Immune checkpoint inhibitors alone or in combination with chemotherapy for treatment of advanced non-small cell lung cancer after first-line platinum-based chemotherapy: A propensity score matching analysis.

Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of several cancer types. However, data are lacking with regard to the clinical responsiveness of ICIs in patients with advanced non-small cell lung cancer (NSCLC) after standard first-line chemotherapy. Therefore, we aimed to evaluate the clinical efficacy of ICI alone or in combination with chemotherapy for patients with advanced NSCLC after first-line platinum-based chemotherapy. Methods: We retrospectively collected patients with confirmed advanced NSCLC who underwent ICI monotherapy or ICI plus chemotherapy after first-line platinum-based chemotherapy between January 2018 and December 2020. A propensity score matching analysis was used to balance baseline characteristics between the two treatment groups. Kaplan-Meier methods and multivariable Cox regressions were used for survival analyses. Results: Among 832 eligible patients, 222 received ICI monotherapy and 610 received ICI plus chemotherapy. The median overall survival (OS) of patients who received ICI plus chemotherapy was 16.0 months compared with 13.1 months in patients who received ICI monotherapy (HR: 0.64, 95% CI: 0.49-0.85, P = 0.002). After 1:1 propensity score matching, all baseline characteristics were well-balanced between the two treatment groups. Patients who received ICI plus chemotherapy had significantly longer OS than those who received ICI monotherapy (NR vs. 13.1 months, HR: 0.50, 95% CI: 0.34-0.71, P < 0.001). Meanwhile, the median time to treatment discontinuation was 4.4 months in the ICI-chemo group and 3.5 months in the ICI-mono group (HR: 0.72, 95% CI: 0.58-0.89, P = 0.002). The multivariate analysis indicated that treatment regimen was an independent prognostic factor for OS (HR: 0.488, 95% CI: 0.337-0.707, P < 0.001). Moreover, a nomogram that integrated both treatment regimens and clinicopathological factors was created for survival prediction. Conclusion: Our study indicated that patients with advanced NSCLC who received ICI plus chemotherapy after first-line platinum-based chemotherapy tended to have longer OS than those who received ICI monotherapy. The multivariate analysis showed that treatment regimen was an independent prognostic factor for OS. Future prospective studies are needed to confirm these findings.

Long Noncoding RNA CASC2 Facilitated Wound Healing through miRNA-155/HIF-1α in Diabetic Foot Ulcers.

Diabetic foot ulcers (DFU) are among the serious complications which are closely linked to diabetes mellitus. However, there is still a lack of accurate and effective standard prevention and treatment programs for DFU. In this manuscript, we have investigated the function of lncRNA cancer susceptibility candidate 2 (CASC2)/miR-155/hypoxia-inducible factor 1-alpha (HIF-1α) in the wound healing of DFU. We have analyzed lncRNA CASC2`s expression in the marginal tissues of ulcers in patients and mice with DFU. Additionally, the interaction relationship and mechanism between lncRNA CASC2, miR-155, and HIF-1α were determined, which proved the effects of lncRNA CASC2/miR-155/HIF-1α on fibroblasts apoptosis, proliferation, and migration. According to our study, the lncRNA CASC2's expression was low in the tissues of ulcers of DFU mice and patients. lncRNA CASC2's overexpression promoted fibroblasts migration, proliferation, and inhibited apoptosis and was beneficial for the healing of wounds, preferably in the DFU mice. In addition, lncRNA CASC2 directly targets miR-155 and HIF-1α functions as miR-155's target gene. Overexpression of miR-155 abrogated the function of lncRNA CASC2. Similarly, HIF-1α's inhibition has reversed the effect of miR-155 downregulation on fibroblasts. In general, overexpression of lncRNA CASC2 facilitated wound healing through miR-155/HIF-1α in DFU.

Transcriptome-wide Association Study Identifies Genetically Dysregulated Genes in Diabetic Neuropathy.

BACKGROUND: Complications are the main cause of the disease burden of diabetes. Genes determining the development and progression of diabetic complications remain to be identified. Diabetic neuropathy is the most common and debilitating complication and mainly affects the nerves of legs and feet. In this study, we attempted to identify diabetic neuropathy-specific genes from reliable large-scale genome-wide association studies (GWASs) for diabetes perse. METHODS: Taking advantage of publicly available data, we initially converted the GWAS signals to transcriptomic profiles in the tibial nerve using the functional summary-based imputation (FUSION) algorithm. The FUSION-derived genes were then checked to determine whether they were differentially expressed in the sciatic nerve of mouse models of diabetic neuropathy. The dysregulated genes identified in the sciatic nerve were explored in the blood of patients with diabetes. RESULTS: We found that eleven out of 452 FUSION-derived genes were regulated by diabetes GWAS loci and were altered in the sciatic nerve of mouse models with early-stage neuropathy. Among the eleven genes, significant (P-value<0.05) expression alterations of HSD17B4, DHX32, MERTK, and SFXN4 could be detected in the blood of human patients. CONCLUSIONS: Our analyses identified genes with an effect in the sciatic nerve and provided the possibility of noninvasive early detection of diabetic neuropathy.

PD-1 regulates CXCR5+ CD4 T cell-mediated proinflammatory functions in non-small cell lung cancer patients.

PD-1 inhibitors have been used to revive exhausted T cell responses in non-small cell lung cancer (NSCLC) and other malignancies. CXCR5+ T follicular helper (Tfh) cells are characterized by constitutive high PD-1 expression and have been associated with the formation of tertiary lymphoid structures and implicated in antitumor immunity. In this study, we investigated the effect of PD-1 and PD-1 inhibition on CXCR5+ CD4 T cells. Data showed that CXCR5+ CD4 T cells in both healthy subjects and NSCLC patients presented markedly higher PD-1 expression than CXCR5- CD4 T cells. Both CXCR5- and CXCR5+ CD4 T cells from NSCLC patients presented higher PD-1 expression than their counterparts in healthy subjects. PD-1+ CXCR5+ CD4 T cells were functional, could express IL-21, IL-10, and CXCL13 upon stimulation, demonstrated auxiliary effects toward CD8 T cell-mediated IFN-γ production and proliferation, and promoted IgM and IgG production. However, the potency of PD-1+ CXCR5+ CD4 T cells was lower than the potency of PD-1- CXCR5+ CD4 T cells. PD-1 blocking could significantly enhance the effector functions of PD-1+ CXCR5+ CD4 T cells. Overall, this study demonstrated that PD-1+ CXCR5+ CD4 T cells could promote CD8 T cell and B cell inflammation and could be modulated by PD-1 inhibition.