Development and validation of a model based on immunogenic cell death related genes to predict the prognosis and immune response to bladder urothelial carcinoma

BackgroundImmunogenic cell death (ICD) has been categorized as a variant of regulated cell death that is capable of inducing an adaptive immune response. A growing body of evidence has indicated that ICD can modify the tumor immune microenvironment by releasing danger signals or damage-associated molecular patterns (DAMPs), potentially enhancing the efficacy of immunotherapy. Consequently, the identification of biomarkers associated with ICD that can classify patients based on their potential response to ICD immunotherapy would be highly advantageous. Therefore the goal of the study is to better understand and identify what patients with bladder urothelial carcinoma (BLCA) will respond to immunotherapy by analyzing ICD signatures and investigate ICD-related prognostic factors in the context of BLCA.MethodsThe data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases regarding BLCA and normal samples was categorized based on ICD-related genes (IRGs). Specifically, we conducted an immunohistochemical (IHC) experiment to validate the expression levels of Calreticulin (CALR) in both tumor and adjacent tissues, and evaluated its prognostic significance using the Kaplan-Meier (KM) curve. Subsequently, the samples from TCGA were divided into two subtypes using consensus clustering. To obtain a more comprehensive comprehension of the biological functions, we utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The calculation of immune landscape between two subtypes was performed through ESTIMATE and CIBERSORT. Risk models were constructed using Cox and Lasso regression and their prognosis predictive ability was evaluated using nomogram, receiver operating characteristic (ROC), and calibration curves. Finally, Tumor Immune Dysfunction and Exclusion (TIDE) algorithms was utilized to predict the response to immunotherapy.ResultsA total of 34 IRGs were identified, with most of them exhibiting upregulation in BLCA samples. The expression of CALR was notably higher in BLCA compared to the adjacent tissue, and this increase was associated with an unfavorable prognosis. The differentially expressed genes (DEGs) associated with ICD were linked to various immune-related pathways. The ICD-high subtypes exhibited an immune-activated tumor microenvironment (TME) compared to the ICD-low subtypes. Utilizing three IRGs including CALR, IFNB1, and IFNG, a risk model was developed to categorize BLCA patients into high- and low-risk groups. The overall survival (OS) was considerably greater in the low-risk group compared to the high-risk group, as evidenced by both the TCGA and GEO cohorts. The risk score was identified as an independent prognostic parameter (all p < 0.001). Our model demonstrated good predictive ability (The area under the ROC curve (AUC), AUC1-year= 0.632, AUC3-year= 0.637, and AUC5-year =0.653). Ultimately, the lower risk score was associated with a more responsive immunotherapy group.ConclusionThe potential of the ICD-based risk signature to function as a marker for evaluating the prognosis and immune landscape in BLCA suggests its usefulness in identifying the suitable population for effective immunotherapy against BLCA

Cross-shopping and shopping orientation : consumer perceived value in today's dynamic retail environment

"The purpose of this research was to explore and understand better how consumers perceive the value of their shopping experiences in two key retail outlets--mass merchandisers and department stores--as well as how consumers' shopping orientations, recreational or functional, relate to consumer perceived value (CPV). An initial qualitative approach was used, i.e., in-depth, lightly structured interviews, to explore the perceptions consumers have of the value they gain during their shopping experiences in retail stores. Findings from the qualitative study were combined with an in-depth literature review to develop a survey to measure consumers' perceptions of transaction value, acquisition value, efficiency value, choice value, esthetic value, curiosity value, social interaction value, social status value, and self-gratification value when shopping in mass merchandisers and department stores. 800 surveys were disseminated, which resulted in 372 usable questionnaires for analysis, a 46.5% response rate. The findings indicated that consumers do have different levels of perception on some of the value dimensions tested when they shop at mass merchandisers versus department stores. Specifically, consumers perceived higher levels of acquisition value and efficiency value at mass merchandisers than at department stores, and they perceived higher levels of transaction value, esthetic value, curiosity value, social interaction value, social status value, and self-gratification value at department stores than at mass merchandisers. Choice value was not perceived as different when consumers shopped at the two different retail outlets. It was also found that shopping orientation, a recreational or functional shopping approach, significantly affected consumers' value perceptions when they shopped. Recreational shoppers perceived significantly higher levels of all the value dimensions investigated than functional shoppers at both department stores and mass merchandisers. The study results suggest that retailers may first want to target the perceived values most salient to consumers in order to increase their profitability, and, second, they may want to focus on the less salient values identified in the study to gain a better understanding of why consumers rated these values much lower when shopping in their establishments."--Abstract from author supplied metadata

Simultaneous Determination of Selegiline, Desmethylselegiline, R/S-methamphetamine, and R/S-amphetamine on Dried Urine Spots by LC/MS/MS: Application to a Pharmacokinetic Study in Urine

Objective: Chiral analysis is a crucial method to differentiate selegiline intake from drug abuse. A dried urine spot (DUS) analytical method based on spotting urine samples (10 μL) onto dried spot collection cards, and followed by air-drying and extraction, was developed and validated for the determination of selegiline, desmethylselegiline, R/S-methamphetamine, and R/S-amphetamine.Methods: Methanol (0.5 mL) was found to be the ideal extraction solvent for target extraction from DUSs under orbital-horizontal stirring on a lateral shaker at 1,450 rpm for 30 min. Determinations were performed by direct electrospray ionization tandem mass spectrometry (ESI-MS/MS) under positive electrospray ionization conditions using multiple reaction monitoring mode. The chromatographic system consisted of a ChirobioticTM V2 column (2.1 × 250 mm, 5 μm) and a mobile phase of methanol containing 0.1% (v/v) glacial acetic acid and 0.02% (v/v) ammonium hydroxide.Results and conclusions: The calibration curves were linear from 50 to 5,000 ng/mL, with r > 0.995 for all analytes, imprecisions ≤ 15% and accuracies between −11.4 and 11.7%. Extraction recoveries ranged from 48.6 to 105.4% with coefficients of variation (CV) ≤ 13.7%, and matrix effects ranged from 45.4 to 104.1% with CV ≤ 10.3%. The lower limit of quantification was 50 ng/mL for each analyte. The present method is simple, rapid (accomplished in 12 min), sensitive, and validated by a pharmacokinetic study in human urine collected after a single oral administration of SG

Mining interesting locations and travel sequences from GPS trajectories

The increasing availability of GPS-enabled devices is changing the way people interact with the Web, and brings us a large amount of GPS trajectories representing people’s location histories. In this paper, based on multiple users ’ GPS trajectories, we aim to mine interesting locations and classical travel sequences in a given geospatial region. Here, interesting locations mean the culturally important places, such as Tiananmen Square in Beijing, and frequented public areas, like shopping malls and restaurants, etc. Such information can help users understand surrounding locations, and would enable travel recommendation. In this work, we first model multiple individuals ’ location histories with a tree-based hierarchical graph (TBHG). Second, based on the TBHG, we propose a HITS (Hypertext Induced Topic Search)-based inference model, which regards a

Case Report: Clinical benefit from multi-target tyrosine kinase inhibitor and PARP inhibitor in a patient with cancer of unknown primary with BRCA1 large genomic rearrangement

Background: Cancer of unknown primary (CUP), which accounts for 3%–5% of new cancer cases every year, involves the presence of a type of histologically confirmed metastatic tumors whose primary site cannot be confirmed by conventional diagnostic methods. This difficulty in identifying the primary site means that CUP patients fail to receive precisely targeted therapy. Most patients are treated with empiric chemotherapy, with a median survival of 6 months and even poorer prognosis within an unfavorable subset of CUP.Case report: An 80-year-old woman presented with masses in the abdomen. Following comprehensive imagological and immunohistochemical examinations, she was diagnosed with CUP. She emphatically declined chemotherapy; thus, anlotinib has been administered with patient consent since 02/07/2019, and stable disease (SD) was observed for 2 years. During subsequent treatment, a large genomic rearrangement in BRCA1 was identified in the patient via NGS, and SD was observed for a further 6 months following olaparib treatment. The type of LGR identified in this patient was discovered to be BRCA1 exon 17-18 inversion (inv), which has never been previously reported.Conclusion: For CUP patients, a chemo-free regimen seems to be acceptable as a first-line treatment, and NGS-guided targeted treatment could improve patient outcomes

Distinct Clinical Effects of Two RP1L1 Hotspots in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report 4

PURPOSE: To characterize the clinical effects of two RP1L1 hotspots in patients with East Asian occult macular dystrophy (OMD). METHODS: Fifty-one patients diagnosed with OMD harboring monoallelic pathogenic RP1L1 variants (Miyake disease) from Japan, South Korea, and China were enrolled. Patients were classified into two genotype groups: group A, p.R45W, and group B, missense variants located between amino acids (aa) 1196 and 1201. The clinical parameters of the two genotypes were compared, and deep learning based on spectral-domain optical coherence tomographic (SD-OCT) images was used to distinguish the morphologic differences. RESULTS: Groups A and B included 29 and 22 patients, respectively. The median age of onset in groups A and B was 14.0 and 40.0 years, respectively. The median logMAR visual acuity of groups A and B was 0.70 and 0.51, respectively, and the survival curve analysis revealed a 15-year difference in vision loss (logMAR 0.22). A statistically significant difference was observed in the visual field classification, but no significant difference was found in the multifocal electroretinographic classification. High accuracy (75.4%) was achieved in classifying genotype groups based on SD-OCT images using machine learning. CONCLUSIONS: Distinct clinical severities and morphologic phenotypes supported by artificial intelligence-based classification were derived from the two investigated RP1L1 hotspots: a more severe phenotype (p.R45W) and a milder phenotype (1196-1201 aa). This newly identified genotype-phenotype association will be valuable for medical care and the design of therapeutic trials