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Background: Tuberculosis (TB) is a serious public health problem to human health, but the pathogenesis of TB remains elusive., Methods: To identify novel candidate genes associated with TB susceptibility, we performed a population-based case control study to genotype 41SNPs spanning 21 genes in 435 pulmonary TB patients and 375 health donors from China., Results: We found Notch4 gene rs206018 and rs422951 polymorphisms were associated with susceptibility to pulmonary tuberculosis. The association was validated in another independent cohort including 790 TB patients and 1,190 healthy controls. Moreover, we identified that the rs206018 C allele was associated with higher level of Notch4 in PBMCs from pulmonary TB patients. Furthermore, Notch4 expression increased in TB patients and higher Notch4 expression correlated with the severer pulmonary TB. Finally, we explored the origin and signaling pathways involved in the regulation of Notch4 expression in response to Mycobacterium tuberculosis (Mtb) infection. We determine that Mtb induced Notch4 and its ligand Jagged1expression in macrophages, and Notch4 through TLR2/P38 signaling pathway and Jagged1 through TLR2/ERK signaling pathway., Conclusion: Our work further strengthens that Notch4 underlay an increased risk of TB in humans and is involved in the occurrence and development of TB, which could serve as a novel target for the host-targeted therapy of TB., 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 © 2023 Fang, Liu, Qin, Wang, Huang, Pan and Zheng.)

Background: NRAS wildtype melanoma accounts for approximately 80% of melanomas. Previous studies have shown that NRAS wildtype melanoma had higher response rates and better prognoses than NRAS-mutant patients following immunotherapy, while as major actors in tumor cells and tumor microenvironment (TME), the association between NOTCH family genes and response to immunotherapy in NRAS wildtype melanoma remains indistinct., Objective: We aim to explore whether NOTCH family gene variation is associated with genomic factors in immune checkpoint inhibitor (ICI) response in NRAS wildtype melanoma and with clinical results in these patients., Method: This research used genomic data of 265 NRAS wildtype ICI-pretreatment samples from five ICI-treated melanoma cohorts to analyze the relationship between NOTCH family gene mutation and the efficacy of ICI therapy., Results: NRAS wildtype melanomas with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in both the discovery (HR: 0.30, 95% CI: 0.11-0.83, P = 0.01) and validation cohorts(HR: 0.21, 95% CI: 0.07-0.68, P = 0.003). Moreover, NOTCH4-Mut melanoma had a superior clinical response in the discovery cohort (ORR, 40.0% vs 13.11%, P = 0.057) and validation cohort (ORR, 68.75% vs 30.07%, P = 0.004). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) ( P < 0.05). NOTCH4-Mut tumors had a significantly increased mutation in the DNA damage response (DDR) pathway. Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity., Conclusion: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guide immunotherapeutic responsiveness., Competing Interests: Authors QZ, QD, YT, TS, and CQ were employed by Jiangsu Simcere Diagnostics Co., Ltd., the Nanjing Simcere Medical Laboratory Science Co., Ltd., and The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd. The remaining author declares 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 © 2022 Li, Zhang, Duan, Tan, Sun and Qi.)

NOTCH4 is a member of the NOTCH family of receptors whose expression is intensively induced in macrophages after their activation by Toll-like receptors (TLR) and/or interferon-γ (IFN-γ). In this work, we show that this receptor acts as a negative regulator of macrophage activation by diminishing the expression of proinflammatory cytokines, such as IL-6 and IL-12, and costimulatory proteins, such as CD80 and CD86. We have observed that NOTCH4 inhibits IFN-γ signaling by interfering with STAT1-dependent transcription. Our results show that NOTCH4 reprograms the macrophage response to IFN-γ by favoring STAT3 versus STAT1 phosphorylation without affecting their expression levels. This lower activation of STAT1 results in diminished transcriptional activity and expression of STAT1-dependent genes, including IRF1, SOCS1 and CXCL10. In macrophages, NOTCH4 inhibits the canonical NOTCH signaling pathway induced by LPS; however, it can reverse the inhibition exerted by IFN-γ on NOTCH signaling, favoring the expression of NOTCH-target genes, such as Hes1 . Indeed, HES1 seems to mediate, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 also affects TLR signaling by interfering with NF-κB transcriptional activity. This effect could be mediated by the diminished activation of STAT1. These results provide new insights into the mechanisms by which NOTCH, TLR and IFN-γ signal pathways are integrated to modulate macrophage-specific effector functions and reveal NOTCH4 acting as a new regulatory element in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excess of inflammation., 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 López-López, Romero de Ávila, Hernández de León, Ruiz-Marcos, Baladrón, Nueda, Laborda, García-Ramírez, Monsalve and Díaz-Guerra.)