Development and validation of a UPLC-MS method for determination of atazanavir sulfate by the “analytical quality by design” approach

A UPLC-MS method for the estimation of atazanavir sulfate was developed using the “analytical quality by design” approach. The critical chromatographic quality attributes identified were retention time, theoretical plates and peak tailing. The critical method parameters established were percent of organic modifier, flow rate and injection volume. Optimization performed using Box-Behnken Design (BBD) established 10 % organic modifier, 0.4 mL min–1 flow rate and 6-µL injection volume as the optimum method conditions. Atazanavir sulfate eluted at 5.19 min without any interference. Method validation followed international guidelines. The method has proven linearity in the range of 10–90 µg mL–1. Recovery was between 100.2–101.0 % and precision within the accepted limits (RSD 0.2–0.7 %). LOD and LOQ were 2.68 and 8.14 µg mL–1, resp. Stress testing stability studies showed atazanavir sulfate to degrade under acidic and basic conditions. The suggested technique is simple, rapid and sustainable.It is, therefore, suggested for routine analysis of atazanavir sulfate

Numerical investigation into discontinuity-induced bifurcations in an aeroelastic system with coupled non-smooth nonlinearities

peer reviewedThe present study focuses on investigating the bifurcation characteristics of a pitch–plunge aeroelastic system possessing coupled non-smooth nonlinearities, both in structural and aerodynamic fronts. To this end, a freeplay nonlinearity is considered in the stiffness of the pitch degree-of-freedom. The effects of dynamic stall arising due to large instantaneous angles-of-attackare incorporated using the semi-empirical Leishman–Beddoes aerodynamic model. A systematic response analysis is carried out to discern the bifurcation characteristics of the aeroelastic system considering the airspeed as the system parameter. At low airspeeds, a series of dynamical transitions, including aperiodic responses, occur predominantly due to the structural freeplay nonlinearity while the flow remains attached to the surface of the wing. However, beyond a critical value of airspeed, the system response is dominated by high amplitude pitch-dominated limit-cycle oscillations, which can be attributed to stall flutter. It is demonstrated that the freeplay gap plays a key role in combining the effects of structural and aerodynamic nonlinearities. At higher values of the freeplay gap, interesting discontinuity-induced bifurcation scenarios, such as grazing and boundary equilibrium bifurcations arise due to coupled nonlinear interactions, which can significantly impact the safety of the aeroelastic system

Multiple urinary bladder masses from metastatic prostate adenocarcinoma

We present an unusual case of metastatic prostate adenocarcinoma that manifested with multiple exophytic intravesical masses, mimicking a multifocal primary bladder tumor. Biopsy with immunohistochemical analysis confirmed metastatic prostate adenocarcinoma. The patient was treated palliatively with external beam radiotherapy to prevent possible symptoms from local tumor progression. This case illustrates that when a patient with known prostate cancer presents with multifocal bladder tumors, the possibility of metastatic prostate cancer should be considered

A clinical trial of treatment of uncomplicated typhoid fever: efficacy of ceftriaxone-azithromycin combination

Background: Typhoid fever is a systemic infection caused by Gram-negative bacterium Salmonella enterica serovar typhi (S. typhi). It is a major health problem in India. It carries significant morbidity and mortality. Antimicrobial therapy is critical for the management of typhoid fever. Emergence of multidrug-resistant (MDR) and nalidixic acid-resistant (NAR) strains of S. typhi has complicated therapy by limiting treatment options. Hence, this study was conducted to evaluate the efficacy and safety profile of ceftriaxone and azithromycin combination therapy in uncomplicated typhoid fever.Methods: Adults patients of blood culture proven uncomplicated typhoid fever admitted in the medicine ward of Teerthanker Mahaveer Medical College and Research Centre were treated with ceftriaxone intravenously (2 g daily for 14 days) and azithromycin orally (500 mg daily for 7 days). Patients were clinically and bacteriologically evaluated during the study period and follow-up.Results: 96% cure rate was observed. No relapse was recorded.Conclusion: Ceftriaxone-azithromycin combination may be considered as an empirical therapy for treatment of uncomplicated typhoid fever in view of the emergence of MDR and NAR strains of S. typhi

Gallbladder reporting and data system (GB-RADS) for risk stratification of gallbladder wall thickening on ultrasonography:an international expert consensus

The Gallbladder Reporting and Data System (GB-RADS) ultrasound (US) risk stratification is proposed to improve consistency in US interpretations, reporting, and assessment of risk of malignancy in gallbladder wall thickening in non-acute setting. It was developed based on a systematic review of the literature and the consensus of an international multidisciplinary committee comprising expert radiologists, gastroenterologists, gastrointestinal surgeons, surgical oncologists, medical oncologists, and pathologists using modified Delphi method. For risk stratification, the GB-RADS system recommends six categories (GB-RADS 0–5) of gallbladder wall thickening with gradually increasing risk of malignancy. GB-RADS is based on gallbladder wall features on US including symmetry and extent (focal vs. circumferential) of involvement, layered appearance, intramural features (including intramural cysts and echogenic foci), and interface with the liver. GB-RADS represents the first collaborative effort at risk stratifying the gallbladder wall thickening. This concept is in line with the other US-based risk stratification systems which have been shown to increase the accuracy of detection of malignant lesions and improve management. Graphical abstract: [Figure not available: see fulltext.]

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment