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NK2 Homeobox 1 (NKX2‐1) is a well‐characterized pathological marker that delineates lung adenocarcinoma (LUAD) progression. The advancement of LUAD is influenced by the immune tumor microenvironment through paracrine signaling. However, the involvement of NKX2‐1 in modeling the tumor immune microenvironment is still unclear. Here, the downregulation of NKX2‐1 is observed in high‐grade LUAD. Meanwhile, single‐cell RNA sequencing and Visium in situ capturing profiling revealed the recruitment and infiltration of neutrophils in orthotopic syngeneic tumors exhibiting strong cell‐cell communication through the activation of CXCLs/CXCR2 signaling. The depletion of NKX2‐1 triggered the expression and secretion of CXCL1, CXCL2, CXCL3, and CXCL5 in LUAD cells. Chemokine secretion is analyzed by chemokine array and validated by qRT‐PCR. ATAC‐seq revealed the restrictive regulation of NKX2‐1 on the promoters of CXCL1, CXCL2, and CXCL5 genes. This phenomenon led to increased tumor growth, and conversely, tumor growth decreased when inhibited by the CXCR2 antagonist SB225002. This study unveils how NKX2‐1 modulates the infiltration of tumor‐promoting neutrophils by inhibiting CXCLs/CXCR2‐dependent mechanisms. Hence, targeting CXCR2 in NKX2‐1‐low tumors is a potential antitumor therapy that may improve LUAD patient outcomes. [ABSTRACT FROM AUTHOR]

Tensin family members, including tensin2 (TNS2), are present as major components of the focal adhesions. The N-terminal end of TNS2 contains a C1 region (protein kinase C conserved region 1) that is not found in other tensin members. Three isoforms of TNS2 have been identified with previous reports describing the shortest V3 isoform as lacking the C1 region. Although TNS2 is known to regulate cell proliferation and migration, its role in tumorigenicity is controversial. By gain-of-function overexpression approaches, results supporting either promotion or reduction of cancer cell tumorigenicity were reported. Here we report that the complete V3 isoform also contains the C1 region and describe the expression patterns of the three human TNS2 isoforms. By loss-of-function approaches, we show that silencing of TNS2 up-regulates the activities of Akt, Mek, and IRS1, and increases tumorigenicities in A549 and Hela cells. Using public database analyses we found that TNS2 is down-regulated in head and neck, esophageal, breast, lung, liver, and colon cancer. In addition, patients with low TNS2 expression showed poor relapse-free survival rates for breast and lung cancers. These results strongly suggest a role of tensin2 in suppressing cell transformation and reduction of tumorigenicity.

This study examines the extent to which capital thresholds induce insurers to strategically exert accounting discretion to forestall regulatory actions. Using a sample of US property-liability insurers during 1994-2009, we find that when managing their claim loss reserves, the average insurers are insensitive to the pressure of capital regulation as measured by the distance of their RBC ratio to the action threshold. Yet, when the insurers are virtually partitioned by their reserving tendency, the effect of regulatory pressure is significantly related to the downward reserve bias in the under-reserving insurer cohorts. This finding continues to hold even after we utilize the number of ratio violations in the insurance regulatory information systems to purge the financial weakness effect embedded in the distance to RBC bound ratio. Hence, our empirical evidence suggests that insurers that are about to trigger the regulatory threshold will have the incentives to understate their loss reserves to preclude the impending authorized preventive actions. Finally, our analyses also shed light on the heterogeneity of incentives to managing loss reserves among over- and under-reserving insurers. [ABSTRACT FROM AUTHOR]

X-linked retinoschisis (XLRS) is an inherited retinal disorder with severe retinoschisis and visual impairments. Multiomics approaches integrate single-cell RNA-sequencing (scRNA-seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and revealing cell-cell interactions involved in biomolecular pathomechanisms. Herein, a multimodal approach is demonstrated combining high-throughput scRNA-seq and ST to elucidate XLRS-specific transcriptomic signatures in two XLRS-like models with retinal splitting phenotypes, including genetically engineered (Rs1 emR209C ) mice and patient-derived retinal organoids harboring the same patient-specific p.R209C mutation. Through multiomics transcriptomic analysis, the endoplasmic reticulum (ER) stress/eukryotic initiation factor 2 (eIF2) signaling, mTOR pathway, and the regulation of eIF4 and p70S6K pathways are identified as chronically enriched and highly conserved disease pathways between two XLRS-like models. Western blots and proteomics analysis validate the occurrence of unfolded protein responses, chronic eIF2α signaling activation, and chronic ER stress-induced apoptosis. Furthermore, therapeutic targeting of the chronic ER stress/eIF2α pathway activation synergistically enhances the efficacy of AAV-mediated RS1 gene delivery, ultimately improving bipolar cell integrity, postsynaptic transmission, disorganized retinal architecture, and electrophysiological responses. Collectively, the complex transcriptomic signatures obtained from Rs1 emR209C mice and patient-derived retinal organoids using the multiomics approach provide opportunities to unravel potential therapeutic targets for incurable retinal diseases, such as XLRS., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Mutations in genes involved in the PI3K/AKT pathway and amplifications of the PIK3CA gene in gastric cancer and their associations with clinicopathological characteristics and EBV infection were analyzed in this study. A total of 431 patients with gastric adenocarcinomas were enrolled, and 39 mutation hotspots were evaluated in these patients using MALDI-TOF mass spectrometry were analyzed. PIK3CA amplifications were analyzed using real-time quantitative PCR. Regarding patients with intestinal-type gastric cancer, those with mutations in PI3K/AKT pathway genes were also more likely to have tumors located in the lower-third of the stomach than were those without mutations. Regarding patients with diffuse-type gastric cancer, those with PI3K/AKT pathway mutations were more likely to have tumors located in the upper-third of the stomach and to have more hematogenous metastases, particularly in the liver and lungs, than were patients without such mutations (22.2% vs. 4.5%). No significant survival difference was observed between patients with vs. without PI3K/AKT pathway mutations. Mutations in PI3K/AKT pathway genes were associated with hematogenous metastasis in patients with diffuse-type gastric cancer. Only when the tumors were located in the middle-third of stomach, tumor with mutations of the PIK3CA gene or mutations of the PI3K/AKT pathway genes were associated with more EBV infection than those without mutations. Patients with PIK3CA amplifications were more likely to have diffuse-type and poorly differentiated gastric cancers and were more likely to experience peritoneal recurrence compared with those without PIK3CA amplifications. Even upon subgroup analysis, PI3KCA amplifications were found to not affect the patients' outcomes.

Recent emerging studies suggest that a substantial fraction of microRNA (miRNA) genes is likely to form clusters in terms of evolutionary conservation and biological implications, posing a significant challenge for the research community and shifting the bottleneck of scientific discovery from miRNA singletons to miRNA clusters. In addition, the advance in molecular sequencing technique such as next-generation sequencing (NGS) has facilitated researchers to comprehensively characterize miRNAs with low abundance on genome-wide scale in multiple species. Taken together, a large scale, cross-species survey of grouped miRNAs based on genomic location would be valuable for investigating their biological functions and regulations in an evolutionary perspective. In the present chapter, we describe the application of effective and efficient bioinformatics tools on the identification of clustered miRNAs and illustrate how to use the recently developed Web-based database, MetaMirClust (http://fgfr.ibms.sinic.aedu.tw/MetaMirClust) to discover evolutionarily conserved pattern of miRNA clusters across metazoans.

MicroRNAs are derived from endogenous stem-loop precursors, and play important roles in various biological processes. From next-generation sequencing data, it is suggested that both the 5p-arm and 3p-arm of mature miRNAs could be generated from a single miRNA hairpin precursor; however, the current miRNA databases fail to provide comprehensive arm annotation features, which could result in ambiguous and incomplete analyses. In the present report, we have annotated over 99.7% of miRNAs with the correct 5p-arm and 3p-arm features. The length distribution of all annotated miRNAs is around 22 nucleotides; however, the 5p-arm miRNAs seem to be longer than those of the 3p-arm, which is evident in the 23-nucleotide group. Our study effort generates comprehensive miRNA arm-feature annotation which can be utilized for better interrogation of miRNAs. In further analysis of human gastric cancer tissues, we identified 38 down-regulated miRNAs and 22 up-regulated arm-specific miRNAs using this new comprehensives miRNA list., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)