Elderly care needs 'set to treble'

19 September 2013 Last updated at 15:33 ETBy Tulip Mazumdar Global health reporter

Care needs can put huge pressure on families

The number of older people needing care is set to nearly treble globally by 2050, campaigners say.

Currently 101 million people require care, but a report from Alzheimer's Disease International warns the figure will rise to to 277 million.

Many needing care have dementia, and the report warns there will be a "global Alzheimer's epidemic".

The report's author said countries like India and China would be hard hit - and must start planning services now.

Alzheimer's is the most common cause of dementia. Symptoms include loss of memory, mood changes, and problems with communicating and reasoning.

More than 35 million people live with dementia across the world, according to the World Health Organization. More than half are living in low and middle income countries.

The report reveals that as the world population ages, the traditional system of informal care by family, friends and the community will need much greater support.

Just over one in 10 people aged 60 or over needs long-term care, according to the report. This includes daily help with things like washing, eating, dressing and using the toilet.

It can put huge pressure on families. Carers often have to give up work to look after elderly relatives.

'Older people left behind'

Treating and caring for people with dementia currently costs the world more than ￡376bn per year. That includes the cost of health and social care as well as the loss of earnings.

Prof Martin Prince, from King's College London's Institute of Psychiatry, the author of the report, said lower and middle income countries including India and China need to urgently start planning services to deal with the "epidemic".

"The social and economic changes happening in those countries are inevitably going to mean that family carers will be less available.

"Things like the decline in fertility rates mean people are going to have fewer children.

"Women are also better educated so are more likely to join the paid workforce and are going to be less likely to be available to provide care."

And he said an increase in migration between countries, and from rural to urban areas amongst younger people meant there would be a lot of older people "left behind".

The report makes a range of recommendations including giving paid and unpaid carers "appropriate financial rewards" and monitoring the quality of care both in care homes and in the community.

A spokesperson for the Alzheimer's Society in the UK said: "Dementia is the biggest health crisis facing the world today.

"This report is a wake-up call to governments across the world about the immediate need to put in place more care and support.

"The UK government's G8 summit on dementia this year will be a key opportunity to rally support from world leaders to tackle dementia together. We need to see political leadership to avoid a spiralling global crisis," the spokesperson added.

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'Cascade of events' caused sudden explosion of animal life

Sep. 19, 2013 — The explosion of animal life on Earth around 520 million years ago was the result of a combination of interlinked factors rather than a single underlying cause, according to a new study.

Dozens of individual theories have been put forward over the past few decades for this rapid diversification of animal species in the early Cambrian period of geological time.

But a paper by Professor Paul Smith of Oxford University and Professor David Harper of Durham University suggests a more holistic approach is required to discover the reasons behind what has become known as the Cambrian Explosion.

Theories for the Cambrian Explosion fall into three main categories -- geological, geochemical and biological -- and most have been claimed as standalone processes that were the main cause of the explosion.

Whatever the cause, this major evolutionary event led to a wide range of biological innovation, including the origin of modern ecosystems, a rapid increase in animal diversity, the origin of skeletons and the first appearance of specialist modes of life such as burrowing and swimming.

Among the weird and wonderful creatures to emerge in the early Cambrian was Anomalocaris, the free-swimming, metre-long top predator of the time with a mouth composed of 32 overlapping plates that could constrict to crush prey. It is distantly related to modern arthropods, including crabs and lobsters.

Vertebrate animals also made their first appearance in the Cambrian Explosion, the distant ancestors of modern fish, reptiles, birds and mammals.

Professor Smith, Professor Harper and a team of scientists have spent four years working on data from a site in northernmost Greenland, facing the Arctic Ocean.

The site, at Siriuspasset, is located at 83°N, just 500 miles from the North Pole in a remote part of north Greenland. Although logistically very difficult to reach, Siriuspasset attracted the team because of the high quality of its fossil material and the insights it provides.

Professor Smith and Professor Harper's findings are published in the latest edition of the journal Science.

Professor Smith, lead author of the report and Director of the Oxford University Museum of Natural History, said: 'This is a period of time that has attracted a lot of attention because it is when animals appear very abruptly in the fossil record, and in great diversity. Out of this event came nearly all of the major groups of animals that we recognise today.

'Because it is such a major biological event, it has attracted much opinion and speculation about its cause.'

Described by the researchers as a 'cascade of events', the interacting causes behind the explosion in animal life are likely to have begun with an early Cambrian sea level rise. This generated a large increase in the area of habitable seafloor, which in turn drove an increase in animal diversity. These early events then translate into the complex interaction of biological, geochemical and geological processes described in individual hypotheses.

Professor Harper, Professor of Palaeontology in the Department of Earth Sciences at Durham University, said: 'The Cambrian Explosion is one of the most important events in the history of life on our planet, establishing animals as the most visible part of the planet's marine ecosystems.

'It would be naive to think that any one cause ignited this phenomenal explosion of animal life. Rather, a chain reaction involving a number of biological and geological drivers kicked into gear, escalating the planet's diversity during a relatively short interval of deep time.

'The Cambrian Explosion set the scene for much of the subsequent marine life that built on cascading and nested feedback loops, linking the organisms and their environment, that first developed some 520 million years ago.'

Professor Smith said: 'Work at the Siriuspasset site in north Greenland has cemented our thinking that it wasn't a matter of saying one hypothesis is right and one is wrong. Rather than focusing on one single cause, we should be looking at the interaction of a number of different mechanisms.

'Most of the hypotheses have at least a kernel of truth, but each is insufficient to have been the single cause of the Cambrian explosion. What we need to do now is focus on the sequence of interconnected events and the way they related to each other -- the initial geological triggers that led to the geochemical effects, followed by a range of biological processes.'

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New insights into the ribosome; important implications for disease

Sep. 19, 2013 — In molecular biology, the ribosome represents the machinery necessary to assemble proteins, the building blocks of life. In this process, information encoded in the genome's DNA is first transcribed to messenger RNA in the nucleus, then transported to the ribosome where protein-assembly instructions are put in motion to translate the code into actual proteins.

But in recent years, it has been demonstrated that the ribosome is far more than just a processing unit; indeed, current research points to an important role for this complex structure in actively regulating biological processes.

Now, in a first-of-its-kind study that broadly examines the composition of the riboproteome, a scientific team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) reveals previously unappreciated components of the ribosome, uncovering a large and dynamic structure that, among other things, can be altered in cancer. Published in today's on-line issue of the journal Cell Reports, the study additionally describes the development of an analytic platform that can be widely applied to numerous biological systems to highlight the functional roles of possible disease genes associated with the riboproteome.

"A primary goal of our lab is to gain a better understanding of translation and its impact on cancer," explains senior author Pier Paolo Pandolfi, MD, PhD, Scientific Director of the Cancer Center at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School (HMS). "So a key focus of our work has been the role of the ribosome. While the conventional wisdom has been that ribosome composition is absolutely fixed, we have recently pursued the hypothesis that it is, in fact, flexible and dynamic. Moreover, it has become apparent during the course of our investigations that the functional deregulation of the ribosome is implicated in disease initiation and progression, and could serve as a potential target for therapeutic intervention."

In this new study, a scientific team led by Pandolfi lab members John Clohessy, PhD, and Markus Reschke, PhD, examined the ribosome on a large scale to get a clearer picture of the relationship and interactions between ribosomes and the associated proteins required for efficient and correct translation of messenger RNA (mRNA).

"We wanted to find out what was happening in the ribosome on a global scale," explains Clohessy. "So we incorporated into our analysis those proteins that associate with either the ribosome itself or with the mRNA being translated, and which could represent important regulators of translation."

Until recently a lack of high-throughput ribosomal analysis has limited researchers' abilities to characterize the ribosomal proteome, which consists of the ribosome itself and a host of other proteins that interact with this cellular machine to regulate translation. In this new study, the scientists optimized and adapted a SILAC-based mass spectrometry approach to probe this complex microscopic structure through the analysis of far more data than was ever available before.

An acronym for stable isotopic labeling by amino acids in cell culture, SILAC utilizes non-radioactive isotope labeling to detect quantitative differences in protein abundance among cell samples. "A SILAC-based approach offers an elegant way of comparing two different cellular populations," explains Reschke. "The metabolic incorporation into the proteins of amino acids that have been differentially labeled with carbon and nitrogen isotopes results in a mass shift of the corresponding peptides, and it is this shift that can be detected by a mass spectrometer.

"The beauty of this system is that you're keeping the cells in their natural environment, you're simply substituting one amino acid with another," he adds. "This enables you to conduct a direct comparison without other chemical modifications."

Using a panel of cell lines, as well as genetic and pharmacological perturbations, the team embarked on their characterization of the prostate riboproteome. "Mass spectrometry enabled us to look at thousands of proteins at the same time," explains Clohessy. Through SILAC-based mass spec, the investigators were able to gain the first comprehensive overview of proteins within this space and examine how the riboproteome is altered in disease.

"We compared a number of different things," adds Clohessy. "We compared different cancer cell lines. We looked at changes to the riboproteome within a single specific cell line, both with and without use of a pharmacological inhibitor. And, we looked at a cell line in the context of genetic alteration. We essentially got a clear snapshot of which proteins were in this space at any particular time, and saw how they responded to cellular signals and stresses."

The authors then carried out a computational analysis on this extensive dataset to determine if there were specific protein networks or pathways that were highly represented in the data. Their survey revealed a number of exciting and surprising findings -- with important therapeutic implications.

"Among other things, our analysis uncovered a high incidence of genetic alterations to the riboproteome components in cancer, with a distinct bias towards genetic amplification, [whereby cells accumulate multiple copies of genes which can support cancer growth and survival]" explains Reschke, adding that it also revealed the presence of a significant population of RNA binding proteins (RBPs), important regulators of mRNA translation, some of which are also associated with disease.

"Changes in ribosome amounts have been shown to be associated with cancer for more than a century," notes Nahum Sonenberg, PhD, James McGill Professor of Biochemistry at McGill University. "However, the mechanism that links ribosomes and cancer is not well understood. This paper from the Pandolfi laboratory is a very important step towards the understanding of the full gamut of functions of the ribosome and its associated translation mRNA machinery in cancer."

This novel method additionally opens up a new direction in terms of how to study the ribosome in the context of both disease and therapy. "By now, we know a lot about the genes and pathways that converge on translation, and many of them are well-known oncogenes, including MYC and PI3K," explains Pandolfi. 'But the translational dimension we are now describing offers a new perspective on yet another layer of proteins that seem to be amplified in cancer. These findings provide us with a completely new set of proteins that may be used to better understand the process of translation in cancer, and help identify new targets for therapeutic intervention."

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A genome-forward approach to tackling drug-resistant cancers

Sep. 19, 2013 — If you really want to understand why a particular human cancer resists treatment, you have to be able to study that tumor -- really study it -- in a way that just isn't possible in humans. Cancer biologists have been developing a new approach to this challenge, by transplanting human cancers directly from patients to mice whose crippled immune systems will allow those human tissues to grow. According to research published in the Cell Press publication Cell Reports on September 19th, this new approach permits analysis of human cancer in unprecedented detail. The new work shows that those transplanted cancers, known as PDX (for patient-derived xenografts), are very good genomic replicas of the original at every level of analysis.

Overall, the PDX approach promises to speed the development of new drugs along with doctors' ability to make more precise choices about how those drugs are used to treat patients, the researchers say.

"The development of precision pharmacology is clearly the current focus in PDX research," said Matthew Ellis of Washington University in St Louis. "Human testing is hugely expensive, and often the response rates for the patients on experimental drugs are low because the biology of each patient is not well defined. Panels of clinically and genomically annotated PDX can therefore be very valuable for studying drug action and developing predictive biomarkers. Extensive pre- and post-drug sampling can be conducted to study drug effects and drug resistance in a way that would be impossible in the clinical setting."

In the new study, Ellis and his team transplanted drug-resistant human breast cancers into mice and then made very detailed comparisons of those transplanted tumors versus the originals.

The researchers' deep whole-genome analyses showed a high degree of genomic fidelity. In other words, the complex human tumor tissues in the mice looked very much like those in the people they originally came from. While some new mutations did arise after transplantation, those genetic changes rarely had functional significance.

The researchers were surprised to discover that the original and PDX cancers were similar at the cellular level as well. Cancer cells carrying mutations that were relatively rare in the patient were also maintained at lower frequencies in the mice. Likewise, more dominant clones in the original tumor tended to stay dominant in the mice. This suggests that the frequency of genetically distinct tumor cells is in an equilibrium that survives transplantation into mice for reasons that aren't yet clear.

An analysis of multiple estrogen receptor-positive PDX from patients with endocrine therapy-resistant disease shows just how this approach can yield tumor-specific explanations for therapy resistance. Resistant tumors were associated with different kinds of alterations to the estrogen receptor gene ESR1, the researchers found, producing different responses to endocrine therapy.

"The prevalence of ESR1 mutations and gene arrangements in the luminal PDX was a deep surprise to me as I thought these events were rare," Ellis said. "There had been very sporadic reports of ESR1 point mutations in clinical samples over the years, but to find them at high prevalence in the PDX and therefore in a setting where the link to endocrine therapy resistance can be directly studied was, for me, a critical breakthrough in our understanding of this critical problem."

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Cutting off all points of escape for melanoma cells

Sep. 19, 2013 — Despite the success of recent approved therapeutics to treat advanced melanoma, metastatic cancer cells inevitably evolve resistance to drugs. In the journal Cell Reports, a team of researchers based at The Wistar Institute, report on the mechanics by which melanoma can evolve resistance to a powerful combination of drugs -- BRAF and MEK inhibitors.

They found that resistant melanomas acquired a mutation in the MEK2 gene and multiple copies of the mutant BRAF oncogene, simultaneously decreasing the sensitivity to both drug targets. Their findings also uncovered a new potential target for melanoma therapy, a protein called S6K. Additionally, early studies in a laboratory model for melanoma show that a triple combination of drug inhibitors halted the growth of resistant tumors.

"Melanoma tumors are particularly adept at rewiring themselves so that anticancer drugs lose their effectiveness, and we must continue to outthink the disease in order to block off all points at which it can evade therapy," said Jessie Villanueva, Ph.D., assistant professor in Wistar's NCI-designated Cancer Center and member of The Wistar Institute Melanoma Research Center. "There are currently therapeutics available that can block the pathway that leads to S6K, but we are also interested in developing inhibitors to S6K itself."

Melanoma is the deadliest, most aggressive form of skin cancer. While surgical treatment of early-stage melanoma leads to 90 percent cure rates, advanced melanoma is notoriously resistant to chemotherapy and has a tendency to metastasize, or spread, throughout the body. According to the World Health Organization, cases of the disease continue to rise internationally, which has helped spur research into therapies such as BRAF and MEK inhibitors.

BRAF inhibitors were developed in response to discoveries that a specific mutation in the BRAF gene was responsible for nearly 50 percent of melanoma cases. The BRAF protein is part of the MAP kinase pathway, a chain of enzymatic reactions -- including the enzyme MEK -- that is commonly over-activated in cancers.

"Combining BRAF and MEK inhibitors was conceived as a one-two punch against the MAP kinase pathway," Villanueva said, "and while it is considered successful in the clinic, some tumors do not respond and others develop resistance, underscoring the need for new therapeutic strategies."

As cancer clinicians began to see patients develop resistance to BRAF and MEK inhibitors, the Wistar team began to explore the mechanisms by which tumors develop resistance. They found that melanoma cells used different tactics for each enzyme. Mutations in MEK2, for example, would render anti-MEK therapies ineffective. To defeat BRAF inhibitors, surviving melanoma cells exhibited numerous copies of the mutant BRAF gene, enough to overpower anti-BRAF drugs.

"There were simply too many copies of BRAF to block, it became a numbers game and the mutation was winning," Villanueva said. "Increasing the dosage of BRAF inhibitors could be one solution, but that cannot be done in patients without causing serious toxic effects."

A possible answer, they reasoned, was in the PI3K/mTOR pathway, a network of signaling enzymes often active within melanoma cells. However, they could find no sign that any of the "usual suspects" -- points along the pathway commonly known to be involved in cancers -- had any evident part in BRAF/MEK resistance. It was not until they examined farther "downstream" that they found persistent activation of S6K, an enzyme that appears to be at the point where P13K/mTOR and MAP kinase pathways merge.

So the researchers tried combinations of inhibitors against BRAF, MEK and PI3K/mTOR (as there are currently no effective S6K inhibitors) in a mouse model of melanoma. "With a triple combination of drugs, the tumors slow down and just stop growing," Villanueva explained.

Although a cocktail of two drugs (a combination of BRAF and PI3K/mTOR inhibitors, for example) might work, they postulated that using three drugs could be more potent and counter intuitively less toxic at the same time. "We followed these mice with melanoma for three weeks, tumors remain stable, and mice did not show any evident signs of toxicity, " Villanueva said

"For patients, it is not a simple matter of introducing triple combination therapies into use," Villanueva said, " but now we have a mechanism and a rational approach to develop both new drugs and more effective combinations aimed at solving drug resistance in melanoma. Our findings might also offer important lessons for other forms of metastatic cancer."

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Navy Yard shooter seemed to aim at random, FBI chief says

By David Ingram and Ian Simpson

WASHINGTON (Reuters) - The contract worker who opened fire at the Washington Navy Yard this week appeared to have no particular target as he moved through a building and shot and killed 12 people, FBI Director James Comey said on Thursday.

Comey, whose agency is leading the investigation into the shooting, said that in surveillance video the man identified as 34-year-old Aaron Alexis "appears to be moving without particular direction or purpose."

Thousands of workers streamed back into the Washington Navy Yard on Thursday, three days after Alexis, a former reservist working at the site as a contractor, opened fire with a shotgun as he wandered several floors and hallways.

The sprawling, walled complex, which covers about 16 blocks of the U.S. capital, had been closed to all but essential personnel and those involved in the investigation into why Alexis, who died in a gun battle with police, mounted his attack.

Three people were wounded and one, a woman shot in the head and hand, was discharged on Tuesday, MedStar Washington Hospital Center said in a statement. The other two, a Washington police officer with leg wounds and a woman shot in the shoulder, are in good condition, it said.

Comey told reporters in a briefing at FBI headquarters that he would not comment on a possible motive for the shooting but said investigators continued to examine evidence, including Alexis' mental condition.

It was not clear how Alexis hid the shotgun that was his primary weapon, Comey said. Video shows Alexis entering a bathroom on the building's fourth floor with a bag and then emerging with the shotgun, but investigators do not know if the shotgun was disassembled, he said.

"The shotgun was cut down at both ends," Comey said. "The stock was sawed off, and the barrel was sawed off a little bit."

Alexis also fired a semi-automatic pistol that he took from a security guard he shot, Comey said. Alexis died after exchanging gunfire with law enforcement officers, about 30 minutes after he began shooting.

Alexis, a U.S. Navy Reserves veteran, entered the base on Monday with a security clearance that allowed him onto military facilities to work as an information technology contractor.

He had been working on a computer server project in the same building where he launched the attack, Comey said.

HEARD VOICES

The Department of Veterans Affairs said on Wednesday that Alexis was treated for insomnia in August at hospitals run by the VA, but that he said he did not have violent thoughts and did not seek care from a VA mental health specialist.

His credentials were still valid, although Rhode Island police had warned the Navy in August that Alexis had reported "hearing voices" and said he believed people were following him and "sending vibrations into his body," according to a Newport police report.

A senior Navy official said on Thursday the service was reviewing why that report had not been shared more widely.

"We don't have any indications that the reports from the Newport police went any higher than the local base security officers there at Newport," Rear Admiral John Kirby, Navy chief of information, told CNN.

"We're taking a hard look at that as well to see why that report didn't go any higher and what should have been done better to make authorities at a higher level than their base security aware of it," Kirby said.

The attack was the second mass shooting on a military base inside the United States in four years. In November 2009, a gunman killed 13 people and wounded 32 at the Fort Hood Army base in Texas.

That shooter, Major Nidal Hasan, said the attack was intended as retaliation for U.S. wars in the Muslim world. Last month a military jury sentenced him to death.

Both incidents shed light on a security conditions within military installations, where military personnel other than security forces are typically prohibited from carrying firearms.

After Monday's attack, Defense Secretary Chuck Hagel ordered a worldwide review of security at U.S. military installations.

The same company that scrutinized former spy agency contractor Edward Snowden for a U.S. government security clearance said on Thursday it also checked the background of Alexis, allowing him to obtain a "secret" clearance.

USIS, working as a contractor for the Office of Personnel Management (OPM), conducted a background review of Alexis in 2007, but declined to provide more information on the grounds that it was contractually barred from retaining case data from such checks.

Earlier this year, USIS became the focus of congressional scrutiny when it was disclosed that the company handled the background investigation of Snowden, accused of disclosing top secret materials taken from the National Security Agency facility where he worked.

USIS does about 65 percent of all background check investigations conducted by government contractors and more than half of those conducted by the OPM, according to Senator Claire McCaskill, who heads the Senate Subcommittee on Financial and Contracting Oversight.

"From Edward Snowden to Aaron Alexis, what's emerging is a pattern of failure on the part of this company, and a failure of this entire system, that risks nothing less than our national security and the lives of Americans," McCaskill said in a statement on Thursday.

USIS has been undergoing an investigation by OPM's inspector general since before the Snowden and Alexis incidents. OPM's inspector general's office had no comment.

Washington Navy Yards, on the Anacostia River, was established in 1799 as a shipbuilding site and a base for defending the city. The complex houses the Naval Sea Systems Command, as well as a human resources operation for Navy civilian workers and a museum and art gallery.

(Reporting by David Ingram and Ian Simpson; Editing by Karey Van Hall and Eric Walsh)

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TV pitchman Trudeau released after day in jail

By Lisa Maria Garza

(Reuters) - Infomercial pitchman Kevin Trudeau was released from a Chicago jail on Thursday, a day after a federal judge ordered him locked up for failing to pay $38 million in fines over allegedly false promises made in a weight-loss book.

The Federal Trade Commission sued Trudeau, now 50, in 1998, determining that he made misleading claims in six infomercials he produced promoting products that allegedly cured ailments ranging from cancer to memory loss.

In 2004, Trudeau entered a consent order with the FTC that required him to pay $2 million and banned him from advertising products in infomercials.

An exception allowed Trudeau to advertise books, but not the products he touted as cures. The FTC argued that his weight loss book include inaccurate information and violated the agreement.

In 2008, Judge Robert Gettleman ruled Trudeau violated the terms of the settlement with his book promoting "easy" weight-loss techniques such as prescription hormone therapy, colon hydrotherapy and a 500-calorie-a-day diet. He was ordered to pay nearly $38 million, an amount based on the number of books sold.

Trudeau, whose marketing business is based in Chicago, has repeatedly insisted that he is broke and cannot pay the fine.

Federal Trade Commission lawyers on Wednesday presented evidence to demonstrate that Trudeau recently spent thousands of dollars on haircuts, liquor, cigars and high-end meat products.

Gettleman ordered him to be locked up overnight on Wednesday and to meet with a court-ordered receiver on Thursday.

The Chicago Sun-Times reported the federal judge warned Trudeau on Thursday that he's on a "tight leash" and could be jailed again at his scheduled court appearance next week if he is not truthful about his financial assets.

Trudeau has battled federal regulators over his marketing of "cures" for AIDS, hair loss, memory loss and obesity.

(Reporting By Lisa Maria Garza; Editing by Sharon Bernstein and Stacey Joyce)

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New protein knowledge offers hope for better cancer treatment

Sep. 19, 2013 — When the pharmaceutical industry develops new medicines -- for example for cancer treatment -- it is important to have detailed knowledge of the body's molecular response to the medicine.

"With a better knowledge of the many complex processes which are activated in connection with illness and medication, the better the possibility of developing new drugs. We have now moved closer to targeting and treating certain cancers using the so-called PARP inhibitors -- medical inhibitors used in the latest types of cancer treatment. Certain types of tumours rely heavily on PARP proteins in order to self-repair, and PARP inhibitors can be used specifically to kill cancer cells," says Michael Lund Nielsen, Associate Professor at The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

The researchers have developed an advanced method for identifying the proteins which are modified with ADP-ribosylation -- a biological modification affecting a cell's ability to repair DNA damage. The research findings have just been published in the scientific journal Molecular Cell.

The forms of cancer causing most deaths among women are lung cancer, breast cancer, colon cancer, pancreatic cancer and ovarian cancer. PARP inhibitors appear to be an effective treatment for hereditary breast and ovarian cancer, but little is known about the treatment details. Our new analysis method can help shed light on precisely how the PARP inhibitor treatment is working because it can offer us more knowledge about the biological function of PARP proteins. In the long term, it will enable us to design better and more precise PARP inhibitors, says Michael Lund Nielsen, Associate Professor at the Novo Nordisk Foundation Center for Protein Research.

DNA repair crucial for cell health

Every day, our DNA is exposed to damage which our healthy cells are capable of repairing and thus keep healthy. But the ability of certain cancer cells to repair their own DNA damage is impaired compared to standard cells and this is exploited using PARP inhibitors which block the repair systems of cancer cells. In principle, PARP inhibitors both damage healthy and cancer cells, but normal cells have different survival mechanisms in comparison to cancer cells. PARP inhibitors therefore appear to offer new and much improved cancer treatment options.

Treatment with PARP inhibitors

PARP treatment is a new and individualised type of cancer treatment. It is a so-called targeted treatment which exploits a weakness inherent in cancer cells. PARP inhibitors have yet to be marketed, but many companies are testing them in clinical (phase 1-3) trials. So far, the PARP inhibitors are only available for experimental purposes.

"Our analysis method makes it possible to map the movement of PARP inhibitors, opening up possibilities for the optimised treatment of breast and ovarian cancers with fewer side effects. It is also being examined whether PARP inhibitors can be used in combination with chemotherapy and/or radiation therapy in connection with other cancers. In particular, radiation therapy produces many unpleasant side effects, but there are indications that optimised treatment could be achieved by combining radiation therapy with PARP inhibitors, as PARP inhibitors make cancer cells more susceptible to radiation therapy," says Michael Lund Nielsen.

Using radiation and chemical compounds, the researchers started by damaging the DNA in cells. They then isolated proteins modified with the ADP-ribosylation and identified them using mass spectrometry, a technique making it possible to determine a protein's identity and the sites where the ADP-ribosylation chemical changes occur.

ADP-ribosylation

ADP-ribosylation is a biological protein modification controlling several key cellular processes, such as the repair of DNA damage. Every day, our DNA suffers damage between one thousand and one million times and it is therefore crucial that the cells can repair their DNA. Certain cancer cells are incapable of self-repair without ADP-ribosylation and this can be exploited for targeted cancer treatment via PARP inhibitors. By inhibiting the PARP proteins that perform ADP-ribosylation, it is thought that these cancer cells are prevented from self-repair and will therefore perish.

PARP and PARP inhibitors

PARP is a group of DNA repair proteins that play an important role in some cancers as certain types of tumours are highly dependent on PARP in order to repair themselves. These tumours are therefore vulnerable to targeted treatment using PARP-inhibiting compounds. PARP inhibitors block the DNA repair system of cancer cells, but few details are known about the molecular aspects surrounding the PARP inhibitors, including which proteins are affected by them. The researchers' new analysis method makes it possible to map the movement of PARP inhibitors, which enables optimised treatment with fewer side effects.

Protein modifications

Proteins are chain-shaped biological macromolecules built up of amino acids. The cells are predominantly controlled by proteins, and many of the characteristics of the protein functions are controlled by, among others, molecular modifications that can be attached to amino acids. Functions that are controlled by protein modifications include: the localisation of proteins at specific locations in the cell, the marking of proteins for degradation and the turning on/off of the biological activity of the protein. Studies of the modifications that proteins contain are therefore important for understanding a wide range of cellular processes.

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Warning of three-person IVF 'risks'

19 September 2013 Last updated at 15:10 ETBy James Gallagher Health and science reporter, BBC News

Concerns about the safety of a pioneering therapy which would create babies with DNA from three people have been raised by researchers.

The advanced form of IVF could eliminate debilitating and potentially fatal mitochondrial diseases.

Writing in the journal Science, the group warned that the mix of DNA could lead to damaging side effects.

The expert panel which reviewed the safety of the technique said the risks described would be "trivial".

The UK is leading the world in the field of 'mitochondrial replacement'. Draft regulations to allow the procedure on a case-by-case basis will be produced this year and some estimate that therapies could be offered within two years.

Power source

Mitochondria are the tiny, biological "power stations" that provide nearly every cell, which make up the body, with energy. They are passed from a mother, through the egg, to her child.

But if the mother has defective mitochondria then it leaves the child starved of energy, resulting in muscle weakness, blindness and heart failure. In the most severe cases it is fatal and some families have lost multiple children to the condition.

The proposed therapy aims to replace the defective mitochondria with those from a donor egg.

Continue reading the main story

1) Two eggs are fertilised with sperm, creating an embryo from the intended parents and another from the donors 2) The pronuclei, which contain genetic information, are removed from both embryos but only the parents' is kept 3) A healthy embryo is created by adding the parents' pronuclei to the donor embryo, which is finally implanted into the womb

1) Eggs from a mother with damaged mitochondria and a donor with healthy mitochondria are collected 2) The majority of the genetic material is removed from both eggs 3) The mother's genetic material is inserted into the donor egg, which can be fertilised by sperm.

Continue reading the main story

previous slide next slide

But mitochondria have their own DNA, albeit a tiny fraction of the total. It means a baby would have genetic information from mum, dad and a second woman's mitochondria.

The concerns raised - by scientists at the University of Sheffield, the University of Sussex and Monash University in Australia - are about a poor match between the mitochondrial DNA and that from the parents.

Continue reading the main story

The woman who lost all her children

Every time Sharon Bernardi became pregnant, she hoped for a healthy child.

But all seven of her children died from a rare genetic disease that affects the central nervous system - three of them just hours after birth.

When her fourth child, Edward, was born, doctors discovered the disease was caused by a defect in Sharon's mitochondria.

Edward was given drugs and blood transfusions to prevent the lactic acidosis (a kind of blood poisoning) that had killed his siblings.

Five weeks later Sharon and her husband, Neil, were allowed to take Edward to their home in Sunderland for Christmas - but his health slowly began to deteriorate.

Edward survived into adulthood, dying in 2011 at the age of 21.

Now Sharon is supporting medical research that would allow defective mitochondria to be replaced by DNA from another woman.

• Sharon's full story
• Three-person IVF: Your stories

They said there was an interaction between the DNA in the mitochondria and the rest which is packaged in a cell's nucleus.

Their studies on fruit flies suggested that a poor match of genetic information between the nucleus and mitochondria could affect fertility, learning and behaviour.

"Describing it as like changing the batteries in a camera is too simplistic," Dr Klaus Reinhardt from the University of Sheffield told the BBC.

He added : "It is not at all our intention to be a roadblock, we think it is fantastic that for women affected there could be a cure.

"We have pointed out one or two points which need to be looked at."

'Trivial'

The Human Fertilisation and Embryology Authority, which regulates fertility treatment in the UK, commissioned a review into the safety of the technique.

Prof Robin Lovell-Badge, who was on the review panel, disagreed. He said humans had diverse mitochondrial and nuclear DNA, so any consequences of poor matches would have already become apparent.

He told the BBC news website: "Humans are breeding between races and producing healthy children all the time. If there is an effect then it must be very trivial as it's not been noticed."

He has called for further safety testing, such as research into the risks posed by any defective mitochondria which might still be passed onto a child.

Prof Doug Turnbull, who is developing the mitochondrial replacement therapy at Newcastle University, insisted: "One of our prime interests is about the safety of these techniques.

"It's perfectly reasonable to draw some of these concerns, I just don't share the same concerns.

"Mismatch between the mitochondrial and nuclear genome is a potential risk, but I don't think it's personally as big a risk as they're saying."

Hundreds of mitochondria in every cell provide energy

In a statement, the Human Fertilisation and Embryology Authority said: "The panel of experts convened by the HFEA to examine the safety and efficacy of mitochondria replacement carefully considered the interaction between nuclear and mitochondrial DNA and concluded that the evidence did not show cause for concern.

"As in every area of medicine, moving from research into clinical practice always involves a degree of uncertainty. Experts should be satisfied that the results of further safety checks are reassuring and long term follow-up studies are crucial.

"Even then patients will need to carefully weigh up the risk and benefits for them."

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A New Delivery for Cancer Drugs

May 7, 2013, 1:47PM

By Jennie Bragg

Posted in: cancer | nanotechnology

Scott McNeil, director of the Nanotechnology Characterization Lab at the Frederick National Laboratory for Cancer Research

The protein tumor necrosis factor-alpha (TNF-alpha) is a powerful weapon in the arsenal to control cancer. Unfortunately, as is the case with many potent cancer therapies, the use of TNF-alpha as an anti-cancer therapy has been severely limited. “It was so toxic that it caused death,” and researchers gave up on it, explains Scott McNeil, director of the Nanotechnology Characterization Lab at the Frederick National Laboratory for Cancer Research.

That was back in the 1990s. Today, TNF-alpha is a prime example of how to safely and effectively deliver toxic substances to cancer cells through the use of nanotechnology.

McNeil’s lab, part of the federally funded research and development center operated by SAIC-Frederick for the National Cancer Institute, worked with a drug company to reformulate TNF-alpha by coupling it with gold nanoparticles. Using the nanotechnology-enhanced protein, it appears possible to safely inject up to three times the amount that had been lethal with previous versions. The modified drug has been through a Phase 1 clinical trial and is entering Phase 2.

In McNeil’s lab, and for other scientists using nanotechnology for drug delivery, stories like this one are increasingly common. Researchers are looking to accelerate the development of potential nanotechnology drugs for cancer by exploring ways to reduce side effects and make treatments hit their targets more effectively. This can mean using nanotechnology to reformulate drugs that may have failed in previous clinical trials. In some cases, by attaching a nanoparticle to an existing drug, researchers may not only be able to lower its toxicity, but they may also see significant life expectancy gains for patients.

Many cancer drugs are approved based on how long they delay the progression of disease. Some drugs on the market “only improve life expectancy by maybe five weeks,” says McNeil. He sees nanomedicine as a potential game-changer for cancer drugs in the future.

McNeil, both a chemist and biologist, has spent the majority of his career working in nanotechnology, but when he was asked to apply his expertise to find better drugs for cancer, he was skeptical. “My professional career was mostly military,” says the former Army officer. “I was using nanotech for military applications at SAIC, using quantum dots to see if you scatter things, where they land. I got a call out of the blue in December of 2003 and the message was, ‘We want to use nanotech for cancer applications.’ I thought, ‘What are they thinking? You are going to put a cadmium quantum dot in a human? There is no way!’ I discounted it at first and I actually ignored the emails, hoping it would go away.”

But it did not go away.? In fact, much has changed in the last 10 years. Now, nanopharmaceuticals are beginning to demonstrate their capacity to place the drugs directly in the tumor, where they will do the most good, rather than let them roam freely in the body. A drug is attached to a nanoparticle, which is often a tiny little sphere. To put it in perspective, a nanometer is one billionth of a meter; the width of a single strand of hair is about 10,000 nanometers. The nanoparticle is small enough to flow through blood vessels and into a tumor, where the particle dissociates, and the drug is released. In the end, the goal of nanomedicine is that the only part of the body affected by the drug is the tumor, the area of need.

McNeil’s Nanotechnology Characterization Lab was founded in 2004 in collaboration with the Food and Drug Administration and the National Institute of Standards and Technology. There is one thing the lab does not do: develop nanotechnology drugs. Instead, researchers there—ranging in expertise from cancer biology and toxicology to chemistry, immunology, and physics—help investigators from around the world create the best drugs possible. “We help investigators get from proof of concept, where they are generating a few tens of milligrams of material and get into clinical trials, where they are going to need kilograms of materials,” say McNeil. “That translational research, as we call it, is absolutely germane to getting into clinical trials.”

The majority of scientists who apply for assistance from the NCL are seeking FDA approval for their nanotech drugs but they don’t have the resources to optimize their formula. The NCL can help. “We help them understand what is involved with their particle because they don’t have the tools that we have to be able to characterize,” says McNeil. “They may have a nice picture or cartoon of it but until they see our electron micrographs, they don’t know what it looks like.”

The Nanotechnology Characterization Lab serves two purposes. After a molecule has been through the NCL’s assay cascade which consists of a set of tests that evaluate the preclinical toxicology, pharmacology, and efficacy of nanoparticles, the NCL is able to offer an evaluation. “The investigator is going to need $40 million dollars to get into Phase 2 trials. Investigators need to justify the investment. We help them generate data they need to further their work and then we serve as a third-party evaluation.” That is crucial, McNeil says, for an investigator seeking funding. “A venture capital company can come to us and say, ‘Well, what do you really think of this? Let’s see your data, and explain it and defend it.’ We, obviously, cannot endorse it but we can discuss the data in the context of what they are trying to do. That really holds a lot of weight.”

Consider the example of Abraxane (paclitaxel), which was approved for use by the FDA in 2005. Abraxane, a variably toxic but widely prescribed cancer drug, has been enhanced by attaching it to a nanoparticle, thereby creating a new, targeted treatment. “Because of the size and the binding to a different receptor, that drug now has decreased toxicity compared to the former drug. For the nanoparticle-Abraxane conjugate toxicity is very marginal, at least for immunotoxicity and hypersensitivity,” says McNeil.

Since 2005, the Nanotechnology Characterization Lab has characterized nearly 300 different particles. Six of them are in clinical trials. “Depending upon what community you are from, either that is a terrific ratio or that is a poor ratio,” explains McNeil. “We view it as a super terrific ratio. A pharmaceutical company can make hundreds of thousands of different drugs and only about one out of 100,000 gets into clinical trials.”

Nanotechnology’s place in the cancer treatment arsenal also appears secure. A new report from Infiniti Research Limited, a marketing research firm specializing in pharmaceuticals and health care, forecasts that the nanotechnology drug delivery market is on track to double within the next five years.

For more information about NCL, visit: http://ncl.cancer.gov/.

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Staudt elected to National Academy of Sciences

May 28, 2013, 11:10AM

By Chelsey Jahn

Posted in: Scientist Spotlight | lymphoma

Tags: scientist

Louis M. Staudt, M.D., Ph.D., deputy chief of NCI’s Metabolism Branch in the Center for Cancer Research, has recently been elected into The National Academy of Sciences.? The NAS is a private, non-profit society, established in 1863 by Congress. It serves as an objective science and technology resource for the nation.

Members include experts in the scientific, engineering, and health professional fields, all of whom volunteer their time to provide reports that have significantly improved the welfare of citizens worldwide.

Staudt is just one of the 84 new members who were nominated by peers, in recognition of their notable and ongoing achievements in original research. All newly appointed members will be officially inducted into the NAS during an April 2014 ceremony.

Staudt is known as a pioneer of gene expression profiling His laboratory currently studies the molecular basis of human lymphoid malignancies through the use of functional genomics, chemical genetics and molecular biological techniques. His groundbreaking developments in cancer research and genomics include the discovery of previously unknown types of diffuse large B cell lymphoma, the use of gene expression profiling to identify distinct cancer subgroups, the prediction of cancer patient survival with the use of gene expression signatures, and the discovery of new therapeutic targets in molecularly-defined subtypes of cancer using loss-of-function RNA interference (RNAi) genetic screens.

“This nomination is very gratifying because it validates some of the ideas about lymphoma diagnosis and treatment that we have been trying to promote over the past decade,” Staudt said.? “It establishes that we are on a path of making progress for patients. Also, it is a true testament to the strong support given to our lab by the NCI and especially to the outstanding post docs, students, and technicians working in the lab over the past 25 years.”

In this video from March 2012, Staudt discusses the basic biology of targeted therapy for Diffuse B-cell Lymphoma and about ibrutinib, a drug with a high degree of efficacy—and only modest side effects—in the treatment of the ABC form of Diffuse B-cell Lymphoma.

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Heart Infection Causing Fewer Hospitalizations, Researchers Say

THURSDAY, Sept. 19 (HealthDay News) -- Hospitalizations for a deadly heart infection that affects mainly older people have declined in recent years, a new study finds. This was seen even with recommendations for more limited use of antibiotics to prevent the illness, called endocarditis.

Specifically, endocarditis is inflammation of the inside living of the heart valve and chambers, according to the U.S. National Heart, Lung, and Blood Institute. The risk of endocarditis increases when people have surgery, and it's considered the most serious infection of the cardiovascular system.

There was a significant increase in rates of hospitalization for endocarditis in the 1990s, which led many doctors to prescribe antibiotics before dental procedures and certain types of surgery.

However, the American Heart Association has narrowed the recommended use of antibiotics to prevent endocarditis to only a subgroup of patients undergoing dental procedures.

In this study, Yale School of Medicine researchers looked at the annual rates of endocarditis-related hospitalizations and related outcomes among more than 262,000 Medicare patients 65 and older between 1999 and 2010.

An increase in hospitalizations for endocarditis occurred between 1999 and 2005, but there was a decline between 2006 and 2010, according to the study in the August Journal of the American College of Cardiology.

"We were surprised to see reduced rates of endocarditis hospitalizations during this time period," study first author Dr. Behnood Bikdeli, a postdoctoral associate in cardiovascular medicine, and an internal medicine resident, said in a Yale news release.

"This downward trend was consistent in all major study subgroups, but certain subgroups, including black participants, had higher hospitalization rates and worse outcomes in the study period," he added.

This racial disparity in outcomes, as well as reasons for the overall decline in hospitalizations, require further investigation, Bikdeli said.

"Clinicians should consider the risks and benefits of antibiotic use on a case-by-case basis and should share the information with their patients for appropriate decision making," he concluded.

More information

The U.S. National Heart, Lung, and Blood Institute has more about endocarditis.

Copyright c 2013?HealthDay. All rights reserved.

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First real-time detector for IV drugs may help eliminate medical errors

Sep. 19, 2013 — Today, computerized smart systems can deliver drugs intravenously in exact volumes to hospital patients. However, these systems cannot recognize which medications are in the tubing nor can they determine the concentration of the drug in the tubing. This lack of precise information can lead to medication errors with serious consequences.

Now, a new optical device developed by a team of electrical and computer engineering students at the University of Illinois at Urbana-Champaign (UIUC) can identify the contents of the fluid in an intravenous (IV) line in real-time, offering a promising way to improve the safety of IV drug delivery. The team, led by Prof. Brian T. Cunningham, interim director of the Micro and Nanotechnology Laboratory at UIUC, will present its work at The Optical Society's (OSA) Annual Meeting, Frontiers in Optics (FiO) 2013, being held Oct. 6-10 in Orlando, Fla.

The vulnerability of IV drug-delivery systems due to human error is a chief concern in hospital safety, Cunningham said. Errors can include incorrect dosage, unintentional substitution of one drug for another, and co-delivery of incompatible drugs.

"Up to 61 percent of all life-threatening errors during hospitalization are associated with IV drug therapy," Cunningham said, citing a recent report. "So for all the really good things hospitals can do, the data shows that mistakes can occasionally happen."

To approach this problem, Cunningham and colleagues turned to the very small -- to structures and processes at the nanoscale (one-billionth of a meter), where novel physical and chemical properties arise. The researchers use a technology called Surface-Enhanced Raman Scattering (SERS), a powerful analytical tool prized for its extreme sensitivity in obtaining molecular signals that can be used to identify chemicals. To determine the identity of a particular IV medication, researchers shine laser light onto a nanostructured gold surface that contains millions of tiny "nano-domes" that are separated from each other by as little as 10 nanometers. The nano-domes are incorporated into the inner surface of IV tubing, where they are exposed to drugs that are dispersed in liquid. They capture the light scattered from drug molecules that are in contact with the nano-domes and use SERS to determine the drug's molecular signature. Finally, they match the signature to known signatures for the drug in order to confirm the presence of a specific medication in the IV line.

While other groups have demonstrated excellent nanostructured surfaces for SERS, those developed by the Cunningham group are unique because they are inexpensively produced on flexible plastic surfaces by a replica molding process with nanometer scale accuracy.

Early data show that the Cunningham group's system can identify medications including morphine, methadone, phenobarbital, the sedative promethazine, and mitoxantrone, which is used to treat multiple sclerosis. The system is extremely sensitive: it can detect drugs in amounts 100 times lower than the clinically delivered drug concentrations commonly used. So far, the researchers have also shown their system can sense a two-drug combination, which has its own unique signature.

The next step is further evaluation for combinations of up to ten drugs being delivered at the same time. Computer algorithms are also being developed to automatically interpret the SERS spectra, and Cunningham's team reports that the system is now being evaluated for possible commercialization.

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Protein 'motif' crucial to telomerase activity

Sep. 19, 2013 — It is difficult to underestimate the importance of telomerase, an enzyme that is the hallmark of both aging and the uncontrolled cell division associated with cancer. In an effort to understand and control telomerase activity, researchers at The Wistar Institute have discovered a protein "motif," named TFLY, which is crucial to the function of telomerase. Altering this motif disrupts telomerase function, they found, a fact that they believe will help them in their efforts to identify inhibitors of telomerase with potential cancer therapeutic properties.

Their findings are published in the October 8 issue of the journal Structure, available online now.

"Telomerase is a unique protein-RNA complex where the protein subunit uses its RNA component as a template to add identical fragments of DNA to the end of chromosomes," said Emmanuel Skordalakes, Ph.D., associate professor in the Gene Expression and Regulation program of Wistar's NCI-designated Cancer Center. "We identified a motif in the protein component of telomerase that controls how the enzyme carries out its activity in vertebrates such as ourselves."

"If you disrupt this segment of the protein, by altering its amino acid sequence, you disrupt the ability of telomerase to function," Skordalakes explained. "Obviously, this information can be used in our efforts to identify drug therapies that kill cancer cells by targeting telomerase activity."

Telomerase is an enzyme that replicates the ends of chromosomes (sections of DNA called telomeres), replacing the DNA lost when chromosomes are copied before cell division and, therefore, maintaining the stability of the genome. It performs this critical service in embryonic development, growing organisms and in a few specialized adult cell lines, including stem cells.

In most normal adult cells, however, telomerase is switched off almost entirely to prevent the dangers of runaway cell proliferation. Without telomerase, adult cells senesce (grow old) after about 50-55 rounds of cell division because the telomeres get too short to provide the buffer required to protect the ends of chromosomes and stabilize the cell's genetic code.

It is now established that nearly 90 percent of cancers develop a way of reactivating telomerase as a means of survival. Inhibiting telomerase function has been viewed as an ideal way to put the brakes on a wide range of cancers. According to Skordalakes, one way to do so would be to disrupt the protein RNA complex that comprises the core of the telomerase enzyme. The RNA binding domain (TRBD) of telomerase is a crucial component to this process and, therefore, the enzyme's ability to work.

In 2007, the Skordalakes laboratory was the first to obtain the three-dimensional structure of TRBD. Since then, his team has been creating molecular inhibitors to target the TRBD RNA-binding pockets as means to inhibit telomerase enzymatic activity.

The present study arose as the Skordalakes laboratory sought to better understand the role of TRBD in telomerase function. They engineered a truncated version of the protein subunit of a vertebrate telomerase, consisting of TRBD and a conserved portion of the N-terminal region of the protein. Within this portion they identified the TFLY, a conserved element that they showed is involved in binding the RNA component of telomerase and this interaction is important for telomerase protein-RNA assembly and activity.

"This TFLY motif comprises a significant part of the binding pocket that enables the enzyme to grapple the RNA template and guide it to the active site of the enzyme for catalysis," Skordalakes said, "but it also facilitates the stable association of the protein with its RNA component thus forming a fully functional telomerase enzyme."

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Sanofi in $40 million settlement over obesity drug linked to suicidal thoughts

By Jonathan Stempel

NEW YORK (Reuters) - Sanofi SA has reached a $40 million settlement of a U.S. lawsuit accusing the French drugmaker of misleading investors about the safety of a weight loss pill that a U.S. regulatory panel linked to suicidal thoughts.

The all-cash settlement was disclosed in a court filing on Thursday, and requires approval by U.S. District Judge George Daniels in Manhattan.

It resolves claims that arose after a U.S. Food and Drug Administration advisory committee on June 13, 2007 urged that the agency reject Sanofi's drug rimonabant, known by the trade names Acomplia and Zimulti, on concern that using it could increase suicidal thinking and depression.

Sanofi is the world's fourth-largest pharmaceutical company as measured by prescription drug sales. European regulators had approved use of rimonabant prior to the FDA panel action, but sales were later suspended.

Plaintiffs led by the Hawaii Annuity Trust for Operating Engineers accused Sanofi of touting the drug as a possible "blockbuster" to treat obesity, with only mild side effects.

But they said Sanofi concealed clinical tests that showed a statistically significant increase in "suicidality" among people taking the drug.

The release of the advisory committee recommendation caused Sanofi's shares in Europe and American depository receipts in the United States to fall in price.

Thursday's settlement covers investors in Sanofi ADRs between February 24, 2006 and June 13, 2007, and equates to about 37 cents for each of Sanofi's roughly 108 million ADRs at the time.

It also resolves claims against Gerard Le Fur, the former chief executive, and Hanspeter Spek, an executive vice president of pharmaceutical operations, court papers show.

"The settlement, in light of all the risks, was exceedingly fair, and represented a high percentage of the total damages suffered by the class," said Tor Gronborg, a partner at Robbins Geller Rudman & Dowd who represents the plaintiffs, in an interview.

Sanofi did not immediately respond to requests for comment.

The plaintiffs' law firm plans to seek a fee of $11 million, or 27.5 percent of the settlement amount, court papers show.

The case is In re: Sanofi-Aventis Securities Litigation, U.S. District Court, Southern District of New York, No. 07-10279.

(Editing by Eric Walsh)

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Could dog food additive prevent disabling chemo side effect?

Sep. 19, 2013 — Working with cells in test tubes and in mice, researchers at Johns Hopkins have discovered that a chemical commonly used as a dog food preservative may prevent the kind of painful nerve damage found in the hands and feet of four out of five cancer patients taking the chemotherapy drug Taxol.

The Food and Drug Administration-approved preservative, an antioxidant called ethoxyquin, was shown in experiments to bind to certain cell proteins in a way that limits their exposure to the damaging effects of Taxol, the researchers say.

The hope, they say, is to build on the protective effect of ethoxyquin's chemistry and develop a drug that could be given to cancer patients before taking Taxol, in much the same way that anti-nausea medication is given to stave off the nausea that commonly accompanies chemotherapy. While half of Taxol users recover from the pain damage, known as peripheral neuropathy, the other half continue to have often debilitating pain, numbness and tingling for the rest of their lives.

"Millions of people with breast cancer, ovarian cancer and other solid tumors get Taxol to treat their cancer and 80 percent of them will get peripheral neuropathy as a result," says Ahmet Hoke, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and director of the Neuromuscular Division. "They're living longer thanks to the chemotherapy, but they are often miserable. Our goal is to prevent them from getting neuropathy in the first place."

A report on Hoke's research is published online in the Annals of Neurology.

Hoke and his team knew from previous experiments that adding Taxol to a nerve cell line growing in a petri dish would cause neurodegeneration. In a series of experiments, they set out to hunt for compounds that might interrupt the degenerative process by adding Taxol to nerve cells along with some 2,000 chemicals -- one at a time -- to see which, if any, could do that.

Ethoxyquin did so, Hoke says, apparently by making the cells resistant to the toxic effects of the Taxol.

Once they identified ethoxyquin's effects, they gave intravenous Taxol to mice, and saw nerves in their paws degenerate in a couple of weeks. But when they gave ethoxyquin to the mice at the same time as the Taxol, it prevented two-thirds of the nerve degeneration, which Hoke says would have a big impact on quality of life if the same effects were to occur in humans.

Specifically, Hoke and his team discovered that molecules of ethoxyquin were binding to Hsp90, one of the so-called heat shock proteins that cells defensively make more of whenever they are stressed. Hsp90 acts as a cell's quality control officer, determining whether a protein is properly formed before sending it out where it is needed. When ethoxyquin binds to Hsp90, two other proteins -- ataxin-2 and Sf3b2 -- can't bind to Hsp90. When they can't bind, the cell senses that these two proteins are flawed, so they are degraded and their levels in the cell diminished.

Hoke says his team is not certain why too much of those two proteins appears to have a negative effect on nerves, but reducing their levels clearly appears in their studies to make cells more resistant to Taxol toxicity.

Hoke and his colleagues are looking into whether this medication could also make nerves more resistant to damage in peripheral neuropathy caused by HIV and diabetes, two other major causes of the pain. A previous study, Hoke says, showed that ataxin-2 may cause degeneration in motor neurons in a rare form of ALS, commonly known as Lou Gehrig's disease, suggesting that ethoxyquin or some version of it might also benefit people with this disorder.

Twenty to 30 million Americans suffer from peripheral neuropathy. Hoke says it's a "huge public health issue" that doesn't get much attention because it is not fatal.

Hoke's team is hoping to conduct safety studies with ethoxyquin in animals in advance of possible testing in people. He says that while too much ethoxyquin is thought to be potentially harmful to dogs, the needed dose for humans would likely be 20-to-30-fold lower than what is found in dog food. Ethoxyquin was developed in the 1950s as an antioxidant, a compound to prevent pears and other foods from becoming discolored and spoiling.

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Paralysis promises smart silk technology

Sep. 19, 2013 — Oxford University researchers have harnessed the natural defence mechanism of silkworms, which causes paralysis, in what is a major step towards the large-scale production of silks with tailor-made properties.

Professor Fritz Vollrath and colleagues from the Oxford Silk Group at Oxford University's Department of Zoology collected silk directly from paralysed silkworms by injecting a chemical that is naturally produced by the animal. In the wild silkworms produce this hormone when they are injured since, as they move their bodies through hydrostatic pressure, without this self-induced paralysis their wounds would get worse and they would risk 'bleeding out'.

The team's report in the journal Biomacromolecules this week concludes that, in comparison to unparalysed silkworms, paralysis allows longer and more consistent silks to be collected by eliminating the ability of the silkworm to break and alter its silk fibre.

The direct 'forced reeling' of silk has been used in spiders for many years. However, reeling large amounts of silk directly from silkworms has not previously been possible. By tricking the silkworm into performing its natural response to injury and becoming paralysed the Oxford scientists show that it is possible to reel hundreds of meters of silk under full control.

Unlike unravelling cocoons, as in the silk textile industry, silkworm forced reeling allows the silk properties to be modified to suit particular purposes. This has important implications for the large-scale reeling of silkworms for industrial production of environmentally-friendly fibres for use in a range of applications -- from biomedical implants through to super-tough composite panels.

Silkworm paralysis may open the door to a range of silk technologies, using these animals which, unlike spiders, can be farmed at high-densities. Reeling of silk from paralysed worms is the subject of a recent patent, which also highlights the exciting potential for genetically modifying silkworms to induce paralysis 'on-demand', a particularly useful feature for mass-rearing.

'This is an interesting result as the paralysis prevents the silkworms breaking the fibre, but still allows silk spinning and collection,' said Beth Mortimer of the Oxford Silk Group, an author of the report.

'The commercial implications of this process are self evident: now we can make silks to order by manipulating the mechanical properties while at the same time adding functionality,' said Professor Vollrath.

Dr Alex Woods, an entomologist and Oxford-based medical researcher responsible for the original discovery said: 'importantly, this may allow us to make high-quality silks with a variety of desirable mechanical properties, in practical quantities, to finally expand this exceptionally well-suited biomaterial into key medical applications.'

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NCI Grantees Receive Breakthrough Prizes in Life Sciences

March 8, 2013, 10:47AM

By Aleea Farrakh Khan

Posted in: Scientist Spotlight

Tags: award

The Breakthrough Prize in Life Sciences recognizes “excellence in research aimed at curing intractable diseases and extending human life.” The inaugural set of prizes, awarded in February 2013 by a not-for-profit corporation dedicated to advancing breakthrough research, are backed by well-known personalities such as Sergey Brin, Google co-founder and his wife, Anne Wojcicki, co-founder of a personal genomics and biotech company 23andMe; Facebook founder Mark Zuckerberg? and his wife, Priscilla Chan; Russian entrepreneur?Yuri Milner; and ?Art Levinson, chairman of Apple and Genentech.

The 11 recipients will each receive $3 million for their outstanding work in the field of science; eight of them have received NCI grants to further their research:

• David Botstein Ph.D., director of the Lewis-Sigler Institute for Integrative Genomics and the Anthony B. Evnin professor of genomics at Princeton University, was recognized for linkage mapping of Mendelian disease in humans using variations in a DNA sequence.

• Lewis C. Cantley, Ph.D., director of the Cancer Center at Weill Cornell Medical College and New York-Presbyterian Hospital, was awarded for his discovery of PI 3-Kinase and its role in cancer metabolism. His research discovered that human cancers frequently have mutations in PI3K and he has worked to identify new treatments for cancers that result from defects in this pathway.

• Titia de Lange Ph.D., head of the Laboratory of Cell Biology and Genetics, and director of the Anderson Center for Cancer Research at the Rockefeller University, was awarded for her research on telomeres, illuminating how they protect chromosome ends and their role in genome instability in cancer. De Lange identified a protein complex within telomeres, called shelterin, and has shown how this complex hides the chromosome end from cellular machinery that detects and repairs broken DNA tips.

• Napoleone Ferrara, M.D., distinguished professor of pathology and senior deputy director for basic sciences at Moores Cancer Center at the University of California, San Diego, was awarded for his discoveries in the mechanisms of angiogenesis that led to therapies for cancer and eye diseases.? Ferrara’s research has helped identifying the role of the human VEGF gene in promoting angiogenesis—the formation of new blood vessels that can feed tumor growth—and subsequent development of two major drugs: bevacizumab (Avastin) which is used to treat multiple forms of cancer and ranibizumab (Lucentis), which treats age-related macular degeneration, a leading cause of blindness in the elderly.

• Eric Lander, Ph.D., founding director and core member of the Broad Institute of MIT and Harvard, was awarded for the discovery of general principles for identifying human disease genes, and enabling their application to medicine through the creation and analysis of genetic, physical and sequence maps of the human genome. Lander was one of the leaders of the Human Genome Project.

• Charles L. Sawyers, M.D., chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center, was awarded for his work in cancer genes and targeted therapy. ?Sawyers research focuses on cancer drug resistance, which?led him to the discovery of the drug enzalutamide (Xtandi), used for advanced prostate cancer.

• Bert Vogelstein, M.D., co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator,?was awarded for his work in cancer genomics and tumor suppressor genes. Vogelstein’s identification of p53 gene mutations in colon cancer was groundbreaking and resulted in further research linking this gene mutation to other cancers. It is now known as the most common gene mutation in all cancers.

• Robert A. Weinberg, Ph.D., professor for cancer research at MIT and director of the MIT/Ludwig Center for Molecular Oncology, was awarded for his characterization of human cancer genes. Weinberg is known for his discoveries of the first human oncogene—a gene that causes normal cells to form tumors—and the first tumor suppressor gene.

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Geologists simulate deep earthquakes in lab

Sep. 19, 2013 — More than 20 years ago, geologist Harry Green, now a distinguished professor of the graduate division at the University of California, Riverside, and colleagues discovered a high-pressure failure mechanism that they proposed then was the long-sought mechanism of very deep earthquakes (earthquakes occurring at more than 400 km depth).

The result was controversial because seismologists could not find a seismic signal in Earth that could confirm the results.

Seismologists have now found the critical evidence. Indeed, beneath Japan, they have even imaged the tell-tale evidence and showed that it coincides with the locations of deep earthquakes.

In the Sept. 20 issue of the journal Science, Green and colleagues show just how such deep earthquakes can be simulated in the laboratory.

"We confirmed essentially all aspects of our earlier experimental work and extended the conditions to significantly higher pressure," Green said. "What is crucial, however, is that these experiments are accomplished in a new type of apparatus that allows us to view and analyze specimens using synchrotron X-rays in the premier laboratory in the world for this kind of experiments -- the Advanced Photon Source at Argonne National Laboratory."

The ability to do such experiments has now allowed scientists like Green to simulate the appropriate conditions within Earth and record and analyze the "earthquakes" in their small samples in real time, thus providing the strongest evidence yet that this is the mechanism by which earthquakes happen at hundreds of kilometers depth.

The origin of deep earthquakes fundamentally differs from that of shallow earthquakes (earthquakes occurring at less than 50 km depth). In the case of shallow earthquakes, theories of rock fracture rely on the properties of coalescing cracks and friction.

"But as pressure and temperature increase with depth, intracrystalline plasticity dominates the deformation regime so that rocks yield by creep or flow rather than by the kind of brittle fracturing we see at smaller depths," Green explained. "Moreover, at depths of more than 400 kilometers, the mineral olivine is no longer stable and undergoes a transformation resulting in spinel. a mineral of higher density"

The research team focused on the role that phase transformations of olivine might play in triggering deep earthquakes. They performed laboratory deformation experiments on olivine at high pressure and found the "earthquakes" only within a narrow temperature range that simulates conditions where the real earthquakes occur in Earth.

"Using synchrotron X-rays to aid our observations, we found that fractures nucleate at the onset of the olivine to spinel transition," Green said. "Further, these fractures propagate dynamically so that intense acoustic emissions are generated. These phase transitions in olivine, we argue in our research paper, provide an attractive mechanism for how very deep earthquakes take place."

Green was joined in the study by Alexandre Schubnel at the Ecole Normale Superieure, France; Fabrice Brunet at the Universite de Grenoble, France; and Nadege Hilairet, Julian Gasc and Yanbin Wang at the University of Chicago, Ill.

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Worm research: Right combination of sugars regulates brain development

Sep. 19, 2013 — If the development of our nervous system is disturbed, we risk developing serious neurological diseases, impairing our sensory systems, movement control or cognitive functions. This is true for all organisms with a well-developed nervous system, from man to worm. New research from BRIC, University of Copenhagen reveals how a tiny molecule called mir-79 regulates neural development in roundworms. The molecule is required for correct migration of specific nerve cells during development and malfunction causes defects in the nervous system of the worm. The research has just been published in the journal Science.

Hundreds of worms lie in a small plastic plate under the laboratory microscope. Over the last three years, the group of Associate Professor Roger Pocock has used the roundworm C. elegans to study the development of the nervous system. They have just made an important discovery.

"Our new results show that a small molecule called mir-79 is indispensable for development of the worm's nervous system. mir-79 acts by equipping special signal molecules with a transmitter, which tells the nerve cells how they should migrate during development of the worm. If we remove mir-79 with gene technology, development of the worm nervous system goes awry," says postdoc Mikael Egebjerg Pedersen, who is responsible for the experimental studies.

Mir-79 adds just the right combination of sugar

The research shows that mir-79 acts by controlling the addition of certain groups of sugars to selected signaling molecules. In the world of cells, sugar molecules act as transmitters.

When the nerve cells come into contact with the sugar-transmitters, they are informed where to locate themselves during neural development. If the researchers remove mir-79, the migration of the nerve cells is misguided causing neuronal defects in the worms.

"It has earlier been shown that signaling molecules guide nerve migration, but our research shows that mir-79 regulates nerve cell migration by controlling the correct balance of sugar-transmitters on signaling molecules. If mir-79 does not function, the worm nervous system is malformed. In the wild, such defects would be harmful for worm survival," says Roger Pocock who leads the research group behind the finding.

Worm studies reveal important clues for neuronal repair

A version of mir-79 called mir-9 is found in humans. Therefore, these results are important for understanding how our nervous system develops during fetal development. In addition, the results add to the understanding of how nerve cells may be stimulated to repair damage in our brain or spinal cord.

"Our nervous system is a tissue which is not easily repaired after damage. So, how certain molecular cues can stimulate nerve cells to migrate is an important brick in the puzzle. This will enable us to understand how nerve tissue can be regenerated after, for example, a stroke or an accident. If we can use such knowledge to mimic the signals, we may be able to stimulate nerve cells to migrate into a damaged area," says Roger Pocock.

Worms are a fantastic model to study how the nervous system develops and how nerve cells form neuronal circuits. Most of the genes that control nervous system development in the worm are also found in humans. At the same time, the reduced complexity of the worm nervous system allows researchers to investigate central biological mechanisms. With new technologies they can mark single cells or molecules, and as worms are transparent, the researchers can track the marked molecules or cells live during worm development.

The next step for the researchers is to investigate how the regulatory pathway they have revealed is regulated in cultures of human cells.

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Groundbreaking pain research

Sep. 19, 2013 — The bodies of mammals, including humans, respond to injury by releasing endogenous opioids -- compounds that mitigate acute pain. A team of researchers led by those at the University of Kentucky has uncovered groundbreaking new information about how the body responds to traumatic injury with the development of a surprisingly long-lasting opioid mechanism of natural chronic pain control. Remarkably, the body develops both physical and physiological dependence on this opioid system, just as it does to opiate narcotic drugs. The research is featured on the cover of the current issue of the prestigious journal Science.

The paper, titled Constitutive Mu-Opioid Receptor Activity Leads to Long-term Endogenous Analgesia and Dependence, was authored by a team including lead author Bradley Taylor of the University of Kentucky College of Medicine Department of Physiology. Other authors include: Gregory Corder, Suzanne Doolen and Renee Donahue of the UK Department of Physiology; Brandon Jutras of the UK College of Medicine Department of Microbiology, Immunology and Molecular Genetics; Michelle Winter and Kenneth McCarson of the University of Kansas; Ying He, Zaijie Wang and Xiaoyu Hu of the University of Illinois; Jeffrey Wieskopf and Jeffrey Mogil of McGill University; and Daniel Storm of the University of Washington.

The scientists examined opioid function at sites of pain modulation in the spinal cord. When the opioids act at opioid receptor proteins, they "put the brakes" on the transmission of pain signals to the brain. For example, opioids are released when a patient undergoes surgery, a soldier is wounded in battle, or an athlete runs a marathon. Researchers have known for a while that blocking opioid receptors can increase the intensity of acute pain -- the pain occurring immediately after injury. But up to this point, scientists had been unsure whether blocking opioids could increase chronic, long-term pain. They began their work with the idea that the opioid system is much more important than previously recognized, with an ability to indefinitely oppose chronic pain. If true, they reasoned, then blocking opioids should increase chronic pain.

To simulate human injury, the researchers produced inflammation, or skin incision, in a mouse model, then waited several weeks for signs of pain-like behaviors to subside. They then administered opioid receptor blockers, effectively halting the pain-relieving actions of the opioid system. When the opioid system (which the authors use the term MORCA, for mu opioid receptor constitutive activity) was blocked, the mice reverted to a set of behaviors associated with the experience of pain. Surprisingly, they also experienced symptoms similar to the known effects of opioid withdrawal in the drug addict: tremor, jumping and shakiness. These results were observed even up to six and a half months after pain had seemingly resolved. The long-lasting nature of the phenomenon suggests that endogenous opioid analgesia silently continues long after an injury has healed.

In other words, long after an acute injury has healed, MORCA continues to "put the brakes" on pain. When MORCAis blocked, the "accelerator" is allowed to run free, and chronic pain reappears.

Because the body appears to develop a reliance on MORCA that parallels the addiction of a synthetic opioid user, and because it is known that stress is a key factor in causing relapse in opioid addicts, it follows that stress may also be a key factor in relapse in chronic pain patients. Thus, the authors speculate that stress could interfere with endogenous MORCA analgesia, leading to the emergence of widespread, rampant chronic pain such as is observed in a range of conditions, including fibromyalgia.

This research provides some answers to how the body responds to pain, but also raises questions. To return to the "brake and accelerator" metaphor, future studies are needed to better understand the long-term consequences of simultaneously pressing the accelerator and the brake on pain. In other words, how can we either prevent the "brake pads" from wearing out, or replace them when they do?

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