disease vector mosquitoes may help us understand why, for example, some types of mosquitoes can transmit a particular human pathogen while others cannot. If those that cannot have evolved an effective immune system that fights off the pathogen, we may be able to use this knowledge to enhance specific reactions of the immune systems in other mosquitoes to control the spread of the disease.”

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Multifunctional nanoparticle platforms for targeting and imaging cancer cells

Dead on Target

There has been much recent interest in how nanotechnology will impact the field of medicine. Unfortunately, a number of promising nanostructured systems have turned out to be extremely toxic to humans, thus precluding their use in clinical applications and dashing hopes of an early success for the interdisciplinary field of nanobiotechnology. Now a group of researchers at the University of Michigan Nanotechnology Institute for Medicine and Biological Sciences have devised a multifunctional nanoparticle platform comprising nanoparticles synthesized within dendrimers equipped with targeting molecules and dyes. These dendrimer nanoparticle systems are able to seek out and specifically bind to cancer cells.

Xiangyang Shi, Suhe Wang, James R. Baker Jr., and their colleagues have designed dendrimer nanoparticle systems that are stable, water soluble, and biocompatible. The researchers start out by synthesizing gold nanoparticles within amine-terminated dendrimers. Next, dye molecules and a targeting molecule, folic acid, are attached to the ends of the dendrimers. Finally, the remaining amine groups are acetylated to ensure that the complex particles do not bear any surface charges. This last step is especially important to ensure the biocompatibility of these systems and to prevent the nonspecific adhesion of other materials. Molecular dynamics simulations indicate that the folic acid attachments project out into the solvent and are readily available for binding to cells, whereas the dye molecules stay far removed from the metal nanoparticles and thus retain their bright fluorescence.

Many cancer cells, including those implicated in cancers of the ovary, kidney, uterus, testis, brain, colon, and lungs, tend to overexpress folic acid receptors. Owing to the folic acid attachments grafted onto the dendrimer nanoparticles, the dendrimer nanoparticles are seen to latch onto the cancer cells via these folic acid receptors. Since the dendrimer nanoparticles are also equipped with dye molecules, the high concentrations of nanoparticles accumulated in the cancer cells can be imaged by confocal microscopy, and indeed diseased cells can be easily told apart from healthy cells. Further verification comes from electron microscopy experiments. The high contrast provided by the gold nanoparticles allows the determination of the specific sites in the cell machinery where the nanoparticles are attached. Shi pointed out that it should be possible to design dendrimer nanoparticles with other biological ligands such as proteins and antibodies to image and target various biological systems.

“Beyond imaging, it may also be possible to specifically target and destroy cancer cells that internalize the nanoparticles by applying laser heat that intensifies in the presence of gold nanoparticles”, said Wang. “Another possibility is the attachment of drug molecules to these dendrimer nanoparticle systems”, added Baker, “since this will allow the direct delivery of drugs to the target cells”. The researchers are currently conducting further in vivo experiments to evaluate the suitability of this system for clinical applications.

Contact: Xiangyang Shi, University of Michigan, Ann Arbor (USA)

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Paving the way toward a vaccine against Alzheimer’s disease

Contact: Pat Pages
ppages@asbmb.org
301-634-7366
American Society for Biochemistry and Molecular Biology

Bethesda, MD – Scientists have provided new details about how proteins used to destroy bacteria and viruses may help treat Alzheimer’s disease. Gunnar K. Gouras, associate professor of neurology and neuroscience at Weill Medical College of Cornell University, New York, and colleagues provide new insights into how these proteins, called antibodies, reduce the main hallmarks of Alzheimer’s disease and raise hopes for a vaccine against the disease.

“Antibodies are probably the most promising experimental approach to fight Alzheimer’s disease at this time,” Gouras says. “The discoveries made using antibodies are so encouraging that results of ongoing vaccine trials against the disease are much anticipated.”

Alzheimer’s disease, the most common form of dementia, gradually destroys a person’s memory and ability to learn, communicate, and carry out daily activities. According to the American Health Assistance Foundation, more than 4.5 million people in the United States live with the disease and more than 26 million people are affected worldwide. By 2050, the number of people who will suffer from the disease is estimated to nearly triple in the United States and to be four times as high worldwide.

Although no cure for the disease is available yet, scientists are actively looking for new treatments. One of the main goals of such treatments is to destroy clumps of a protein called beta amyloid, which are found in the brains of people with the disease, either inside the nerve cells or around them. Antibodies have been shown to be effective at removing these clumps but how they do it is not completely understood.

In their new study, appearing as the cover story of the June 29 issue of the Journal of Biological Chemistry, Gouras and his colleagues provide new details about how the antibodies attack these clumps inside the nerve cells. The study was selected as a “Paper of the Week” by the journal’s editor, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.

Using cultured cells from mice, the scientists showed that the antibodies first bind to the surface of the cells and connect to a protein called amyloid precursor protein (APP), which is already present on the cell surface. Then both proteins are internalized inside the cell.

Once inside the cell, APP is broken down into pieces, some of which are the amyloid beta proteins. If the antibodies are not present, the proteins start clustering and ultimately kill the cell. The scientists showed that the antibodies prevent this from happening by reducing accumulation of the amyloid beta proteins in vesicles inside the cell called endosomes.

“A lot of research has been done on protein clusters outside nerve cells,” Gouras says. “In this study, we investigated for the first time what happens inside the cells and how antibodies can help prevent clusters from forming.”

The researchers also found that the antibodies helped restore communication between nerve cells. In Alzheimer’s patients, the protein clusters alter parts of the cell surfaces – the synapses – that help nerve cells talk to one another. As a result, thoughts are not transmitted, memory is lost, and new learning is hindered. But Gouras and his team showed that the antibodies cleared the protein clusters and helped cells talk to one another again.

Over the past seven years, research results on the use of antibodies against Alzheimer’s disease have been so promising that two pharmaceutical companies, Ireland’s Elan Corp. and U.S. partner Wyeth, have been conducting clinical trials of a potential vaccine. Although the first trials were stopped when 6 percent of the patients developed encephalitis – an inflammation of brain tissue – other clinical tests on the treated patients have been encouraging. In the second half of this year, the two companies will test a potential drug, called Bapineuzumab, on patients with mild to moderate Alzheimer’s symptoms.

If successful, these trials could result in a new type of vaccine containing antibodies that would directly attack the amyloid beta protein clusters. Unlike common vaccines, which, in this case, would contain pieces of amyloid beta proteins and would stimulate the immune system to produce antibodies, the new vaccine would directly provide the antibodies to patients.

“These new developments are encouraging, but possible side effects may arise,” Gouras says. He adds that although clinical trials need to be conducted as soon as possible to help alleviate the suffering of the increasing number of Alzheimer’s patients, more research is still needed both to understand how amyloid beta proteins wreak havoc in the brain and to improve potential drugs.

Gouras and his colleagues are now trying to figure out how the protein clusters inside and outside the cells work together to destroy the cells. They already noticed that the clusters outside the cells affect those inside cells by making them grow. Another challenge will be to better understand what the clusters do inside the cells that leads to their death. The scientists are also using imaging and biochemical techniques to see, in cultured cells, how the antibodies affect the clusters.

“We have many indications that antibodies work,” Gouras says. “Now we need to understand how they do it.”

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ARTICLE: “Internalized antibodies to the A-beta domain of APP reduce neuronal A-beta and protect against synaptic alterations,” by Davide Tampellini, Jordi Magrane’, Reisuke H. Takahashi, Feng Li, Michael T. Lin, Claudia G. Almeida, and Gunnar K. Gouras

MEDIA CONTACT: Gunnar K. Gouras, Weill Medical College of Cornell University, New York; tel. 212-746-6598; e-mail: gkgouras@med.cornell.edu

The American Society for Biochemistry and Molecular Biology is a nonprofit scientific and educational organization with over 11,900 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions and industry. The Society’s student members attend undergraduate or graduate institutions.

Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society’s purpose is to advance the science of biochemistry and molecular biology through publication of the Journal of Biological Chemistry, the Journal of Lipid Research, and Molecular and Cellular Proteomics, organization of scientific meetings, advocacy for funding of basic research and education, support of science education at all levels, and promoting the diversity of individuals entering the scientific work force.

For more information about ASBMB, see the Society’s Web site at http://www.asbmb.org

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