Diabetic Atherosclerosis Management Can Be Personalized Using Coronary Artery Calcium Score

MedicalResearch.com Interview with:
Dr. MalikDr. Shaista Malik MD PhD MPH
Director of Samueli Center For Integrative Medicine
Assistant Professor, School of Medicine
University of California, Irvine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Having diabetes has been considered to be a risk equivalent to already had a myocardial infarction for predicting future cardiovascular events.  We were interested in testing whether further risk stratification in those with diabetes and metabolic syndrome, using coronary artery calcium (CAC), would result in improved prediction of cardiovascular events.

We found that CAC score was associated with incident coronary heart disease and cardiovascular disease more than a decade after the scoring was performed.  We also found that even after we controlled for the duration of diabetes (of 10 years or more), insulin use, or hemoglobin A1c level, coronary artery calcium remained a predictor of cardiovascular events.

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Refined Biomarker Model Can Guage Risk of Alzheimer’s In Patients With Mild Cognitive Impairment

MedicalResearch.com Interview with:
Ingrid S. van Maurik, MSc
Department of Neurology and Alzheimer Center
Department of Epidemiology and Biostatistics
Amsterdam Neuroscience
VU University Medical Center
Amsterdam, the Netherlands

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: CSF and MRI biomarkers are increasingly used in clinical practice, but their diagnostic and prognostic value is not perfect. Furthermore, criteria do not specify how to deal with conflicting or borderline results, or how to take patient characteristics into account. Therefore, optimal use of these biomarkers in clinical practice remains challenging.

As part of the ABIDE project, we constructed biomarker-based prognostic models (CSF, MRI and combined) that enable prediction of future Alzheimer’s disease, or any type of dementia, in individual patients with mild cognitive impairment. When using these models, any value can be entered for the variables, resulting in personalized probabilities with confidence intervals.

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TeloView Measures Genomic Stability To Predict Disease Aggressiveness

MedicalResearch.com Interview with:

3D SignaturesJason Flowerday, CEO
Director of 3D Signatures 

MedicalResearch.com: What is the background for 3D Signatures?

Response: 3D Signatures, and its clinical lab tests, which incorporate its proprietary TeloViewTM software analytics, is the culmination of over 20 years of ground-breaking research conducted by Dr. Sabine Mai and her colleagues. It is the only technology in the world that quantifies genomic instability, which is the hallmark of cancer and other proliferative diseases at the whole-cell level.

By measuring the degree of genomic instability from different tissues, TeloViewTM has produced clinically actionable distinctions in the stage of disease, rate of progression of disease, drug efficacy, and drug toxicity. The technology is well developed and supported by 22 clinical studies on over 2,000 patients on 13 different cancers including Alzheimer’s disease. The results have been exceptional and represent a universal biomarker platform across all disease areas that the company has investigated to date.

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Frequency of Retinal Screening in Diabetes May Be Tailored to Individual

MedicalResearch.com Interview with:
John M. Lachin, Sc.D.
Research Professor of Biostatistics and of Epidemiology, and of Statistics
The George Washington University Biostatistics Center and
David Matthew Nathan, M.D.
Professor of Medicine, Diabetes Unit
Massachusetts General Hospital 

MedicalResearch.com: What is the background for this study?

Response: Traditional guidelines for screening for retinopathy, based on indirect evidence, call for annual examinations. The automatic annual screening for retinopathy, without considering potential risk factors for progression,  appears excessive based on the slow rate of progression through sub-clinical states of retinopathy.

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Precision Therapy In Early Stages For Triple Negative Breast Cancer

MedicalResearch.com Interview with:
Eran Andrechek, PhD

Eran Andrechek, PhD Associate Professor Department of Physiology Michigan State University East Lansing, MI

Associate Professor
Department of Physiology
Michigan State University
East Lansing, MI 

MedicalResearch.com: What is the background for this study?

Response: Of the various types of breast cancer, triple negative breast cancer (lacking estrogen receptor, progesterone receptor and HER2) has the worst outcome and is largely limited to chemotherapy for treatment.  Other types can be treated with personalized medicine, resulting in better outcome.  For instance, a HER2+ve breast cancer can be treated with Herceptin, which targets HER2 itself.  The fact that triple negative breast cancer lacks these sort of targeted treatments presents a clear need in breast cancer therapy.

The goal of this study was to bring together our computational work using large databases from breast cancer with research into therapeutic options.  Essentially we wanted to ask if we could use patterns in what genes were being expressed to predict optimal therapy for triple negative breast cancer.  Continue reading

Genomic Testing Can Improve Confidence in Prostate Cancer Treatment Strategy

MedicalResearch.com Interview with:

Dr. John L. Gore, MD Associate Professor Adjunct Associate Professor-Surgery Department of Urology University of Washington

Dr. John Gore

Dr. John L. Gore, MD
Associate Professor
Adjunct Associate Professor-Surgery
Department of Urology
University of Washington

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The rationale for our study derives from the uncertainty that both patients and clinicians confront when trying to make decisions about adjuvant therapy for prostate cancers found to have aggressive pathologic features at the time of radical prostatectomy. There is level 1 evidence in support of adjuvant radiation therapy in this setting, but several factors restrain providers from recommending adjuvant radiation. We found that interjecting a genomic test that predicts the risk of clinical metastases 5 years after surgery impacts the treatment recommended and helps men and clinicians feel more confident in the decision they are making or recommending.

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AI plus Genetic Database Drives Personalized Cancer Treatment

MedicalResearch.com Interview with:

Dr. Kai Wang Zilkha Neurogenetic Institute, University of Southern California Institute for Genomic Medicine, Columbia University

Dr. Kai Wang

Dr. Kai Wang
Zilkha Neurogenetic Institute, University of Southern California
Institute for Genomic Medicine, Columbia University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Cancer is a genetic disease caused by a small number of “driver mutations” in the cancer genome that drive disease initiation and progression. To understand such mechanism, there are increasing community efforts in interrogating cancer genomes, transcriptomes and proteomes by high-throughput technologies, generating huge amounts of data. For example, The Cancer Genome Atlas (TCGA) project has already made public 2.5 petabytes of data describing tumor and normal tissues from more than 11,000 patients. We were interested in using such publicly available genomics data to predict cancer driver genes/variants for individual patients, and design an “electronic brain” called iCAGES that learns from such information to provide personalized cancer diagnosis and treatment.

iCAGES is composed of three consecutive layers, to infer driver variants, driver genes and drug treatment, respectively. Unlike most other existing tools that infer driver genes from a cohort of patients with similar cancer, iCAGES attempts to predict drivers for individual patient based on his/her genomic profile.

What we have found is that iCAGES outperforms other tools in identifying driver variants and driver genes for individual patients. More importantly, a retrospective analysis on TCGA data shows that iCAGES predicts whether patients respond to drug treatment and predicts long-term survival. For example, we analyzed two groups of patients and found that using iCAGES recommend drugs can increase patients’ survival probability by 66%. These results suggest that whole-genome information, together with transcriptome and proteome information, may benefit patients in getting optimal and precise treatment. Continue reading

Supermagnetized Crystals May Deliver Precision Drugs Directly To Medical Targets

MedicalResearch.com Interview with:
Dr. Kezheng Chen

Lab of Functional and Biomedical Nanomaterials
College of Materials Science and Engineering
Qingdao University of Science and Technology
Qingdao China

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: From a view point of practical applications, superparamagnetism is usually highly desirable, because it can prevent the magnetic particles from irreversible aggregation and ensure an excellent dispersity once the applied magnetic field is removed.

Up to now, the largest size of reported superparamagnetic clusters is around several hundreds of nanometers, which are composed of numerous nanocrystals, and hence exhibiting polycrystalline nature. In this sense, how to realize well pronounced superparamagnetism in large-size single crystals is of great interest to the general public.

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Penn Reports Successful Pilot Study of Liquid Biopsy To Monitor Advanced Lung Cancer

MedicalResearch.com Interview with:

Erica L. Carpenter, MBA, PhD Research Assistant Professor, Department of Medicine Director, Circulating Tumor Material Laboratory Division of Hematology/Oncology Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania

Dr. Erica Carpenter

Erica L. Carpenter, MBA, PhD
Research Assistant Professor, Department of Medicine
Director, Circulating Tumor Material Laboratory
Division of Hematology/Oncology
Abramson Cancer Center
Perelman School of Medicine at the University of Pennsylvania

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The advent of precision medicine practices for cancer patients, including the use of drugs that target specific tumor mutations, has necessitated improved diagnostics with real-time molecular monitoring of patients’ tumor burden. While biopsy material, obtained surgically or through fine needle aspirate, can provide tissue for next generation sequencing (NGS) and mutation detection, this requires an invasive often painful procedure for the patient. In many cases, especially in more advanced disease when multiple metastases are present, such tissue cannot be obtained or can only be obtained from a single tumor site, thus limiting the sensitivity of tissue-based biopsy.

Here we report on a prospective cohort of 102 consecutively enrolled patients with advanced non-small lung cancer (NSCLC) for whom a non-invasive liquid biopsy was used for real-time detection of therapeutically targetable mutations. Tissue samples were only obtainable for 50 of the 102 patients, and these tissue biopsies were analyzed using a 47-gene Next Generation Sequencing (NGS) panel at Penn’s Center for Personalized Diagnostics. Concordance of results for the 50 patients who received both tests was close to 100% when the samples were obtained concurrently.

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Biomarker May Predict Response to Common Leukemia Treatment

MedicalResearch.com Interview with:

Dr Laura Eadie PhD Post Doctoral Researcher Affiliate Lecturer Discipline of Medicine University of Adelaide

Dr. Laura Eadie

Dr Laura Eadie PhD
Post Doctoral Researcher
Affiliate Lecturer Discipline of Medicine
University of Adelaide

Summary: Researchers based at SAHMRI (South Australian Health and Medical Research Institute) in Adelaide, South Australia have recently demonstrated the significance of early increases in the expression of ABCB1 in predicting long-term response to imatinib therapy. Lead researcher, Dr Laura Eadie, has recently had these findings published in the journal Leukemia and says that she hopes “the evidence provided by the study could be used to inform better patient treatment in the future”.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: ABCB1 (p-glycoprotein) is a membrane transporter known to be involved in the efflux of the tyrosine kinase inhibitors (TKIs) that are used to treat chronic myeloid leukaemia (CML). Overexpression of ABCB1 has also been demonstrated to cause resistance to the TKIs imatinib, nilotinib and dasatinib in vitro. Although studied previously in CML patients, the predictive value of ABCB1 in determining a patient’s long-term response to imatinib had not been realized … until now.

Previous studies investigating ABCB1 as a predictive biomarker focused on expression levels of ABCB1 at one time point in isolation. For our study, we have measured the levels of ABCB1 at two separate time points specified in the TIDEL II trial protocol: day 1 (prior to the start of imatinib therapy) and day 22 (three weeks on imatinib). We then calculated the fold rise in ABCB1 expression levels at day 22 compared with day 1 and grouped patients about the median into high and low fold rise. When we compared molecular outcomes for patients within these two ABCB1 expression groups we noticed a striking difference in outcome to imatinib therapy.

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Panel of Nine Proteins Improves Risk Assessment in Patients With Stable Coronary Artery Disease

MedicalResearch.com Interview with:

Peter Ganz, MD Chief, Division of Cardiology Director, Center of Excellence in Vascular Research Zuckerberg San Francisco General Hospital Maurice Eliaser Distinguished Professor of Medicine University of California, San Francisco

Dr. Peter Ganz

Peter Ganz, MD
Chief, Division of Cardiology
Director, Center of Excellence in Vascular Research
Zuckerberg San Francisco General Hospital
Maurice Eliaser Distinguished Professor of Medicine
University of California, San Francisco

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Ganz:  The research described in the JAMA paper involved measuring 1,130 different proteins in nearly 2000 individuals with apparently stable coronary heart disease, who were followed up to 11 years. Initially, two hundred different proteins were identified whose blood levels could be related to the risk of heart attacks, strokes, heart failure and death, and ultimately a combination of nine proteins was selected for a risk prediction model, based on their combined accuracy and sensitivity.

Application of these findings to samples of patients with stable coronary heart disease demonstrated that some of those who were deemed clinically stable instead had a high risk of adverse cardiovascular outcomes, while other patients with the same clinical diagnosis had a very low risk. Thus, individuals who all carried the same clinical diagnosis of stable coronary heart disease had a risk of an adverse cardiovascular event that varied by as much as 10-fold, as revealed by analysis of the levels of the nine proteins in their blood. Given such large differences in risk and outcomes, patients could reasonably opt to be treated differently, depending on their level of risk. We hope that in the future, management of patients with stable angina will at least in part rely on risk assessment based on levels of blood proteins.

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Biomarker Based Chemotherapy Approach Improved Outcomes

MedicalResearch.com Interview with:

Maria Schwaederle PharmD Clinical Research Scientist Center for Personalized Cancer Therapy UCSD Moores Cancer Center La Jolla, CA 92093

Dr. Maria Schwaederle

Maria Schwaederle PharmD
Clinical Research Scientist
Center for Personalized Cancer Therapy
UCSD Moores Cancer Center
La Jolla, CA 92093

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Schwaederle: We performed this analysis with experts in the field, including but not limited to Drs Schilsky, Lee, Mendelsohn and Kurzrock, all known for their experience in the area of precision/personalized medicine.
Historically, phase I trials (which are often first in human or highly experimental in other ways) were believed to be examining only toxicity. Our meta-analysis of 13,203 patients shows that in the era of precision medicine, this historical belief needs to be discarded. Second, it is the use of precision medicine that makes this belief outdated.
Indeed, Phase I trials that utilized a biomarker-driven approach that is the essence of precision medicine had a median response rate of about 31%, which is higher than many FDA approved drugs, and this is in spite of the fact that phase I patients are a highly refractory group having failed multiple lines of conventional therapy.

Importantly, however, it was not the use of targeted agents alone that was important. It was the biomarker-based approach where patients are matched to drugs. Without matching, response rates were dismal—about 5%.

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Monitoring Circulating Tumor Cells May Further Personalized Cancer Treatment

MedicalResearch.com Interview with:

Dr. Elodie Sollier
Chief Scientific Officer at Vortex Biosciences

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Circulating Tumor Cell (CTC) burden may be a useful biomarker of response to targeted therapy in PDX (Patient Derived Xenograft) mouse models. Vortex Biosciences’ technology has been proven to enrich CTCs from human blood, but use of the technology with mouse blood had not yet been explored. In this poster, human CTCs are isolated with both high efficiency and purity from xenograft model of breast cancer using Vortex’s technology. Circulating Tumor Cell enumeration increased as the tumor burden increased in the mouse demonstrating its utility as a biomarker for drug treatment response.

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Decipher Genomic Testing Moves Prostate Cancer Prognosis into Precision Medicine Era

MedicalResearch.com Interview with:

Eric A. Klein, MD Chairman, Glickman Urological and Kidney Institute Cleveland Clinic

Dr. Eric Klein

Eric A. Klein, MD
Chairman, Glickman Urological and Kidney Institute
Cleveland Clinic

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Klein: Prostate cancer is an enigma. While this tumor is the second leading cause of cancer death among American men, most newly diagnosed disease detected by PSA screening is biologically indolent and does not require immediate therapy. Currently, the main clinical challenge in these men is to distinguish between those who can be managed by active surveillance from those who require curative intervention. Current clinical and pathological tools used for risk stratification are limited in accuracy for distinguishing between these scenarios.

An abundance of research in the last decade has provided evidence that genomics can offer meaningful and clinically actionable biological information to help inform decision making, and current National Comprehensive Cancer Network (NCCN) guidelines on prostate cancer endorse the use of commercially available genomic tools for men considering active surveillance.[1] It has been previously shown that the 22-gene genomic classifier, Decipher, accurately predicts the likelihood of metastasis and prostate cancer specific mortality when measured on tissue from radical prostatectomy specimens.[2] In multiple validation studies, it performed with higher accuracy and discrimination compared to clinical risk factors alone.

The current study[3] is the first to examine whether the use of Decipher might aid decision making when measured on biopsy tissue at the time of diagnosis. Men with available needle biopsy samples were identified from a study cohort that previously had Decipher performed on their matched radical prostatectomy tissue. In this cohort of mixed low, intermediate and high risk men, Biopsy Decipher predicted the risk of metastasis 10 years post RP with high accuracy, outperforming NCCN clinical risk categorization, biopsy Gleason score and pre-operative PSA. Furthermore, this study showed that Decipher reclassified 46% of patients into lower or higher risk classification compared to NCCN classification alone. The study also showed that Biopsy Decipher can identify men that are at high risk for adverse pathology as defined by the presence of primary Gleason pattern 4 or greater.

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Genetic Markers Help Individually Identify Melanoma Patients At Risk For Metastases

Tomas Kirchhoff, PhD Assistant Professor, Departments of Population Health and Environmental Medicine NYU Langone Medical Center Member, Laura and Isaac Perlmutter Cancer Center NYU Langone

Dr. Thomas Kirchhoff

MedicalResearch.com Interview with:
Tomas Kirchhoff, PhD
Assistant Professor, Departments of Population Health and Environmental Medicine
NYU Langone Medical Center
Member, Laura and Isaac Perlmutter Cancer Center
NYU Langone 

Medical Research: What is the background for this study?
Dr. Kirchhoff: Melanoma is the deadliest form of skin cancer, and the cause of approximately 80% of all skin cancer patients annually. One factor that can help reverse this negative trend is efficient prediction of which patients at early melanoma stage will likely progress to more advanced metastatic disease. Current clinical predictors of patient survival, based on tumor characteristics, are important, but are relatively non-specific to inform melanoma prognosis to an individual patient level. It is critical to identify other factors that can serve as more personalized markers of predicting the course of melanoma.

Medical Research: What are the main findings?

Dr. Kirchhoff: In our study, we found that inherited genetic markers that impact activity of certain immune genes correlate with melanoma survival. More specifically, our findings show that patients with more frequent forms of these genetic markers (genotypes) have, on average, a five-year shorter survival than patients with less common genotypes. We suggest that these genetic markers are independent of the current tumor surrogates and, as such, can serve as novel personalized markers of melanoma prognosis.

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Virtual Tumor Model Allows Precision Treatment of Glioblastomas

Dr. Chirag Patil, MD American Board Certified Neurosurgeon, Brain & Spine Tumor Program Lead Investigator, Precision Medicine Initiative Against Brain Cancer Program Director, Neurosurgical Residence training program Director, Center for Neurosurgical Outcomes Research – Cedars-Sinai Medical Center, Los Angeles, California

Dr. Chirag Patil

MedicalResearch.com Interview with:
Dr. Chirag Patil, MD

American Board Certified Neurosurgeon
Brain & Spine Tumor Program
Lead Investigator, Precision Medicine Initiative Against Brain Cancer
Program Director, Neurosurgical Residence training program
Director, Center for Neurosurgical Outcomes Research Cedars-Sinai Medical Center, Los Angeles, California

MedicalResearch.com Editor’s note: Dr. Patil’s research is focused on developing a method of personalized cancer treatment through the harnessing of genome wide mutational analysis of a specific patient’s cancer.

MedicalResearch.com: Would you tell us a little about yourself and your research interests?

Dr. Patil: I am a Stanford-trained, Board Certified Neurosurgeon and cancer researcher at Cedars-Sinai Medical Center in Los Angeles, California. I primarily focus on the care of patients with malignant brain tumors, particularly glioblastomas. I received my undergraduate degree from Cornell, followed by a medical degree from the University of California, San Francisco (UCSF), where I was a Regent’s scholar. I completed a residency in neurosurgery and a fellowship in stereotactic radiology at Stanford University. I also have a master’s degree in epidemiology with a focus on clinical trial design and mathematical modeling from Stanford.

MedicalResearch.com: Can you tell us about some of your research interests?

Dr. Patil: I am keenly interested in and focused on developing precision science-powered novel brain tumor therapies, immuno-therapies, and patient-centered “big data” outcomes research. I lead the recently-funded Cedars-Sinai Precision Medicine Initiative Against Brain Cancer, which utilizes tumor genomics to build a mathematical computer model, i.e., a virtual cancer cell of each patient’s unique tumor. The White House and several other stakeholders have taken keep interest in this research initiative as an example of a leading precision medicine program.

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canSAR Database Analysis Speeds Identification of New Cancer Targets

Dr Bissan Al-Lazikani Team leader in computational biology The Institute of Cancer Research London

Dr. Bissan Al-Lazikini

MedicalResearch.com Interview with:
Dr Bissan Al-Lazikani
Team leader in computational biology
The Institute of Cancer Research
London

Medical Research: What is the background for the canSAR database? What are the main uses for the tool?

Dr. Al-Lazikani: Drug discovery is a difficult, time consuming and expensive venture that frequently ends in late stage drug failures – especially in oncology.

As with any complex venture, decisions throughout the drug discovery pipeline can be empowered by having access to the right information at the right time. But for drug discovery this means bringing together billions of experimental data from very diverse areas of science spanning genomics, proteomics, chemistry and more.

We developed canSAR to help guide our own drug discovery efforts by integrating these huge, diverse data and by analysing the data and deriving hidden links and knowledge from them. This means that we can answer questions in minutes that would have taken weeks using previously available public resources. But, more importantly, canSAR analyses and links these data in a way that allows us  to derive knowledge that was hidden before. For example, one of the main ways canSAR is used is to help select the best druggable targets for drug discovery. Using canSAR we were able to uncover many druggable cancer proteins that were previously overlooked, and we are delighted to see that several of these proteins are now the subjects of drug discovery and development projects both by us and by others.

We took the decision to make canSAR publicly and freely available because we believe that cancer drug discovery is a vast challenge that requires openness and data sharing worldwide. It has been embraced by the community is being used by tens of thousands of cancer scientists worldwide, both in academia and industry, to generate hypotheses for experiments and select targets for drug discovery.

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Cross Border Pharmaceutical Alliances Present Challenges and Opportunities

Diane Frenier Esq Reed Smith Corporate Partner Member of Corporate & Securities Group and Life Sciences Health Industry Group

Diana Frenier

MedicalResearch.com Interview with:
Diane Frenier Esq

Reed Smith Corporate Partner
Member of Corporate & Securities Group and Life Sciences Health Industry Group

Background: Diane Frenier Esq discusses the M&A boom in the pharmaceutical and retail drug industry including a the “global study of 100 senior executives at life sciences companies by global law firm Reed Smith, in partnership with Mergermarket, reveals that 94% are planning to make an acquisition in the next year”.

Medical Research: What are the main drivers behind the pursuit of cross-border life sciences deals?

Ms Frenier: I think companies are trying to strengthen their capabilities in areas that are a core focus for them (e.g., in certain therapeutic areas, or for orphan drugs), and that includes adding products in those core focus areas and, in some cases, broadening geographically so they can market products in those core focus areas on a more global basis.  This will allow them to use their resources more efficiently and take advantage of saving from reducing redundancies.

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Histone Biomarker May Guide Treatment of Pediatric Malignant Gliomas

Timothy Humphrey DPhil. CRUK/MRC Oxford institute for Radiation Oncology University of Oxford, UKMedicalResearch.com Interview with
Timothy Humphrey DPhil.
CRUK/MRC Oxford institute for Radiation Oncology
University of Oxford, UK

Medical Research: What is the background for this study? What are the main findings?

Response: Multiple mutations resulting in loss of a particular histone mark (H3K36me3) are frequently found in a number of cancer types. These include mutations resulting in loss of the tumour suppressor SETD2 (which trimethylates H3K36) and over-expression of the oncogene KDM4A (which demethylates H3K36me3), which together are observed in more than 10% of a number of cancer types. Notably, loss of H3K36me3 has been reported in more than 50% of pediatric high-grade gliomas. While loss of this histone mark is associated with poor prognosis, there is no targeted therapy yet.

Following observations made in fission yeast, we have found a new way to selectively target H3K36me3-deficient cancers using the WEE1 inhibitor, AZD1775. Surprisingly, treatment of H3K36me3-deficient cancer cells with the WEE1 inhibitor resulted in S-phase arrest. Further analysis revealed ribonucleotide reductase to be the target of this synthetic lethal interaction, thereby leading to dNTP starvation, replication fork collapse and cell death.
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Genome Wide Testing May Make Transplantation More Personalized

MedicalResearch.com Interview with:
Brendan J. Keating, DPhil
Assistant professor of Transplant Surgery
Penn Medicine

Medical Research: What is the background for this study? What are the main findings?

Response: Genetic studies in transplantation have been plagued by small samples and very complex phenotypes/outcomes of patients. Transplanted individuals are typically on potent immunosuppression drugs for the rest of their lives, as they have 3.5 million to 10 million variants difference from an unrelated transplanted donor organ. Such populations would certainly benefit from large well-powered genetic studies but only 3 transplant genome-wide genotyping studies comprising a few hundred individuals have been published.

The papers outline the resources in hand for the International Genetics & Translational
Research in Transplantation Network, comprising 22 studies to date (since the publication it has now expanded to 25 studies and > 32,000 subjects with genome-wide genotyping data). We show significant statistical power in iGeneTRAiN to detect main effect association signals across regions such as the MHC region (which harbors the HLA Class I/II regions which are well established to associate with transplantation outcomes). We also show strong genome-wide power to detect transplant outcomes that span all solid organs including graft survival, acute rejection, new onset of diabetes after transplantation (fast becoming the most common comorbidity post-transplantation), and delayed graft function (to date we have looked at this in kidney transplant patients only). We show that iGeneTRAiN is statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid-organ transplant studies.

The transplant specific GWAS array that we designed (described in depth in the Genome Medicine paper) show that the coverage in key transplant associated regions is much higher than conventional arrays, and we describe the ‘imputation’ pipeline to expand the 780,000 or so variants examined in any given individual to > 15 millions of variants using whole genome sequencing reference datasets.

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Targeted Melanoma Panel Identifies Genetic Subsets of Melanoma

Melissa Wilson, MD, PhD Assisstant Professor Perlmutter Cancer Center NYU Langone Medical Center New York, NYMedicalResearch.com Interview with:
Melissa Wilson, MD, PhD
Assisstant Professor
Perlmutter Cancer Center
NYU Langone Medical Center
New York, NY

Medical Research: What is the background for this study? What are the main findings?

Dr. Wilson: Metastatic cutaneous melanoma is an extremely aggressive form of skin cancer.  Traditionally, it has been characterized by clinicopathologic characteristics.  More recently, melanoma tumors have also been stratified by common somatic mutations for which targeted therapies have been developed or are under investigation, including BRAF, NRAS and KIT.  In addition to somatic mutations, aberrant intracellular signaling pathways and cell cycle disruption contribute to melanoma pathogenesis.  Indeed, recent next generation sequencing studies have identified a number of new genes involved in melanomagenesis.  A comprehensive evaluation and understanding of concurrent and mutually exclusive mutations in tumors has been lacking.  Therefore, we developed a comprehensive custom targeted capture of 108 genes previously implicated in melanoma pathogenesis.  We used the targeted panel to perform massively parallel sequencing on 94 well-established human melanoma cell lines, 67 patient-derived xenografts (PDX), and 5 cell lines made from PDX, all untreated.

Samples were clustered based on deleterious mutations.  Eighty-three percent of samples had deleterious mutations in the MAPK signaling pathway (including BRAF, RAS) and NF1.  Ten percent of samples had PI3K pathway mutations which were predominantly associated with BRAF mutations.  TP53 was found to be mutated in 24% of the samples and were also associated with mutations in the MAPK pathway.  Mutations in chromatin remodeling genes were mutually exclusive with each other, but were associated with BRAF and NRAS mutations.  Of particular interest, five of the 10 NF1mutated samples harbored likely deleterious mutations in MAP3K5 or MAP3K9, suggesting the potential involvement of JNK signal transduction pathway in a cohort of samples.

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Mobile Health Technologies Will Change Chronic Disease Management

Ryan Jeffrey Shaw, PhD, MS, RN Assistant Professor School of Nursing Center for Health Informatics Center for Precision Medicine Duke University MedicalResearch.com Interview with:
Ryan Jeffrey Shaw, PhD, MS, RN

Assistant Professor School of Nursing
Center for Health Informatics
Center for Precision Medicine
Duke University

Medical Research: What is the background for this study? What are the main findings?

Dr. Shaw: Primary care delivery revolves around a series of episodes, rather than functioning as a continuum. When patients come to a clinic data on their health is collected as a single data point. This model neglects potentially meaningful data from patients’ daily lives and results in less informed treatment and scheduling of follow-up visits. Lack of meaningful data further blinds clinicians to patients’ health outside of the clinic and can contribute to unnecessary emergency department visits and hospitalizations.

Personalized care through mobile health technologies inspires the transition from isolated snapshots based on serial visits to real time and trended data. By using technologies from cell phones to wearable sensors, providers have the ability to monitor patients and families outside of the traditional office visit.

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Gene Signature May Predict Risk of Metastases and Death From Melanoma

Pedram Gerami MD Associate Professor of Dermatology and Pathology Northwestern UniversityMedicalResearch.com Interview with:
Pedram Gerami MD
Associate Professor of Dermatology and Pathology
Northwestern University

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Gerami: The outcomes for patients with cutaneous melanoma are highly variable and there are limitations to the conventional staging system for melanoma. For example while the status of the sentinel lymph node biopsy is considered the strongest prognosticator, approximately 2/3 of cutaneous melanoma patients that ultimately die from their melanoma will have a negative sentinel lymph node biopsy result. In this study we showed that using a technique known as mRNA expression profiling to determine which genes are highly active and which are not that a molecular prognostic assay with accuracy could be developed. This assay can accurately classify patients based on their gene signature as having a high or low risk for metastasis and death from their melanoma. In an independent validation cohort, patients with a class I or low risk signature had a 5 year disease free survival rate of 97% while those with a class II or high risk signature had a 5 year disease free survival rate of only 31%.

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Study Examines Use Of Oncotype DX® Breast Cancer Test In Medicare Patients

Dr. Michaela A. Dinan Ph.D Department of Medicine Duke UniversityMedicalResearch.com Interview with:
Dr. Michaela A. Dinan Ph.D

Department of Medicine
Duke University

Medical Research: What is the background for this study? What are the main findings?

Dr. Dinan: We wanted to examine how  Oncotype DX® Breast Cancer Test (ODX) was being used in real-world practice at the population level. ODX has been examined in clinical trials and limited academic settings but we know that these patients are often younger, have fewer medical comorbidities, and do not necessarily accurately reflect the majority patients with cancer.  In our study, we observed that Oncotype DX® Breast Cancer Test was being used predominately in accordance with guidelines which recommend the test for women with estrogen-receptor positive, node negative disease. We also looked just at women under the age of 70 who met guideline criteria for testing, because this population would include those women who were more likely to be chemotherapy candidates, and we saw a rapid uptake of the test between 2005 and 2009, with use of the test increasing from 8% to 39%.

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Melanoma: Assaying Multiple Proteins Helps Identify BRAF-Inhibitor Resistance

Linda Chin, MD Department Chair, Department of Genomic Medicine, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TXMedicalResearch.com Interview with:
Linda Chin, MD

Department Chair, Department of Genomic Medicine, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

Medical Research: What is the background for this study? What are the main findings?

Dr. Chin: BRAF inhibitors have worked very well against melanoma in the clinic, but when the tumors relapse on treatment, it is not always clear what causes it. Without this information, it can be difficult for doctors to identify specific second-line therapies likely to overcome the drug resistance. In this study, we used both mouse and patient melanoma samples to identify patterns of selected protein levels that can categorize modes of drug resistance when other assays such as DNA sequencing are uninformative. We hope that this information can provide missing clues for clinicians. Continue reading

Personalized Medicine: Tailoring Surgical Approach To Ovarian Cancer

Dr. Anil Sood MD Professor of Gynecologic Oncology and Reproductive Medicine The University of Texas MD Anderson Cancer CenterMedicalResearch.com Interview with:
Dr. Anil Sood MD

Professor of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center

Medical Research: What is the background for this study? What are the main findings?

MedicalResearch: What is the background for this approach? What are the main findings?

Dr. Sood: The background involves several different issues: management approaches have varied quite a bit across the US; definition of “optimal” surgery and rates of complete surgical removal of tumor (R0) have also varied. It is quite apparent that patients who benefit the most from surgery upfront are those who have removal of tumor resection. To address these issues, we have implanted a much more personalized approach whereby patients with suspected advanced ovarian cancer undergo laparoscopic assessment using a validated scoring system (based on the pattern and extent of disease noted during laparoscopic assessment); patients with a score <8 undergo upfront debulking surgery and those with a score ≥8 receive neoadjuvant chemotherapy followed by surgery after 3-4 cycles. To date, this program has been fully implemented as part of the Moonshot Program at M.D. Anderson. This program has already resulted in several benefits – for example, prior to this algorithm being put into place among all patients with suspected advanced ovarian cancer, around 20% would have removal of tumor resection; after the implementation of the algorithm, of those going to upfront debulking surgery (after laparoscopic assessment), almost 85% of times removal of tumor resection can be achieved. Also, this method of treatment is allowing for new and innovative clinical trial designs. Continue reading

Molecular Biomarkers May Help Determine Which Melanomas Will Spread

Iman Osman, MD Professor, Departments of Dermatology, Medicine and Urology Associate Director, NYU Cancer Institute  Director, Interdisciplinary Melanoma Program  New York University Langone Medical Center New York, NY 10016MedicalResearch.com Interview with:
Iman Osman, MD

Professor, Departments of Dermatology, Medicine and Urology
Associate Director
The Laura and Isaac Perlmutter Cancer Center
Director, Interdisciplinary Melanoma Program
New York University Langone Medical Center
New York, NY 10016

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Osman: We were interested in exploring molecules that could be biomarkers or functional regulators of metastasis in melanoma in early-stage tumor lesions on the skin. Though these tumors are treated largely the same (by surgical removal ), patients with these tumors have vastly different outcomes (apparent cure vs. metastatic spread of the disease). The reasons for these disparities are unclear and we have little ability to identify or predict the patients that will be cured and those that won’t. We also don’t have much data to know even if these tumors have differences at the molecular level. Our findings indicate that there are molecular differences in these tumors and that some of these differences contribute to tumor spread.  Continue reading

Personalized Advice May Help Risky Drinkers Reduce Alcohol

Sean M. Murphy, Ph.D. Assistant Professor  Department of Health Policy & Administration Washington State University MedicalResearch.com Interview with:
Sean M. Murphy, Ph.D.
Assistant Professor  Department of Health Policy & Administration
Washington State University

Medical Research: What is the background for this study? What are the main findings?

Dr. Murphy: Professional healthcare advice regarding excessive alcohol consumption has been shown to reduce demand in a controlled setting. However, success in a clinical trial isn’t always indicative of an intervention’s effectiveness in everyday use. Studies testing the effect of provider advice on alcohol demand in a non-controlled environment are few, and have failed to control for non-moderate drinkers.  Therefore, it is possible that the estimated effect of professional-health advice primarily reflected moderate-drinkers’ responses. The distinction between moderate and non-moderate drinkers is an important one, as society bears a large cost for those who consume above-moderate quantities, while moderate drinkers have been shown to be relatively productive and healthy. Excise taxes may not be efficient given that they impose negative externalities on moderate drinkers, while excessive drinkers have been shown to be relatively unresponsive to price increases. We found that personalized information from a healthcare professional was negatively associated with reported alcohol consumption among both “risky” and “binge” drinkers. Moreover, we found that personalized drinking advice may have an impact on those who are reluctant to state that they were given such advice.

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Cerebral Palsy Sometimes Due To Genetics, Not Birth Trauma

Prof. Jozef GECZMedicalResearch.com Interview with:
Prof. Jozef Gecz
NH&MRC Senior Principal Research Fellow
Professor of Human Genetics
School of Paediatrics and Reproductive Health
Faculty of Health Sciences The University of Adelaide at the Women’s and Children’s Hospital North Adelaide, SA

Medical Research: What is the background for this study? What are the main findings?

Prof. Gecz: Cerebral palsy is the most frequent movement disorder of children for many years considered to be due to brain injury. Given that cerebral palsy incidence has not changed dramatically over many years while medical care is constantly improving, we look for other causes and specifically genetic mutation. By investigating 183 children with cerebral palsy and for many also one or both of their parents we find that for at least 14% of these we can find plausible explanation in genetic mutation being involved in the causation of their cerebral palsy. Importantly, we find that 10% of these mutations are de novo, which means that these mutations are not present in the parents (specifically in their blood as that is the tissue source we tested). 4% of mutations were inherited from unaffected mothers to affected sons. Previous estimates suggested 2% genetic contribution to Cerebral palsy. We now know that it is at least 14% and likely more.

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Order of Mutations Affects Disease Pattern in Chronic Blood Disorders

David G. Kent, Ph.D From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of CambridgeMedicalResearch.com Interview with:
David G. Kent, Ph.D

From the Cambridge Institute for Medical Research and Wellcome Trust–Medical Research Council Stem Cell Institute University of Cambridge

Medical Research: What is the background for this study? What are the main findings?

Dr. Kent: Cancers are the result of the sequential acquisition of errors in the genetic code.  Most studies have focused on the sum of these mutations (e.g., A+B+C = cancer) but no study in patients has asked the question of whether or not the order of genetic mutations impacts the disease (e.g., does A to AB equal B to BA).  We studied patients with chronic blood disorders (known as myeloproliferative neoplasms, or MPNs) that are precursors to cancer to access the earliest stages of tumour development and studied whether or not the order of mutation acquisition impacted disease.  We studied patients with mutations in two genes (JAK2 and TET2) and showed that the order of acquisition of these mutations impacted timing of clinical presentation, disease subtype, frequency of thrombotic events, and differed in their response to targeted therapy in the lab. Continue reading

Parental Performance Influences Genetic Neurodevelopmental Disability

Andres Moreno De Luca, MD Investigator and Resident Physician Autism & Developmental Medicine Institute Department of Radiology Geisinger Health System Danville, PA 17822MedicalResearch.com Interview with:
Andres Moreno De Luca, MD
Investigator and Resident Physician
Autism & Developmental Medicine Institute
Department of Radiology Geisinger Health System
Danville, PA 17822

 

Medical Research: What is the background for this study? What are the main findings?

Response: The main finding of our study is that family background contributes to the variability in cognitive, behavioral, and motor performance seen in children with 16p11.2 deletions, and perhaps other genetic syndromes, and this may be attributed in part to genetic background effects.

In the general population the best predictor of a child’s outcomes in traits such as cognitive ability, height, BMI, etc. is the biparental mean performance in such domains and this is due in part to genetic background. For example, if a child’s parents have IQ scores of 130 and 110, it is expected that the child will have an IQ within 2 standard deviations of 120 (bi-parental mean). However, when studying individuals with genetic conditions, most researchers tend to overlook the influence of familial/genetic background on the affected child’s outcomes and commonly attribute the manifestations (or lack thereof) to the genetic mutation alone.

This creates confusion when studying children with neurodevelopmental disorders, such as autism, which show significant clinical variability, as some children with a specific genetic mutation (e.g. deletion 16p11.2) may have intellectual disability without autism, while other children with the same mutation may have autism without intellectual disability. Based on these observations, some researchers have argued that deletion 16p11.2 is incompletely penetrant. However, our study showed that the 16p11.2 deletion has a detrimental effect on cognitive and behavioral performance for all children, but the clinical status (affected vs. unaffected) and ultimate performance level is influenced by the parental performance.

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