AVIAN VIRUS-AN ANTICANCER DRUG.......????!!!!!!!!!!

Avian Virus May Be Harmful to Cancer Cells

Dr. Elankumaran Subbiah. A new study has identified a chicken-killing virus as a promising treatment for prostate cancer in humans. (Credit: Image courtesy of Virginia Tech)

Apr. 8, 2013 — A study at the Virginia-Maryland Regional College of Veterinary Medicine has identified a chicken-killing virus as a promising treatment for prostate cancer in humans.

Researchers have discovered that a genetically engineered Newcastle disease virus, which harms chickens but not humans, kills prostate cancer cells of all kinds, including hormone-resistant cancer cells. The work of Dr. Elankumaran Subbiah, associate professor of virology in the Department of Biomedical Sciences and Pathobiology, along with Dr. Siba Samal, associate dean and chairman of the University of Maryland's Department of Veterinary Medicine, and Shobana Raghunath, a graduate student in Subbiah's laboratory, appears in the April 2013 issue of the Journal of Virology.

"This potential treatment is available for immediate pre-clinical and clinical trials, but these are typically not done at the university level," Subbiah said. "We are looking for commercial entities that are interested in licensing the technology for human clinical trials and treatment. Newcastle disease virus has yet to be tested as a treatment for prostate cancer in patients."

About one in six men will develop prostate cancer. Patients typically receive hormone treatments or chemotherapy, both of which have adverse side effects. Subbiah hopes that the development of new treatment methodologies will not only better fight prostate cancer, but also lessen the side effects commonly associated with hormone treatments and chemotherapy.

Newcastle disease virus affects domestic and wild bird species, especially chickens, and is one of the most economically important viruses to the poultry industry. Although it can cause mild conjunctivitis and flu-like symptoms in humans who have been in close contact with infected birds, it does not pose a threat to human health.

Scientists first documented the cancer-fighting properties of Newcastle disease virus in the 1950s, but it is only with recent advances in reverse genetics technology that they have turned to the genetically engineered virus as a possible treatment.

"We modified the virus so that it replicates only in the presence of an active prostate-specific antigen and, therefore, is highly specific to prostate cancer. We also tested its efficacy in a tumor model in vitro," Subbiah said. "The recombinant virus efficiently and specifically killed prostate cancer cells, while sparing normal human cells in the laboratory, but it would take time for this to move from the discovery phase to a treatment for prostate cancer patients."

Earlier human clinical trials for other types of cancer with naturally occurring strains of Newcastle disease virus required several injections of the virus in large quantities for success. Subbiah believes that the recombinant virus would be able to eradicate prostate cancer in much lower doses. It would also seek out metastatic prostate cancer cells and remove them. Because it is cancer cell-type specific, "the recombinant virus will be extremely safe and can be injected intravenously or directly into the tumor," Subbiah added.

Subbiah received a $113,000 concept award from the U.S. Department of Defense to develop his prostate cancer treatment under a Congressionally-directed medical research program. He is seeking additional foundation and corporate funds to take his research to the next level.

The researchers have also received a National Institutes of Health exploratory grant to develop the cell type-specific Newcastle disease virus for several other types of cancer cells, including breast, pancreas, brain, prostate, and multiple myeloma. "Although the virus can potentially treat many different types of cancer, we are focusing on these five," Subbiah said.

MNEMONIC TO REMEMBER MUSCLES OF FIRST ARCH.........

MUSCLES OF FIRST ARCH.........

MDT(Multi Drug Therapy)

M-Muscles of mastication(masseter,temporalis,medial n lateral pterygoid)

    -Mylohyoid

D-ant.belly of Digastric

T-Tensor tympani

  -Tensor palati

MNEMONIC TO REMEMBER DRUGS CAUSING GYNAECOMASTIA...........

Drugs causing gynaecomastia..........

"DISCO King"

D-digoxin

I-isoniazid

S-spironolactone

C-cimitidine

O-oestrogen

K-ketoconazole

AMAZING!! ANTIBODY CAN TRANSFORM STEM CELLS INTO BRAIN CELLS

Antibody Transforms Stem Cells Directly Into Brain Cells

Apr. 22, 2013 — In a serendipitous discovery, scientists at The Scripps Research Institute (TSRI) have found a way to turn bone marrow stem cells directly into brain cells.

                                                                                                                                                                                                                                                                       Scientists at The Scripps Research Institute have found a simple way to turn bone marrow stem cells directly into brain precursor cells, such as those shown here. (Credit: Image courtesy of the Lerner lab, The Scripps Research Institute)

Current techniques for turning patients' marrow cells into cells of some other desired type are relatively cumbersome, risky and effectively confined to the lab dish. The new finding points to the possibility of simpler and safer techniques. Cell therapies derived from patients' own cells are widely expected to be useful in treating spinal cord injuries, strokes and other conditions throughout the body, with little or no risk of immune rejection.

"These results highlight the potential of antibodies as versatile manipulators of cellular functions," said Richard A. Lerner, the Lita Annenberg Hazen Professor of Immunochemistry and institute professor in the Department of Cell and Molecular Biology at TSRI, and principal investigator for the new study. "This is a far cry from the way antibodies used to be thought of -- as molecules that were selected simply for binding and not function."

The researchers discovered the method, reported in the online Early Edition of the Proceedings of the National Academy of Sciences the week of April 22, 2013, while looking for lab-grown antibodies that can activate a growth-stimulating receptor on marrow cells. One antibody turned out to activate the receptor in a way that induces marrow stem cells -- which normally develop into white blood cells -- to become neural progenitor cells, a type of almost-mature brain cell.

Nature's Toolkit

Natural antibodies are large, Y-shaped proteins produced by immune cells. Collectively, they are diverse enough to recognize about 100 billion distinct shapes on viruses, bacteria and other targets. Since the 1980s, molecular biologists have known how to produce antibodies in cell cultures in the laboratory. That has allowed them to start using this vast, target-gripping toolkit to make scientific probes, as well as diagnostics and therapies for cancer, arthritis, transplant rejection, viral infections and other diseases.

In the late 1980s, Lerner and his TSRI colleagues helped invent the first techniques for generating large "libraries" of distinct antibodies and swiftly determining which of these could bind to a desired target. The anti-inflammatory antibody Humira®, now one of the world's top-selling drugs, was discovered with the benefit of this technology.

Last year, in a study spearheaded by TSRI Research Associate Hongkai Zhang, Lerner's laboratory devised a new antibody-discovery technique -- in which antibodies are produced in mammalian cells along with receptors or other target molecules of interest. The technique enables researchers to determine rapidly not just which antibodies in a library bind to a given receptor, for example, but also which ones activate the receptor and thereby alter cell function.

Lab Dish in a Cell

For the new study, Lerner laboratory Research Associate Jia Xie and colleagues modified the new technique so that antibody proteins produced in a given cell are physically anchored to the cell's outer membrane, near its target receptors. "Confining an antibody's activity to the cell in which it is produced effectively allows us to use larger antibody libraries and to screen these antibodies more quickly for a specific activity," said Xie. With the improved technique, scientists can sift through a library of tens of millions of antibodies in a few days.

In an early test, Xie used the new method to screen for antibodies that could activate the GCSF receptor, a growth-factor receptor found on bone marrow cells and other cell types. GCSF-mimicking drugs were among the first biotech bestsellers because of their ability to stimulate white blood cell growth -- which counteracts the marrow-suppressing side effect of cancer chemotherapy.

The team soon isolated one antibody type or "clone" that could activate the GCSF receptor and stimulate growth in test cells. The researchers then tested an unanchored, soluble version of this antibody on cultures of bone marrow stem cells from human volunteers. Whereas the GCSF protein, as expected, stimulated such stem cells to proliferate and start maturing towards adult white blood cells, the GCSF-mimicking antibody had a markedly different effect.

"The cells proliferated, but also started becoming long and thin and attaching to the bottom of the dish," remembered Xie.

To Lerner, the cells were reminiscent of neural progenitor cells -- which further tests for neural cell markers confirmed they were.

A New Direction

Changing cells of marrow lineage into cells of neural lineage -- a direct identity switch termed "transdifferentiation" -- just by activating a single receptor is a noteworthy achievement. Scientists do have methods for turning marrow stem cells into other adult cell types, but these methods typically require a radical and risky deprogramming of marrow cells to an embryonic-like stem-cell state, followed by a complex series of molecular nudges toward a given adult cell fate. Relatively few laboratories have reported direct transdifferentiation techniques.

"As far as I know, no one has ever achieved transdifferentiation by using a single protein -- a protein that potentially could be used as a therapeutic," said Lerner.

Current cell-therapy methods typically assume that a patient's cells will be harvested, then reprogrammed and multiplied in a lab dish before being re-introduced into the patient. In principle, according to Lerner, an antibody such as the one they have discovered could be injected directly into the bloodstream of a sick patient. From the bloodstream it would find its way to the marrow, and, for example, convert some marrow stem cells into neural progenitor cells. "Those neural progenitors would infiltrate the brain, find areas of damage and help repair them," he said.

While the researchers still aren't sure why the new antibody has such an odd effect on the GCSF receptor, they suspect it binds the receptor for longer than the natural GCSF protein can achieve, and this lengthier interaction alters the receptor's signaling pattern. Drug-development researchers are increasingly recognizing that subtle differences in the way a cell-surface receptor is bound and activated can result in very different biological effects. That adds complexity to their task, but in principle expands the scope of what they can achieve. "If you can use the same receptor in different ways, then the potential of the genome is bigger," said Lerner.

In addition to Lerner and Xie, contributors to the study, "Autocrine Signaling Based Selection of Combinatorial Antibodies That Transdifferentiate Human Stem Cells," were Hongkai Zhang of the Lerner Laboratory, and Kyungmoo Yea of The Scripps Korea Antibody Institute, Chuncheon-si, Korea.

Funding for the study was provided by The Scripps Korea Antibody Institute and Hongye Innovative Antibody Technologies (HIAT).

                         courtesy:science daily                            

ON WESTERN DIET?? BEWARE IT MAY REDUCE UR LYF SPAN

Following a Western Style Diet May Lead to Greater Risk of Premature Death

Apr. 15, 2013 — Data from a new study of British adults suggest that adherence to a "Western-style" diet (fried and sweet food, processed and red meat, refined grains, and high-fat dairy products) reduces a person's likelihood of achieving older ages in good health and with higher functionality. Study results appear in the May issue of The American Journal of Medicine.

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Data from a new study of British adults suggest that adherence to a "Western-style" diet (fried and sweet food, processed and red meat, refined grains, and high-fat dairy products) reduces a person's likelihood of achieving older ages in good health and with higher functionality. (Credit: © draghicich / Fotolia)

"The impact of diet on specific age-related diseases has been studied extensively, but few investigations have adopted a more holistic approach to determine the association of diet with overall health at older ages," says lead investigator Tasnime Akbaraly, PhD, Inserm, Montpellier, France. "We examined whether diet, assessed in midlife, using dietary patterns and adherence to the Alternative Healthy Eating Index (AHEI), is associated with aging phenotypes, identified after a mean 16-year follow-up."

The AHEI is a validated index of diet quality, originally designed to provide dietary guidelines with the specific intention to combat major chronic conditions such as cardiovascular diseases and diabetes.

Investigators analyzed findings from the British Whitehall II cohort study, which suggest that following the AHEI can double the odds of reversing metabolic syndrome, a condition known to be a strong predictor of heart disease and mortality. The research team sought to identify dietary factors that can not only prevent premature death, but also promote ideal aging.

Researchers followed 3,775 men and 1,575 women from 1985-2009 with a mean age of 51 years from the Whitehall II study. Using a combination of hospital data, results of screenings conducted every five years, and registry data, investigators identified mortality and chronic diseases among participants. The outcomes at follow-up stage, classified into 5 categories were:

1. Ideal aging, defined as free of chronic conditions and high performance in physical, mental, and cognitive functioning tests -- 4.0 percent

2. Nonfatal cardiovascular event -- 12.7 percent

3. Cardiovascular death -- 2.8 percent

4. Noncardiovascular death -- 7.3 percent

5. Normal aging -- 73.2 percent

The study determined that participants with low adherence to the AHEI increased their risk of cardiovascular and noncardiovascular death. Those who followed a "Western-type diet" consisting of fried and sweet food, processed food and red meat, refined grains, and high-fat dairy products lowered their chances for ideal aging.

"We showed that following specific dietary recommendations such as the one provided by the AHEI may be useful in reducing the risk of unhealthy aging, while avoidance of the 'Western-type foods' might actually improve the possibility of achieving older ages free of chronic diseases and remaining highly functional," notes Dr. Akbaraly. "A better understanding of the distinction between specific health behaviors that offer protection against diseases and those that move individuals towards ideal aging may facilitate improvements in public health prevention packages."

                                                                                                            courtesy:science daily

mnemonic

Inferior vena cava tributaries

"I Like To Rise So High":

Illiacs

Lumbar

Testicular

Renal

Suprarenal

Hepatic vein.

Think of the IVC wanting to rise high up to the heart.

TELOMERASE:KEY FACTOR IN CANCER N AGING; ITS STRUCTURE UNVEILED

Scientists Map Elusive 3-D Structure of Telomerase Enzyme, Key Actor in Cancer, Aging

Apr. 11, 2013 — Like finally seeing all the gears of a watch and how they work together, researchers from UCLA and UC Berkeley have, for the first time ever, solved the puzzle of how the various components of an entire telomerase enzyme complex fit together and function in a three-dimensional structure.

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The three-dimensional electron microscopy structure of the complete Tetrahymena telomerase enzyme complex, with previously solved high-resolution structures modeled in. (Credit: Jiansen Jiang, Edward Miracco/UCLA Chemistry and Biochemistry)

The creation of the first complete visual map of the telomerase enzyme, which is known to play a significant role in aging and most cancers, represents a breakthrough that could open up a host of new approaches to fighting disease, the researchers said.

"Everyone in the field wants to know what telomerase looks like, and there it was. I was so excited, I could hardly breathe," said Juli Feigon, a UCLA professor of chemistry and biochemistry and a senior author of the study. "We were the first to see it."

The scientists report the positions of each component of the enzyme relative to one another and the complete organization of the enzyme's active site. In addition, they demonstrate how the different components contribute to the enzyme's activity, uniquely correlating structure with biochemical function.

The research appears April 11 in the print edition of the journal Nature.

"We combined every single possible method we could get our hands on to solve this structure and used cutting-edge technological advances," said co-first author Jiansen Jiang, a researcher who works with Feigon and the study's co-senior author, Z. Hong Zhou, director of the Electron Imaging Center for Nanomachines at the California NanoSystems Institute at UCLA and a professor of microbiology, immunology and molecular genetics. "This breakthrough would not have been possible five years ago."

"We really had to figure out how everything fit together, like a puzzle," said co-first author Edward Miracco, a National Institutes of Health postdoctoral fellow in Feigon's laboratory. "When we started fitting in the high-resolution structures to the blob that emerged from electron microscopy, we realized that everything was fitting in and made sense with decades of past biochemistry research. The project just blossomed, and the blob became a masterpiece."

The telomerase enzyme is a mixture of components that unite inside our cells to maintain the protective regions at the ends of our chromosomes, which are called telomeres. Telomeres act like the plastic tips at the end of shoelaces, safeguarding important genetic information. But each time a cell divides, these telomeres shorten, like the slow-burning fuse of a time bomb. Eventually, the telomeres erode to a point that is no longer tolerable for cells, triggering the cell death that is a normal part of the aging process.

While most cells have relatively low levels of telomerase, 80 percent to 90 percent of cancer cells have abnormally high telomerase activity. This prevents telomeres from shortening and extends the life of these tumorigenic cells -- a significant contributor to cancer progression.

The new discovery creates tremendous potential for pharmaceutical development that takes into account the way a drug and target molecule might interact, given the shape and chemistry of each component. Until now, designing a cancer-fighting drug that targeted telomerase was much like shooting an arrow to hit a bulls-eye while wearing a blindfold. With this complete visual map, the researchers are starting to remove that blindfold.

"Inhibiting telomerase won't hurt most healthy cells but is predicted to slow down the progression of a broad range of cancers," said Miracco. "Our structure can be used to guide targeted drug development to inhibit telomerase, and the model system we used may also be useful to screen candidate drugs for cancer therapy."

The researchers solved the structure of telomerase in Tetrahymena thermophila, the single-celled eukaryotic organism in which scientists first identified telomerase and telomeres, leading to the 2009 Nobel Prize in medicine or physiology. Research on Tetrahymena telomerase in the lab of co-senior author Kathleen Collins, a professor of molecular and cell biology at UC Berkeley, laid the genetic and biochemical groundwork for the structure to be solved.

"The success of this project was absolutely dependent on the collaboration among our research groups," said Feigon.

"At every step of this project, there were difficulties," she added. "We had so many technical hurdles to overcome, both in the electron microscopy and the biochemistry. Pretty much every problem we could have, we had, and yet at each stage these hurdles were overcome in an innovative way."

One of the biggest surprises, the researchers said, was the role of the protein p50, which acts as a hinge in Tetrahymena telomerase to allow dynamic movement within the complex; p50 was found to be an essential player in the enzyme's activity and in the recruitment of other proteins to join the complex.

"The beauty of this structure is that it opens up a whole new world of questions for us to answer," Feigon said. "The exact mechanism of how this complex interacts with the telomere is an active area of future research."

"The atmosphere and collaboration at UCLA really amazes me, and that is combined with some of the most advanced facilities around," Zhou said. "We have a highly advanced electron microscopy facility here at UCLA that even researchers without a strong background in electron microscopy can learn how to use and benefit from. This will be really useful as we move forward."

This research was funded by the National Science Foundation and the National Institutes of Health. Equal contributions to the publication were made by co-first authors Jiang and Miracco, postdoctoral researchers at UCLA with Zhou and Feigon. Members of Kathleen Collins' UC Berkeley laboratory who contributed to this research included technician Kyungah Hong, postdoctoral researcher Barbara Eckert and former graduate researcher Bosun Min. Other co-authors included Henry Chan and Darian D. Cash, UCLA graduate student researchers in Feigon's laboratory.

                                                                                                                       courtesy science daily

BIRD FLU: EVOLVING AS A NEW GLOBAL EPIDEMIC

Could New Flu Spark Global Flu Pandemic? New Bird Flu Strain Seen Adapting to Mammals, Humans

Apr. 12, 2013 — A genetic analysis of the avian flu virus responsible for at least nine human deaths in China portrays a virus evolving to adapt to human cells, raising concern about its potential to spark a new global flu pandemic.

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Artist's rendering of virus. A genetic analysis of the avian flu virus responsible for at least nine human deaths in China portrays a virus evolving to adapt to human cells, raising concern about its potential to spark a new global flu pandemic. (Credit: iStockphoto)

The collaborative study, conducted by a group led by Masato Tashiro of the Influenza Virus Research Center, National Institute of Infectious Diseases, and Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo, appears in the current edition (April 11, 2013) of the journal Eurosurveillance. The group examined the genetic sequences of H7N9 isolates from four of the pathogen's human victims as well as samples derived from birds and the environs of a Shanghai market.

"The human isolates, but not the avian and environmental ones, have a protein mutation that allows for efficient growth in human cells and that also allows them to grow at a temperature that corresponds to the upper respiratory tract of humans, which is lower than you find in birds," says Kawaoka, a leading expert on avian influenza.

The findings, drawn from genetic sequences deposited by Chinese researchers into an international database, provide some of the first molecular clues about a worrisome new strain of bird flu, the first human cases of which were reported on March 31 by the Chinese Center for Disease Control and Prevention. So far, the new virus has sickened at least 33 people, killing nine. Although it is too early to predict its potential to cause a pandemic, signs that the virus is adapting to mammalian and, in particular, human hosts are unmistakable, says Kawaoka.

Access to the genetic information in the viruses, he adds, is necessary for understanding how the virus is evolving and for developing a candidate vaccine to prevent infection.

Influenza virus depends on its ability to attach to and commandeer the living cells of its host to replicate and spread efficiently. Avian influenza rarely infects humans, but can sometimes adapt to people, posing a significant risk to human health.

"These viruses possess several characteristic features of mammalian influenza viruses, which likely contribute to their ability to infect humans and raise concerns regarding their pandemic potential," Kawaoka and his colleagues conclude in the Eurosurveillance report.

Kawaoka, a faculty member in the UW-Madison School of Veterinary Medicine who also holds a faculty appointment at the University of Tokyo, explains that the majority of the viruses in the study -- from both humans and birds -- display mutations in the surface protein hemagglutinin, which the pathogen uses to bind to host cells. Those mutations, according to Kawaoka, allowed them to easily infect human cells.

In addition, the isolates from patients contained another mutation that allows the virus to efficiently replicate inside human cells. The same mutation, Kawaoka notes, lets the avian virus thrive in the cooler temperatures of the human upper respiratory system. It is in the cells of the nose and throat that flu typically gains a hold in a mammalian or human host.

Kawaoka and his colleagues also assessed the response of the new strain to drugs used to treat influenza, discovering that one class of commonly used antiviral drugs, ion channel inhibitors which effectively bottle up the virus in the cell, would not be effective; the new strain could be treated with another clinically relevant antiviral drug, oseltamivir.

In addition to Kawaoka and Tashiro, co-authors of the Eurosurveillance report include Tsutomu Kageyama, Seiichiro Fujisaki, Emi Takashita, Hong Xu, Shinya Yamada, Yuko Uchida, Gabriele Neumann and Takehiko Saito. The work was supported by Grants-in-Aid for Pandemic Influenza Research and Grant-in-Aid for Specially Promoted Research from the Ministry of Health, Labour and Welfare, Japan; by the NIAID Center for Research on Influenza Pathogenesis (CRIP, HHSN266200700010C); by a Grant-in-Aid for Specially Promoted Research, by the Japan Initiative for Global Research Network on Infectious Diseases from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; and by ERATO, Japan.

                                                                                                                            courtesy:science daily

Leg: anterior compartmnt of leg

The Hospitals Are Not Dirty Places

T : tibialis anterior
H :extensor hallucis longus
A : anterior tibial artery
N ; deep fibular nerve
D :extensor digitorum longus
P :peroneus tertius