The mammalian heart possesses entire regeneration capacity after birth, which is lost in adulthood. The role of the kinase network in myocardial regeneration remains largely elusive. SGK3 (threonine-protein kinase 3) is a functional kinase we identified previously with the capacity to promote cardiomyocyte proliferation and cardiac repair after myocardial infarction. However, the upstream signals regulating SGK3 are still unknown. Based on the quantitative phosphoproteomics data and pulldown assay, we identified cyclin-dependent kinase 9 (CDK9) as a novel therapeutic target in regeneration therapy. The direct combination between CDK9 and SGK3 was further confirmed by co-immunoprecipitation (Co-IP). CDK9 is highly expressed in the newborn period and rarely detected in the adult myocardium. In vitro, the proliferation ratio of primary cardiomyocytes was significantly elevated by CDK9 overexpression while inhibited by CDK9 knockdown. In vivo, inhibition of CDK9 shortened the time window of cardiac regeneration after apical resection (AR) in neonatal mice, while overexpression of CDK9 significantly promoted mature cardiomyocytes (CMs) to re-enter the cell cycle and cardiac repair after myocardial infarction (MI) in adult mice. Mechanistically, CDK9 promoted cardiac repair by directly activating SGK3 and downstream GSK-3β/β-catenin pathway. Consequently, our study indicated that CDK9 might be a novel target for MI therapy by stimulating myocardial regeneration.
Neonatal mice achieve complete cardiac repair through endogenous myocardial regeneration after apical resection (AR), but this capacity is rapidly lost 7 days after birth. As an upstream inhibitor of cyclin-dependent kinase 4/6- (CDK4/6-) mediated cell cycle activity, p16INK4a is widely involved in regulating tumor and senescence. Given that p16INK4a had a significant negative regulation on cell proliferation, targeting cardiomyocytes (CMs) to inhibit p16INK4a seems to be a promising attempt at myocardial regeneration therapy. The p16INK4a expression was upregulated during perimyocardial regeneration time. Knockdown of p16INK4a stimulated CM proliferation, while p16INK4a overexpression had the opposite effect. In addition, p16INK4a knockdown prolonged the proliferation time window of newborn myocardium. And p16INK4a overexpression inhibited cell cycle activity and deteriorated myocardial regeneration after AR. The quantitative proteomic analysis showed that p16INK4a knockdown mediated the cell cycle progression and intervened in energy metabolism homeostasis. Mechanistically, overexpression of p16INK4a causes abnormal accumulation of reactive oxygen species (ROS) to induce autophagy, while scavenging ROS with N-acetylcysteine can alleviate autophagy and regulate p16INK4a, CDK4/6, and CyclinD1 in a covering manner. And the effect of inhibiting the proliferation of p16INK4a-activated CMs was significantly blocked by the CDK4/6 inhibitor Palbociclib. In summary, p16INK4a regulated CM proliferation progression through CDK4/6 and ROS-related autophagy to jointly affect myocardial regeneration repair. Our study revealed that p16INK4a might be a potential therapeutic target for myocardial regeneration after injury.
Background Papillary thyroid carcinoma (PTC) is the most common thyroid carcinoma, and is prone to cervical lymph node metastases (CLNM). We aim to analyze the correlation between clinical information, ultrasonic parameters of PTC and CLNM. Methods 1335 patients who had pathologically confirmed unifocal PTC were enrolled. Univariate and multivariate logistic analysis were performed to predict CLNM in PTC patients. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance. Results Univariate analysis showed that gender, age, maximum tumor diameter and volume, cross-sectional and longitudinal aspect ratio were related to CLNM (P<0.05). Multivariate logistic analysis showed that gender, age, maximum tumor diameter and volume were independent correlative factors, cross-sectional aspect ratio had significant difference for PTC2 to predict CLNM. The area under the curve (AUC) of the maximum tumor diameter and volume was 0.738 and 0.733, respectively. Maximum tumor diameter and volume, and cross-sectional and longitudinal aspect ratio were statistically significant following analysis of variance (P < 0.05). Conclusions Younger age, male, and larger tumor were high risk factors for CLNM in patients with unifocal PTC. Cross-sectional aspect ratio had a more effective predictive value for CLNM in patients with larger thyroid tumors.
Background: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) plays a vital role in providing the major part of the catalytic site of the active enzyme. Emerging evidence has revealed that P4HA1 participates in the initiation and development of several malignant tumors, nevertheless, the pan-analysis of P4HA1 remains unspecified. Methods: In this study, we carried out an in-depth analysis of the expression patterns and prognostic value of P4HA1 across the datasets of The Cancer Genome Atlas (TCGA ) and Kaplan-Meier Plotter. The genomic and epigenetic alterations, correlation with immune infiltration and DNA methylation of P4HA1 in different cancers were also analyzed across multiple databases. Moreover, we further explored the biological function and mechanism of P4HA1 in renal cell carcinoma (RCC). Results: The results characterized the different expression profile and prognostic values of P4HA1 in pan-cancer. Remarkably, P4HA1 expression was increased in kidney renal clear cell carcinoma (KIRC) and positively correlated with the OS and DFS of patients with kidney renal papillary cell carcinoma (KIRP). In addition, a positive correlation between P4HA1 expression and immune cell infiltration in KIRC was observed. We also identified a strong correlation between P4HA1 expression and immune checkpoint gene expression, microsatellite instability and tumor mutation burden in kidney chromophobe (KICH). Finally, the results of in vitro experiments verified that overexpression of P4HA1 promoted the proliferation, migration, invasion and the epithelial–mesenchymal transition (EMT) of RCC cells. Conclusion: Overall, our study suggested that P4HA1 might play a significant role in tumorigenesis and have the potential to be the target for the prognosis and therapy for several malignant tumors, especially for RCC.
Background Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid carcinoma. We aim to evaluate the correlation between sonographic features of PTC and cervical lymph node metastasis (CLNM). Methods A total of 1335 patients who underwent thyroidectomy and had pathologically confirmed unifocal PTC were enrolled in the retrospective research. Univariate analysis and logistic analysis were performed to predict CLNM by several independent variables. Receiver operating characteristic (ROC) curve was executed to evaluate the diagnostic performance. Results Univariate analysis showed that location, aspect ratio, margin, echogenic foci, TI-RADS score and grade were related to CLNM (P<0.05). Logistic analysis on sonographic features showed that margin and echogenic foci were independent correlative factors. Meanwhile, logistic analysis included clinical information, ultrasonic measurements and sonographic features showed that gender, age, tumour maximum diameter and volume, cross-sectional aspect ratio, location, margin and echogenic foci were independent correlative factors. The ROC curves were established based on the relevant factors, the AUC of tumour maximum diameter, tumour volume and margin were 0.738, 0.733, and 0.711, respectively. The regression model was constructed with AUC of 0.813, specificity of 70.3%, and sensitivity of 78.5%. ANOVA variance analysis on positive and negative group, tumour maximum diameter, margin, echogenic foci, TI-RADS score and grade had statistical significance (P < 0.05). Conclusion Lower location, larger lesion, margin and echogenic foci were high risk factors for CLNM in PTC, cross-sectional aspect ratio≥1 had more effective predictive value than longitudinal-sectional aspect ratio. Tumor volume was more effective to evaluate the lateral metastasis than maximum tumour diameter, it could guide preoperative FNA for CLNM.
Background: Underactive bladder (UAB) is a common clinical problem but related research is rarely explored. As there are currently no effective therapies, the administration of adipose stromal vascular fraction (ad-SVF) provides a new potential method to treat underactive bladder. Methods: Male Sprague-Dawley rats were induced by partial bladder outlet obstruction (PBOO) for four weeks and randomly divided into three groups: rats treated with PBS (Sham group); rats administrated with ad-SVF (ad-SVF group) and rats performed with ad-SVF spheroids (ad-SVFsp group). After four weeks, urodynamic studies were performed to evaluate bladder functions and all rats were sacrificed for further studies.Results: We observed that the bladder functions and symptoms of UAB were significantly improved in the ad-SVFsp group than that in the Sham group and ad-SVF group. Meanwhile, our data showed that ad-SVF spheroids could remarkably promote angiogenesis, suppress cell apoptosis and stimulate cell proliferation in bladder tissue than that in the other two groups. Moreover, ad-SVF spheroids increased the expression levels of bFGF, HGF and VEGF-A than ad-SVF. IVIS Spectrum small-animal in vivo imaging system revealed that ad-SVF spheroids could increase the retention rate of transplanted cells in bladder tissue. Conclusions: Ad-SVF spheroids improved functions and symptoms of bladder induced by PBOO, which contributes to promote angiogenesis, suppress cell apoptosis and stimulate cell proliferation. Ad-SVF spheroids provide a potential treatment for the future patients with UAB.
Background Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid carcinoma. We aim to evaluate the association of sonographic features of PTC and cervical lymph node metastasis (CLNM) at the initial surgery.Methods Clinical information, ultrasonographic measurements and features for 1335 patients were acquired in data collection. Univariate analysis was performed to test CLNM by 7 independent variables. Receiver operating characteristic (ROC) curve was created to evaluate the diagnostic performance.Results Univariate analysis showed that gland, location, aspect ratio, margin and echogenic foci were independently associated with CLNM metastatic status (P < 0.05). Binary linear regression analysis showed that sex, age, tumour maximum diameter and volume, location, margin and echogenic foci were independent correlative factors. The ROC curves were established based on the relevant factors, the AUC of tumour maximum diameter, tumour volume and margin were 0.74, 0.73, and 0.71, respectively. The multiple-variable linear regression model was constructed with AUC of 0.81, specificity of 72.8%, and sensitivity of 75.0%. ANOVA variance analysis for sub-positive groups, tumour maximum diameter, tumour volume, margin and echogenic foci had statistical significance (P < 0.05).Conclusion Younger age, male, larger tumour, margin, and echogenic foci were high risk factors for CLNM in PTC. Cross-sectional aspect ratio with value ≥ 1 had higher predictive value for CLNM in PTC patients excluding papillary thyroid microcarcinoma (PTMC).
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