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951.
Marco Carbone Laura Cristoferi Paolo Angelo Cortesi Matteo Rota Antonio Ciaccio Stefano Okolicsanyi Marta Gemma Luciana Scalone Giancarlo Cesana Luca Fabris Michele Colledan Stefano Fagiuoli Gaetano Ideo Luca Saverio Belli Luca Maria Munari Lorenzo Mantovani Mario Strazzabosco 《生物化学与生物物理学报:疾病的分子基础》2018,1864(4):1415-1422
Background
Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis represent the three major autoimmune liver diseases (AILDs). Their management is highly specialized, requires a multidisciplinary approach and often relies on expensive, orphan drugs. Unfortunately, their treatment is often unsatisfactory, and the care pathway heterogeneous across different centers. Disease-specific clinical outcome indicators (COIs) able to evaluate the whole cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. Aim of our study was to generate a set of COIs for the three AILDs. We then prospectively validated these indicators based on a series of consecutive patients recruited at three tertiary clinical centers in Lombardy, Italy.Methods
In phase I using a Delphi method and a RAND 9-point appropriateness scale a set of COIs was generated. In phase II the indicators were applied in a real-life dataset.Results
Two-hundred fourteen patients were enrolled and followed-up for a median time of 54 months and the above COIs were recorded using a web-based electronic medical record program. The COIs were easy to collect in the clinical practice environment and their values compared well with the available natural history studies.Conclusions
We have generated a comprehensive set of COIs which sequentially capture different clinical outcome of the three AILDs explored. These indicators represent a critical tool to implement a value-based approach to patients with these conditions, to monitor, compare and improve quality through benchmarking of clinical performance and to assess the significance of novel drugs and technologies. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. 相似文献952.
953.
Grapevine field experiments reveal the contribution of genotype,the influence of environment and the effect of their interaction (G×E) on the berry transcriptome
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Silvia Dal Santo Sara Zenoni Marco Sandri Gabriella De Lorenzis Gabriele Magris Emanuele De Paoli Gabriele Di Gaspero Cristian Del Fabbro Michele Morgante Lucio Brancadoro Daniele Grossi Marianna Fasoli Paola Zuccolotto Giovanni Battista Tornielli Mario Pezzotti 《The Plant journal : for cell and molecular biology》2018,93(6):1143-1159
954.
Yong-Jin Wu Jason Guernon Andrea McClure Brian Venables Ramkumar Rajamani Kevin J. Robbins Ronald J. Knox Michele Matchett Rick L. Pieschl James Herrington Linda J. Bristow Nicholas A. Meanwell Richard Olson Lorin A. Thompson Carolyn Dzierba 《Bioorganic & medicinal chemistry letters》2018,28(5):958-962
Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs. 相似文献
955.
956.
William R. Shadrick Peter J. Slavish Sergio C. Chai Brett Waddell Michele Connelly Jonathan A. Low Cynthia Tallant Brandon M. Young Nagakumar Bharatham Stefan Knapp Vincent A. Boyd Marie Morfouace Martine F. Roussel Taosheng Chen Richard E. Lee R. Kiplin Guy Anang A. Shelat Philip M. Potter 《Bioorganic & medicinal chemistry》2018,26(1):25-36
Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates. 相似文献
957.
Roberta Loddo Valeria Francesconi Erik Laurini Silvia Boccardo Suzana Aulic Maurizio Fermeglia Sabrina Pricl Michele Tonelli 《Bioorganic & medicinal chemistry》2018,26(4):855-868
Bovine viral diarrhea virus (BVDV) infection is still a plague that causes important livestock pandemics. Despite the availability of vaccines against BVDV, and the implementation of massive eradication or control programs, this virus still constitutes a serious agronomic burden. Therefore, the alternative approach to combat Pestivirus infections, based on the development of antiviral agents that specifically inhibit the replication of these viruses, is of preeminent actuality and importance.Capitalizing from a long-standing experience in antiviral drug design and development, in this work we present and characterize a series of small molecules based on the 9-aminoacridine scaffold that exhibit potent anti-BVDV activity coupled with low cytotoxicity. The relevant viral protein target – the RNA-dependent RNA polymerase – the binding mode, and the mechanism of action of these new antivirals have been determined by a combination of in vitro (i.e., enzymatic inhibition, isothermal titration calorimetry and site-directed mutagenesis assays) and computational experiments. The overall results obtained confirm that these acridine-based derivatives are promising compounds in the treatment of BVDV infections and, based on the reported structure-activity relationship, can be selected as a starting point for the design of a new generation of improved, safe and selective anti-BVDV agents. 相似文献
958.
Daniel Apel Michele Brunelli Mohammed El-Gahry J. Christoph Geller Bernward Lauer Marc-Alexander Ohlow 《Indian pacing and electrophysiology journal》2018,18(5):159-164
Aims
The aim of this study was to analyze whether local application of 3% hydrogen peroxide (H2O2) additionally to standard antibiotic prophylaxis following implantation of cardiac implantable electronic devices (CIED) reduces the incidence of pocket infections (PI).Methods
In this observational case-control study every patient from the group additionally treated with H2O2 was matched with two patients out of the control group for age, male-gender, body-mass-index and operation time. The incidence of PI within 365 days after device implantation was compared.Results
During the 5-year study period, 429 consecutive patients were additionally treated with H2O2 and matched with 858 patients undergoing standard treatment (mean age 69?±?12 years, 876 males (67.4%), body-mass-index 28?±?4.0?kg/m2 and operation time 45?±?23?min). Except for a more frequent use of dual-platelet-inhibition in the H2O2-group, clinical characteristics were otherwise similar. A total of 23 (1.78%) PIs occurred, most of them (14/23; 61%) during the first 45 days after implantation procedure. The use of H2O2 was associated with a significant reduction (3/429?=?0.69% versus 20/858?=?2.33%; p?=?0.04), although patients of the H2O2 treated group received more complex procedures increasing the risk of PI.Conclusion
Intraoperative local application of 3% H2O2 seems to be associated with a significant reduced incidence of PI following implantation of CIED. Because of its non-randomized character this trial should be considered as a hypothesis generating study. 相似文献959.
960.