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https://www.readbyqxmd.com/read/28108251/discovery-of-7-3-piperazin-1-yl-phenyl-pyrrolo-2-1-f-1-2-4-triazin-4-amine-derivatives-as-highly-potent-and-selective-pi3k%C3%AE-inhibitors
#1
Lan-Ying Qin, Zheming Ruan, Robert J Cherney, T G Murali Dhar, James Neels, Carolyn A Weigelt, John S Sack, Anurag S Srivastava, Lyndon A M Cornelius, Joseph A Tino, Kevin Stefanski, Xiaomei Gu, Jenny Xie, Vojkan Susulic, Xiaoxia Yang, Melissa Yarde-Chinn, Stacey Skala, Ruth Bosnius, Christine Goldstein, Paul Davies, Stefan Ruepp, Luisa Salter-Cid, Rajeev S Bhide, Michael A Poss
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model...
January 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28107624/tocilizumab-alendronate-conjugate-for-treatment-of-rheumatoid-arthritis
#2
Hwiwon Lee, Suk Ho Bhang, Jeong Ho Lee, Hyemin Kim, Sei Kwang Hahn
An autoimmune disease of rheumatoid arthritis (RA) causes severe inflammation on the synovial membrane, which results in the destruction of articular cartilage and bone. Here, Tocilizumab (TCZ) - Alendronate (ALD) conjugate is synthesized for the early intervention of RA. A humanized monoclonal antibody of TCZ shows an immunosuppressive effect, targeting interleukin-6 (IL-6) receptor in the RA pathogenesis. ALD is an anti-inflammatory bisphosphonate drug which can bind to the exposed bone surface. ALD is conjugated selectively to N-glycan on Fc region of TCZ using a chemical linker of 3-(2-pyridyldithio) propionyl hydrazide (PDPH) - poly(ethylene glycol) - N-hydroxysuccinimide (PDPH-PEG-NHS)...
January 20, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28107533/improvement-of-therapeutic-efficacy-of-oral-immunotherapy-in-combination-with-regulatory-t-cell-inducer-kakkonto-in-a-murine-food-allergy-model
#3
Yuka Nagata, Takeshi Yamamoto, Michie Hayashi, Shusaku Hayashi, Makoto Kadowaki
Oral immunotherapy (OIT) has been considered a promising approach for food allergies (FAs). However, the current OIT strategy is limited in terms of the long-term efficacy and safety. We have previously demonstrated that kakkonto, a traditional Japanese herbal medicine, suppresses the occurrence of allergic symptoms in a murine model of ovalbumin (OVA)-induced FA, which is attributed to the induction of the Foxp3+ CD4+ regulatory T cells. In this study, we established an OIT model using the FA mice with already established allergic symptoms and determined whether kakkonto could improve the efficacy of OIT...
2017: PloS One
https://www.readbyqxmd.com/read/28107378/polymorphisms-in-stat4-ptpn2-psors1c1-and-traf3ip2-genes-are-associated-with-the-response-to-tnf-inhibitors-in-patients-with-rheumatoid-arthritis
#4
Paola Conigliaro, Cinzia Ciccacci, Cristina Politi, Paola Triggianese, Sara Rufini, Barbara Kroegler, Carlo Perricone, Andrea Latini, Giuseppe Novelli, Paola Borgiani, Roberto Perricone
OBJECTIVE: Rheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients...
2017: PloS One
https://www.readbyqxmd.com/read/28106666/a-tailored-guided-internet-based-cognitive-behavioral-intervention-for-patients-with-rheumatoid-arthritis-as-an-adjunct-to-standard-rheumatological-care-results-of-a-randomized-controlled-trial
#5
M Ferwerda, S van Beugen, H van Middendorp, S Spillekom-van Koulil, A R T Donders, H Visser, E Taal, M C W Creemers, P C L M van Riel, A W M Evers
For patients with chronic pain conditions such as rheumatoid arthritis (RA), who experience elevated levels of distress, tailored guided internet-based cognitive behavioral treatment may be effective in improving psychological and physical functioning, and reducing impact the impact of RA on daily life. A multicenter randomized controlled trial was conducted for RA patients with elevated levels of distress asassessed by a disease-specific measure. The control group (n=71) received standard care and the intervention group (n= 62) additionally received an internet-based tailored cognitive-behavioral intervention...
January 12, 2017: Pain
https://www.readbyqxmd.com/read/28105738/glucagon-like-peptide-1-agonists-and-risk-of-acute-pancreatitis-in-patients-with-type-2-diabetes
#6
Heidi Storgaard, Frederik Cold, Lise L Gluud, Tina Vilsbøll, Filip K Knop
Glucagon-like peptide-1 receptor agonist (GLP-1RAs) labels warn about acute pancreatitis (AP) and impose doctors to inform patients about symptoms of AP. Here we systematically reviewed the risk of AP in randomized placebo-controlled trials (RCTs) investigating the effect of GLP-1RAs in type 2 diabetes. We performed a systematic review with meta-analysis of long-term (minimum 24 months), placebo-controlled GLP-1RA RCTs in which AP was a predefined adverse event and adjudicated by blinded and independent adjudicating committees...
January 20, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28102734/fibroblast-like-synoviocytes-dependent-effector-molecules-as-a-critical-mediator-for-rheumatoid-arthritis-current-status-and-future-directions
#7
Ramamoorthi Ganesan, Mahaboobkhan Rasool
Rheumatoid arthritis (RA) is a systemic-autoimmune-mediated disease characterized by synovial hyperplasia and progressive destruction of joint. Currently available biological agents and inhibitor therapy that specifically target tumor necrosis factor-α, interleukin 1β (IL-1β), IL-6, T cells, B cells, and subcellular molecules (p38 mitogen-activated protein kinase and janus kinase) cannot facilitate complete remission in all patients and are unable to cure the disease. Therefore, further potent therapeutic targets need to be identified for effective treatment and successful clinical outcomes in patients with RA...
January 19, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/28101910/a-practical-approach-to-vaccination-of-patients-with-autoimmune-inflammatory-rheumatic-diseases-in-australia
#8
REVIEW
Peter Kk Wong, Hanish Bagga, Claire Barrett, Paddy Hanrahan, Doug Johnson, Amel Katrib, Karin Leder, Mona Marabani, Peta Pentony, John Riordan, Ray White, Laurel Young
Autoimmune inflammatory rheumatic diseases (AIIRD) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are often complicated by infection, which results in significant morbidity and mortality. The increased risk of infection is probably due to a combination of immunosuppressive effects of the AIIRD, comorbidities, and the use of immunosuppressive conventional synthetic disease modifying anti-rheumatic drugs (DMARDS) and more recently, targeted synthetic DMARDS and biologic DMARDS which block specific pro-inflammatory enzymes, cytokines or cell types...
January 19, 2017: Internal Medicine Journal
https://www.readbyqxmd.com/read/28100868/growth-inhibition-of-refractory-human-gallbladder-cancer-cells-by-retinol-and-its-mechanism-of-action
#9
Chuan Li, Masahiko Imai, Shinya Hasegawa, Masahiro Yamasaki, Noriko Takahashi
Among the constituents of the essential nutrient vitamin A, retinol is a potent suppressor of refractory cancer cell growth linked to tumor progression, showing greater efficacy than retinoic acid (RA). However, the mechanisms of retinol action on human refractory cancer are not known well. In the current study, we examined the actions of retinol on proliferation of human gallbladder cancer NOZ C-1 cells. Retinol and RA inhibited the proliferation of human NOZ C-1 cells in dose-dependent manner, while RA was less potent than retinol...
January 18, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28099214/rheumatoid-arthritis-selecting-monotherapy-versus-combination-therapy
#10
Nimish Mehta, Lynne Kolton Schneider, Emilie McCardell
The overall goal of therapy for patients with rheumatoid arthritis (RA) is to achieve low disease activity or remission and to prevent or control joint damage, prevent loss of function, and decrease pain. However, many patients with RA do not have the disease adequately controlled, and only a minority attain consistent remission. To successfully treat to target, rheumatologists need practical guidance to select monotherapy and combination therapy regimens based on available data. Differences in study design, dosing regimens, and data from defined and specific patient populations pose challenges to clinicians who treat patients with diverse characteristics and needs...
January 18, 2017: Journal of Clinical Rheumatology: Practical Reports on Rheumatic & Musculoskeletal Diseases
https://www.readbyqxmd.com/read/28099148/suberoylanilide-hydroxamic-acid-increases-anti-cancer-effect-of-tumor-necrosis-factor-%C3%AE-through-up-regulation-of-tnf-receptor-1-in-lung-cancer-cells
#11
Bo Ra You, Bo Ram Han, Woo Hyun Park
Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells...
January 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28098354/concealed-accessory-pathways-with-a-single-ventricular-and-two-discrete-atrial-insertion-sites
#12
Ryan T Kipp, Raed Abu Sham'a, Ito Hiroyuki, Frederick T Han, Marwan Refaat, Jonathan C Hsu, Michael E Field, Douglas E Kopp, Gregory M Marcus, Melvin M Scheinman, Kurt S Hoffmayer
BACKGROUND: Atrioventricular reciprocating tachycardia utilizing a concealed accessory pathway is common. It is well appreciated that some patients may have multiple accessory pathways with separate atrial and ventricular insertion sites. METHODS: We present three cases of AVRT utilizing concealed pathways with evidence that each utilizing a single ventricular insertion and two discrete atrial insertion sites. RESULTS: In case one, two discrete atrial insertion sites were mapped in two separate procedures, and only during the second ablation was the Kent potential identified...
January 18, 2017: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/28097393/comparative-efficacy-and-safety-of-baricitinib-2%C3%A2-mg-and-4%C3%A2-mg-in-patients-with-active-rheumatoid-arthritis-a%C3%A2-bayesian-network-meta-analysis-of-randomized-controlled-trials
#13
Y H Lee, S-C Bae
OBJECTIVE: This study aimed to assess the relative efficacy and safety of once-daily baricitinib 2 mg and 4 mg administration in patients with active rheumatoid arthritis (RA). METHODS: In this network meta-analysis, randomized controlled trials (RCTs) examining the efficacy and safety of baricitinib in patients with active RA were included. A Bayesian network meta-analysis was conducted to combine the direct and indirect evidence from the RCTs. RESULTS: Seven RCTs involving 3461 patients met the inclusion criteria...
January 17, 2017: Zeitschrift Für Rheumatologie
https://www.readbyqxmd.com/read/28096457/the-predictive-value-of-serum-s100a9-and-response-to-etanercept-is-not-confirmed-in-a-large-uk-rheumatoid-arthritis-cohort
#14
Samantha Louise Smith, Darren Plant, Stephen Eyre, Kimme Hyrich, Ann W Morgan, Anthony G Wilson, John D Isaacs, Anne Barton
OBJECTIVE: The aim was to correlate protein concentrations of S100A9 in pretreatment serum samples with response to the tumour-necrosis factor (TNF) inhibitor drugs etanercept in a large UK replication cohort. METHODS: Pretreatment serum samples from patients with RA (n = 236) about to commence treatment with etanercept had S100A9 serum concentration measured using an ELISA. Following the experimental procedure, S100A9 concentrations were analysed with respect to EULAR response...
January 16, 2017: Rheumatology
https://www.readbyqxmd.com/read/28094760/treat-to-target-biologic-therapy-in-patients-with-rheumatoid-arthritis-is-more-efficacious-and-safe-compared-to-delayed-initiation-of-biologics-a-real-world-study
#15
Christos E Lampropoulos, Philippos Orfanos, Menelaos N Manoussakis, Athanasios G Tzioufas, Haralampos M Moutsopoulos, Panayiotis G Vlachoyiannopoulos
OBJECTIVES: Rheumatoid arthritis (RA) is a chronic, devastating disease. Treat-to-target strategy (T2T) more than the usual care, reduces disease activity by using aggressively all therapeutic options. The aim of the study was to evaluate our hypothesis that T2T strategy using biologic disease-modifying anti-rheumatic drugs (bDMARDs), when needed, is also safer than the usual care characterised by delayed initiation of bDMARDs. METHODS: Disease activity was regularly measured by DAS-28 until the end of treatment with the first bDMARD...
January 16, 2017: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/28094753/quantifying-cutaneous-adverse-effects-of-systemic-glucocorticoids-in-patients-with-rheumatoid-arthritis-a-cross-sectional-cohort-study
#16
Jonna Amann, Anne-Marie Wessels, Friederike Breitenfeldt, Dörte Huscher, Johannes W J Bijlsma, Johannes W G Jacobs, Frank Buttgereit
OBJECTIVES: EULAR guidelines state that adverse effects (AEs) of glucocorticoid (GC) therapy should be considered and discussed with the patient before treatment is initiated. However, reliable quantitative data, especially on cutaneous AEs of low-to-medium dose GCs are lacking. We performed a study assessing the occurrence of cutaneous AEs of GCs and its association with current and cumulative GC doses in patients with rheumatoid arthritis (RA). METHODS: In a cross-sectional study performed in 2 outpatient rheumatology centres, 381 RA patients were enrolled...
January 15, 2017: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/28093980/emerging-advances-in-nanomedicine-as-a-nanoscale-pharmacotherapy-in-rheumatoid-arthritis-state-of-the-art
#17
Mahfoozur Rahman, Gajanand Sharma, Kanika Thakur, Firoz Anwar, O P Katare, Vijay G Goni, Vikas Kumar, Mazin A Zamzami, Sohail Akhter
There are several significant setbacks including limited bioavailability, high clearance, and further current therapies require higher and frequent dosing to gain desired therapeutic effects. Nanomedicines have been widely investigated for rheumatoid arthritis (RA). Though, higher doses also increase the incidence of dreadful adverse effects. Further, nanocarrier properties are tuned by the use of different approaches like varied methods of loading, hydrophilic polymers and targeting ligands, to change the physicochemical properties including higher encapsulation, better penetrating ability to biological barriers, thus preventing the uptake of various nanocarriers by liver and spleen...
2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28093699/anti-alzheimer-s-disease-activity-of-compounds-from-the-root-bark-of-morus-alba-l
#18
Eun Bi Kuk, A Ra Jo, Seo In Oh, Hee Sook Sohn, Su Hui Seong, Anupom Roy, Jae Sue Choi, Hyun Ah Jung
The inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays important roles in prevention and treatment of Alzheimer's disease (AD). Among the individual parts of Morus alba L. including root bark, branches, leaves, and fruits, the root bark showed the most potent enzyme inhibitory activities. Therefore, the aim of this study was to evaluate the anti-AD activity of the M. alba root bark and its isolate compounds, including mulberrofuran G (1), albanol B (2), and kuwanon G (3) via inhibition of AChE, BChE, and BACE1...
January 16, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28092129/bortezomib-in-the-treatment-of-antibody-mediated-rejection-in-pediatric-kidney-transplant-recipients-a-multicenter-midwest-pediatric-nephrology-consortium-study
#19
Sarah Kizilbash, Donna Claes, Isa Ashoor, Ashton Chen, Sara Jandeska, Raed Bou Matar, Jason Misurac, Joseph Sherbotie, Katherine Twombley, Priya Verghese
Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients...
January 16, 2017: Pediatric Transplantation
https://www.readbyqxmd.com/read/28091942/all-trans-retinoic-acid-supplementation-prevents-cardiac-fibrosis-and-cytokines-induced-by-methylglyoxal
#20
Umadevi Subramanian, Devipriya Nagarajan
Methylglyoxal (MG), a metabolic intermediate of glycolysis is a precursor for endogeneous production of advanced glycation end-products. The increased production of MG have negative influence over the structure and function of different biomolecules and thus plays an important role in the pathogenesis of diabetic cardiac complications. Retinoic acid (RA), an active metabolite of vitamin A, has a major role in preventing cardiac remodeling and ventricular fibrosis. Hence, the objective of the present study was to determine whether rats administered with all-trans retinoic acid (RA) could attenuate MG induced pathological effects...
January 14, 2017: Glycoconjugate Journal
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