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Tumor‐associated macrophages (TAMs) greatly contribute to immune checkpoint inhibitor (ICI) resistance of cancer. However, its underlying mechanisms and whether TAMs can be promising targets to overcome ICI resistance remain to be unveiled. Through integrative analysis of immune multiomics data and single‐cell RNA‐seq data (iMOS) in lung adenocarcinoma (LUAD), lymphotoxin β receptor (LTBR) is identified as a potential immune checkpoint of TAMs, whose high expression, duplication, and low methylation are correlated with unfavorable prognosis. Immunofluorescence staining shows that the infiltration of LTBR+ TAMs is associated with LUAD stages, immunotherapy failure, and poor prognosis. Mechanistically, LTΒR maintains immunosuppressive activity and M2 phenotype of TAMs by noncanonical nuclear factor kappa B and Wnt/β‐catenin signaling pathways. Macrophage‐specific knockout of LTBR hinders tumor growth and prolongs survival time via blocking TAM immunosuppressive activity and M2 phenotype. Moreover, TAM‐targeted delivery of LTΒR small interfering RNA improves the therapeutic effect of ICI via reversing TAM‐mediated immunosuppression, such as boosting cytotoxic CD8+ T cells and inhibiting granulocytic myeloid‐derived suppressor cells infiltration. Taken together, we bring forth an immune checkpoint discovery pipeline iMOS, identify LTBR as a novel immune checkpoint of TAMs, and propose a new immunotherapy strategy by targeting LTBR+ TAMs. Highlights: Integrative analysis of immune multiomics data and single‐cell RNA‐seq data pipeline is developed and finds lymphotoxin β receptor (LTBR) expression specific in tumor‐associated macrophages (TAMs).LTΒR+ TAMs correlate with lung adenocarcinoma stages, immunotherapy resistance, and prognosis.LTΒR maintains TAM immunosuppressive activity and M2 phenotype by noncanonical nuclear factor kappa B signaling and Wnt/β‐catenin signaling.Disruption of LTΒR in TAMs enhances the therapeutic effect of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Aim: Achondroplasia is the most common of the skeletal dysplasias that cause fatal and disabling growth and developmental disorders in children, and is caused by a mutation in the fibroblast growth factor receptor, type 3 gene(FGFR3). This study aims to analyse the clinical characteristics and gene mutations of ACH to accurately determine whether a patient has ACH and to raise public awareness of the disease. Methods: The database of Pubmed, Cochrane Library, Wanfang and CNKI were searched with terms of "Achondroplasias" or "Skeleton-Skin-Brain Syndrome" or "Skeleton Skin Brain Syndrome" or "ACH" and "Receptor, Fibroblast Growth Factor, Type 3" or "FGFR3". Results: Finally, four hundred and sixty-seven patients with different FGFR3 mutations were enrolled. Of the 138 patients with available gender information, 55(55/138, 40%) were female and 83(83/138, 60%) were male. Among the patients with available family history, 47(47/385, 12%) had a family history and 338(338/385, 88%) patients were sporadic. The age of the patients ranged from newborn babies to 36 years old. The mean age of their fathers was 37 ± 7 years (range 31–53 years). Patients came from 12 countries and 2 continents, with the majority being Asian (383/432, 89%), followed by European (49/432, 11%). Short stature with shortened arms and legs was found in 112(112/112) patients, the abnormalities of macrocephaly in 94(94/112) patients, frontal bossing in 89(89/112) patients, genu valgum in 64(64/112) patients and trident hand were found in 51(51/112) patients. The most common mutation was p.Gly380Arg of the FGFR3 gene, which contained two different base changes, c.1138G > A and c.1138G > C. Ten rare pathogenic mutations were found, including c.831A > C, c.1031C > G, c.1043C > G, c.375G > T, c.1133A > G, c.1130T > G, c.833A > G, c.649A > T, c.1180A > T and c.970_971insTCTCCT. Conclusion: ACH was caused by FGFR3 gene mutation, and c.1138G > A was the most common mutation type. This study demonstrates the feasibility of molecular genetic testing for the early detection of ACH in adolescents with short stature, trident hand, frontal bossing, macrocephaly and genu valgum. [ABSTRACT FROM AUTHOR]

Aims: Diabetic kidney disease (DKD) is a severe microvascular complication frequently associated with type 1 and type 2 diabetes mellitus. The objective of this work was to evaluate the relevance of PI3K/Akt pathway polymorphisms and DKD susceptibility by a meta‐analysis. Methods: Case–control studies related to the relationship between PI3K/Akt pathway polymorphisms and DKD risk were searched from Pubmed, Embase, Cochrane Library, SINOMED, CNKI, and Wanfang databases. Statistical analysis and heterogeneity test were conducted by Review Manager 5.4. Results: Totally, 52 eligible studies were enrolled, including seven single nucleotide polymorphisms (SNPs) for four genes in the PI3K/AKT pathway (GNB3: rs5443; eNOS: rs1799983, rs869109213, rs2070744; IL‐6: rs1800795, rs1800796; TNFα: rs1800629). The "M" allele of eNOS rs1799983 was related to the increased risk of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 75%, OR = 1.29, 95%CI 1.07–1.56; MM + WM vs. WW: I2 = 75%, OR = 1.50, 95%CI 1.21–1.86). The "M" allele of eNOS rs869109213 was implicated with higher prevalence of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 63%, OR = 1.43, 95%CI 1.22–1.68; MM + WM vs. WW: I2 = 50%, OR = 1.36, 95%CI 1.16–1.58; MM vs. WM + WW: I2 = 59%, OR = 2.20, 95%CI 1.41–3.43). The "M" allele of eNOS rs2070744 was implicated with higher prevalence of DKD under random effects model, especially in Indian population (Overall: M vs. W: I2 = 47%, OR = 1.35, 95%CI 1.15–1.59; MM + WM vs. WW: I2 = 45%, OR = 1.32, 95%CI 1.07–1.62; MM vs. WM + WW: I2 = 65%, OR = 2.29, 95%CI 1.39–3.77). The "M" allele of IL‐6 rs1800796 was predominately associated with higher DKD risks under random effects model, especially in Asian population (Overall: M versus W: I2 = 23%, OR = 1.49, 95%CI 1.21–1.84; MM + WM vs. WW: I2 = 1%, OR = 1.43, 95%CI 1.15–1.77; MM + WM vs. WW: I2 = 71%, OR = 2.77, 95%CI 1.09–7.06). Conclusions: This meta‐analysis indicated that polymorphisms in the PI3K/Akt pathway in eNOS rs1799983, rs869109213, rs2070744, and IL‐6 rs1800796 were related to the increased risk of DKD. [ABSTRACT FROM AUTHOR]