Science Weekly: Carols for godless people

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A variety show for atheists, UN secretary general Ban Ki-moon on climate change, and relationship advice from our evolutionary agony aunt

Target e*CTMSTM Version 1.1 Released

Target Health is pleased to announce the release of Target e*CTMSTM version 1.1. This version adds a series of reports both within projects and across projects. Target e*CTMSTM was developed in part with our colleagues from Cato based in Israel. Cato saw our original CTMS version for a joint project we were working on and then sent over their requirements. Together we came up with a really terrific system. The next version will have a budget module as well as full integration with Target Document® our premier Document viewing and document management system. If you want a paperless TMF or a paperless clinical trial, just let us know.

Other Target Health Inc. software products include:

  • Target e*CRF®
  • Target Encoder®
  • Target Document®
  • Target NewsletterTM
  • Target e*PharmacovigilanceTM
  • Target Batch Edit ChecksTM
  • Target e*RandomizationTM
  • Target Time ManagementTM
  • Target e*CTRTM (eClinical Trial Record)

For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at: www.targethealth.com

Tiny Molecule Slows Progression of Lou Gehrig’s Disease in Mice

Researchers at UT Southwestern Medical Center have found that a molecule produced naturally by muscles in response to nerve 1) ___ can reduce symptoms and prolong life in a mouse model of amyotrophic lateral sclerosis (ALS). “We believe we can apply this research toward drug development,” said Dr. Eric Olson, chairman of molecular biology at UT Southwestern and senior author of the study, which appears in the Dec. 11 issue of Science. ALS, also known as Lou Gehrig’s disease, damages motor nerve cells that control 2) ___, leading to muscle weakness, paralysis and death. There is no treatment that can slow it, and no cure. As ALS kills 3) ___, the muscles they control begin to wither. The damaged muscles, however, can “re-innervate” themselves by prompting healthy nerves to send new branches their way, like limbs in a damaged hedge filling in a gap. Dr. Olson said skeletal muscles produce a 4) ___ called microRNA-206 (miR-206) to serve as a chemical signal to steer the new nerve endings and maintain their interactions with muscles. But the research suggests that miR-206 can only work for so long. As nerves continue to die, there comes a point where the surviving nerves can no longer carry the load, and symptoms like muscle weakness appear. “While miR-206 initially prompts nearby surviving nerves to send new branches to the muscles, it only delays the inevitable,” Dr. Olson said. “Our findings correlate with the observation in ALS patients that the disease is nearly asymptomatic until a large fraction of motor neurons has died, at which point the few remaining ones can’t compensate sufficiently. These results provide a new perspective on the mechanisms of ALS,” he said. “MiR-206 seems to sense nerve injury and promote 5) ___. “Because miR-206 only exists in 6) ___ muscle, a drug based on it might not affect other tissues. That limits its risk of side effects and is a key part of its appeal as a potential therapy.”

ANSWERS: 1) damage; 2) muscles; 3) nerves; 4) molecule; 5) regeneration; 6) skeletal

Tuberculosis

Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of bison dated 18,000 years before the present. Whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor infecting a different species, is currently unclear. Skeletal remains from a Neolithic Settlement in the Eastern Mediterranean around 7000 BCE show that prehistoric humans had TB, and tubercular decay has been found in the spines of mummies from 3000-2400 BCE. Around 460 BCE, Hippocrates identified phthisis (Greek term for tuberculosis) as the most widespread disease of the times involving coughing up blood and fever. The disease was almost always fatal. In South America, the earliest evidence of tuberculosis is associated with the Paracas-Caverna culture (circa 750 BCE to circa 100 CE). In the past, tuberculosis has been called consumption, because it seemed to consume people from within, with a bloody cough, fever, pallor, and long relentless wasting. Other names include phthisis pulmonalis; scrofula (in adults), affecting the lymphatic system and resulting in swollen neck glands; tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague, because sufferers appear markedly pale; king’s evil, because it was believed that a king’s touch would heal scrofula; and Pott’s disease, or gibbus of the spine and joints. Miliary tuberculosis – now commonly known as disseminated TB – occurs when the infection invades the circulatory system, resulting in lesions which have the appearance of millet seeds on X-ray. TB is also called Koch’s disease, after the scientist Robert Koch. Heinrich Herman Robert Koch (1843 – 1910) was a German physician, who became famous for isolating Bacillus anthracis (1877), the Tuberculosis bacillus (1882) and the Vibrio cholera (1883) and for his development of Koch’s postulates. He was awarded the Nobel Prize in Physiology or Medicine for his tuberculosis findings in 1905. In Berlin, Koch improved the methods he used for staining and purification techniques, and bacterial growth media, including agar plates and the Petri dish, named after its inventor, his assistant Julius Richard Petri. These devices are still used today. With these techniques, Koch was able to discover the bacterium causing tuberculosis (Mycobacterium tuberculosis) in 1882 (he announced the discovery on 24 March). Tuberculosis was the cause of one in seven deaths in the mid-19th century. The Robert Koch Prize and Medal were created to honour Microbiologists who make groundbreaking discoveries or who contribute to global health in a unique way.

Behavioral Training Improves Connectivity and Function in the Brain

According to an article published in the journal Neuron (2009;64,624-631), children with poor reading skills who underwent an intensive, six-month training program to improve their reading ability, showed increased connectivity in a particular brain region, in addition to making significant gains in reading. According to NIMH Director Thomas R. Insel, M.D. “This finding with reading deficits suggests an exciting new approach to be tested in the treatment of mental disorders, which increasingly appear to be due to problems in specific brain circuits.” For the study, 35 poor readers 8-12 years of age, were randomly assigned to an intensive, remedial reading program, and 12 poor readers to a control group that received normal classroom instruction. For comparison, the study included 25 children of similar age who were rated as average or above-average readers by their teachers. The average readers also received only normal classroom instruction. Four remedial reading programs were offered, but few differences in reading improvements were seen among them. As such, results for participants in these programs were evaluated as a group. All of the programs were given over a six month schooling period, for five days a week in 50-minute sessions (100 hours total), with three students per teacher. The focus of these programs was improving readers’ ability to decode unfamiliar words. Using a technology called diffusion tensor imaging (DTI), the study was able to measure structural properties of the children’s white matter, the insulation-clad fibers that provide efficient communication in the central nervous system. Specifically, DTI shows the movement of water molecules through white matter, reflecting the quality of white matter connections. The better the connection, the more the water molecules move in the same direction, providing a higher “bandwidth” for information transfer between brain regions. At the outset of the study, poor readers showed lower quality white matter than average readers in a brain region called the anterior left centrum semiovale. Six months later, at the completion of the intensive training, the poor readers showed significant increases in the quality of this region. Children who did not receive the training did not show this increase, suggesting that the changes seen in the remedial training group were not due to natural maturation of the brain. In an effort to further pinpoint the mechanism underlying this change, the researchers deduced that a process called myelination may be key. Myelin is akin to electrical insulation, allowing for more rapid and efficient communication between nerve cells in the brain. However, the directional association between brain changes and reading improvements remains unclear – whether intensive training brings about increased myelination that results in improved word decoding skills, or whether improved word decoding skills leads to changes in reading habits that result in greater myelination.

Blood Stem-Cell Transplant Regimen Reverses Sickle Cell Disease in Adults

In the US, approximately 80,000 people have sickle cell disease, found mainly, but not exclusively, in people of African ancestry. Worldwide, millions of people have sickle cell disease. The pain and complications associated with sickle cell disease can have a profound impact on patients’ quality of life, ability to work, and long-term health and well-being. Sickle cell disease is caused by an altered gene that produces abnormal hemoglobin. When affected red cells lose oxygen, they collapse into a sickle, or C, shape and become stiff and sticky. Clumps of these cells block blood flow and can cause severe pain, organ damage from lack of oxygen, and stroke. Anemia often develops in people with the disease because sickle cells die off quickly and bone marrow does not make new ones fast enough. An article published in the New England Journal of Medicine (2009;361:2309-2317), reported that after 2.5 years, modified blood adult stem-cell transplant regimen has effectively reversed sickle cell disease in 9 of 10 severely affected adults. Previously, nearly 200 children with severe sickle cell disease were cured with bone marrow transplants after undergoing a regimen in which their own marrow was completely destroyed with chemotherapy. That regimen, however, had proven too toxic for adults, who have years of accumulated organ damage from the disease and are less able to tolerate complete marrow transplantation. In contrast to the established method in children, this adult trial sought to reduce toxicity by only partially replacing the bone marrow. The much longer lifespan of normal red blood cells, compared to sickle red blood cells, allowed the healthy cells to outlast and completely replace the disease-causing cells. To achieve this goal, the investigators used a low dose of radiation to the whole body and two drugs, alemtuzumab and sirolimus, to suppress the immune system. The radiation favorably conditions the bone marrow, where donor stem cells move in and begin producing new, healthy red blood cells. Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma targets CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. Sirolimus, also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation. Sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island – an island also known as “Rapa Nui”, hence the name. Sirolimus does not block the activation of immune cells, but inhibits their proliferation, creating a balance that potentially helps prevent rejection of the new stem cells. To reduce the possibility of the immune system’s rejection of the graft or development of graft-versus-host disease, in which immune cells from the donor attack the recipient’s tissues, investigators tested the patient and the potential donor to determine if they are a good immunological match. This is called human leukocyte antigen (HLA) typing. The investigators performed HLA typing on 112 people with severe sickle cell disease and 169 healthy siblings. Of these, 10 patient-sibling identical matches were found. Blood stem cells collected from the blood of healthy donors were then infused into their siblings, ages 16 to 45 years. This relatively low toxicity regimen allowed patients to become tolerant to the donor immune cells and to achieve stable mixed donor chimerism. Chimerism is a condition in which an individual has two genetically distinct types of cells in the blood. This mixture of host and donor cells was sufficient to reverse sickle cell disease. In most patients the donor’s red blood cells completely replaced the recipient’s. One of the main obstacles in treating a larger number of African-Americans with sickle cell disease is the relative lack of an available HLA-matched donor. While most white Americans can easily find a matched donor in the unrelated bone marrow or cord blood registries, for this indication, when the study screened a number of the people who were without an HLA-matched sibling donor, it was not possible find a compatible unrelated donor. According to the authors, one solution may be to move to “haplo-transplantation,” or a half-match from a sibling, parent or child. What this means is that when doing a Class 1 and a Class 2 Tissue typing, it is found that each individual has two sets of each ‘A’, ‘B’, ‘Cw’ and ‘DR’ antigens. One set of A, B, Cw and DR is inherited from the father and one set from the mother. Each set of A, B, Cw, and DR antigens is known as a haplotype. With only rare exceptions then, each parent will be haplo-compatible, or half-matched, with his or her child.

Gene’s Position in the Nucleus Can Be Used to Distinguish Cancerous From Normal Breast Tissue

Chromosomes and individual genes have been found to occupy specific locations relative to one another and to landmarks within the cell nucleus. Alterations of spatial organization also occur in disease states such as cancer. The distinctive changes in shape and size of the cell nucleus, which pathologists use routinely as indicators of whether or not cancer is present, suggest that major changes in spatial gene organization also occur in cancer cell nuclei. According to an article published in the Journal of Cell Biology (2009;187:733-747), several genes have been identified whose spatial position inside the cell nucleus is altered in invasive breast cancer. The findings suggest that cancer cells may have disease-specific, three-dimensional gene arrangements and raise the possibility that such gene positioning patterns could be used as a new diagnostic strategy to distinguish cancer tissue from normal tissue. To identify genes which occupy distinct positions inside the nucleus in normal and malignant cells, the study visualized a set of 20 genes in a set of 11 normal human breast and 14 invasive cancer tissue specimens using fluorescent in situ hybridization (FISH), a technique to detect and localize specific DNA sequences in intact cells. The study identified eight genes with a high frequency of repositioning in cancer specimens. Only a minority of tested genes underwent significant repositioning in a given cancer tissue, suggesting that repositioning is gene-specific and does not reflect a large-scale alteration in gene organization. The repositioning events were also not due to a common cellular occurrence known as genomic instability, which is often associated with cancer, because repositioning did not correlate with changes in the number of copies of the gene present in the cell. The study next used the tissue specimens to test whether gene repositioning could distinguish cancer from normal and non-cancerous tissues. They found that the position of a single gene, HES5, allowed identification of invasive breast cancer tissue with nearly 100% accuracy. HES5 is a gene commonly associated with cancer and affects biological pathways that have been implicated in cancer. Additionally, several combinations of two or three genes allowed identification of cancerous tissues with low false-negative and false-positive rates (that is, the combinations identified most cancer tissues as cancer and few non-cancerous tissues as cancer). This approach compares favorably with current standard breast cancer diagnostic tests that rely on fine needles or larger core needles to biopsy small amounts of tissue for examination. Identification of genes that are localized differently in normal and cancer cells allows the possibility of using spatial gene positioning as a novel diagnostic tool, although the authors note that the findings will need to be replicated in a set of larger tissue samples. As required for such an application, the researchers found low variability of gene positioning among individuals. They also found that cancer tissues could accurately be identified by comparison to a standardized normal gene distribution. A distinct advantage of this approach over existing methods is the very small quantity of material required. Differences in spatial positioning were routinely detected by analysis of 100 to 200 cells despite the lack of uniformity in cancer samples. Furthermore, this approach is suitable for adaptation in a routine laboratory setting because all individual steps of the procedure rely on standard methods, including embedding of biopsy material and FISH detection. The use of spatial genome positioning for detection of tumors could reduce human error in making a diagnosis because the method gives a quantifiable readout and is not based on subjective criteria or the individual expertise of the pathologist who performs an evaluation with a microscope.

For a client, Target Health has been involved in a regulatory and clinical program in Hereditary Angioedema since 2003.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

FDA Approves Kalbitor for Treating Potentially Life-Threatening Attacks of Hereditary Angioedema

Hereditary angioedema (HAE) is caused by a defect in the blood protein C1 esterase-inhibitor, which plays a role in regulating how certain immune system and blood clotting pathways function. Decreased function of this protein can lead to rapid and serious swelling of the face or other parts of the body, which may result in permanent disfigurement, disability or death. Swelling of the digestive tract may cause excruciating abdominal pain, nausea, and vomiting, while airway swelling puts patients at risk of suffocation. About 10,000 people in the United States have HAE.

FDA has approved Kalbitor (ecallantide) to treat sudden and potentially life-threatening fluid buildup that can occur in people with HAE. Kalbitor is a liquid that is intended to be injected under the skin for patients age 16 and older who experience HAE attacks. The medication’s most serious side effect is anaphylaxis, a severe allergic reaction that can close a person’s airways and stop them from breathing. Other side effects include headache, nausea, diarrhea, swelling in the nose and throat, fever, and skin irritations. Kalbitor should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis. The drug is marketed by Dyax Corp., Cambridge, Mass. The second HAE drug, Berinert, is marketed by CSL Behring Inc., Marburg, Germany.

For more information about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing. Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMSTM, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTRTM (electronic medical record for clinical trials). Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

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