Kick Cancer Where It Counts

Organ Transplants Without Life-Long Drugs

 

A new method allowed kidney transplant recipients to eventually stop taking harsh immune-suppressing medications, even though they’d received mismatched organs. These preliminary findings may one day reduce the need for anti-rejection drugs and lead to more options for patients awaiting organ transplants.

Organ transplants are life-saving, but finding well-matched donor organs can be difficult. Patients must also take immunosuppressive drugs for the rest of their lives to keep the immune system from attacking transplanted organs. But these drugs can make it hard to fight off infections. The drugs may also boost the risk for diabetes, cancer and other conditions. Scientists have been searching for new ways to train the immune system to tolerate organ transplants.

Small NIH-funded clinical studies have shown the potential of infusing donor bone marrow cells into transplant recipients. The marrow is home to blood-forming stem cells that generate a variety of immune cells. In some patients, the technique temporarily created a chimeric immune system—a combination of both donor and recipient cells within the body. For a time, these patients better tolerated the donated organs and survived drug-free.

In the new study, scientists led by Dr. Suzanne Ildstad of the University of Louisville set out to create long-term chimerism in kidney recipients. The organs came from unrelated or highly mismatched donors. The research was funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Eight patients had pre-surgical treatment with chemotherapy and radiation to partly knock down their own immune systems. A day after transplant surgery, they received infusions of a complex cellular cocktail derived from the donor’s bone marrow. The mixture included not only blood-forming stem cells but also rare “graft facilitating” cells. These cells, first isolated by Ildstad nearly 20 years ago, are thought to help foreign stem cells get established in recipient bone marrow. The researchers also removed donor immune cells likely to attack the transplant recipient’s own body. This type of immune attack, called graft-versus-host disease, is a common and sometimes deadly complication of bone marrow transplants.

As reported in the March 7, 2012, issue of Science Translational Medicine,one month after transplantation, all 8 patients had a variety of immune cells derived from the kidney donor in their bloodstream. Within a year, 5 of the 8 patients had achieved long-lasting chimerism, with the donated immune cells eventually crowding out the recipient’s own immune cells. By then, these patients had stopped taking immunosuppressant drugs, and their transplanted organs continued to thrive. None of the patients showed signs of graft-versus-host disease.

“The preliminary results from this ongoing study are exciting and may have a major impact on organ transplantation in the future,” says the study’s first author, Dr. Joseph Leventhal of Northwestern Memorial Hospital. “With refinement, this approach may prove to be applicable to the majority of patients receiving the full spectrum of solid organ transplants.”

—by Vicki Contie

Source:NIH

Arsenic turns stem cells cancerous, spurring tumor growth

 

Researchers at the National Institutes of Health have discovered how exposure to arsenic can turn normal stem cells into cancer stem cells and spur tumor growth. Inorganic arsenic, which affects the drinking water of millions of people worldwide, has been previously shown to be a human carcinogen. A growing body of evidence suggests that cancer is a stem-cell based disease. Normal stem cells are essential to normal tissue regeneration, and to the stability of organisms and processes. But cancer stem cells are thought to be the driving force for the formation, growth, and spread of tumors.

Michael Waalkes, Ph.D., and his team at the National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, part of NIH, had shown previously that normal cells become cancerous when they are treated with inorganic arsenic. This new study shows that when these cancer cells are placed near, but not in contact with normal stem cells, the normal stem cells very rapidly acquire the characteristics of cancer stem cells. It demonstrates that malignant cells are able to send molecular signals through a semi-permeable membrane, where cells can't normally pass, and turn the normal stem cells into cancer stem cells.

“This paper shows a different and unique way that cancers can expand by recruiting nearby normal stem cells and creating an overabundance of cancer stem cells,” said Waalkes. “The recruitment of normal stem cells into cancer stem cells could have broad implications for the carcinogenic process in general, including tumor growth and metastases.”

This reveals a potentially important aspect of arsenic carcinogenesis and may help explain observances by researchers working with arsenic that arsenic often causes multiple tumors of many types to form on the skin or inside the body. The paper is online in Environmental Health Perspectives.

Waalkes' lab started working with stem cells about five years ago. The researchers used a prostate stem cell line, not embryonic stem cells.

“Using stem cells to answer questions about disease is an important new growing area of research. Stem cells help to explain a lot about carcinogenesis, and it is highly likely that stem cells are contributing factors to other chronic diseases,” Waalkes said.

Stem cells are unique in the body. They stay around for a long time and are capable of dividing and renewing themselves. “Most cancers take 30 or 40 years to develop,” said Linda Birnbaum, Ph.D., director of NIEHS and NTP. “It makes sense that stem cells may play a role in the developmental basis of adult disease. We know that exposures to toxicants during development and growth can lead to diseases later in life.”

Next, the laboratory team will look to see if this finding is unique to arsenic or if it is applicable to other organic and inorganic carcinogens.

The NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

Source:NIH

Label-Free Protein Assays for Process Development, Kinetic Characterization, Protein Folding, and Crystallization Screens, WEBINAR

GEN | Webinars: Label-Free Protein Assays for Process Development, Kinetic Characterization, Protein Folding, and Crystallization Screens

FDA approves LINX Reflux Management System to treat gastroesophageal reflux disease

The Food and Drug Administration today approved the LINX Reflux Management System for people diagnosed with gastroesophageal reflux disease (GERD) who continue to have chronic symptoms, despite the use of maximum medical therapy for the treatment of reflux.

GERD is a condition in which food or liquid in the stomach flows back into the esophagus. This can irritate the esophagus, causing heartburn and other symptoms.

Patients with GERD are first advised to make dietary and lifestyle changes such as losing weight, eating smaller meals and avoiding certain types of foods that may trigger symptoms. There are medications available, such as antacids and proton pump inhibitors, for those who do not respond to dietary and lifestyle measures.

Surgical treatment usually is reserved for people who have severe symptoms such as chronic GERD or a large hiatal hernia, a condition in which part of the stomach pushes upward through the diaphragm. Surgery is also an option for those who do not follow their recommended medical therapy or who want to avoid a lifetime of medical therapy.

“The LINX Reflux Management System is a sterile, single-use, surgically placed device used to treat the symptoms associated with GERD,” said Christy Foreman, director of the Office of Device Evaluation in FDA’s Center for Devices and Radiological Health. “LINX offers an option to patients and their health care providers and is an alternative to current surgical procedures.”

The LINX system is composed of a series of titanium beads, each with a magnetic core, connected together with independent titanium wires to form a ring shape. It is implanted at the lower esophageal sphincter (LES), a circular band of muscle that closes the last few centimeters of the esophagus and prevents the backward flow of stomach contents.

The force of the magnetic beads is designed to provide additional strength to keep a weak LES closed. Upon swallowing, the magnetic force between the beads is overcome by the higher pressures of swallowing forces, and the device expands to accommodate a normal swallow of food or liquid. Once the food passes though the LES, the device returns to its resting state. 

The company conducted a feasibility study of 44 patients at four centers with a five-year follow-up plan. In addition, the company conducted a pivotal study of 100 patients at 14 centers with a five-year follow-up plan. Patients enrolled had GERD and chronic GERD symptoms, despite medical therapy. Results from both the feasibility and pivotal trials indicate that the benefits obtained with the LINX Reflux Management System outweigh its risks.

As a condition of approval, the company will institute a required training program to educate new users on patient selection, device implantation and post-procedural care of patients treated with LINX.

The most common adverse events experienced with the LINX included difficulty swallowing, pain when swallowing food, chest pain, vomiting, and nausea.

It is important to note that patients with LINX will no longer be able to undergo Magnetic Resonance Imaging (MRI) procedures. The magnetic beads interfere with the machine and can cause the device to be damaged and the patient to be injured.

The LINX Reflux Management System is manufactured by Torax Medical Inc. in St. Paul, Minn.

Source: U.S. FDA

Stem Cells for Drug Developers by Hanson Wade

Stem Cells for Drug Developers by Hanson Wade

Novel Cytotoxic Drugs / Novel Cytotoxic Drugs by Hanson Wade

Novel Cytotoxic Drugs / Novel Cytotoxic Drugs by Hanson Wade

FDA approves generic copies of Roche’s Boniva

The US Food and Drug Administration (FDA) have approved three generic versions of Roche's osteoporosis medication Boniva.

Copies of the once-monthly, 150mg tablets, produced by Mylan, Apotex and Orchid Chemicals & Pharmaceuticals, can now be marketed towards sufferers of the bone condition.

US FDA Centre for Drug Evaluation and Research Office of Pharmaceutical Science deputy director Keith Webber heralded the arrival of generic treatments for the disease.

"For people who must manage their health conditions over time, it is important to have affordable treatment options," added Webber.

Osteoporosis is the most common type of bone disease, affecting more than 40 million people in the US, and leads to bone fragility and an increased risk of bone fractures due to low bone mass and bone tissue deterioration.

Boniva, belonging to the bisphosphonate class of drugs, directly competes with other bisphosphonates including Novartis' Reclast/Aclasta/Zometa and Merck & Co's Fosamax for a target group estimated to be around 5 million people in the US alone.

Sales of Boniva are now widely predicted to take a further fall, following on from a 31.3% decrease recorded in 2011.FDA approves generic copies of Roche’s Boniva - Pharmaceutical Technology

How Sulfa Drugs Work

Researchers have finally found out how sulfa drugs—the first class of antibiotics ever discovered—work at the molecular level. The finding offers insights into designing more robust antibiotic therapies.

Bacillus anthracis. Image courtesy of CDC/ Dr. William A. Clark.

Sulfa antibiotics were first used in the 1930s, and they revolutionized medicine. After a few years, bacteria started to develop resistance to the drugs, and eventually penicillin replaced them as a first-line treatment. While antibiotic resistance remains a problem for this class of antibiotics, sulfa drugs are still commonly used to treat a variety of bacterial infections.

Sulfa drugs work by binding and inhibiting a specific enzyme called dihydropteroate synthase (DHPS). This enzyme is critical for the synthesis of folate, an essential nutrient. Mammals get folate from their diet, but bacteria must synthesize this vitamin. Folate synthesis requires a chemical reaction between 2 molecules, DHPP and PABA, that is catalyzed by DHPS.

Bacteria resistant to sulfa drugs often have mutations in the DHPS enzyme. These mutations occur on 2 floppy loops that sit near the enzyme's active site. Previous research had described most of the structure of DHPS, but the structure of the floppy, highly conserved loops remained elusive. Moreover, researchers didn't know how the chemical reaction occurs between DHPP and PABA.

A team of scientists led by Dr. Stephen White of St. Jude Children's Research Hospital set out to determine the structure of the loops and the chemical reactions that are helped along by DHPS. Their research, which appeared in the March 2, 2012, issue of Science, was funded primarily by NIH's National Institute of Allergy and Infectious Disease (NIAID).

The scientists isolated the DHPS enzyme from 2 bacterial species: Bacillus anthracis, which causes anthrax, and Yersinia pestis, which causes plague. The scientists embedded DHPP and PABA in crystals of the enzyme. They then used X-ray crystallography to find high-resolution structures of these molecules at different stages of the chemical reaction.

The researchers found that the 2 floppy loops wrap around PABA early on and hold the molecule in place. The chemical reaction linking portions of PABA and DHPP takes place, and then the loops release the chemical reaction product. The structures also revealed the exact chemical reaction steps that occur between PABA and DHPP.

Sulfa antibiotics work because they fit into the DHPS active site and take PABA's place. By embedding sulfa antibiotics into the enzyme crystals, the scientists found that the sulfa drugs are held in place by the floppy loop structures. However, a small portion of the drug sticks out of the binding pocket. The researchers discovered that DHPS mutations in drug-resistant bacteria occur near this small stuck-out portion.

“The structure we found was totally unexpected and really opens the door for us and others to design a new class of inhibitors targeting DHPS that will help us avoid side effects and other problems associated with sulfa drugs,” says White.

—by Lesley Earl, Ph.D.

Source: NIH

Confused by genetic tests? NIH’s new online tool may help

 

An online tool launched today by the National Institutes of Health will make it easier to navigate the rapidly changing landscape of genetic tests. The free resource, called the Genetic Testing Registry (GTR), is available at http://www.ncbi.nlm.nih.gov/gtr/.

"I’m delighted that NIH has created this powerful, new tool. It is a tremendous resource for all who are struggling to make sense of the complex world of genetic testing," said NIH Director Francis S. Collins, M.D., Ph.D., who unveiled GTR at NIH's observance of international Rare Disease Day. "This registry will help a lot of people — from health care professionals looking for answers to their patients’ diseases to researchers seeking to identify gaps in scientific knowledge."

Genetic tests currently exist for about 2,500 diseases, and the field continues to grow at an astonishing rate. To keep pace, GTR will be updated frequently, using data voluntarily submitted by genetic test providers. Such information will include the purpose of each genetic test and its limitations; the name and location of the test provider; whether it is a clinical or research test; what methods are used; and what is measured. GTR will contain no confidential information about people who receive genetic tests or individual test results.

Genetic tests that the Food and Drug Administration has cleared or approved as safe and effective are identified in the GTR. However, most laboratory developed tests currently do not require FDA premarket review. Genetic test providers will be solely responsible for the content and quality of the data they submit to GTR. NIH will not verify the content, but will require submitters to agree to a code of conduct that stipulates that the information they provide is accurate and updated on an annual basis. If submitters do not adhere to this code, NIH can take action, including requiring submitters to correct any inaccuracies or to remove such information from GTR.

In addition to basic facts, GTR will offer detailed information on analytic validity, which assesses how accurately and reliably the test measures the genetic target; clinical validity, which assesses how consistently and accurately the test detects or predicts the outcome of interest; and information relating to the test’s clinical utility, or how likely the test is to improve patient outcomes.

"Our new registry features a versatile search interface that allows users to search by tests, conditions, genes, genetic mutations and laboratories," said Wendy Rubinstein, M.D., Ph.D., director of GTR. "What's more, we designed this tool to serve as a portal to other medical genetics information, with context-specific links to practice guidelines and a variety of genetic, scientific and literature resources available through the National Library of Medicine at NIH."

GTR is built upon data pulled from the laboratory directory of GeneTests, a pioneering NIH-funded resource that will be phased out over the coming year. GTR is designed to contain more detailed information than its predecessor, as well as to encompass a much broader range of testing approaches, such as complex tests for genetic variations associated with common diseases and with differing responses to drugs. GeneReviews, which is the section of GeneTests that contains peer-reviewed, clinical descriptions of more than 500 conditions, is also now available through GTR.

The GTR database was developed by the National Center for Biotechnology Information (NCBI), part of NIH’s National Library of Medicine, under the oversight of the NIH Office of the Director and with extensive input from researchers, testing labs, health care providers, patients and other stakeholders. To view video tutorials on how to use GTR, go tohttp://www.youtube.com/playlist?list=PL1C4A2AFF811F6F0B.

The Office of the Director, the central office at NIH, is responsible for setting policy for NIH, which includes 27 Institutes and Centers. This involves planning, managing, and coordinating the programs and activities of all NIH components. The Office of the Director also includes program offices which are responsible for stimulating specific areas of research throughout NIH. Additional information is available at http://www.nih.gov/icd/od/.

NCBI creates public databases in molecular biology, conducts research in computational biology, develops software tools for analyzing molecular and genomic data, and disseminates biomedical information, all for the better understanding of processes affecting human health and disease. NCBI is a division of the National Library of Medicine, the world's largest library of the health sciences.