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Shuhang Wang, Yongping Song, Feifei Yan, Delong Liu
The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy...
October 21, 2016: Frontiers of Medicine
Alan P Brown, Philip Drew, Brian Knight, Philippe Marc, Sean Troth, Kuno Wuersch, Joyce Zandee
Histopathology data comprise a critical component of pharmaceutical toxicology studies and are typically presented as finding incidence counts and severity scores per organ, tabulated on multiple pages which can be challenging for review and aggregation of results. However, the SEND (Standard for Exchange of Nonclinical Data) standard provides a means for collecting and managing histopathology data in a uniform fashion which can allow informatics systems to archive, display and analyze data in novel ways. Various software applications have become available to convert histopathology data into graphical displays for analyses...
October 18, 2016: Regulatory Toxicology and Pharmacology: RTP
Giulia Cattaneo, Daniela Ubiali, Enrica Calleri, Marco Rabuffetti, Georg C Höfner, Klaus T Wanner, Marcela C De Moraes, Leonardo K B Martinelli, Diógenes Santiago Santos, Giovanna Speranza, Gabriella Massolini
Mycobacterium tuberculosis (Mtb) purine nucleoside phosphorylase (PNP, EC has been identified as a target for the development of specific inhibitors with potential antimycobacterial activity. We hereby described the development and validation of a new 96-well LC-ESI-MS/MS method to assess the inhibition activity of nucleoside analogues towards MtbPNP and the human PNP (HsPNP). Enzyme activity was determined by monitoring the phosphorolysis of inosine (Ino) to hypoxanthine (Hpx). The enzymatic assay (v = 0...
November 2, 2016: Analytica Chimica Acta
Sanja Dacic, Liza C Villaruz, Shira Abberbock, Alyssa Mahaffey, Pimpin Incharoen, Marina N Nikiforova
Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK -FISH patterns to next -generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib...
October 17, 2016: Oncotarget
Marco A Ferraz Nogueira Filho, Cody J Peer, Jeffers Nguyen, Amy McCalla, Lee Helman, William D Figg
The Aurora kinase family facilitates cell division through various processes and is overexpressed in a wide variety of human cancers, leading to aneuploidy. For that reason, these enzymes are currently targets of a rising class of anticancer drugs, with some molecules already in therapeutic use. In this study, a new UHPLC-MS/MS method was developed and validated to quantitate a new pan Aurora kinase inhibitor still in preclinical development, SCH-1473759. This bioanalytical method employed a liquid-liquid extraction from plasma using ethyl acetate before evaporation...
October 5, 2016: Journal of Pharmaceutical and Biomedical Analysis
Kristina R Kesely, Antonella Pantaleo, Francesco M Turrini, Peter Olupot-Olupot, Philip S Low
With half of the world's population at risk for malaria infection and with drug resistance on the rise, the search for mutation-resistant therapies has intensified. We report here a therapy for Plasmodium falciparum malaria that acts by inhibiting the phosphorylation of erythrocyte membrane band 3 by an erythrocyte tyrosine kinase. Because tyrosine phosphorylation of band 3 causes a destabilization of the erythrocyte membrane required for parasite egress, inhibition of the erythrocyte tyrosine kinase leads to parasite entrapment and termination of the infection...
2016: PloS One
Aaron S Kesselheim, Wesley Eddings, Tara Raj, Eric G Campbell, Jessica M Franklin, Kathryn M Ross, Lisa A Fulchino, Jerry Avorn, Joshua J Gagne
BACKGROUND: Generic drugs are cost-effective versions of brand-name drugs approved by the Food and Drug Administration (FDA) following proof of pharmaceutical equivalence and bioequivalence. Generic drugs are widely prescribed by physicians, although there is disagreement over the clinical comparability of generic drugs to brand-name drugs within the physician community. The objective of this survey was to assess physicians' perceptions of generic drugs and the generic drug approval process...
2016: PloS One
Tonya L K Miller, Raymond Park, Lena S Sun
On April 16 and 17, 2016, the Pediatric Anesthesia and Neurodevelopment Assessment (PANDA) study held its fifth biennial symposium at the Morgan Stanley Children's Hospital of New York. The PANDA symposium has served as a key forum for clinicians, researchers, and other major stakeholders to gather and review the current state of preclinical and clinical research related to anesthetic neurotoxicity in children. Goals of the meeting included assessing how current knowledge has translated and impacted clinical care of patients who may be at risk, and future directions for research and policy...
October 2016: Journal of Neurosurgical Anesthesiology
Erik Norberg, Ana Lako, Pei-Hsuan Chen, Illana A Stanley, Feng Zhou, Scott B Ficarro, Bjoern Chapuy, Linfeng Chen, Scott Rodig, Donghyuk Shin, Dong Wook Choi, Sangho Lee, Margaret A Shipp, Jarrod A Marto, Nika N Danial
Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components...
October 21, 2016: Cell Death and Differentiation
Gianluigi Franci, Federica Sarno, Angela Nebbioso, Lucia Altucci
Epigenetic modifications are functionally involved in gene expression regulation. In particular, histone posttranslational modifications play a crucial role in functional chromatin organization. Several drugs able to inhibit or stimulate some families of proteins involved in epigenetic histone regulation have been found, a number of which are FDA-approved for the treatment of cutaneous T-cell lymphoma or are in phase I/II/III clinical trials for solid tumors. Although some protein families, such as histone deacetylases and their inhibitors, are well characterized, our understanding of histone lysine demethylases is still incomplete...
October 21, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Ryan Eshleman, Rahul Singh
BACKGROUND: Adverse drug events (ADEs) constitute one of the leading causes of post-therapeutic death and their identification constitutes an important challenge of modern precision medicine. Unfortunately, the onset and effects of ADEs are often underreported complicating timely intervention. At over 500 million posts per day, Twitter is a commonly used social media platform. The ubiquity of day-to-day personal information exchange on Twitter makes it a promising target for data mining for ADE identification and intervention...
October 6, 2016: BMC Bioinformatics
Young Joon Kwon, Marni J Falk, Michael J Bennett
CLN3 disease (Spielmeyer-Vogt-Sjogren-Batten disease, previously known as classic juvenile neuronal ceroid lipofuscinosis, NCL) is a pediatric-onset progressive neurodegenerative disease characterized by progressive vision loss, seizures, loss of cognitive and motor function, and early death. While no precise biochemical mechanism or therapies are known, the pathogenesis of CLN3 disease involves intracellular calcium accumulation that may trigger apoptosis. Our prior work in in vitro cell models of CLN3 deficiency suggested that FDA-approved calcium channel antagonists may have therapeutic value...
October 20, 2016: Journal of Inherited Metabolic Disease
Emily E Regier, Manu V Venkat, Kelly L Close
IN BRIEF Concerns raised about the cardiovascular safety of type 2 diabetes medications such as rosiglitazone prompted the U.S. Food and Drug Administration to issue draft guidance in 2008 that, in practice, has required large cardiovascular outcomes trials (CVOTs) for all new type 2 diabetes therapies. After more than 7 years and six completed and published trials to date, this is an opportune time to consider whether these studies, as currently designed and conducted, accurately assess the long-term benefit/risk profile of new therapies and whether they represent an optimal use of limited health care resources...
October 2016: Clinical Diabetes: a Publication of the American Diabetes Association
Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Andrew Silapaswan, Douglas Krakower, Kenneth H Mayer
Since FDA approval of HIV pre-exposure prophylaxis (PrEP) for HIV prevention, attention has been focused on PrEP implementation. The CDC estimates that 1.2 million U.S. adults might benefit from PrEP, but only a minority are using PrEP, so there is a significant unmet need to increase access for those at risk for HIV. Given the large numbers of individuals who have indications for PrEP, there are not enough practicing specialists to meet the growing need for providers trained in providing PrEP. Moreover, since PrEP is a preventive intervention for otherwise healthy individuals, primary care providers (PCPs) should be primary prescribers of PrEP...
October 19, 2016: Journal of General Internal Medicine
Young Kwang Chae, Lauren Chiec, Nisha Mohindra, Ryan Gentzler, Jyoti Patel, Francis Giles
Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab, now FDA-approved for use in treating several types of cancer, have been associated with immune-related adverse effects. Specifically, the antibodies targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and nivolumab, have been rarely reported to induce the development of type 1 diabetes mellitus. Here we describe a case of a patient who developed antibody-positive type 1 diabetes mellitus following treatment with pembrolizumab in combination with systemic chemotherapy for metastatic adenocarcinoma of the lung...
October 19, 2016: Cancer Immunology, Immunotherapy: CII
V R Knight-Schrijver, V Chelliah, L Cucurull-Sanchez, N Le Novère
Recent growth in annual new therapeutic entity (NTE) approvals by the U.S. Food and Drug Administration (FDA) suggests a positive trend in current research and development (R&D) output. Prior to this, the cost of each NTE was considered to be rising exponentially, with compound failure occurring mainly in clinical phases. Quantitative systems pharmacology (QSP) modelling, as an additional tool in the drug discovery arsenal, aims to further reduce NTE costs and improve drug development success. Through in silico mathematical modelling, QSP can simulate drug activity as perturbations in biological systems and thus understand the fundamental interactions which drive disease pathology, compound pharmacology and patient response...
2016: Computational and Structural Biotechnology Journal
Connie M Rhee, Csaba P Kovesdy, Kamyar Kalantar-Zadeh
Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction...
October 20, 2016: Nephron
V R Badhwar, S Ganapathy, P P Prabhudesai, N K Tulara, A Y Varaiya, D Vyas
In community and family practice, infections are a common OPD presentation. In the management of common bacterial infections seen in community especially RTI, UTI, SSTI; cefuroxime a second generation cephalosporin with a broad spectrum of activity can be used for empirical treatment. To know current place of cefuroxime in the management of infections, physicians, surgeons, microbiologist, chest physician, gynecologist and pediatrician came together to discuss and debate their experience with cefuroxime and its place in today's world...
July 2016: Journal of the Association of Physicians of India
Guang-Ming Tan, Bryan P Yan
Colchicine is a well-established drug approved by the Food and Drug Administration (FDA) for the prevention and treatment of gout. It processes unique anti-inflammatory properties. Interests in the usage of colchicine in cardiovascular medicine have been rekindled recently with several large trials been carried out to investigate its efficacy in treatment of various cardiac conditions including pericarditis, postpericardiotomy syndrome, atrial fibrillation and coronary artery disease. In this review, the basic pharmacological properties of colchicine will be discussed, and the evidences of its benefits for different applications in cardiovascular medicine will be reviewed...
October 13, 2016: Current Cardiology Reviews
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