Science Weekly: Maggie Philbin on science books and Tomorrow’s World

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Maggie Philbin discusses science books and Tomorrow’s World; plus, James Randi and PZ Myers at TAM London

Target e*CTR® Solves the Challenges of Direct Data Entry

Target Health is pleased to announce the release of Target e*CTR® (Target e*Clinical trial Record), the electronic clinical trial source document which is fully integrated with Target e*CRF® and the Target e*CTR™ Viewer as well as the Life-On-Key Electronic Medical Record. A phase 2 study is beginning shortly and a Phase 3 program is planned for Q3 2011. The software is currently being used in the background of several clinical trials as part of performance qulalification (PQ). Dr. Jules Mitchel, President of Target Health Inc. is leading the project team and Target Health is rewriting it’s monitoring and data management standard operating procedures to address this novel software. We are confident that this 21 CFR Part 11 compliant software addresses both FDA and EMA regulatory issues related to original clinical trial data that are entered directly into electronic systems.

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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

Protein Implicated in Many Cancers

Follicle-Stimulating Hormone


A Receptor for hormone may be a good drug target. A protein involved in hormone signaling is also produced by blood vessel cells in 1) ___. The protein showed up in 11 kinds of tumors examined by a French-U.S. research team but was notably absent in most healthy tissues. As a result, this receptor may be a valuable 2) ___ for tumor suppression. The discovery, reported on 21 October 2010 in the New England Journal of Medicine, suggests that the protein may help cancer gain a foothold by recruiting blood vessels to nourish the tumor.

Earlier work had linked the protein, called a follicle stimulating hormone receptor, to prostate 3) ___. In the new study the receptor was detected in every one of 773 prostate tumor samples they tested, noting that the receptor turned up in blood vessel cells on the tumors. The FSH receptor didn’t show up at all in healthy prostate tissues from these patients. The study also found this pattern when examining 10 other types of tumors obtained from 563 other patients.

The fact that it is not a phenomenon confined to prostate cancer only makes this a much more interesting finding. Activating the 4) ___ probably confers a worse prognosis. The FSH receptor is a protein displayed by cells that latches onto the FSH protein, a 5) ___ that plays several roles in the reproductive system. This binding also might play a role in angiogenesis, the formation of new blood vessels. The FSH receptor normally shows up in ovaries and testes, and did so in these tests. It also appeared in samples of placental tissue.

While new vessel growth is fine in the 6) ___ – helping the fetus gain nutrition from the mother’s body and grow rapidly – such angiogenesis has a dark side: Tumors fuel their own growth by triggering angiogenesis to obtain blood and nutrients. The driving force in tumor growth is the proliferation of the cancer 7) ___, which in turn induces angiogenesis.

The study also found that cells with activated 8) ___ receptors tended to cluster at the edges of a tumor. This location is consistent with the view that the tumor cells at the invasive front attract surrounding blood vessels toward the tumor.

The researchers are now trying to confirm in animal studies that the FSH receptor really does contribute to tumor growth. The researchers also want to determine whether compounds that inhibit the receptor or the FSH protein itself might constitute new anticancer 9) ___.

ANSWERS: 1) tumors; 2) target; 3) cancer; 4) receptor; 5) hormone; 6) placenta; 7) cells; 8) FSH; 9) drugs

Mark Twain On Medicine (The New York Times, March 9, 1902)

He Discusses the Progress Made in the Science..

Mark Twain was the principal speaker at the Hotel Savoy last night at the dinner in celebration of the twentieth anniversary of the foundation of the Society of Medical Jurisprudence. He said at the outset of his remarks that it was a pleasure to watch a company of gentlemen “in that condition which is peculiar to gentlemen who have had their dinners.” That was a time, said Mr. Clemens, when the real nature of man came out.

“As a rule,” he continued, “we go about with masks, we go about looking honest, and we are able to conceal ourselves all through the day. But when the time comes that man has had his dinner, then the true man comes to the surface. I could see it here this evening. I noticed the burst of applause when Judge O’Brien got up to speak, and I knew that he was either an exceedingly able man or else that a lot of you practice in his court. [Laughter.] You have been giving yourselves away all evening. One speaker got up here and urged you to be honest, and there was no response.

“Now, I want you to remember that medicine has made all its progress during the past fifty years. One member of this society sent me a typewritten judicial decision of the year 1809 in a medical case with the suggestion that this was the kind of medicine to have, and that the science of medicine had not progressed, but gone back. This decision went on and described a sort of medicine I used to take myself fifty years ago, and which was in use also in the time of the Pharaohs, and all the knowledge up to fifty years ago you got from five thousand years before that.

“I now hold in my hand Jaynes’ Medical Dictionary, published in 1745. In that book there is a suggestion as to what medicine was like a long time ago. How many operations that are in use now were known fifty years ago? – they were not operations, they were executions. [Laughter.]

“I read in this book the case of a man who ‘died from a severe headache.’ Why ‘severe?’ The man was dead. Didn’t that cover the ground? [Laughter.] This book goes on to say: ‘A certain merchant about fifty years of age, of a melancholy habit, and deeply involved in affairs of the world, was, during the dog days’ – with a capital D-‘seized with a violent pain of his head, which some time after kept him in bed. I being called’ – remember this man was a regular – ‘ordered vennisection in the arms, bleeding; I also ordered the application of leeches to the vessels of his nostrils; I also ordered the application of leeches to his forehead and temples, and also behind his ears.’

“Now you see,” continued Mark Twain, holding the old medical book in his hand, “he has got him fringed all over with leeches. But that was not enough, for he goes on to say: ‘I likewise ordered the application of cup glasses, with scarification on his back.’ Now, he has township maps carved all over him, and all this is for a headache. But notwithstanding these precautions the man dies, or rather, perhaps, I might have said, because of these precautions the man dies. [Laughter.] Now this physician goes on to say: ‘If any surgeon skilled in arterial anatomy had been present, I should also have ordered an operation.’ [Laughter.] He was not satisfied with what he had done, with the precautions he had already taken, but he wanted apparently to put a pump into that man and pump out what was left. [Laughter.]

“Now all that has passed away, and modern medicine and surgery have come in. Medicine was like astronomy, which did not move for centuries. When a comet appeared in the heavens it was a sign that a Prince was going to die! It was also a sign of earthquakes and of pestilence and other dreadful things. But they began to drop one thing after another. They finally got down to earthquakes and the death of a Prince as the result of the appearance of a comet, until in 1818 a writer in The Gentlemen’s Magazine found at least one thing that a comet was sent for, because it was of record that when the comet appeared in 1818 all the flies in London went blind and died. [Laughter.] Now they had got down to flies. [Laughter.]

“In 1829 a clergyman found still one thing that a comet was sent for, because while it was in the heavens all the cats in Westphalia got sick. But in 1868 that whole scheme was swept away and the comet was recognized to be only a pleasant summer visitor, and as for the cats and flies they never were so healthy as they were then. [Laughter.] From that time dates the great step forward that your profession has taken.” [Laughter and applause.]

Justice John Woodward spoke on the value of expert testimony as viewed by appellate tribunals. He said that the subject was a very important one, but that the solution of the problem was to be found in common honesty.

“When a witness swears in favor of his side, ” said Justice Woodward, “because he has got a fee, then he is no longer worthy to be received in decent society or respected by self-respecting men. [Applause.] The value of an expert’s testimony rests on the value of the man who gives it. The expert who does not tell the whole truth is as much a perjurer before God as the man who says he saw an accident which occurred ten miles away from him. If when an expert is known among his professional brethren to have given false testimony, he were shunned by them, if he were treated in the same manner as a man would be in society for having committed perjury on any other subject, that kind of swearing would soon be a matter of the past. [Applause.]

“On the other hand, the man who masters his art or science and practices it conscientiously and then in the course of affairs, by reason of the knowledge that he has acquired consents to testify in a particular case and gives the benefit of his great experience and knowledge to the Judge and jury, then that man is entitled to credence and standing.”

Justice Morgan J. O’Brien answered to the toast of “The Law.” He related some incidents of judicial life that excited much amusement, and concluded with a definition of constitutional law and its place in human society that was loudly cheered.

The Rev. Dr. Howard Duffield responded to the toast “The Triple Alliance,” speaking briefly on the three learned professions – law, medicine, and theology.

Charles V. Fornes, President of the Board of Aldermen, was the last speaker. He spoke on “Fusion or Confusion” and attributed the Fusion victory in the last municipal campaign largely to the newspapers.

Theodore Sutro, President of the society, acted as the toastmaster.

PS: The first volume of autobiography is to be published by the University of California in November 2010, 100 years after his death as Twain wished.

NIH Scientists Discover Secrets of Helper T Cells Involved in Autoimmunity

The immune systems of mice and humans mainly consist of B cells and T cells. While B cells fight infections and can induce autoimmunity by producing antibodies that directly target foreign antigens or a person’s own tissue, T cells are involved in overall cell-mediated immunity. Importantly, how a T helper (Th) cell differentiates (develops from an immature, unspecialized cell into a mature, specialized cell) determines how it mediates immune responses. Th17 cells produce IL-17, a powerful inflammatory cytokine, and have been implicated in multiple autoimmune diseases, including rheumatoid arthritis, psoriasis and multiple sclerosis. The established belief has been that Th17 cells initially differentiate in response to activation by IL-6 and TGF-beta. However, previous research has shown that TGF-beta is primarily associated with suppressing immune functions and promoting regulatory T cells (Treg), which can produce inhibitory cytokines that dampen inflammatory immune responses.

According to an article published in Nature (2010;467: 967-971), the roles of several cytokines involved in the generation of immune cells implicated in severe autoimmune diseases have been redefined. The study in mice showed that development of Th17 immune cells can occur without the presence of transforming growth factor (TGF)-beta, a mediator thought to be required for Th17 cell development. The study demonstrates that the interaction of three inflammatory cytokines (proteins that influence the behavior of cells) – IL-23, interleukin-6 (IL-6) and IL-1-beta – is responsible for the creation of Th17 cells that are more active in promoting autoimmunity than Th17 cells generated with TGF-beta, IL-6 and IL-1-beta. These findings reemphasize the separate roles of IL-23 and TGF-beta in immunity and autoimmunity, and open up possibilities for the development of new therapies.

The present study tried several different in vitro cocktails of cytokines to see which combinations would promote Th17 development from naïve T cells. Results showed that two combinations efficiently induced Th17 differentiation. As previously described, IL-6, IL-1-beta, and TGF-beta-1 together created Th17 cells. Surprisingly, IL-6, IL-1-beta, and IL-23 without TGF-beta also created Th17 cells. Most interestingly, the action of Th17 cells generated with IL-23, designated Th17(23), was different from the action of Th17 cells generated with TGF-beta (Th17(beta)). The study then compared transcription factors, receptors and mediators of the two Th17 subtypes and looked at the pathogenic activity of both Th17 subtypes in mice during experimental autoimmune encephalomyelitis (EAE), a common model of autoimmunity that mimics some aspects of multiple sclerosis. They found that Th17(23) cells provoked significantly more severe disease than did Th17(beta) cells.

These findings suggest a new model for Th17 generation and the existence of functionally different subtypes of Th17 cells. This study also provides a better understanding of the array of immune components involved in autoimmunity and suggests possibilities for new targeted therapies.

Effect of DHA Supplementation During Pregnancy on Maternal Depression and Neurodevelopment of Young Children

Uncertainty about the benefits of dietary docosahexaenoic acid (DHA) for pregnant women and their children exists, despite international recommendations that pregnant women increase their DHA intakes. As a result, a study publised in JAMA (2010;304:1675-1683) was performed to determine whether increasing DHA during the last half of pregnancy will result in fewer women with high levels of depressive symptoms and enhance the neurodevelopmental outcome of their children.

A double-blind, multicenter, randomized controlled trial (DHA to Optimize Mother Infant Outcome [DOMInO] trial) was carried out in 5 Australian maternity hospitals. The study followed 2,399 women who were less than 21 weeks’ gestation with singleton pregnancies and who were recruited between October 31, 2005, and January 11, 2008. Follow-up of children (n = 726) was completed December 16, 2009.

For the study subjects received docosahexaenoic acid-rich fish oil capsules (providing 800 mg/d of DHA) or matched vegetable oil capsules without DHA from study entry to birth. The main outcome measures were high levels of depressive symptoms in mothers as indicated by a score of more than 12 on the Edinburgh Postnatal Depression Scale at 6 weeks or 6 months postpartum; and cognitive and language development in children as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition, at 18 months of age.

Of the 2,399 women enrolled, 96.7% completed the trial. The percentage of women with high levels of depressive symptoms during the first 6 months postpartum did not differ between the DHA and control groups (9.67% vs 11.19%; adjusted relative risk, 0.85; P = .09). Mean cognitive composite scores (adjusted mean difference, 0.01; P = .99) and mean language composite scores (adjusted mean difference, –1.42; P = .09) of children in the DHA group did not differ from children in the control group.

According to the authors, the use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in lower levels of postpartum depression in mothers or improved cognitive and language development in their offspring during early childhood.

Role of Th17 Cells in Human Autoimmune Arthritis

According to an article published in Arthritis & Rheumatism (2010;62:2876–2885), a study was performed to delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides.

For the study, Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts.

Expression of T lineage-specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell–inducing conditions were analyzed in vitro.

Results showed that the frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients.

According to the authors, Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease.

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Personalized Medicine, Comparative Effectiveness – Allies or Adversaries?

A recent conference at the NIH organized by ECRI Institute, The Agency for Healthcare Research and Quality (AHRQ), and the National Institutes for Health (NIH), assembled clinicians, scientists, patient advocates, regulators, venture capitalists and policy wonks to consider the interface between accelerating initiatives to evaluate comparative effectiveness, enabled by the Affordable Care Act, and the clinical potential of “personalized medicine”, enabled by advances in mapping the human genome.

Key among the questions debated was the potential conflict between the promise of “genomically” empowered personalized medicine to individualize therapy and the ‘threat’ that comparative effectiveness research, (the responsibility assigned to the new Patient Centered Outcomes Research Institute authorized by the Affordable Care Act), will lead to ‘one size fits all’ interventions based upon statistically determined population means. It is fair to say that, overall, presenters and audience responders did not see a conflict. Instead, they saw aligned objectives and viewed Comparative Effectiveness Research (CER) and Personalized Medicine as complementary approaches focused on determining the proper therapy for individuals. These new tools will help providers understand and objectively adjust for the heterogeneity of treatment effect among patients. While the methods differ, their objective – precisely targeted therapy achieving improved outcomes more safely – is the same.

Also noteworthy (although requiring a bit of ‘reading between the lines’): Despite the increasing interest in and hope for observational trials, concerns were raised by both regulators and academics about inevitable confounding and consequent bias in observational studies. It seems that even in the brave new world of genomics, personalized medicine, and comparative effectiveness randomized clinical trials remains sacrosanct. However, there was concern that the cost and complexity of randomized clinical trials (RCTs) are excessive and unsustainable and that efficiencies must be increased. The CTTI (Clinical Trial Transformation Initiative) collaboration among FDA, Industry, & Academia, designed to address this problem, was specifically mentioned. (Of interest to “On-Target” readers, Target Health is a member of the CTTI, and Dr. Mitchel represents Target Health on the Steering Committee).

Of great concern to all were the clearly surprising comments from the venture capital community whose representatives spoke frankly about the increased risk and detrimental effect on capital availability caused by reimbursement uncertainty due to comparative effectiveness data requirements.

Unclear and evolving requirements for the comparative data required for reimbursement increase investment risk; venture capital, concerned by this uncertainty, will seek alternative investments with more predictable returns. This detrimental impact on funding for new medicines and devices will worsen if not addressed. Judging by the questions, many attendees were surprised by this predictable reality; happily, audience concern was palpable suggesting that attention will be paid to this significant threat to US biomedical leadership.

In sum this event offered mixed messages; there was excitement about the science and medicine, an acknowledgement of the need to maintain and protect the RCT gold standard by increasing its efficiency, and a concern that the commercial translational model is threatened by unpredictable CER standards.

How will this all play out? It’s too early to tell, but watch this space!

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