Stroke Treatment Academic Industry Roundtable

Jovin, Tudor G; Albers, Gregory W.; Liebeskind, David S

doi:10.1161/strokeaha.116.013578

Cited by 51 publications

(26 citation statements)

References 29 publications

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“…Coupled with its optimal pharmacokinetic characteristics 26 , this may posit MCC950 as a promising candidate for clinical trials in stroke patients. In accordance with Stroke Treatment Academic Industry Roundtable (STAIR) suggestion for rigorous preclinical research and to consider large vessels occlusion models 27 , 28 , our experimental findings show specific NLRP3 inhibition with MCC950 protect the brain against MCAO in mice.…”

Section: Introductionsupporting

confidence: 79%

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke

Ismael

Zhao

Nasoohi

et al. 2018

Sci Rep

193

120

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Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60 min tMCAO followed by intraperitoneal administration of MCC950 (50 mg/kg) or saline at 1 h and 3 h post-occlusion. After 24 h of I/R, mice were tested for neurological outcome and were sacrificed for the analysis of infarct size and estimating NLRP3-inflammasome and apoptotic markers as well. Spectrophotometric method was used to determine hemoglobin (Hb) content as a marker of intracerebral hemorrhage. MCC950-treated mice showed a substantial reduction in infarction, edema and Hb content compared to saline controls in parallel with improved neurological deficits. MCC950 reduced expression of NLRP3-inflammasome cleavage products Caspase-1 and interlukin-1β (IL-1β) in penumbral region. These protective effects of MCC950 were associated with decreased TNF-α levels as well as poly (ADP-ribose) polymerase (PARP) and Caspase-3 cleavage and paralleled less phosphrylated NFκBp65 and IκBα levels. Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 has therapeutic potential in ischemic stroke models. Further investigations into the therapeutic efficacy and protocols are needed to confirm whether MCC950 treatment could be a promising candidate for clinical trials.

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Section: Introductionsupporting

confidence: 79%

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke

Ismael

Zhao

Nasoohi

et al. 2018

Sci Rep

193

120

View full text Add to dashboard Cite

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“…Confounders affect the signal-to-noise ratio and thus the sensitivity, specificity, and predictive value of the biomarker [7,8]. It is more likely that multiple biomarkers or panels from "Big Data" could improve precision [8,[12][13][14][15][16]. Big Data in stroke effectively aids in the identification of relevant biomarkers from the myriad possibilities [17].…”

Section: Challenges In Biomarker Utilizationmentioning

confidence: 99%

Biomarker Application for Precision Medicine in Stroke

Simpkins

Janowski

et al. 2019

Transl. Stroke Res.

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Stroke remains one of the leading causes of long-term disability and mortality despite recent advances in acute thrombolytic therapies. In fact, the global lifetime risk of stroke in adults over the age of 25 is approximately 25%, with 24.9 million cases of ischemic stroke and 18.7 million cases of hemorrhagic stroke reported in 2015. One of the main challenges in developing effective new acute therapeutics and enhanced long-term interventions for stroke recovery is the heterogeneity of stroke, including etiology, comorbidities, and lifestyle factors that uniquely affect each individual stroke survivor. In this comprehensive review, we propose that future biomarker studies can be designed to support precision medicine therapeutic interventions after stroke. The current challenges in defining ideal biomarkers for stroke are highlighted, including consideration of disease course, age, lifestyle factors, and subtypes of stroke. This overview of current clinical trials includes biomarker collection, and concludes with an example of biomarker design for aneurysmal subarachnoid hemorrhage. With the advent of "-omics" studies, neuroimaging, big data, and precision medicine, well-designed stroke biomarker trials will greatly advance the treatment of a disease that affects millions globally every year.

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“…However, recommendations for stroke trial design have been inconsistent regarding the appropriate duration of follow‐up. The second STAIR (Stroke Treatment Academic Industry Roundtable) encouraged follow‐up beyond 3 months to evaluate late treatment effects,5 as did NINDS (the National Institute of Neurological Disorders and Stroke),6, 7 but the most recent STAIR even proposed that a 7‐day assessment might be preferable as a primary outcome measure, given the risk of “contamination” by non‐stroke‐related morbidity 8…”

Section: Introductionmentioning

confidence: 99%

Time Course of Evolution of Disability and Cause‐Specific Mortality After Ischemic Stroke: Implications for Trial Design

Ganesh

Luengo-Fernández

Wharton

et al. 2017

JAHA

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BackgroundOutcome in stroke trials is often based on a 3‐month modified Rankin scale (mRS). How 3‐month mRS relates to longer‐term outcomes will depend on late recovery, delayed stroke‐related deaths, recurrent strokes, and nonstroke deaths. We evaluated 3‐month mRS and death/disability at 1 and 5 years in a population‐based cohort study.Methods and ResultsIn 3‐month survivors of ischemic stroke (Oxford Vascular Study; 2002‐2014), we related 3‐month mRS to disability (defined as mRS >2) at 1 and 5 years and/or death rates (age/sex adjusted). Accrual of disability and index‐stroke‐related and nonstroke deaths in each poststroke year was categorized according to 3‐month mRS. Among 1606 patients with acute ischemic stroke, 181 died within 3 months, but 126 index‐stroke‐related deaths and 320 other deaths occurred during the subsequent 4866 patient‐years of follow‐up up to 5 years. Although 69/126 (54.8%) post‐3‐month index‐stroke‐related deaths occurred after 1 year, mRS>2 at 1 year strongly predicted these deaths (adjusted hazard ratio=21.94, 95%CI 7.88‐61.09, P<0.0001). Consequently, a 3‐month mRS >2 was a strong independent predictor of death at both 1 year (adjusted hazard ratio=6.67, 95%CI 4.16‐10.69, P<0.0001) and 5 years (adjusted hazard ratio=2.93, 95%CI 2.38‐3.60, P<0.0001). Although mRS improved by ≥1 point from 3 months to 1 year in 317/1266 (25.0%) patients with 3‐month mRS ≥1, improvement in mRS after 1 year was limited (improvement by ≥1 point: 91/858 [10.6%]; improvement to mRS ≤2: 13/353 [3.7%]).ConclusionsOur results reaffirm use of the 3‐month mRS outcome in stroke trials. Although later recovery does occur, extending follow‐up to 1 year would capture most long‐term stroke‐related disability. However, administrative mortality follow‐up beyond 1 year has the potential to demonstrate translation of early disability gains into additional reductions in long‐term mortality without much erosion by non‐stroke‐related deaths.

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Stroke Treatment Academic Industry Roundtable

Cited by 51 publications

References 29 publications

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke

Biomarker Application for Precision Medicine in Stroke

Time Course of Evolution of Disability and Cause‐Specific Mortality After Ischemic Stroke: Implications for Trial Design

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