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Background: The IMvigor210 trial demonstrated clinical benefit and manageable toxicity with atezolizumab monotherapy [anti-programmed death-ligand 1 (PD-L1)] in patients with metastatic urothelial carcinoma (UC) in primary analyses. Final efficacy and safety results after long-term follow-up are reported., Patients and Methods: This phase II single-arm trial of atezolizumab monotherapy in patients with advanced UC included two cohorts: untreated patients ineligible for cisplatin-based chemotherapy (cohort 1; n = 119) and those previously treated with platinum-based chemotherapy (cohort 2; n = 310). Atezolizumab was administered i.v. (1200 mg every 21 days) until progression or unacceptable toxicity. Primary endpoints were independent review facility-assessed confirmed objective response rate (ORR) per RECIST 1.1 in cohort 1 and independent review facility-assessed ORR per RECIST 1.1 and investigator-assessed modified (m)RECIST in cohort 2. Overall survival (OS), efficacy by PD-L1 status, and safety were also assessed., Results: At data cut-off (1 June 2023), the median survival follow-up was 96.4 months (range, 0.2-103.4 months) in cohort 1 and 46.2 months [0.2 (censored)-54.9 months] in cohort 2. In cohort 1, the ORR [95% confidence interval (CI)] was 23.5% (16.2% to 32.2%) in all patients and 28.1% (13.8% to 46.8%) in the PD-L1 tumor-infiltrating immune cell (IC)2/3 subgroup. Median OS (95% CI) was 16.3 months (10.4-24.5 months) overall and 12.3 months (6.0-49.8 months) in the PD-L1 IC2/3 subgroup. In cohort 2, the ORR (95% CI) was 16.5% (12.5% to 21.1%) per RECIST 1.1 and 19.7% (95% CI 15.4% to 24.6%) per mRECIST in all patients and 27.0% (18.6% to 36.8%) and 28.0% (19.5% to 37.9%), respectively, in the PD-L1 IC2/3 subgroup. Median OS (95% CI) was 7.9 months (6.7-9.3 months) in all patients and 11.9 months (9.0-22.8 months) in the IC2/3 subgroup. Treatment-related grade 3/4 adverse events occurred in 21.8% (cohort 1) and 18.7% (cohort 2); one treatment-related death occurred in cohort 1., Conclusions: With long-term follow-up, atezolizumab monotherapy demonstrated clinically meaningful efficacy with durable responses in a subset of patients with metastatic UC; there were no new safety signals., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antimicrobial resistance (AMR) is a global health concern. Targetting AMR, we present an in situ lactonization mechanism generating 4-nitroisobenzofuran-1(3 H )-one (IITK2020), an exclusive S. aureus inhibitor at 2-4 μg mL -1 MIC including multidrug-resistant S. aureus clinical strains, that prevents peptidoglycan biosynthesis.

Pancreatic lipase is a digestive enzyme involved in the hydrolysis of dietary fats. Orlistat, a potent pancreatic lipase inhibitor, is widely prescribed for long-term obesity treatment. Nevertheless, orlistat is reported for severe adverse effects including hepatotoxicity and pancreatitis. In the present study, a novel series of 11 benzyloxy substituted indole glyoxylamides were designed, synthesized and evaluated for in vitro pancreatic lipase inhibitory activity. Three analogues, 10b , 11b and 11c , exhibited potent activity (IC 50 ≤ 2.5 µM), with 11b exhibiting a potent IC 50 of 1.68 µM comparable to orlistat (IC 50 = 0.99 µM). Further, 11b exhibited reversible competitive inhibition with an inhibitory constant value of 0.98 μM. Molecular docking of these analogues was in agreement with in vitro results, wherein the MolDock scores exhibited significant correlation with their inhibitory activity (Pearson's r  = 0.7122). A 50 ns molecular dynamics simulation of 11b- pancreatic lipase complex confirmed the role of extended alkyl interactions along with π-π stacking and π-cation interactions, in stabilizing the ligand (Maximum RMSD ≈ 3 Å) in the active site. Gastro-intestinal absorption and toxicity prediction of the three potent analogues highlighted the suitability of 11b for in vivo experiments. 11b at a dose of 20 mg/kg exhibited anti-obesity efficacy comparable to orlistat (10 mg/kg), wherein the serum triglycerides were found to be 94.95 and 83.85 mg/dL, respectively. Further, faecal triglyceride quantification indicated 11b to act through pancreatic lipase inhibition similar to orlistat. The present study identified a novel pancreatic lipase inhibitory benzyloxy substituted bis(indolyl) glyoxylamide 11b, with promising anti-obesity activity.Communicated by Ramaswamy H. Sarma.

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome., Objective: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium., Design, Setting, and Participants: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC., Outcome Measurements and Statistical Analysis: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility., Results and Limitations: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology., Conclusions: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy., Patient Summary: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability., (Copyright © 2020. Published by Elsevier B.V.)

Background: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting., Patients and Methods: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks)., Results: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001)., Conclusions: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker., Competing Interests: Disclosures KNC reports honoraria and/or consulting fees from Astellas, AstraZeneca, Constellation Pharmaceuticals, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Point Biopharma, Roche, Sanofi, and grants and research funding from Astellas, AstraZeneca, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi. AWW reports a commercial research grant from Janssen and honoraria from AstraZeneca, Astellas, Janssen, and Merck. AAA reports honoraria, consulting fees, and/or research funding from Astellas, AstraZeneca, Janssen, Novartis, Sanofi, Tolmar, Telix, Merck Serono, Bristol Myers Squibb (BMS), Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Aptevo Therapeutics, Glaxo Smith Kline, MedImmune, SYNthorx, Bionomics, Merck Sharpe Dome, and Sanofi Aventis. LAW reports serving on advisory boards (with no personal financial contribution) for Pfizer, EISAI, AstraZeneca, Merck, BMS, and Ipsen, and grants from Pfizer, Merck, AstraZeneca, Roche, and BMS. BT reports grants and personal fees from Amgen, AstraZeneca, BMS, Janssen, Pfizer, MDS, Ipsen and Bayer, grants from Astellas, and personal fees from Sanofi, Tolmar, Novartis, IQVIA, and Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Immunotherapy agents are an innovative oncological treatment modality and as a result their use has expanded widely. Understanding the treatment-related adverse events (AEs) of these drugs compared with traditional chemotherapy is crucial for clinical practice., Design: A systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to 14 February 2019 was conducted. Randomized clinical trials comparing immunotherapy [cytotoxic T-lymphocyte protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1)] with standard-of-care chemotherapy in the treatment of advanced solid-organ neoplasms were included if AEs were reported as an outcome. Primary outcome was AEs ≥ grade 3 in severity. Secondary outcomes were proportion of overall AEs, treatment discontinuation due to AEs, deaths due to AEs, and specific AEs [fatigue, diarrhea, acute kidney injury (AKI), colitis, pneumonitis, and hypothyroidism]. Paule-Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects., Results: Among 10 598 abstracts screened, we included 22 studies involving 12 727 patients. In the immunotherapy group, 16.5% of patients developed an AE ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm [OR = 0.26, 95% confidence interval (CI) 0.19-0.35, I 2  = 92%]. Patients receiving immunotherapy also had lower odds of developing an AE overall (OR = 0.35, 95% CI 0.28-0.44; I 2  = 77%), terminating therapy due to an AE (OR = 0.55, 95% CI 0.39-0.78, I 2  = 80%), or dying from a treatment-related AE (OR = 0.67, 95% CI 0.46-0.98, I 2  = 0%). When treated with chemotherapy versus immunotherapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhea (14.97% versus 11.13%), and AKI (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immunotherapy., Conclusions: Treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of AEs., (Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Present work reports the synthesis of a novel Chitosan-Polytetrafluoroethylene composite membrane with solvent resistant property for efficient separation of methanol/toluene mixture by pervaporation. The composite was crossed with tetraethyl orthosilicate (TEOS) to prevent or reduce membrane swelling and improve the separation factor. The synthesized membranes were characterized by SEM, FTIR and DSC analysis. Molecular dynamics (MD) simulation and computational fluid dynamics were coupled to predict the structural and diffusive properties besides concentration profile inside the membrane. Diffusion coefficients of methanol and toluene were found to be 1.7 × 10 -9 and 1.8 × 10 -12  m 2 /s, respectively. The effect of crosslinking on process parameters such as flux and separation factor was analyzed. The study confirmed that increasing TEOS concentration reduced the methanol flux but enhanced separation factor with respect to this alcohol. The membranes exhibited a flux of 0.13 kg/m 2  h and separation factor of 58.4 for azeotropic feed composition of 68 wt% methanol., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A series of novel diaryl substituted pyrazolyl 2,4-thiazolidinediones were synthesized via reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinedione (TZD) and nitrobenzyl substituted 2,4-thiazolidinedione. The resulting compounds were screened in vitro for pancreatic lipase (PL) inhibitory activity. Two assay protocols were performed viz., methods A and B using p-nitrophenyl butyrate and tributyrin as substrates, respectively. Compound 11e exhibited potent PL inhibitory activity (IC 50 =4.81µM and X i50 =10.01, respectively in method A and B), comparable to that of the standard drug, orlistat (IC 50 =0.99µM and X i50 =3.72). Presence of nitrobenzyl group at N-3 position of TZD and nature of substituent at para position of phenyl ring at C-3 position of pyrazole ring notably affected the PL inhibitory activity of the tested compounds. Enzyme inhibition kinetics of 11e revealed its reversible competitive inhibition, similar to that of orlistat. Molecular docking studies validated the rationale of pharmacophoric design and are in accordance to the in vitro results. Compound 11e exhibited a potential MolDock score of -153.349kcal/mol. Further, the diaryl pyrazolyl wing exhibited hydrophobic interactions with the amino acids of the hydrophobic lid domain. Moreover, the carbonyl group at 2 nd position of the TZD ring existed adjacent to Ser 152 (≈3Å) similar to that of orlistat. A 10ns molecular dynamics simulation of 11e-PL complex revealed a stable binding conformation of 11e in the active site of PL (Maximum RMSD≈3Å). The present study identified novel thiazolidinedione based leads with promising PL inhibitory activity. Further development of the leads might result in potent PL inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Submerged membrane bioreactor (SMBR) is a relatively advanced technology for waste water treatment that involves integrated aerobic and anaerobic biological processes with membrane filtration. In the present investigation, hydrophobic polyvinylidene fluoride (PVDF) and hydrophilic polyacrylonitrile (PAN) hollow fiber (HF) membranes were tested in an indigenously fabricated SMBR for dairy effluent treatment under aerobic conditions using mixed microbial consortia. Effect of operating parameters such as suction pressure, degree of aeration and trans-membrane pressure (TMP) on membrane performance in terms of flux, rejection of turbidity, BOD and COD besides fouling characteristics was investigated. The observed optimum permeabilities of PVDF and PAN HF membranes were approximately 108 and 115 LMH bar(-1) with high extent of impurity removal. The rejection of COD was found to be 93% for PVDF and 91% for PAN HF membranes whereas corresponding rejection of BOD was observed to be 92% and 86%. A two-dimensional comprehensive model was developed to predict the hydrodynamic profile inside the module. Regression analysis revealed that the simulation results agreed well with experimental data., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Based on the TAX 327 phase III trial, docetaxel-based chemotherapy is the standard first-line treatment for hormone-resistant prostate cancer (HRPC); however, there is some heterogeneity in the use of this agent in routine clinical practice. The aim of the present study was to examine the patterns of docetaxel use in routine clinical practice at our institution and to compare them with docetaxel use in the TAX 327 clinical trial., Methods: We conducted a retrospective chart review of HRPC patients treated with first-line docetaxel between 2005 and 2007 at the Princess Margaret Hospital., Results: In the first-line setting, 88 patients with HRPC received docetaxel. The main reasons for initiating docetaxel were rising prostate-specific antigen (PSA, 98%) and progressive symptoms (77%). The PSA response rate was 67%; median time to response was 1.5 months, and duration of response was 6.8 months. Median survival was 15.9 months (95% confidence interval: 12.4 to 20.5 months). Patients received a median of 7 cycles of treatment, and the main toxicities were fatigue (35%) and neuropathy (24%). Post docetaxel, 36 patients received second-line treatment with a 22% response rate., Conclusions: In routine clinical practice, HRPC patients received docetaxel mainly because of symptomatic disease progression. Overall response rates and toxicities were comparable to those in the TAX 327 trial. However, our patients received a median of only 7 cycles of treatment versus the 9.5 administered on trial, and survival was slightly shorter in our single-institution study. A larger prospective multicentre analysis, including performance status and quality-of-life parameters, may be warranted to determine if docetaxel performs as well in routine clinical practice as it does in the clinical trial setting.

Forty-nine patients with chronic left bundle branch block and a normal frontal axis were compared with 53 patients with left bundle branch block and left axis deviation. The following clinical variables were more frequent (P less than 0.05) in patients with left axis deviation: greater age, exertional angina, congestive heart failure, cardiomegaly, cardiac functional class II to IV, coronary artery disease and presence of organic heart disease. Absence of organic heart disease (primary conduction disease) was seen only in patients with a normal axis. Patients with left axis deviation had longer (P less than 0.05) mean P-R, A-H and H-V intervals and atrial and atrioventricular (A-V) nodal effective refractory periods. All patients were prospectifely followed up for 30 to 2,271 days with a mean +/- standard error of the mean follo-up period of 538 +/- 72 for the group with a normal axis and 604 +/- 72 days for the group with left axis deviation (difference not significant). A-V block developed in three patients (6 percent) with left axis deviation and in none of those with a normal axis. The cumulative 4 year mortality rate for the entire group approached 75 percent. The patients with left axis deviation had greater cardiovascular mortality (P less than 0.05). In conclusion, among patients with left bundle branch block, those with left axis deviation have a greater incidence of myocardial dysfunction, more advanced conduction desease and greater cardiovascular mortality than those with a normal axis.