Melbourne researchers have discovered that the death of immune system cells is an important safeguard against the development of diseases such as type 1 diabetes, rheumatoid arthritis and lupus, which occur when the immune system attacks the body's own tissues.

The finding suggests that these so-called autoimmune diseases could be treated with existing medications that force long-lived immune system cells to die.

In the development of the immune system, some cells are produced that have the potential to attack the body's own tissues, causing autoimmune disease. The death of these 'self-reactive' immune cells through a process called apoptosis is an important safeguard against autoimmune disease.

But Dr Kylie Mason, Dr Lorraine O'Reilly, Dr Daniel Gray, Professor Andreas Strasser and Professor David Huang from the Walter and Eliza Hall Institute, and Professor Paul Waring from the University of Melbourne have discovered that when immune cells lack two related proteins, called Bax and Bak, the cells can attack many healthy tissues, causing severe autoimmune disease. The research is published online January 22 in the journal Proceedings of the National Academy of Sciences.

Bax and Bak are members of the 'Bcl-2 protein family', a large group of proteins that control cell death. Dr O'Reilly said it was thought that Bax and Bak acted like an irreversible switch in cells, determining when cells die by apoptosis. In healthy cells, Bax and Bak are in an 'inactive' form, but when cells are under stress or receive external signals instructing them to die, Bax and Bak switch into an 'active' form that starts the destruction of the cell by apoptosis. Without Bax and Bak, cells are highly protected against apoptosis.

Dr O'Reilly said that some immune cells that lacked the proteins Bax and Bak were able to attack healthy tissues in many organs of the body. "Normally, these 'self-reactive' immune cells are deleted during development," she said. "In the absence of Bax and Bak, enough self-reactive cells survive development to persist in the body and cause autoimmune disease in organs such as the kidneys (glomerulonephritis), similar to what is seen in the most severe form of lupus.

"Our findings confirm that defective apoptosis of immune cells can cause autoimmune disease, and that Bax and Bak are important determinants of immune cell death. We were also interested to see that, in our model, loss of Bak on its own was sufficient to cause autoimmune disease, albeit to a lesser extent than losing both Bak and Bax. This supports a recent discovery that humans with mutations in the BAK gene are predisposed to certain autoimmune diseases."

The research provides hope for people with autoimmune diseases as Bax and Bak activity can be triggered by a new class of potential anti-cancer agents, called BH3-mimetics, which are currently in clinical trials for certain types of leukemia in Melbourne, Dr O'Reilly said. "Our findings suggest that BH3-mimetics might be an exciting new option for treatment for autoimmune conditions, by activating Bax and Bak and making the self-reactive immune cells which are causing the autoimmune disease to die," she said.

Methadone reduces the risk of HIV transmission in people who inject drugs (PWID), as reported by an international team of researchers in a paper published October 5 in the online edition of theBritish Medical Journal. This team included Dr. Julie Bruneau from the CHUM Research Centre (CRCHUM) and the Department of Family Medicine at the University of Montreal.

"There is good evidence to suggest that opiate substitution therapies (OST) reduce drug-related mortality, morbidity and some of the injection risk behaviors among PWID. However, to date there has been no quantitative estimate of the effect of OST in relation to HIV transmission. This new study provides solid evidence demonstrating the link between these treatments and a reduced risk of HIV transmission," notes Dr. Bruneau, one of the six investigators who worked with Dr. Matthew Hickman, the study's principal investigator and Professor in Public Health and Epidemiology at the University of Bristol (UK).

"These results are important given that increases in HIV incidence have been reported among PWID in a number of countries in recent years, where opiate substitution therapies are illegal or severely restricted," adds Dr. Bruneau. 

Injection drug use is a major risk factor for the transmission of HIV and AIDS. It is estimated that around 5-10% of HIV infections worldwide are due to injection drug use. Methadone and buprenorphine are the main forms of drug prescribed for addicts and are frequently prescribed as opiate substitution therapies.

The results of this study are the fruit of an international collaborative effort. Authors from the US, Canada, Italy and Australia carried out a review and pooled analysis (known as a meta-analysis) of several published and unpublished studies from multiple countries (including the USA, Canada, the UK, the Netherlands, Austria, Italy, Thailand, Puerto Rico and China) to determine the association between OST and HIV transmission among PWID. The nine selected studies looked predominantly at males between 26 and 39 years old and totalled 819 incidents of HIV infection with 23,608 person-years of follow-up.

After analysing these studies, authors found that OST was associated with a 54% reduction in risk of HIV infection among PWID. There were differences between the studies, including different background rates of HIV infection, making it impossible to calculate an "absolute risk reduction" for HIV infection that would translate to all settings. And not all studies reported adjustments to the intervention to take account of other factors that might influence the association between OST and HIV infection. But the impact of OST on HIV was strong and consistent in further analyses in the paper. There was weak evidence to suggest that longer duration of OST exposure may be associated with greater benefit.

For Dr. Bruneau, the results of this study favour the promotion of opiate substitution therapies: "These therapies can reduce HIV transmission among PWID not only in countries in which there is a high incidence of this disease, but also in Quebec where there has been an increase in the use of illicit opiates intravenously, particularly among youths, and where access to OST is problematic."

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Scientists have corrected the genetic fault that causes Down's syndrome– albeit in isolated cells – raising the prospect of a radical therapy for the disorder.

In an elegant series of experiments, US researchers took cells from people with DS and silenced the extra chromosome that causes the condition. A treatment based on the work remains a distant hope, but scientists in the field said the feat was the first major step towards a "chromosome therapy" for Down's syndrome.

"This is a real technical breakthrough. It opens up whole new avenues of research," said Elizabeth Fisher, professor of neurogenetics at UCL, who was not involved in the study. "This is really the first sniff we've had of anything to do with gene therapy for Down's syndrome."

Around 750 babies are born with DS in Britain each year while globally between one in a 1000 and one in 1100 births are DS babies. Most experience learning difficulties.

Despite advances in medical care that allow most to live well into middle age, those who have the disorder are at risk of heart defects, bowel and blood disorders, and thyroid problems.

Though a full treatment is still many years off, the work will drive the search for therapies that improve common symptoms of DS, from immune and gastrointestinal problems, to childhood leukaemia and early-onset dementia.

"This will accelerate our understanding of the cellular defects in Down's syndrome and whether they can be treated with certain drugs," said Jeanne Lawrence, who led the team at the University of Massachusetts.

"The long-range possibility – and it's an uncertain possibility – is a chromosome therapy for Down's syndrome. But that is 10 years or more away. I don't want to get people's hopes up."

In a healthy person, almost every cell in the body carries 23 pairs of chromosomes, which hold nearly all of the genes needed for human life. But glitches in the early embryo can sometimes leave babies with too many chromosomes. Down's syndrome arises when cells have an extra copy of chromosome 21.

Lawrence's team used "genome editing", a procedure that allows DNA to be cut and pasted, to drop a gene called XIST into the extra chromosome in cells taken from people with Down's syndrome.

Once in place, the gene caused a buildup of a version of a molecule called RNA, which coated the extra chromosome and ultimately shut it down.

Previous studies found that the XIST gene is crucial for normal human development. Sex is determined by the combination of X and Y chromosomes a person inherits: men are XY, and women are XX. TheXIST gene sits on the X chromosome, but is only active in women. When it switches on, it silences the second X chromosome.

Lawrence's work shows that the gene can shut down other chromosomes too, a finding that paves the way for treating a range of other "trisomy" disorders, such as Edward syndrome and Patau syndrome, caused by extra copies of chromosomes 18 and 13 respectively.

Writing in the journal Nature, the team describes how cells corrected for an extra chromosome 21 grew better, and developed more swiftly into early-stage brain cells. The work, the researchers write, "surmounts the major first step towards potential development of chromosome therapy".

The work is already helping scientists to tease apart how an extra chromosome 21 causes a raft of problems that strike people with Down's syndrome at various ages. "By the time people with Down's syndrome are in their 60s, about 60% will succumb to dementia. One question is, if we could turn off the extra chromosome in adults, would that stop or ameliorate their dementia?" said Fisher. Another approach would cut the risk of leukaemia by silencing the extra chromosome in bone marrow cells.

The US team has already begun work that aims to prevent Down's syndrome in mice, by silencing the extra chromosome 21 in early-stage embryos. "That would correct the whole mouse, but it's not really practical in humans," said Lawrence.

A chromosome therapy for humans would be fraught with practical and ethical difficulties. To prevent Down's syndrome, the genome editing would have to be performed on an embryo or foetus in the womb, and correct most, if not all, of the future child's cells. That is far beyond what is possible, or allowed, today.

The process researchers use to generate induced pluripotent stem cells (iPSCs) -- a special type of stem cell that can be made in the lab from any type of adult cell -- is time consuming and inefficient. To speed things up, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) turned to kinase inhibitors. These chemical compounds block the activity of kinases, enzymes responsible for many aspects of cellular communication, survival, and growth.

As they outline in a paper published September 25 in Nature Communications, the team found several kinase inhibitors that, when added to starter cells, help generate many more iPSCs than the standard method. This new capability will likely speed up research in many fields, better enabling scientists around the world to study human disease and develop new treatments.

"Generating iPSCs depends on the regulation of communication networks within cells," explained Tariq Rana, Ph.D., program director in Sanford-Burnham's Sanford Children's Health Research Center and senior author of the study. "So, when you start manipulating which genes are turned on or off in cells to create pluripotent stem cells, you are probably activating a large number of kinases. Since many of these active kinases are likely inhibiting the conversion to iPSCs, it made sense to us that adding inhibitors might lower the barrier."

According to Tony Hunter, Ph.D., professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies and director of the Salk Institute Cancer Center, "The identification of small molecules that improve the efficiency of generating iPSCs is an important step forward in being able to use these cells therapeutically. Tariq Rana's exciting new work has uncovered a class of protein kinase inhibitors that override the normal barriers to efficient iPSC formation, and these inhibitors should prove useful in generating iPSCs from new sources for experimental and ultimately therapeutic purposes." Hunter, a kinase expert, was not involved in this study.

The promise of iPSCs

At the moment, the only treatment option available to many heart failure patients is a heart transplant. Looking for a better alternative, many researchers are coaxing stem cells into new heart muscle. In Alzheimer's disease, researchers are also interested in stem cells, using them to reproduce a person's own malfunctioning brain cells in a dish, where they can be used to test therapeutic drugs. But where do these stem cells come from? Since the advent of iPSC technology, the answer in many cases is the lab. Like their embryonic cousins, iPSCs can be used to generate just about any cell type -- heart, brain, or muscle, to name a few -- that can be used to test new therapies or potentially to replace diseased or damaged tissue.

It sounds simple enough: you start with any type of differentiated cell, such as skin cells, add four molecules that reprogram the cells' genomes, and then try to catch those that successfully revert to unspecialized iPSCs. But the process takes a long time and isn't very efficient -- you can start with thousands of skin cells and end up with just a few iPSCs.

Inhibiting kinases to make more iPSCs

Zhonghan Li, a graduate student in Rana's laboratory, took on the task of finding kinase inhibitors that might speed up the iPSC-generating process. Scientists in the Conrad Prebys Center for Chemical Genomics, Sanford-Burnham's drug discovery facility, provided Li with a collection of more than 240 chemical compounds that inhibit kinases. Li painstakingly added them one-by-one to his cells and waited to see what happened. Several kinase inhibitors produced many more iPSCs than the untreated cells -- in some cases too many iPSCs for the tiny dish housing them. The most potent inhibitors targeted three kinases in particular: AurkA, P38, and IP3K.

Working with the staff in Sanford-Burnham's genomics, bioinformatics, animal modeling, and histology core facilities -- valuable resources and expertise available to all Sanford-Burnham scientists and the scientific community at large -- Rana and Li further confirmed the specificity of their findings and even nailed down the mechanism behind one inhibitor's beneficial actions.

"We found that manipulating the activity of these kinases can substantially increase cellular reprogramming efficiency," Rana said. "But what's more, we've also provided new insights into the molecular mechanism of reprogramming and revealed new functions for these kinases. We hope these findings will encourage further efforts to screen for small molecules that might prove useful in iPSC-based therapies."

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Ian Dworkin, a zoologist at Michigan State University, was part of the team that first demonstrated why everywhere - from Moose rhinoceros beetles - and other decorative ma-attracting structures are sensitive to changes in diet. As reported in the current issue of the journal Science, a key component of this growth is insulin, Dworkin said.
"Sure elk antlers, peacock tail feathers and beetle horns are very different, but it seems to have similar mechanisms such large structures," he said. "A reduction in insulin levels significantly reduces the size of the ornamental structures."
Sexual selection has roots in Darwin's research. Later research showed that the so-called principle of "handicap", which marked a man loaded with such baggage carrying awkward. Dworkin team believes, however, that part of the image insulin, males are actually striking off. In contrast, insulin dependence of these big horns provides a way for men to show how good they are.
"It's a sign that these men are thriving, some pretty robust and certainly worthy companion," said Dworkin, who led the research at the lighthouse, MSU's National Science Foundation Center for the Study of Evolution in Action.
Dworkin and the team discovered that whenever such exaggerated traits evolve, but repeatedly, but independently of each other, seems to use insulin dependence. This suggests that the properties are more likely to have evolved as honest indicators of quality rather than disadvantages.
"While there is work to be done, our results provide an important way to connect and genetic mechanism with the latest evolution exaggerated trait reason," said Dworkin.

Researchers from Thomas Jefferson University's Kimmel Cancer Center have discovered that decorin, a naturally occurring protein that circulates in the blood, acts as a potent inhibitor of tumor growth modulating the tumor microenvironment.

The study, published June 24 online in the Proceedings of the National Academy of Sciences, suggests it may be possible to harness the power of this naturally occurring anticancer agent as a way to treat cancer, including metastases.

In several different publications it has been described the ability of decorin to affect a number of biological processes including inflammatory responses, wound healing, and angiogenesis.

In this new article, the study's senior investigator, Renato Iozzo, M.D., Ph.D., has labeled decorin a "soluble tumor repressor" -- the first to be found that specifically targets new blood vessels, which are pushed to grow by the cancer, and forces the vessel cells to "eat" their internal components. This reduces their potential to feed the cancer overall causing an inhibition of tumor progression.

"The tumor suppressors we all know are genes inside tumors that a cancer deletes or silences in order to continue growing. I call decorin a tumor repressor because its anti-tumor activity comes from the body, outside the cancer," says Dr. Iozzo, Professor of Pathology & Cell Biology, Biochemistry & Molecular Biology at Kimmel Cancer Center.

"Decorin is a soluble compound that we found has a powerful, natural protective effect against cancer -- an exciting finding that we believe will open up a new avenue for both basic research and clinical application," Dr. Iozzo says. "Acting from the outside of the cells, decorin is able to modify the behavior of the cancer cells and of the normal cells in order to slow down the progression of the tumor. For this reason, decorin acts as a guardian of the matrix, the complicated structure built around the cells in our body."

Absence of decorin promotes tumor growth

Decorin has long been known to be involved in human development. It is so named because deposits of decorin "decorate" collagen fibrils after the human body forms.

A second pool of decorin has been found circulating in blood after production by connective tissue throughout the body. This connective tissue is part of the extracellular matrix, which provides both structural support and biological regulation of tissue cells.

But no one has understood the biological function of this second pool of decorin, according to Dr. Iozzo.

The research team, including the two co-first authors, Simone Buraschi, Ph.D., and Thomas Neill, a graduate student, who work in the laboratory of Dr. Iozzo, decoded the function of soluble decorin. They found that addition of exogenous decorin to the tumor microenvironment induces autophagy, a mechanism by which cells discard unnecessary or damaged intracellular structures. "This process regulates a lot of cellular activities," says Dr. Iozzo.

The researchers specifically found that decorin evoked autophagy in both microvascular and macrovascular endothelial cells -- cells that line the interior surface of blood vessels.

"This matters because autophagy can exert a potential oncosupressive function by acting to discard critical cell components that would otherwise be involved in promotion of tumor growth through angiogenesis, the production of new blood vessels that can provide nutrition to the tumor," Dr. Iozzo says. "In contrast, absence of decorin permits tumor growth."

Therefore, the presence of decorin in the surroundings of the tumor is essential to control tumorigenesis and formation of new blood vessels, he says. Moreover, Dr. Iozzo's laboratory has characterized for the first time Peg3, a known tumor-suppressor gene, as a master player in the autophagy process induced by decorin. "This discovery is important as it opens up to the study of new unexplored genes and signaling pathways in the field of autophagy," he says. 

"Circulating decorin represents a fundamental cellular process that acts to combat tumor angiogenesis," Dr. Iozzo says. "Treatment based on systemic delivery of decorin may represent a genuine advance in our ongoing war against cancer."

The study was funded by the National Institutes of Health grants R01 CA39481, R01 CA47282, and R01 CA120975.

Collaborating researchers from LifeCell Corporation, in Branchburg, New Jersey, and Goethe University in Frankfurt, Germany, also contributed to the study.

Scientists at Karolinska Institutet in Sweden, in collaboration with colleagues in Germany and the Netherlands, have identified a previously unknown group of nerve cells in the brain. The nerve cells regulate cardiovascular functions such as heart rhythm and blood pressure. It is hoped that the discovery, which is published in the Journal of Clinical Investigation, will be significant in the long term in the treatment of cardiovascular diseases in humans.

The scientists have managed to identify in mice a previously totally unknown group of nerve cells in the brain. These nerve cells, also known as 'neurons', develop in the brain with the aid of thyroid hormone, which is produced in the thyroid gland. Patients in whom the function of the thyroid gland is disturbed and who therefore produce too much or too little thyroid hormone, thus risk developing problems with these nerve cells. This in turn has an effect on the function of the heart, leading to cardiovascular disease.

It is well-known that patients with untreated hyperthyroidism (too high a production of thyroid hormone) or hypothyroidism (too low a production of thyroid hormone) often develop heart problems. It has previously been believed that this was solely a result of the hormone affecting the heart directly. The new study, however, shows that thyroid hormone also affects the heart indirectly, through the newly discovered neurons.

"This discovery opens the possibility of a completely new way of combating cardiovascular disease," says Jens Mittag, group leader at the Department of Cell and Molecular Biology at Karolinska Institutet. "If we learn how to control these neurons, we will be able to treat certain cardiovascular problems like hypertension through the brain. This is, however, still far in the future. A more immediate conclusion is that it is of utmost importance to identify and treat pregnant women with hypothyroidism, since their low level of thyroid hormone may harm the production of these neurons in the fetus, and this may in the long run cause cardiovascular disorders in the offspring."

The study has been financed with grants from the European Molecular Biology Organisation, Deutsche Forschungsgemeinschaft, the Fredrik and Ingrid Thuring Foundation, Karolinska Institutet Foundation, the American Thyroid Association, the Swedish Research Council, the Swedish Cancer Society, the Söderberg Foundations, the Swedish Heart-Lung Foundation, the Netherlands Organization for Health Research and Development, and the Ludgardine Bouwman Foundation.