Search

The purpose of this study was to determine whether cis-dichlorodiammineplatinum (cisplatin) causes mitochondrial DNA (mtDNA) damage. A specific and sensitive method for quantitation of damage to mtDNA was used, by which the physical forms of mtDNA (supercoiled, open circular and linear forms) were separated by gel electrophoresis. The DNA specificity was then obtained by hybridizing with a mtDNA probe. In vitro incubation of mtDNA with cisplatin showed that the drug did not induce any changes in the proportion of physical forms; similar results were obtained in vivo. Since cisplatin did not cause any strand scission in mtDNA but induces strand breaks in nuclear DNA, which is an indirect effect, a lack of repair for cisplatin-induced adducts in mtDNA is suggested. [ABSTRACT FROM AUTHOR]

We introduce a generalized trace functional TR in the spirit of Kontsevich and Vishik's canonical trace for classical SG-pseudodifferential operators on [ABSTRACT FROM AUTHOR]

Ca2+, as a messenger of signal transduction, regulates numerous target molecules via Ca2+-induced conformational changes. Investigation into the determinants for Ca2+-induced conformational change is often impeded by cooperativity between multiple metal-binding sites or protein oligomerization in naturally occurring proteins. To dissect the relative contributions of key determinants for Ca2+-dependent conformational changes, we report the design of a single-site Ca2+-binding protein (CD2.trigger) created by altering charged residues at an electrostatically sensitive location on the surface of the host protein rat Cluster of Differentiation 2 (CD2). CD2.trigger binds to Tb3+ and Ca2+ with dissociation constants of 0.3 ± 0.1 and 90 ± 25 μm, respectively. This protein is largely unfolded in the absence of metal ions at physiological pH, but Tb3+ or Ca2+ binding results in folding of the native-like conformation. Neutralization of the charged coordination residues, either by mutation or protonation, similarly induces folding of the protein. The control of a major conformational change by a single Ca2+ ion, achieved on a protein designed without reliance on sequence similarity to known Ca2+-dependent proteins and coupled metal-binding sites, represents an important step in the design of trigger proteins. [ABSTRACT FROM AUTHOR]

Background: In order to better understand the perspectives of patients and physicians regarding the treatment and management of rheumatoid arthritis (RA), we present and compare results from a patient-based and a physician-based survey developed by the RA NarRAtive advisory panel.Methods: The RA NarRAtive initiative is directed by a global advisory panel of 39 healthcare providers and patient organization leaders from 17 countries. A survey of patients self-reporting a diagnosis of RA and a physician-based survey, designed by the advisory panel, were fielded online by Harris Poll from September 2014 to April 2016, and from August 2015 to October 2015, respectively.Results: We present findings from 1805 patients whose RA was primarily managed by a rheumatologist, and 1736 physicians managing patients with RA. Results confirmed that RA carries a substantial disease burden; half of the patients surveyed reported stopping participation in certain activities as a result of their disease. While 90% of physicians were satisfied with their communications with their patients regarding RA treatment, 61% of patients felt uncomfortable raising concerns or fears with their physician. Of the patients providing responses, 52% felt that improved dialogue/discussion would optimize their RA management, and 68% of physicians wished that they and their patients talked more about their RA goals and treatment. Overall, 88% of physicians agreed that patients involved in making treatment decisions tend to be more satisfied with their treatment experience.Conclusion: The results of these surveys highlight the impact of RA on patients, and a discrepancy between patient and physician views on communication. Further research, focused on improving patient-physician dialogue, shared goal-setting, and treatment planning, is needed. [ABSTRACT FROM AUTHOR]

La douleur est un symptôme prédominant du rhumatisme psoriasique (RP). L'efficacité et la tolérance d'upadacitinib (UPA) ont été démontrées chez des patients atteint de RP actif lors des études SELECT-PsA 1 et 2. Cette analyse vise à comparer l'efficacité d'UPA sur la douleur vs placebo (PBO) et adalimumab (ADA) au cours des 24 premières semaines. Le programme SELECT-PsA a inclus des patients adultes atteint de RP actif et ayant présenté une réponse inadéquate (RI) ou une intolérance à ≥ 1 DMARD non biologique (SELECT-PsA 1) ou une RI ou une intolérance à ≥ 1 DMARD biologique (SELECT-PsA 2). Les patients ont été randomisés pour recevoir 15 mg ou 30 mg d'UPA une fois par jour (1×/j) ou un PBO (dans les deux études) ou 40 mg d'ADA toutes les 2 semaines (/2 sem ; SELECT-PsA 1 uniquement). La douleur était évaluée par la proportion de patients obtenant une diminution ≥ 30 %, ≥ 50 % ou ≥ 70 % du score (0–10) d'évaluation globale par le patient (PGA) de la douleur sur une échelle numérique (EN) par rapport à l'inclusion (BL), la proportion de patients obtenant une différence minimale cliniquement importante (MCID) des douleurs (diminution ≥ 1 point ou de 15 % du score sur l'EN 0–10 par rapport à BL) et la variation du score sur l'EN de la douleur (0–10) par rapport à BL à chaque évaluation. De plus, la variation du score des questions 2 et 3 du BASDAI et des questions 7 et 8 du SF-36 (36-Item Short Form Survey) a été évaluée aux semaines 12 et 24 par rapport à BL. Une proportion significativement plus élevée des patients des 2 études traités par UPA 15 mg 1×/j et UPA 30 mg 1x/j a obtenu une amélioration de la plupart des critères de douleur dès la semaine 2 vs PBO. Cette amélioration était généralement maintenue ou accrue jusqu'à la semaine 24 (p nominal < 0,05 ; Fig. 1 et 2). Une amélioration significative a également été observée sous UPA vs PBO concernant la variation par rapport à BL du score PGA sur l'EN de la douleur au cours du temps, ainsi que des scores BASDAI de douleurs rachidiennes et gonflement/douleurs articulaires et SF-36 de douleurs physiques et gêne induite par la douleur aux semaines 12 et 24 (Fig. 1 et 2). Lors de SELECT-PsA 1, le taux de patients obtenant une amélioration de la plupart des critères d'évaluation de la douleur était significativement plus élevé sous UPA 30 mg 1×/j vs ADA 40 mg/2 sem, dès la semaine 2 et jusqu'à la semaine 24 ; l'amélioration de plusieurs mesures était de même significativement plus importante sous UPA 15 mg 1×/j vs ADA 40 mg/2 sem à la semaine 24 (p nominal < 0,05 ; Fig. 1). Chez les patients atteint de RP actif et ayant présenté une réponse inadéquate aux DMARD biologiques ou non biologiques, le taux obtention d'une réduction rapide, importante et cliniquement significative de la douleur, évaluée par de multiples critères, était significativement plus élevé sous UPA vs PBO ; et maintenue pendant 24 semaines. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the effect of upadacitinib on pain outcomes in patients with active psoriatic arthritis (PsA) or ankylosing spondylitis (AS) across 3 randomised trials (SELECT-PsA 1 and 2 for PsA; SELECT-AXIS 1 for AS)., Methods: Patients were randomised to upadacitinib 15 mg once daily or placebo (all 3 studies), or adalimumab 40 mg every other week (SELECT-PsA 1 only). Pain outcomes included proportion of patients achieving ≥30%, ≥50% and ≥70% reduction from baseline in patient global assessment of pain and other end points., Results: A higher proportion of patients receiving upadacitinib versus placebo achieved ≥30%, ≥50% and ≥70% reduction in pain end points as early as week 2; these improvements with upadacitinib were generally sustained or increased through year 1 (PsA 1/2 studies: 64%/48%, 58%/42% and 38%/22%, respectively; SELECT-AXIS 1 study: 76%, 72% and 54%). Results were similar with adalimumab in PsA 1 (59%, 49% and 32%). Patients who switched from placebo to upadacitinib 15 mg were able to reach a similar level of improvement as the continuous upadacitinib groups by year 1 (PsA 1/2 studies: 46%-60%, 35%-49% and 15%-34%; AS study: 83%, 72% and 46%). Results were similar with other pain end points., Conclusion: Rapid and sustained improvements in pain outcomes across several end points were consistently shown with upadacitinib over 1 year in patients with active PsA or AS who had either inadequate response to prior non-biologic or biologic disease-modifying antirheumatic drugs (PsA studies) or were biologic-naïve with inadequate response to non-steroidal anti-inflammatory drugs (AS study)., Competing Interests: Competing interests: IBM has received research grants, and/or consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers, Celgene, Janssen, Leo, Lilly, Novartis, Pfizer and UCB. AJKO has served as a consultant and/or on advisory boards for AbbVie, BMS, Gilead, Roche, Janssen, Lilly, Novartis, Paradigm, Pfizer and UCB. PJM has received research grants, consulting fees and/or speaker’s fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers, Celgene, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Leo, Lilly, Merck, Novartis, Pfizer, Sun Pharma and UCB. WT has served on advisory boards or as a consultant or received speaker fees from AbbVie, Amgen, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer and UCB. XB has received honoraria and consultancy fees from AbbVie, Amgen, BMS, Chugai, Galapagos, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz and UCB. KdV has received grant/research support from Celgene and Galapagos; consultancy fees from Celgene, Eli Lilly, Galapagos, Novartis and UCB; and speaker fees from Celgene, Eli Lilly, Galapagos, Novartis and UCB. LB has received grant/research support from AbbVie, Amgen, BMS, Celgene, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, Sanofi and UCB; received speaker fees from AbbVie, Amgen, BMS, Celgene, Fresenius Kabi, Janssen, Lilly, Merck, Novartis, Pfizer, Sanofi, Teva and UCB; and served as an officer or board member for AbbVie, Amgen, BMS, Celgene, Fresenius Kabi, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, Sanofi and UCB. RL, AM, DF, TG, PZ, CS, KK and I-HS are full-time, salaried employees of AbbVie and may own AbbVie stock or stock options. AD has received research grants, consultancy fees, speaker fees and other support (medical writing support) from Novartis and Pfizer; research grants, consultancy fees and other support (medical writing support) from AbbVie, Eli Lilly and UCB Pharma; research grants and consultancy fees from GlaxoSmithKline; consultancy fees and other support (medical writing support) from Galapagos and Janssen; consultancy fees from Boehringer Ingelheim and Celgene; and other support (medical writing support) from Amgen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)