Mccurdyhodges3873

Purpose Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients. Methods This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began less then 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations. Results Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points. Conclusion No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. selleck chemicals These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.Purpose Paramedics are often the first healthcare contact for patients with infection and sepsis and may identify them earlier with improved knowledge of the clinical signs and symptoms that identify patients at higher risk. Methods A 1-year (April 2015 and March 2016) cohort of all adult patients transported by EMS in the province of Alberta, Canada, was linked to hospital administrative databases. The main outcomes were infection, or sepsis diagnosis among patients with infection, in the Emergency Department. We estimated the probability of these outcomes, conditional on signs and symptoms that are commonly available to paramedics. Results Among 131,745 patients transported by EMS, the prevalence of infection was 9.7% and sepsis was 2.1%. The in-hospital mortality rate for patients with sepsis was 28%. The majority (62%) of patients with infections were classified by one of three dispatch categories ("breathing problems," "sick patient," or "inter-facility transfer"), and the probability of infection diagnosis was 17-20% for patients within these categories. Patients with elevated temperature measurements had the highest probability for infection diagnosis, but altered Glasgow Coma Scale (GCS), low blood pressure, or abnormal respiratory rate had the highest probability for sepsis diagnosis. Conclusion Dispatch categories and elevated temperature identify patients with higher probability of infection, but abnormal GCS, low blood pressure, and abnormal respiratory rate identify patients with infection who have a higher probability of sepsis. These characteristics may be considered by paramedics to identify higher-risk patients prior to arrival at the hospital.Purpose Tamoxifen is part of endocrine therapy in breast cancer treatment. Studies have indicated the use of endoxifen concentrations, tamoxifen active metabolite, to guide tamoxifen efficacy. Three endoxifen thresholds have been suggested (5.9 ng/ml, 5.2 ng/ml and 3.3 ng/ml) for therapeutic drug monitoring (TDM). Our aim was to validate these thresholds and to examine endoxifen exposure with clinical outcome in early-breast cancer patients using tamoxifen. Methods Data from 667 patients from the CYPTAM study (NTR1509) were available. Patients were stratified (above or below), according to the endoxifen threshold values for tamoxifen efficacy and tested by Cox regression. Logistic regressions to estimate the probability of relapse and tamoxifen discontinuation were performed. Results None of the thresholds showed a statistically significant difference in relapse-free survival 5.2 ng/ml threshold hazard ratio (HR) 2.545, 95% confidence interval (CI) 0.912-7.096, p value 0.074; 3.3 ng/ml threshold HR 0.728; 95% CI 0.421-1.258, p value 0.255. Logistic regression did not show a statistically significant association between the risk of relapse (odds ratio (OR) 0.971 (95% CI 0.923-1.021, p value 0.248) and the risk for tamoxifen discontinuation (OR 1.006 95% CI 0.961-1.053, p value 0.798) with endoxifen concentrations. Conclusion Our findings do not confirm the endoxifen threshold values for TDM nor does it allow definition of a novel threshold. These findings indicate a limited value of TDM to guide tamoxifen efficacy.Purpose Oxaliplatin and satraplatin demonstrate activity against cisplatin-resistant tumor cells. Although the two platinum analogs are structurally-related, oxaliplatin is more active. Therefore, studies focusing on protein expression profiling were undertaken to identify the molecular mechanism for the difference in antitumor activity. Methods We included cisplatin as reference and DAP as a Pt(IV)-prodrug of oxaliplatin to offset Pt(IV) status of satraplatin, and utilized A2780, cisplatin-resistant 2780CP/Cl-16, U2OS, and HCT-116 tumor cells in the investigation. Protein expressions following drug exposures were examined by reverse-phase protein array and ingenuity pathway analysis. Cell cycle was assessed by flow cytometry, cytotoxicity by growth inhibition assay, and homologous recombination (HR) by a GFP reporter assay. Results Clustering analysis paired oxaliplatin with DAP and, surprisingly, satraplatin with cisplatin. This correlated with differential upregulation of p53/p21 pathway, with S and G2/M arrests by cisplatin and satraplatin in contrast to G1 arrest by oxaliplatin and DAP. Moreover, Rad51 and BRCA1 were severely downregulated by oxaliplatin and DAP, but not cisplatin and satraplatin. As a result, HR was inhibited only by oxaliplatin and DAP and this also contributed to their greater drug activity over cisplatin and satraplatin. Conclusions Oxaliplatin and DAP robustly activate p53 and p21, which downregulate HR proteins to enhance drug activity. More significantly, since oxaliplatin induces a BRCAness state, it may have potential against BRCA-proficient cancers. Satraplatin, on the other hand, resembled cisplatin in its protein expression profile, which indicates that small changes in chemical structure can substantially alter signal transduction pathways to modulate drug activity.