The extracellular signal regulated kinase (ERK1 and ERK2) signal transduction pathways play a critical role in cell proliferation. Hyperactivation of the ERK proteins either through increased expression of membrane-bound growth factor receptors or genetic mutations of upstream proteins is thought to be involved in the pathogenesis of many human cancers. Thus, targeted inhibition of ERK signaling is viewed as a potential approach to prevent cancer cell proliferation. Currently, no specific inhibitors of the ERK proteins exist. Moreover, most kinase inhibitors lack specificity because they target the ATP binding region, which is well conserved among the protein kinase families. Taking advantage of recently identified ERK docking domains, which are reported to facilitate substrate protein interactions, we have used computer-aided drug design (CADD) to identify novel small molecular weight ERK inhibitors. Following a CADD screen of over 800 000 molecules, 80 potential compounds were selected and tested for activity in biological assays. Several compounds inhibited ERK-specific phosphorylation of ribosomal S6 kinase-1 (Rsk-1) or the ternary complex factor Elk-1 (TCF/Elk-1), both of which are involved in promoting cell proliferation. Active compounds showed a dose-dependent reduction in the proliferation of several cancer cell lines as measured by colony survival assays. Direct binding between the active compounds and ERK2 was indicated by fluorescence quenching. These active compounds may serve as lead candidates for development of novel specific inhibitors of ERK-substrate interactions involved in cell proliferation.

Background and Purpose-Tumor necrosis factor-␣ (TNF-␣), an inflammatory cytokine negligibly expressed in normal muscle, is elevated in selected metabolic conditions characterized by muscle wasting and insulin resistance. Inflammation is fundamental to stroke pathogenesis. Stroke patients have gross muscular atrophy and high prevalence of diabetes and insulin resistance. Yet, no previous studies examined TNF-␣ expression in hemiparetic skeletal muscle. This study investigates whether TNF-␣ mRNA levels are elevated in paretic compared with nonparetic leg muscles of chronic ischemic stroke patients and age-matched controls. Method-Total RNA extracted from bilateral vastus lateralis muscle biopsies from nϭ20 hemiparetic stroke patients and nϭ9 healthy controls was reverse transcribed to cDNA, then TNF-␣ transcripts were amplified by real-time quantitative polymerase chain reaction. TNF-␣ mRNA concentrations were normalized against acidic ribosomal phosphoprotein, housekeeping gene. Results-TNF-␣ mRNA levels were 2.8-fold higher in paretic compared with control leg muscle (6.28Ϯ1.86 versus 2.28Ϯ0.67; PϽ0.03) and 1.6-fold higher in nonparetic leg (3.71Ϯ1.02; PϽ0.11) compared with controls. There was a trend for higher TNF-␣ mRNA in paretic compared with nonparetic leg. Key Words: inflammation Ⅲ insulin Ⅲ stroke Ⅲ tumor necrosis factor I nflammation is a fundamental pathogenic mechanism in atherosclerosis and stroke. 1,2 Elevated inflammatory markers predict risk for incident and recurrent stroke. 3,4 Tumor necrosis factor-␣ (TNF-␣), a pivotal cytokine, upregulates systemic inflammatory markers, mediates insulin resistance, and increases cardiovascular risk. 2,5 Associations between type 2 diabetes and muscle TNF-␣ overexpression are strong and are attributed to TNF-␣ actions on muscle insulin signaling. 6 Stroke survivors have a 70% prevalence of diabetes and insulin resistance. 9 Despite evidence linking inflammation with stroke risk, diabetes, and insulin resistance, the tissue source(s) for cytokines have not been systematically investigated in the stroke population. Conclusions-FindingsStroke is a leading cause of chronic disability, possibly attributable to secondary abnormalities in skeletal muscle. 8,10 We report gross muscular atrophy and phenotype shift in hemiparetic thigh that independently predict poor fitness levels and gait severity after stroke. 8,10,11 Although skeletal muscle TNF-␣ can mediate muscular wasting and physical frailty in advancing age, 7 no previous studies investigated TNF-␣ expression in hemiparetic muscle after stroke. The hypothesis of this cross-sectional study is that TNF-␣ mRNA expression is elevated in paretic compared with nonparetic leg muscle after stroke. Because stroke may constitute a systemic biological process, muscle biopsies from healthy age-matched sedentary community reference controls are examined to determine whether hemiparetic leg muscle TNF-␣ is abnormal. Patients and MethodsMen and women Ն45 years of age with hemiparetic gait after remote (Ͼ6 months) ischemic str...

Background Countries in Sub-Saharan Africa (SSA) are moving towards universal health coverage. The process of Health Technology Assessment (HTA) can support decisions relating to benefit package design and service coverage. HTA involves institutional cooperation with agreed methods and procedural standards. We systematically reviewed the literature on policies and capacity building to support HTA institutionalisation in SSA. Methods We systematically reviewed the literature by searching major databases (PubMed, Embase, etc.) until June 2019 using terms considering three aspects: HTA; health policy, decision making; and SSA. We quantitatively extracted and descriptively analysed content and conducted a narrative synthesis eliciting themes from the selected literature, which varied in study type and apporach. Results Half of the 49 papers identified were primary research studies and mostly qualitative. Five countries were represented in six of ten studies; South Africa, Ghana, Uganda, Cameroon, and Ethiopia. Half of first authors were from SSA. Most informants were policy makers. Five themes emerged: (1) use of HTA; (2) decision-making in HTA; (3) values and criteria for setting priority areas in HTA; (4) involving stakeholders in HTA; and (5) specific examples of progress in HTA in SSA. The first one was the main theme where there was little use of evidence and research in making policy. The awareness of HTA and economic evaluation was low, with inadequate expertise and a lack of local data and tools. Conclusions Despite growing interest in HTA in SSA countries, awareness remains low and HTA-related activities are uncoordinated and often disconnected from policy. Further training and skills development are needed, firmly linked to a strategy focusing on strengthening within-country partnerships, particularly among researchers and policy makers. The international community has an important role here by supporting policy- relevant technical assistance, highlighting that sustainable financing demands evidence-based processes for effective resource allocation, and catalysing knowledge-sharing opportunities among countries facing similar challenges.

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This study investigated the efficacy and safety of interleukin-6 (IL-6) receptor antagonists with standard care treatment in patients with coronavirus disease 2019 (COVID-19). The randomized controlled trials were identified through systematic searches of electronic databases through February 10, 2022. In total, 17 trials comprising 8,614 patients were included. Compared with exclusive standard care or placebo, IL-6 receptor antagonists with standard of care treatment were associated with a significantly reduced all-cause mortality at 28 days (pooled risk ratios [RR], 0.88; 95% confidence interval (CI), 0.82–0.95; 17 studies) and progression to invasive mechanical ventilation (RR, 0.79; 95% CI, 0.71–0.88; nine studies). Particularly, the subgroup of patients with moderate-to-severe COVID-19 showed a significant mortality benefit (RR, 0.89; 95% CI, 0.81–0.96; four studies) and a reduced risk for mechanical ventilation (RR, 0.80; 95% CI, 0.70–0.91; three studies) with tocilizumab treatment. The frequency of serious adverse events was lower in the tocilizumab treatment group than in the standard of care treatment group (RR, 0.83; 95% CI, 0.71–0.97; 11 studies), with no significant difference in the sarilumab treatment group (RR, 1.12; 95% CI, 0.89–1.40; four studies). Our meta-analysis demonstrated that tocilizumab treatment showed promising results in reducing 28-day mortality and progression to mechanical ventilation in patients with moderate-to-severe COVID-19, without the burden of serious adverse events. Trial registration: . The proper registration is PROSPERO: registration number CRD42021294120.