A set of 50 genes can be used to reliably identify the four known types of breast cancer, according to research conducted at Washington University School of Medicine in St. Louis and collaborating institutions. Using this 50-gene set, oncologists can potentially predict the most effective therapy for each breast tumor type and thereby personalize breast cancer treatment for all patients.

“Unlike a widely used genomic test that applies only to lymph-node negative, estrogen-receptor positive breast cancer, this new genomic test is broadly applicable for all women diagnosed with breast cancer,” says breast cancer specialist Matthew Ellis, M.D., Ph.D., a member of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University.

The study was reported Feb. 9, 2009, through advance online publication in the Journal of Clinical Oncology. Ellis’ collaborators include co-authors Charles Perou, Ph.D., associate professor of genetics and pathology at the University of North Carolina at Chapel Hill School of Medicine, Philip S. Bernard, M.D., assistant professor of pathology and medical director of the molecular pathology laboratory at the University of Utah Huntsman Cancer Institute, and Torsten Nielsen, M.D., Ph.D., assistant professor of pathology and laboratory medicine at the University of British Columbia.

Breast cancer results from genetic abnormalities in breast tissue, but not all breast cancers have identical genetic alterations. Ellis and his colleagues analyzed the gene activity of more than 1,000 breast tumors to identify and validate the genetic signature of each of the four types of breast cancer. Although the cancer types are distinguished by thousands of genetic differences, the researchers were able to narrow the list down to a set of 50 of these genes that could uniquely identify each type.

These tumor types have been previously defined and are known as luminal A, luminal B, HER2-enriched and basal-like. The latter three types are generally considered types with a poor prognosis. Another genomic test commonly used in clinical practice, OncotypeDX, does not identify all four tumor types.

“Our test is the first to incorporate a molecular profile for the basal-like type breast cancers,” says Ellis, professor of medicine in the Division of Medical Oncology at Washington University School of Medicine. “That’s important because these breast cancers are arguably the most aggressive yet the most sensitive to chemotherapy. By identifying them we can ensure they are treated adequately.”

Breast cancer experts typically also identify a fifth breast cancer type known as normal-like. The 50-gene set also recognizes the normal-like type. But the researchers found that instead of being a fifth type of breast cancer, the normal-like classification is an indicator that a sample contains insufficient tumor cells to make a molecular diagnosis and that a new sample needs to be taken.

In this study, the researchers also compared the activity of the 50-gene set to how well 133 breast cancer patients responded to standard chemotherapy. They found that their genetic test was highly sensitive and very predictive for chemotherapy response. The test was more predictive than typically used clinical molecular markers such as estrogen receptor status, progesterone receptor status or HER2 gene expression status.

They found that luminal A was not sensitive to the chemotherapy, suggesting that patients with this good-prognosis type can forgo chemotherapy in favor of hormone-based therapy. They showed that among the poor-prognosis tumor types, basal-like breast cancer was the most sensitive to the chemotherapy and luminal B the least.

“Luminal B tumors are a very poor prognosis group, and none of the current conventional therapies are particularly effective against it,” Ellis says. “The ability to identify luminal B tumors accurately makes it possible to develop better therapies for this type.”

Ellis says more than 20 drugs are available to treat breast cancer. The researchers are now investigating how each tumor type responds to these drugs to help determine the best treatment for each. Their 50-gene set can be assayed in preserved tumor samples left over from standard diagnostic procedures, so the group plans to study tumor samples from breast cancer cases going back a decade or more. Since the patients in these cases have already been treated, the researchers can relatively quickly discover how well various therapies worked for each breast cancer type.

The genomic test technology is patented and will be distributed through University Genomics, a company co-owned by Washington University, the University of Utah and the University of North Carolina. This year University Genomics is working with Associated Regional and University Pathologists Inc., a reference laboratory at the University of Utah, to provide a site where the 50-gene test will be available. Ellis is one of the inventors of the test and holds patents for the technology described in this news release.

Parker JS, Mullins M, Cheang MCU, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS. Supervised risk predictor of breast cancer based on intrinsic subtypes. Journal of Clinical Oncology. Feb. 9, 2009 (advance online publication).

Funding from the National Cancer Institute, the Breast Cancer Research Foundation, the Susan G. Komen Foundation, the Huntsman Cancer Institute Foundation and the ARUP Institute for Clinical and Experimental Pathology supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.

University of Minnesota Center for Drug Design and Minneapolis VA Medical Center researchers have discovered a new fast-acting antidote to cyanide poisoning. The antidote has potential to save lives of those who are exposed to the chemical namely firefighters, industrial workers, and victims of terrorist attacks.

Current cyanide antidotes work slowly and are ineffective when administered after a certain point, said Steven Patterson, Ph.D., principal investigator and associate director of the University of the Minnesota Center for Drug Design.

Patterson is developing an antidote that was discovered by retired University of Minnesota Professor Herbert Nagasawa. This antidote works in less than three minutes meeting the United States Department of Defense “three minute solution” standard. The research will be featured in the Dec. 27, 2007 issue of the Journal of Medicinal Chemistry.

“It’s much, much faster than current antidotes,” Patterson said. “The antidote is also effective over a wider time window. Giving emergency responders more time is important because it’s not likely that someone will be exposed to cyanide near a paramedic.”

The antidote was tested on animals and has been exceptionally effective, Patterson said. Researchers hope to begin human clinical trials during the next three years.

The antidote is also unique because it can be taken orally (current antidotes must be given intravenously) and may be administered up to an hour prior to cyanide exposure.

Cyanide is a rapid acting toxin that inhibits cellular respiration it prevents the body from using oxygen. This means it rapidly shuts down many of the fundamental biochemical processes the body needs to survive. Symptoms of acute cyanide poisoning include headache, vertigo, lack of motor coordination, weak pulse, abnormal heartbeat, vomiting, stupor, convulsions, coma, and even death.

When released in an enclosed area, cyanide can be particularly deadly and impact a victim very quickly. Survivors of cyanide poisoning are also at risk of short-term memory loss and development of a Parkinson’s-like syndrome.

Because cyanide occurs naturally in pitted fruits, some grasses and other foods, and the body has mechanisms to detoxify small amounts in the diet. The new antidote takes advantage of this natural detoxification pathway by providing the substance the body naturally uses to convert cyanide to non-toxic thiocyanate.

The theory and proof of concept for the research originated from Nagasawa, who has since retired from the University of Minnesota, but Patterson continues this work at the Center for Drug Design.

The study is being funded by a five-year grant from the National Institutes of Health.

The Academic Health Center is home to the University of Minnesota’s six health professional schools and colleges as well as several health-related centers and institutes. Founded in 1851, the University is one of the oldest and largest land grant institutions in the country. The AHC prepares the new health professionals who improve the health of communities, discover and deliver new treatments and cures, and strengthen the health economy.

University of Minnesota

http://www.umn.edu

A RAND Corporation study issued today gives rail security planners and policymakers a framework to develop cost-effective plans to secure their rail systems from terrorist attacks.

More than 12 million Americans travel on passenger-rail lines each weekday, and because of its open nature, rail transit is considered an attractive terrorist target. While there have been no successful attacks on U.S. rail systems recently, attacks on passenger-rail systems around the world — such as the London Underground in 2005 — highlight the vulnerability of rail travel and the importance of rail security for passengers.

The study by RAND, a nonprofit research organization, uses a generic intracity rail system with characteristics similar to existing American systems. An interdisciplinary team of RAND researchers identified 17 security improvement options — such as canine teams, vehicle surveillance systems, and blast resistant containers — and assessed their relative effectiveness when deployed in different parts of the rail system.

“Millions ride the nation’s railways every day, and it is critical to protect them from terrorist attacks. But we need ways to do so while getting the most for the money we invest,” said Jeremy Wilson, the study’s lead author. “By design, rail systems are open and accessible by large numbers of people, and for this reason are difficult to secure.”

The framework RAND researchers developed gives transit officials a guide to help them evaluate their systems and determine the best, and most efficient, ways to improve safety. The study is based on a composite system in order to avoid disclosing confidential details about any specific rail system in the United States.

Brian Jackson, co-author of the report, said terrorists have demonstrated the ability to change strategies and tactics in response to security measures. As a result, passenger-rail officials and policy makers need to adapt in order to protect their riders.

“Rather than providing a static defense, security planners should review their plans regularly to ensure that they remain relevant to any changes in the terrorists’ targeting methods,” Jackson said.

The study focuses on addressing vulnerabilities and limiting consequences, the two components of risk rail security measures can most influence. Additionally, researchers focused on intracity heavy rail systems – characterized by high speed and rapid acceleration cars, such as the Metro in Washington, D.C., MARTA in Atlanta and the Red Line in Los Angeles – and did not include light rail or commuter rail, such as Amtrak.

The study finds that 80 percent of the worldwide attacks on rail systems were bombings, followed by sabotage (6 percent) and armed attack (6 percent). Explosives accounted for 77 percent of the weapons used in rail system terrorist incidents, with 8 percent of the incidents involving hoaxes or threats.

Using the generic rail system as the intended target, researchers took data on past terrorist attacks on rail systems from the RAND-Oklahoma City National Memorial Institute for the Prevention of Terrorism (MIPT) Terrorist Incident Database to develop a risk assessment.

Researchers examined 11 potential attack locations in a rail system, such as underground infrastructure, ground-level stations, and elevated rail lines, and subjected them to eight different forms of attack, including bombings, incendiaries, and unconventional weapons.

Among the lessons learned:

Security measures must address the threat of explosive devices, but not exclusively; while attacks such as those from chemical and radiological weapons are unlikely, their potentially serious results mean they merit attention.

* Most terrorist attacks on rail systems have resulted in few or zero deaths; as a result, even if security measures prevent only the largest-scale attacks, they could significantly reduce the human costs associated with the threat.

* Some rail attack modes are more of a concern than others. For example, the use of small explosives is a high or medium risk for most targets, while hoaxes or threats pose only a risk for a few targets.

* Because terrorists who are trying to kill and injure people target densely populated areas, attacks inside train cars, targeting train cars from outside, and in densely populated stations are of major concern.

* Co-author Jack Riley warns that rail security experts cannot count on terrorists to repeat the past.

“While it isn’t practical, or desirable, to base security planning on every conceivable terrorist threat, it’s important that security personnel not limit their planning to the obvious attacks from the past,” he said. “We simply can’t be certain what terrorists will do next.”

Researchers identified four broad categories of cost-effective security measures for system operators to consider in terms of effectiveness per dollar payoffs:

* Relatively inexpensive solutions with the highest effectiveness, such as enhanced security training.

* Additional inexpensive solutions to consider with reasonable levels of effectiveness; for example, installing retractable bollards at entrances and exits of the central system operations center and power plant.

* Relatively more expensive solutions with highest effectiveness, such as installing fixed barriers at curbsides adjacent to all entrances and passageways leading to ground-level and underground stations.

* Relatively expensive longer-term solutions for future consideration, such as rail vehicle surveillance systems.

Wilson cautions that the options that arise from an analysis using the framework are specific to the particular system analyzed and the analysis captures a point in time. As a result, the appeal of each option is influenced by cost and perceived effectiveness.

America faces a high threat of an anthrax attack by terrorists and is largely unprepared six years after the 2001 incidents, according to an assessment released by ExecutiveAction at the National Press Club in Washington, D.C.

“America is vulnerable to a terrorist attack with anthrax,” said Neil Livingstone, one of America’s premier terrorism experts and CEO of ExecutiveAction. “Just a small amount of anthrax can cause many casualties and severe economic harm. Yet six years after the U.S. experienced its first anthrax strikes, our nation remains largely unprepared.”

The assessment – Spores: The Threat of a Catastrophic Anthrax Attack on America – examines the risk of an anthrax attack on the U.S., the challenges terrorists face to develop or gain access to an anthrax weapon, and our preparedness in the event of a strike.

In addition to Livingstone, attending the press conference were R. James Woolsey, former Director of the CIA; Professor Yonah Alexander, Director of the Center for Terrorism at the Potomac Institute for Policy Studies; and David Wright, CEO of PharmAthene, a leading biodefense company.

“If we manage to become prepared before the next attack, Neil Livingstone and his colleagues will deserve much of the credit for sounding this realistic and stunning alarm,” Woolsey said.

Al Qaeda began to build an anthrax weapon in the late 1990s but was disrupted by the Afghanistan war. Since then, the terrorist organization has regrouped and again has a safe haven to restart its program to develop non-conventional weapons, including anthrax.

“In 1998 Osama bin Laden declared it is the duty of Muslims to prepare as much force as possible to attack the enemies of God,” Yonah Alexander said. “WMDs, including anthrax, are al Qaeda’s weapons of choice. America must be prepared because the worst is yet to come.”

The government has taken steps to stockpile enormous amounts of antibiotics, which are the public’s primary defense against an anthrax attack. They are most effective when taken soon after exposure to anthrax. Symptoms from an infection – aches, fever, and a cough – do not normally appear for several days. But by this time antibiotics are largely ineffective. This means if an anthrax attack is not detected early, it will be too late to treat the public with antibiotics.

To fully protect the public from an anthrax attack, America must have several types of anthrax countermeasures available, including antibiotics, therapeutics (which provide protection after antibiotics lose their effectiveness), and a vaccine.

Anthrax Scenarios – New York, Minneapolis, Las Vegas, California

The assessment describes three anthrax attack scenarios. The first is a strike on New York’s subway system, a “worst case scenario.” After the announcement of the attack, people try to evacuate the city while others seek antibiotics from distribution centers. The government is unable to rapidly distribute antibiotics to everyone, leading to a breakdown in law and order. Thousands of people die, the subway system is closed, and the city stops functioning, causing catastrophic economic consequences.

In the second scenario, a terrorist disperses a small amount of anthrax in a Minneapolis cinema, at a Las Vegas casino, and then a California theme park. After each attack, the facilities are shut down and fear builds in the public. Hundreds of FBI agents work to discover the perpetrator without success, not unlike the 2001 attacks in the U.S. There is no end in sight from the attacks.

The third scenario is an attack with antibiotic resistant anthrax at the Academy Awards ceremony in which many Hollywood stars are killed.

PharmAthene Inc.

PharmAthene Inc., a leading biodefense company headquartered in Annapolis, Maryland, hired ExecutiveAction to conduct an independent assessment of the threat of an anthrax attack on America.

“As a nation, we have the ability to provide protection against a biological weapon attack such as anthrax,” said David Wright, CEO of PharmAthene. “It’s my hope that this monograph will prompt a call to action by the public so we are adequately protected from a potential future attack.”

ExecutiveAction, LLC

ExecutiveAction was founded to solve unique business, political, regulatory, legal and other problems. The firm currently is involved in rebranding foreign businesses, opening new markets both in the U.S. and abroad, and developing strategies for acquisition of companies. ExecutiveAction also provides competitive intelligence services to U.S. clients, along with security, logistics, and investigative support.

http://www.ExecutiveAction.com