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Computed tomography (CT) has become an important technique for assessing skeletal muscle mass. Low skeletal muscle mass (LSMM) is considered an unfavorable factor for postoperative complications in patients with gastric cancer (GC). Patients who underwent laparoscopic gastrectomy for GC were included. Skeletal muscle mass at the third lumbar vertebra (L3) level was measured by preoperatively using CT. The patients were divided into an LSMM group and a non-LSMM group and the intergroup differences were analyzed. Furthermore, we divided the LSMM group into mild and severe LSMM subgroups. The study also analyzed the influence of obesity-related LSMM on postoperative complications. A total of 409 patients were enrolled; of them, 265 had LSMM and 41 had severe LSMM. LSMM was associated with age, body mass index, and Nutritional Risk Screening 2002 score. In the multivariate analysis, LSMM was not related to postoperative complications. Further analysis revealed that severe LSMM was a risk factor for postoperative complications. The study also found that the risk of postoperative complications was significantly increased in patients with obesity-related LSMM. LSMM was not significantly correlated with postoperative complications. Severe LSMM and obesity-related LSMM are unfavorable factors for postoperative complications with GC after gastrectomy. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. LRP1B was initially identified as a cancer suppressor in several cancers. However, the potential biological phenotypes and molecular mechanisms of LRP1B in LUAD have not been fully investigated. In our study, we showed that the expression of LRP1B in LUAD tissues was lower than that in normal tissues. Knockdown of LRP1B markedly enhanced malignancy of LUAD cells. Genomic analysis indicated that the population expressing low-levels of LRP1B had higher genomic instability, which accounted for a larger proportion of aneuploidy and inflammation subtyping. Enrichment analysis of bulk and cell-line transcriptomic data both showed that the low expression of LRP1B could induce the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways. Moreover, our findings revealed that knockdown LRP1B enhanced the secretion of IL-6 and IL-8, as confirmed by ELISA assays. Further validation using PCR and WB confirmed that downregulation of LRP1B mRNA significantly upregulated the activity of the IL-6-JAK-STAT3 pathway. Collectively, this study highlights LRP1B as a tumor suppressor gene and reveals that LRP1B knockdown promotes malignant progression in LUAD by inducing inflammation through the IL-6-JAK-STAT3 pathway., Competing Interests: None., (AJCR Copyright © 2023.)

RNA N6-methyladenosine (m 6 A) modification in tumorigenesis and progression has been highlighted and discovered in recent years. However, the molecular and clinical implications of m 6 A modification in melanoma tumor microenvironment (TME) and immune infiltration remain largely unknown. Here, we utilized consensus molecular clustering with nonnegative matrix factorization based on the melanoma transcriptomic profiles of 23 m 6 A regulators to determine the m 6 A modification clusters and m 6 A-related gene signature. Three distinct m 6 A modification patterns (m 6 A-C1, C2, and C3), which are characterized by specific m 6 A regulator expression, survival outcomes, and biological pathways, were identified in more than 1,000 melanoma samples. The immune profile analyses showed that these three m 6 A modification subtypes were highly consistent with the three known immune phenotypes: immune-desert (C1), immune-excluded (C2), and immune-inflamed (C3). Tumor digital cytometry (CIBERSORT, ssGSEA) algorithm revealed an upregulated infiltration of CD8 + T cell and NK cell in m 6 A-C3 subtype. An m 6 A scoring scheme calculated by principal component of m 6 A signatures stratified melanoma patients into high- and low-m 6 sig score subgroups; a high score was significantly associated with prolonged survival and enhanced immune infiltration. Furthermore, fewer somatic copy number alternations (SCNA) and PD-L1 expression were found in patients with high m 6 Sig score. In addition, patients with high m 6 Sig score demonstrated marked immune responses and durable clinical benefits in two independent immunotherapy cohorts. Overall, this study indicated that m 6 A modification is involved in melanoma tumor microenvironment immune regulation and contributes to formation of tumor immunogenicity. Comprehensive evaluation of the m 6 A modification pattern of individual tumors will provide more insights into molecular mechanisms of TME characterization and promote more effective personalized biotherapy strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Du, Li, Li, Liu, Li, Dang, Chu, Yan, Fang, Wu, Zhang, Zhu and Li.)

Recent studies have highlighted the biological significance of RNA N 6 -methyladenosine (m 6 A) modification in tumorigenicity and progression. However, it remains unclear whether m 6 A modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. Methods : In this study, we curated 23 m 6 A regulators and performed consensus molecular subtyping with NMF algorithm to determine m 6 A modification patterns and the m 6 A-related gene signature in colon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based m 6 Sig scoring scheme was used to evaluate the m 6 A modification patterns of individual tumors with an immune response. Results : Three distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified m 6 A patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the m 6 Sig score, which was extracted from the m 6 A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m 6 Sig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower m 6 Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., PIK3CA and SMAD4 ). In addition, patients with lower m 6 Sig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts. Conclusions : This study highlights that m 6 A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m 6 A modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Immune checkpoint inhibitor (ICI) therapy has achieved remarkable clinical benefit in melanoma and non-small cell lung cancer (NSCLC). Tumor mutational signatures are the fingerprints of endogenous and exogenous factors that have acted throughout tumorigenesis and heterogeneity; however, their association with immune response in ICI-treated samples remains unclear. Here, we leveraged whole-exome sequencing (WES)-based mutational profiles combined with clinicopathologic characteristics from melanoma and NSCLC datasets to examine whether tumor genomic features contribute to clinical benefit of ICI treatment. Mutational data acquired from targeted next-generation sequencing (NGS) assays (MSK-IMPACT panels) were also employed for further corroboration. A mutational signature (known as age-related clock-like processing) characterized by enrichment of C>T mutations at NpCpG trinucleotides were identified to be associated with a worse prognosis and lower tumor mutation load (TML) in both WES and targeted NGS immunotherapy cohorts. We also analyzed gene transcriptomic profiles and identified immune regulation-related gene pathways that were significantly altered in samples with different clock-like signature grouping. Leucocyte subset analysis further revealed that clock-like signature was associated with the reduction of cytotoxic cell infiltration and elevation of regulatory T cells. Overall, our work re-annotated that the age-related clock-like signature was associated with worse prognosis and lower immune activity, offering opportunities to stratify patients into optimal immunotherapy plans based on genomic subtyping., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)