Cardiovascular toxicity profiles of immune checkpoint inhibitors with or without angiogenesis inhibitors: a real-world pharmacovigilance analysis based on the FAERS database from 2014 to 2022

BackgroundImmune checkpoint inhibitors (ICIs) combined with angiogenesis inhibitors (AGIs) have become increasingly available for multiple types of cancers, although the cardiovascular safety profiles of this combination therapy in real-world settings have not been elucidated to date. Therefore, we aimed to comprehensively investigate the cardiovascular toxicity profiles of ICIs combined with AGIs in comparison with ICIs alone.MethodsThe Food and Drug Administration Adverse Event Reporting System (FAERS) database from the 1st quarter of 2014 to the 1st quarter of 2022 was retrospectively queried to extract reports of cardiovascular adverse events (AEs) associated with ICIs alone, AGIs alone and combination therapy. To perform disproportionality analysis, the reporting odds ratios (RORs) and information components (ICs) were calculated with statistical shrinkage transformation formulas and a lower limit of the 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0 with at least 3 reports was considered statistically significant.ResultsA total of 18 854 cardiovascular AE cases/26 059 reports for ICIs alone, 47 168 cases/67 595 reports for AGIs alone, and 3 978 cases/5 263 reports for combination therapy were extracted. Compared to the entire database of patients without AGIs or ICIs, cardiovascular AEs were overreported in patients with combination therapy (IC025/ROR025 = 0.559/1.478), showing stronger signal strength than those taking ICIs alone (IC025/ROR025 = 0.118/1.086) or AGIs alone (IC025/ROR025 = 0.323/1.252). Importantly, compared with ICIs alone, combination therapy showed a decrease in signal strength for noninfectious myocarditis/pericarditis (IC025/ROR025 = 1.142/2.216 vs. IC025/ROR025 = 0.673/1.614), while an increase in signal value for embolic and thrombotic events (IC025/ROR025 = 0.147/1.111 vs. IC025/ROR025 = 0.591/1.519). For outcomes of cardiovascular AEs, the frequency of death and life-threatening AEs was lower for combination therapy than ICIs alone in noninfectious myocarditis/pericarditis (37.7% vs. 49.2%) as well as in embolic and thrombotic events (29.9% vs. 39.6%). Analysis among indications of cancer showed similar findings.ConclusionOverall, ICIs combined with AGIs showed a greater risk of cardiovascular AEs than ICIs alone, mainly due to an increase in embolic and thrombotic events while a decrease in noninfectious myocarditis/pericarditis. In addition, compared with ICIs alone, combination therapy presented a lower frequency of death and life-threatening in noninfectious myocarditis/pericarditis and embolic and thrombotic events

FocusNet: Imbalanced Large and Small Organ Segmentation with an End-to-End Deep Neural Network for Head and Neck CT Images

In this paper, we propose an end-to-end deep neural network for solving the problem of imbalanced large and small organ segmentation in head and neck (HaN) CT images. To conduct radiotherapy planning for nasopharyngeal cancer, more than 10 organs-at-risk (normal organs) need to be precisely segmented in advance. However, the size ratio between large and small organs in the head could reach hundreds. Directly using such imbalanced organ annotations to train deep neural networks generally leads to inaccurate small-organ label maps. We propose a novel end-to-end deep neural network to solve this challenging problem by automatically locating, ROI-pooling, and segmenting small organs with specifically designed small-organ sub-networks while maintaining the accuracy of large organ segmentation. A strong main network with densely connected atrous spatial pyramid pooling and squeeze-and-excitation modules is used for segmenting large organs, where large organs' label maps are directly output. For small organs, their probabilistic locations instead of label maps are estimated by the main network. High-resolution and multi-scale feature volumes for each small organ are ROI-pooled according to their locations and are fed into small-organ networks for accurate segmenting small organs. Our proposed network is extensively tested on both collected real data and the \emph{MICCAI Head and Neck Auto Segmentation Challenge 2015} dataset, and shows superior performance compared with state-of-the-art segmentation methods.Comment: MICCAI 201

Nondestructive detection of Pleurotus geesteranus strain degradation based on micro-hyperspectral imaging and machine learning

In the production of edible fungi, the use of degraded strains in cultivation incurs significant economic losses. Based on micro-hyperspectral imaging and machine learning, this study proposes an early, nondestructive method for detecting different degradation degrees of Pleurotus geesteranus strains. In this study, an undegraded strain and three different degradation-level strains were used. During the mycelium growth, 600 micro-hyperspectral images were obtained. Based on the average transmittance spectra of the region of interest (ROI) in the range of 400-1000 nm and images at feature bands, feature spectra and images were extracted using the successive projections algorithm (SPA) and the deep residual network (ResNet50), respectively. Different feature input combinations were utilized to establish support vector machine (SVM) classification models. Based on the results, the spectra-input-based model performed better than the image-input-based model, and feature extraction improved the classification results for both models. The feature-fusion-based SPA+ResNet50-SVM model was the best; the accuracy rate of the test set was up to 90.8%, which was better than the accuracy rates of SPA-SVM (83.3%) and ResNet50-SVM (80.8%). This study proposes a nondestructive method to detect the degradation of Pleurotus geesteranus strains, which could further inspire new methods for the phenotypic identification of edible fungi

Extracellular histones cause intestinal epithelium injury and disrupt its barrier function in vitro and in vivo.

Extracellular histones are cytotoxic to various cells and have been extensively proven a vital mediator of multiple organ injuries. However, the effect of extracellular histones on the intestine remains largely unknown. This study aimed to clarify the effect of extracellular histones on the intestine. IEC-6, a cell line of rat small intestinal epithelial crypt, and C57BL/6 or ICR mice were treated with histones. The IEC-6 cells treated with histones from 20 μg/mL to 200 μg/mL for 0-24 h displayed a decline of cell viability and an increase of cell death in a concentration- and time-dependent manner. Moreover, histones (100 μg/mL) induced IEC-6 apoptosis through activating caspase 3 and necroptosis through up-regulation of receptor-interacting serine/threonine protein kinase 1 and 3 (RIPK1 and RIPK3), phosphorylated mixed-lineage kinase domain-like protein (p-MLKL) along with the decrease of caspase-8. Histones treatment disturbed zonular occludens 1 (ZO-1) expression and increased permeability of IEC-6 cell monolayer. In vivo, histones 50 mg/kg injection caused mice intestinal edema, loss apex of villus, epithelial lifting down the sides of the villi, and increased neutrophil infiltration. Elevation of serum intestinal fatty acid binding protein (I-FABP), d-lactate, or Diamine oxidase (DAO) and loss of tight junction protein, ZO-1, at 3 h and 6 h after histones injection strongly indicated severe intestinal epithelium injury, which led to increased permeability of the intestine. In conclusion, extracellular histones cause intestinal epithelial damage via direct cytotoxicity. Consequently, intestinal epithelial tight junction and barrier integrity are disrupted, which may play pivotal roles in diverse diseases

Abnormal Degree Centrality Associated With Cognitive Dysfunctions in Early Bipolar Disorder

Delayed diagnosis of bipolar disorder (BD) is common. However, diagnostic validity may be enhanced using reliable neurobiological markers for BD. Degree centrality (DC) is one such potential marker that enables researchers to visualize neuronal network abnormalities in the early stages of some neuropsychiatric disorders. In the present study, we measured resting-state DC abnormalities and cognitive deficits in order to identify early neurobiological markers for BD. We recruited 23 patients with BD who had recently experienced manic episodes (duration of illness <2 years) and 46 matched healthy controls. Our findings indicated that patients with BD exhibited DC abnormalities in frontal areas, temporal areas, the right postcentral gyrus, and the posterior lobe of the cerebellum. Moreover, correlation analysis revealed that psychomotor speed indicators were associated with DC in the superior temporal and inferior temporal gyri, while attention indicators were associated with DC in the inferior temporal gyrus, in patients with early BD. Our findings suggest that DC abnormalities in neural emotion regulation circuits are present in patients with early BD, and that correlations between attention/psychomotor speed deficits and temporal DC abnormalities may represent early markers of BD

Association of IGF-I gene polymorphisms with milk yield and body size in Chinese dairy goats

The association of IGF-I gene polymorphisms with certain traits in 708 individuals of two Chinese dairy-goat breeds (Guanzhong and Xinong Saanen) was investigated. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods were employed in screening for genetic variation. Two novel mutations were detected in the 5'-flanking region and in intron 4 of IGF-I gene, viz., g.1617 G > A and g.5752 G > C (accession D26119.2), respectively. The associations of the g.1617 G > A mutation with milk yield and the body size were not significant (p > 0.05). However, in the case of g.5752 G > C, Xinong Saanen dairy goats with the CG genotype presented longer bodies (p < 0.05). Chest circumference (p < 0.05) was larger in Guanzhong goats with the GG genotype. In Xinong Saanen dairy goats with the CC genotype, milk yields were significantly higher during the first and second lactations (p < 0.05). Hence, the g.5752 G > C mutation could facilitate association analysis and serve as a genetic marker for Chinese dairy-goat breeding and genetics

Transcriptional profiles of drought-responsive genes in modulating transcription signal transduction, and biochemical pathways in tomato

To unravel the molecular mechanisms of drought responses in tomato, gene expression profiles of two drought-tolerant lines identified from a population of Solanum pennellii introgression lines, and the recurrent parent S. lycopersicum cv. M82, a drought-sensitive cultivar, were investigated under drought stress using tomato microarrays. Around 400 genes identified were responsive to drought stress only in the drought-tolerant lines. These changes in genes expression are most likely caused by the two inserted chromosome segments of S. pennellii, which possibly contain drought-tolerance quantitative trait loci (QTLs). Among these genes are a number of transcription factors and signalling proteins which could be global regulators involved in the tomato responses to drought stress. Genes involved in organism growth and development processes were also specifically regulated by drought stress, including those controlling cell wall structure, wax biosynthesis, and plant height. Moreover, key enzymes in the pathways of gluconeogenesis (fructose-bisphosphate aldolase), purine and pyrimidine nucleotide biosynthesis (adenylate kinase), tryptophan degradation (aldehyde oxidase), starch degradation (β-amylase), methionine biosynthesis (cystathionine β-lyase), and the removal of superoxide radicals (catalase) were also specifically affected by drought stress. These results indicated that tomato plants could adapt to water-deficit conditions through decreasing energy dissipation, increasing ATP energy provision, and reducing oxidative damage. The drought-responsive genes identified in this study could provide further information for understanding the mechanisms of drought tolerance in tomato

Concise Approach to Benzisothiazol-3(2<i>H</i>)-one via Copper-Catalyzed Tandem Reaction of <i>o</i>-Bromobenzamide and Potassium Thiocyanate in Water

A concise approach to various benzisothiazol-3­(2<i>H</i>)-one derivatives has been developed by copper-catalyzed the reaction of <i>o</i>-bromobenzamide derivatives with potassium thiocyanate (KSCN) in water. The reaction proceeds via a tandem reaction with S–C bond and S–N bond formation