Science Weekly podcast: What became of Beagle 2?

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The man who lost a spacecraft; Lester Brown on food bubbles; Alzheimer’s; a mission to Mercury; and responding to national emergencies

Current Programs at Target Health

Target Health has always taken a 2-tier approach to its growth. First and foremost is to develop drug, biologics and devices for our clients. Second, is to develop software tools to optimize our development processes.

To date, we have assisted in the approval of 27 products since 1993, including 19 products marketed world-wide that used Target e*CRF® for their pivotal trials. Current development programs include:

1.      Oncology (pancreatic, bladder, ovary, colorectal, prostate and imaging)
2.      Diabetes
3.      Men’s health
4.      Orthopedics
5.      Cystic fibrosis
6.      Wound healing
7.      Orphan diseases
8.      Traumatic brain injury
9.      Topical antimicrobials
10.  Natural products
11.  Multiple diagnostics including molecular diagnostics

In addition to the core business of product development, Target Health excels in software development for the “paperless clinical trial.” In addition to more than 40 ongoing EDC programs (>200 since 1999), there are 2 ongoing programs under US INDs where data are being entered directly into Target e*CRF. The electronic source documents are created within Target e*CTR® (eClinical Trial Record), which is under the control of the clinical sites. Other software products include:

1.      Target Document® (eTMF)
2.      Target Encoder® (MedDRA and WHO Drug Coding, integrated with Target e*CRF)
3.      Target e*Pharmacovigilance® (From 3500A and CIOMS 1, integrated with Target e*CRF)
4.      Target Monitoring Reports™ (integrated with Target e*CRF)
5.      Target e*CTMS®

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel 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:

Liver, Not Brain, May Be Origin of Alzheimer Plaques

Liver instead of the brain may be the source of the
Alzheimer’s disease amyloid brain plaques (Credit: iStockphoto/David Marchal)

Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter ideas about Alzheimer’s disease (AD) – pointing to the liver instead of the brain as the source of the amyloid that deposits as brain plaques associated AD. The findings could offer a relatively simple approach for AD prevention and 1) ___. The study was published online March 3 in The Journal of Neuroscience Research. In the study, a mouse model for AD was used to identify genes that influence the amount of amyloid that accumulates in the brain. Three genes were identified that protected mice from brain 2) ___ accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilin – a cell membrane protein believed to contribute to the development of human AD. “This unexpected finding holds promise for the development of new therapies to fight Alzheimer’s,” said Scripps Research Professor Greg Sutcliffe, who led the study. “This could greatly simplify the challenge of developing therapies and 3) ___.”

An estimated 5.1 million Americans have AD, including nearly half of people age 85 and older. By 2050, the number of people age 65 and over with this disease will range from 11 million to 16 million unless a way is found to prevent or effectively treat it. In addition to the human misery caused by the disease, there is the unfathomable cost. A new report from the AD Association shows that in the absence of disease-modifying treatments, the cumulative costs of care for people with AD from 2010 to 2050 will exceed $20 4) ___.

In trying to help solve the AD puzzle, Sutcliffe and his collaborators have focused on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging 5) ___ activity in different tissues, as measured by mRNA accumulation. These data offer up maps of trait expression that can be superimposed on maps of disease modifier genes.

Sutcliffe’s research builds on previous findings by researchers at Case Western Reserve who mapped three genes that modify the accumulation of pathological beta amyloid in the 6) ___ of a transgenic mouse model of AD to large chromosomal regions, each containing hundreds of genes. The Case Western scientists used crosses between the B6 and D2 strains of mice, studying more than 500 progeny. Using the results from this study, Sutcliffe turned his databases of gene expression to the mouse model of AD, looking for differences in gene expression that correlated with differences in disease susceptibility between the B6 and D2 strains. This work involved writing computer programs that identified each genetic difference that distinguished the B6 and D2 genomes, then running mathematical correlation (regression) analysis  of each difference. Correlations were made between the 7) ___ differences (B6 or D2) and the amount of mRNA product made from each of the more than 25,000 genes in a particular tissue in the 40 recombinant mouse strains. These correlations were repeated 10 times to cover 10 tissues, including the liver.

Sutcliffe’s gene hunt offered up good matches, candidates, for each of the three disease modifier genes discovered by the Case Western scientists, and one of these candidates – the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset 8) ___ disease – was of special interest. “The product of that gene, called Presenilin2, is part of an enzyme complex involved in the generation of pathogenic beta amyloid,” Sutcliffe explained. “Unexpectedly, heritable expression of Presenilin2 was found in the 9) ___ but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of AD-like pathology.”

This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the 10) ___, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain. An in vivo experiment was devised using wild-type mice since they would most closely replicate the natural beta amyloid-producing environment. “We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice,” Sutcliffe said, “and one would predict in 11) ___, too.” The mice were administered imatinib (trade name 12) ___, an FDA-approved cancer drug) currently approved for treatment of chronic myelogenous leukemia and gastrointestinal tumors. The drug, manufactured by Novartis, potently reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein (APP) and also in cell-free extracts prepared from the transfected cells. Importantly, Gleevec has poor penetration of the blood-brain barrier in both mice and humans.

“This characteristic of the 13) ___ is precisely why we chose to use it,” Sutcliffe explained. “Because it doesn’t penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease.”

The mice were injected with Gleevec twice a day for seven days after which the plasma and brain 14) ___ were collected to measure the amount of beta amyloid. Results showed that the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate.

ANSWERS: 1) treatment; 2) amyloid; 3) prevention; 4) trillion; 5) gene; 6) brains; 7) genotype; 8) Alzheimer’s; 9) liver; 10) blood; 11) humans; 12) Gleevec; 13) drug; 14) tissue

Benjamin Rush – First Surgeon General (1745-1813)

Benjamin Rush (1745-1813), a delegate to the Continental Congress convened in 1775 and a signer of the Declaration of Independence, was the most celebrated American physician and the leading social reformer of his time. He was a close friend of both John Adams and Thomas Jefferson and corresponded with many of the prominent figures of the revolutionary generation. Rush’s strong belief in universal salvation helped to promote acceptance of Universalism during its formative period in America.

After earning an A.B. in 1760 from the College of New Jersey, (now Princeton) Rush studied medicine under Dr. John Redman in Philadelphia. On Redman’s advice, he continued his studies at the University of Edinburgh, where he received an M.D. degree in 1768. In Edinburgh he embraced a new explanation of disease, taught by the prominent instructor, Dr. William Cullen. Rejecting the older theory, based upon the balancing of the four humors, Rush believed that the root cause of disease was “irregular convulsive or wrong action,” especially of the blood vessels. The therapy he recommended to restore the circulatory system to normal was blood-letting. Although from the vantage point of two hundred years Rush’s ideas on the origin and treatment of diseases seem poorly founded, in his time they represented advanced thinking and a scientific challenge to traditional medical wisdom. It should be added that bloodletting was based on an ancient system of medicine in which blood and other bodily fluids were considered to be “humors” whose proper balance maintained health. It was also the most common medical practice performed by doctors from antiquity up to the late 19th century, a time span of almost 2,000 years.

Returning to America, Rush joined the faculty of the College of Philadelphia as professor of chemistry, and in 1789 he became professor of the theory and practice of medicine. When the college became part of the University of Pennsylvania he was appointed chair of Institutes of Medicine and Clinical Practice and chair of Theory and Practice of Medicine.

During the Revolutionary War, Rush served briefly as surgeon-general of the armies of the Middle Department. Finding the army hospitals corruptly and incompetently managed and frustrated that his office did not give him power to reform them, Rush wrote letters of complaint to Congress and to General George Washington. He resigned after Washington accused him of personal disloyalty.

In 1787 Rush and James Wilson led the Pennsylvania convention that ratified the federal constitution; two years later they led a successful campaign to develop a more liberal and effective state constitution. This was Rush’s last involvement in politics, for which he had developed an intense dislike. A decade later President John Adams appointed him Treasurer of the United States Mint, a position he held until his death.

As a physician Rush strove to promote the general health of the citizenry. In 1786 he established the first free government-operated dispensary in the country. During the great yellow fever epidemic in Philadelphia in 1793 Rush worked tirelessly and heroically to care for patients and to curb the spread of the disease. In the face of widespread criticism, he persisted in promoting drastic purgation and radical blood-letting as a means of treatment. “The more bleeding, the more deaths,” one critic complained, not without cause. Nevertheless Rush was convinced that his treatment was successful and had it applied to himself. His popular and accessible book, An Account of the Bilious Remitting Yellow Fever, as It Appeared in the City of Philadelphia, in the Year 1793, 1794, brought him international fame.

Rush made many contributions to medicine that have stood the test of time. He advocated the simplification of diagnosis and treatment of disease. “Let us strip our profession of everything that looks like mystery and imposture,” he wrote. He was an early advocate of preventive medicine. In particular, he pointed out that decayed teeth were a source of systemic disease. He promoted innoculation and vaccination against smallpox.

A pioneer in the study and treatment of mental illness, Rush insisted that the insane had a right to be treated with respect. He protested the inhuman accommodation and treatment of the insane at Pennsylvania Hospital. When he received an inadequate response to his complaints from the hospital’s Board of Managers, Rush took his case to the public at large. In 1792 he was successful in getting state funding for a ward for the insane. He constructed a typology of insanity which is strikingly similar to the modern categorization of mental illness and studied factors – such as heredity, age, marital status, wealth, and climate – that he thought predisposed people to madness.

Part of Rush’s treatment of the mentally ill was based upon his idea of the cause of physical disease. One of his prescriptions for a patient was “bleeding….strong purges – low diet – kind treatment, and the cold bath.” Anticipating Freudian analysis by a century, Rush also listened to his patients tell him their troubles and was interested in dreams. He recommended occupational therapy for the institutionalized insane. His Medical Inquiries and Observations, Upon the Diseases of the Mind, 1812, a standard reference for seventy years, earned him the title of “the father of American psychiatry.”

When Thomas Jefferson came to Philadelphia as the newly-elected Vice President in 1797, he and Rush renewed a friendship that had begun in the days of the Revolution. For several years they carried on private conversation on religious matters, a subject that Jefferson ordinarily refused to discuss.

In 1803, Thomas Jefferson sent Meriwether Lewis to Philadelphia to prepare for the Lewis and Clark Expedition under the tutelage of Rush, who taught Lewis about frontier illnesses and the performance of bloodletting. Rush provided the corps with a medical kit that included: Turkish opium for nervousness; emetics to induce vomiting; medicinal wine; 50 dozen (600) Dr. Rush’s Bilious Pills. Dr. Rush’s Bilious Pills were laxatives containing more than 50% mercury, which the corps called “thunderclappers.” Their meat-rich diet and lack of clean water during the expedition gave the men cause to use them frequently. Though their efficacy is questionable, their high mercury content provided an excellent tracer by which archaeologists have been able to track the corps’ actual route to the Pacific.

In his time, Rush had no peer as a social reformer. Among the many causes he championed – most of them several generations in advance of nearly all other reformers – were prison and judicial reform, abolition of slavery and the death penalty, education of women, conservation of natural resources, proper diet, abstinence from the use of tobacco and strong drink, and the appointment of a “Secretary of Peace” to the federal cabinet.

In 1813 Rush died suddenly after a brief illness. He was buried in the graveyard of Christ’s Church in Philadelphia. On learning of his death Jefferson wrote Adams: “Another of our friends of seventy-six is gone, my dear Sir, another of the co-signers of the Independence of our country. And a better man than Rush could not have left us, more benevolent, more learned, of finer genius, or more honest.” Adams, grief-stricken, wrote in reply, “I know of no Character living or dead, who has done more real good in America.”

Association of Active and Passive Smoking with Risk of Breast Cancer Among Postmenopausal Women: A Prospective Cohort Study

According to a study published online in the British Medical Journal (1 March 2011), a study was performed to examine the association between smoking and risk of invasive breast cancer using quantitative measures of lifetime passive and active smoking exposure among postmenopausal women.

The investigation was a prospective cohort study, with 79,990 women aged 50-79 enrolled at 40

clinical centers in the US as part of the Women’s Health Initiative Observational Study during (1993-1998). The main outcome measures were self-reported active and passive smoking, and pathologically confirmed invasive breast cancer.

During the course of the study, a total of 3,520 incident cases of invasive breast cancer were identified during an average of 10.3 years of follow-up. Compared with women who had never smoked, breast cancer risk was elevated by 9% among former smokers and by 16% among current smokers. Significantly higher breast cancer risk was observed in active smokers with high intensity and duration of smoking, as well as with initiation of smoking in the teenage years. The highest breast cancer risk (35%) was found among women who had smoked for >50 years or more compared with all lifetime non-smokers, and 45% when compared with lifetime non-smokers with no exposure to passive smoking. An increased risk of breast cancer persisted for up to 20 years after smoking cessation.

Among women who had never smoked, after adjustment for potential confounders, those with the most extensive exposure to passive smoking (>10 years’ exposure in childhood, >20 years’ exposure as an adult at home, and >10 years’ exposure as an adult at work) had a 32% excess risk of breast cancer compared with those who had never been exposed to passive smoking. However, there was no significant association in the other groups with lower exposure and no clear dose response to cumulative passive smoking exposure.

According to the authors, active smoking was associated with an increase in breast cancer risk among postmenopausal women and there was also a suggestion of an association between passive smoking and increased risk of breast cancer.


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Functional Variants of the HMGA1 Gene and Type 2 Diabetes Mellitus

HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1 gene. This gene encodes a non-histone protein involved in many cellular processes, including regulation of inducible gene transcription, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells. The encoded protein preferentially binds to the minor groove of A+T-rich regions in double-stranded DNA. It has little secondary structure in solution but assumes distinct conformations when bound to substrates such as DNA or other proteins. The encoded protein is frequently acetylated and is found in the nucleus. At least seven transcript variants encoding two different isoforms have been found for this gene.

According to an article published in the Journal of the American Medical Association (2011;305:903-912), a study was performed to examine the association of HMGA1 gene variants with type 2 diabetes mellitus (DM).

The study was a case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. The populations included: 1) Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) who were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; 2) US patients with type 2 DM (n = 970) who were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) who were senior athletes without DM collected in 2004 and 2009; and 3) French patients with type 2 DM (n = 354) and healthy controls (n = 50) who were enrolled at the University of Reims in 1992.

Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus–transformed lymphoblasts from patients with type 2 DM and controls.

Results showed that the most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group, P < 0.001 and 7.23% vs 3.32% in the other control group, P < 0.001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (P = 0.03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls.

According to the authors, compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.

The Results Database – Update and Key Issues

The trial registry was expanded in 2008 to include a database for reporting summary results. According to an article published in the New England Journal of Medicine (2011;364:852-860), a report has been created to 1) summarize the structure and contents of the results database, 2) provide an update of relevant policies, and 3) to show how the data can be used to gain insight into the state of clinical research.

For the report, data were analyzed that were publicly available between September 2009 and September 2010.

Results showed that as of September 27, 2010, received approximately 330 new and 2,000 revised registrations each week, along with 30 new and 80 revised results submissions. From a sample cohort of results records, 78 of 150 (52%) had associated publications within 2 years after posting. Of results records available publicly, 20% reported more than two primary outcome measures and 5% reported more than five. Of a sample of 100 registry record outcome measures, 61% lacked specificity in describing the metric used in the planned analysis. In a sample of 700 results records, the mean number of different analysis populations per study group was 2.5 (median, 1; range, 1 to 25). Of these trials, 24% reported results for 90% or less of their participants.

According to the authors, provides access to study results not otherwise available to the public, and while the database allows examination of various aspects of ongoing and completed clinical trials, its ultimate usefulness depends on the research community to submit accurate, informative data.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

FDA Approves Edarbi For High Blood Pressure

Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps. If blood pressure rises and stays high over time, it can damage the body in many ways. Nearly 1 in 3 adults in the US has high blood pressure, which increases the risks of stroke, heart failure, heart attack, kidney failure, and death.

“High blood pressure is often called the ‘silent killer’ because it usually has no symptoms until it causes damage to the body,” said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiovascular and Renal Drug Products in the FDA’s Center for Drug Evaluation and Research. “High blood pressure remains inadequately controlled in many people diagnosed with the condition, so having a variety of treatment options is important.”

The FDA has approved Edarbi tablets (azilsartan medoxomil; Takeda Pharmaceutical North America) to treat high blood pressure (hypertension) in adults. Edarbi is an angiotensin II receptor blocker (ARB) that lowers blood pressure by blocking the action of angiotensin II, a vasopressor hormone. Data from clinical studies showed Edarbi to be more effective in lowering 24-hour blood pressure compared with two other FDA-approved hypertension drugs, Diovan (valsartan) and Benicar (olmesartan). Edarbi will be available in 80 milligram and 40 mg doses, with the recommended dose set at 80 mg once daily. The 40 mg dose will be available for patients who are treated with high-dose diuretics taken to reduce salt in the body.

Adverse reactions reported by patients taking Edarbi in clinical trials were similar to those reported by those taking an inactive drug (placebo).

Edarbi has a boxed warning that says the use of the drug should be avoided in pregnant women because use of the drug during the second or third trimester can cause injury and even death in the developing fetus. If a woman becomes pregnant while using the drug, it should be discontinued as soon as possible.

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

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