Combining Two Peptide Inhibitors Might Block Tumor Growth

A new study suggests that combining two experimental anticancer peptide agents might simultaneously block formation of new tumor blood vessels while also inhibiting the growth of tumor cells.

This early test of the two agents in a breast cancer model suggests that the double hit can stifle tumor progression, avoid drug resistance and cause few side effects, say researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) who developed the agents and evaluated their effectiveness in laboratory and animal tests.

The scientists designed one of the agents to prevent human epithelial growth factor from interacting with HER-2, a molecule that marks a particularly aggressive form of breast cancer. The other inhibitor blocks the action of vascular endothelial growth factor (VEGF), which stimulates the growth of new blood vessels that tumors need to grow beyond a certain size.

The findings are described in two papers published online in the Journal of Biological Chemistry. One presents the development of a novel VEGF inhibitor; the other describes the HER-2 inhibitor and the preclinical testing of the two agents together.

“When we combined our peptide HER-2 inhibitor with the VEGF peptide that inhibits angiogenesis, we observed significant additive benefits in reducing tumor burdens in preclinical studies,” says principal investigator Pravin Kaumaya, professor of obstetrics and gynecology, of molecular and cellular biochemistry, and of microbiology, and director of the division of vaccine development at the OSUCCC – James.

The strategy of targeting both HER-2 and VEGF pathways should also discourage the development of drug resistance, Kaumaya says, because it simultaneously inhibits two pathways that are essential for tumor survival. “Combined peptide inhibitors might be appropriate in several types of cancer to overcome acquired resistance and provide clinical benefit,” he adds.

Peptide inhibitors consist of short chains of amino acids (the VEGF inhibitor is 22 amino acids long) that conform in shape to the active site of the target receptor. In addition, Kaumaya engineered the VEGF peptide to be resistant to protease, an enzyme, thereby increasing its efficacy. The shape of the peptide HER-2 inhibitor engineered by Kaumaya and his colleagues, for example, is highly specific for the HER-2 receptor. It physically binds to the receptor, which prevents another substance, called epithelial growth factor, from contacting the receptor and stimulating the cancer cells to grow.

Other categories of targeted drugs in clinical use are humanized monoclonal antibodies and small-molecule TKI inhibitors. Both groups are associated with severe side effects and are very expensive, Kaumaya says. “We believe peptide inhibitors offer non-toxic, less-expensive alternatives to humanized monoclonal antibodies and small-molecule inhibitors for the treatment of solid tumors, with the potential for improved efficacy and better clinical outcomes,” he says.

Funding from NIH supported this research.

Other Ohio State researchers involved in the two studies were Kevin C. Foy, Daniele Vicari, Eric Liotta, Zhenzhen Liu, Gary Phillips and Megan Miller.

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (cancer.osu) is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top cancer hospitals in the nation, The James is the 205-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only seven funded programs in the country approved by the NCI to conduct both Phase I and Phase II clinical trials.

Source:
Darrell E. Ward
Ohio State University Medical Center Continue reading

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Living Vascular Grafts: Pitt Team Grows Arteries With Most Elastic Protein Reported

University of Pittsburgh researchers have grown arteries that exhibit the elasticity of natural blood vessels at the highest levels reported, a development that could overcome a major barrier to creating living-tissue replacements for damaged arteries, the team reports in the Proceedings of the National Academy of Sciences.

The team used smooth muscle cells from adult baboons to produce the first arteries grown outside the body that contain a substantial amount of the pliant protein elastin, which allows vessels to expand and retract in response to blood flow. Lead researcher Yadong Wang, a professor of bioengineering in Pitt’s Swanson School of Engineering, his postdoctoral researcher Kee-Won Lee, and Donna Stolz, a professor of cell biology and physiology in Pitt’s School of Medicine, cultured the baboon cells in a nutrient-rich solution to bear arteries with approximately 20 percent as much elastin as an inborn artery.

The Pitt process is notable for its simplicity, Wang said. Elastin – unlike its tougher counterpart collagen that gives vessels their strength and shape – has been notoriously difficult to reproduce. The only successful methods have involved altering cell genes with a virus; rolling cell sheets into tubes; or culturing elastin with large amounts of transforming growth factor, Wang said. And still these previous projects did not report a comparison of elastin content with natural vessels.

Wang and his colleagues had strong, functional arteries in three weeks. The team first seeded smooth-muscle cells from 4-year-old baboons – equivalent to 20-year-old humans – into degradable rubber tubes chambered like honey combs. They then transferred the tubes to a bioreactor that pumped the nutrient solution through the tube under conditions mimicking the human circulatory system – the pump produced a regular pulse, and the fluid was kept at 98.6 degrees Fahrenheit. As the muscle cells grew, they produced proteins that fused to form the vessel.

Mechanical tests revealed that the cultured artery could withstand a burst pressure between 200 and 300 millimeters of mercury (mmHg), the standard unit for blood pressure, Wang said; healthy human blood pressure is below 120 mmHg. In addition to containing elastin, the artery also had approximately 10 percent of the collagen found in a natural vessel, Wang said.

The process the Pitt team used to cultivate the artery resembles how it would be used in a patient, he explained. The cell-seeded tube would be grafted onto an existing artery. As the rubber tube degrades, the vascular graft would develop into a completely biological vessel.

The next steps in the project, Wang said, are to design a vessel that fully mimics the three-layer structure of a human artery and to prepare for surgical trials.

The project received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Source:
Morgan Kelly
University of Pittsburgh Continue reading

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First Crystal Structure Of Enzyme That Works Inside Membranes

The structure of an enzyme that has many regulatory functions and breaks peptide bonds of proteins where they pass through membranes within the cell has been described for the first time by Yale School of Medicine researchers in Nature.

The crystallized rhomboid structure, GlpG, provides the first detailed view of the intramembrane protease and correlates with earlier genetic and biochemical studies. Rhomboids are found in almost all organisms and, although little is known about their function in most species, they have been implicated in biological processes as diverse as mitochondrial function, invasion of host cells by parasites, bacterial communication, and, growth factor signaling.

The biochemical reaction of proteolysis within a membrane is very unusual. By definition, proteolysis involves water, but it is not clear where the water comes from in the oily membrane.

“Because there is seemingly no easy explanation, people always wonder if the protein factors involved are indeed proteases, and if mutations in them really affect proteolysis,” said the senior author, Ya Ha, assistant professor of pharmacology. “Our results suggest that the mechanism is real, which opens up more questions for the next phase of research.”

Intramembrane proteolysis has historical links to research on Alzheimer’s disease. The amyloid peptide deposits thought to be responsible for Alzheimer’s disease is derived from the large protein precursor, APP. The APP is chopped by two proteases and the resulting middle fragment is amyloid peptide.

“All known mutations that cause early-onset Alzheimer’s disease are mapped to three genes-APP, presenilin-1 and presenilin-2,” said Ha. “We now know that the presenilins are the intramembrane protease that chops up APP, converting it to amyloid peptide. Therefore, it is obvious that intramembrane proteolysis is really one of the centerpieces constituting what we now call the ‘amyloid hypothesis’ of Alzheimer’s disease.”

Co-authors at Yale include Yongcheng Wang and Yingjiu Zhang. The research was funded by the U.S. Department of Energy and the National Institutes of Health.

Nature: Published online October 11, 2006 doi:10.1038/nature05255

Yale News Releases are available via the World Wide Web at yale/opa

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Global meeting to develop common approach on avian influenza and human pandemic influenza

The H5N1 avian influenza virus is firmly established among animals in Asia and has begun to extend its reach into Europe. From 7-9 November, more than 400 animal and human health experts, senior policy makers, economists and industry representatives will gather in Geneva to work towards a global consensus to control the virus in domestic animals and prepare for a potential human influenza pandemic.

The disease in animals caused by the H5N1 influenza virus has resulted in the culling of at least 150 million birds in the last two years. H5N1 remains for the moment an animal disease, but the World Health Organization (WHO) has warned that H5N1 is a virus that has the potential to ignite a human influenza pandemic.

While no one can predict the timing or severity of the next influenza pandemic, governments around the world are taking the threat seriously. A series of international meetings held over the last ten weeks will culminate in the Geneva meeting. The meeting is co-organized by WHO, the Food and Agriculture Organisation (FAO), the World Organisation for Animal Health (OIE) and the World Bank. The goal of the meeting is to work towards a global consensus for controlling the disease in animals while simultaneously preparing for a potential human pandemic.

“This virus is very treacherous,” says Dr Margaret Chan, Representative of the WHO Director-General for Pandemic Influenza. “While we cannot predict when or if the H5N1 virus might spark a pandemic, we cannot ignore the warning signs.” Because influenza pandemics have typically caused enormous social and economic disruption, WHO is advising its member states to develop national strategies to cope with such a public health emergency, as well as coordinating with international partners to develop a comprehensive response.

The Geneva meeting will first consider how to contain the H5N1 virus in birds. “There is still a window of opportunity for substantially reducing the risk of a human pandemic evolving from H5N1 by controlling the virus at its source, in animals,” says Joseph Domenech, FAO Chief Veterinary Officer. As the FAO expects avian influenza to reach the Middle East and Africa in the near future, it is essential that the global community and affected countries mobilize more resources to combat the virus, which is thought to be spread in part by migratory birds, before it becomes embedded in new regions.

Strengthening disease surveillance systems worldwide will also be high on the agenda at the Geneva meeting. Early detection and rapid response mechanisms are essential to tracking the evolution of the H5N1 virus. Therefore, delegates will also discuss ways to strengthen veterinary and human health services so that any H5N1 cases–in animals or humans–will be identified quickly. “This is crucial for the prevention of any future global crisis associated with emerging animal diseases potentially transmissible to humans,” says Dr Bernard Vallat, Director-General of the World Organisation for Animal Health (OIE).

At the same time that animal control efforts are to be intensified, several critical issues related to potential human disease remain to be addressed. Meetings in the last several months have identified several key pandemic preparedness issues. For example, many countries are concerned about the lack of access to antiviral medicines and the antiquated production methods for human influenza vaccines. Communication with the public is also a critical issue. These and other topics will be on the agenda for the Geneva meeting.

The meeting comes after a recent gathering of experts in Geneva (2-3 November) to discuss the development of pandemic influenza vaccines. At present, at least ten vaccine developers in about as many countries are carrying out demonstration projects to develop and evaluate vaccines primarily against the H5N1 subtype. Participants expressed the need for continued sharing of technical information, strengthened international coordination of work related to pandemic influenza vaccines so as to avoid duplication of efforts, support to vaccine research initiatives in developing countries and integrating the science into the public health context.

“It’s impossible to exaggerate how important pandemic preparedness is, and how dire the consequences would be for the entire world if some of the worst-case scenarios for a human influenza pandemic were to unfold,” says James Adams, the World Bank’s Vice-President for Operations Policy and Country Services, and head of the Bank’s avian flu taskforce. The Geneva meeting will provide an opportunity for all international partners to mobilize the country commitment and financial resources needed to manage this global threat.

“For the first time in human history, we have a chance to prepare ourselves for a pandemic before it arrives,” says Dr Chan. “It is incumbent upon the global community to act now.”

Mr Dick Thompson – Communications officer
Communicable Diseases
WHO/Geneva
E-mail: thompsondwho.int

Mr Iain Simpson – Communications Officer
Director-General’s Office – WHO
E-mail: simpsoniwho.int

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Ipsogen to present breast cancer program results at the upcoming 96th AACR annual meeting

Marseille, France, March 30, 2005 – Ipsogen SAS, a molecular diagnostic
company developing tests to improve disease management of cancer patients,
announced today that results concerning its breast cancer program have been
selected for presentation in a symposium session at the 2005 AACR Annual
Meeting in Anaheim, California.

The abstract titled “Utilisation of microarray technology to refine
molecular classes and improve clinical management of breast cancer,” is
available on the AACR website (aacr; abstract number: 2628)
and an
oral presentation has been scheduled on Monday, April 18, 2005 at 1:00 PM.
Further results from this program will be separately published in a peer
reviewed journal.

The results concern several gene expression signatures refining molecular
classes of breast cancer. Utilisation of these signatures together with
standard clinical parameters provides a unique combination discriminating
patients responding to standard anthracycline chemotherapy. The test was
validated in an independent cohort with patient samples from distinct
clinical sites. Ipsogen will also release data concerning translation of
these results to its Breast Cancer ProfileChipT, a simple diagnostic device
allowing straightforward utilisation of gene signatures in clinical
pathology laboratories. The study represents part of a research program
Ipsogen is conducting with the Institut Paoli-Calmettes (Marseille, France)
and in partnership with major French and US centres.

Based on these findings and ongoing clinical studies, Ipsogen believes
there is potential for applying this test to identify patients, at
diagnosis, with favorable outcome under standard anthracyclines
chemotherapy to avoid unnecessary intensification.

About Ipsogen

IPSOGEN is an emerging biotechnology company utilising advanced
technologies to analyse gene expression and to improve the disease
management of cancers. IPSOGEN addresses two main markets: (i) The
molecular diagnosis of cancer (i.e.; leukaemia, lymphomas, breast cancer)
to provide innovative diagnostic tools to clinical centres; (ii) the
optimisation of discovery and development of anti cancer drugs, to provide
pharmaceutical companies with high value information at the pre-clinical
and clinical stages, and accelerate drug development through biomarker
discovery and validation. Headquartered in Marseille, France, IPSOGEN has
global partnerships and markets its products worldwide.

This press release contains “forward-looking statements” as defined in the
US Private Securities Litigation Reform Act of 1995. No forward-looking
statement can be guaranteed, and actual results may differ materially from
those projected. Ipsogen SAS does not undertake any obligation to publicly
update any forward-looking statement, whether as a result of new
information, future events, or otherwise. Forward-looking statements in
this document should be evaluated together with the many uncertainties that
affect the business of Ipsogen SAS, among others, the extent to which
Ipsogen’s technology platform can be used in large scale gene expression
analysis, uncertainty of market acceptance of Ipsogen’s technologies or
ability to compete against existing technologies.

CONTACTS
Ipsogen: Vincent Fert, Chief Executive Officer – Tel +33 4 91293090 –
fertipsogen

Global Headquarters
Ipsogen
Luminy Biotech Entreprises
Case 923 – 163 Ave de Luminy
13288 Marseille
France
Tel: +33 4 91 29 30 90
Fax: +33 4 91 29 30 99
infosipsogen

North America – Oncodiagnostics
Ipsogen, Inc
83 Maple Avenue
Windsor
Connecticut 06095
USA
Tel: +1 860 298 0234
Fax: +1 860 298 8586
infosipsogen

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Compounds in plastic packaging act as environmental estrogens altering breast genes

Compounds found in plastic products used to wrap or contain food and beverages have aroused concerns as possible cancer-causing agents because they can sometimes leach out of the plastic and migrate into the food, especially after heating or when the plastic is old or scratched. In two studies funded by the National Institute of Environmental Health Sciences, researchers at Fox Chase Cancer Center in Philadelphia have demonstrated that two plasticizer compounds, BPA and BBP, are environmental estrogens capable of affecting gene expression in the mammary glands of young female laboratory rats exposed to the compounds through their mothers’ milk.

Raquel Moral, Ph.D., a postdoctoral associate in the Fox Chase laboratory of Jose Russo, M.D., presented the results today at the 96th Annual Meeting of the American Association for Cancer Research. Russo is director of the Breast Cancer and the Environment Research Center at Fox Chase. After the morning poster session, he will give an oral presentation on “Estrogens as Carcinogens in the Human Breast.”

“Development of breast cancer entails multiple events, in which estrogen appears to play an important role,” explained Russo. “Our laboratory has pioneered an in vitro system of cell transformation using estrogens and their metabolites as carcinogenic agents in human breast cells. Our data show that each compartment of the breast has specific differentially expressed genes that provide a genomic signature according to the increasing maturation of the organ.

“Estrogenic agents involved in breast development and possibly in breast cancer may include foreign estrogens, or xenoestrogens, that are used in manufacturing a number of products. The studies of BPA and BBP in young rats were designed to see whether exposure to these hormonally active biological compounds could alter the genomic signatures of the mammary gland during critical stages of development.” BPA (bisphenol A) is a synthetic resin used in food packaging, dental sealants and polycarbonate plastic products, which range from CDs and eyeglass lenses to tableware and food and beverage containers, including baby bottles. BBP (n-butyl benzyl phthalate) is a widely used plasticizer used in food wraps and cosmetics.

“In exposing prepubescent female rats to BPA and BBP, our aim was to determine what effects, if any, each compound had on mammary gene expression during at different ages,” said Moral.

“Our results showed that exposure to BPA changes the gene expression profile of mammary tissues as a function of age. That is, there was a significant increase in protein production governed by various genes at increasing ages from 21 to 100 days.”

These included proteins regulating cell proliferation and differentiation, including tumor-suppressing proteins and a large number of unknown proteins. The exception was decreased expression of the GAD1 gene. It encodes a key enzyme of the GABA-ergic system, which could be involved in hormonal regulation and breast cancer development. GAD1 has consistently been overexpressed in primary breast cancer.

“In contrast, the BBP exposure modified the genomic signature of the mammary gland primarily at 21 days of age and had less effect later,” Moral said.

Future studies are needed to determine whether exposure to such xenoestrogens leads to breast cancer in rats and whether these estrogens bring about similar gene alterations in human breast tissue.

In addition to Moral and Russo, Fox Chase co-authors of the BPA and BBP studies include research associate Gabriela A. Balogh, Ph.D., postdoctoral associate Daniel A. Mailo, Ph.D., and research pathologist Irma H. Russo, M.D., as well as Coral Lamartiniere, Ph.D., of the University of Alabama at Birmingham.

Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation’s first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center’s web site at fccc or call 1-888-FOX CHASE.

Contact: Colleen Kirsch
colleen.kirschfccc
215-906-7227
Fox Chase Cancer Center
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Exactech, Inc. Cleared By FDA For U.S. Distribution Of Equinoxe(R) Reverse Shoulder

Exactech Inc.
(Nasdaq: EXAC), a developer and producer of bone and joint restoration
products including orthopaedic implants and biologic materials, announced
today that it has received clearance from the U.S. Food and Drug
Administration (FDA) to market the Equinoxe(R) Reverse Shoulder, the latest
component in the company’s shoulder arthroplasty line.

A “reverse” shoulder is designed for patients who have an irreparable
rotator cuff and osteoarthritis. The Equinoxe Reverse Shoulder is
compatible with the Equinoxe primary stem, allowing surgeons to change from
a primary to a reverse without removing the humeral stem.

Exactech CEO Bill Petty said, “With the introduction of our Equinoxe
Reverse Shoulder, we have continued the precedent of innovation that we
established with the Equinoxe primary and fracture shoulder systems. The
shoulder market is rapidly growing and we are pleased that we have a
prosthesis that will help address the clinical challenges that surgeons
have faced thus far with reverse shoulders.”

Lynn Crosby, M.D., a leading shoulder surgeon and member of the design
team, said, “The Equinoxe Reverse Shoulder is an exciting new product that
has been designed to address some of the limitations or challenges inherent
in other reverse shoulder systems. I’ve been pleased to work with an
international team of surgeons who brought a great deal of clinical and
surgical expertise to this product’s development.”

Exactech plans to initiate targeted clinical evaluation of the Equinoxe
Reverse Shoulder in its second quarter with full-scale release targeted for
the second half of 2007. Reverse shoulders have only recently been
introduced in the U.S. market. According to industry sources, approximately
49,000 shoulder replacements were performed in the U.S. in 2006, which is a
12% increase from 2005. Roughly 6% of that increase is attributed to
reverse shoulder replacement.

About Exactech

Based in Gainesville, Fla., Exactech develops and markets orthopaedic
implant devices, related surgical instruments and biologic materials and
services to hospitals and physicians. The company manufactures many of its
orthopaedic devices at its Gainesville facility. Exactech’s orthopaedic
products are used in the restoration of bones and joints that have
deteriorated as a result of injury or diseases such as arthritis. Exactech
markets its products in the United States and Australia, in addition to
more than 25 countries in Europe, Asia and Latin America. Copies of
Exactech’s press releases, SEC filings, current price quotes and other
valuable information for investors may be found at exac and
hawkassociates.

An investment profile on Exactech may be found at
hawkassociates/exacprofile.aspx.

This release contains various forward-looking statements within the
meaning of Section 27A of the Securities Act of 1933 and Section 21E of the
Securities Exchange Act of 1934, which represent the company’s expectations
or beliefs concerning future events of the company’s financial performance.
These forward-looking statements are further qualified by important factors
that could cause actual results to differ materially from those in the
forward- looking statements. These factors include the effect of
competitive pricing, the company’s dependence on the ability of third party
manufacturers to produce components on a basis which is cost-effective to
the company, market acceptance of the company’s products and the effects of
government regulation. Results actually achieved may differ materially from
expected results included in these statements.

Exactech, Inc.
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‘Reverse-Ecology’ Tool Demonstrated By Analysis Of Bread Mold Genomes

In a demonstration of “reverse-ecology,” biologists at the University of California, Berkeley, have shown that one can determine an organism’s adaptive traits by looking first at its genome and checking for variations across a population.

The study, to be published the week of Jan. 31 in the journal Proceedings of the National Academy of Sciences, offers a powerful new tool in evolutionary genetics research, one that could be used to help monitor the effects of climate change and habitat destruction.

The researchers scanned the genes of 48 different strains of Neurospora crassa, a type of red bread mold commonly used in genetics research. It is considered a model microbe because different strains can be mated and grown very quickly, and its growth occurs in a light-sensitive daily cycle that has been useful for studying circadian rhythms.

Yet for all its popularity in the lab, little was known about this fungus in its natural habitat, so the researchers specifically chose wild samples of the microbe from the Caribbean basin, South America and Africa. From this population-wide analysis, they found a striking pattern of variation in two regions of the genome that indicated the action of natural selection.

Within one of these regions, they found a gene that is known to be important to survival at cold temperatures, and posited that genes in the other region might play the same role. They then showed that members of the population that contained unique variants of their candidate cold-tolerant genes lived in regions with lower minimum temperatures – up to 9 degrees Celsius – on average and were able to grow better at cold temperatures than were strains found in more tropical climates.

The researchers also grew wild strains of Neurospora crassa in the lab alongside strains where the candidate cold-tolerant genes had been deleted from the genome, keeping all things the same except for the temperature. They confirmed that the strains with the genes for cold tolerance disabled fared more poorly in chillier temperatures.

“This is the first time that population genomics has been used to find genes important for adaptation without any idea of the environmental parameters, phenotype, candidate genes or even the population boundaries,” said the study’s principal investigator, John Taylor, UC Berkeley professor of plant and microbial biology.

Taylor pointed out that the normal route for adaptation studies is to first look at obvious differences – such as hair or skin color – between two closely related organisms. Scientists next observe the environment in which the organism lives to see if it might explain those differences, and then examine the genes to see if there is evidence of natural selection.

For example, the researchers referred to a 2003 study noting that rock pocket mice with tan-colored fur are often found among light-colored rocks, while those with black fur were found on dark lava flows. They identified the genetic basis of this adaptive trait by targeting genes for further study that were known to be involved in pigmentation and showed that different gene variants were associated with the different habitats.

“For our study, we turned this around, beginning with genes that showed evidence of selection, and then looking at the environmental factors that might influence those genes,” said Taylor.

This “reverse-adaptation” approach is especially useful when studying microbes, the researchers argued.

“Microbes are inconspicuous by nature and, unlike mice which can have different colored coats, different strains and species look pretty much the same,” said study lead author Christopher Ellison, a UC Berkeley graduate student in plant and microbial biology.

As if to demonstrate this point, the researchers discovered that what had been considered a single group of interrelated strains was instead two distinct populations.

The relative ease of studying a microbe such as Neurospora crassa in the lab may make it an appealing tool to monitor the impact of environmental stress, the researchers said.

“If temperature is a key adaptive factor in populations of fungi and microbes in general, this could have important implications in the study of climate change,” said Ellison. “Adaptation is a crucial part of evolution, so microbes could be used to monitor global temperature change.”

Notes:

Other UC Berkeley co-authors of the study are Rachel Brem, professor of molecular and cell biology; N. Louise Glass, professor of plant and microbial biology; and members of the Glass Lab – Charles Hall, post-doctoral researcher, and staff researchers David Kowbel and Juliet Welch.

The National Institute of General Medical Sciences helped support this research.

Source:
Sarah Yang
University of California – Berkeley Continue reading

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Alzheimer’s Enzyme Acts As A Tumor Suppressor

Researchers at Burnham Institute for Medical Research (“Burnham”) have provided the first evidence that gamma-secretase, an enzyme key to the progression of Alzheimer’s, acts as a tumor suppressor by altering the pathway of epidermal growth factor receptor (EGFR), a potential treatment target for cancer. Expedited to publication online by Proceedings of the National Academy of Sciences, these findings reveal a limitation of targeting gamma-secretase for treatment of Alzheimer’s and potentially other diseases.

Amyloid precursor protein (APP) is found inside all cells. Though its function is unknown, it is associated with Alzheimer’s in the following way. APP can be cleaved by the enzymes beta-secretase and gamma-secretase, sequentially. Upon gamma-secretase cleavage, amyloid-beta (AB) peptides are dispelled into the extracellular matrix region and eventually aggregate into senile plaques, characteristic of Alzheimer’s.

Residing inside cells, gamma-secretase is a complex of four proteins, including a family of proteins known as the presenilins (PS). Mutations in PS are found in approximately 5% of individuals suffering Alzheimer’s, resulting in early onset of the disease.

At the center of the activities governing AB production is gamma-secretase, the subject of intensive interest as a potential therapy target for Alzheimer’s. Mice deficient in PS/gamma-secretase activity tend to develop skin cancer. EGFR is known to be upregulated in a variety of tumors, including various skin cancers. Elevated EGFR levels in tumors are linked with poor clinical prognosis and tumor resistance to chemotherapy. EGFR is therefore the subject of intensive investigation by pharmaceutical companies as a potential treatment target for cancer.

The Xu laboratory set out to determine whether there might be a correlation between PS/gamma-secretase activity and EGFR. They examined mice with reduced PS gene dosage and found that there is an inverse relationship between the level of EGFR and PS. They discovered that APP intracellular domain (AICD), another cleavage product of PS/gamma-secretase, negatively regulates transcription of the EGFR gene by binding the gene’s promoter region. They also demonstrated that deficient levels of APP correlate with increased levels of EGFR.

“Alzheimer’s disease and cancer are two of the most important medical research areas today”, said Huaxi Xu, associate professor and program director at Burnham. “We believe that our studies, which reveal a key role of Alzheimer’s PS/gamma-secretase-generated APP metabolite AICD in gene transcription and in EGFR-mediated tumorigenesis, should have a significant impact on both fields of research.”

This research was supported in part by grants from the Alzheimer’s Association, the American Health Assistance Foundation, and grants from the National Natural Science Foundation in China, and the National Institutes of Health.

Burnham Institute for Medical Research conducts world-class collaborative research dedicated to finding cures for human disease, improving quality of life, and thus creating a legacy for its employees, partners, donors, and community. The La Jolla, California campus was established as a nonprofit, public benefit corporation in 1976 and is now home to three major centers: a National Cancer Institute-designated Cancer Center, the Del E. Webb Center for Neurosciences and Aging, and the Infectious and Inflammatory Disease Center. Burnham today employs more than 750 people and ranks consistently among the world’s top 20 organizations for the impact of its research publications. In 2006, Burnham established a center for vascular mapping and bionanotechnology in Santa Barbara, California. Burnham is also establishing a campus at Lake Nona in Orlando, Florida that will focus on diabetes and obesity research and will expand the Institute’s drug discovery capabilities, employing over 300 people. For additional information about Burnham and to learn about ways to support its research, visit burnham/.

Contact: Nancy Beddingfield

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Antibiotic-resistance, Avian Flu And Other Viral Epidemics At ECCMID In Nice

16th European Congress of Clinical Microbiology and Infectious Diseases

Nice, France – Globalisation is a phenomenon involving ever wider spheres: economic, social, cultural, and religious. But these are not the only areas to be affected. Fading national boundaries caused by intensification of commercial trading and increased migration, as well as the tendency for more “exotic” tourism, has caused a globalisation of infectious diseases that is involving all European countries.

This is the background to the importance of a European organisation such as ESCMID (European Society of Clinical Microbiology and Infectious Diseases), which pursues as its major goal the improvement of the diagnosis, prevention and clinical management of infections, including those with a high public health impact.

Indeed, there is currently a paradoxical situation: despite the enormous progress made in medical science, there are new diseases emerging, either as adaptations of existing diseases which lose their responsiveness to traditional treatments, or as new diseases based on previously unknown pathogens for which a mode of transmission and control still have to be established and treatment regiments still to be developed.

The ECCMID (European Congress of Clinical Microbiology and Infectious Diseases), organized by ESCMID in Nice from 1 – 4 April 2006, is the most important annual event of its kind in Europe. Now in its 16th edition, the Congress unites a large number of European and other international experts and over 6000 delegates with the aim of increasing knowledge and discussing future research, treatment and public health strategies needed to tackle infectious diseases.

Resistance to antibiotics

The first problem, the loss of efficacy in treating some common infectious diseases, is predominantly due to antibiotic resistance. The alarm raised by infection experts is serious: the dramatic increase of bacteria resistant to antibiotics paralleled by a lack of new antibiotics has already led to infections being no longer curable.

In fact, it has been seen that some pathogens, particularly those occurring in hospitals (e.g. Staphylococcus aureus and Pseudomonas aeruginosa), are now extensively resistant to widely used antibiotics. Furthermore, recent studies have demonstrated that genes conveying antibiotic resistance can spread between different strains even across species barriers. Combined, all of the above leads to an ever increasing number of difficult-to-treat bacterial infections. In the case of Pseudomonas, but now even in the case of common and “easy-to-treat” bacteria such as Escherichia coli, the most recent and dangerous mechanisms of resistance are the so-called “carbapenemase” enzymes, which attack and destroy the most frequently used antibiotics and make bacteria, which produce these enzymes, resistant to all drugs.

The problem of antibiotic-resistance is further worsened by the disinvestment of several pharmaceutical companies in the field of antibiotic research and development and the resulting shortage of new drugs.

The experts at ECCMID therefore consider measures to contain antibiotic resistance by optimally using the currently available drugs absolutely essential.

“The key to controlling the development of antibiotic resistance”, explains Prof. Hermann Goossens of the Department of Medical Microbiology at Antwerp University Hospital, Edegem, Belgium, “is the ability to choose antibiotics selectively.” Making a precise diagnosis and understanding the probable aetiology should enable the correct treatment of the main community-acquired infections. “However, in order to do this,” continues Goossens, “it is very important that fast, new diagnostic tools are developed for the identification of diseases of bacterial origin. This would permit the prescription of antibiotics only in the case of real need.”

Although the main cause of antibiotic resistance in community-acquired infections is inappropriate prescribing of antibiotics, another important factor is patients’ non-compliance.

It has, in fact, been demonstrated that the therapeutic efficacy of antibiotics also depends heavily on patients respecting the prescriptions and instructions received from their doctors about the correct dose, the dosing interval and the duration of treatment.

Prevention is another aspect that should not be forgotten when discussing antibiotic resistance. It was found that the introduction of the pneumococcal conjugate vaccine in Europe often coincided with a decrease in the resistance to macrolides and to penicillin. Streptococcus pneumoniae, also called pneumococcus, is one of the most important pathogens of the respiratory tract, with a high frequency of resistance to commonly used antibiotics.

Another important factor for treating infectious diseases and surveillance of resistance is the definition of “susceptible” or “resistant” pathogens; paradoxically, these definitions are not the same in all European countries.

In this regard, ESCMID has convened a strategically important committee, called EUCAST (European Committee on Antimicrobial Susceptibility Testing), with the goal to produce uniform guidelines for susceptibility testing of antibacterial drugs and to define “breakpoints” (that is, the values differentiating susceptible form resistant bacteria) in Europe.

The importance of tackling resistance through co-ordinated action of all European countries is further confirmed by the support that ESCMID gave to the creation of GRACE (Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe), a network of excellence financed by the European Union which brings together major European experts to increase knowledge, guarantee the practical application of research, develop new diagnostic tests and improve the prescribing habits and training of health care workers.

Avian flu

Another issue discussed in particular detail by the experts at ECCMID was avian flu. “Also in this case,” said Albert Osterhaus, Head of the Department of Virology and Director of the National Influenza Centre, Erasmus Medical Centre, Rotterdam, “a better co-ordination is needed in Europe among all the stakeholders, researchers, public health care workers and veterinarians in order to prevent a possible pandemic. This can be achieved by creating a European task force to share knowledge and to tackle the possible risks.”

Osterhaus continued, “So far, the crisis in Europe has predominantly affected the avicultural sector. Community regulations to safeguard this production chain and those working in the sector are needed. The most important message to convey to the population is that of not confusing the problems related to the avicultural sector with the possibility of a pandemic developing.”

Scientific societies, such as ESCMID, which have access to a network of experts throughout the continent, can contribute to this co-operation by acting as interlocutor with academia, health authorities of individual states, the European Commission and the EDCD (European Centre for Disease Prevention and Control).

Ragnar Norrby, Director of the Swedish Institute for Infectious Diseases Control in Stockholm and current President of the ESCMID, re-addressed the “basic” information to be conveyed to the population, confirming that “avian flu is a disease of birds and that the risk of humans catching the infection, although theoretically possible, is very low and limited to those people who have direct contact with infected birds. However, as of today, there is no convincing evidence of man-to-man transmission.”

Turkey, the only large reservoir so far observed in Europe, is a paradigmatic example: the cases of transmission of the virus to humans was limited mainly to the rural areas, where direct contact with animals is frequent, and did particularly involve children who have deliberately touched dead or sick birds. Also in these cases, the danger can be limited by applying ordinary rules of hygiene such as frequent hand-washing, not eating meat that is of suspicious provenance or poorly cooked and prohibiting hunting within a 10 km radius of where an animal infected by H5N1 has been found.

Although the H5N1 virus (responsible for avian flu) can cross the barriers between species and infect other animals, such as cats, so far the virus has not spread from cats to different species.

Concerning the possibility of a pandemic to occur, Norrby emphasized that “the worldwide spread of influenza among humans occurs when a new influenza virus develops, usually as a result of recombination of genetic material from a human influenza virus with genetic material from an animal influenza virus. A pandemic virus can, therefore, arise anywhere in the world, but the probability is higher in countries with a high population density and many domestic birds and pigs such as in Asia or Africa.”

“So far,” continued Norrby, “pandemics have developed at irregular intervals (Spanish ‘flu in 1918, the Asiatic pandemic of 1957 and the one arising in Hong Kong in 1968). Therefore, although it can be presumed that another will occur, no-one is able to predict when and with what variant of the influenza virus”.

Norrby concluded, “it is important to emphasize two aspects: although the high density of H5N1 virus in birds from all over the world (and particularly in Asian and African countries) facilitates the development of a pandemic infection caused by the virus, the fact that millions of Asians have probably been in contact with infected, dead birds since 1997 (the year in which the first severe spread of avian flu occurred in Hong Kong) without the virus having mutated into a pandemic variant, speaks against a variant of H5N1 virus becoming a pandemic virus.”

As far as regards the availability of a human vaccine against avian flu, it was repeated during the ECCMID Congress that large-scale production of such a vaccine requires from four to six months. Considering that avian influenza has had a seasonal trend so far, affecting the population during the winter in countries with a temperate climate, it is probable that if a vaccine is needed it will be scarce during the first wave of infections, but fully available for the second season.

The most important antiviral drug on the market is oseltamivir (Tamiflu), since it has few side effects and is easy to administer. It is important to highlight that oseltamivir can be used for prophylaxis, but considering that the influenza season lasts four to six months it is not feasible to store the supplies necessary to administer the drug to a large number of people. Although studies have not been carried out in patients infected by H5N1, it has been documented that in order to reduce the duration and the severity of symptoms, oseltamivir-based treatment must be administered within 48 hours of the onset of the symptoms. It is also important to remember that treatment with antiviral agents can lead to the development of resistance.

Finally, it should be appreciated that – even in the absence of a vaccine against avian influenza – primary prevention, in particular vaccination against “common” influenza and pneumococcal respiratory infections, plays an essential role in the defence against a possible pandemic.

In fact, immunization could increase resistance to strains never previously encountered, such as a potentially pandemic virus. For example, in the case of the H5N1 strain, it is known that N1 (neuroaminidase 1) is contained in other viruses and vaccines. It is, therefore, possible that a previous infection or vaccination with virus containing N1 can provoke a certain response that then remains in the immunological “memory” of the individual.

Antipneumococcal vaccination should also play a strategic role in prevention, since it has been demonstrated that a considerable proportion of the pulmonary complications in previous pandemics was linked to superimposed bacterial infections, including those caused by pneumococci.

Chikungunya

During the ECCMID another epidemic was discussed: chikungunya, a rare viral disease transmitted by mosquitoes (Aedes albopictus). This epidemic appeared one year ago in La RŠ¹union, where 186,000 cases, including 93 deaths, have been registered so far. The infection has spread to Mayotte (924 cases), to the Seychelles (4650 suspected cases), to Mauritius (2553 cases notified, of which 1173 confirmed) and to Madagascar (sporadic cases). In Europe “imported” cases have been reported in France (n=160), Switzerland (n=12) and Germany (n=4).

The current level of risk of chikungunya (a fever that causes violent joint pains) being introduced into Europe is low, given the unfavourable climatic conditions in this period of the year, although the risk cannot be excluded completely. There is lack of consensus on whether there will be a real risk of autoctonous spread of the virus in the warmer season, when the number of mosquitoes increases.

What is certain, as concluded by the experts meeting at the ECCMID, is the need to activate close monitoring of the epidemic at a European level and to identify efficient diagnostic tools.

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