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duminică, 5 august 2012

Breast Cancer Slowed By Plant-Based Compound In Mouse Model

The natural plant compound phenethyl isothiocyanate (PEITC) hinders the development of mammary tumors in a mouse model with similarities to human breast cancer progression, according to a study published in the Journal of the National Cancer Institute.

Edible plants are gaining ground as chemopreventative agents. PEITC has shown to be effective as a chemopreventative agent in mice for colon, intestinal, and prostate cancer, by inducing apoptosis.

In order to determine the efficacy of PEITC in mammary tumors in mice, Shivendra V. Singh, Ph.D., of the University of Pittsburgh Cancer Institute and colleagues, placed mice on two diets: a control diet, and a diet supplemented with PEITC for 29 weeks. The researchers performed histopathological assessments, and measured the incidence and size of the mammary tumors, along with cell proliferation, apoptosis, and neoangiogenesis, which were determined in tumor sections.

The researchers found that administering PEITC for 29 weeks was linked with a 56.3% reduction in mammary carcinoma lesions greater than 2mm. "Although PEITC administration does not confer complete protection against mammary carcinogenesis, mice placed on the PEITC-supplemented diet, compared with mice placed on the control diet, clearly exhibited suppression of carcinoma progression," the authors write. PEITC was also well-tolerated. Since chemoprevention trials are both expensive and time-consuming and necessitate years of follow-up, the authors feel that, "The discovery of biomarker(s) associated with exposure and activity is critical for clinical development of promising cancer chemopreventative agents." This study was able to identify certain biomarkers that may be useful in future clinical investigations.

The authors also point out certain limitations of their study, namely that the results may be different in humans than in mice; also both the relevance of other altered proteins from PEITC and the mechanism by which PEITC causes apoptosis are unclear.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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joi, 15 decembrie 2011

New Food Allergy Model For Fenugreek Developed

Main Category: Nutrition / Diet
Also Included In: Allergy
Article Date: 15 Dec 2011 - 1:00 PST

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A mouse model to investigate allergy to fenugreek has been developed by Norwegian researchers. The model can also be used to study cross-reactivity to peanut, soy and lupin, major food allergens with public health relevance.

Fenugreek is a member of the legume family and is used as an ingredient in curries, chutneys and teas. Allergic reactions to fenugreek may be severe yet its presence is rarely declared in ingredient listings. There is also great concern about potential cross-reactivity with other legumes such as peanut, soy and lupin.

"Allergens that are hidden in generic terms like spices, pose a special problem for food-allergic people. Fenugreek is a well-known food ingredient in Asian dishes, and as dietary patterns are changing, we will be more exposed to fenugreek also in Norway. Mouse models are important research tools that give valuable information in the understanding of food allergies, and may contribute to develop specific therapies for these food allergies" says Nina Eriksen Vinje, researcher at the Division of Environmental Medicine at the Norwegian Institute of Public Health. Vinje is the first author of the paper published in the Scandinavian Journal of Immunology.

Cross-reactivity between peanut and fenugreek first came to attention in 2006. The Norwegian Food Allergy Register received reports about allergic reactions to food containing curry powder, and cross-reactivity between peanut and fenugreek was confirmed in two peanut-allergic patients. It has since been discovered that fenugreek gives a stronger cross-reaction to peanut than other legumes such as soy and green peas.

Mouse models

New foods need to be tested on specific food-allergy models for each potential allergen. Mice are used as they have a well-characterised immune system that resembles the human immune system, allowing researchers to study complex immune reactions. The food-allergy model for fenugreek developed by the Norwegian Institute of Public Health can also be used to understand suspected cross-reactivity to peanuts and other legumes.

Article adapted by Medical News Today from original press release. Source: Wiley-Blackwell
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Prognostic Model Developed For MDS Related To Prior Cancer Therapy

Main Category: Cancer / Oncology
Article Date: 15 Dec 2011 - 2:00 PST

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A large-scale analysis of patients whose myelodysplastic syndrome is related to earlier cancer treatment overturns the notion that all of them have a poor prognosis, researchers from The University of Texas MD Anderson Cancer Center report at the 53rd Annual Meeting of the American Society of Hematology.

"MDS patients whose disease springs from earlier radiation, chemotherapy or both treatments are usually told that they have a poor prognosis. But by analyzing survival risk factors in a large patient population, we've found these patients fall into good, intermediate and poor prognostic groups," said study leader Guillermo Garcia-Manero, M.D., Ph.D., professor in MD Anderson's Department of Leukemia.

Understanding their differing characteristics will better inform treatment decisions for these patients, Garcia-Manero said.

Myelodysplastic syndrome consists of a group of diseases in which the bone marrow progenitor cells that normally morph into red and white blood cells and platelets fail to respond to normal growth controls. That results in too many progenitor cells (also known as blasts) and too few mature blood cells, and in about 30 percent of patients, the disease progresses to acute myeloid leukemia (AML).

Treatment-related MDS is often more resistant to therapy

Therapy-related MDS generally differs from other MDS cases by having more chromosomal abnormalities, a higher rate of conversions to acute myeloid leukemia and high resistance to standard MDS therapy. Even so, Garcia-Manero notes, a one-size-fits-all poor prognosis is not accurate.

The research team analyzed 1,950 MD Anderson patients treated between 1998 and 2007. It found 438 had a history of one or more previous cancers that were treated before their MDS diagnosis. Of these, 279 cases who had received chemotherapy, radiotherapy or both were analyzed.

A first round of analysis identified at least 15 factors associated with overall survival when considered as isolated, single variables.

Next, the researchers conducted a multi-variable analysis that narrowed factors reducing overall survival to seven:

Age 65 or older.

ECOG performance status scores of 2-4. (Eastern Cooperative Oncology Group criteria range from 0, which means fully active, to 4, signifying complete disability).

Cytogenetics. Having at least seven chromosomal alterations and/or complex cytogenetics.

Two MDS subgroups as determined by World Health Organization Criteria. RARS and RAEB-1/2.

Serum hemoglobin levels of less than 11g/dL.

Platelet levels of less than 50.

Dependency on blood transfusions.

Prognostic model sorts patients into three risk groups

Garcia-Manero and colleagues created a novel prognostic model that incorporated these multivariate factors and divided patients into three categories:

Good prognosis - 57 patients fell into this group by having 0-2 of the multivariate risk characteristics. Their median survival was 34 months.

Intermediate prognosis - 154 patients in this category had 3-4 risk factors and a median survival of 12 months.

Poor prognosis - 61 patients had 5-7 risk factors and a median survival of only five months.

The model also predicted one-year leukemia-free survival of 96 percent in the good category, 84 percent for intermediate, and 72 percent for the poor.

Model validated in a test group of patients

The researchers validated the model by applying it to an additional 189 treatment-related cases diagnosed between 2008 and 2010. Median survival rates in the test group were:

Good - 26 months

Intermediate - 13 months

Poor - 7 months.

"We believe this model will facilitate development of risk-adapted treatment strategies for patients with treatment-related myelodysplastic syndromes," Garcia-Manero said.

Article adapted by Medical News Today from original press release. Source: University of Texas M. D. Anderson Cancer Center
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marți, 13 decembrie 2011

In Rat Model Of Lou Gehrig's, Disease Progression Halted

Main Category: Neurology / Neuroscience
Also Included In: Genetics
Article Date: 13 Dec 2011 - 1:00 PST

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Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is an incurable adult neurodegenerative disorder that progresses to paralysis and death. Genetic mutations are the cause of disease in 5% of patients with ALS.

Of immense interest, Hongxia Zhou, Xu-Gang Xia, and colleagues, at Thomas Jefferson University, Philadelphia, now show that progressive neuron degeneration can be halted in a rat model of familial ALS linked to mutations in the gene that carries the instructions for making the protein TDP-43.

Progressive motor neuron degeneration was stopped when expression of the ALS-associated mutant human TDP-43 was switched off. If expression of the mutant protein was switched off before many motor neurons had degenerated, the rats recovered function. Conversely, if expression was switched off after most motor neurons had degenerated, functional recovery was minimal. These data indicate that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that progression of motor neuron degeneration (and thereby progression of disease) is partially reversible in the rat model.

TITLE: Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats

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vineri, 9 decembrie 2011

Cellular Automaton Model Predicts How Hair Follicle Stem Cells Regenerate

Main Category: Dermatology
Also Included In: Stem Cell Research
Article Date: 09 Dec 2011 - 0:00 PST

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Your hair -- or lack of hair -- is the result of a lifelong tug-of-war between activators that wake up, and inhibitors that calm, stem cells in every hair follicle on your body, according to Cheng-Ming Chuong, M.D., Ph.D., of the University of Southern California (USC).

Chuong presented the findings at the American Society for Cell Biology 2011 Annual Meeting in Denver.

Building on research reported last April in Science, Chuong and his colleagues teamed with Oxford University mathematicians Philip Maini, Ph.D., and Ruth E. Baker, Ph.D., to use a "cellular automaton" model to describe the population behavior of hair follicles.

Using the predictive model, the researchers found that each adult human hair follicle could count only on its intrinsic growth-promoting signals, without the help of adjacent follicles in the macro-environment. In contrast, the growth of both rabbit and mice hair follicles depended on signals from neighboring follicles.

The cellular automaton model consists of a regular mathematical grid of automata, each of which represents one hair follicle in one of its four functional cyclic stages. Surrounding each automaton are eight automata, the hair follicle's neighbors.

The state of each automaton changes according to rules that dictate whether hair on a human scalp or in an animal's fur coat will be caught up in waves of growth called the anagen phase, or remain in the resting or telogen phase. Under the right conditions -- winter season or a new physiological stage in an organism's life such as puberty -- a collective regeneration wave can sweep through the skin, activating hair stem cells in individual follicles and those in front of them, by the tens of thousands.

In other seasons or life stages, individual follicles may remain locked in telogen by the inhibitors in their macro-environment. Inhibitor levels are modulated in part by intradermal adipose tissue and the central endocrine system. These multiple layers of control create a balance between inhibitory BMP (bone morphogenic protein) signaling that keeps hair stem cells in quiescent state and activating Wnt signaling that wakes them up.

Chuong reported robust wave spreading in rabbits, gradual spreading in mice, and random growth with loss of follicle coupling in human skin. The data suggest a new approach to androgenic alopecia, the most common form of alopecia in aging males: It may be easier to get hair follicles growing again by improving their environment, rather than implanting stem cells.

The success of the cellular automaton method could be applied to a broad range of biological pattern formation situations, including the spread of infectious diseases or neural networking in the developing brain, said Chuong.

Chuong and his colleagues determined that spacing between hair stem cell clusters was critical. Because rabbits have compound follicles (multiple hairs from one follicle), their stem cells were tightly coupled, and their coats regenerated so rapidly that the patterns resembled rapidly changing fractals. In humans, coupling of hair follicles was much lower, probably as a result of human evolution, Chuong said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our dermatology section for the latest news on this subject. Minisymposium: Collective Cell Behavior and Morphogenesis in Development Presentation 184
The research is funded in part by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases. M. Plikus was supported by a training grant from the California Institute of Regenerative Medicine. C. Chen was supported by funding from Taipei VA Hospital and Yang Ming University. Collaborators at Oxford University, UK, were supported by EPSRC first grant and Royal Society Wolfson Research merit award.
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Important Milestone Toward 3D Model Of The Brain

Main Category: Neurology / Neuroscience
Also Included In: IT / Internet / E-mail; Medical Devices / Diagnostics
Article Date: 09 Dec 2011 - 1:00 PST

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Researchers from the lab of Nobel laureate Bert Sakmann, MD, PhD at the Max Planck Florida Institute (MPFI) are reporting that, using a conceptually new approach and state-of-the-art research tools, they have created the first realistic three-dimensional diagram of a thalamocortical column in the rodent brain. A vertically organized series of connected neurons that form a brain circuit, the cortical column is considered the elementary building block of the cortex, the part of the brain that is responsible for many of its higher functions.

This achievement is the first step toward creating a complete computer model of the brain, and may ultimately lead to an understanding of how the brain computes and how it goes awry in neurological, neurodevelopmental and psychiatric disorders. The study is published online in the journal Cerebral Cortex.

"This is the first complete 3D reconstruction of a realistic model of a cortical column," said Marcel Oberlaender, PhD, first author on the paper. "This is the first time that we have been able to relate the structure and function of individual neurons in a live, awake animal, using complete 3D reconstructions of axons and dendrites. By creating this model, we hope to begin understanding how the brain processes sensory information and how this leads to specific behaviors."

The electrically excitable axon extends from the body of the neuron (brain cell) and often gives rise to many smaller branches before ending at nerve terminals. Dendrites extend from the neuron cell body and receive messages from other neurons.

In addition to recreating the structure of the cortical column, the study also sheds significant light on the function of its constituent neurons, and the relationship between their functionality and structure. In looking at neurons' response to sensory stimulation, the researchers discovered that sensory-evoked activity in some of the cells can be directly correlated with their structure and connectivity, which marks a first step toward understanding basic organizational principles of the brain.

Working with both awake and anesthetized rats, and also examining stained brain slices, the neuroscientists used sophisticated new light microscopy as well as custom designed tools to examine 15,000 neurons of nine identified cell types. Using a painstaking, six-step process, the researchers identified and reconstructed the column's constituent parts using sophisticated software and a range of other new state-of-the-art tools and processes.

Described in a related paper co-authored by Drs. Sakmann and Oberlaender, these new methods, which were developed in part at the Max Planck Florida Institute, allow researchers, for the first time, to simulate electrical signaling in a computer model at subcellular and millisecond resolution.

"We can now quantify the number of neurons of each cell type, their three-dimensional structure, connectivity within these networks, and response to sensory stimulation, in both an anesthetized and awake animal," said Dr. Oberlaender. "Such a quantitative assessment of cortical structure and function is unprecedented and marks a milestone for future studies on mechanistic principles that may underlie signal flow in the brain, during such functions as decision making."

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. Dr. Oberlaender is part of the Max Planck Florida Institute's Digital Neuroanatomy group, led by Dr. Bert Sakmann. The group focuses on the functional anatomy of circuits in the cerebral cortex that form the basis of simple behaviors (e.g. decision making). One of the group's most significant efforts is a program dedicated to obtaining a three-dimensional map of the rodent brain. This work will provide insight into the functional architecture of entire cortical areas, and will lay the foundation for future studies on degenerative brain diseases, such as Alzheimer's.
Dr. Oberlaender and Dr. Christiaan de Kock contributed equally to this work. Dr. de Kock is with the Neuroscience Campus Amsterdam, VU University Amsterdam, the Netherlands. The research team also included scientists from Max Planck Institute for Medical Research (Heidelberg, Germany), Columbia University and Zuse Institute (Berlin).
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joi, 8 decembrie 2011

Supercomputer Reveals New Details Behind Drug-Processing Protein Model

Main Category: Pharma Industry / Biotech Industry
Also Included In: IT / Internet / E-mail
Article Date: 08 Dec 2011 - 1:00 PST

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Supercomputer simulations at the Department of Energy's Oak Ridge National Laboratory are giving scientists unprecedented access to a key class of proteins involved in drug detoxification.

Jerome Baudry and Yinglong Miao, who are jointly affiliated with ORNL and the University of Tennessee, have performed simulations to observe the motions of water molecules in a class of enzymes called P450s. Certain types of P450 are responsible for processing a large fraction of drugs taken by humans.

The supercomputer simulations were designed to help interpret ongoing neutron experiments.

"We simulated what happens in this enzyme over a time scale of 0.3 microseconds, which sounds very fast, but from a scientific point of view, it's a relatively long time," Baudry said. "A lot of things happen at this scale that had never been seen before. It's a computational tour de force to be able to follow that many water molecules for that long."

The team's study of the water molecules' movements contributes to a broader understanding of drug processing by P450 enzymes. Because some populations have a slightly different version of the enzymes, scientists hypothesize that mutations could partially explain why people respond differently to the same drug. One possibility is that the mutations might shut down the channels that bring water molecules in and out of the enzyme's active site, where the chemical modification of drugs takes place. This could be investigated by using the computational tools developed for this research.

By simulating how water molecules move in and out of the protein's centrally located active site, the team clarified an apparent contradiction between experimental evidence and theory that had previously puzzled researchers. X-ray crystallography, which provides a static snapshot of the protein, had shown only six water molecules present in the active site, whereas experimental observations indicated a higher number of water molecules would be present in the enzyme.

"We found that even though there can be many water molecules -- up to 12 at a given time that get in and out very quickly -- if you look at the average, those water molecules prefer to be at a certain location that corresponds to what you see in the crystal structure," Miao said. "It's a very dynamic hydration process that we are exploring with a combination of neutron scattering experiments and simulation."

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 simulation research is published in Biophysical Journal as "Active-Site Hydration and Water Diffusion in Cytochrome P450cam: A Highly Dynamic Process."
The team was supported by an Experimental Program to Stimulate Competitive Research (EPSCOR) grant from the DOE Office of Science and funding from the University of Tennessee. Computing time on the Kraken supercomputer was supported by a National Science Foundation TeraGrid award.
ORNL is managed by UT-Battelle for the Department of Energy's Office of Science.
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In Polycystic Kidney Disease Model, Vasodilator Hormone Improved Kidney Function & Blood Flow

Main Category: Urology / Nephrology
Also Included In: Genetics; Endocrinology
Article Date: 08 Dec 2011 - 0:00 PST

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After a four-week course of the vasodilator hormone relaxin, kidney function and blood flow immediately improved in lab rats genetically altered to model polycystic kidney disease (PKD), a life-threatening genetic disorder, according to research presented at the American Society for Cell Biology Annual Meeting in Denver.

In addition to widening the blood vessels, relaxin lowered the collagen scores of the PKD rats, indicating that the drug had slowed scar formation or helped dissolve the old fibroid tissue that characterizes the kidneys of animals and humans with the disease, according to Heather Ward, Ph.D., and Angela Wandinger-Ness, Ph.D., of the University of New Mexico and collaborators.

PKD is a life-threatening genetic disorder that affects 600,000 Americans, according to the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). About 50% of individuals diagnosed with PKD develop end-stage renal disease by age 60.

The researchers also noted that in rats, relaxin reduced the size of the large fluid-filled cysts that gradually encroach on kidney function in human PKD patients.

PKD was the first disease to be recognized as a ciliopathy, a disorder characterized by defects in primary cilia, tiny hair-like structures that protrude from virtually every cell in the human body.

In the search of effective treatments, most PKD researchers have concentrated on halting or reversing PKD's characteristic cyst formation.

Ward and her colleagues instead examined the non-cystic aspects of PKD progression, particularly the poor blood flow and extensive internal scarring called fibrosis that encroaches on the glomeruli, the vital clusters of looping blood vessels that filter wastes and excess water from the blood.

They decided to evaluate relaxin because the hormone is a powerful vasodilator. It was first identified in pregnant women but also occurs in men.

Prompted by the hormone's positive effects on the PKD animals, Ward and colleagues explored the differences in kidney gene expression between relaxin and control-treated rats. The results of the gene expression analysis suggested that relaxin, in part, affects genes associated with epithelial trafficking.

The researchers said that they hypothesize that relaxin's direct effect on signaling pathways of kidney fibroblasts and vascular cells improves the renal environment, indirectly affecting cystic epithelia and slowing cyst growth.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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