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https://www.readbyqxmd.com/read/28431010/clinical-trial-of-the-anti-pd-l1-antibody-bms-936559-in-hiv-1-infected-participants-on-suppressive-antiretroviral-therapy
#1
Cynthia L Gay, Ronald J Bosch, Justin Ritz, Jason M Hataye, Evgenia Aga, Randall L Tressler, Stephen W Mason, Carey K Hwang, Dennis M Grasela, Neelanjana Ray, Josh C Cyktor, John M Coffin, Edward P Acosta, Richard A Koup, John W Mellors, Joseph J Eron
Background.: Reversing immune exhaustion with an anti-PD-L1 antibody may improve HIV-1-specific immunity and increase clearance of HIV-1 expressing cells. Methods.: Phase I, randomized, double-blind, placebo-controlled dose-escalating study of BMS-936559including HIV-1-infected adults ≥18 to ≤70 years on suppressive antiretroviral therapy with CD4+ counts ≥350 cells/μL and detectable plasma HIV-1 RNA by single copy assay. Data on single infusions of BMS-936559 (0...
April 18, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28430437/discovery-of-an-hcv-ns5b-replicase-palm-site-allosteric-inhibitor-bms-929075-advanced-to-phase-1-clinical-studies
#2
Kap-Sun Yeung, Brett R Beno, Kyle Parcella, John A Bender, Katherine A Grant-Young, Andrew Nickel, Prashantha Gunaga, Prakash Anjanappa, Rajesh Onkardas Bora, Kumaravel Selvakumar, Karen Rigat, Ying-Kai Wang, Mengping Liu, Julie A Lemm, Kathy Mosure, Steven Sheriff, Changhong Wan, Mark Witmer, Kevin Kish, Umesh M Hanumegowda, Xiaoliang Zhuo, Yue-Zhong Shu, Dawn Parker, Roy Haskell, Alicia Ng, Qi Gao, Elizabeth Colston, Joseph Raybon, Dennis M Grasela, Kenneth S Santone, Min Gao, Nicholas A Meanwell, Michael W Sinz, Matthew G Soars, Jay O Knipe, Susan B Roberts, John F Kadow
The hepatitis C virus NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high throughput screening hit anthranilic acid 4, the known benzofuran analog 5 and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued...
April 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28424224/novel-strategies-to-reduce-femoropopliteal-restenosis-low-dose-paclitaxel-coated-balloons-and-paclitaxel-coated-balloons-plus-stenting
#3
Andrew M Goldsweig, Herbert D Aronow
Peripheral artery disease (PAD) affects more than 200 million individuals worldwide, and those with exertional leg discomfort, rest pain, and tissue or limb loss have significantly impaired functional status and quality of life. Despite their lower associated risk of repeat revascularization, open surgical procedures have been largely supplanted by endovascular intervention for symptomatic PAD given the lower associated morbidity and mortality. Although standalone plain-old percutaneous transluminal angioplasty (PTA) was previously the standard endovascular strategy for these patients, high procedural failure and restenosis rates led to the development of new therapeutic technologies...
April 19, 2017: Circulation
https://www.readbyqxmd.com/read/28424209/the-sulfilimine-cross-link-of-collagen-iv-contributes-to-kidney-tubular-basement-membrane-stiffness
#4
Gautam Bhave, Selene Colon, Nicholas Ferrell
Basement membranes (BMs) are a specialized form of extracellular matrix (ECM) which underlie nearly all cell layers and provide structural support for tissues and interact with cell surface receptors to determine cell behavior. Both macromolecular composition and stiffness of BM influence cell-BM interactions. Collagen IV is major constituent of BM that forms an extensively cross-linked oligomeric network. Its deficiency leads to BM mechanical instability as observed with glomerular basement membrane (GBM) in Alport Syndrome...
April 19, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28415808/ikk-inhibition-by-bms-345541-suppresses-breast-tumorigenesis-and-metastases-by-targeting-gd2-cancer-stem-cells
#5
Venkata Lokesh Battula, Khoa Nguyen, Jeff Sun, Mary Kathryn Pitner, Bin Yuan, Chandra Bartholomeusz, Numsen Hail, Michael Andreeff
We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2- cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415787/knockdown-of-p4ha1-inhibits-neovascularization-via-targeting-glioma-stem-cell-endothelial-cell-transdifferentiation-and-disrupting-vascular-basement-membrane
#6
Yiqiang Zhou, Guishan Jin, Ruifang Mi, Junwen Zhang, Jin Zhang, Hengzhou Xu, Sen Cheng, Yunsheng Zhang, Wenjie Song, Fusheng Liu
Emerging evidence has demonstrated transdifferentiation process of glioma stem cells (GSCs) into endothelial cells (ECs) in glioma neovascularization. Herein, we focused on screening for genes that were differentially expressed in the transdifferentiation process using microarray analysis. Bioinformatics analysis revealed differential expression of the prolyl 4-hydroxylase subunit alpha-1 (P4HA1) gene. We determined that P4HA1 expression was correlated with histological grade, the level of Ki67 and microvessel density (MVD) in human glioma specimens...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28412183/structure-activity-relationship-analysis-of-mitochondrial-toxicity-caused-by-antiviral-ribonucleoside-analogs
#7
Zhinan Jin, April Kinkade, Ishani Behera, Shuvam Chaudhuri, Kathryn Tucker, Natalia Dyatkina, Vivek K Rajwanshi, Guangyi Wang, Andreas Jekle, David B Smith, Leo Beigelman, Julian A Symons, Jerome Deval
Recent cases of severe toxicity during clinical trials have been associated with antiviral ribonucleoside analogs (e.g. INX-08189 and balapiravir). Some have hypothesized that the active metabolites of toxic ribonucleoside analogs, the triphosphate forms, inadvertently target human mitochondrial RNA polymerase (POLRMT), thus inhibiting mitochondrial RNA transcription and protein synthesis. Others have proposed that the prodrug moiety released from the ribonucleoside analogs might instead cause toxicity. Here, we report the mitochondrial effects of several clinically relevant and structurally diverse ribonucleoside analogs including NITD-008, T-705 (favipiravir), R1479 (parent nucleoside of balapiravir), PSI-7851 (sofosbuvir), and INX-08189 (BMS-986094)...
April 12, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28411244/long-term-follow-up-of-the-padi-trial-percutaneous-transluminal-angioplasty-versus-drug-eluting-stents-for-infrapopliteal-lesions-in-critical-limb-ischemia
#8
Marlon I Spreen, Jasper M Martens, Bob Knippenberg, Lukas C van Dijk, Jean-Paul P M de Vries, Jan Albert Vos, Gert Jan de Borst, Evert-Jan P A Vonken, Okker D Bijlstra, Jan J Wever, Randolph G Statius van Eps, Willem P Th M Mali, Hendrik van Overhagen
BACKGROUND: Clinical outcomes reported after treatment of infrapopliteal lesions with drug-eluting stents (DESs) have been more favorable compared with percutaneous transluminal angioplasty with a bailout bare metal stent (PTA-BMS) through midterm follow-up in patients with critical limb ischemia. In the present study, long-term results of treatment of infrapopliteal lesions with DESs are presented. METHODS AND RESULTS: Adults with critical limb ischemia (Rutherford category ≥4) and infrapopliteal lesions were randomized to receive PTA-BMS or DESs with paclitaxel...
April 14, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28409156/curcumin-analogue-ca15-exhibits-anticancer-effects-on-hep-2-cells-via-targeting-nf-%C3%AE%C2%BAb
#9
Jian Chen, Linlin Zhang, Yilai Shu, Liping Chen, Min Zhu, Song Yao, Jiabing Wang, Jianzhang Wu, Guang Liang, Haitao Wu, Wulan Li
Laryngeal carcinoma remains one of the most common malignancies, and curcumin has been proven to be effective against head and neck cancers in vitro. However, it has not yet been applied in clinical settings due to its low stability. In the current study, we synthesized 34 monocarbonyl analogues of curcumin with stable structures. CA15, which exhibited a stronger inhibited effect on laryngeal cancer cells HEp-2 but a lower toxicity on hepatic cells HL-7702 in MTT assay, was selected for further analysis. The effects of CA15 on cell viability, proliferation, migration, apoptosis, and NF-κB activation were measured using MTT, Transwell migration, flow cytometry, Western blot, and immunofluorescence assays in HEp-2 cells...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28406018/synthesis-of-hiv-maturation-inhibitor-bms-955176-from-betulin-by-an-enabling-oxidation-strategy
#10
Adrian Ortiz, Maxime Soumeillant, Scott A Savage, Neil A Strotman, Matthew Haley, Tamas Benkovics, Jeffrey Nye, Zhongmin Xu, Yichen Tan, Sloan Ayers, Qi Gao, Susanne Kiau
A concise and scalable 2nd generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a CuI mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps, 47% overall yield, and begins from the abundant and inexpensive natural product betulin...
April 13, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28405802/vasculo-protective-effect-of-bms-309403-is-independent-of-its-specific-inhibition-of-fatty-acid-binding-protein-4
#11
Yuta Okamura, Kosuke Otani, Akihiro Sekiguchi, Taisuke Kogane, Chiharu Kakuda, Yuzaburo Sakamoto, Tomoko Kodama, Muneyoshi Okada, Hideyuki Yamawaki
Fatty acid-binding protein (FABP) 4 is an adipocytokine mainly expressed in adipocyte and macrophage. Blood FABP4 is related not only to metabolic disorders including insulin resistance and atherosclerosis but also increased blood pressure. We tested the hypothesis that FABP4 plays roles in pathogenesis of hypertension development including proliferation, migration, and inflammation of vascular smooth muscle cells (SMCs) as well as contractile reactivity. FABP4 alone had no influence on proliferation, migration, and inflammation of rat mesenteric arterial SMCs, while it significantly enhanced smooth muscle contraction and increases of systolic blood pressure (SBP) induced by noradrenaline (NA)...
April 13, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28404622/choice-of-stent-for-percutaneous-coronary-intervention-of-saphenous-vein-grafts
#12
Javaid Iqbal, Chun Shing Kwok, Evangelos Kontopantelis, Mark A de Belder, Peter F Ludman, Adrian Large, Rob Butler, Amr Gamal, Tim Kinnaird, Azfar Zaman, Mamas A Mamas
BACKGROUND: There are limited data on comparison of contemporary drug-eluting stent (DES) platforms, previous generation DES, and bare-metal stents (BMS) for percutaneous coronary intervention in saphenous vein grafts (SVG). We aimed to assess clinical outcomes following percutaneous coronary intervention to SVG in patients receiving bare-metal stents (BMS), first-generation DES, and newer generation DES in a large unselected national data set from the BCIS (British Cardiovascular Intervention Society)...
April 2017: Circulation. Cardiovascular Interventions
https://www.readbyqxmd.com/read/28403786/immune-checkpoint-inhibitors-and-cardiac-toxicity-an-emerging-issue
#13
Gilda Varricchi, Giancarlo Marone, Valentina Mercurio, Maria Rosaria Galdiero, Domenico Bonaduce, Carlo G Tocchetti
Although survival of patients with different types of cancer has improved, cardiotoxicity induced by anti-neoplastic drugs remains a critical issue. Cardiac dysfunction after treatment with anthracyclines has historically been a major problem. However, also targeted therapies and biological molecules can induce reversible and irreversible cardiac dysfunction. Cancer immunotherapies over the last years have revolutionized the clinical management of a wide spectrum of solid and hematopoietic malignancies previously endowed with poor prognosis...
April 7, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28401421/redox-active-transition-metal-ions-make-melanin-susceptible-to-chemical-degradation-induced-by-organic-peroxide
#14
Andrzej Zadlo, Anna Pilat, Michal Sarna, Anna Pawlak, Tadeusz Sarna
With aging, retinal pigment epithelium melanosomes, by fusion with the age pigment lipofuscin, form complex granules called melanolipofuscin. Lipofuscin granules may contain oxidized proteins and lipid hydroperoxides, which in melanolipofuscin could chemically modify melanin polymer, while transition metal ions present in melanin can accelerate such oxidative modifications. The aim of this research was to examine the effect of selected transition metal ions on melanin susceptibility to chemical modification induced by the water-soluble tert-butyl hydroperoxide used as an oxidizing agent...
April 11, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28395947/efficacy-of-bone-marrow-stimulating-technique-in-rotator-cuff-repair
#15
Kerem Bilsel, Fatih Yildiz, Mehmet Kapicioglu, Gokcer Uzer, Mehmet Elmadag, Anil Pulatkan, Mukaddes Esrefoglu, Ergun Bozdag, Giuseppe Milano
BACKGROUND: This study used a chronic rotator cuff (RC) tear model to investigate the effect of microfracture as a bone marrow-stimulating (BMS) technique for RC healing. METHODS: A chronic retracted RC tendon tear model was created bilaterally in the subscapularis tendons of 20 New Zealand rabbits. The tendons were repaired after 8 weeks using a single-row configuration. Tendons in the right shoulder were repaired in standard fashion (control group). Microfractures were performed in the left shoulders before repair (microfracture group)...
April 7, 2017: Journal of Shoulder and Elbow Surgery
https://www.readbyqxmd.com/read/28394130/revisiting-a-classic-transformation-a-lossen-rearrangement-initiated-by-nitriles-and-pseudo-catalytic-in-isocyanate
#16
Neil A Strotman, Adrian Ortiz, Scott A Savage, Christopher R Wilbert, Sloan Ayers, Susanne Kiau
The direct conversion of a hydroxamic acid to an amine has been accomplished in a single step in the synthesis of HIV drug candidate BMS-955176. This process utilizes catalytic base and proceeds under mild conditions (CH3CN, cat. DBU, 60 °C), without the need for strong electrophiles required for typical Lossen rearrangements, and can be applied to aliphatic and aromatic hydroxamic acids. Through investigation of the kinetics of this transformation, a mechanism was revealed involving a novel initiation pathway and a self-propagation cycle...
April 12, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28392837/denosumab-treatment-in-the-management-of-patients-with-advanced-prostate-cancer-clinical-evidence-and-experience
#17
REVIEW
Miriam Hegemann, Jens Bedke, Arnulf Stenzl, Tilman Todenhöfer
Osteoprotective therapies have become an essential component in the management of advanced prostate cancer (PC) patients as bone metastases (BMs) have a major impact on morbidity and mortality. Denosumab is a fully humanized antibody targeting the receptor activator of nuclear factor κB ligand (RANKL), which has been approved by the European Medicines Agency (EMA) in Europe and the United States (US) Food and Drug Administration (FDA) in the US for prevention of skeletal-related events (SREs) in patients with solid tumors and BMs, including PC...
March 2017: Therapeutic Advances in Urology
https://www.readbyqxmd.com/read/28390603/velopharyngeal-insufficiency-managed-by-autologous-fat-grafting-in-patients-with-aberrant-courses-of-internal-carotid-arteries
#18
Emilie Bois, Charlotte Celerier, Kahina Belhous, Michel Maulet, Nicolas Leboulanger, Noël Garabedian, Françoise Denoyelle
INTRODUCTION: Velopharyngeal insufficiency (VPI) is usually managed, besides speech therapy, by performing a velopharyngoplasty. An alternative approach is autologous fat grafting (AFG) of the posterior pharyngeal wall. About 5% of the population has internal carotid arteries (ICA) with an aberrant course. This anatomic variation can be responsible for surgical difficulties while when performing a velopharyngoplasty, and therefore lead surgeons to only consider a speech reeducation of VPI...
May 2017: International Journal of Pediatric Otorhinolaryngology
https://www.readbyqxmd.com/read/28390063/psychological-profiles-in-patients-with-symptomatic-reticular-forms-of-oral-lichen-planus-a-prospective-cohort-study
#19
Daniela Adamo, Marco Cascone, Antonio Celentano, E Ruoppo, Stefania Leuci, Massimo Aria, Michele D Mignogna
OBJECTIVES: To analyze intra, extra-oral symptoms and psychological profiles in symptomatic patients with reticular (R) forms of oral lichen planus (OLP). MATERIALS AND METHODS: Thirty symptomatic R-OLP (sR-OLP) patients were compared with an equal number of non-symptomatic R-OLP (nsR-OLP) patients, burning mouth syndrome (BMS) patients and healthy subjects (HS). The Numeric Rating Scale (NRS), the Total Pain Rating Index (T-PRI) and the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) were administered...
April 8, 2017: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/28369474/marketing-of-breast-milk-substitutes-in-zambia-evaluation-of-compliance-to-the-international-regulatory-code
#20
P Funduluka, S Bosomprah, R Chilengi, R H Mugode, P A Bwembya, B Mudenda
Background: We sought to assess the level of non-compliance with the International Code of Marketing breast-milk substitutes (BMS) and/or Statutory Instrument (SI) Number 48 of 2006 of the Laws of Zambia in two suburbs, Kalingalinga and Chelstone, in Zambia. Methods: This was a cross sectional survey. Shop owners (80), health workers (8) and mothers (214) were interviewed. BMS labels and advertisements (62) were observed. The primary outcome was mean non-compliance defined as the number of article violations divided by the total 'obtainable' violations...
March 25, 2017: Journal of Public Health
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