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HOXA transcript at the distal tip (HOTTIP), belonging to the family of long non-coding RNA (lncRNA), is an important biomarker for ovarian cancer (OC) prognosis. Nevertheless, the function of HOTTIP in immune evasion of OC cells remains undecided. In the current study, the effect of HOTTIP on the development of OC was assessed and the mechanism was discovered as well. The neutrophils were isolated from the clinical samples, and the correlation between programmed death-ligand 1 (PD-L1) and interleukin-6 (IL-6) in neutrophils was analyzed. The relationships among HOTTIP, c-jun and IL-6 were investigated by RIP, CHIP, and the dual luciferase reporter gene assay. The roles of PD-L1, IL-6 and HOTTIP on the T cell proliferation and infiltration were measured in vitro and in vivo. Moreover, the association between HOTTIP and IL-6 in OC tissue and the connection between HOTTIP and OC prognosis were evaluated. Positive relationships were observed between IL-6 expression in peripheral blood and the PD-L1 expression in neutrophils of OC patients, and between the HOTTIP and IL-6 expression in OC tissues. HOTTIP could induce the release of IL-6 via c-jun. Besides, HOTTIP boosted the PD-L1 expression in neutrophils and inhibited the T cell proliferation, thus potentiating the immune evasion of OC cells. The prognosis of patients with higher expression of HOTTIP was worse. In summary, the HOTTIP/IL-6/PD-L1 axis was demonstrates as a novel regulatory signaling pathway involving in the progression of OC. Funding Statement: This work is supported by National Natural Science Foundation of China (81472179, 81873975, 81808084), the Excellent Academic Leader Training Program of Shanghai Health System (2018BR31), the Fundamental Research Funds for the Central Universities (22120170071) and the Clinical Research And Cultivation Project of Shanghai Tongji Hospital (ITJ(ZD)1803). We would like to acknowledge the reviewers for their helpful comments on this paper. Declaration of Interests: The authors declare: "None." Ethics Approval Statement: This study was permitted by the Ethics Committee of Tongji Hospital of Tongji University and The Sixth People’s Hospital of Yancheng City. Written informed consents were provided by all participants. All animal experiments were conducted under the review from the Animal Ethical and Experimental Committee of Tongji Hospital of Tongji University and The Sixth People’s Hospital of Yancheng City.

Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related death. The current study aimed to elucidate the mechanism by which exosomes carrying KRAS mutant contribute to neutrophil recruitment as well as the formation of the neutrophil extracellular traps (NETs) in CRC. Methods: APC-WT and APC-KRASG12D mouse models were initially established. The peripheral blood, spleen, bone marrow (BM) and mesenteric lymph nodes (mLN) were isolated to detect neutrophil content. Next, exosomes isolated from APC-WT and APC-KRASG12D mice were injected into APC-WT and APC-KRASG12D mice. The neutrophil ratio, NETs formation and IL-8 protein content in colon tissue were subsequently quantified. DKs-8 (wild type) and DKO-1 (KRAS mutant) cells were employed for in vitro experimentation. Then, DKs-8 cells were cultured with exosome-treated PMA stimulated neutrophil-forming NETs culture medium, with cell viability, invasion, migration, and adhesion evaluated. Results: Compared with APC-WT mice, the number of polyps and neutrophils in the peripheral blood, spleen and mLNs increased in APC-KRASG12D mice, with increased NETs formation, IL-8 expression, and exosomes. IL-8 upregulation, neutrophil recruitment and NETs formation were observed in mice injected with exosomes derived from APC-KRASG12D. The in vitro investigation results revealed that more NETs were formed by DKO-1-Exosomes, which were inhibited by DNAse. In addition, DKs-8 and DKO-1 cells-derived exosomes can adhere to NETs under static conditions in vitro. Exosomal KRAS mutants were noted to exert a stimulatory effect on the production of IL-8 while promoting NETs formation as well as CRC promotion. Conclusion: The results obtained provide evidence suggesting that exosomes may transfer mutant KRAS to recipient cells and trigger an increase in IL-8 production, promote neutrophil recruitment and form NETs, ultimately leading to the promotion of CRC. Funding Statement: This work was supported by the National Natural Science Foundation of China (81873975, 81802084, 81974314, 81902984), the Excellent Academic Leader Training Program of Shanghai Health System (2018BR31), the Medical Guidace Science and Technology Support Project of Shanghai (19411964800), the Natural Science Foundation of Shanghai (19ZR1448800), the Clinical Research and Cultivation Project of Shanghai Tongji Hospital [ITJ(ZD)1803, ITJ(ZD)1905, ITJ(QN)1905]. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study protocol was approved by the Ethics Committee of Tongji Hospital of Tongji University. All subjects have written informed consent. All animal use and experiments were performed in strict accordance with the procedures approved by the National Cancer Institute Animal Care and Use Committee (ACUC).

Aims To design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity. Main methods First, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9–39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed. Key findings We screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders. Significance XFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.

Objective The purpose of this study was to establish and validate a nomogram to predict the prognosis in patients with non-small cell lung cancer (NSCLC) from multiple perspectives. Results A total of 98,640 eligible patients were randomly divided into a training set (n = 69,048) and a validation set (n = 29,592). The baseline characteristics of the two sets were similar. We used clinical data from patients in the training set for univariate and multivariate Cox regression analyses. Twelve independent risk factors were incorporated for constructed a prognostic nomogram. And the nomogram with a concordance index of 0.777 (95 % CI, 0.775 to 0.779) for overall survival. The calibration curve results showed that the actual survival rate was consistent with the predicted survival rate. The area under curve of the receiver operating characteristic curves demonstrated that the nomogram has a high prediction of the overall survival rate in patients with NSCLC. Conclusion We have developed a nomogram with high prediction accuracy and discrimination ability, which can help clinicians making personalized survival predictions for NSCLC patients.