Benzimidazole-2-Phenyl-Carboxamides as Dual-Target Inhibitors of BVDV Entry and Replication

Bovine viral diarrhea virus (BVDV), also known as Pestivirus A, causes severe infection mostly in cattle, but also in pigs, sheep and goats, causing huge economical losses on agricultural farms every year. The infections are actually controlled by isolation of persistently infected animals and vaccination, but no antivirals are currently available to control the spread of BVDV on farms. BVDV binds the host cell using envelope protein E2, which has only recently been targeted in the research of a potent and efficient antiviral. In contrast, RdRp has been successfully inhibited by several classes of compounds in the last few decades. As a part of an enduring antiviral research agenda, we designed a new series of derivatives that emerged from an isosteric substitution of the main scaffold in previously reported anti-BVDV compounds. Here, the new compounds were characterized and tested, where several turned out to be potent and selectively active against BVDV. The mechanism of action was thoroughly studied using a time-of-drug-addition assay and the results were validated using docking simulations.     

Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.     

Comparing the accuracy of transcutaneous sensor and 90-day implantable glucose sensor

Background and aimsContinuous glucose monitoring improves glycemic control in diabetes. This study compared the accuracy of the Dexcom G5 Mobile (Dexcom, San Diego, CA) transcutaneous sensor (DG5) and the first version of Eversense (Senseonics,Inc., Germantown, MD) implantable sensor (EVS).Methods and resultsSubjects with type 1 diabetes (T1D) and using EVS wore simultaneously DG5 for seven days. At day 3, patients were admitted to a clinical research center (CRC) to receive breakfast with delayed and increased insulin bolus to induce glucose excursions. At CRC, venous glucose was monitored every 15 min (or 5 min during hypoglycemia) for 6 h by YSI 2300 STAT PLUS? glucose and lactate analyzer. At home patients were requested to perform 4 fingerstick glucose measurements per day.Eleven patients (9 males, age 47.4 ± 11.3 years, M±SD) were enrolled. During home-stay the median [25th-75th percentile] absolute relative difference (ARD) over all CGM-fingerstick matched-pairs was 11.64% [5.38–20.65]% for the DG5 and 10.75% [5.15–19.74]% for the EVS (p-value = 0.58). At CRC, considering all the CGM-YSI matched-pairs, the DG5 showed overall smaller median ARD than EVS, 7.91% [4.14–14.30]% vs 11.4% [5.04–18.54]% (p-value<0.001). Considering accuracy during blood glucose swings, DG5 performed better than EVS when glucose rate-of-change was ?0.5 to ?1.5 mg/dL/min, with median ARD of 7.34% [3.71–12.76]% vs 13.59% [4.53–20.78]% (p-value<0.001), and for rate-of-change < -1.5 mg/dl/min, with median ARD of 5.23% [2.09–15.29]% vs 12.73% [4.14–20.82]% (p-value = 0.02).ConclusionsDG5 was more accurate than EVS at CRC, especially when glucose decreased. No differences were found at home.     

Has hyperglycemia a different prognostic role in STEMI patients with or without diabetes?

Background and aimsHyperglycemia at hospital admission is a common finding in patients with STEMI. However, whether elevated acute glycemia in these patients may have a direct impact on worsening prognosis or is just a marker of a greater neurohormonal activation in response to the infarction is still unsettled.We sought to investigate the prognostic impact of hyperglycemia at hospital admission in patients undergoing primary PCI (pPCI) for STEMI, and the influence of the presence of diabetes mellitus (DM) on its prognostic impact.Methodsand Results, We enrolled 2958 consecutive STEMI patients treated by pPCI. Hyperglycemia was defined as plasma glucose >198 mg/dL (or >11 mmol/L). Patients with hyperglycemia showed a greater risk-profile; they also experienced a higher mortality both at univariable (17.6% vs 5.2%, p < 0.001) and multivariable (HR 1.9, 95%IC 1.5–2.9, p = 0.001) analysis. However, after stratification for DM presence, hyperglycemia resulted as an independent predictor of mortality only in patients without DM (HR 2, 95%IC 1.2–3.4, p = 0.01).ConclusionHyperglycemia in the setting of myocardial infarction treated with primary PCI in an independent predictor of all-cause mortality in patients without diabetes; in patients with diabetes, its prognostic impact seems attenuated.