Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis.

Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.

Biomimicking covalent organic frameworks nanocomposite coating for integrated enhanced anticorrosion and antifouling properties of a biodegradable magnesium stent.

The utilization of biodegradable magnesium (Mg) alloys in the fabrication of temporary non-vascular stents is an innovative trend in biomedical engineering. However, the heterogeneous degradation profiles of these biomaterials, together with potential bacterial colonization that could precipitate infectious or stenotic complications, are critical obstacles precluding their widespread clinical application. In pursuit of overcoming these limitations, this study applies the principles of biomimicry, particularly the hydrophobic and anti-fouling characteristics of lotus leaves, to pioneer the creation of nanocomposite coatings. These coatings integrate poly-trimethylene carbonate (PTMC) with covalent organic frameworks (COFs), to modify the stent's surface property. The strategic design of the coating's topography, porosity, and self-polishing capabilities collectively aims to decelerate degradation processes and minimize biological adhesion. The protective qualities of the coatings were substantiated through rigorous testing in both in vitro dynamic bile tests and in vivo New Zealand rabbit choledochal models. Empirical findings from these trials confirmed that the implementation of COF-based nanocomposite coatings robustly fortifies Mg implantations, conferring heightened resistance to both biocorrosion and biofouling as well as improved biocompatibility within bodily environments. The outcomes of this research elucidate a comprehensive framework for the multifaceted strategies against stent corrosion and fouling, thereby charting a visionary pathway toward the systematic conception of a new class of reliable COF-derived surface modifications poised to amplify the efficacy of Mg-based stents. STATEMENT OF SIGNIFICANCE: Biodegradable magnesium (Mg) alloys are widely utilized in temporary stents, though their rapid degradation and susceptibility to bacterial infection pose significant challenges. Our research has developed a nanocomposite coating inspired by the lotus, integrating poly-trimethylene carbonate with covalent organic frameworks (COF). The coating achieved self-polishing property and optimal surface energy on the Mg substrate, which decelerates stent degradation and reduces biofilm formation. Comprehensive evaluations utilizing dynamic bile simulations and implantation in New Zealand rabbit choledochal models reveal that the coating improves the durability and longevity of the stent. The implications of these findings suggest the potential COF-based Mg alloy stent surface treatments and a leap forward in advancing stent performance and endurance in clinical applications.

The survival outcomes of very young and elderly patients with high-risk prostate cancer after radical treatments: A population-matched study.

Objective: This study evaluated the survival outcomes of young (<50 years) and elderly patients (>80 years) with high-risk prostate cancer (PCa) postradical local treatments. Materials and Methods: We identified <50 and >80-year-old patients with high-risk PCa between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database. The patients aged 65 and 66 years were also identified as the control group. The propensity-score matching method was adopted to compare the young and elderly patients with the control group. Kaplan-Meier analysis and Cox regression were conducted to evaluate the PCa-specific survival (PCSS) and overall survival. Results: A total of 17726 patients were identified, and 3355 were under 50 years old, whereas 4798 of them were >80 years old. The young patient group (<50 years) had similar PCSS with the control group (65-66 years) in both the overall cohort (hazard ratio [HR]: 0.88, 95% confidence interval [CI] [0.73-1.06], P = 0.132) and matched cohort (HR: 0.96, 95% CI [0.74-1.24], P = 0.527). Young patients with both high-risk and very high-risk PCa after radical prostatectomy (RP) treatment had apparent longer mean cancer-specific survival time than those after external-beam radiotherapy (EBRT) and/or brachytherapy (BT) treatment (high-risk group: 153.38 ± 0.82 months vs. 149.72 ± 3.03 months; very high-risk group: 148.3 ± 1.84 months vs. 139.33 ± 3.25 months). For the elderly patients (>80 years), the PCSS outcomes were significantly worse than the control group (65-66 years) in both overall cohort (HR: 2.69, 95% CI [2.31-3.13], P < 0.001) and matched cohort (HR: 1.61, 95% CI [1.34-1.94], P < 0.001). Patients receiving RP treatment had similar PCSS outcomes with those receiving EBRT and/or BT in the high-risk PCa group (139.45 ± 9.98 months vs. 139.41 ± 1.84 months), and better PCSS in very high-risk PCa group (132.73 ± 13.56 months vs. 128.82 ± 3.43 months). Conclusion: The PCSS outcomes of young PCa patients (<0 years) were identical to those of the control group (65-66 years). RP had similar or better PCSS benefits than EBRT and/or BT in both young (<50 years) and elderly patients (>80 years).

The Prognosis of Radical Prostatectomy, External Beam Radiotherapy plus Brachytherapy, and External Beam Radiotherapy Alone for Patients above 70 Years with Very High-Risk Prostate Cancer: A Population-Matched Study.

OBJECTIVE: The aim of this study was to evaluate the survival outcomes of radical prostatectomy (RP), external beam radiotherapy plus brachytherapy (EBRT + BT), and EBRT alone among elderly men (aged 70 years and above) with very high-risk (VHR) prostate cancer (PCa). METHODS: We identified elderly men diagnosed with VHR PCa between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database. The propensity score-matching method was adopted to balance the covariates and generate new cohorts. -Kaplan-Meier and Cox analyses were conducted to build up survival curves and evaluate the overall survival (OS) and PCa-specific survival (PCSS) outcomes. RESULTS: A total of 9,818 patients were identified. Of them, 5,839 were in the EBRT group, 725 in the EBRT + BT group, and 3,254 in the RP group. The survival curves of the overall cohort showed that RP was associated with the best OS, followed by EBRT + BT and EBRT (p < 0.001). As for the PCSS, RP shared similar outcomes with EBRT + BT (hazard ratio [HR]: 1.25 [0.93-1.69], p = 0.175). EBRT was associated with significantly worse PCSS than both RP (HR: 1.88, 95% confidence interval [95% CI] [1.64-2.15], p < 0.001) and EBRT + BT (HR: 1.48, 95% CI [1.19-1.85], p = 0.002). In the matched cohorts, RP presented better OS (HR: 1.41, 95% CI [1.07-1.86], p = 0.041) and similar PCSS with EBRT + BT (HR: 1.50, 95% CI [0.91-2.47], p = 0.12). RP was associated with significantly better OS and PCSS outcomes than EBRT alone (OS HR: 1.58, 95% CI [1.59-2.12], p < 0.001; PCSS HR: 2.08 [1.60-2.72], p < 0.001). EBRT + BT also had significantly better OS and PCSS outcomes than EBRT alone (OS HR: 1.33, 95% CI [1.11-1.60], p < 0.001; PCSS HR: 1.57 [1.13-2.19], p = 0.003). CONCLUSIONS: For patients above 70 years with VHR PCa, RP was associated with better OS and similar PCSS than EBRT + BT. Both RP and EBRT + BT have better OS and PCSS than EBRT alone.

Transperitoneal versus retroperitoneal approaches of pyeloplasty in management of ureteropelvic junction obstruction: A meta-analysis.

The aim of this study was to evaluate the benefits and safety of transperitoneal and retroperitoneal pyeloplasty for ureteropelvic junction obstruction by a meta-analysis. We searched the databases including PubMed, Cochrane Library and Embase database from their inception to December 1st, 2020. Relevant literatures comparing retroperitoneal pyeloplasty with transperitoneal pyeloplasty were identified. A meta-analysis was conducted with Revman 5.3. The main outcomes included success rate, operative time, hospital stay, conversion rate of open surgery, overall complications, and detailed postoperative complications/indicators. 15 studies with 1881 patients were included. The results revealed that there were no significant differences between two approaches in success rate [OR = 1.51, 95%CI (0.94, 2.41), p = 0.09], hospital stay [MD = 0.21, 95%CI (-0.12, 0.54), p = 0.21] and overall complications [OR = 1.07, 95%CI (0.76, 1.50), p = 0.69]. The retroperitoneal approach was associated with longer operative time [MD = -26.91, 95%CI (-40.97, -12.84), p < 0.001], higher conversion rate [OR = 0.23, 95%CI (0.11, 0.47), p < 0.001] than the transperitoneal approach. As for the detailed postoperative complications/indicators, there were no significant differences between two approaches in the urinary leak, mild hematuria, fever, UPJO recurrence, infection and subcutaneous emphysema, as well as split renal function, renal pelvis anteroposterior diameter. The funnel plots showed that there were no obvious publication biases in our analysis. Therefore, we concluded that transperitoneal and retroperitoneal approaches had similar benefits and safety in success rate, hospital stay, overall complications and detailed postoperative complications/indicators. However, retroperitoneal was associated with longer operative time and higher conversion rate than transperitoneal approach. With the limitations of our study, additional high-quality studies are still essential for further evaluation.

Reduced survival of young patients under 55 years with metastatic prostate cancer: a population-based study.

Objective: The aim of this study was to evaluate the prognosis of patients with metastatic prostate cancer (mPCa) in different age groups. Methods: Patients with mPCa from 2004 to 2016 in the Surveillance, Epidemiology and End Results (SEER) database were identified. Seven groups were divided according to the age at diagnosis, including ≤55 years, 56-60 years, 61-65 years, 66-70 years, 71-75 years, 76-80 years and >80 years. Fine and Gray's competing risks model and Kaplan-Meier analysis were conducted to evaluate the cancer-specific survival (CSS). Results: A total of 36231 patients with mPCa were included. The CSS curves of the overall cohort showed that patients aged ≤55 years had significantly worse CSS than patients in age groups of 56-60 [HR:0.93 (0.87~1.00), p=0.039], 61-65 [HR:0.91 (0.85~0.97), p=0.003] and 66-70 [HR:0.90 (0.84~0.96), p=0.001]. After removing patients dead for other reasons, the differences of CSS curves between ≤55 years group and 56-70 years groups were not significant. However, the mean survival time of ≤55 years group (55.78±2.48 months) was still shorter than 56-60 years (57.28±2.35 months), 61-65 years (57.64±2.07 months), and 66-70 years (57.11±2.11 months). When stratified by M stages, similar results were found in M1a, M1b and M1c stage groups. According to Fine-Gray competing risks models, patient ≤55 years featured significantly higher sub-distribution hazard ratio (sdHR) than 61-65 years group [sdHR: 0.94(0.88~1.00); p=0.046]. Conclusions: The mPCa patients ≤55 years seemed to be associated with worse prognosis in comparison with patients aging 56-70 years.

Clinical Characteristics and Prognosis of Patients With Pulmonary Mucoepidermoid Carcinoma: A SEER-Based Analysis.

BACKGROUND: Primary pulmonary mucoepidermoid carcinoma (PMEC) is an extremely rare malignancy. Its clinical characteristics and prognosis are not fully understood. This study evaluated clinical characteristics and prognostic factors of PMEC and established a nomogram to predict its 1-, 3-, 5- and 10-year cancer-specific survival (CSS) rates. METHODS: In the Surveillance, Epidemiology, and End Results database from January 1, 2016 to December 31, 2016, patients pathologically diagnosed with PMEC were identified. Kaplan-Meier analysis and Cox regression were performed to evaluate the CSS stratified by different covariates. A predictive nomogram model was built and validated by the concordance index (C-index) and calibration curves. RESULTS: A total of 585 PMEC patients were identified. A total of 408 (70%) of patients were placed into the training cohort, and 177 (30%) patients were placed into the validation cohort. The 5- and 10-year CSS rates of stage I-II PMEC patients were 91.4 and 88.9, respectively. The 1-, 3- and 5-year CSS rates of stage III-IV PMEC were 56.5, 39.45, and 32.1%, respectively. Survival curves showed that older age, large tumor size, poor differentiation, and high TNM stage were associated with a significantly worse prognosis. CSS outcomes were significantly better in patients who received surgical treatments (surgical alone, surgery plus radiation and/or chemotherapy). Patients who received radiation and/or chemotherapy had the worst prognosis. Multivariate Cox results revealed that covariates, including age, tumor laterality, tumor sizes, pathological differentiation, lymph node metastasis, distant metastasis, TNM stage and therapy, were independent prognostic factors for PMEC. These factors were used to construct a nomogram. The C-index of the nomogram was 0.921. The calibration curve presented favorable consistency between the predicted CSS and actual observations. This nomogram was validated by the validation cohort. The C-index of the validation cohort was 0.968. CONCLUSION: Age, bilateral tumors, tumor size, pathological differentiation grade, lymph node metastasis, distant metastasis, TNM stage and therapy were independent prognostic factors of PMEC patients. The first nomogram for predicting the CSS of PMEC was built and validated, showing its potential value in practice.

Superior survival benefits of Radical Prostatectomy than External Beam Radiotherapy in aging 75 and older men with high-risk or very high-risk Prostate Cancer: a population-matched study.

Objective: To evaluate the survival difference of radical prostatectomy (RP) and external beam radiotherapy (EBRT) in elderly men (75 years and older) with high-risk (HR) or very high-risk (VHR) prostate cancer (PCa). Methods: Elderly men diagnosed with HR/VHR PCa from 2004-2015 in the Surveillance, Epidemiology and End Results (SEER) database were identified. Propensity-score matching (PSM) was conducted to balance the covariates; Kaplan-Meier and Cox analysis were performed to evaluate the overall survival (OS) and prostate cancer-specific survival (PCSS). Results: 11698 patients with HR PCa and 4415 patients with VHR PCa were identified and divided into RP and EBRT group. After PSM, 964 patients with HR PCa and 538 patients with VHR PCa were included in each group. The 10-year OS and PCSS of men with HR PCa were 60.1% vs 40.9% and 90.6% vs 83.4%, respectively. The 10-year rate of OS and PCSS in men with VHR PCa were 55.9% vs 33.3% and 82.4% vs 75.6%, respectively. The OS curve of patients with HR PCa revealed that RP was significantly better than EBRT in both overall cohort [HR: 0.533, 95%CI (0.485~0.586), p<0.001] and the matched cohort [HR: 0.703, 95%CI (0.595~0.832), p<0.001]. However, the PCSS curve of patients with HR PCa showed that RP was significantly better than EBRT in overall cohort [HR: 0.453, 95%CI (0.368~0.559), p<0.001] but was similar to EBRT in matched cohort [HR: 0.820, 95%CI (0.552~1.218), p=0.327]. As for patients with VHR PCa, RP was associated with better OS than EBRT whether in overall cohort [HR: 0.520, 95%CI (0.457~0.592), p<0.001] or matched cohort [0.695, 95%CI (0.551~0.876), p=0.002]. The PCSS of RP was significantly better than that of EBRT in overall cohort [HR: 0.538, 95%CI (0.422~ 0.685), p<0.001], but was similar in matched cohort [HR: 0.787, 95%CI (0.510 ~1.214), p=0.281]. Conclusions: RP has more survival benefits than EBRT in men aged 75 years and older with HR or VHR PCa.

Prognosis of men with high-risk prostate cancer stratified by risk factors: a population-based retrospective cohort study.

BACKGROUND: The aim was to evaluate the prognosis of men with all possible high-risk prostate cancers (PCa) stratified by risk factors. METHODS: Within the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2015, men with non-metastasis high-risk PCa were identified. Kaplan-Meier analysis and Cox regressions were adopted to evaluate the overall survival (OS) and prostate cancer-specific survival (PCSS). Nomograms were conducted to build a predictive model. Concordance index (C-index) and calibration curves were used to validate the model. RESULTS: A total of 151,799 patients were included. Seven risk groups were divided including one high-risk factor of T3-4 (A1), prostate-specific antigen (PSA) >20 ng/mL (A2), and Gleason score (GS) 8-10, two high-risk factors of T3-4 PSA >20 ng/mL (B1), T3-4 GS 8-10 (B2), PSA >20 ng/mL GS 8-10 (B3), and three high-risk factors of T3-4 PSA >20 ng/mL GS 8-10 (C). The survival curves of PCSS showed that A1 was the best among all groups. A2, A3 and B1 had similar results and were all better than B2 [with A2 as reference, A3 hazard ratio (HR): 1.09 (1.02-1.17), P=0.046; B1 HR: 0.93 (0.82-1.05), P=0.103; B2 HR: 1.42 (1.32-1.53), P<0.001]. There is no significant difference between B3 and C [HR: 0.94 (0.86-1.03), P=0.029] and these two present the worst survival in prognosis. The 10-year PCSS of A1, A2, A3, B1, B2, B3, and C groups were 95.8%, 86.9%, 86.1%, 86.9%, 80.8%, 64.7% and 65.6%, respectively. Three simplified groups were divided including a good prognosis group (A1), an intermediate prognosis group (A2, A3, B1 and B2), and a poor prognosis group (B3 and C). Compared to the good prognosis group, the HR of the intermediate and the poor prognosis group were 4.21 (3.96-4.48), P<0.001 and 11.36 (10.59-12.19), P<0.001. A nomogram was built based on these factors. The C-index of the nomogram was 0.772, indicating a good accuracy of the model. CONCLUSIONS: Men with the combination of PSA >20 ng/mL and GS 8-10 had the worst PCSS among all patients. PCa with three high-risk factors was not more aggressive than that with two high-risk factors of GS 8-10 and PSA >20 ng/mL.