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duminică, 5 august 2012

New Method Could Enable Reprogramming Of Mammalian Cells

Through the assembly of genetic components into "circuits" that perform logical operations in living cells, synthetic biologists aim to artificially empower cells to solve critical problems in medicine, energy and the environment. To succeed, however, they'll need far more reliable genetic components than the small number of "off-the-shelf" bacterial parts now available.

Now a new method developed by Boston University biomedical engineers Ahmad S. Khalil and James J. Collins -- and collaborators at Harvard Medical School, Massachusetts General Hospital and MIT -- could significantly increase the number of genetic components in synthetic biologists' toolkit and, as a result, the size and complexity of the genetic circuits they can build. The development could dramatically enhance their efforts not only to understand how biological organisms behave and develop, but also to reprogram them for a variety of practical applications.

Described in the August 2 online edition of Cell, the method offers a new paradigm for constructing and analyzing genetic circuits in eukaryotes -- or organisms whose cells contain nuclei, which include everything from yeasts to humans. Instead of constructing these circuits with off-the-shelf parts from bacteria and porting them into eukaryotes, as most synthetic biologists do, Khalil and his collaborators have engineered these circuits using modular, functional parts from the eukaryotes themselves.

With funding from the Howard Hughes Medical Institute, the Defense Advanced Research Projects Agency and other sources, the research team built their synthetic genetic circuit parts from a class of proteins, known as zinc fingers, which can be programmed to bind desired DNA sequences. The modularity of the new parts enables a wide range of functions to be engineered, the construction of much larger and more complex genetic circuits than what's now possible with bacteria-based parts, and ultimately, the development of much more powerful applications.

"Our research may lead to therapeutic applications, such as the dynamic modification and control of genes and genetic networks that are important in human disease," said Khalil. Potential medical applications include stem cell therapeutics for a wide variety of injuries and diseases and in-cell devices and circuits for diagnosing early stages of cancer and other diseases. The new method may also equip groups of cells to perform higher-order computational tasks for processing signals in the environment in sensing applications.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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New Computer Method Finds New Uses For Old Drugs

With the cost of putting a single new drug on the pharmacy shelves topping a staggering $1 billion, scientists are reporting development of a way to determine if an already-approved drug might be used to treat a different disease. The technique for repurposing existing medicines could cut drug development costs and make new medicine available to patients faster, they report in ACS' Journal of Medicinal Chemistry.

Sivanesan Dakshanamurthy and colleagues explain that drug companies must limit efforts to market new drugs because the current approach is so expensive, time-consuming and prone to failure. Scientists long have known that drugs already approved for one disease might be effective for others. However, existing methods to identify new uses for old drugs lack accuracy and have other disadvantages. So Dakshanamurthy's team developed a comprehensive new computer method called "Train-Match-Fit-Streamline" (TMFS) that uses 11 factors to quickly pair likely drugs and diseases.

They describe using TMFS to discover evidence that Celebrex, the popular prescription medicine for pain and inflammation, has a chemical signature and architecture suggesting that it may work against a difficult-to-treat form of cancer. Likewise, they found that a medicine for hookworm might be repurposed to cut off the blood supply that enables many forms of cancer to grow and spread. "We anticipate that expanding our TMFS method to the more than 27,000 clinically active agents available worldwide across all targets will be most useful in the repositioning of existing drugs for new therapeutic targets," they said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pharma industry / biotech industry section for the latest news on this subject. The authors acknowledge funding from the National Institutes of Health and the Department of Defense.
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Mindfulness: Psychology Of Possibilities Can Enhance Health, Happiness

First-time mothers who pay attention to their emotional and physical changes during their pregnancy may feel better and have healthier newborns than new mothers who don't, according to research to be presented at American Psychological Association's 120th Annual Convention.

"These findings continue more than 40 years of research that has made clear that whether you are mindless or mindful makes a big difference in every aspect of your health and well-being -- from competence to longevity," Ellen Langer, professor of psychology at Harvard University and a pioneer in researching mindfulness, said in an interview. Langer is a past recipient of APA's Award for Distinguished Contributions to Psychology in the Public Interest.

For Langer's recent study, researchers trained women pregnant with their first child in mindfulness with instructions to notice subtle changes in their feelings and physical sensations each day, she said. When compared with two other groups of first-time pregnant mothers who did not have the mindfulness training, these women reported more well-being and positive feelings and less emotional distress. "They had higher self-esteem and life satisfaction during this period of their pregnancy and up to at least a month after birth," Langer said. "And this also had a positive impact on their deliveries and overall health of the newborns."

Teaching mindfulness through attention to variability may be helpful for many disorders, including asthma, depression and learning disabilities, to name a few, according to Langer.

"Noticing even subtle fluctuations in how you feel can counter mindlessness, or the illusion of stability. We tend to hold things still in our minds, despite the fact that all the while they are changing. If we open up our minds, a world of possibility presents itself," she said.

Author of the popular books "Mindfulness," "The Power of Mindful Learning," "On Becoming an Artist: Reinventing Yourself Through Mindful Creativity," and most recently, "Counterclockwise: Mindful Health and the Power of Possibility," Langer is known for her work on the illusion of control, aging, decision-making and mindfulness theory.

In her lecture, Langer will describe her research to test possibilities rather than find out what is typical. "Psychologists have traditionally studied the 'norm' rather than exceptions that could show that we are capable of far more than we currently realize," she said. Among other research, she will describe her work showing how a change in mindset has resulted in weight loss and improved vision and hearing, and how subtle differences in choice of words can improve health.

Langer first demonstrated the psychology of possibilities in her landmark 1981 "counterclockwise" experiment in which a group of elderly men spent time immersed in a retreat created to reflect daily life in the 1950s and where they were told to speak of the past in the present tense. Men in a comparison group reminisced for the week and were given no instructions regarding verb tense. The experimental group showed greater improvement in vision, strength, joint flexibility, finger length (their arthritis diminished and they could straighten their fingers more) and manual dexterity. On intelligence tests, 63 percent of the experimental group improved their scores, compared to 44 percent of the control group, Langer said.

BBC television recently replicated the study with British celebrities in a program that has been viewed in Great Britain, Australia, India and Hong Kong. It's currently being replicated with local celebrities in Germany and the Netherlands, Langer said.

"It is important for people to realize there can be enhanced possibilities for people of all ages and all walks of life," Langer emphasized. "My research has shown how using a different word, offering a small choice or making a subtle change in the physical environment can improve our health and well-being. Small changes can make large differences, so we should open ourselves to the impossible and embrace a psychology of possibility."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our psychology / psychiatry section for the latest news on this subject. Presentation: "The Psychology of Possibility," Ellen J. Langer, PhD, Session 2254, American Psychological Foundation Arthur W. Staats Lecture on Unifying Psychology, Friday, Aug. 3, 2 p.m. to 2:50 p.m., Room W304E, Level III, Orange County Convention Center.
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Awareness, Detection And Treatment Programs Required To Improve Breast Health Care In Pakistan

Among most women in Pakistan, there is limited awareness of breast cancer occurrence, detection, and screening practices, or the importance of self-breast exams and clinical breast exams, according to a study in the August issue of the Journal of the American College of Radiology. In Pakistan, breast cancer is the most common cancer affecting women and the incidence is rising. It is usually diagnosed in later stages and often at a younger age compared with populations in the West.

"Breast cancer care in limited-resource countries generally suffers because of multiple obstacles, including a lack of recognition of breast health as a public health priority, a shortage of trained health care workers and social or cultural barriers. An improved understanding of existing obstacles in breast cancer care is critical to identify those factors that may be correctable and thereby devise effective interventions for improving early breast cancer detection and treatment in disadvantaged countries," said Sughra Raza, MD, co-author of the study.

Questionnaires were developed to address demographics, financial and educational levels, knowledge regarding breast cancer occurrence and treatment, and religious and cultural beliefs that may affect seeking care for breast disease. Using the questionnaires, one-on-one surveys were administered by community health workers in Karachi to 200 women and 100 general practitioners.

Survey results showed that women's knowledge of breast cancer incidence, diagnosis and treatment was proportionate to educational level, while willingness to address breast health issues and interest in early detection were high regardless of education level. Very few women had ever undergone clinical breast examinations or mammography. Among general practitioners, most understood major risk factors and importance of early detection. However, 20 percent did not believe breast cancer occurs in Pakistan, and 30 percent believed that it is a fatal disease. Female general practitioners were more likely to perform clinical breast examinations than male general practitioners.

"Although there is limited awareness regarding breast cancer occurrence, detection, and screening practices, as well as the importance of self-breast exams and clinical breast exams, the majority of women are very keen to learn more, to participate in their own care and to lower their risk," said Raza.

"Awareness and educational activities, including training female clinical health workers to perform clinical breast exams, will be beneficial, as we begin instituting awareness, detection and treatment programs in the face of a rapidly rising incidence and late-stage detection of breast cancer in Pakistan," said Raza.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Improved Diagnosis For Essential Tremor

Researchers at the University of Montreal and its affiliated CHU Sainte-Justine and CHUM hospitals have linked some cases of Essential Tremor (ET) to a specific genetic problem. ET is the most common movement disorder, becoming increasingly frequent with increasing age, which is characterized by an involuntary shaking movement (tremor) that occurs with motion, particularly when doing precise fine movement. The researchers published their findings tomorrow in The American Journal of Human Genetics.

Exactly why this shaking occurs has remained unknown, despite the work of many clinicians and researchers for decades. While it is known that there is a problem with the parts of the brain that control certain muscles, it has been a challenging endeavor to identify what exactly is malfunctioning in the nervous system of affected individuals. Despite strong evidence that the disease has a genetic basis and years of research effort, no actual genetic link had been identified until today.

Scientists already knew that mutations in a gene called FUS (Fused in Sarcoma) cause amyotrophic lateral sclerosis (ALS), a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. The ET research team was successful in identifying mutations that cause ET in this gene, and they also proved that the disease mechanisms for ET and ALS FUS mutations are different. "When I started my post-doctoral work in the Rouleau laboratory, I felt compelled to study essential tremor. I saw a great opportunity to identify the first ET gene considering the plethora of families collected for study in the laboratory, and the availability of new sequencing technologies that has revolutionized gene discovery efforts," said lead author Dr. Nancy Merner. "As a proof of principle study, we chose one family to sequence and took a simple approach to overcome particular clinical barriers that have hindered previous gene discovery attempts."

The other members of the research team share her clinical focus. "This discovery has provided the world with the first insight toward the disease mechanism of essential tremor, which is crucial for disease management, particularly for future drug developments. It also presents a logical approach that can be used for additional ET gene discoveries, which we are currently pursuing" said Dr. Guy Rouleau. "There is currently a lack of consensus on the diagnostic criteria of ET thus a genetic diagnosis can be beneficial, especially for familial cases. Transitioning to a genetic diagnosis would cut down on ET misdiagnosis," added Dr. Patrick Dion who is another key researcher on this project. Misdiagnosis occurs in 37-50% of individual cases.

To affected individuals, the tremors are generally annoying and embarrassing, and can interfere with everyday tasks such as working, writing, eating, or drinking, since tremors affecting the hands are the most common and affected individuals can have trouble holding or using small objects. "Our overall goal in this endeavor is to improve the quality of life of affected individuals," said Dr. Merner. "The road is now paved for improvement."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our neurology / neuroscience section for the latest news on this subject. The identification of FUS was performed in the Rouleau laboratory and supported by the Chaire Jeanne-et-J.-Louis-Lévesque en Génétique des Maladies du Cerveau de l'Université de Montréal. The Canadian Institutes of Health Research has also funded the pursuit for additional ET genes.
About the study:
"Exome sequencing identifies FUS mutations as a cause of essential tremor." Authors: Nancy D. Merner, Simon L. Girard, Hélène Catoire, Cynthia V. Bourassa, Veronique V. Belzil, Jean-Baptiste Rivière, Pascale Hince, Annie Levert, Alexandre Dionne-Laporte, Dan Spiegelman, Anne Noreau, Sabrina Diab, Anna Szuto, Hélène Fournier, John Raelson, Majid Belouchi, Michel Panisset, Patrick Cossette, Nicolas Dupré, Geneviève Bernard, Sylvain Chouinard, Patrick A. Dion, and Guy. A Rouleau
About the researchers:
Dr. Guy Rouleau, M.D., PhD, Professor, Faculty of Medicine, Université de Montréal, Director of the CHU Ste-Justine Research Centre, Investigator at the Research Centre of the Centre hospitalier de l'Université de Montréal.
Dr. Nancy Merner, Ph.D., post-doctoral fellow, Faculty of Medicine, Université de Montréal
Dr. Patrick Dion, Ph.D., Research associate, Faculty of Medicine, Université de Montréal
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Alzheimer's Found To Be More Aggressive Among Younger Elderly But Slows In Advanced Age

The greatest risk factor for Alzheimer's disease (AD) is advancing age. By age 85, the likelihood of developing the dreaded neurological disorder is roughly 50 percent. But researchers at the University of California, San Diego School of Medicine say AD hits hardest among the "younger elderly" - people in their 60s and 70s - who show faster rates of brain tissue loss and cognitive decline than AD patients 80 years and older.

The findings, reported online in the journal PLOS One, have profound implications for both diagnosing AD - which currently afflicts an estimated 5.6 million Americans, a number projected to triple by 2050 - and efforts to find new treatments. There is no cure for AD and existing therapies do not slow or stop disease progression.

"One of the key features for the clinical determination of AD is its relentless progressive course," said Dominic Holland, PhD, a researcher at the Department of Neurosciences at UC San Diego and the study's first author. "Patients typically show marked deterioration year after year. If older patients are not showing the same deterioration from one year to the next, doctors may be hesitant to diagnose AD, and thus these patients may not receive appropriate care, which can be very important for their quality of life."

Holland and colleagues used imaging and biomarker data from participants in the Alzheimer's Disease Neuroimaging Initiative, a multi-institution effort coordinated at UC San Diego. They examined 723 people, ages 65 to 90 years, who were categorized as either cognitively normal, with mild cognitive impairment (an intermediate stage between normal, age-related cognitive decline and dementia) or suffering from full-blown AD.

"We found that younger elderly show higher rates of cognitive decline and faster rates of tissue loss in brain regions that are vulnerable during the early stages of AD," said Holland. "Additionally cerebrospinal fluid biomarker levels indicate a greater disease burden in younger than in older individuals."

Holland said it's not clear why AD is more aggressive among younger elderly.

"It may be that patients who show onset of dementia at an older age, and are declining slowly, have been declining at that rate for a long time," said co-author Linda McEvoy, PhD, associate professor of radiology. "But because of cognitive reserve or other still-unknown factors that provide 'resistance' against brain damage, clinical symptoms do not manifest till later age."

Another possibility, according to Holland, is that older patients may be suffering from mixed dementia - a combination of AD pathology and other neurological conditions. These patients might withstand the effects of AD until other adverse factors, such as brain lesions caused by cerebrovascular disease, take hold. At the moment, AD can only be diagnosed definitively by an autopsy. "So we do not yet know the underlying neuropathology of participants in this study," Holland said.

Clinical trials to find new treatments for AD may be impacted by the differing rates, researchers said. "Our results show that if clinical trials of candidate therapies predominately enroll older elderly, who show slower rates of change over time, the ability of a therapy to successfully slow disease progression may not be recognized, leading to failure of the clinical trial," said Holland. "Thus, it's critical to take into account age as a factor when enrolling subjects for AD clinical trials."

The obvious downside of the findings is that younger patients with AD lose more of their productive years to the disease, Holland noted. "The good news in all of this is that our results indicate those who survive into the later years before showing symptoms of AD will experience a less aggressive form of the disease."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our alzheimer's / dementia section for the latest news on this subject. Co-authors are Rahul S. Desikan, Department of Radiology, UCSD and Anders M. Dale, Departments of Neurosciences and Radiology, UCSD.
Funding for this research came, in part, from the National Institutes of Health (grants R01AG031224, R01AG22381, U54NS056883, P50NS22343 and P50MH08755); the National Institute on Aging (grant K01AG029218) and the National Institute of Biomedical Imaging and Bioengineering (grant T32EB005970).
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Critical Tumor Suppressor Identified For Cancer

Scientists from the Florida campus of The Scripps Research Institute have identified a protein that impairs the development and maintenance of lymphoma (cancer of the lymph nodes), but is repressed during the initial stages of the disease, allowing for rapid tumor growth.

While the study, published in the journal Cell, largely focuses on the role of this new tumor suppressor in lymphoma induced by Myc oncoproteins (the cancer-promoting products of Myc oncogenes), the authors show this circuit is apparently operational in all human tumors with MYC involvement, which is more than half of all human tumor types.

"This opens a new therapeutic avenue to exploit for cancers with Myc involvement - including relapsed metastatic tumors and refractory tumors, those that have not responded to treatment," said John Cleveland, a Scripps Research professor and chair of the Department of Cancer Biology, who led the study.

The Myc family of oncoproteins (c-Myc, N-Myc, and L-Myc) regulate critical pathways that contribute to tumors; c-Myc expression, which is activated in human Burkitt lymphoma, is sufficient to induce the growth of several tumor types in animal models.

In the new study, the scientists focused on precancerous and malignant Myc-expressing B cells, part of the immune system affected in human lymphoma. Using transgenic animal models, Cleveland and his team, led by the efforts of senior postdoctoral fellow Robert Rounbehler, showed that Myc-directed repression of a protein called tristetraprolin (TTP/ZFP36) was important for both the development and maintenance of cancer. The suppression of TTP is a hallmark of human cancers with MYC involvement, Cleveland noted.

The scientists' results showed that overriding this pathway by forced expression of TTP more than doubled the lifespan of Myc transgenic mice. Strikingly, Rounbehler discovered that re-introduction of TTP into Myc-driven lymphoma totally disabled these tumors, indicating an important therapeutic target.

The authors showed that Myc regulates hundreds of genes that contain adenylate-uridylate-rich elements (AU-rich elements), which play an important role in RNA stability and are found in many messenger RNAs (mRNAs) that code for oncogenes, nuclear transcription factors, and cytokines. AU-rich elements direct the mRNA for degradation; they are thought to be vital for controlling expression during cell growth.

"Myc regulates the expression of select AU-binding proteins to control the destruction of certain mRNAs," Cleveland said. "Also, our study strongly suggests that other AU-binding proteins may also, in fact, function as tumor suppressors in other cancers."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our lymphoma / leukemia / myeloma section for the latest news on this subject. The first author of the study, "Tristetraprolin is a Tumor Suppressor That Impairs Myc-Induced Lymphoma and Abolishes the Malignant State," is Robert J. Rounbehler of Scripps Research. Other authors include Mohammad Fallahi, Chunying Yang, Meredith A. Steeves, Weimin Li, Joanne R. Doherty, and Franz X. Schaub of Scripps Research; Sandhya Sanduja and Dan A. Dixon of the University of South Carolina; and Perry J. Blackshear of the National Institute of Environmental Health Sciences.
The study was supported by the National Institutes of Health (grant numbers DK44158, CA167093, F32-CA115075, and CA134609), ThinkPink Kids Foundation, the State of Florida, the National City Charitable Contributions Committee, the Glenn W. Bailey Postdoctoral Fellowship, and the PGA National Women’s Cancer Awareness Days.
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