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https://www.readbyqxmd.com/read/28346540/fragment-library-screening-identifies-hits-that-bind-to-the-non-catalytic-surface-of-pseudomonas-aeruginosa-dsba1
#1
Biswaranjan Mohanty, Kieran Rimmer, Róisín M McMahon, Stephen J Headey, Mansha Vazirani, Stephen R Shouldice, Mathieu Coinçon, Stephanie Tay, Craig J Morton, Jamie S Simpson, Jennifer L Martin, Martin J Scanlon
At a time when the antibiotic drug discovery pipeline has stalled, antibiotic resistance is accelerating with catastrophic implications for our ability to treat bacterial infections. Globally we face the prospect of a future when common infections can once again kill. Anti-virulence approaches that target the capacity of the bacterium to cause disease rather than the growth or survival of the bacterium itself offer a tantalizing prospect of novel antimicrobials. They may also reduce the propensity to induce resistance by removing the strong selection pressure imparted by bactericidal or bacteriostatic agents...
2017: PloS One
https://www.readbyqxmd.com/read/28346237/current-and-future-pharmacologic-treatment-of-nonalcoholic-steatohepatitis
#2
Bubu A Banini, Arun J Sanyal
PURPOSE OF REVIEW: Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD), can progress to cirrhosis and hepatocellular cancer in 5-15% of patients and is rapidly becoming the leading cause for end-stage liver disease. Dietary caloric restriction and exercise, currently the cornerstone of therapy for NAFLD, can be difficult to achieve and maintain, underscoring the dire need for pharmacotherapy. This review presents the agents currently used in managing NAFLD and their pharmacologic targets...
March 24, 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28344315/proteomic-characterization-of-human-multiple-myeloma-bone-marrow-extracellular-matrix
#3
S V Glavey, A Naba, S Manier, K Clauser, S Tahri, J Park, M R Reagan, M Moschetta, Y Mishima, M Gambella, A Rocci, A Sacco, M E O'Dwyer, J M Asara, A Palumbo, A M Roccaro, R O Hynes, I M Ghobrial
The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared to healthy donor-derived BM ECM...
March 27, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28337147/3d-proximal-tubule-tissues-recapitulate-key-aspects-of-renal-physiology-to-enable-nephrotoxicity-testing
#4
Shelby M King, J William Higgins, Celina R Nino, Timothy R Smith, Elizabeth H Paffenroth, Casey E Fairbairn, Abigail Docuyanan, Vishal D Shah, Alice E Chen, Sharon C Presnell, Deborah G Nguyen
Due to its exposure to high concentrations of xenobiotics, the kidney proximal tubule is a primary site of nephrotoxicity and resulting attrition in the drug development pipeline. Current pre-clinical methods using 2D cell cultures and animal models are unable to fully recapitulate clinical drug responses due to limited in vitro functional lifespan, or species-specific differences. Using Organovo's proprietary 3D bioprinting platform, we have developed a fully cellular human in vitro model of the proximal tubule interstitial interface comprising renal fibroblasts, endothelial cells, and primary human renal proximal tubule epithelial cells to enable more accurate prediction of tissue-level clinical outcomes...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28337021/different-drugs-for-bad-bugs-antivirulence-strategies-in-the-age-of-antibiotic-resistance
#5
REVIEW
Seth W Dickey, Gordon Y C Cheung, Michael Otto
The rapid evolution and dissemination of antibiotic resistance among bacterial pathogens are outpacing the development of new antibiotics, but antivirulence agents provide an alternative. These agents can circumvent antibiotic resistance by disarming pathogens of virulence factors that facilitate human disease while leaving bacterial growth pathways - the target of traditional antibiotics - intact. Either as stand-alone medications or together with antibiotics, these drugs are intended to treat bacterial infections in a largely pathogen-specific manner...
March 24, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28331841/resistance-testing-for-the-treatment-of-chronic-hepatitis-c-with-direct-acting-antivirals-when-and-for-how-long
#6
Ana Belén Pérez, Natalia Chueca, Federico García
The need to test for resistance associated substitutions (RAS) has been intensively debated in the past two years. In the absence of pangenotypic combinations, it seems reasonable that, if available, RAS testing in the NS5A gene at baseline for genotypes 1a and 3 may help to avoid overtreatment in terms of ribavirin usage and/or prolonged treatment duration. When patients fail treatment, RAS testing may also be useful to guide the selection of the new regimen, especially for those that need urgent retreatment and that have failed a combination including an NS5A inhibitor...
March 2017: Germs
https://www.readbyqxmd.com/read/28325278/preclinical-and-clinical-advances-of-galnac-decorated-nucleic-acid-therapeutics
#7
REVIEW
Yuanyu Huang
A main challenge in realizing the full potential of nucleic acid therapeutics is efficient delivery of them into targeted tissues and cells. N-acetylgalactosamine (GalNAc) is a well-defined liver-targeted moiety benefiting from its high affinity with asialoglycoprotein receptor (ASGPR). By conjugating it directly to the oligonucleotides or decorating it to a certain delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28323287/experimental-medication-treatment-approaches-for-depression
#8
REVIEW
D F Ionescu, G I Papakostas
Depression is one of the most common psychiatric conditions. Symptoms can lead to significant disability, which result in impairments in overall quality of life. Though there are many approved antidepressant treatments for depression-including selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors-about a third of patients do not respond to these medications. Therefore, it is imperative for drug discovery to continue towards the development of novel and rapidly acting compounds, especially for patients with treatment-resistant depression...
March 21, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28322067/the-future-of-pre-exposure-prophylaxis-prep-for-human-immunodeficiency-virus-hiv-infection
#9
Ayşe Elif Özdener, Tae Eun Park, Julie Kalabalik, Rachna Gupta
People at high risk for HIV acquisition should be offered pre-exposure prophylaxis (PrEP). Tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) is currently the only medication recommended for pre-exposure prophylaxis (PrEP) by the Centers for Disease Control and Prevention (CDC) in people at high risk for HIV transmission. This article will review medications currently under investigation and the future landscape of PrEP therapy. Areas covered: This article will review clinical trials that have investigated nontraditional regimens of TDF/FTC, antiretroviral agents from different drug classes such as integrase strand transfer inhibitors (INSTI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) as potential PrEP therapies...
March 21, 2017: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/28319995/clinical-trials-of-therapeutics-for-the-prevention-of-congenital-zika-virus-disease-challenges-and-potential-solutions
#10
Alex P Salam, Amanda Rojek, Jake Dunning, Peter W Horby
Zika virus (ZIKV) infection in pregnancy is associated with adverse fetal outcomes, such as microcephaly and other congenital malformations. No therapeutic options are available to pregnant women with ZIKV infection to prevent these effects. Drug trials in pregnancy raise several scientific, ethical, and logistical challenges, which are compounded further in ZIKV because of limited knowledge of the disease pathophysiology and a product development pipeline in its infancy. We evaluate the major challenges in choosing therapeutics to prevent congenital ZIKV disease and conducting clinical trials of these treatments, with a focus on preventing congenital central nervous system malformations...
March 21, 2017: Annals of Internal Medicine
https://www.readbyqxmd.com/read/28319618/new-biologics-in-psoriasis-an-update-on-il-23-and-il-17-inhibitors
#11
Joanna Dong, Gary Goldenberg
As immune-related pathways involved in the pathogenesis of psoriasis are elucidated, new biologic treatments targeting these steps of the psoriatic immune cascade are developed. In this article, we review the literature on IL-23 and IL-17 inhibitors in the pipeline for use in moderate to severe psoriasis. Numerous pipeline biologic therapies, including risankizumab, guselkumab, tildrakizumab, ixekizumab, and brodalumab, are being investigated in phase 2 and 3 studies to establish the efficacy and safety of these new agents...
February 2017: Cutis; Cutaneous Medicine for the Practitioner
https://www.readbyqxmd.com/read/28317082/current-review-on-high-risk-multiple-myeloma
#12
REVIEW
Henry S H Chan, Christine I Chen, Donna E Reece
PURPOSE OF REVIEW: New risk stratification systems and treatment strategies have been introduced in recent years. We aim to provide an overview of these recent changes and summarise these data in a concise article that would be useful for clinicians. RECENT FINDINGS: Apart from clinical stage, disease genetics are now recognised as important prognostic risk factors, and various new cytogenetic changes with negative prognostic impact have been identified. New technologies such as minimal residual disease detection are also playing an important role in prognostic assessment...
March 20, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28306360/the-antibiotic-pipeline-reviving-research-and-development-and-speeding-drugs-to-market
#13
Katherine H Luepke, John F Mohr
The combination of growing antimicrobial resistance with a dry pipeline has resulted in infections that can no longer be treated. Specific reasons have led to companies' exit from the antibacterial space, however recent incentives are spurring interest to reinvigorate the pipeline. Areas Covered: This article summarizes the available information on the discovery, developmental, and regulatory challenges in antibacterial development that have led to disinterest in the space, as well as ongoing incentives such as public-private partnerships and streamlined pathways to mend these challenges and bring new antibiotics to patients in need...
March 17, 2017: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/28303005/ligand-co-crystallization-of-aminoacyl-trna-synthetases-from-infectious-disease-organisms
#14
Spencer O Moen, Thomas E Edwards, David M Dranow, Matthew C Clifton, Banumathi Sankaran, Wesley C Van Voorhis, Amit Sharma, Colin Manoil, Bart L Staker, Peter J Myler, Donald D Lorimer
Aminoacyl-tRNA synthetases (aaRSs) charge tRNAs with their cognate amino acid, an essential precursor step to loading of charged tRNAs onto the ribosome and addition of the amino acid to the growing polypeptide chain during protein synthesis. Because of this important biological function, aminoacyl-tRNA synthetases have been the focus of anti-infective drug development efforts and two aaRS inhibitors have been approved as drugs. Several researchers in the scientific community requested aminoacyl-tRNA synthetases to be targeted in the Seattle Structural Genomics Center for Infectious Disease (SSGCID) structure determination pipeline...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28301793/advances-in-rheumatoid-arthritis
#15
Graeme Jones, Peter Nash, Stephen Hall
There are now eight approved biological disease-modifying antirheumatic drugs (bDMARDs), two biosimilars and one targeted synthetic DMARD in Australia with a number of new products and biosimilars in the pipeline. bDMARDs have excellent efficacy, especially when combined with traditional DMARDs, and a well characterised but manageable safety profile. These expanded therapeutic options have revolutionised patient care and made remission (including drug free remission) a realistic goal. Evidence of a "window of opportunity" that changes the long term phenotype of the disease has been well established, so therapy should be commenced as early as possible in the disease process and a shared care model between general practitioner and rheumatologist provides the best outcomes...
March 20, 2017: Medical Journal of Australia
https://www.readbyqxmd.com/read/28301705/reprioritizing-research-activity-for-the-post-antibiotic-era-ethical-legal-and-social-considerations
#16
Spencer Phillips Hey, Aaron S Kesselheim
Many hold that the so-called golden era of antibiotic discovery has passed, leaving only a limited clinical pipeline for new antibiotics. A logical conclusion of such arguments is that we need to reform the current system of antibiotic drug research-including clinical trials and regulatory requirements-to spur activity in discovery and development. The United States Congress in the past few years has debated a number of bills to address this crisis, including the 2012 Generating Antibiotic Incentives Now Act and the 2016 21st Century Cures Act...
March 2017: Hastings Center Report
https://www.readbyqxmd.com/read/28299152/ebola-viral-disease-in-west-africa-a-threat-to-global-health-economy-and-political-stability
#17
Semeeh Akinwale Omoleke, Ibrahim Mohammed, Yauba Saidu
The West African sub-continent is currently experiencing its first, and ironically, the largest and longest Ebola viral diseases (EVD) outbreak ever documented in modern medical history. The current outbreak is significant in several ways, including longevity, magnitude of morbidity and mortality, occurrence outside the traditional niches, rapid spread and potential of becoming a global health tragedy. The authors provided explicit insights into the current and historical background, drivers of the epidemic, societal impacts, status of vaccines and drugs development and proffered recommendations to halt and prevent future occurrences...
August 17, 2016: Journal of Public Health in Africa
https://www.readbyqxmd.com/read/28298523/identification-of-c3b-binding-small-molecule-complement-inhibitors-using-cheminformatics
#18
Brandon L Garcia, D Andrew Skaff, Arindam Chatterjee, Anders Hanning, John K Walker, Gerald J Wyckoff, Brian V Geisbrecht
The complement system is an elegantly regulated biochemical cascade formed by the collective molecular recognition properties and proteolytic activities of more than two dozen membrane-bound or serum proteins. Complement plays diverse roles in human physiology, such as acting as a sentry against invading microorganisms, priming of the adaptive immune response, and removal of immune complexes. However, dysregulation of complement can serve as a trigger for a wide range of human diseases, which include autoimmune, inflammatory, and degenerative conditions...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28280889/end-points-in-heart-failure-are-we-doing-it-right
#19
REVIEW
Luxitaa Goenka, Melvin George, Sandhiya Selvarajan
PURPOSE: Heart Failure (HF) continues to be associated with high mortality and morbidity. We attempted to identify the most common end points used in phase 3 clinical trials of heart failure and discuss their merits and demerits. METHODS: Literature evaluation was done using the databases PubMed and Clinicaltrials.gov from January 2010 to December 2016 to identify randomised clinical trials (RCTs) evaluating the effect of therapeutic drugs on heart failure. Following the literature search, the data on the primary end points were extracted from each of the selected trials...
March 9, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28279838/modulation-of-sphingosine-1-phosphate-in-inflammatory-bowel-disease
#20
REVIEW
Laurent Peyrin-Biroulet, Ronald Christopher, Dominic Behan, Cheryl Lassen
Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, involve an inappropriate immune reaction in the digestive tract, causing a variety of disabling symptoms. The advent of monoclonal antibodies (anti-tumor necrosis factor, anti-integrin, anti-interleukin -23) has revolutionized IBD management. Nevertheless, these agents, with potential for immunogenicity, are associated with high rates of response loss and disease relapse over time. They are also associated with high production costs...
March 6, 2017: Autoimmunity Reviews
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