TOPK/PBK (T-LAK Cell-Originated Protein Kinase) is a serine/threonine kinase that is highly expressed in a variety of human tumors and is associated with poor prognosis in many types of human malignancies. Its activation mechanism is not yet fully understood. A bidirectional signal transduced between TOPK and ERK2 (extracellular signal-regulated kinase 2) has been reported, with ERK2 able to phosphorylate TOPK at the Thr9 residue. However, mutated TOPK at Thr9 cannot repress cellular transformation. In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2. Phospho-TOPK (S32) was found to be involved in the resistance of renal cell carcinoma (RCC) to sorafenib. Herein, combined a TOPK inhibitor with sorafenib could promoted the apoptosis of sorafenib-resistant RCC. High expression of HGF/c-met contributes to activation of p-TOPK (S32) during the development of sorafenib resistance in RCC. The current research presents a possible mechanism of sorafenib resistance in RCC and identifies a potential diagnostic marker for predicting sorafenib resistance in RCC, providing a valuable supplement for the clinically targeted treatment of advanced RCC.

Refractory diabetic wounds can cause persistent inflammation and delayed healing due to hypoxia. Currently, no optimal solution is available. Exosomes of adipose stem cells (ADSCs-exo) may promote skin wound healing, however, molecular mechanisms remains mysterious. We found significantly enhanced survival and proliferation of adipose stem cells after hypoxia induction compared to normoxia. Here, we aimed to investigate if hypoxic adipose stem cells exosomes (HypADSCs-exo) participate in hypoxia adaptability and accelerate diabetic wound healing. Based on high-throughput sequencing, 215 microRNAs (miRNAs) were upregulated and 369 miRNAs downregulated in HypADSCs-exo compared to ADSCs-exo. Up-regulated miR-21-3p, miR-126-5p, miR-31-5p whereas down-regulated gene miR-99b and miR-146-a correlated with wound healing. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), these miRNAs might regulate cell metabolism, differentiation and Transforming growth factor-β (TGF-β) function. Consistently, HpyADSCs-exo could promote diabetic wounds healing and inhibit inflammation through PI3K/AKT signaling pathway. Collectively, HpyADSCs-exo may potentially be applied in clinical therapy as an alternative strategy to improve wound healing.

ObjectivesTo explore the value of T1 mapping on gadoxetic acid-enhanced magnetic resonance imaging (MRI) in preoperative predicting cytokeratin 19 (CK19) expression for hepatocellular carcinoma (HCC).MethodsThis retrospective study included 158 patients from two institutions with surgically resected treatment-native solitary HCC who underwent preoperative T1 mapping on gadoxetic acid-enhanced MRI. Patients from institution I (n = 102) and institution II (n = 56) were assigned to training and test sets, respectively. univariable and multivariable logistic regression analyses were performed to investigate the association of clinicoradiological variables with CK19. The receiver operating characteristic (ROC) curve and precision-recall (PR) curve were used to evaluate the performance for CK19 prediction. Then, a prediction nomogram was developed for CK19 expression. The performance of the prediction nomogram was evaluated by its discrimination, calibration, and clinical utility.ResultsMultivariable logistic regression analysis showed that AFP>400ng/ml (OR=4.607, 95%CI: 1.098-19.326; p=0.037), relative apparent diffusion coefficient (rADC)≤0.71 (OR=3.450, 95%CI: 1.126-10.567; p=0.030), T1 relaxation time in the 20-minute hepatobiliary phase (T1rt-HBP)>797msec (OR=4.509, 95%CI: 1.301-15.626; p=0.018) were significant independent predictors of CK19 expression. The clinical-quantitative model (CQ-Model) constructed based on these significant variables had the best predictive performance with an area under the ROC curve of 0.844, an area under the PR curve of 0.785 and an F1 score of 0.778. The nomogram constructed based on CQ-Model demonstrated satisfactory performance with C index of 0.844 (95%CI: 0.759-0.908) and 0.818 (95%CI: 0.693-0.902) in the training and test sets, respectively.ConclusionsT1 mapping on gadoxetic acid-enhanced MRI has good predictive efficacy for preoperative prediction of CK19 expression in HCC, which can promote the individualized risk stratification and further treatment decision of HCC patients.

Purpose This study aimed to evaluate the efficacy and safety of neoadjuvant programmed cell death-1 (PD-1) inhibitors plus apatinib and chemotherapy (PAC) in patients with locally advanced gastric cancer (LAGC). Materials and Methods Seventy-three patients with resectable LAGC were enrolled and named the PAC group (n=39) or apatinib plus chemotherapy (AC) group (n=34) based on the treatment they chose. Neoadjuvant therapy was administered in a 21-day cycle for 3 consecutive cycles, after which surgery was performed. Results The PAC group exhibited a higher objective response rate than the AC group (74.4% vs. 58.8%, P=0.159). Moreover, the PAC group showed a numerically better response profile than the AC group (P=0.081). Strikingly, progression-free survival (PFS) (P=0.019) and overall survival (OS) (P=0.049) were prolonged, whereas disease-free survival (DFS) tended to be longer in the PAC group than in the AC group (P=0.056). Briefly, the 3-year PFS, DFS, and OS rates were 76.1%, 76.1%, and 86.7% in the PAC group and 46.9%, 49.9%, and 70.3% in the AC group, respectively. Furthermore, PAC (vs. AC) treatment (hazard ratio=0.286, P=0.034) was independently associated with prolonged PFS in multivariate Cox regression analyses. The incidence of adverse events did not differ between the two groups (all P>0.05), where leukopenia, anemia, hypertension, and other adverse events were commonly observed in the PAC group. Conclusions Neoadjuvant PAC therapy may achieve a preferable pathological response, delayed progression, and prolonged survival compared to AC therapy with a similar safety profile in patients with LAGC; however, further validation is warranted.