Discovering for the first time that copy number variation or CNV, where a strip of DNA is duplicated or missing, may
increase risk of developing cancer, US scientists found a link between a particular CNV and neuroblastoma, a deadly
cancer that mostly affects children.

The study was led by Dr John M Maris, chief of Oncology and director of the Cancer Center at The Children’s Hospital of Philadelphia and is
published in the 18 June issue of the journal Nature. Maris is also on the faculty of the University of Pennsylvania School of Medicine, and
scientists from several other research centres worked on the research with him.

The discovery is particularly remarkable because it is the first to show that repeated or deleted strips of genetic code may be linked to cancer as
opposed to variations in the code sequence or single nucleotide polymorphisms (SNPs or “snips”).

Using a grammatical comparison, a CNV would be a repeated or missing word in a phrase while an SNP would be one or more words
spelled incorrectly.

Maris said the finding opens the door to studying how CNVs might increase cancer risk.

Neuroblastoma is the most common solid cancer of young children, sometimes beginning before birth, and accounts for 15 per cent of all early
childhood deaths. It forms in the nerve tissue and usually begins in the adrenal glands that sit above the kidneys, but it can also start in the neck, chest
or spinal cord. Unfortunately it has often already spread to other parts of the body before diagnosis.

Maris told the press:

“Only two years ago we had very little idea of what causes neuroblastoma.”

“Now we have unlocked a lot of the mystery of why neuroblastoma arises in some children and not in others,” he added.

Last month the team published the result of the largest gene study to date in childhood cancer research where they reported the result of a genome-wide
association study that showed variants in the BARD1 gene increased a child’s susceptibility to a high-risk type of neuroblastoma.

This month they report the findings of a second genome-wide association study where using highly automated gene-analyzing technology they found a
CNV along a structurally weak section of chromosome 1 that may be linked to developing neuroblastoma.

They used specimens from around the world that had been collected through the Children’s Oncology Group, and technology from the Hospital’s
Center for Applied Genomics which is directed by Dr Hakon Hakonarson, a co-author on both studies.

Talking about the first study, Maris said that:

“Researchers have suspected that variants in BARD1 also increased the risk of breast cancer, but no one has found compelling evidence of
this.”

But they were surprised, he added, when their genome-wide association studies “found that BARD1 is a susceptibility gene for neuroblastoma, and
perhaps other cancers as well”.

He and his team are now trying to understand the underlying mechanism by which BARD1 variants affect nervous system cells to become cancerous while
the child is in the womb or soon after.

Meanwhile, in the second study, with lead author Dr. Sharon Diskin, also of The Children’s Hospital of Philadelphia, Maris and colleagues found that
a common CNV at a chromosome 1q21.1 is associated with the childhood cancer neuroblastoma.

That region of the chromosome contains many genes that are involved in the development of the nervous system, and the researchers found that a
transcript within the inherited CNV, called NBPF23, a previously unknown neuroblastoma breakpoint family gene, is involved in the early stages of
tumor formation.

These findings build on previous work by Maris and colleagues such as last year when they found the ALK gene was involved in making patients
susceptible to a rare familial form of neuroblastoma. In another study they also found a region on chromosome 6 that raised the risk of a non-
hereditary form of the disease.

As scientists reveal more of the genetic landscape of neuroblastoma, the better the chances of developing targeted treatments that improve the quality
of life for children with this complex disease said Maris.

“Copy number variation at 1q21.1 associated with neuroblastoma.”
Sharon J. Diskin, Cuiping Hou, Joseph T. Glessner, Edward F. Attiyeh, Marci Laudenslager, Kristopher Bosse, Kristina Cole, Ya?«l P. Moss?©, Andrew
Wood, Jill E. Lynch, Katlyn Pecor, Maura Diamond, Cynthia Winter, Kai Wang, Cecilia Kim, Elizabeth A. Geiger, Patrick W. McGrady, Alexandra I.
F. Blakemore, Wendy B. London, Tamim H. Shaikh, Jonathan Bradfield, Struan F. A. Grant, Hongzhe Li, Marcella Devoto, Eric R. Rappaport, Hakon
Hakonarson & John M. Maris.
Nature, 459, 987
-991, Published online 18 June 2009.
doi:10.1038/nature08035

Additional sources: Children’s Hospital of Philadelphia, NIH .

Written by: Catharine Paddock, PhD

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Scientists are beginning to unravel the question why people distinctly vary in size. In cooperation with scientists of the HelmholtzZentrum M??nchen, an international genome-wide study has discovered ten new genes that influence body height and thus provides new insights into biological pathways that are important for human growth.

This meta-analysis, published in the latest issue of Nature Genetics, is based on data from more than 26,000 study participants. It verifies two already known genes, but also discovered ten new genes. Altogether they explain a difference in body size of about 3.5 centimeters.

The analysis produced some biologically insightful findings. Several of the identified genes are targeted by the microRNA let-7, which affects the regulation of other genes. This connection was completely unknown until now. Several other SNPs may affect the structure of chromatin, the chromosome-surrounding proteins. Moreover, the results could have relevance for patients with inherited growth problems, or with problems in bone development, because some of the newly discovered genes have rare mutations, known to be associated with anomalous skeletal growth. Further functional studies are necessary to completely elucidate the biological mechanisms behind this growing list of genes related to height.

As German contribution to the meta-analysis, data from about 5,600 participants of the KORA study were analyzed by the HelmholtzZentrum scientists, Dr. Christian Gieger, Dr. Susana Eyheramendy, PD Dr. Thomas Illig, Dr. Iris M. Heid and Prof. Dr. Dr. H.-Erich Wichmann. In order to genotype 500,000 of the most frequent variants in the human genome, DNA chips were analyzed at the Institute for Human Genetics and the Institute of Epidemiology of the HelmholtzZentrum M??nchen under the direction of Prof. Dr. Thomas Meitinger. The coordinator of the study was Dr. Guillaume Lettre; Prof. Joel Hirschhorn acted as the principal investigator. Both scientists work at the Broad Institute of the MIT and the Harvard University, Cambridge. All investigators are part of the recently formed international consortium to study height and obesity-related traits (GIANT, Genetic Investigation of ANthropometric Traits).

Along with the results of a British study that was published simultaneously in Nature Genetics, the total number of known “height genes” now amounts to 26.

HELMHOLTZ ZENTRUM MUENCHEN – GERMAN RESEARCH CENTRE FOR ENVIRONMENTAL HEALTH
Ingolstaedter Landstra??e 1
D-85764 Neuherberg
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Diabetes patients who are hospitalized for non-critical illnesses, and develop hypoglycemia while hospitalized, are likely to remain hospitalized longer and face greater risk of mortality both during and after hospitalization, according to a study published in the July issue of Diabetes Care.

This retrospective cohort study of more than 4,300 admissions, by researchers at Boston’s Brigham and Women’s Hospital, was the first to examine mortality risks for hospitalized diabetes patients outside a critical care setting. Previous research found an association between hypoglycemia in ICU patients and an increased risk of morality, seizures and coma.

However, the majority of hospitalized diabetes patients are treated on the general ward. This study found that each hospital day in which a person with diabetes had at least one episode of hypoglycemia was associated with an 85.3 percent increased risk of dying as an inpatient and a 65.8 percent increased risk of dying within one year of discharge. The odds of inpatient death also tripled for every 10 mg/dl decrease in the lowest blood glucose during hospitalization. And, a patient’s length of stay increased by 2.5 days for each day spent in the hospital with a hypoglycemia episode.

As a result of these findings, the researchers recommend carefully monitoring people with diabetes admitted to the general ward of the hospital for hypoglycemia and suggest interpreting its appearance as “a warning sign of impending clinical deterioration.”

“It could serve as a useful indicator for the necessity of increased monitoring, more aggressive treatment of infections, transitioning to a more intensive care setting, and case management,” the study concludes.

Diabetes Care, published by the American Diabetes Association, is the leading peer-reviewed journal of clinical research into one of the nation’s leading causes of death by disease. Diabetes also is a leading cause of heart disease and stroke, as well as the leading cause of adult blindness, kidney failure, and non-traumatic amputations.

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Roche, the maker of ACCU-CHEK blood glucose monitoring systems and insulin pumps, announced today its long-term commitment to tackle the growing epidemic of diabetes by its Behavior Change through Patient Engagement (SM) program – a wide array of educational programs and tools that promote more effective self-care.

“As the world leader in diabetes diagnostics, we have a responsibility to provide solutions that overcome a critical gap in diabetes management,” said Head of Roche Diabetes Care North America Luc Vierstraete. “Traditional diabetes management tends to focus on telling people with diabetes what to do but that, by itself, doesn’t necessarily fully engage patients. Our initiative, Behavior Change through Patient Engagement, is all about helping patients take an active role in their diabetes self-care. We know that keeping patients engaged and focused on self-care is critical to long-term success and better outcomes. We are so committed to this effort, we have already invested more than $14 million toward this initiative and will continue to do so.”

Roche’s Behavior Change through Patient Engagement program offers:

– Coaching skills for healthcare professionals to help achieve breakthroughs in engagement of patients;

– Free patient education programs to help adults, children and teens make self-management easier; and

– Easy tools that help patients discover that the actions they take every day matters – understanding how things like changes in therapy, foods or activities affect their blood glucose.

“Diabetes is a difficult, frustrating disease,” said Roche Diabetes Care Medical Director Dr. Andreas Stuhr. “Our Behavior Change program helps healthcare professionals address things like diabetes burnout and other psychological barriers to effective self-care. In addition, we have devised unique and powerful tools to help patients discover that change is worthwhile and achievable.”

New educational programs and tools within the Behavior Change through Patient Engagement will continue to be rolled out throughout the year. Meanwhile, existing programs have been further enhanced to fully complement the Behavior Change program.

“We are confident that, together, we can change the future of people who have diabetes,” Vierstraete added. “That core belief – that behavior change is worthwhile and achievable – is essential and Roche is committed to helping provide the foundation needed for lasting change.”

About Roche Diabetes Care

Roche Diabetes Care is a pioneer in the development of blood glucose monitoring systems and a global leader for diabetes management systems and services. For more than 30 years, Roche has been committed to helping people with diabetes live lives that are as normal and active as possible and has been helping healthcare professionals manage their patients’ condition in an optimal way. Today, the ACCU-CHEK portfolio offers people with diabetes and healthcare professionals innovative products, services and comprehensive solutions for convenient, efficient and effective diabetes management – from blood glucose monitoring through information management to insulin delivery. The ACCU-CHEK brand encompasses blood glucose meters, infusion pumps, lancing and data management systems.

About Roche

Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients.

In 2008, Roche had over 80,000 employees worldwide and invested almost 9 billion Swiss francs in R & D. The Group posted sales of 45.6 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan.

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Resolvyx Pharmaceuticals, Inc., the leading resolvin therapeutics company, announced positive data from a Phase 2 clinical study evaluating RX-10045, a resolvin administered as a topical eye drop for the treatment of patients with chronic dry eye syndrome. In this 28-day, randomized, placebo-controlled, 232-patient trial, RX-10045 produced dose-dependent, statistically significant improvement on the primary endpoints for both the signs and symptoms of dry eye, and was generally shown to be safe and well tolerated. These Phase 2 results represent the first demonstration of clinical efficacy for the novel class of resolvin compounds and suggest that resolvins have the potential to treat a broad range of inflammatory diseases.

“There is an urgent need for new treatment options in dry eye and the results of this Phase 2 study are as strong as any I have seen,” said Stephen Pflugfelder, MD, an expert in dry eye at Baylor College of Medicine. “Based both on these clinical results and on its unique mode of action, I am confident that RX-10045 can be an important new treatment modality for these patients.”

The 28-day, randomized, multi-center, placebo-controlled study in 232 patients with moderate dry eye patients was designed to evaluate the safety, tolerability and efficacy of RX-10045 administered twice daily. The Phase 2 study examined three doses of RX-10045 and utilized a controlled adverse environment (CAE) to measure corneal staining in a stressful drying environment, as well as daily patient diaries using a standard visual analog scale to assess symptom improvement over the course of the study.

RX-10045 produced a significant dose-dependent improvement from baseline in symptoms recorded in daily patient diaries. The improvement was observed across all symptoms evaluated in the study, including dryness, stinging, burning, grittiness, ocular discomfort and the composite of each patient’s most severe symptom (Worst Symptom Score). RX-10045 was superior to placebo on the primary symptomatic endpoint of Worst Symptom Score (p < 0.02), as well as on several individual symptoms. The onset of symptom relief occurred within the first week of treatment, and symptoms continued to improve over the course of the 28-day study, suggesting the potential for even greater benefit with longer treatment durations.

“I am very encouraged by the symptom relief achieved with RX-10045,” said Ira Udell, M.D., Chairman of the Department of Ophthalmology at the North Shore-Long Island Jewish Health System and Professor of Ophthalmology and Visual Sciences, Albert Einstein College of Medicine. “Symptomatic improvement is what really matters to patients.”

RX-10045 also produced a 75% reduction from baseline in CAE-induced staining of the central cornea (p < 0.00001), the primary sign endpoint in the study. This improvement was greater than that observed for placebo, the difference approaching statistical significance (p = 0.11). RX-10045 also produced a significant improvement in CAE-induced staining in the inferior cornea and in the composite of central and inferior cornea, which also approached statistical significance over placebo (p = 0.09).

“We are very enthusiastic about the results of this Phase 2 study which, in only a 28-day study, achieved what we believe is unprecedented dose-dependent improvement in the symptoms of dry eye, as well as strong improvement in the signs of dry eye. The results of this study will help Resolvyx design the pivotal trials for RX-10045, which are currently targeted to begin in the first half of 2010,” said Greg Weinhoff, Executive Chairman of Resolvyx. “In addition to demonstrating the potential of RX-10045 to treat dry eye patients, this study also shows the potential of the entire resolvin class to treat a range of inflammatory diseases.”

Resolvyx is also currently conducting a Phase 1 study with a second resolvin, RX-10001, an orally-administered drug candidate for the treatment of systemic inflammatory diseases such as asthma, inflammatory bowel disease and other inflammatory diseases.

About RX-10045

RX-10045 is Resolvyx’s lead resolvin therapeutic, and is a synthetic analog of RvE1, a naturally occurring resolvin. RX-10045 has been shown to have potent anti-inflammatory and cell-survival benefits in laboratory testing. In preclinical studies, RX-10045 was highly effective in preventing signs of dry eye, including decreasing corneal inflammation, reducing corneal epithelial damage, preventing loss of goblet cells (cells that play an important role in maintaining tear film integrity) and improving tear volume. In addition, those studies demonstrated that RX-10045 potently inhibited the release of several key pro-inflammatory mediators from corneal epithelial cells and accelerated corneal tissue repair with an effect level comparable to that seen with epidermal growth factor, the most potent previously-known mediator of corneal tissue repair. RX-10045 is formulated as a clear, aqueous, preservative-free solution for ocular administration.

About Dry Eye Syndrome

Dry eye syndrome is one of the most common problems treated by eye physicians; an estimated 25-30 million Americans suffer from dry eye and the worldwide prevalence closely parallels that of the United States. Dry eye is a chronic, multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Dry eye can make it more difficult to perform some visual activities for an extended period of time, and it can decrease tolerance for dry environments.

About Resolvins

Resolvins are a recently discovered family of naturally-occurring, small molecule lipid mediators that can be targeted to treat a wide range of diseases. In particular, resolvins act to protect healthy tissue during an inflammatory response to infection, injury or other environmental challenge, and then act to resolve inflammation and promote healing after the insult has passed. Resolvins are shown to be highly potent and efficacious in pre-clinical models of asthma, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, dry eye and retinal disease, among others.

Resolvins are potential drug candidates to treat a broad range of acute and chronic diseases caused by a failure to resolve the inflammatory response and restore immune homeostasis. Such diseases include auto-immune diseases (like Crohn’s disease, psoriasis and rheumatoid arthritis), allergic diseases (like asthma) and chronic inflammatory diseases (like atherosclerosis, degenerative retinal diseases, chronic dry eye and Alzheimer’s disease). Resolvins offer an entirely novel biological approach to treating significant inflammatory diseases, with a decreased potential for immuno-suppression.

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Sequenom, Inc. (NASDAQ:SQNM) announced the introduction of its Cancer EpiPanel for high-throughput methylation profiling of DNA samples over hundreds of validated cancer-associated genes. Using Sequenom’s proprietary EpiTYPER™ technology, the pre-designed Cancer EpiPanel, for research use only, offers a first-of-its-kind simplified method of rapid and quantitative methylation profiling of commonly analyzed genes.

Changes in DNA methylation markers have been correlated to gene expression and there is an accumulating body of scientific evidence that indicates that changes in DNA methylation patterns play an important role in early cancer detection and prognosis. The precise characterization of methylation changes in cancer-associated genes will be instrumental for the discovery of biomarkers for early detection of cancer, prognosis and therapy monitoring.

“Our new Cancer EpiPanel offers researchers the speed and convenience of using off-the-shelf validated assays, combined with fast, cost-effective quantitative analysis of a large set of cancer-related genes,” said Harry Stylli, Ph.D., Sequenom’s President and CEO. “Like our Standard EpiPanel, our new Cancer EpiPanel sets a new mark in high-resolution fine-mapping panels for epigenetic research and reflects our focus on improving customer experience. We believe the Cancer EpiPanel will become an indispensable tool for medium to large scale cancer methylation studies.”

Several cancer genes are known to be hypermethylated and are often coupled with decreased or completely inhibited gene expression. Sequenom’s Cancer EpiPanel contains quantitative DNA methylation profiles and assay information for more than 400 cancer-related genes run on 62 cell lines (NCI60) derived from six different tissue types. The panel includes pre-validated assays covering over 12000 CpG sites in promoter regions of genes known to be involved in neoplastic transformation and imprinting. The assays are designed to be run with Sequenom’s EpiTYPER technology. Sequenom’s new EpiBrowser software allows investigators to browse the Cancer Epipanel database to quickly display methylation profiles and assay information in easy to read charts, tables and heatmaps.

About Sequenom

Sequenom is committed to providing the best genetic analysis products for research and the molecular diagnostic markets. The Company makes available superior solutions for genetic analysis in biomedical research, livestock and agricultural applications and molecular medicine, as well as for various diagnostic markets, including noninvasive prenatal testing, oncology and infectious diseases. Sequenom’s proprietary MassARRAY® system delivers reliable and specific data from complex biological samples and from genetic target materials available only in trace amounts.

Sequenom®, EpiTYPER™ and MassARRAY® are trademarks of Sequenom, Inc.

Except for the historical information contained herein, the matters set forth in this press release, including statements regarding the effect or impact of characterization of methylation changes in cancer-associated genes on the discovery of biomarkers for early detection of cancer, prognosis, and therapy monitoring, and the belief that the Cancer EpiPanel will become an indispensable tool for medium to large scale cancer methylation studies, are forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially, including the risks and uncertainties associated with demand for and market acceptance of the Company’s products, services, and technologies, new technology and product development and commercialization particularly for new technologies such as the Cancer EpiPanel, competition, and other risks detailed from time to time in the Company’s SEC reports, including the Company’s Annual Report on Form 10-K for the year ended December 31, 2006 and subsequent periodic reports. These forward-looking statements are based on current information that is likely to change and speak only as of the date hereof. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and Sequenom undertakes no obligation to revise or update any forward-looking statement to reflect events or circumstances after the issuance of this press release.

Sequenom, Inc. Continue reading →

chinaview.cn

??BEIJING, China – A senior WHO official has cautioned women to guard against heart disease that leads to death of millions femeals worldwide each year.

??Although most women fear cancer, particularly breast cancer, they do not make the same efforts to safeguard themselves against heart disease, which is eminently preventable, reported AFP, citing Catherine Le Gales-Camus, WHO assistant director-general.

??’We must strive to make women aware that to keep their hearts healthy they need to eat smart, kick smoking and move for health,’ Gales-Camus advised.

??The UN’s health body along with the World Heart Federation will hold activities worldwide on Sunday to increase awareness about cardiovascular diseases that claim some 16.5 million lives annually — 8.6 million of the victims are female.

??To coincide with World Heart Day, the WHO also published the biggest ever collection of reports into heart disease, which gathered information from studies taken in 21 countries between the mid-1980s and mid-1990s, said Hugh Tunstall-Pedoe, editor of the document.

??’Heart disease is the major cause of death in most countries,’ he told AFP.

??The report, named MONICA (Monitoring Cardiovascular disease), measured the level of disease and documented trends in different nations, helping to develop prevention policies, the WHO said.

??It ‘throws down the gauntlet’ to people to compile similar studies on other major diseases, said Tunstall-Pedeo.

??’MONICA is a model for others, of how collaboration across political and national boundaries can tackle problems shared by the whole of humankind,’ he noted. Continue reading →

Stem Cell Therapeutics Corp. (“SCT” or the “Company”) (TSX VENTURE:SSS) is pleased to announce the acceptance and publication of the paper entitled “Open labeled, uncontrolled pharmacokinetic study of single intramuscular hCG dose in healthy male volunteers” by the International Journal of Clinical Pharmacology and Therapeutics, Vol. 47, August 2009. This paper was authored by Drs. Alan Moore, President & CEO, Allen Davidoff, VP Product Development and Yan Yang, Clinical Research Associate, all of SCT; Dr. Michael D. Hill of Foothills Hospital at the University of Calgary, and Dr. Steven C. Cramer, from the University of California, Irvine.

Dr. Allen Davidoff, VP of Product Development, commented as follows:

“Acceptance by this highly respected, peer reviewed journal not only permits us to share more of our knowledge of hCG’s novel effects with the scientific community but it is also a meaningful developmental step for NTx®-265. Importantly, this study demonstrated for the first time that hCG circulating in the blood crosses the blood brain barrier leading to concentrations of hCG in the cerebral-spinal fluid. This fundamental evidence, combined with strong supportive basic science studies, supported initiation of the BETAS Phase IIa clinical trial in patients with acute ischemic stroke.”

This study was designed to compare blood and cerebrospinal fluid (“CSF”) pharmacokinetic characteristics of two forms of human chorionic gonadotropin (“hCG”): Pregnyl® and Ovitrelle®. Two separate groups, each with six older male human subjects, were administered a single dose of either form of the drug at 10,000 IU intramuscularly (“IM”), and then followed over a 36-hour period. No significant difference was observed when plasma levels of hCG were measured for either preparation of hCG (Peak plasma concentration: 316?±53 versus 270?±60 at 12 hours, 311?±38 versus 321?±60 IU/L at 24 hours; AUC: 10053?±1268 versus 8793?±1768, Pregnyl® and Ovitrelle®, mean ?± SD, respectively). Additionally, both forms of circulating hCG distributed to the central nervous system (“CNS”) as manifest by an increased number of subjects whose CSF samples showed detectable levels of hCG in their CSF over a 36-hour period. Similarly, there was no significant difference between the two forms when distribution to the CSF was compared at 36 hours (2.0 and 1.2 IU/L; range 1.9-2.1 and 1-1.4 IU/L for Pregnyl® and Ovitrelle®, respectively). This preliminary study in normal human volunteers suggested that the two forms of hCG tested, Pregnyl® and Ovitrelle®, when administered IM, distribute in a similar fashion into the circulation and CSF. Consequently, SCT concluded that these two drugs likely demonstrate bioequivalent pharmacokinetics with respect to the CSF.

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Researchers at Mayo Clinic have found that the experimental drug they are testing to treat a deadly form of thyroid cancer turns on a powerful tumor suppressor capable of halting cell growth. Few other cancer drugs have this property, they say.

In the Feb. 15 issue of Cancer Research (available online Jan. 20), they report that RS5444, being tested in a Phase 1/2 clinical trial to treat anaplastic thyroid cancer, might be useful for treating other cancers. The agent is also known as CS-7017.

From previous research, the investigators knew that RS5444 binds to a protein known as PPAR-gamma, a transcriptional factor that increases the expression of many genes. They had found that human anaplastic thyroid tumor cells treated with RS5444 expressed a protein known as p21, which inhibited cell replication and tumor growth. But they did not understand how. They have now discovered that the agent actually forces PPAR-gamma to turn on the RhoB tumor suppressor gene, which in turn induces p21 expression.

“This is very unusual,” says the study’s lead investigator, John Copland, Ph.D., a cancer biologist at the Mayo Clinic campus at Jacksonville. “Drugs typically target genes and proteins that are over-expressed and turn them off. We found that RS5444 turns on a valuable tumor suppressor gene. We rarely find a drug that can take a suppressed gene and cause it to be re-expressed.”

This finding suggests that other cancers in which RhoB is deactivated might respond to RS5444 or to similar drugs, says co-author Robert Smallridge, M.D., who treats thyroid cancer patients at Mayo Clinic in Jacksonville.

“This study provides a hint that this class of drugs could have a significant effect on cancer biology because of its action on this tumor suppressor gene,” says Dr. Smallridge.

According to Dr. Copland, “RS5444 and other so-called PPAR-gamma drugs, which were originally created to treat diabetes because they help regulate glucose metabolism, are in development or being tested as cancer therapies. Taken orally, RS5444 requires 1,000-fold less dosage than current Food and Drug Administration-approved drugs in this class of compounds to inhibit tumor growth.”

The researchers have been seeking to identify and characterize the molecular mechanisms underlying the cause and progression of human anaplastic thyroid carcinoma. Their goal is to develop effective molecular targeted therapies.

This cancer is extremely rare – fewer than 600 cases are diagnosed in the U.S. annually – but may be better known of late because it may have been the type of thyroid cancer that led to the death of William Rehnquist, chief justice of the United States. “It is also one of the most aggressive and deadliest known cancers, since it doesn’t respond to any known treatment,” says Dr. Smallridge. “The rate of survival hasn’t changed in 25 years. Eighty-five percent of patients die within a year of diagnosis.”

In previous work, the investigators identified a combination of drugs that reduced tumor size in animal models, strongly implicating that this regimen might benefit patients with the cancer. RS5444, developed by Daiichi Sankyo, Co., Ltd., in Japan, was one agent tested in combination with chemotherapy. Sankyo researchers discovered RS5444 in a screen for antitumor activity and then sought help from Mayo Clinic Cancer Center to further study its properties. Their encouraging findings in preclinical studies led to the launch of a multicenter Phase 1/2 clinical trial, testing use of RS5444 and paclitaxel chemotherapy in patients with the cancer. The study, led by Dr. Smallridge, is being conducted at Mayo Clinic campuses in Jacksonville and Rochester, Minn. and at eight other sites nationally.

Clinical Trial Information

This study was designed to look at the specific signaling pathways within anaplastic thyroid cancer cells that are disrupted by RS5444. Researchers had thought that because PPAR-gamma was mutated in a subset of thyroid cancers, PPAR-gamma might be acting as a tumor suppressor gene, and that turning it back on restored that function. This hypothesis made sense, because PPAR-gamma is a powerful nuclear receptor that activates genes involved in such cellular processes as differentiation, apoptosis, cell-cycle control, carcinogenesis, and inflammation.

But they found that PPAR-gamma regulates transcription of the RhoB gene. “Within several hours of administering the drug, we can see that it binds to the PPAR-gamma protein in cancer cells and activates RhoB transcription, causing expression of RhoB messenger RNA that is translated into protein. By a yet-to-be-identified mechanism, RhoB then induces the transcription of p21, thereby shutting down the cell cycle and blocking tumor growth,” Dr. Copland says.

“That shows us that turning RhoB back on may be a key mechanism for regulating growth of this cancer,” he says.

For proof, the researchers then turned off expression of RhoB in cells that were treated with the drug, and demonstrated that p21 could not be activated. “That shows RhoB is required for p21 transcription,” Dr. Copland says.

“RhoB acts as a tumor suppressor, and it is turned off in anaplastic thyroid cancers. Turning this gene back on may lead to an effective molecular targeted chemotherapy regimen to fight this cancer,” he says.

Dr. Smallridge adds, “Hitting this pathway inhibits tumor growth up to fourfold in laboratory cells and in animal experiments, and we are optimistic that it could be one cancer pathway capable of manipulation in patients. We hope there are other cancers in which RhoB is silenced, such as head and neck, brain, and lung cancers, that could benefit as well where RhoB has been shown to be down-regulated in patient tumor tissues.”

Co-authors included researchers from Daiichi Sankyo, Co., Ltd., Eastern Virginia Medical School, and Mayo Clinic.

The study was funded by grants from the National Institutes of Health, Mayo Clinic Research Committee, the Florida Department of Health Bankhead Coley grant, and a grant for Rare Cancers from Dr. Ellis and Dona Brunton. Funding from the company is being used to conduct the clinical trial. Drs. Copland and Smallridge have a patent application pending on the use of molecular markers to confirm response to PPAR-gamma drugs.

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The U.S. Food and Drug Administration approved a surgical kit that allows neurosurgeons to reroute blood flow around an aneurysm or a tumor in the brains of patients at greater risk of stroke during standard bypass surgery.

The ELANA (Excimer Laser Assisted Non-Occlusive Anastamosis) Surgical Kit allows neurosurgeons to create a bypass without shutting off the blood flow. It consists of a small platinum ring and a hand piece connected to a surgical laser and suction tubing.

Standard bypass surgery in the brain requires clipping the artery to halt blood flow during the procedure. The surgery is not considered safe for about 1,000 patients annually in the United States because temporarily shutting off their blood flow would put them at high risk of stroke. The group includes patients ages 13 and older who have an enlarged, weak area in a brain artery (cerebral aneurysm), tumors at the base of the skull that could impact blood flow in brain arteries, or other issues that could complicate conventional surgery.

“The ELANA Surgical Kit may help those with a rare condition for whom there previously was no treatment option,” said Jeffrey Shuren, M.D., director of the FDA’s Center for Devices and Radiological Health.

To create the bypass, a surgeon sutures the ring and a section of replacement blood vessel onto the surface of the affected artery. Once attached, the surgeon tunnels the tip of the laser handpiece down the open end of the replacement blood vessel until the tip of the laser touches the ring.

The laser then cuts a circular hole in the affected artery, and suction removes the cut tissue. The process is repeated with a second replacement blood vessel. Once both replacement blood vessels are in place, the open ends of the two replacement blood vessels are sutured together to complete the path around the aneurysm or tumor.

The FDA approved the ELANA Surgical Kit as a Humanitarian Use Device, which is a device that is designed to treat or diagnose a disease or condition in fewer than 4,000 people in the United States each year. To obtain approval for humanitarian use, a company must demonstrate the safety of the device and that the probable benefit outweighs the risk of illness or injury. The company must also show that no comparable devices are available to treat or diagnose the disease or condition.

The clinical data in support of approval demonstrated that a bypass created using the ELANA kit had the same types and similar incidences of adverse events reported in the medical literature as conventional bypass procedures.

A patient should not undergo laser bypass surgery using the Elana kit if the arteries show signs of arteriosclerosis or calcification at the surgery site, the walls of the affected artery are thicker than a carotid artery, or have an abnormality. Bypass surgery with the Elana should not be done on an aneurysm or on vessels other than large (> 2.5 mm), intracranial arteries.

In some cases, the laser does not completely cut through an artery wall leaving a tissue flap that potentially could block blood flow and result in an embolism. As part of the approval, the FDA required a post approval registry study to collect performance information about the kit, including flap retention rate, mortality, and stroke.

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