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Objective: β-Cell and islet endothelial cell destruction occurs during the progression of type 1 diabetes, but, paradoxically, β-cell proliferation is increased during this period. Altered glucose tolerance may affect β-cell mass and its association with endothelial cells. Our objective was to study the effects of glucose and inflammation on islet vascularity and on β function, mass, and insulin in immunologically tolerant anti-CD3 monoclonal antibody (mAb)-treated and prediabetic NOD mice.Research Design and Methods: The effects of phloridzin or glucose injections on β-cells and endothelial cells were tested in prediabetic and previously diabetic NOD mice treated with anti-CD3 mAbs. Glucose tolerance, immunofluorescence staining, and examination of islet cultures ex vivo were evaluated.Results: Islet endothelial cell density decreased in NOD mice and failed to recover after anti-CD3 mAb treatment despite baseline euglycemia. Glucose treatment of anti-CD3 mAb-treated mice showed increased islet vascular density and increased insulin content, which was associated with improved glucose tolerance. The increase in the vascular area was dependent on islet inflammation. Increased islet endothelial cell density was associated with increased production of vascular endothelial growth factor (VEGF) by islets from NOD mice. This response was recapitulated ex vivo by the transfer of supernatants from NOD islets cultured in high-glucose levels.Conclusions: Our results demonstrate a novel role for glucose and inflammation in the control of islet vasculature and insulin content of β-cells in prediabetic and anti-CD3-treated NOD mice. VEGF production by the islets is affected by glucose levels and is imparted by soluble factors released by inflamed islets. [ABSTRACT FROM AUTHOR]

PURPOSE: Mutations involved in neoplastic progression may be able to serve as markers for the presence of small numbers of neoplastic cells that would otherwise escape detection in diagnostic assays. Previous retrospective studies have suggested that the sensitivity of the cytologic diagnosis of pancreatic and biliary tract carcinomas is improved when analysis includes Ki-ras exon 1, which is commonly mutated in these neoplasms. We report our experience with the systematic prospective application of Ki-ras gene analysis to the evaluation of fine-needle aspirates and brushings from the pancreatobiliary tract. MATERIALS AND METHODS: Between September 1996 and April 1999, 75 pancreatic fine-needle aspirates and common bile duct brushings submitted for routine cytologic diagnosis were also evaluated for mutations in Ki-ras exon 1 by polymerase chain reaction/single-strand conformation polymorphism analysis. After routine preparation of the specimens, residual material was used for molecular analysis. Results are compared with the morphologic diagnosis and available clinical information. RESULTS: Single-strand conformation polymorphism mutation patterns in Ki-ras were detected in 22 of the 70 consecutive clinical specimens with adequate DNA and at least 6 months of available clinical follow-up. Sensitivity, specificity, and positive predictive value for the presence of concurrent or subsequent pancreatobiliary carcinoma were 33%, 97%, and 93%, respectively, for definitive cytologic diagnosis alone, and 53%, 97%, and 95% for positive Ki-ras single-strand conformation polymorphism mutation pattern alone. If definitive positive cytology or atypical/suspicious cytology with a positive Ki-ras single-strand conformation polymorphism mutation pattern is used, sensitivity is 55%, specificity is 97%, and positive predictive value is 96% for the presence of pancreatobiliary carcinoma. DISCUSSION: Results support the routine use of Ki-ras mutational analysis to increase the sensitivity of the cytologic evaluation of pancreatobiliary fine-needle aspirates and common bile duct brushings with atypical or suspicious morphology without compromising specificity. [ABSTRACT FROM AUTHOR]

Basal Cell Adhesion Molecule (BCAM), a receptor for laminin subunit α5, plays a crucial role in the pathogenesis of various malignancies. Notably, evidence of hypermethylation at multiple immune checkpoints in patients with low BCAM expression suggests these individuals may respond favorably to immunotherapy using ICIs (immune checkpoint inhibitors). This finding lays the foundation for the hypothesis that BCAM may serve as an important biomarker in cancer patients. To investigate this potential, we evaluated BCAM expression patterns in 3114 patients from both discovery and validation cohorts, spanning seven cancer types, using quantitative immunofluorescence (QIF). We also explored the correlation between BCAM and PD-L1 expressions within these cohorts, aiming to establish its potential predictive value for immunotherapy response. Our findings indicate that BCAM was highly expressed in ovarian (79.2%) and lung (78.5%) tumors, with lower yet significant expression in breast (37.7%), head and neck (31.3%), and bladder-urothelial tumors (27.6%). Notably, high BCAM expression was associated with better OS in NSCLC. More importantly, BCAM expression did not correlate with PD-L1 protein expression in any of these tumors, highlighting its independent predictive potential. The widespread expression of BCAM across multiple tumor types, coupled with its lack of correlation with PD-L1 expression, highlights its potential as a predictive novel biomarker across various cancer types., (© 2024. The Author(s).)

Purpose: We aim to improve the prediction of response or resistance to immunotherapies in patients with melanoma. This goal is based on the hypothesis that current gene signatures predicting immunotherapy outcomes show only modest accuracy due to the lack of spatial information about cellular functions and molecular processes within tumors and their microenvironment., Experimental Design: We collected gene expression data spatially from three cellular compartments defined by CD68+ macrophages, CD45+ leukocytes, and S100B+ tumor cells in 55 immunotherapy-treated melanoma specimens using Digital Spatial Profiling-Whole Transcriptome Atlas. We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification., Results: We achieved robust performance of compartment-specific signatures in predicting the outcome of immune checkpoint inhibitors in the discovery cohort. Of the three signatures, the S100B signature showed the best performance in the validation cohort (N = 45). We also compared our compartment-specific signatures with published bulk signatures and found the S100B tumor spatial signature outperformed previous signatures. Within the eight-gene S100B signature, five genes (PSMB8, TAX1BP3, NOTCH3, LCP2, and NQO1) with positive coefficients predict the response, and three genes (KMT2C, OVCA2, and MGRN1) with negative coefficients predict the resistance to treatment., Conclusions: We conclude that the spatially defined compartment signatures utilize tumor and tumor microenvironment-specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical assessment., (©2024 American Association for Cancer Research.)