Archive for August, 2012

Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Chemical Biology and its relations to Metabolic Disease, Health Economics and Outcomes Research, tagged Chronic kidney disease, Creatinine, kidney disease, Renal function, Tufts Medical Center, University of Minnesota on August 16, 2012| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)

Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C

Lesley A. Inker, M.D., Christopher H. Schmid, Ph.D., Hocine Tighiouart, M.S., John H. Eckfeldt, M.D., Ph.D., Harold I. Feldman, M.D., Tom Greene, Ph.D., John W. Kusek, Ph.D., Jane Manzi, Ph.D., Frederick Van Lente, Ph.D., Yaping Lucy Zhang, M.S., Josef Coresh, M.D., Ph.D., and Andrew S. Levey, M.D. for the CKD-EPI Investigators

N Engl J Med 2012; 367:20-29 July 5, 2012

BACKGROUND

Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR.

METHODS

Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials.

RESULTS

Mean measured GFRs were 68 and 70 ml per minute per 1.73 m² of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine–cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m² with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m² with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m², respectively [P=0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m², the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m² or greater than or equal to 60 ml per minute per 1.73 m² (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m² as having a GFR of 60 ml or higher per minute per 1.73 m².

CONCLUSIONS

Supported by grants (UO1 DK 053869, UO1 DK 067651, and UO1 DK 35073) from the National Institute of Diabetes and Digestive and Kidney Diseases.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was updated on July 5, 2012, at NEJM.org.

We thank Dr. Aghogho Okparavero for providing assistance with communications and manuscript preparation. (Additional acknowledgments are provided in the Supplementary Appendix.)

SOURCE INFORMATION

From Tufts Medical Center, Boston (L.A.I., C.H.S., H.T., Y.L.Z., A.S.L.); the University of Minnesota, Minneapolis (J.H.E.); the University of Pennsylvania School of Medicine, Philadelphia (H.I.F.); the University of Utah, Salt Lake City (T.G.); National Institutes of Health, Bethesda, MD (J.W.K.); Johns Hopkins University, Baltimore (J.M., J.C.); and Cleveland Clinic Foundation, Cleveland (F.V.L.).

Address reprint requests to Dr. Inker at the Division of Nephrology, Tufts Medical Center, 800 Washington St., Box 391, Boston, MA 02111, or at linker@tuftsmedicalcenter.org.

Additional investigators in the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are listed in the Supplementary Appendix, available at NEJM.org.

N Engl J Med 2012; 367:20-29

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Nitric Oxide and Platelet Aggregation

Posted in Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Innovations in Neurophysiology & Neuropsychology, Nitric Oxide in Health and Disease, Pharmacotherapy of Cardiovascular Disease, tagged cell fragments, Conditions and Diseases, Dr. Venkat S. Karra, health, Hematology, hemolytic uremic syndrome, Idiopathic thrombocytopenic purpura, ITP, Platelet, platelet count, SUNY Downstate Medical Center, Thrombus, Von Willebrand disease, Von Willebrand factor on August 16, 2012| 13 Comments »

Author: Dr. Venkat S. Karra, Ph.D.

Platelets are a natural source of growth factors and they circulate in the blood. They are involved in hemostasis, leading to the formation of blood clots. Platelets, otherwise known as thrombocytes, are small, irregularly shaped clear cell fragments derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is 5 to 9 days. An abnormality or disease of the platelets leads to a condition called thrombocytopathy.

For example:
1. If the number of platelets is too low (called thrombocytopenia), excessive bleeding can occur.

Disorders leading to a reduced platelet count are:
Thrombocytopenia
Idiopathic thrombocytopenic purpura – also known as immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura
Drug-induced thrombocytopenic purpura (for example heparin-induced thrombocytopenia (HIT))
Gaucher’s disease
Aplastic anemia
Onyalai
Alloimmune disorders
Fetomaternal alloimmune thrombocytopenia

2. If the number of platelets is too high (called thrombocytosis), blood clots (thrombosis) can form. Such clots in the blood may obstruct blood vessels and result in events like stroke, myocardial infarction, pulmonary embolism or the blockage of blood vessels to other parts of the body (e.g., arms, legs).

Disorders featuring an elevated count are:
Thrombocytosis, including essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease).

3. Thrombasthenia is a condition in which a decrease in function of platelets is observed.

Disorders leading to platelet dysfunction or reduced count are:
HELLP syndrome
Hemolytic-uremic syndrome
Chemotherapy
Dengue

Platelets play a significant role in the repair and regeneration of connective tissues. They release a multitude of growth factors, which have been used as an adjunct to wound healing, include:

Platelet-derived growth factor (PDGF), a potent chemotactic agent,
TGF beta, which stimulates the deposition of extracellular matrix.
Fibroblast growth factor,
Insulin-like growth factor 1,
Platelet-derived epidermal growth factor,
Vascular endothelial growth factor.

As said earlier, the function of platelets is the maintenance of hemostasis (the opposite of hemostasis is hemorrhage). This is achieved primarily by the formation of thrombi. When a damage to the endothelium of blood vessels occurs, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor which initiate the maintenance of hemostasis after injury.

Hemostasis has three major steps: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a clot that seals the hole until tissues are repaired.

The platelets get activated when a damage occurs to the blood vessel and the platelets clump at the site of blood vessel injury as a protective mechanism – a process that precedes the formation of a blood clot. This is the case if there is a damage to the endothelium otherwise thrombus formation should be considered seriously and must be inhibited immediately.

Vascular spasm is the first response as the blood vessels constrict to allow less blood to be lost during the injury to the blood vessel. In the second step – platelet plug formation – platelets stick together to form a temporary seal to cover the break in the vessel wall. The third and last step is called coagulation or blood clotting. Coagulation reinforces the platelet plug with fibrin threads that act as a “molecular glue”

Disorders of platelet adhesion or aggregation are:
Bernard-Soulier syndrome
Glanzmann’s thrombasthenia
Scott’s syndrome
von Willebrand disease
Hermansky-Pudlak Syndrome
Gray platelet syndrome

In normal hemostasis a thin layer of endothelial cells, that are lined with the inner surface of blood vessels, act to inhibit platelet activation by producing nitric oxide, endothelial-ADPase (which clears away the platelet activator, ADP – this activator otherwise can be blocked by the famous blockbuster clopidogrel), and PGI2 (also known as prostacyclin or eicosanoids, like PGD2, PGI2 is an inflammatory product that inhibits the aggregation of platelets). Intact blood vessels are central to moderating blood’s tendency to clot because the endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin and prevent platelet aggregation with
1. Nitric oxide (NO), and
2. Prostacyclin (PGI2) – a member of eicosanoids family.

In this post, nitric oxide role in inhibiting platelet aggregation will be presented. Similarly Interaction of NO and prostacyclin (PGI2) in vascular endothelium will be presented as a separate post.

Nitric oxide (NO) and its role in inhibiting platelet aggregation:

Nitric oxide (NO) is known as the ‘endothelium-derived relaxing factor’, or ‘EDRF’. The endothelium (inner lining) of blood vessels uses NO to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. NO is biosynthesized endogenously from L-arginine, oxygen and NADPH by various nitric oxide synthase (NOS) enzymes. Nitric oxide is highly reactive and yet diffuses freely across membranes that makes it ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule.

This is an important cellular signaling molecule involved in many physiological and pathological processes. It is a powerful vasodilator with a short half-life of a few seconds in the blood. Low levels of nitric oxide production are important in protecting organs such as the liver from ischemic damage. Nitric oxide is considered an antianginal drug as it causes vasodilation, which can help with ischemic pain, known as angina, by decreasing the cardiac workload. By dilating the veins, nitric oxide lowers arterial pressure and left ventricular filling pressure. This vasodilation does not decrease the volume of blood the heart pumps, but rather it decreases the force the heart muscle must exert to pump the same volume of blood.

Chronic expression of NO is associated with various carcinomas and inflammatory conditions including Type-1 diabetes, multiple sclerosis, arthritis and ulcerative colitis.

Endothelium-derived relaxing factor (EDRF), the best-characterized is nitric oxide (NO), is produced and released by the endothelium to promote smooth muscle relaxation. EDRF was discovered and characterized by Robert F. Furchgott, a winner of the Nobel Prize in Medicine in 1998 with his co-researchers Louis J. Ignarro and Ferid Murad.

According to Furchgott’s website at SUNY Downstate Medical Center, “…we are investigating whether the endothelium-derived relaxing factor (EDRF) is simply nitric oxide or a mixture of substances”.

Although there is strong evidence that nitric oxide elicits vasodilation, there is some evidence tying this effect to neuronal rather than endothelial reactions. http://www.nature.com/jhh/journal/v15/n4/abs/1001165a.html.

The article says that “The possibility that neuronal rather than endothelial production of NO might play a significant role in the aetiology of essential hypertension is a promising area for future human research”.

Mechanism of Platelet Aggregation:

Platelets aggregate, or clump together, using fibrinogen and von Willebrand factor (vWF) as a connecting agent. The most abundant platelet aggregation receptor is glycoprotein IIb/IIIa (gpIIb/IIIa) which is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin, and vWF. Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen).

Activated platelets will adhere, via glycoprotein (GP) Ia, to the collagen that is exposed by endothelial damage. Aggregation and adhesion act together to form the platelet plug. Myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug. Platelet aggregation is stimulated by ADP, thromboxane, and α2 receptor-activation, and further enhanced by exogenous administration of anabolic steroids.

In an injury to the blood vessel, once the blood clot takes control of the bleeding, the aggregated platelets help the healing process by secreting chemicals that promote the invasion of fibroblasts from surrounding connective tissue into the wounded area to completely heal the wound or form a scar. The obstructing clot is slowly dissolved by the fibrinolytic enzyme, plasmin, and the platelets are cleared by phagocytosis.

Possible usefulness of measuring GP IIb-IIIa content as a marker of increased platelet reactivity is discussed in the following very recent (2011) reveiw article: “Glycoprotein IIb-IIIa content and platelet aggregation in healthy volunteers and patients with acute coronary syndrome”. http://www.ncbi.nlm.nih.gov/pubmed/21329420

Further readings:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134593/?tool=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/2620689

http://pharmaceuticalintelligence.com/2012/07/25/nitric-oxide-production-in-systemic-sclerosis/

http://pharmaceuticalintelligence.com/2012/08/10/nitric-oxide-chemistry-and-function/

http://pharmaceuticalintelligence.com/2012/08/05/nitric-oxide-a-short-historic-perspective-7/

http://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

http://pharmaceuticalintelligence.com/2012/07/16/nitric-oxide-in-bone-metabolism/

http://pharmaceuticalintelligence.com/2012/06/22/bone-remodelling-in-a-nutshell/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717403/?tool=pubmed

http://www.ncbi.nlm.nih.gov/pubmed/7605019

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Artificial Vision: Cornell and Stanford Researchers crack Retinal Code

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Medical Devices R&D Investment, Stem Cells for Regenerative Medicine, tagged Blade Runner, Cornell University, Ganglion cell, Proceedings of the National Academy of Sciences of the United States of America, Retina, Sheila Nirenberg, Stanford University, Visual acuity on August 15, 2012| 5 Comments »

Researchers crack retinal code to deliver artificial vision

Reporter: Aviva Lev-Ari, PhD, RN

Getty Images/Flickr RF

Cornell University researchers have devised a new method for restoring human vision by looking into the way retinal cells communicate with the brain and each other. The result, they claim, is an enormous leap in quality over existing visual prosthetics.

Artificial vision may seem like science fiction, and it’s true that the kind you see in “Star Trek” or “Blade Runner” still is, but there are projects all over the world that are successfully giving back partial vision to to blind patients. There are, however, a number of obstacles: the size of the microelectrodes, the way of powering the device, the type of blindness the person has and other factors prevent current treatments from doing much more than letting patients see a few monochrome blobs.

That’s enough to safely navigate a room or street (no small improvement), but what about recognizing faces and objects, or reading signs and symbols? New research by Dr Sheila Nirenberg at Cornell and Chethan Pandarinath at Stanford University claims to make such levels of acuity possible.

Their method doesn’t rely on just making electrodes smaller or increasing the size of the image sensor. Instead, they looked at how the healthy retina communicates with the brain and tried to emulate that.

T. Anderson, D. Benson via The Cell

A rat neuron, illustrating the level of interconnection common in such cells

The retina is a complicated, multi-layered web of cells that are networked together and constantly communicating. Some forms of blindness result from a degeneration of the light-sensitive cells (rods and cones) while the rest of the neural circuitry remains in place. Loss of any entire cell type would cause blindness as well, but when this particular type happens, that means that the ganglion cells, which collect information from multiple rods and cones and collate it, are intact and could still potentially send signals to the brain.

It’s as if two people were talking on the telephone: the conversation will end either if the line itself is disrupted, or if one of the people hangs up. In this type of blindness, the line is fine and the brain is still listening, but no one is talking on the other end. And as it turns out, the replacement signals sent by existing retinal implants have been extremely garbled. What the researchers did was to find out how to send a signal that is much more easily understood.

By studying ganglion cells closely, Nirenberg arrived at a sort of algorithm that describes how the ganglion cells expect to be fed information from the rods and cones. By taking the normal image signal and passing it through an “encoder” running this algorithm, their device can send that image to ganglion cells in such a way that a much clearer image is sent to the brain. You can see the differences in this diagram:

Sheila Nirenberg / Cornell University

The technique, which they call “optogenic stimulation,” works like this: the digital image, provided by a camera or image sensor in the eye, is sent to the encoder, which then sends the special encoded image to a microscopic projector. The projector shines onto the ganglion cells, which have received gene therapy so that they respond to light somewhat in the way the missing cells would have. And then the ganglion cells send that image along.

With it, they claim that 9,800 ganglion cells, properly treated and exposed with the device, will be able to “bring prosthetic capabilities into the realm of normal image representation.” That is to say, a grid of 100-by-100 of them would give enough visual information that a person would have a serious semblance or real vision.

The experiments thus far, successful as they have been, were all performed on mouse retinas. But the researchers see no reason why it should not be attempted for humans as well; Nirenberg says that the gene therapy portion is the most important thing to test thoroughly, though similar techniques have already been used in the retina for other diseases.

Nirenberg and Pandarinath’s paper, “Retinal prosthetic strategy with the capacity to restore normal vision,” was published recently in the Proceedings of the National Academy of Sciences.

Devin Coldewey is a contributing writer for NBC News Digital. His personal website is coldewey.cc.

http://www.futureoftech.msnbc.msn.com/technology/futureoftech/researchers-crack-retinal-code-deliver-artificial-vision-942282

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Sequenom Center for Molecular Medicine diagnostic services: MaterniT21 Plus test detects for T18 and T13.

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, tagged Coventry Health Care, Down syndrome, Molecular Medicine, Pathwork Diagnostics, Sequenom, T13, T18, T21, Tufts University on August 15, 2012| Leave a Comment »

Tufts Health Plan to Cover Sequenom’s MaterniT21, Pathwork’s Tissue of Origin Tests

Reporter: Aviva Lev-Ari, PhD, RN

http://www.genomeweb.com/mdx/tufts-health-plan-cover-sequenoms-maternit21-pathworks-tissue-origin-tests

August 06, 2012

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Tufts Health Plan will begin covering Sequenom’s MaterniT21 Plus trisomy 21 test and Pathwork Diagnostics‘ Tissue of Origin test starting Oct. 1.

In an update to providers posted on its website, the health plan said that it may authorize coverage of the MaterniT21 test for patients who are plan members if they are at least 35 years old when they give birth; have a fetal aneuploidy screening test result including maternal serum screening and/or ultrasound evaluation that indicates the possibility of trisomy 21; or the plan member has a family history or prior pregnancy involving aneuploidy.

In a research note Oppenheimer analyst David Ferreiro said that Tufts Health Plan has approximately 1 million lives under coverage and a network of 90 hospitals and 25,000 healthcare providers.

“We view this decision as an incremental positive for [Sequenom] and as validation of the value proposition MaterniT21 presents to payors,” he said. “The adoption rate is encouraging and could positively impact payor decisions, further entrenching,” the company.

Two weeks ago, Sequenom said that in the second quarter revenues from its Sequenom Center for Molecular Medicine diagnostic services rose five-fold to $8.1 million driven by the MaterniT21 Plus test, which was launched in the fall. The test also detects for T18 and T13.

As adoption of the test continues to ramp at an increasing rate, the San Diego-based company increased its internal goal of billed MaterniT21 Plus tests for 2012 to 50,000 from an earlier goal of 40,000.

The company has stopped announcing coverage decisions by individual plans following an incident in the spring in which Coventry Health Care National Networkterminated a coverage decision for MaterniT21 Plus one week after Sequenom said that Coventy would cover the test. Sequenom said at the time that Coventry’s decision was without cause and was not a judgment on the company, Sequenom CMM, or its products.

In a statement today to GenomeWeb Daily News, a Sequenom spokesperson declined to disclose the terms of the contract with Tufts Health Plan. She said that Sequenom CMM has more than 26 million live under contract, and “we operate as an out-of-network laboratory where we are not yet contracted and bill payors accordingly.”

Tufts Health Plan also said that it will begin coverage of Pathwork Diagnostics’ Pathwork Tissue of Origin test, beginning on Oct. 1. The test is for the identification of challenging tumors, including poorly differentiated, undifferentiated, and metastatic cancers.

The plan said it may authorize coverage of the test if it is ordered by an oncologist and the plan member is diagnosed with metastatic cancer; the clinical evaluation has not identified the primary site of the cancer; the pathology report is submitted to Tufts Health Plan for review; and the pathology examination is unable to conclusively identify the primary site, or has identified two or more possible primary sites.

Use of the test to confirm a diagnosis will not be covered by the health plan.

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Angiogenic Disease Research Utilizing microRNA Technology: UCSD and Regulus Therapeutics

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged Angiogenic Disease, David A. Cheresh, GlaxoSmithKline, MicroRNA, Regulus Therapeutics, University of California San Diego on August 15, 2012| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Regulus Therapeutics and UC San Diego to Collaborate on Angiogenic Disease Research Utilizing microRNA Technology

http://www.fiercebiotech.com/press-releases/regulus-therapeutics-and-uc-san-diego-collaborate-angiogenic-disease-resear-0

– UC Discovery Grant award to support collaborative research –

La Jolla, Calif., April 14, 2011 – Regulus Therapeutics Inc., a biopharmaceutical company leading the discovery and development of innovative new medicines targeting microRNAs, today announced it is collaborating with researchers at the University of California, San Diego (UCSD) School of Medicine seeking novel treatments for angiogenic diseases using microRNA therapeutics. The research will combine Regulus’ leading microRNA platform with UCSD’s expertise in animal models of angiogenesis to discover anti-angiogenic microRNA-targeted therapies that could be rapidly translated for treatment of human disease. The collaborative research program was the recent recipient of a UC Discovery Grant that promotes collaborations between the university’s researchers and industry partners. Financial terms of the grant were not disclosed.

“We are pleased to collaborate with leading scientific institutes like UCSD and to provide industry support for programs such as the UC Discovery Grant,” said Hubert C. Chen, M.D., Regulus’ vice president of translational medicine. “Regulus continues to demonstrate a leadership position in the field of microRNA therapeutics and is committed to forging partnerships with leading academic and clinical laboratories to advance microRNA biology and therapeutic discovery. Our network of nearly 30 academic collaborations assists us with the investigation of new microRNAs and supports microRNA discovery efforts that feed the Company’s pipeline.”

Angiogenesis, which is the formation of new blood vessels, is an important event that contributes to the severity of cancer, diabetes, macular degeneration, inflammatory disease and arthritis. microRNAs have been implicated in regulating biological networks involved in angiogenesis.

“Our research published last year in Nature Medicine demonstrated that microRNA-132 functions as a novel angiogenic switch that turns on angiogenesis in quiescent endothelial cells, and that targeting with an anti-miR-132 decreases blood vessel formation,” said David A. Cheresh, Ph.D., professor of pathology in the UCSD School of Medicine, associate director for translational research at UCSD Moores Cancer Center and principal investigator on the grant. “The objective of our collaborative work with Regulus is to advance these initial discoveries and discover additional microRNAs involved in angiogenic diseases.”

The UC Discovery Grant program promotes collaborations between the university’s researchers and industry partners in the interest of supporting cutting-edge research, strengthening the state’s economy and serving the public good.

About microRNAs

The discovery of microRNA in humans during the last decade is one of the most exciting scientific breakthroughs in recent history. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. More than 700 microRNAs have been identified in the human genome, and over one-third of all human genes are believed to be regulated by microRNAs. A single microRNA can regulate entire networks of genes. As such, these molecules are considered master regulators of the human genome. microRNAs have been shown to play an integral role in numerous biological processes, including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. Most microRNAs are conserved across multiple species, indicating the evolutionary importance of these molecules as modulators of critical biological pathways. Indeed, microRNA expression or function, has been shown to be significantly altered in many disease states, including cancer, heart failure and viral infections. Targeting microRNAs with anti-miRs, antisense oligonucleotide inhibitors of microRNAs, or miR-mimics, double-stranded oligonucleotides to replace microRNA function opens potential for a novel class of therapeutics and offers a unique approach to treating disease by modulating entire biological pathways. To learn more about microRNAs, please visit http://www.regulusrx.com/microrna/microrna-explained.php.

About Regulus Therapeutics Inc.

Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative new medicines targeting microRNAs. Regulus is using a mature therapeutic platform based on technology that has been developed over 20 years and tested in more than 5,000 humans. In addition, Regulus works with a broad network of academic collaborators and leverages the oligonucleotide drug discovery and development expertise of its founding companies, Alnylam Pharmaceuticals (NASDAQ:ALNY) and Isis Pharmaceuticals (NASDAQ:ISIS). Regulus is advancing microRNA therapeutics towards the clinic in several key areas including hepatitis C infection, immuno-inflammatory diseases, fibrosis, oncology and cardiovascular/metabolic diseases. Regulus’ intellectual property estate contains both the fundamental and core patents in the field and includes over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In April 2008, Regulus formed a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In February 2010, Regulus and GlaxoSmithKline entered into a new collaboration to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of hepatitis C infection. In June 2010, Regulus and sanofi-aventis entered into the largest-to-date strategic alliance for the development of microRNA therapeutics. This alliance is focused initially on fibrosis. For more information, please visit http://www.regulusrx.com.

Forward-Looking Statements

This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Regulus’ business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus. Any statement describing Regulus’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause the results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of Regulus’ management, these statements are based only on facts and factors currently known by Regulus. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus’ programs are described in additional detail in each of Alnylam’s and Isis’ annual report on Form 10-K for the year ended December 31, 2010, which are on file with the SEC. Copies of these and other documents are available from either Alnylam or Isis.

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“To Die or Not To Die” – Time and Order of Combination drugs for Triple Negative Breast Cancer cells: A Systems Level Analysis

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Statistical Methods for Research Evaluation, Uncategorized, tagged Apoptosis, cancer therapy, combination drugs, Doxorubicin, ertolinib, high-throughput assay, mathematical model, PCA, PLS, systems biology, time stagger, western blot analysis on August 15, 2012| 9 Comments »

Author and Reporter: Anamika Sarkar, Ph.D.

Today, the gold standard treatment for cancer is still chemo therapy or radiation therapy. Drugs are administered to treat patients with different doses, frequencies and combinations. It is recognized that the side effects of all these therapies lead to DNA damage responses (DDR) and their subsequent signaling alterations resulting in cellular functions. Moreover, it is well known that DDR is responsible for complex cross talks and feedback of signaling pathways for progrowth and apoptosis within intracellular as well as extracellular networks (in tissues).

Optimal combinations of drugs in respect of doses or frequencies or order of treatments of different drugs have been recognized as a powerful method of treatment of complex diseases. However, executing experiments of multiple possible combinations of drugs and cell lines can easily lead to very costly proposition. Lee et.al in their paper published in Cell (2012), titled “Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks”, reported from experimental results that when triple negative breast cancer (TNBC) cells are treated, with a combination of drugs – erlotinib, which is an EGFR inhibitor, at least 4 hours before of another drug, doxorubicin – the cells show higher apoptotic (cell death) responses. Other forms of treatments like, single administration of the drugs or treating the cells together with two drugs at same time, did not show any increased levels of apoptosis in TNBC cells.

They complemented their understanding of reason behind such unique behavior of TNBC cells, when exposed to time -stagger treatment of drugs, with systems level modeling. They used quantitative analysis of high throughput reverse-phase protein microarrays and quantitative western blotting of experiments. They chose to measure activation states of 35 signaling proteins at 12 time points following exposure to ertolinib and doxorubicin individually and in combinations. The authors used PLS (Partial Least Square) and PCA (Principle Component Analysis) methods for predictive analysis from data driven model.

They report from their systems level analysis that time – stagger treatment of TNBC with two drugs ertolinib and doxorubicin activate Caspase 8, a key apoptotic signaling component, which remains absent in other combinations of treatments of drugs. They hypothesized that early treatment of ertolinib, inhibits EGFR responses, which increases levels of activated Caspase 8 and gets amplified after getting exposed to the second drug doxorubicin.

Combination therapy in treating complicated diseases like cancer has many importance in making the dose and treatment efficient. However, due to complex nature of signaling pathways, it poses increasing amount of challenges. Lee et. al., address some of those challenges by bringing in synergistic collaborations among different fields – experiments and mathematical modeling, which is the future of drug development.

Sources:

http://www.ncbi.nlm.nih.gov/pubmed/22579283

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Obstructive Coronary Artery Disease diagnosed by RNA levels of 23 genes – CardioDx, a Pioneer in the Field of Cardiovascular Genomic Diagnostics

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Genetics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Medical and Population Genetics, Medical Devices R&D Investment, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, tagged Andrew Guggenhime, CardioDx, Computed tomography angiography, Coronary artery disease, Diagnostic test, Heart disease, Initial public offering, Myocardial perfusion imaging, NanoString Technologies, obstructive coronary artery disease., RNA level of 23 genes, US Securities and Exchange Commission on August 14, 2012| 11 Comments »

Obstructive Coronary Artery Disease diagnosed by RNA levels of 23 genes – CardioDx, a Pioneer in the Field of Cardiovascular Genomic Diagnostics

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 11/15/2013

CardioDx, Inc. Nixes IPO, Cites Unfavorable Market Conditions

11/15/2013 10:31:01 AM

CardioDx postpones its initial public offering, citing ‘unfavorable market conditions.’ California molecular diagnostics company CardioDx spiked its initial public offering, citing “unfavorable market conditions,” according to news reports. The 5.8-million-share offering by Palo Alto-based CardioDx was slated to raise $92 million at a share price of $14-$16 apiece. The IPO, originally scheduled for yesterday, would have seen CardioDx shares trade under the “CDX” symbol.

SOURCE

http://www.devicespace.com/news_story.aspx?NewsEntityId=315972&type=email&source=DS_111513

CardioDx had planned to use some of the funds to expand its commercial efforts, including its sales and marketing workforce; to fund operations as the company pursues more insurance coverage and reimbursement; to “conduct additional clinical and marketing activities” for the company’s Corus CAD blood-based gene expression test; to fund R&D activity; and for “general corporate purposes.” CardioDx will later specify just the how much it plans to put toward each of those activities.

Investors in the company include V-Sciences Investments, Longitude Venture Partners, Artiman Ventures, Kleiner Perkins Caufield & Byers, JP Morgan and Mohr Davidow Ventures.

SOURCE

http://www.massdevice.com/news/cardiodx-spikes-ipo

CardioDX pulls IPO, citing poor market conditions

CardioDX, led by David Levison, was one of three medical technology companies to postpone their IPOs on Thursday due to poor market conditions.

Cromwell Schubarth: Senior Technology Reporter-Silicon Valley Business Journal; CardioDX postponed an IPO on Thursday after deciding that the market is unfavorable at this time.

The Palo Alto company led by CEO David Levison was one of three planned medical tech companies that postponed going public on Thursday. San Diego-basedCelladon and Monrovia-based Xencor also decided to hold off due to poor market conditions.

Redwood City pharmaceutical developer Relypsa, meanwhile, went ahead with a drastically reduced IPO that raised about half of what it had been projected for it.

CardioDX, which sells diagnostic tests for cardiovascular disease, reported total revenue in in 2012 of $2.5 million and a net loss of $25.6 million. The company expects to continue to show losses for the next several years and has an accumulated deficit through June totaling $165.9 million. As of June 30, it had $46.8 million in cash, equivalents and investments.

The company’s biggest existing stakeholder is V-Sciences Investments, a wholly owned subsidiary of Temasek Life Sciences Private Ltd., which holds 19.9 percent of outstanding shares.

Other big stakeholders are Longitude Venture Partners, with a 17.9 percent stake; Artiman Ventures, 13.9 percent; Kleiner Perkins Caufield & Byers, 9.5 percent; JP Morgan, 6.4 percent; and Mohr Davidow Ventures, 5.8 percent.

SOURCE

http://www.bizjournals.com/sanjose/news/2013/11/15/cardiodx-pulls-ipo-citing-poor-market.html

Cardiovascular MDx Firm CardioDx Files to Go Public

UPDATED on 10/14/2013

October 14, 2013

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Cardiovascular molecular diagnostics firm CardioDx has filed with the US Securities and Exchange Commission to go public with an intended offering of up to $86.3 million of common stock.

The Palo Alto, Calif.-based firm has not priced its offering yet or said how many shares it plans on offering. Bank of America Merrill Lynch and Jefferies are listed as joint book-running managers on the offering, while Piper Jaffray and William Blair are co-managers.

The company plans on listing on the Nasdaq Global Market under ticker symbol “CDX.”

In its Form S-1, CardioDx said that its tests provide healthcare professionals with “critical, actionable information to improve patient care and management,” with an initial focus on coronary artery diseases (CAD), arrhythmia, and heart failure.

Its flagship product is the Corus CAD, a gene expression-based test for assessing non-diabetic patients who display symptoms suggestive of obstructive CAD. The test was launched in 2009 and through June 30, CardioDx delivered results for more than 40,000 tests, it said.

Corus CAD received Medicare Part B coverage in August 2012, making it a covered benefit for about 48 million Medicare beneficiaries, the company added.

In 2012, CardioDx posted $2.5 million in revenues with a net loss of $25.6 million. Through the first six months of 2013, the firm had revenues $2.9 million and a net loss of $18.4 million.

It had $46.8 million in cash, cash equivalents, and investments as of June 30, it said.

In August 2012, CardioDx raised $58 million in private financing. Before that, it raised $60 million in a financing round. In 2010, GE Healthcare invested $5 million in the company as part of a Series D financing round.

David Levison heads the firm as President and CEO. Other members of the management team include CFO Andrew Guggenhime; Chief Scientific Officer Steven Rosenberg; Chief Medical Officer Mark Monane; and Chief Commercial Officer Deborah Kilpatrick.

CardioDx is the latest in a recent string of omics-related companies who have gone public or have filed to go public in the US. Cancer Genetics, NanoString Technologies, and Foundation Medicine launched their IPOs earlier this year. Meanwhile, Veracyte, Biocept, and Evogene have filed to float.

CardioDx Announces Publication of COMPASS Study Demonstrating the Corus CAD Test Outperforms Myocardial Perfusion Imaging in Overall Diagnostic Accuracy for Obstructive Coronary Artery Disease

February 24, 2013

CardioDx Announces Publication of COMPASS Study Demonstrating the Corus CAD Test Outperforms Myocardial Perfusion Imaging in Overall Diagnostic Accuracy for Obstructive Coronary Artery Disease

Tue Feb 19, 2013 8:30am EST

– Study Highlights the Validity of Corus CAD as a First-Line Test to Help Clinicians Exclude Obstructive CAD as a Cause of the Patient’s Symptoms – PALO ALTO, Calif., Feb. 19, 2013

/PRNewswire/ — CardioDx, Inc., a pioneer in the field of cardiovascular genomic diagnostics, today announced the publication of the COMPASS (Coronary Obstruction Detection by Molecular
Personalized Gene Expression) study in Circulation: Cardiovascular Genetics, a journal of the American Heart Association.

Results of the prospective, multi-center U.S. study showed that Corus® CAD, a blood-based gene expression test, demonstrated high accuracy with both a high negative predictive value (96 percent) and high sensitivity (89 percent) for assessing obstructive coronary artery disease (CAD) in a population of patients referred for stress testing with myocardial perfusion imaging (MPI). The study’s authors conclude that using Corus CAD earlier in the diagnostic algorithm could reduce the number of invasive cardiac tests by more accurately evaluating the presence of obstructive coronary artery disease compared to the traditional algorithm of stress myocardial perfusion imaging (MPI) in these patients.

COMPASS enrolled stable patients with symptoms suggestive of CAD who had been referred for MPI at 19 U.S. sites. A blood sample was obtained in all 431 patients prior to MPI and Corus CAD gene expression testing was performed with study investigators blinded to Corus CAD test results. Following MPI, patients underwent either invasive coronary angiography or coronary CT angiography, gold-standard anatomical tests for the diagnosis of coronary artery disease.

The study was designed to provide additional independent validation of the Corus CAD test in a real-world intended use patient population of patients presenting for MPI, a common noninvasive test for CAD, and builds on the results of the previous PREDICT validation study. Corus CAD requires only a simple blood draw for testing, making it safe, convenient, and easy to administer. The study evaluated results in stable non-diabetic patients with typical or atypical symptoms suggestive of CAD and found that Corus CAD surpassed the accuracy of MPI, a test that was administered more 10 million times in the U.S. in 2010.[1]

“The evaluation of stable patients with chest pain and other symptoms suggestive of CAD is a common challenge for clinicians, accounting for as many as 10,000 outpatient visits each day,” said the publication’s lead author, Gregory S. Thomas, M.D., M.P.H., Medical Director of the MemorialCare Heart & Vascular Institute at Long Beach Memorial Medical Center and Clinical Professor of Medicine and Director of Nuclear Cardiology Education at the University of California-Irvine School of Medicine. “In the U.S., MPI testing is often performed in these patients and is followed by referral to invasive coronary angiography. Based on the results of this study of the Corus CAD gene expression test, we now have a reliable diagnostic approach for evaluating patients with symptoms of obstructive CAD. With its high sensitivity and negative predictive value, Corus CAD may help clinicians accurately and efficiently exclude the diagnosis of obstructive CAD early in the diagnostic pathway, so they can assess for other causes of their patients’ symptoms.”

The pre-specified primary endpoint of the COMPASS study was the receiver-operator characteristics (ROC) analysis to evaluate the ability of Corus CAD to identify coronary arterial blockages of 50 percent or greater by quantitative coronary angiography. Corus CAD outperformed MPI in overall diagnostic accuracy for assessing obstructive CAD, with an area under the curve (AUC) of 0.79 for the Corus CAD test compared to MPI site and core-lab read AUCs of 0.59 and 0.63 respectively (p<0.001). In addition, Corus CAD performed better than MPI in sensitivity (89 percent vs. 27 percent, p<0.001) and negative predictive value (96 percent vs. 88 percent, p<0.001) parameters, thus demonstrating excellent performance for excluding obstructive CAD as the cause of a patient’s symptoms. The COMPASS results corroborated earlier findings from the PREDICT multicenter U.S. validation study[2] demonstrating that the Corus CAD score is proportional to coronary artery stenosis severity.

“Corus CAD can help solve an enormous unmet need in healthcare by providing clinicians with a safe, convenient and reliable tool to help evaluate common patient symptoms and triage them more appropriately for subsequent therapy or additional testing,” said David Levison, President and CEO of CardioDx. “In addition to its higher diagnostic accuracy, Corus CAD holds potential to reduce a major healthcare expense category – unnecessary noninvasive imaging and/or invasive coronary angiography procedures and their associated risks and side effects. We have worked closely with leading clinicians to build a solid clinical and economic foundation for Corus CAD, leading to its growing acceptance in the medical and payer communities as evidenced by the more than 35,000 tests performed to date and Medicare’s decision to cover the test.”

SOURCE:

http://www.fiercemedicaldevices.com/press-releases/cardiodx-announces-publication-compass-study-demonstrating-corus-cad-test-o

By Mark Hollmer

CardioDx is promoting yet another post-marketing study whose data may help the company’s gene expression test for obstructive coronary artery disease reach more patients, better compete with the standard of care and also build vital market share.

Executives at the California-based 2012 Fierce 15 company say they wanted more data on Corus CAD‘s real-world use, building on its previous PREDICT validation trial as a result. The test has been on sale commercially since 2009 and won crucial Medicare reimbursement last fall. Chief Scientific Officer Steven Rosenberg told FierceMedicalDevices via email that the results from the latest study pointed in a number of positive directions.

“It demonstrates performance at least as good as that seen in the PREDICT study, but in the population the Corus CAD is indicated for,” Rosenberg said, “It shows significantly higher performance for obstructive CAD than MPI, which is the most common non-invasive imaging test used in this regard.”

A 431-patient clinical study of the blood diagnostic rated the test with a 96% negative predictive value and 89% high sensitivity, in assessing the condition in patients who were referred for stress testing with myocardial perfusion imaging (MPI). (Last November, CardioDx heralded similar results from another study using Corus CAD on 98 geriatric patients.) Details are published in the journal Circulation: Cardiovascular Genetics.

The blood test, conducted at 19 U.S. sites through multiple academic institutions, determined that using Corus CAD earlier in the diagnostic process better assessed the presence of coronary artery disease versus MPI. This might encourage doctors to cut back on invasive, more expensive cardiac tests by ruling out obstructive CAD sooner. In other words, determining a patient doesn’t have obstructive CAD eliminates the need for diagnostic procedures such as coronary angiography or coronary CT angiography, the company explains.

Post-marketing studies are increasingly important in today’s health care market, with the need to demonstrate the utility of a device or diagnostic in as most detailed a way possible. And it’s not just boosting the standard of care; the Affordable Care Act means value matters, too, more than ever before. Success with this mission can help broaden market share and also increase the chance of private as well as government insurance coverage. Additionally, new post-marketing trials can also set the stage for expanded indications down the line.

SOURCE:

http://www.fiercemedicaldevices.com/story/cardiodx-cad-dx-passes-another-post-marketing-test/2013-02-24?utm_medium=nl&utm_source=internal

A Blood Based Gene Expression Test for Obstructive Coronary Artery Disease Tested in Symptomatic Non-Diabetic Patients Referred for Myocardial Perfusion Imaging: The COMPASS Study

+Author Affiliations

¹Long Beach Memorial Medical Center, Long Beach & University of California, Irvine, CA
²Stony Brook University Medical Center, Stony Brook, NY
³Vanderbilt University, Nashville, TN
⁴Yale University School of Medicine, New Haven, CN
⁵Scripps Translational Science Institute, La Jolla, CA
⁶University of Missouri, Kansas City, MO
⁷CardioDx, Inc., Palo Alto, CA
⁸New York University School of Medicine, New York, NY
⁹University of Rochester, Rochester, NY
¹⁰Duke Clinical Research Institute, Duke University, Durham, NC

↵* MemorialCare Heart and Vascular Institute, Long Beach Memorial Medical Center, 2801 Atlantic Avenue, Long Beach, CA 90806 gthomas@mimg.com

Abstract

Background—Obstructive coronary artery disease (CAD) diagnosis in symptomatic patients often involves non-invasive testing before invasive coronary angiography (ICA). A blood-based gene expression score (GES) was previously validated in non-diabetic patients referred for ICA but not in symptomatic patients referred for myocardial perfusion imaging (MPI).

Methods and Results—This prospective multi-center study obtained peripheral blood samples for GES before MPI in 537 consecutive patients. Patients with abnormal MPI usually underwent ICA; all others had research coronary CT-angiography (CTA), with core laboratories defining coronary anatomy. A total of 431 patients completed GES, coronary imaging (ICA or CTA), and MPI. Mean age was 56±10 (48% women). The pre-specified primary endpoint was GES receiver-operator characteristics (ROC) analysis to discriminate ≥50% stenosis (15% prevalence by core laboratory analysis). ROC curve area (AUC) for GES was 0.79 (95% CI 0.73-0.84, p<.001), with sensitivity, specificity, and negative predictive value (NPV) of 89%, 52%, and 96%, respectively, at a pre-specified threshold of ≤15 with 46% of patients below this score. The GES outperformed clinical factors by ROC and reclassification analysis and also showed significant correlation with maximum percent stenosis. Six-month follow-up on 97% of patients showed that 27/28 patients with adverse cardiovascular events or revascularization had GES >15. Site and core-lab MPI had AUCs of 0.59 and 0.63, respectively, significantly less than GES.

Conclusions—A GES has high sensitivity and NPV for obstructive CAD. In this population clinically referred for MPI, the GES outperformed clinical factors and MPI.

Clinical Trial Registration Information—www.clinicaltrials.gov; Identifier: NCT01117506.

Received June 6, 2012.
Revision received January 15, 2013.
Accepted February 5, 2013.

http://circgenetics.ahajournals.org/content/early/2013/02/15/CIRCGENETICS.112.964015.abstract?sid=74741525-8453-460e-8407-f11022fe9a24

http://www.bizjournals.com/sanfrancisco/blog/biotech/2012/08/cardiodx-corus-medicare-heart-disease.html

CardioDx heart disease test wins Medicare coverage

San Francisco Business Times by Ron Leuty, Reporter

Date: Wednesday, August 8, 2012, 4:00am PDT

Enlarge Image

Photo supplied by CardioDx

CardioDx’s test for obstructive heart disease will be covered by Medicare retroactive to Jan. 1.

Ron Leuty: Reporter- San Francisco Business Times

A key national Medicare contractor will cover the cost of a coronary artery disease test developed by CardioDx Inc.

The move is important for Palo Alto-based CardioDx because private insurers tend to follow the federal government’s Medicare health insurance program. The company has had to seek reimbursement on a case-by-case basis with those private insurers since its Corus CAD gene expression test hit the market in June 2009.

The decision disclosed Tuesday by Palmetto GBA, a national contractor that administers Medicare benefits in Columbia, S.C., means that Medicare will cover the test for as many as 40 million enrollees. Coverage is retroactive to Jan. 1.

Corus CAD is a shoebox-size kit that uses a simple blood draw to measure the RNA levels of 23 genes. Using an algorithm, it then creates a score that determines the likelihood that a patient has obstructive coronary artery disease.

“By providing Medicare beneficiaries access to Corus CAD, this coverage decision enables patients to avoid unnecessary procedures and risks associated with cardiac imaging and elective invasive angiography, while helping payers address an area of significant healthcare spending,” CardioDx President and CEO David Levison said in a press release.

The decision represents the latest Medicare-coverage win for Bay Area diagnostic test makers. Palmetto earlier this year opted to cover the Afirma gene expression test from South San Francisco’s Veracyte Inc. to diagnosis thyroid nodules, and last summer Palmetto said it would cover Redwood City-based Genomic Health Inc.’s (NASDAQ: GHDX)colon cancer recurrence test.

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The 6th Annual Pain Therapeutics Summit, San Jose, CA 10/3 – 10/4/2012

Posted in Pain: Etiology, Genetics & Innovations in Treatment, tagged Allosteric Inhibitors of the NGF/TrkA Pathway, Analgesic Efficacy and Safety of Tanezumab, Anti-NGF Antibody for Treatment of Chronic Pain, Conotoxins: Molecular Tools to Dissect Pain Pathways, Inhibiting Peripherally Mediated Pain, neuropathic pain, Pain Therapy, Transition from Acute to Chronic Pain States, TRPA1 for the treatment of pain on August 14, 2012| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

http://www.paintherapeuticsummit.com/agenda

Agenda

WEDNESDAY OCTOBER 3, 2012

7:45 Registration and Continental Breakfast

8:30 Chairperson’s Opening Remarks

William K. Schmidt, Ph.D. (biography), President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical Development, CrystalGenomics (CG Pharmaceuticals)

8:45 Pain, Addiction, Abuse and Psychiatric Co-morbidities
Dr. Medve will discuss managing critical interplays and putting the patient at the center of the treatment team.
The session will cover:

Addiction – what is it?
Animal models – can they predict human addiction?
Psychiatric illness vs pain vs addiction – how do these interplays work?
Opioids and the future of pain care
How best to manage patients in a complicated care system

Dr. Medve will also discuss Nektar’s recently Fast Tracked NCE opioid NKTR-181, which is designed to have a slow rate of entry into the brain to reduce the attractiveness of the molecule as a target of abuse and to reduce its CNS-mediated side effects.

Robert Medve, MD (biography), Vice President & Chief Medical Officer, Nektar Therapeutics

9:15 Allosteric Inhibitors of the NGF/TrkA Pathway: a Novel, Small Molecule Approach to Inhibiting Peripherally Mediated Pain
Nerve Growth Factor (NGF) plays a significant role in the generation and maintenance of the nociceptive pain associated with a variety of human diseases. Array Biopharma has used a structural biology driven approach to develop potent, highly selective small molecules that inhibit TrkA kinase activity through allosteric modulation. The efficacy of TrkA inhibitors in rodent models of peripheral pain will be detailed. Additionally, potential mechanistic differentiation from the anti-NGF strategy will be discussed as will in vivo efficacy and long term safety associated with their small molecule inhibitors.

Steven Andrews, Ph.D., Associate Director, Drug Discovery, Array BioPharma

9:45 New Models of Pain in Freely Moving Rodents
The pain field has been frustrated by the limitations of the current evoked nociception models that are used for screening or target discovery. Regeneron has been working on several non-evoked models of visceral pain and deep tissue pain that are providing some interesting mechanistic insights. Dr. LaCroix-Fralish’s in vivo pharmacology team is seeking to develop therapeutics for the treatment of pain and neurological disability. In this presentation, he will discuss his team’s efforts to develop new models for visceral and deep tissue pain.

Michael LaCroix-Fralish, Ph.D.,(biography) Staff Scientist, Pain Therapeutics Group, Regeneron Pharmaceuticals

10:15 Poster Viewing & Refreshment Break

10:45 TRPA1 as a Pain Target: Progress and Challenge
A gain of function mutation of TRPA1 has been linked to familial episodic pain syndrome in humans. This result, coupled with a growing preclinical literature, has made TRPA1 an attractive pain target. Dr. Chen will address several key biology and drug discovery issues, including physiological/pathological function of TRPA1, species difference, therapeutic profile and drug discovery strategies.

Jun X. Chen, Ph.D. (biography), Principal Research Scientist GPRD, Neuroscience, Abbott Laboratories

11:15 Gene Therapy to Control Intractable Pain in Cancer Patients: A New Paradigm?
A very high proportion (up to 85%) of terminal cancer patients suffer from severe pain; current therapies, principally opioids, are of limited use. Benitec Biopharma Ltd. is developing a gene therapy strategy to control pain in such patients using intrathecal delivery of lentiviral particles expressing shRNA constructs designed to inactivate the Protein Kinase C gamma gene (PKCg) in neurones of the spinal cord. Others have demonstrated the strategy works in neuropathic pain models in rats. Benitec has developed constructs that strongly inactivate PKCg in vitro; these particular shRNAs target sequences within PKCg that are absolutely conserved between rat and humans as well as pre-clinical test species (dogs and macaques), simplifying pre-clinical testing. These new constructs are being validated in rat pain models and protocols for pre-clinical testing are being developed. Benitec believes a gene therapy approach for pain control in terminal cancer patients is warranted, the approach is relatively low risk and offers the prospect of a single treatment providing long term pain relief.

Peter French, Ph.D. (biography), Chief Executive Officer, Benitec Biopharma

11:45 Pain in Children: Challenges in Conducting Pediatric and Neonatal Pain Studies and Treating Pain in Children
This presentation will cover the following:

Developmental physiology and pharmacology, including enzyme maturation and drug metabolism
Pain measures: assessments from neonates through adolescents
Challenges in clinical study design, including: recruitment, use of placebo, blood volume restrictions and formulations
Current concepts in the treatment of pain in children

Ernest A. Kopecky Ph.D, MBA, VP Clinical Development, Head, Neuroscience TA, COLLEGIUM Pharmaceutical

12:15 Luncheon

1:30 Transition from Acute to Chronic Pain States

Tony L. Yaksh, Ph.D. (biography), Professor & Vice Chair for Research, Department of Anesthesiology and Professor of Pharmacology, University of California, San Diego

2:00 Minimizing Experimental Error in Analgesic Research by Reducing Placebo Response and Variability
The properly educated patient can be your greatest ally in producing a positive analgesic clinical trial. A significant portion of an analgesic investigation’s variability is produced secondary to cognitive gaps that the patient may have when interpreting the various protocol mandated scales and questions. All pharmaceutical companies spend a large amount of time perfecting their protocol and selecting/educating quality sites so that the efficacy of their drug can be statistically demonstrated. However, an equal amount of effort is rarely placed on patient education. This piece of the puzzle is the responsibility of the site and as such, we have developed educational materials to reduce placebo response and garner data that is as “true” as possible. This talk will discuss placebo response training and other ways to mitigate variability in analgesic clinical trials.

Neil Singla, MD (biography), Founder & Chief Scientific Officer, Lotus Clinical Research, LLC

2:30 Analgesic Potential of TRPA1 Antagonists
TRPA1 serves as a broad sensor for the detection of both endogenous and exogenous reactive chemicals. This presentation will review the rationale for targeting TRPA1 for the treatment of pain, including peri-operative, inflammatory, visceral and neuropathic conditions. In addition, recent progress on the clinical development of TRPA1 antagonists will be summarized, including data from Cubist and Hydra Bioscience’s clinical development programs.

Magdalene Moran, Ph.D. (biography), Vice President, Biology, Hydra Biosciences

3:00 Poster Viewing & Refreshment Break

3:30 Overview of Analgesic Efficacy and Safety of Tanezumab, a Monoclonal Antibody Targeting Nerve Growth Factor for Treatment of Chronic Pain
Nerve growth factor (NGF) has been increasingly implicated as a facilitator of pain in human diseases and related animal disease models. Monoclonal antibodies targeting NGF have shown compelling efficacy in relieving pain in a number of painful conditions. This presentation will review the current analgesic efficacy and safety profile of tanezumab, a monoclonal antibody in late-stage development for chronic pain.

Mark T. Brown, MD (biography), Executive Director, Clinical Program Leader for Osteoarthritis and Cancer Pain Studies, Pfizer Inc.

4:00 Conotoxins: Molecular Tools to Dissect Pain Pathways
Conotoxins are disulfide-rich peptides isolated from the venom of the predatory cone snail. Millions of years of natural selection fine-tuned this complex mixture of venom peptides to be highly potent and selective to various ion channels, transporters and GPCRs. In particular their subtype selectivity make them preferred tools for the study of receptors (e.g. ionchannels) involved in neuropathic pain. With ready access to sequencers we are now able to mine the transcriptome of the venom ducts, providing us with more sequence information than we can produce, certainly putting the pressure back on developing better synthetic methodologies. In this presentation, Dr. Muttenthaler will describe the discovery, synthesis and application of this class of compounds with a focus on the latest advancement in creating a diverse toolbox for neuroscientists.

Markus Muttenthaler, Ph.D. (biography), Departments of Chemistry and Cell Biology, The Scripps Research Institute

4:30 Making Investment Choices in Pain Management
In this presentation, Dr. Meltzer will walk the audience through some top line discussions of how Purdue Pharma is looking at the current and future marketplace of pain management and how that influences investment choices.

Brian Meltzer, MD, (biography) Executive Director, R&D Innovation, Purdue Pharma

5:00 Cocktail Reception

THURSDAY OCTOBER 4, 2012

8:15 Chairperson’s Opening Remarks

William K. Schmidt, Ph.D. (biography), President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical Development, CrystalGenomics (CG Pharmaceuticals)

8:20 Addressing Acute and Persistent Pain at its Origins: Transcription Factor Decoys For Pain Prevention and Treatment
Adynxx Inc. is developing a transformative technology platform addressing pain at its molecular roots – preventing the development of pain following surgery or trauma and resolving established chronic pain syndromes. The Adynxx platform utilizes a proprietary form of oligonucleotide technology – small pieces of DNA that bind to transcription factors and inhibit their activity. Adynxx’s lead compound, AYX1, is designed to prevent acute post-surgical pain and the transition to persistent or chronic pain with a single intrathecal administration at the time of surgery. AYX1 acts by inhibiting the spinal cord activity of transcription factor EGR1, a powerful molecular switch whose function is critical in the establishment and maintenance of post-surgical or trauma-related pain. In this presentation, Dr. Manning will discuss the concept of transcription factor decoys, the preclinical data from several rodent models of post-surgical pain, mechanical hyperalgesia and functional recovery. AYX1 entered clinical trials in Q2 2012 and data from Phase 1 safety and general development plans will be discussed.

Donald C. Manning, MD, Ph.D. (biography), Chief Medical Officer, Adynxx Inc.

8:50 Overview of Fulranumab, an Anti-NGF Antibody for Treatment of Chronic Pain
A variety of anti-NGF compounds are currently in development. Fulranumab is a fully human anti-NGF antibody that shows promise in relief of a variety of pain models. This presentation will review the clinical efficacy and safety profile that has been developed to date.

David Upmalis, MD, Senior Director and Compound Development Team Leader, fulranumab, Janssen Research Foundation

9:20 Selective A3 Adenosine Receptor Agonists for Chronic Neuropathic Pain
The clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current analgesics such as opiates, gabapentanoid or drugs that modulate the noradrenergic/serotonergic pathway: novel analgesics are therefore needed. Dr. Salvemini’s findings identify therapeutic use of selective A3 adenosine receptor (A3AR) agonists in chronic neuropathic pain of distinct etiologies including chemotherapy-induced neuropathic pain caused by paclitaxel, oxaliplatin and bortezomib. In addition, A3AR agonists increase the potency and efficacy of morphine, gabapentin and amitriptyline. Her team’s findings provide the pharmacological rationale for therapeutic development of A3AR agonists, as novel analgesics for the management of chronic neuropathic pain.

Daniela Salvemini, Ph.D., Professor, Saint Louis University School of Medicine

9:50 Poster Viewing & Refreshment Break

10:15 Mechanisms and Novel Treatment of Neuropathic Pain

Allan Basbaum, Ph.D. (biography), Professor and Chair, Department of Anatomy, University of California, San Francisco

10:45 Panel Session: Treating Pain in the Clinic – the Physician’s Perspective on Unmet Need and the Challenges Facing Pain Drug Developers

Chair: William K. Schmidt, Ph.D. (biography), President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical Development, CrystalGenomics (CG Pharmaceuticals)

Sean Mackey, MD, Ph.D. (biography), Chief, Division of Pain Management, Stanford University School of Medicine, Associate Professor of Anesthesiology, Director, Stanford Systems Neuroscience & Pain Lab

Lynn Webster, MD, (biography) Medical Director, CRI Lifetree, President-Elect, The American Academy of Pain Medicine

Michael S. Leong, MD, Clinic Chief, Stanford Pain Medicine Center, Clinical Associate Professor, Anesthesia, Stanford University

11:45 Neuroimaging Based Pain Detection: Findings and Applications
Dr. Mackey will cover recent advances in neuroimaging as an objective tool for the detection of pain. He will discuss recent data for both detection of acute and chronic pain, and potential applications.

Sean Mackey, MD, Ph.D. (biography), Chief, Division of Pain Management, Stanford University School of Medicine, Associate Professor of Anesthesiology, Director, Stanford Systems Neuroscience & Pain Lab

12:15 Luncheon

1:15 An NGF Inhibitor Update: Thoughts and Observations Regarding the Future of this Class of Pain Therapeutics
Dr. Lane will discuss results from Phase 2 and 3 studies that have come out in past months. She will also cover status of their development and what the FDA Arthritis Advisory Committee’s recent recommendation to lift the hold on NGF inhibitors in clinical development means for the future of this class of pain therapeutics.

Nancy E. Lane, MD (biography), Endowed Professor of Medicine and Rheumatology, Director, Musculoskeletal Diseases of Aging Research Group Director, Academic Geriatric Resource Program, Co-Director, Building Interdisciplinary Research Careers in Women’s Health (BIRCWH), Co-Director, Center for Translational Research in Osteoarthritis, UC Davis Health System

1:45 Panel Session: NGF Antagonists Back on Track: Clinical Development Challenges and Opportunities Moving Forward

Mark T. Brown, MD (biography), Executive Director, Clinical Program Leader for Osteoarthritis and Cancer Pain Studies, Pfizer Inc.

Nancy E. Lane, MD (biography), Endowed Professor of Medicine and Rheumatology, Director, Musculoskeletal Diseases of Aging Research Group Director, Academic Geriatric Resource Program, Co-Director, Building Interdisciplinary Research Careers in Women’s Health (BIRCWH), Co-Director, Center for Translational Research in Osteoarthritis, UC Davis Health System

David Upmalis, MD, Senior Director and Compound Development Team Leader, fulranumab, Janssen Research Foundation

Steven Andrews, Ph.D., Associate Director, Drug Discovery, Array Biopharma

2:45 End of Conference

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Missing Gene may drive more than a quarter of Breast Cancers

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, tagged breast cancer on August 14, 2012| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

http://www.news.cornell.edu/stories/Aug12/BreastCancerNf1.html

Aug. 14, 2012

Missing gene may drive more than a quarter of breast cancers

Schimenti Lab

The image shows two tumors in mice from transplanted tumor-prone mammary gland stem cells. The tumor on the left was manipulated to have a reduced amount of NF1 protein (expressed by the NF1 gene), while the one on the right has normal NF1 levels. This preliminary experiment supports a critical role for NF1 in suppressing breast cancer.

By Krishna Ramanujan

A new study shows that the lack of a certain gene occurs in almost 28 percent of human breast cancers, playing a role in some 60,000 breast cancer cases in the United States and 383,000 worldwide this year.

Recent studies have observed loss of the gene NF1 in glioblastoma (an aggressive brain cancer), lung and ovarian cancers, but the significance has been overlooked because it was thought that two copies of the gene (one from each parent) needed to be missing to cause cancer. The study, published online July 30 in the journal Genetics, reports that in most human breast cancer cases where NF1 is a factor, only one copy is missing.

The finding has important clinical implications. It suggests that several existing drugs may be effective in treating breast cancers with missing NF1; it also suggests that the commonly used breast cancer drug tamoxifen could make the disease worse in these specific cancers.

The NF1 gene negatively regulates one of the most important oncogenes — genes that when mutated or expressed at high levels contribute to turning a normal cell into a cancerous one. This oncogene, called RAS, is involved in signaling inside the cell to control growth. When NF1 is missing or depleted, RAS becomes hyperactivated and can lead to tumor formation.

In the study, Cornell researchers used a mouse model with elevated mutation rates that lead to breast cancer in 80 percent of the mice.

“These mice almost always get mammary tumors, and when we looked at their genomes, nearly all of them were missing this NF1 gene,” said John Schimenti, professor of genetics and the paper’s senior author. “There are many big cancer studies that identify the most commonly mutated genes, but they don’t prove experimentally that those genes are the drivers of cancer.”

In humans, there are many causes of breast cancer, and each patient’s cancer has a slightly different set of natural gene variants as well as new mutations in their tumors, so identifying individual genes that drive cancer can be problematic. But the model mice are inbred and get exactly the same tumor every time. “So we’ve eliminated all the noise,” allowing the researchers to identify NF1 as a driver of these tumors, said Schimenti.

In the mouse model, RAS is hyperactivated. Since RAS is one of the most important oncogenes, many drugs have been already developed to interrupt the RAS pathway to treat cancer.

“If NF1 is missing and it is causing cancer by activating RAS, then these drugs may help,” said Schimenti. “Therefore, there doesn’t need to be any more drug development to test this possibility right now,” he added.

The study also suggests that tamoxifen, one of the most common breast cancer treatments, may exacerbate the disease when the missing NF1 is the driver. Another study reported that NF1 protein depletion makes cancer cells resistant to tamoxifen, and tamoxifen-treated patients whose tumors have low NF1 levels had poorer clinical outcomes.

Schimenti and his colleagues plan to test whether they can reverse growth of tumors in mice missing the NF1 gene by inserting a replacement gene. They are also testing how effective RAS inhibitor drugs are at curbing cancer in mice. The paper shows that RAS inhibitors curb growth of these tumor cells in culture.

Marsha Wallace, a graduate student working in Schimenti’s lab, is the paper’s lead author. Researchers from the University of North Carolina and Sloan Kettering Cancer Center co-authored the study.

The study was funded by the National Institutes of Health, the Empire State Stem Cell Fund, the National Cancer Institute and the Breast Cancer Research Foundation.

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Assisted Reproductive Technology Cycles and Cumulative Birth Rates

Posted in Bio Instrumentation in Experimental Life Sciences Research, Health Economics and Outcomes Research, Personalized and Precision Medicine & Genomic Research, Reproductive Biology & Bio Instrumentation, tagged Assisted Reproductive technology, Birth Rate, In vitro fertilization on August 14, 2012| 3 Comments »

Cumulative Birth Rates with Linked Assisted Reproductive Technology Cycles

Reporter: Aviva Lev-Ari, PhD, RN

Barbara Luke, Sc.D., M.P.H., Morton B. Brown, Ph.D., Ethan Wantman, M.B.A., Avi Lederman, B.A., William Gibbons, M.D., Glenn L. Schattman, M.D., Rogerio A. Lobo, M.D., Richard E. Leach, M.D., and Judy E. Stern, Ph.D.

N Engl J Med 2012; 366:2483-2491 June 28, 2012

BACKGROUND

Live-birth rates after treatment with assisted reproductive technology have traditionally been reported on a per-cycle basis. For women receiving continued treatment, cumulative success rates are a more important measure.

METHODS

We linked data from cycles of assisted reproductive technology in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database for the period from 2004 through 2009 to individual women in order to estimate cumulative live-birth rates. Conservative estimates assumed that women who did not return for treatment would not have a live birth; optimal estimates assumed that these women would have live-birth rates similar to those for women continuing treatment.

RESULTS

The data were from 246,740 women, with 471,208 cycles and 140,859 live births. Live-birth rates declined with increasing maternal age and increasing cycle number with autologous, but not donor, oocytes. By the third cycle, the conservative and optimal estimates of live-birth rates with autologous oocytes had declined from 63.3% and 74.6%, respectively, for women younger than 31 years of age to 18.6% and 27.8% for those 41 or 42 years of age and to 6.6% and 11.3% for those 43 years of age or older. When donor oocytes were used, the rates were higher than 60% and 80%, respectively, for all ages. Rates were higher with blastocyst embryos (day of transfer, 5 or 6) than with cleavage embryos (day of transfer, 2 or 3). At the third cycle, the conservative and optimal estimates of cumulative live-birth rates were, respectively, 42.7% and 65.3% for transfer of cleavage embryos and 52.4% and 80.7% for transfer of blastocyst embryos when fresh autologous oocytes were used.

CONCLUSIONS

Our results indicate that live-birth rates approaching natural fecundity can be achieved by means of assisted reproductive technology when there are favorable patient and embryo characteristics. Live-birth rates among older women are lower than those among younger women when autologous oocytes are used but are similar to the rates among young women when donor oocytes are used. (Funded by the National Institutes of Health and the Society for Assisted Reproductive Technology.)

The views expressed in this article are those of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Supported by the National Cancer Institute, National Institutes of Health (grant R01 CA151973), and the Society for Assisted Reproductive Technology (SART).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank all the members of SART for providing clinical information to the SART Clinic Outcome Reporting System database for use by patients and researchers.

SOURCE INFORMATION

From the Departments of Obstetrics, Gynecology, and Reproductive Biology (B.L., R.E.L.), Michigan State University, East Lansing; the Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor (M.B.B.); and the Department of Obstetrics, Gynecology, and Women’s Health, Spectrum Health Medical Group, Grand Rapids (R.E.L.) — all in Michigan; Redshift Technologies (E.W., A.L.), the Department of Obstetrics and Gynecology, Cornell Medical Center (G.L.S.), and the Department of Obstetrics and Gynecology, Columbia University Medical Center (R.A.L.) — all in New York; the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston (W.G.); and the Department of Obstetrics and Gynecology, Dartmouth–Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH (J.E.S.).

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Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C

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Cumulative Birth Rates with Linked Assisted Reproductive Technology Cycles

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