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Terzian T.,Charles tes Center For Regenerative Medicine And Stem Cell Biology | Torchia E.C.,Charles tes Center For Regenerative Medicine And Stem Cell Biology | Dai D.,Charles tes Center For Regenerative Medicine And Stem Cell Biology | Murao K.,Charles tes Center For Regenerative Medicine And Stem Cell Biology | And 8 more authors.
Pigment Cell and Melanoma Research | Year: 2010

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the 'high-p53'Mdm4+/- mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/- background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/- mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53. © 2010 John Wiley & Sons A/S.

Tgen | Date: 2014-12-09

Dietary supplements; Herb teas for medicinal purposes; Homeopathic supplements; Nutritional supplements; Protein supplements; Vitamins.

Now, researchers at the Translational Genomics Research Institute (TGen) are showing how an even more detailed genetic analysis using RNA sequencing can vastly enhance that understanding, providing doctors and their patients with more precise tools to target the underlying causes of disease, and help recommend the best course of action. In their review, published today in the journal Nature Reviews Genetics, TGen scientists highlight the many advantages of using RNA-sequencing in the detection and management of everything from cancer to infectious diseases, such as Ebola and the rapidly spreading Zika virus. RNA's principal role is to act as a messenger carrying instructions from DNA for the synthesis of proteins. Building on the insights provided by DNA profiling, the analysis of RNA provides an even more precise look at how cells behave and how medicine can intervene when things go wrong. "RNA is a dynamic and diverse biomolecule with an essential role in numerous biological processes," said Dr. Sara Byron, Research Assistant Professor in TGen's Center for Translational Innovation, and the review's lead author. "From a molecular diagnostic standpoint, RNA-based measurements have the potential for broad application across diverse areas of human health, including disease diagnosis, prognosis, and therapeutic selection." DNA (deoxyribonucleic acid) sequencing spells out —in order— the billions of chemical letters that make up the genes that drive all of our biologic make up and functions, from hair and eye color to whether an individual may be predisposed to cancer or other diseases. RNA (ribonucleic acid) sequencing provides information on the genes that are actively being made into RNA in a cell and are important for cell function. While more complex, RNA holds the promise of more precise measurement of the human physical condition. There simply are more forms, or species, that RNA takes, explains Dr. Byron. "RNA-sequencing provides an deeper view of a patient's genome, revealing detailed information on the diverse spectrum of RNAs being expressed." One of the most promising aspects of RNA-based measurements is the potential of using extracellular RNA (exRNAs) as a non-invasive diagnostic indicator of disease. Monitoring exRNA simply takes a blood sample, as opposed to doing a tumor biopsy, which essentially is a minor surgery with greater risks and costs. "The investigation of exRNAs in biofluids to monitor disease is an area of diagnostic research that is growing rapidly," said Dr. Kendall Van Keuren-Jensen, TGen Associate Professor of Neurogenomics, Co-Director of TGen's Center for Noninvasive Diagnostics, and one of the review's authors. "Measurement of exRNA is appealing as a non-invasive method for monitoring disease. With increased access to biofluids, more frequent sampling can occur over time." The first test measuring exRNA was released earlier this year, the review said, for use measuring specific exRNAs in lung cancer patients. And, the potential for using RNA-seq in cancer is expanding rapidly. Commercial RNA-seq tests are now available, and provide the opportunity for clinicians to more comprehensively profile cancer and use this information to guide treatment selection for their patients, the review said. In addition, the authors reported on several recent applications for RNA-seq in the diagnosis and management of infectious diseases, such as monitoring for drug resistant populations during therapy and tracking the origin and spread of the Ebola virus. Using examples from discovery and clinical research, the authors also describe how RNA-seq can help guide interpretation of genomic DNA sequencing results. The utility of integrative sequencing strategies in research studies is growing across broad health applications, and points to the promise for incorporation of RNA-seq into clinical medicine, the review said. The paper, Translating RNA-sequencing into Clinical Diagnostics: Opportunities and Challenges, was published online today in the journal Nature Reviews Genetics. Explore further: New method reveals hidden population of regulatory molecules in cells

Chen J.C.,Columbia University | Alvarez M.J.,Columbia University | Talos F.,Columbia University | Dhruv H.,TGen | And 7 more authors.
Cell | Year: 2014

Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a framework for the systematic discovery of genetic alterations that are causal determinants of disease, by prioritizing genes upstream of functional disease drivers, within regulatory networks inferred de novo from experimental data. We tested this framework by identifying the genetic determinants of the mesenchymal subtype of glioblastoma. Our analysis uncovered KLHL9 deletions as upstream activators of two previously established master regulators of the subtype, C/EBPβ and C/EBPδ. Rescue of KLHL9 expression induced proteasomal degradation of C/EBP proteins, abrogated the mesenchymal signature, and reduced tumor viability in vitro and in vivo. Deletions of KLHL9 were confirmed in > 50% of mesenchymal cases in an independent cohort, thus representing the most frequent genetic determinant of the subtype. The method generalized to study other human diseases, including breast cancer and Alzheimer's disease. © 2014 Elsevier Inc.

Wang-Gillam A.,University of Washington | Li C.-P.,Taipei Veterans General Hospital | Bodoky G.,St. Laszlo Teaching Hospital | Dean A.,St. John of God Hospital | And 18 more authors.
The Lancet | Year: 2016

Background Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. Methods We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks, equivalent to 100 mg/m2 of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. Findings Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6·1 months (95% CI 4·8-8·9) vs 4·2 months (3·3-5·3) with fluorouracil and folinic acid (hazard ratio 0·67, 95% CI 0·49-0·92; p=0·012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4·9 months [4·2-5·6] vs 4·2 months [3·6-4·9]; 0·99, 0·77-1·28; p=0·94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). Interpretation Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. Funding Merrimack Pharmaceuticals. © 2016 Elsevier Ltd.

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