Compound Kills Highly Contagious Flu Strain by Activating Antiviral Protein

A compound tested by UT Southwestern Medical Center investigators destroys several viruses, including the deadly Spanish flu that killed an estimated 30 million people in the worldwide pandemic of 1918.

This lead compound -- which acts by increasing the levels of a human antiviral protein -- could potentially be developed into a new drug to combat the flu, a virus that tends to mutate into strains resistant to anti-influenza drugs.

"The virus is 'smart' enough to bypass inhibitors or vaccines sometimes. Therefore, there is a need for alternative strategies. Current drugs act on the virus, but here we are uplifting a host/human antiviral response at the cellular level," said Dr. Beatriz Fontoura, associate professor of cell biology and senior author of the study available online in Nature Chemical Biology.

According to National Institutes of Health, influenza hospitalizes more than 200,000 people in the U.S. each year, with about 36,000 fatalities related to the illness. Worldwide, flu kills about 500,000 people annually.

In the latest cell testing, the compound successfully knocked out three types of influenza as well as a smallpox-related virus and an animal virus. Because of the highly contagious nature of the 1918 flu, those tests took place at Mount Sinai School of Medicine in New York, one of the few places that stores and runs tests on that flu strain.

The compound is among others that the research team is testing that induce an infection-fighting human protein called REDD1. Until this study, researchers had not demonstrated that REDD1 had this important antiviral function.

"We've discovered that REDD1 is a key human barrier for infection," said Dr. Fontoura, "Interestingly, REDD1 inhibits a signaling pathway that regulates cell proliferation and cancer."

The UT Southwestern-led research team tested 200,000 compounds for those that would inhibit flu virus infection. A total of 71 were identified.

Using the two most promising compounds, researchers at UT Southwestern and colleagues at Mount Sinai next will work to strengthen their potencies for further testing. Dr. Fontoura said it can take more than 10 years before successful compounds are developed into drugs.

UT Southwestern researchers involved in the study were lead author Miguel Mata and Neal Satterly, both graduate students in Dr. Fontoura's laboratory; Dr. Doug Frantz, former assistant professor of biochemistry; Shuguang Wei, a senior researcher in biochemistry; Dr. Noelle Williams, associate professor of biochemistry; Samuel Pena-Llopis, assistant instructor in developmental biology; Dr. James Brugarolas, assistant professor of internal medicine; Dr. Christian Forst, assistant professor of clinical sciences; Dr. Michael White, professor of cell biology; and Dr. Michael Roth, professor of biochemistry.

The research was supported by nine National Institutes of Health grants and by the Diane and Hal Brierley Distinguished Chair Fund.

Journal Reference:

1. Miguel A Mata, Neal Satterly, Gijs A Versteeg, Doug Frantz, Shuguang Wei, Noelle Williams, Mirco Schmolke, Samuel Peña-Llopis, James Brugarolas, Christian V Forst, Michael A White, Adolfo García-Sastre, Michael G Roth, Beatriz M A Fontoura. Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor. Nature Chemical Biology, 2011; 7 (10): 712 DOI: 10.1038/nchembio.645

Courtesy: ScienceDaily

Edible Carbon Dioxide Sponge: All-Natural Nanostructures Could Address Pressing Environmental Problem

A year ago Northwestern University chemists published their recipe for a new class of nanostructures made of sugar, salt and alcohol. Now, the same team has discovered the edible compounds can efficiently detect, capture and store carbon dioxide. And the compounds themselves are carbon-neutral.

The porous crystals -- known as metal-organic frameworks (MOFs) -- are made from all-natural ingredients and are simple to prepare, giving them a huge advantage over other MOFs. Conventional MOFs, which also are effective at adsorbing carbon dioxide, are usually prepared from materials derived from crude oil and often incorporate toxic heavy metals.

Other features of the Northwestern MOFs are they turn red when completely full of carbon dioxide, and the carbon capture process is reversible.

The findings, made by scientists working in the laboratory of Sir Fraser Stoddart, Board of Trustees Professor of Chemistry in the Weinberg College of Arts and Sciences, are published in the Journal of the American Chemical Society (JACS).

"We are able to take molecules that are themselves sourced from atmospheric carbon, through photosynthesis, and use them to capture even more carbon dioxide," said Ross S. Forgan, a co-author of the study and a postdoctoral fellow in Stoddart's laboratory. "By preparing our MOFs from naturally derived ingredients, we are not only making materials that are entirely nontoxic, but we are also cutting down on the carbon dioxide emissions associated with their manufacture."

The main component, gamma-cyclodextrin, is a naturally occurring biorenewable sugar molecule that is derived from cornstarch.

The sugar molecules are held in place by metals taken from salts such as potassium benzoate or rubidium hydroxide, and it is the precise arrangement of the sugars in the crystals that is vital to their successful capture of carbon dioxide.

"It turns out that a fairly unexpected event occurs when you put that many sugars next to each other in an alkaline environment -- they start reacting with carbon dioxide in a process akin to carbon fixation, which is how sugars are made in the first place," said Jeremiah J. Gassensmith, lead author of the paper and also a postdoctoral fellow in Stoddart's laboratory. "The reaction leads to the carbon dioxide being tightly bound inside the crystals, but we can still recover it at a later date very simply."

The fact that the carbon dioxide reacts with the MOF, an unusual occurrence, led to a simple method of detecting when the crystals have reached full capacity. The researchers place an indicator molecule, which detects changes in pH by changing its color, inside each crystal. When the yellow crystals of the MOFs are full of carbon dioxide they turn red.

The simplicity of the new MOFs, allied with their low cost and green credentials, have marked them as candidates for further commercialization. Ronald A. Smaldone, also a postdoctoral fellow in Stoddart's group and a co-author of the paper, added, "I think this is a remarkable demonstration of how simple chemistry can be successfully applied to relevant problems like carbon capture and sensor technology."

The National Science Foundation, the U.S. Department of Energy, the Engineering and Physical Sciences Research Council in the U.K., the King Abdulaziz City of Science and Technology (KACST) in Saudi Arabia and the Korea Advanced Institute of Science and Technology (KAIST) in Korea supported the research.

Journal Reference:

1. Jeremiah J. Gassensmith, Hiroyasu Furukawa, Ronald A. Smaldone, Ross S. Forgan, Youssry Y. Botros, Omar M. Yaghi, J. Fraser Stoddart. Strong and Reversible Binding of Carbon Dioxide in a Green Metal–Organic Framework. Journal of the American Chemical Society, 2011; 110913144109022 DOI: 10.1021/ja206525x

Courtesy: ScienceDaily

Targeting HIV's Sugar Coating: New Microbicide May Block AIDS Virus from Infecting Cells

University of Utah researchers have discovered a new class of compounds that stick to the sugary coating of the AIDS virus and inhibit it from infecting cells -- an early step toward a new treatment to prevent sexual transmission of the virus.

Development and laboratory testing of the potential new microbicide to prevent human immunodeficiency virus infection is outlined in a study set for online publication in the journal Molecular Pharmaceutics.

Despite years of research, there is only one effective microbicide to prevent sexual transmission of HIV, which causes AIDS, or acquired immune deficiency syndrome. Microbicide development has focused on gels and other treatments that would be applied vaginally by women, particularly in Africa and other developing regions.

To establish infection, HIV must first enter the cells of a host organism and then take control of the cells' replication machinery to make copies of itself. Those HIV copies in turn infect other cells. These two steps of the HIV life cycle, known as viral entry and viral replication, each provide a potential target for anti-AIDS medicines.

"Most of the anti-HIV drugs in clinical trials target the machinery involved in viral replication," says the study's senior author, Patrick F. Kiser, associate professor of bioengineering and adjunct associate professor of pharmaceutics and pharmaceutical chemistry at the University of Utah.

"There is a gap in the HIV treatment pipeline for cost-effective and mass-producible viral entry inhibitors that can inactivate the virus before it has a chance to interact with target cells," he says.

Kiser conducted the study with Alamelu Mahalingham, a University of Utah graduate student in pharmaceutics and pharmaceutical chemistry; Anthony Geonnotti of Duke University Medical Center in Durham, N.C.; and Jan Balzarini of Catholic University of Leuven in Belgium.

The research was funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, the Catholic University of Leuven, Belgium, and the Fund for Scientific Research, also in Belgium.

Synthetic Lectins Inhibit HIV from Entering Cells

Lectins are a group of molecules found throughout nature that interact and bind with specific sugars. HIV is coated with sugars that help to hide it from the immune system. Previous research has shown that lectins derived from plants and bacteria inhibit the entry of HIV into cells by binding to sugars found on the envelope coating the virus.

However, the cost of producing and purifying natural lectins is prohibitively high. So Kiser and his colleagues developed and evaluated the anti-HIV activity of synthetic lectins based on a compound called benzoboroxole, or BzB, which sticks to sugars found on the HIV envelope.

Kiser and his colleagues found that these BzB-based lectins were capable of binding to sugar residues on HIV, but the bond was too weak to be useful. To improve binding, they developed polymers of the synthetic lectins. The polymers are larger molecules made up of repeating subunits, which contained multiple BzB binding sites. The researchers discovered that increasing the number and density of BzB binding sites on the synthetic lectins made the substances better able to bind to the AIDS virus and thus have increased antiviral activity.

"The polymers we made are so active against HIV that dissolving about one sugar cube's weight of the benzoboroxole polymer in a bath tub of water would be enough to inhibit HIV infection in cells," says Kiser.

Depending on the strain, HIV displays significant variations in its viral envelope, so it is important to evaluate the efficacy of any potential new treatment against many different HIV strains.

Kiser and his colleagues found that their synthetic lectins not only showed similar activity across a broad spectrum of HIV strains, but also were specific to HIV and didn't affect other viruses with envelopes.

The scientists also tested the anti-HIV activity of the synthetic lectins in the presence of fructose, a sugar present in semen, which could potentially compromise the activity of lectin-based drugs because it presents an alternative binding site. However, the researchers found that the antiviral activity of the synthetic lectins was fully preserved in the presence of fructose.

"The characteristics of an ideal anti-HIV microbicide include potency, broad-spectrum activity, selective inhibition, mass producibility and biocompatibility," says Kiser. "These benzoboroxole-based synthetic lectins seem to meet all of those criteria and present an affordable and scalable potential intervention for preventing sexual transmission in regions where HIV is pandemic."

Kiser says future research will focus on evaluating the ability of synthetic lectins to prevent HIV transmission in tissues taken from the human body, with later testing in primates. Kiser and his colleagues are also developing a gel form of the polymers, which could be used as a topical treatment for preventing sexual HIV transmission.

Journal Reference:

1. Alamelu Mahalingam, Anthony R Geonnotti, Jan Balzarini, Patrick Franklin Kiser. Activity and Safety of Synthetic Lectins Based on Benzoboroxole-Functionalized Polymers for Inhibition of HIV Entry. Molecular Pharmaceutics, 2011; 110831135436035 DOI: 10.1021/mp2002957

Courtesy: ScienceDaily

Scientists Take First Step Towards Creating 'Inorganic Life'

Scientists at the University of Glasgow say they have taken their first tentative steps towards creating 'life' from inorganic chemicals potentially defining the new area of 'inorganic biology'.

Professor Lee Cronin, Gardiner Chair of Chemistry in the College of Science and Engineering, and his team have demonstrated a new way of making inorganic-chemical-cells or iCHELLs.

Prof Cronin said: "All life on earth is based on organic biology (i.e. carbon in the form of amino acids, nucleotides, and sugars, etc.) but the inorganic world is considered to be inanimate.

"What we are trying do is create self-replicating, evolving inorganic cells that would essentially be alive. You could call it inorganic biology."

The cells can be compartmentalised by creating internal membranes that control the passage of materials and energy through them, meaning several chemical processes can be isolated within the same cell -- just like biological cells.

The researchers say the cells, which can also store electricity, could potentially be used in all sorts of applications in medicine, as sensors or to confine chemical reactions.

The research is part of a project by Prof Cronin to demonstrate that inorganic chemical compounds are capable of self-replicating and evolving -- just as organic, biological carbon-based cells do.

The research into creating 'inorganic life' is in its earliest stages, but Prof Cronin believes it is entirely feasible.

Prof Cronin said: "The grand aim is to construct complex chemical cells with life-like properties that could help us understand how life emerged and also to use this approach to define a new technology based upon evolution in the material world -- a kind of inorganic living technology.

"Bacteria are essentially single-cell micro-organisms made from organic chemicals, so why can't we make micro-organisms from inorganic chemicals and allow them to evolve?

"If successful this would give us some incredible insights into evolution and show that it's not just a biological process. It would also mean that we would have proven that non carbon-based life could exist and totally redefine our ideas of design."

The paper is published in the journal Angewandte Chemie.

Journal Reference:

1. Geoffrey J. T. Cooper, Philip J. Kitson, Ross Winter, Michele Zagnoni, De-Liang Long, Leroy Cronin. Modular Redox-Active Inorganic Chemical Cells: iCHELLs. Angewandte Chemie International Edition, 2011; DOI: 10.1002/anie.201105068

Courtesy: ScienceDaily

Potential Molecular Target to Prevent Growth of Cancer Cells Identified

Researchers have shown for the first time that the protein fortilin promotes growth of cancer cells by binding to and rendering inert protein p53, a known tumor suppressor. This finding by researchers at the University of Texas Medical Branch may lead to treatments for a range of cancers and atherosclerosis, which p53 also helps prevent, and appears in the current print issue of the Journal of Biological Chemistry.

"The p53 protein is a critical defense against cancer because it activates genes that induce apoptosis, or the death of cells. However, p53 can be made powerless by mutations and inhibitors like fortilin," said Dr. Ken Fujise, lead author of the study and director, Division of Cardiology at UTMB.

Fortilin, an amino acid polypeptide protein, works in direct opposition to p53, protecting cells from apoptosis. Fujise discovered fortilin in 2000 and the protein has become a central focus of his research. This study marks the first time that scientists have been able to show the exact mechanism whereby fortilin exerts its anti-apoptotic activity.

Fujise and his team used cell cultures and animal models to show that fortilin binds to and inhibits p53, preventing it from activating genes, such as BAX and Noxa, that facilitate cell death. Thus, cells that would be killed are allowed to proliferate.

"When normal cells become cancer cells, our bodies' natural biological response is to activate p53, which eliminates the hopelessly damaged cells," said Fujise. "This process explains why the majority of people are able to stay cancer-free for most of their lives. Conversely, mutated p53 genes are seen in more than half of all human cancers, making them the most frequently observed genetic abnormality in cancer."

According to Fujise, upon further research and validation of the biological mechanism described in this study, scientists can begin exploring compounds that could modulate fortilin's activity on p53.

Such a compound would be a powerful chemotherapy agent and, because p53 inhibition has also been associated with atherosclerosis, could also protect against coronary disease and its many complications, including heart attack and stroke.

"Though we are in the early stages of this research, once screening for compounds is initiated, we could have a potential new drug to investigate in a very short period of time," said Fujise. With the support of National Institutes of Health high-throughput screening programs, which make it possible to screen very large numbers of compounds against a drug target, the process of identifying a new drug could potentially be shortened to months rather than years, he added.

Other authors include scientists at UTMB and other institutions: Yanjie Chen, Takayuki Fujita, Di Zhang, Hung Doan, Decha Pinkaew, Zhihe Liu, Jiaxin Wu, Yuichi Koide, Andrew Chiu, Curtis Chen Jun Lin, Jui-Yoa Chang; and Ke-He Ruan.

The study was supported in part by the National Institutes of Health, the American Heart Association, and MacDonald General Research Fund.

Journal Reference:

1. Y. Chen, T. Fujita, D. Zhang, H. Doan, D. Pinkaew, Z. Liu, J. Wu, Y. Koide, A. Chiu, C. C.-J. Lin, J.-Y. Chang, K.-H. Ruan, K. Fujise. Physical and Functional Antagonism between Tumor Suppressor Protein p53 and Fortilin, an Anti-apoptotic Protein. Journal of Biological Chemistry, 2011; 286 (37): 32575 DOI: 10.1074/jbc.M110.217836

Courtesy: ScienceDaily

World-First Viral Therapy Trial in Cancer Patients

Researchers from the Ottawa Hospital Research Institute (OHRI), the University of Ottawa (uOttawa), Jennerex Inc. and several other institutions have just reported promising results of a world-first cancer therapy trial in journal Nature. The trial is the first to show that an intravenously-delivered viral therapy can consistently infect and spread within tumours without harming normal tissues in humans. It is also the first to show tumour-selective expression of a foreign gene after intravenous delivery.

The trial involved 23 patients (including seven at The Ottawa Hospital), all with advanced cancers that had spread to multiple organs and failed to respond to standard treatments. The patients received a single intravenous infusion of a virus called JX-594, at one of five dose levels, and biopsies were obtained eight to 10 days later. Seven of eight patients (87 per cent) in the two highest dose groups had evidence of viral replication in their tumour, but not in normal tissues. All of these patients also showed tumour-selective expression of a foreign gene that was engineered into the virus to help with detection. The virus was well tolerated at all dose levels, with the most common side effect being mild to moderate flu-like symptoms that lasted less than one day.

"We are very excited because this is the first time in medical history that a viral therapy has been shown to consistently and selectively replicate in cancer tissue after intravenous infusion in humans," said Dr. John Bell, a Senior Scientist at OHRI, Professor of Medicine at uOttawa and senior co-author on the publication. "Intravenous delivery is crucial for cancer treatment because it allows us to target tumours throughout the body as opposed to just those that we can directly inject. The study is also important because it shows that we can use this approach to selectively express foreign genes in tumours, opening the door to a whole new suite of targeted cancer therapies."

Dr. Bell and his team have been investigating cancer-fighting (oncolytic) viruses at OHRI for more than 10 years. JX-594 was developed in partnership with Jennerex Inc., a biotherpeutics company co-founded by Dr. Bell in Ottawa and Dr. David Kirn in San Francisco. JX-594 is derived from a strain of vaccinia virus that has been used extensively as a live vaccine against smallpox. It has a natural ability to replicate preferentially in cancer cells, but it has also been genetically engineered to enhance its anti-cancer properties.

"Oncolytic viruses are unique because they can attack tumours in multiple ways, they have very mild side effects compared to other treatments, and they can be easily customized for different kinds of cancer," said Dr. Bell. "We're still in the early stages of testing these viruses in patients, but I believe that someday, viruses and other biological therapies could truly transform our approach for treating cancer."

Although the current trial was designed primarily to assess safety and delivery of JX-594, anti-tumour activity was also evaluated. Six of eight patients (75%) in the two highest dose groups experienced a shrinking or stabilization of their tumour, while those in lower dose groups were less likely to experience this effect.

"These results are promising, especially for such an early-stage trial, with only one dose of therapy," said Dr. Bell. "But of course, we will need to do more trials to know if this virus can truly make a difference for patients. We are working hard to get these trials started, and at the same time, we are also working in the laboratory to advance our understanding of these viruses and figure out how best to use them."

This research was supported by Jennerex Inc., the Terry Fox Foundation, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, The Ottawa Hospital Foundation, the Canada Foundation for Innovation, the Natural Sciences and Engineering Research Council of Canada and the Republic of Korea. OHRI / uOttawa authors on the paper include Dr. John Bell, Dr. Derek Jonker, Dr. Laura Chow, Dr. Fabrice Le Boeuf, Joe Burns, Laura Evgin, Naomi De Silva, Sara Cvancic, Dr. Kelley Parato, Dr. Jean-Simon Diallo and Dr. Manijeh Daneshmand, as well as alumnus Dr. Caroline Breitbach.

Journal Reference:

1. Caroline J. Breitbach, James Burke, Derek Jonker, Joe Stephenson, Andrew R. Haas, Laura Q. M. Chow, Jorge Nieva, Tae-Ho Hwang, Anne Moon, Richard Patt, Adina Pelusio, Fabrice Le Boeuf, Joe Burns, Laura Evgin, Naomi De Silva, Sara Cvancic, Terri Robertson, Ji-Eun Je, Yeon-Sook Lee, Kelley Parato, Jean-Simon Diallo, Aaron Fenster, Manijeh Daneshmand, John C. Bell, David H. Kirn. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature, 2011; 477 (7362): 99 DOI: 10.1038/nature10358

Courtesy: ScienceDaily

Nanosensors Made from DNA May Light Path to New Cancer Tests and Drugs

Sensors made from custom DNA molecules could be used to personalize cancer treatments and monitor the quality of stem cells, according to an international team of researchers led by scientists at UC Santa Barbara and the University of Rome Tor Vergata.

The new nanosensors can quickly detect a broad class of proteins called transcription factors, which serve as the master control switches of life. The research is described in an article published in Journal of the American Chemical Society.

"The fate of our cells is controlled by thousands of different proteins, called transcription factors," said Alexis Vallée-Bélisle, a postdoctoral researcher in UCSB's Department of Chemistry and Biochemistry, who led the study. "The role of these proteins is to read the genome and translate it into instructions for the synthesis of the various molecules that compose and control the cell. Transcription factors act a little bit like the 'settings' of our cells, just like the settings on our phones or computers. What our sensors do is read those settings."

When scientists take stem cells and turn them into specialized cells, they do so by changing the levels of a few transcription factors, he explained. This process is called cell reprogramming. "Our sensors monitor transcription factor activities, and could be used to make sure that stem cells have been properly reprogrammed," said Vallée-Bélisle. "They could also be used to determine which transcription factors are activated or repressed in a patient's cancer cells, thus enabling physicians to use the right combination of drugs for each patient."

Andrew Bonham, a postdoctoral scholar at UCSB and co-first author of the study, explained that many labs have invented ways to read transcription factors; however, this team's approach is very quick and convenient. "In most labs, researchers spend hours extracting the proteins from cells before analyzing them," said Bonham. "With the new sensors, we just mash the cells up, put the sensors in, and measure the level of fluorescence of the sample."

This international research effort -- organized by senior authors Kevin Plaxco, professor in UCSB's Department of Chemistry and Biochemistry, and Francesco Ricci, professor at the University of Rome, Tor Vergata -- started when Ricci realized that all of the information necessary to detect transcription factor activities is already encrypted in the human genome, and could be used to build sensors. "Upon activation, these thousands of different transcription factors bind to their own specific target DNA sequence," said Ricci. "We use these sequences as a starting point to build our new nanosensors."

The key breakthrough underlying this new technology came from studies of the natural biosensors inside cells. "All creatures, from bacteria to humans, monitor their environments using 'biomolecular switches' -- shape-changing molecules made from RNA or proteins," said Plaxco. "For example, in our sinuses, there are millions of receptor proteins that detect different odor molecules by switching from an 'off state' to an 'on state.' The beauty of these switches is that they are small enough to operate inside a cell, and specific enough to work in the very complex environments found there."

Inspired by the efficiency of these natural nanosensors, the research group teamed with Norbert Reich, also a professor in UCSB's Department of Chemistry and Biochemistry, to build synthetic switching nanosensors using DNA, rather than proteins or RNA.

Specifically, the team re-engineered three naturally occurring DNA sequences, each recognizing a different transcription factor, into molecular switches that become fluorescent when they bind to their intended targets. Using these nanometer-scale sensors, the researchers could determine transcription factor activity directly in cellular extracts by simply measuring their fluorescence level.

The researchers believe that this strategy will ultimately allow biologists to monitor the activation of thousands of transcription factors, leading to a better understanding of the mechanisms underlying cell division and development. "Alternatively, since these nanosensors work directly in biological samples, we also believe that they could be used to screen and test new drugs that could, for example, inhibit transcription-factor binding activity responsible for the growth of tumor cells," said Plaxco.

This work was funded by the National Institute of Health, the Fond Québécois de la Recherche sur la Nature et les Technologies, the Italian Ministry of University and Research (MIUR) project "Futuro in Ricerca," and the Tri-County Blood Bank Santa Barbara Foundation.

Journal Reference:

1. Alexis Vallée-Bélisle, Andrew J. Bonham, Norbert O. Reich, Francesco Ricci, Kevin W. Plaxco. Transcription Factor Beacons for the Quantitative Detection of DNA Binding Activity. Journal of the American Chemical Society, 2011; 133 (35): 13836 DOI: 10.1021/ja204775k

Courtesy: ScienceDaily

Doctors' and Nurses' Hospital Uniforms Contain Dangerous Bacteria a Majority of the Time, Study Shows

More than 60 percent of hospital nurses' and doctors' uniforms tested positive for potentially dangerous bacteria, according to a study published in the September issue of the American Journal of Infection Control, the official publication of APIC -- the Association for Professionals in Infection Control and Epidemiology.

A team of researchers led by Yonit Wiener-Well, MD, from the Shaare Zedek Medical Center in Jerusalem, Israel, collected swab samples from three parts of the uniforms of 75 registered nurses (RNs) and 60 medical doctors (MDs) by pressing standard blood agar plates at the abdominal zone, sleeves' ends and pockets.

The researchers at this 550-bed, university-affiliated hospital found that exactly half of all the cultures taken, representing 65 percent of the RN uniforms and 60 percent of the MD uniforms, harbored pathogens. Of those, 21 cultures from RN uniforms and six cultures from MD uniforms contained multi-drug resistant pathogens, including eight cultures that grew methicillin-resistant Staphylococcus aureus (MRSA). Although the uniforms themselves may not pose a direct risk of disease transmission, these results indicate a prevalence of antibiotic resistant strains in close proximity to hospitalized patients.

"It is important to put these study results into perspective," said APIC 2011 President Russell Olmsted, MPH, CIC. "Any clothing that is worn by humans will become contaminated with microorganisms. The cornerstone of infection prevention remains the use of hand hygiene to prevent the movement of microbes from these surfaces to patients."

"New evidence such as this study by Dr. Wiener-Well is helpful to improve the understanding of potential sources of contamination but, as is true for many studies, it raises additional questions that need to be investigated," added Olmsted.

According to the World Health Organization, the risk of healthcare-associated infection (HAI) in some developing countries is as much as 20 times higher than in developed countries. Even in hospitals in developed countries like Israel, the site of this investigation, and the U.S., HAIs occur too often, can be deadly, and are expensive to treat. HAI prevention is therefore the best approach for patient safety. Infection preventionists, in collaboration with direct care providers, can prevent more than half of HAIs by applying proven prevention practices as part of a comprehensive infection prevention and control program.

Journal Reference:

1. Yonit Wiener-Well, Margalit Galuty, Bernard Rudensky, Yechiel Schlesinger, Denise Attias, Amos M. Yinnon. Nursing and physician attire as possible source of nosocomial infections. American Journal of Infection Control, 2011; 39 (7): 555 DOI: 10.1016/j.ajic.2010.12.016

Courtesy: ScienceDaily

New Strategy for Overcoming Resistance to Targeted Cancer Drug

Scientists at Dana-Farber Cancer Institute and colleagues overseas have discovered a pair of backup circuits in cancer cells that enable the cells to dodge the effect of a widely used cancer drug. Jamming those circuits with targeted therapies may heighten or restore the drug's potency, according to a study published in the Sept. 7 issue of Science Translational Medicine.

The research focused on the drug cetuximab, an antibody that interferes with cancer cell growth by blocking a structure known as the epidermal growth factor receptor (EGFR). Cetuximab is effective in many patients with colorectal cancer or squamous cell cancer of the head and neck, but the benefits rarely last longer than a year, and some patients receive no benefit from the drug.

Until now, scientists haven't known why cancers that initially respond to cetuximab become resistant to it, or how to overcome such resistance.

In the new study, researchers led by Pasi Janne, MD, PhD, of Dana-Farber and Kimio Yonesaka, MD, PhD, formerly of Dana-Farber and now at Kinki University School of Medicine, in Osaka, Japan, found that in some cetuximab-resistant cancer cells, a protein known as ERBB2 was actively sending "grow" signals, circumventing the "stop growing" signals triggered by cetuximab. The researchers discovered that ERBB2's activity sprang from an oversupply of the protein's parent gene, Her2/neu, or by a related protein, ERBB3, when prompted by high levels of the protein heregulin. In both cases, the new growth messages are unaffected by cetuximab.

"ERBB2 activates a critical signaling pathway that is not normally blocked by cetuximab, and in this way subverts cetuximab's function," says Janne, the study's co-senior author with Kazuhiko Nakagawa, MD, PhD, of Kinki University. "Because ERBB2 isn't affected by cetuximab, this is an easy way for cancers to become resistant to the drug."

The findings suggest that combining cetuximab with ERBB2-inhibiting drugs could be an effective therapy for cancers that are cetuximab-resistant from the start or for those that become resistant over time, the study authors say. Several such inhibitors have already been approved, while others are undergoing clinical study.

"We hope the findings of our study will inspire the development of clinical trials aimed at overcoming cetuximab resistance," Yonesaka remarks. "We've identified biomarkers that can be used to select cetuximab-resistant patients who may benefit from a combination of cetuximab and ERBB2 inhibitors."

Janne estimates that up to 40 percent of colorectal cancers are cetuximab-resistant when first diagnosed. He notes that although the ERBB2 pathway may be responsible for many cases of cetuximab resistance, there are undoubtedly other pathways, yet to be discovered, that play a similar role. Further research is needed to confirm ERBB2's role in cetuximab resistance and to develop strategies for testing ERBB2 inhibitors and cetuximab in clinical trials.

Funding for the study was provided by grants from the National Institutes of Health, the American Cancer Society, the William Randolph Hearst Foundation, and the Hazel and Samuel Bellin research fund.

Co-authors of the paper include Kreshnik Zejnullahu, Dalia Ercan, Andrew Rogers, Juliet Philips, MS, Jason Sun, Takafumi Okabe, MD, PhD, Jeffrey Swanson, MD, and Ramesh Shivdasani, MD, PhD, Dana-Farber; Isamu Okamoto, MD, PhD, Taroh Satoh, MD, Masayuki Takeda, MD, PhD, Yasuhito Fujisaka, MD, Toshio Shimizu, MD, PhD, Osamu Maenishi, Hiroyuki Itoh, MD, Kiyotaka Okuno, MD, Minoru Takada, MD, Masahiro Fukuoka, MD, and Kazuto Nishio, MD, PhD, Kinki University, Osaka, Japan; Federico Cappuzzo, MD, Massimo Roncalli, MD, and Annarita Destro, PhD, Instituto Clinico Humanitas, Rozzano, Italy; John Souglakos, MD, PhD, University of Crete, Heraklion, Greece; Yonggon Cho, and Marileila Varella-Garcia, University of Colorado Cancer Center, Denver; Koichi Taira, MD, and Koji Takeda, MD, Osaka City General Hospital, Japan; and Eugene Lifshits and Jeffrey Engelman, MD, PhD, Massachusetts General Hospital.

Journal Reference:

1. Kimio Yonesaka, Kreshnik Zejnullahu, Isamu Okamoto, Taroh Satoh, Federico Cappuzzo, John Souglakos, Dalia Ercan, Andrew Rogers, Massimo Roncalli, Masayuki Takeda, Yasuhito Fujisaka, Juliet Philips, Toshio Shimizu, Osamu Maenishi, Yonggon Cho, Jason Sun, Annarita Destro, Koichi Taira, Koji Takeda, Takafumi Okabe, Jeffrey Swanson, Hiroyuki Itoh, Minoru Takada, Eugene Lifshits, Kiyotaka Okuno, Jeffrey A. Engelman, Ramesh A. Shivdasani, Kazuto Nishio, Masahiro Fukuoka, Marileila Varella-Garcia, Kazuhiko Nakagawa, Pasi A. Jänne. Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab. Science Translational Medicine, 2011; 3 (99): 99ra86 DOI: 10.1126/scitranslmed.3002442

Courtesy: ScienceDaily

Scientists Pinpoint Shape-Shifting Mechanism Critical to Protein Signaling

In a joint study, scientists from the California and Florida campuses of The Scripps Research Institute have shown that changes in a protein's structure can change its signaling function and they have pinpointed the precise regions where those changes take place.

The new findings could help provide a much clearer picture of potential drugs that would be both effective and highly specific in their biological actions.

The study, led by Patrick Griffin of Scripps Florida and Raymond Stevens of Scripps California, was published in a recent edition of the journal Structure.

The new study focuses on the β2-adrenergic receptor, a member of the G protein-coupled receptor family. G protein-coupled receptors convert extracellular stimuli into intracellular signals through various pathways. Approximately one third of currently marketed drugs (including for diabetes and heart disease) target these receptors.

Scientists have known that when specific regions of the receptor are activated by neurotransmitters or hormones, the structural arrangement (conformation) of the receptor is changed along with its function.

"While it's accepted that these receptors adopt multiple conformations and that each conformation triggers a specific type of signaling, the molecular mechanism behind that flexibility has been something of a black box," said Griffin, who is chair of the Scripps Research Department of Molecular Therapeutics and director of the Scripps Florida Translational Research Institute. "Our findings shed significant light to it."

The study describes in structural detail the various regions of the receptor that are involved in the changes brought about by selective ligands (ligands are molecules that bind to proteins to form an active complex), which, like a rheostat, run the gamut among activating the receptor, shutting it down, and reversing its function, as well as producing various states in between.

To achieve the results described in the study, the team used hydrogen-deuterium (HDX) mass spectrometry to measure the impact of interaction of various functionally selective ligands with the β2-adrenergic receptor. A mass spectrometer determines the mass of fragments from the receptor by measuring the mass-to-charge ratio of their ions. HDX has been used to examine changes in the shape of proteins and how these shape changes relate to protein function. The approach is often used to characterize protein-protein interactions that are critical for signal transduction in cells and to study protein-folding pathways that are critical to cell survival.

"At this early stage in understanding GPCR structure and function, it is important to view the entire receptor in combination with probing very specific regions," said Stevens, who is a professor in the Scripps Research Department of Molecular Biology. "Hydrogen-deuterium exchange mass spectrometry has the right timescale and resolution to asked important questions about complete receptor conformations in regards to different pharmacological ligand binding. The HDX data combined with the structural data emerging will really help everyone more fully understand how these receptors work."

"Using the HDX technology we can study the intact receptor upon interaction with ligands and pinpoint regions of the receptor that have undergone change in position or flexibility," Griffin said. "By studying a set of ligands one can start to develop patterns that are tied to activation of the receptor or shutting it down. Once we get a picture of what a functional ligand looks like, it might be possible to develop a drug to produce a highly selective therapeutic effect."

The lead author of the study, "Ligand-Dependent Perturbation of the Conformational Ensemble for the GPCR b2 Adrenergic Receptor Revealed by HDX," is Graham M. West of Scripps Research. Other authors include Ellen Y.T. Chien, Jovylyn Gatchalian, and Michael J. Chalmers of Scripps Research, and Vsevolod Katritch of the University of California, San Diego.

The study was supported by the National Institutes of Health.

Journal Reference:

1. Graham M. West, Ellen Y.T. Chien, Vsevolod Katritch, Jovylyn Gatchalian, Michael J. Chalmers, Raymond C. Stevens, Patrick R. Griffin. Ligand-Dependent Perturbation of the Conformational Ensemble for the GPCR β2 Adrenergic Receptor Revealed by HDX. Structure, 2011; DOI: 10.1016/j.str.2011.08.001

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Cognitive Changes May Predict Alzheimer's Disease Development More Accurately Than Biomarkers

Compared with changes in biomarkers, changes in cognitive abilities appear to be stronger predictors of whether an individual with mild cognitive impairment (MCI) will develop Alzheimer's disease, according to a report in the September issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Biomarkers such as changes in brain volume or in cerebrospinal fluid levels of some proteins have helped scientists learn about how Alzheimer's disease develops and whether treatments for it are effective, according to background information in the article. Behavioral markers such as cognitive changes, genetic risk factors and demographic variables also seem to be associated with the condition. However, the authors write, "despite formidable evidence for the predictive validity of individual biomarkers and behavioral markers, they have rarely been examined in combined models."

Jesus J. Gomar, Ph.D., from the Benito Menni Complex Assistencial en Salut Mental, Barcelona, Spain, and colleagues sought to determine how well different classes of biomarkers and cognitive markers could predict whether patients with MCI would develop Alzheimer's disease. They also wanted to assess whether any of these factors was associated with a disproportionate magnitude of decline. The longitudinal study used information from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The study included 116 participants with MCI that converted to Alzheimer's disease in two years, 204 participants with MCI that did not convert to Alzheimer's disease and 197 cognitively healthy participants as controls.

The researchers used a variety of neuropsychological tests to assess participants' cognition and ability to function. They obtained cerebrospinal fluid samples when the study began and at annual visits for two years. At the beginning of the study, participants gave a blood sample which was examined for the presence of genes associated with Alzheimer's disease. The researchers also obtained information about participants' brain volume and cortical thickness from magnetic resonance imaging results included in the ADNI.

Analysis of the variables showed that two measures of delayed memory, as well as the cortical thickness of the left middle temporal lobe in the brain, were associated with a higher chance of converting from MCI to Alzheimer's disease at two years. A change in participants' scores on a measure of functional activities appeared to show a larger rate of decline than did changes in biomarkers. In particular, a decline in scores on the Functional Assessment Questionnaire and the Trail Making Test, part B, appeared to predict whether an individual with MCI would develop Alzheimer's disease within one year.

"Cognitive markers at baseline were more robust predictors of conversion than most biomarkers," write the authors. "Longitudinal analyses suggested that conversion appeared to be driven less by changes in the neurobiologic trajectory of the disease than by a sharp decline in functional ability and, to a lesser extent, by declines in executive function." The researchers add that in clinical practice and in clinical trials, the optimal way to accurately predict conversion to Alzheimer's disease is to use all available data.

Journal Reference:

1. J. J. Gomar, M. T. Bobes-Bascaran, C. Conejero-Goldberg, P. Davies, T. E. Goldberg. Utility of Combinations of Biomarkers, Cognitive Markers, and Risk Factors to Predict Conversion From Mild Cognitive Impairment to Alzheimer Disease in Patients in the Alzheimer's Disease Neuroimaging Initiative. Archives of General Psychiatry, 2011; 68 (9): 961 DOI: 10.1001/archgenpsychiatry.2011.96

Courtesy: ScienceDaily

Scientists Create Mammalian Cells With Single Chromosome Set

Researchers have created mammalian cells containing a single set of chromosomes for the first time in research funded by the Wellcome Trust and EMBO. The technique should allow scientists to better establish the relationships between genes and their function.

Mammal cells usually contain two sets of chromosomes -- one set inherited from the mother, one from the father. The genetic information contained in these chromosome sets helps determine how our bodies develop. Changes in this genetic code can lead to or increase the risk of developing disease.

To understand how our genes function, scientists manipulate the genes in animal models -- such as the fruit fly, zebrafish and mice -- and observe the effects of these changes. However, as each cell contains two copies of each chromosome, determining the link between a genetic change and its physical effect -- or 'phenotype' -- is immensely complex.

Now, in research published in the journal Nature, Drs Anton Wutz and Martin Leeb from the Wellcome Trust Centre for Stem Cell Research at the University of Cambridge report a technique which enables them to create stem cells containing just a single set of chromosomes from an unfertilised mouse egg cell. The stem cells can be used to identify mutations in genes that affect the cells' behaviour in culture. In an additional step, the cells can potentially be implanted into the mouse for studying the change in organs and tissues.

The technique has previously been used in zebrafish, but this is the first time it has been successfully used to generate such mammalian stem cells.

Dr Wutz, a Wellcome Trust Senior Research Fellowship, explains: "These embryonic stem cells are much simpler than normal embryonic mammalian stem cells. Any genetic change we introduce to the single set of chromosomes will have an easy-to-determine effect. This will be useful for exploring in a systematic way the signalling mechanisms within cell and how networks of genes regulate development."

The researchers hope that this technique will help advance mammalian genetics and our understanding of the gene-function relationship in the same way that a similar technique has helped geneticists understand the simpler zebrafish animal model.

Understanding how our genetic make-up functions and how this knowledge can be applied to improve our health is one of the key strategic challenges set out by the Wellcome Trust. Commenting on this new study, Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust, says:

"This technique will help scientists overcome some of the significant barriers that have so far made studying the functions of genes so difficult. This is often the first step towards understanding why mutations lead to disease and, ultimately, to developing new drugs treatments."

Journal Reference:

1. Martin Leeb, Anton Wutz. Derivation of haploid embryonic stem cells from mouse embryos. Nature, 2011; DOI: 10.1038/nature10448

Courtesy: ScienceDaily

Research Aims to Starve Breast Cancer Cells

The most common breast cancer uses the most efficient, powerful food delivery system known in human cells and blocking that system kills it, researchers report.

This method of starving cancer cells could provide new options for patients, particularly those resistant to standard therapies such as tamoxifen, Georgia Health Sciences University researchers said.

Human estrogen receptor-positive breast cancer cells thriving in a Petri dish or transplanted onto mice die when exposed to a drug that blocks the transporter, called SLC6A14, said Dr. Vadivel Ganapathy, Chairman of GHSU's Department of Biochemistry and Molecular Biology.

"It basically starves the cancer cell," said Ganapathy, corresponding author of the study published in the Journal of Biological Chemistry. The transporter can carry 18 of the known 20 amino acids, fuel all cells need in some combination. Amino acids enable cells to make proteins, which they need to function and survive. The cell type determines its amino acid needs and delivery system. Rapidly growing, dividing estrogen receptor-positive breast cancer needs nearly every amino acid so it makes the smart choice of utilizing the transporter that can deliver the biggest load, Ganapathy said.

SLC6A14 is the only transporter known to carry all 10 essential amino acids, essential because the body can't make them so they have to be delivered via the bloodstream from food. The transporter also takes eight of the nonessential amino acids along for the ride, Ganapathy said.

And it is a fast ride. The transporter has three energy sources instead of the usual one or two, he said.

Interestingly, SLC6A14 is expressed at low levels in most of the body. "There are specialized features of this transport system which could be used by every cell to its advantage but they do not seem to do that. It's expressed only at low levels in normal tissues," Ganapathy noted. While that may seem like a loss for healthy cells, it bolsters the cancer-fighting potential for drugs that block SLC6A14 by making it a more specific cancer target. "Since the normal cells do not depend on this transporter, you can use a drug that selectively blocks it to target cancer cells" Ganapathy said.

The compound they used is alpha-methyl-DL-tryptophan, already used in humans for short periods when they are getting a PET scan in certain areas of the brain. When the researchers treated estrogen receptor-positive breast cancer cells with it or put it in the drinking water of the mice with the cells, rapid growth stopped and the cancer cells died. Further studies showed alpha-methyl-DL-tryptophan seemed to impact only cells expressing the SLC6A14 transport system. Even another type of breast cancer, estrogen receptor-negative, wasn't impacted.

Researchers are now determining the most potent version of the compound.

The research was supported by the National Institutes of Health.

Journal Reference:

1. S. Karunakaran, S. Ramachandran, V. Coothankandaswamy, S. Elangovan, E. Babu, S. Periyasamy-Thandavan, A. Gurav, J. P. Gnanaprakasam, N. Singh, P. V. Schoenlein, P. D. Prasad, M. Thangaraju, V. Ganapathy. SLC6A14 (ATB0, ), a highly concentrative and broad-specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer. Journal of Biological Chemistry, 2011; DOI: 10.1074/jbc.M111.229518

Courtesy: ScienceDaily

New Method Reveals Parts of Bacterial Genome Essential to Life

A team at the Stanford University School of Medicine has cataloged, down to the letter, exactly what parts of the genetic code are essential for survival in one bacterial species, Caulobacter crescentus.

They found that 12 percent of the bacteria's genetic material is essential for survival under laboratory conditions. The essential elements included not only protein-coding genes, but also regulatory DNA and, intriguingly, other small DNA segments of unknown function. The other 88 percent of the genome could be disrupted without harming the bacteria's ability to grow and reproduce.

The study, which was enabled by the team's development of an extremely efficient new method of genetic analysis, paves the way for better understanding of how bacterial life evolved and for improving identification of DNA elements that are essential for many bacterial processes, including the survival of pathogenic bacteria in an infected person. It will be published online Aug. 30 in Molecular Systems Biology.

"This work addresses a fundamental question in biology: What is essential for life?" said Beat Christen, PhD, one of the co-first authors of the new paper and a postdoctoral scholar in developmental biology. "We came up with a method to identify all the parts of the genome required for life."

The bacteria studied is a non-pathogenic freshwater species that has long been used in molecular biology research. Its complete genome was sequenced in 2001, but knowing the letters in its genetic code did not tell the researchers which bits of DNA were important to the bacteria.

"There were many surprises in the analysis of the essential regions of Caulobacter's genome," said Lucy Shapiro, PhD, the paper's senior author. "For instance, we found 91 essential DNA segments where we have no idea what they do. These may provide clues to lead us to new and completely unknown bacterial functions." Shapiro is a professor of developmental biology and the director of the Beckman Center for Molecular and Genetic Medicine at Stanford.

Caulobacter's DNA, like that of most bacteria, is a single, ring-shaped chromosome. To perform their experiment, the researchers mutated many Caulobacter cells so that each cell incorporated one piece of artificial DNA at a random location in its chromosome. The artificial DNA, which was labeled so the scientists could find it later, disrupted the function of the region of bacterial DNA where it landed. Over two days, the researchers grew these mutants until they had about 1 million bacterial cells, and then sequenced their DNA. After intensive computer analysis, they created a detailed map of the entire bacterial genome to show exactly where the artificial DNA segments had been inserted in the chromosome of the surviving cells.

This mutation map contained many gaps -- the regions of the DNA where no living bacteria had survived with an artificial DNA insertion. These regions, the researchers reasoned, must be essential for bacterial life since disrupting them prevented bacterial survival.

"We were looking for the dog that didn't bark," Shapiro said.

Scientists have used a similar mapping strategy to find essential genetic elements before, but the Stanford team added several innovations that greatly improved the speed and resolution of the method.

"Our method is very streamlined," Christen said. "We can do an analysis that would have taken years in a few weeks. We can immediately go to the answer."

The new method collapses into a single experiment work that used to take dozens of experimental steps, and shifts the majority of the time needed for the research from laboratory work to data analysis.

In total, the essential Caulobacter genome was 492,941 base pairs long and included 480 protein-coding genes that were clustered in two regions of the chromosome. The researchers also identified 402 essential promoter regions that increase or decrease the activity of those genes, and 130 segments of DNA that do not code for proteins but have other roles in modifying bacterial metabolism or reproduction. Of the individual DNA regions identified as essential, 91 were non-coding regions of unknown function and 49 were genes coding proteins whose function is unknown. Learning the functions of these mysterious regions will expand our knowledge of bacterial metabolism, the team said.

The research team anticipates that the new technique will have several interesting uses in both basic and applied research. For instance, the technique provides a rapid and economical method to learn which genetic elements are essential in any microbial species.

"This would give fundamental information so we could determine which essential genetic elements are conserved through evolution," said co-author Harley McAdams, PhD, professor of developmental biology.

The scientists also pointed out that the method could be used to examine which DNA segments are essential for bacterial survival in specific circumstances, such as when pathogenic bacteria invade a host animal or plant. Developing a comprehensive list of genetic elements that make a bacterial species infectious could lead to the identification of new anti-infective agents including new antibiotics.

The research team included co-first author Eduardo Abeliuk, an electrical engineering graduate student; research associate John Collier, PhD; senior research scientist Virginia Kalogeraki, PhD; Ben Passarelli, director of computing at the Stanford Functional Genomics Facility; John Coller, PhD, director of the Stanford Functional Genomics Facility; and Michael Fero, PhD, a National Institute of General Medical Sciences Quantitative Research Fellow at Stanford.

The research was funded by grants from the Department of Energy's Office of Science, the National Institutes of Health, the Swiss National Foundation and a LaRoche Foundation Fellowship.

Journal Reference:

1. Beat Christen, Eduardo Abeliuk, John M Collier, Virginia S Kalogeraki, Ben Passarelli, John A Coller, Michael J Fero, Harley H McAdams and Lucy Shapiro. The essential genome of a bacterium. Molecular Systems Biology, 2011; DOI: 10.1038/msb.2011.58

Courtesy: ScienceDaily