Pancreatic β cell failure is a hallmark of diabetes. However, the causes of β cell failure remain incomplete. Here, we report the identification of tetranectin (TN), an adipose tissue–enriched secretory molecule, as a negative regulator of insulin secretion in β cells in diabetes. TN expression is stimulated by high glucose in adipocytes via the p38 MAPK/TXNIP/thioredoxin/OCT4 signaling pathway, and elevated serum TN levels are associated with diabetes. TN treatment greatly exacerbates hyperglycemia in mice and suppresses glucose-stimulated insulin secretion in islets. Conversely, knockout of TN or neutralization of TN function notably improves insulin secretion and glucose tolerance in high-fat diet–fed mice. Mechanistically, TN binds with high selectivity to β cells and inhibits insulin secretion by blocking L-type Ca 2+ channels. Our study uncovers an adipocyte–β cell cross-talk that contributes to β cell dysfunction in diabetes and suggests that neutralization of TN levels may provide a new treatment strategy for type 2 diabetes.

Objective: To establish reference ranges of adrenal artery Doppler indices for the the inferior adrenal artery (IAA) and middle adrenal artery (MAA).

Background: Previously, our team identified a seven-gene mutation panel in urine sediment to discriminate UBC from benign urological diseases. In the present study, we aimed to validate the panel in an expanded and close to natural population cohort of hematuria. Also, we tried to optimize the panel by incorporating methylation biomarkers. We performed external validation to investigate the robustness and stability of the novel panel. Methods: Patients with urothelial carcinomas and controls were prospectively recruited in clinical trial ChiCTR2000029980. The mutation panel was validated in the expanded cohort(n=333) from Hunan multicenter. Several UBC-specific methylation biomarkers were identified by comprehensive analyses of a series of TCGA, GEO and an independent cohorts, and examined in the expanded cohort. Random Forest algorithm was used to construct an optimal panel. External validation of the optimal panel was carried out in Beijing single center cohort(n=89). NGS technique was used to analyze the DNA point mutations and MS-PCR for methylation.Results: The AUC, sensitivity and specificity of the mutation panel in expanded cohort were 0.81, 0.67 and 0.90, respectively. After screening, only cg16966315, cg17945976 and cg24720571 were left for further analysis. The optimal panel consisted of cg24720571 and 8 point mutations, including TERT 228(G_A), FGFR3 568(C_T), TERT 250(G_A), FGFR3 099(A_G), PIK3CA 091(G_A), PIK3CA 085(A_G), PIK3CA 082 (G_A) and HRAS 874(T_C). The AUC, sensitivity and specificity of the optimal panel in training group were 0.89, 0.84 and 0.79, respectively, and in test group were 0.95, 0.91 and 0.95, respectively. In the external validation, the AUC, sensitivity and specificity were 0.98, 0.93 and 0.93, respectively.Conclusions: The optimal panel was obviously superior to previous mutation panel and showed a highly specific and robust performance. The optimal panel may be used as a replaceable approach for early detection of UC.Trial registration: This research was registered in Chinese Clinical Trial Registry(ChiCTR2000029980).

BackgroundOncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, OVs could activate the host innate immunity, then impair the viral propagation in tumor cells. In this study, we explored the effect of propranolol, a non-selective β-blocker , on the antitumor efficacy of T1012G virus in gastric cancer models.Results Cell viability assay detected a 97.9% decrease of T1012G IC50 in HGC-27 when it was pretreated with propranolol along with a 7-fold increase of virus titers compared with T1012G only group (P < 0.001). Moreover, propranolol pretreatment caused sustained tumor regression (335.3± 36.92 mm3 vs. 1118 ± 210.0 mm3, P<0.01) and enhanced the viral propagation (4-fold increase, P < 0.01) compared with T1012G only group. Propranolol pretreatment significantly enhanced the p-STAT3 (2.9-fold, P<0.05) and suppressed p-PKR (65.94% ± 10.11%, P<0.05) compared with T1012G only group. In addition, propranolol could counteract IFN-α/β-mediated inhibition of viral propagation (compared with IFNα: 5.1-fold, P<0.001; IFNβ: 4.6-fold, P<0.01) or enhancement of PKR activation (IFNα: 92.57% ± 1.77%, P<0.001, IFNβ: 99.34%± 0.13% decrease, P<0.001). Conclusions In summary, β-blocker pretreatment could improve the propagation and therapeutic efficacy of T1012G in human gastric cancer by regulating STAT3-PKR signaling cascade, even in the presence of type I IFNs . These data support new strategies of improving the efficacy of OVs in gastric cancer.