Elraglusib (formerly 9-ING-41) possesses potent anti-lymphoma properties which cannot be attributed to GSK3 inhibition.

Elraglusib (formerly 9-ING-41) is an ATP-competitive inhibitor of glycogen synthase kinase-3ß (GSK3ß) undergoing clinical trials for the treatment of various cancers including non-Hodgkin lymphoma (NHL). The drug reduces proliferation of several NHL cell lines and has efficacy in xenograft models of the disease. To confirm the importance of its action on GSK3ß, we treated 3 lymphoma cell lines with selective, structurally distinct GSK3 inhibitors: CT99021, SB216763, LY2090314, tideglusib, and elraglusib. Stabilization of ß-catenin and reduced phosphorylation of CRMP2, two validated targets of GSK3, were used as functional read-outs for GSK3 inhibition. CT99021, SB216763, and LY2090314 failed to reduce proliferation or viability in any cell line at concentrations that stabilized ß-catenin and reduced CRMP2 phosphorylation. There was partial reduction of CRMP2 phosphorylation but no significant effect on ß-catenin at cytotoxic doses of elraglusib. There was no indication of GSK3 inhibition at doses of tideglusib that affected cell viability and apoptosis. Cell-free kinase screening confirmed several other targets of elraglusib, distinct from the GSK3 inhibitors with no anti-lymphoma actions, including PIM kinases and MST2. These data question GSK3 as the target of elraglusib in lymphoma, and hence the utility of GSK3 expression as a 'stand-alone', therapeutic biomarker in NHL. Video Abstract.

Metformin selectively targets redox control of complex I energy transduction.

Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.

The effect of introducing point-of-care or dried blood spot analysis on the uptake of hepatitis C virus testing in high-risk populations: A systematic review of the literature.

BACKGROUND: Testing for hepatitis C virus (HCV) infection typically relies upon blood samples taken by traditional phlebotomy for laboratory processing. Novel testing methods, including using dried blood spots (DBS) and point-of-care (PoC) testing enable easier access to high risk populations who have less frequent contact with healthcare professionals. Many of these individuals have been exposed to HCV but have not previously been tested. We aimed to establish whether the availability of these novel testing methods increased either uptake of testing or the number of new diagnoses of HCV. METHODS: The PubMed, Cochrane and SCOPUS databases were searched for terms relating to the study. References and associated bibliographies were also examined for further relevant articles. Studies were included if they contained quantitative data on frequency of testing and/or new diagnoses following the introduction of PoC and/or DBS testing of high-risk populations. Studies were then examined for findings and limitations and graded upon the quality of evidence provided. RESULTS: No studies were found which introduced PoC testing and determined its effect on frequency of testing or new diagnoses. Six studies were identified in which DBS testing was introduced and its effect evaluated. Two of the studies were randomised controlled trials, two were prospective cohort studies, one was an ecological study and one was a clinical audit. Populations studied included those attending substance misuse clinics, prisons and needle exchanges. Injection drug use was the commonest risk factor for HCV. Five of the six studies provided evidence that the introduction of DBS testing increased the number of tests, new diagnoses or both. CONCLUSION: Current evidence indicates that DBS testing availability may increase the uptake of testing for HCV in high-risk populations. There is currently no evidence regarding the efficacy of PoC testing in these populations.

What is the evidence for the duration of antibiotic therapy in Gram-negative bacteraemia caused by urinary tract infection? A systematic review of the literature.

The frequency of secondary bacteraemia is variable depending on the site of infection but is often associated with significant morbidity and mortality. The most common source of Gram-negative bacteraemia is urinary tract infection (UTI). Current guidelines on the treatment of UTI provide no clear guidance on whether the presence of bacteraemia influences the duration or choice of therapy. Here we systematically review the current evidence base for the duration of treatment of Gram-negative bacteraemia secondary to UTI. The available evidence is sparse and of variable quality to draw any firm conclusions. However, in the absence of urgently required high-quality studies, current limited evidence appears to indicate that short courses of antibiotics are as effective at obtaining clinical and bacteriological cure as longer courses.