tbuckley/cabot-search huggingface dataset:
Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity
Authors: Rohit Sharma, Bryn Reinstadler, Kristin Engelstad, Owen S. Skinner, Erin Stackowitz, Ronald G. Haller, Clary B. Clish, Kerry Pierce, Melissa A. Walker, Robert Fryer, Devin Oglesbee, Xiangling Mao, Dikoma C. Shungu, Ashok Khatri, Michio Hirano, Darryl C. De Vivo, Vamsi K. Mootha
Journal: Journal of Clinical Investigation (2021)

Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.3243A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.3243A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, α-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, β-hydroxy acylcarnitines, and β-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease.
THU0069 Relationships between synovial fluid metalloproteinases and interleukin-1b, and serum crp in osteoarthritis of the knee
Authors: M Pianon, L Punzi, A Pozzuoli, F Oliviero, GP Salvati, C Valvason, S Todesco
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Interleukin (IL)-1 and metalloproteinases (MMP) are thought to play a crucial role in the cartilage degradation of osteoarthritis (OA). Recently it has been proposed that CRP may be useful index of OA activity and severity. <h3>Objectives</h3> We studied the relationships between synovial fluid (SF) IL-1b, MMP1 and MMP3, and serum levels of CRP in patients with OA of the knee (KOA) to investigate the role of CRP in KOA. <h3>Methods</h3> In the SF from 25 patients with KOA (Altman criteria, Kellgren and Lawrence score of 2 or greater on X-ray plan films) we determined the levels of IL-1b, MMP-1 and MMP-3 (ELISA), along with WBC number. In the same patients serum concentration of CRP was analysed by ultrasensitive rate nephelometry. No patients were taking NSAIDs or other antirheumatic drugs. <h3>Results</h3> In SF, MMP1 was correlated with MMP3 (r = 0.61, p = 0.0009), and MMP3 with IL-1b (r = 0.67, p = 0.0002). In turn, serum CRP was correlated with MMP3 (r = 0.76, p &lt; 0.0001) and, at lower level, with MMP1 (r = 0.49, p = 0.01) and IL-1b (r = 0.49, p = 0.01). <h3>Conclusion</h3> The correlations found between serum CRP and SF levels of substances believed to be crucial in OA cartilage degradation, such as MMPs and IL-1, confirm the role of marker of disease severity recently proposed for this acute phase protein.
Designing and undertaking randomised implementation trials: guide for researchers
Authors: Luke Wolfenden, Robbie Foy, Justin Presseau, Jeremy M Grimshaw, Noah M Ivers, Byron J Powell, Monica Taljaard, John Wiggers, Rachel Sutherland, Nicole Nathan, Christopher M Williams, Melanie Kingsland, Andrew Milat, Rebecca K Hodder, Sze Lin Yoong
Journal: BMJ (2021)

Implementation science is the study of methods to promote the systematic uptake of evidence based interventions into practice and policy to improve health. Despite the need for high quality evidence from implementation research, randomised trials of implementation strategies often have serious limitations. These limitations include high risks of bias, limited use of theory, a lack of standard terminology to describe implementation strategies, narrowly focused implementation outcomes, and poor reporting. This paper aims to improve the evidence base in implementation science by providing guidance on the development, conduct, and reporting of randomised trials of implementation strategies. Established randomised trial methods from seminal texts and recent developments in implementation science were consolidated by an international group of researchers, health policy makers, and practitioners. This article provides guidance on the key components of randomised trials of implementation strategies, including articulation of trial aims, trial recruitment and retention strategies, randomised design selection, use of implementation science theory and frameworks, measures, sample size calculations, ethical review, and trial reporting. It also focuses on topics requiring special consideration or adaptation for implementation trials. We propose this guide as a resource for researchers, healthcare and public health policy makers or practitioners, research funders, and journal editors with the goal of advancing rigorous conduct and reporting of randomised trials of implementation strategies.
Immune dysregulation as a driver of idiopathic pulmonary fibrosis
Authors: Kevin Shenderov, Samuel L. Collins, Jonathan D. Powell, Maureen R. Horton
Journal: Journal of Clinical Investigation (2021)

Idiopathic pulmonary fibrosis (IPF) affects hundreds of thousands of people worldwide, reducing their quality of life and leading to death from respiratory failure within years of diagnosis. Treatment options remain limited, with only two FDA-approved drugs available in the United States, neither of which reverse the lung damage caused by the disease or prolong the life of individuals with IPF. The only cure for IPF is lung transplantation. In this review, we discuss recent major advances in our understanding of the role of the immune system in IPF that have revealed immune dysregulation as a critical driver of disease pathophysiology. We also highlight ways in which an improved understanding of the immune system’s role in IPF may enable the development of targeted immunomodulatory therapies that successfully halt or potentially even reverse lung fibrosis.
A phase I/II study of safety and efficacy of the arginase inhibitor INCB001158 plus chemotherapy in patients (Pts) with advanced biliary tract cancers.
Authors: Milind M. Javle, John A. Bridgewater, Olumide B. Gbolahan, Christiane Jungels, May Thet Cho, Kyriakos P. Papadopoulos, Fiona C. Thistlethwaite, Jean-Luc Re Canon, Lulu Cheng, Sonia Ioannidis, Sven Gogov, Aung Naing
Journal: Journal of Clinical Oncology (2021)

311 Background: Arginase, secreted in the tumor microenvironment by myeloid suppressor cells, is a major regulator of arginine-mediated immune response. Arginase inhibition by INCB001158 increases arginine, which reverses the immunosuppressive effects of neutrophils and myeloid-derived suppressor cells on T cells. The current standard first-line (1L) treatment for advanced biliary tract cancers (BTC) is gemcitabine/cisplatin chemotherapy. The combination of INCB001158 immunotherapy and standard 1L treatment may provide additional clinical benefit in pts with advanced or metastatic BTC. Methods: This open-label phase 1/2 study evaluated the safety, tolerability, and antitumor activity of INCB001158 in pts with advanced or metastatic solid tumors. In phase I, dose escalation of INCB001158 (50, 75, and 100 mg twice daily [BID]) was used to determine the recommended phase II dose (RP2D) of INCB001158 + gemcitabine/cisplatin. Phase II used a Simon 2-stage design and evaluated objective response rate (ORR; RECIST v1.1), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) of INCB001158 RP2D + gemcitabine (1000 mg/m 2 )/cisplatin (25 mg/m 2 Days 1 and 8 of 21-day cycle). Here we report preliminary safety and activity from the cohort of pts with BTC. Results: The phase I dose-escalation group identified a RP2D for INCB001158 of 100 mg BID. At a data cutoff of July 1, 2020, 33 pts with BTC in phase II treated with INCB001158 100 mg BID + gemcitabine/cisplatin were evaluable. Adverse events (AEs) related to INCB001158 and/or chemotherapy occurred in 88% of pts and 73% of pts had AEs related specifically to INCB001158 (Table). Treatment was interrupted due to INCB001158-related TEAEs in 30% of pts (n=10); discontinuation related to INCB001158 occurred in 3% (n=1). Treatment did not result in immune-related or significant additive chemotherapy-associated toxicity. ORR was 24% (8/33; 95% CI, 11.1–42.3) based on confirmed response per investigator’s assessment; stable disease occurred in 42% of pts. Median DOR (95% CI) was 5.8 (4.1–not reached) mo, and the DCR was 67%. Median PFS (95% CI) was 8.5 (5.7–10.1) mo. Conclusions: Preliminary data suggest the combination of INCB001158 100 mg BID + gemcitabine/cisplatin was tolerable and did not result in significant added toxicity. Response rates and PFS suggest that some pts with BTC may benefit from this combination. Clinical trial information: NCT03314935. [Table: see text]
Disease-free and overall survival in nonmetastatic esophageal or gastroesophageal junctional cancer after treatment with curative intent: A nationwide population-based study.
Authors: Marieke Pape, Pauline A.J. Vissers, Laurens Beerepoot, Mark I. Van Berge Henegouwen, Sjoerd Lagarde, Stella Mook, David Bertwistle, Laura McDonald, Hanneke W.M. Van Laarhoven, Rob Verhoeven
Journal: Journal of Clinical Oncology (2021)

246 Background: Among patients with potentially curable esophageal cancer (EC) or gastroesophageal junctional cancer (GEJC) treated with curative intent, survival remains poor and around half of these patients have disease recurrence within a few years. This study addresses the need for real-world data on disease-free survival (DFS) and overall survival (OS) in patients with EC or GEJC who underwent potentially curative treatment. Methods: Patients selected from the nationwide Netherlands cancer registry (NCR) had received a primary diagnosis of non-metastatic EC or GEJC (excluding patients with T4b tumors) in 2015 or 2016 and received treatment with curative intent. Curative intent was defined as receiving resection (with or without [neo]adjuvant therapy) or definitive chemoradiotherapy (dCRT) without surgery. DFS and OS were analysed using Kaplan-Meier curves with Log-Rank test from resection date or end of dCRT. A sub-analysis was performed for NCR patients selected to align with the population of the CheckMate-577 phase 3 study of adjuvant nivolumab, i.e. patients with non-cervical stage II/III disease, R0 resection and residual pathological disease after neoadjuvant CRT (nCRT) and surgery. Results: We identified 1916 patients of median age of 67 years and predominantly male (76%). The majority (79%) received surgery and 21% of patients received dCRT. In resected patients, 83% received nCRT, 10% neoadjuvant chemotherapy (with or without adjuvant CRT) and 7% received no (neo)adjuvant treatment. Compared to the resected group, the population receiving dCRT had significantly fewer males (65% vs 78%), a higher median age (72 vs 65 years) and worse performance status. Patients receiving dCRT significantly shorter median DFS (14.2 months) and OS (20.9 months) compared to resected patients (DFS: 26.4 months, p &lt; 0.001; OS: 40.5 months, p &lt; 0.001). The 1- and 3-year DFS probabilities were 68% and 44%, respectively, in resected patients, and 56% and 24%, respectively, in patients receiving dCRT. In patients receiving nCRT followed by surgery, the median DFS and OS were 25.2 and 38.0 months, respectively, and 1- and 3-year DFS probabilities were 67% and 43%, respectively. In the sub-analysis (n = 725) the median DFS and OS were 19.2 and 29.4 months, respectively, and the 1- and 3-year DFS rates were 62% and 36%, respectively. Conclusions: Although patients are treated with curative intent, a considerable amount of patients with non-metastatic EC or GEJC experienced recurrence within two years. Resected patients had a higher DFS and OS compared to patients receiving dCRT.
The Hunt for Ancient Prions: Archaeal Prion-Like Domains Form Amyloid-Based Epigenetic Elements
Authors: Tomasz Zajkowski, Michael D Lee, Shamba S Mondal, Amanda Carbajal, Robert Dec, Patrick D Brennock, Radoslaw W Piast, Jessica E Snyder, Nicholas B Bense, Wojciech Dzwolak, Daniel F Jarosz, Lynn J Rothschild
Journal: Molecular Biology and Evolution (2021)

Abstract Prions, proteins that can convert between structurally and functionally distinct states and serve as non-Mendelian mechanisms of inheritance, were initially discovered and only known in eukaryotes, and consequently considered to likely be a relatively late evolutionary acquisition. However, the recent discovery of prions in bacteria and viruses has intimated a potentially more ancient evolutionary origin. Here, we provide evidence that prion-forming domains exist in the domain archaea, the last domain of life left unexplored with regard to prions. We searched for archaeal candidate prion-forming protein sequences computationally, described their taxonomic distribution and phylogeny, and analyzed their associated functional annotations. Using biophysical in vitro assays, cell-based and microscopic approaches, and dye-binding analyses, we tested select candidate prion-forming domains for prionogenic characteristics. Out of the 16 tested, eight formed amyloids, and six acted as protein-based elements of information transfer driving non-Mendelian patterns of inheritance. We also identified short peptides from our archaeal prion candidates that can form amyloid fibrils independently. Lastly, candidates that tested positively in our assays had significantly higher tyrosine and phenylalanine content than candidates that tested negatively, an observation that may help future archaeal prion predictions. Taken together, our discovery of functional prion-forming domains in archaea provides evidence that multiple archaeal proteins are capable of acting as prions—thus expanding our knowledge of this epigenetic phenomenon to the third and final domain of life and bolstering the possibility that they were present at the time of the last universal common ancestor.
OP0001 Redox-sensitive changes in conformation and cellular localization of lat and downstream tcr signalling lead to hyporesponsiveness of synovial fluid t cells in rheumatoid arthritis
Authors: SI Gringhuis, PH Remans, EA Papendrecht-van der Voort, A Leow, EN Levarht, FC Breedveld, CL Verweij
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In rheumatoid arthritis (RA), the synovial fluid (SF) T lymphocytes present in the inflamed joints, display hyporesponsiveness upon engagement of the TCR/CD3 complex despite phenotypic evidence of former activation. We have previously shown that the central and crucial adaptor protein LAT (linker for activation of T cells), which plays a central and crucial role in the T cell receptor (TCR)-mediated signalling pathways, exhibits deficient phosphorylation due to displacement of the integral membrane protein from the plasma membrane in SF T lymphocytes. SF T lymphocytes exhibit several features of chronic oxidative stress, e.g. severely decreased intracellular levels of glutathione (GSH), and our previous studies have indicated that the subcellular localization of LAT is sensitive to changes in the intracellular GSH levels. The cysteine-to-serine substitutions of several cysteine residues (C26/29 or C117) within LAT creates LAT mutants that are resistant to reduced intracellular GSH levels and remain membrane-anchored in GSH-depleted cells. <h3>Objectives</h3> <h3>Methods</h3> <h3>Results</h3> In this study, we have used the redox-insensitive LAT mutants to study the effect of redox balance alterations, like in SF T lymphocytes, on TCR signalling pathways downstream from LAT and on CD28 signalling pathways. In co-transfection experiments, we show that the presence of the redox-insensitive LAT mutants allows for the partial restoration of the TCR-mediated signalling pathways, but not the signalling pathways induced through the CD28 receptor. The data are indicative that the Raf1-ERK and the calcium-calcineurin pathways leading to transcriptional activation of AP-1 and NFAT, respectively, are very sensitive to reduced intracellular GSH levels, while the activation of the p38/Mpk2 pathway leading to AP-1-mediated transcription is mostly unaffected by chronic oxidative stress. A very proximal event in the CD28-mediated signalling pathways seems to be extremely sensitive to GSH depletion since costimulation did not affect the transcriptional activity of either AP-1 or NF-kappaB. <h3>Conclusion</h3> We conclude that the signalling pathways in SF T lymphocytes from RA patients are affected at several levels by chronic oxidative stress, all contributing to the observed hyporesponsiveness of these cells.
OP0094 Steady-state plasma concentrations of rofecoxib in children with juvenile rheumatoid arthritis
Authors: KE Truitt, M Ferrandiz, M Kiss, OT Forre, AG Porras, P Wong, E St. Rose, LM DeTora
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To compare the steady-state AUC(0–24 h) of rofecoxib, dosed @ approx 0.32 mg/kg/day in children aged 2 to 17 years vs. adult historical controls who received one 25-mg tablet daily (mean weight of 77.7 kg, corresponding to ~0.32 mg/kg/day). <h3>Methods</h3> Two trials were performed. In one, adolescent JRA patients (12 to 17 years) received 12.5 mg or 25 mg tablets to approximate 0.32 mg/kg/day. In another, JRA patients aged 2–11 years received rofecoxib 2.5 mg/ml suspension to approx. 0.32 mg/kg/day. Both formulations have equivalent bioavailability. All patients received once-daily rofecoxib for at least 8 days (to presumptive steady state) then trough and post-dose blood samples were obtained for up to 24 h. To minimise the number of blood samples for 2–5 year-olds, 2 sampling schedules with different time points were used. Comparison to adult historical controls was made by calculating AUC(0–24 hr) geometric mean ratio (GMR) with corresponding 90% confidence intervals (CI) for specific paediatric age groups: 12–17 yrs; 6–11 yrs; and 2–5 yrs; relative to adult controls. Similar comparisons were made for Cmax. Summary statistics for AUC(0–24 hr) were calculated for each treatment (12.5 mg or 25 mg Rofecoxib) in patients 12–17 years. <h3>Results</h3> See Table 1. 12–17 yr-old patients taking 12.5 mg or 25 mg rofecoxib showed similar exposure to adult controls receiving the same dose. Rofecoxib was generally well-tolerated in all patients and age ranges studied. <h3>Conclusion</h3> Based on these results, children aged 2–11 yrs require a higher mg/kg/day dose of rofecoxib for similar steady-state systemic exposure to adult historical controls receiving 25 mg. Assuming linear dose proportionality, a dose of ~0.6 mg/kg/day in children aged 2–11 yrs, should approximate the exposure of 25 mg in adults and adolescents aged 12–17 yrs showed similar systemic exposure to adults taking identical doses of rofecoxib. Funded by a grant from Merck and Co., Inc.
AB0217 Intravenous pulse corticosteroid therapy in patient fith eosinophilic fascitis
Authors: W Samborski, R Eaba
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Eosinophilic fascitis is a disorder characterised by the apperance over weeks or months of tender swelling of the arms and legs with inflammation and sclerosis of the deep fascia and subcutis. Long lasting therapy with prednisone is often unsatisfasctory. <h3>Objectives</h3> A 40-year-old man suffering from eosinophilic fascitis is reported with skin rush and induration of subcutaneous tissue of the forearm, typical ?groove sign? and contractures of the elbow joints (pict.1,2,3). Skin involvement was accompanied by peripheral eosinophilia (0,33) hypergammaglobulinemia (0,24), an elevated erythrocyte sedimentation rate (28/h) increased concentration of acute phase reactants (C-reactive protein 52 mg/l), alpha-1 acid glycoprotein 1489 mg/l) as well as leukocytosis (14,5 G/l). <h3>Methods</h3> The typical treatment with dosis of 20 mg prednisone caused only slight improvement. Moreover the patient has suffered from typical poststeroideal skin changes. Therefore we decided to performe an intravenous pulse methylprednisolone therapy as follows: 3 days-every day 500 mg methylprednisolone as solution in 5% NaCl (two courses with 4 weeks pause). As a continuation the patient has got oraly dosis 7,5 mg prednisone every second day in the morning. <h3>Results</h3> After pulse therapy the remission of the symptoms with regression of skin changes and improvement of the acute phase reactants levels (ESR 14/h, CRP 28 mg/l) as well as the normalisation of leukocytosis (10,8 G/L) and eosinophilia (0,03) were observed. After one year observation the patient was still in remission without signs of active inflammatory process and without eosinophilia in blood wet. <h3>Conclusion</h3> We recommend in patients with fascitis eosinophilica the intravenous pulse corticosteroids therapy and reduced dosis of prednisone as an alternative to high-dose oral corticosteroids.
FRI0024 Effectiveness and toxicity profiles of traditional disease modifying antirheumatic drugs for rheumatoid arthritis
Authors: D Aletaha, JS Smolen
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine the state of application and the fate of traditional disease modifying antirheumatic drugs (DMARDs) during the years before the introduction of new DMARDs including biologic agents. <h3>Methods</h3> In a historical prospective analysis the fate of DMARD therapies in 593 patients, comprising a total number of 1319 courses of DMARDs over a period of 2378 patient years, were analysed. DMARD dosages, treatment durations, reasons for discontinuation and adverse events reported by either the patients or physicians as well as CRP and ESR were analysed. Drug retention rates were estimated using Kaplan-Meier-analysis. <h3>Results</h3> Methotrexate (MTX), chloroquine (CQ), and sulfasalazine (SSZ) emerged as the drugs most commonly applied during the past 15 years,<sup>1</sup> whereas gold salts and D-penicillamine (DPA) were used less frequently during the past decade. Three of four therapies had to be terminated for either inefficacy (37%) or adverse events (42%).<sup>2</sup> Patients on high dose therapy had significantly longer median retention rates than those on low dose therapy (SSZ: 34 vs. 7 months; MTX: 73 vs. 39 months). Interestingly, rather than inefficacy, toxicity was the main reason for discontinuation of MTX and SSZ at low doses. The most commonly encountered adverse events leading to discontinuation were nausea, abdominal pain and rashes (the latter mainly with gold salts and DPA).<sup>2,3</sup> Median retention rates lasted 36 months). <h3>Conclusion</h3> MTX, SSZ and antimalarials became the most commonly used traditional DMARDs for RA. High dose therapy can be continued longer than low dose therapy, and DMARD use is rather limited by toxicity than by inefficacy. Once tolerated, DMARDs can be retained for long periods of time. <h3>References</h3> Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum. 1992;35:1117–25 Fries JF, Williams CA, Ramey D, Bloch DA. The relative toxicity of disease-modifying antirheumatic drugs. Arthritis Rheum. 1993;36:297–306 Wolfe F. Adverse drug reactions of DMARDs and DC-ARTs in rheumatoid arthritis. Clin Exp Rheumatol. 1997;15(Suppl 17):S75–81