Aptamer-Functionalized Iron-Based Metal-Organic Frameworks (MOFs) for Synergistic Cascade Cancer Chemotherapy and Chemodynamic Therapy.

Hypoxia-activated prodrugs (HAPs) with selective toxicity in tumor hypoxic microenvironments are a new strategy for tumor treatment with fewer side effects. Nonetheless, the deficiency of tumor tissue enrichment and tumor hypoxia greatly affect the therapeutic effect of HAPs. Herein, we design an active targeted drug delivery system driven by AS1411 aptamer to improve the tumor tissue enrichment of HAPs. The drug delivery system, called TPZ@Apt-MOF (TA-MOF), uses iron-based MOF as a carrier, surface-modified nucleolin aptamer AS1411, and the internal loaded hypoxia activation prodrug TPZ. Compared with naked MOF, the AS1411-modified MOF showed a better tumor targeting effect both in vitro and in vivo. MOF is driven by GSH to degrade within the tumor, producing Fe2+, and releasing the cargo. This process leads to a high consumption of the tumor protective agent GSH. Then, the Fenton reaction mediated by Fe2+ not only consumes the intracellular oxygen but also increases the intracellular production of highly toxic superoxide anions. This enhances the toxicity and therapeutic effect of TPZ. This study provides a new therapeutic strategy for cancer treatment.

Development and validation of a nomogram to predict overall survival for patients with metastatic renal cell carcinoma.

BACKGROUND: Heterogeneity of metastatic renal cell carcinoma (RCC) constraints accurate prognosis prediction of the tumor. We therefore aimed at developing a novel nomogram for accurate prediction of overall survival (OS) of patients with metastatic RCC. METHODS: We extracted 2010 to 2016 data for metastatic RCC patients in the Surveillance, Epidemiology, and End Results (SEER) database, and randomly stratified them equally into training and validation sets. Prognostic factors for OS were analyzed using Cox regression models, and thereafter integrated into a 1, 3 and 5-year OS predictive nomogram. The nomogram was validated using the training and validation sets. The performance of this model was evaluated by the Harrell's concordance index (C-index), calibration curve, integrated discrimination improvement (IDI), category-free net reclassification improvement (NRI), index of prediction accuracy (IPA), and decision curve analysis (DCA). RESULTS: Overall, 2315 metastatic RCC patients in the SEER database who fulfilled our inclusion criteria were utilized in constructing a nomogram for predicting OS of newly diagnosed metastatic RCC patients. The nomogram incorporated eight clinical factors: Fuhrman grade, lymph node status, sarcomatoid feature, cancer-directed surgery and bone, brain, liver, and lung metastases, all significantly associated with OS. The model was superior to the American Joint Committee on Cancer (AJCC) staging system (7th edition) both in training (C-indices, 0.701 vs. 0.612, P < 0.001) and validation sets (C-indices, 0.676 vs. 0.600, P < 0.001). The calibration plots of the nomogram corresponded well between predicted and observed values. NRI, IDI, and IPA further validated the superior predictive capability of the nomogram relative to the AJCC staging system. The DCA plots revealed reliable clinical application of our model in prognosis prediction of metastatic RCC patients. CONCLUSIONS: We developed and validated an accurate nomogram for individual OS prediction of metastatic RCC patients. This nomogram can be applied in design of clinical trials, patient counseling, and rationalizing therapeutic modalities.

Evaluation of Effectiveness of Atorvastatin in Treating Chronic Subdural Hematoma not Requiring Surgery: A Meta-Analysis of Randomized Controlled Trials.

Chronic subdural hematoma (CSDH) is a chronic space-occupying lesion formed by blood accumulation between the arachnoid membrane and the dura mater. Atorvastatin is of increasing clinical interest for CSDH. We performed a meta-analysis of published randomized controlled trials (RCTs) and used objective data as the primary outcomes to provide an evidence-based analysis of the efficacy of atorvastatin for CSDH treatment. Databases of MEDLINE (via PubMed), EMBASE, the Cochrane Library, Scopus, Web of Science, ScienceDirect, Chinese National Knowledge Infrastructure (CNKI), Cqvip database (CQVIP), and Wanfang database were systematically searched for RCTs reporting the use of atorvastatin for CSDH treatment. Odds ratio (OR), standard mean difference (SMD), and 95% confidence intervals (CIs) were used as summary statistics. I-square (I2) test was performed to assess the impact of study heterogeneity on the results of the meta-analysis. Nine relevant RCTs with 611 patients were identified for inclusion in this meta-analysis. Compared to controls, atorvastatin treatment had a significantly higher effectiveness (OR: 7.41, 95% CI: 3.32-16.52, P < 0.00001, I2 = 0%), lower hematoma volume (SMD: -0.46. 95% CI: -0.71 to -0.20, P = 0.0005, I2 = 0%), higher activities of daily living-Barthel Index (ADL-BI) (SMD: 2.07, 95% CI: 1.06-3.09, P < 0.0001, I2 = 92%), and smaller Chinese stroke scale (CSS) (SMD: -1.10, 95% CI: -1.72 to -0.48, P = 0.0005, I2 = 57%). In view of these findings, we conclude that the outcomes of experimental group are superior to the control group with respect to effectiveness, hematoma volume, ADL-BI, and CSS based on nine RCTs with 611 patients. Atorvastatin is beneficial to CSDH patients without surgery.

Nomogram prediction of overall survival based on log odds of positive lymph nodes for patients with penile squamous cell carcinoma.

PURPOSE: This study aimed to establish a nomogram to predict the long-term overall survival (OS) for patients with penile squamous cell carcinoma (PSCC). METHOD: The PSCC patients receiving regional lymph node dissection (RLND) were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The dataset of all eligible patients were used to develop the predictive model. The significant independent predictors were identified through Cox regression modeling based on the Bayesian information criterion and then incorporated into a nomogram to predicted 1-, 3-, and 5-year OS. Internal validation was performed using the bootstrap resampling method. The model performance was evaluated using Harrell's concordance index (C-index), calibration plots, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA). RESULTS: Totally, 384 eligible PSCC patients were enrolled from the SEER database. A nomogram for OS prediction was developed, in which three clinical variables significantly associated with OS were integrated, including age, N classification, and log odds of positive lymph nodes (LODDS). The C-index of the nomogram (0.746, 95% CI: 0.702-0.790) was significantly higher than that of the American Joint Committee on Cancer (AJCC) staging system (0.692, 95% CI: 0.646-0.738, P = .020). The bootstrap optimism-corrected C-index for the nomogram was 0.739 (95% CI: 0.690-0.784). The bias-corrected calibration plots showed the predicted risks were in good accordance with the actual risks. The results of NRI, IDI, and DCA exhibited superior predictive capability and higher clinical use of the nomogram compared with the AJCC staging system. CONCLUSION: We successfully constructed a simple and reliable nomogram for OS prediction among PSCC patients receiving RLND, which would be beneficial to clinical trial design, patient counseling, and therapeutic modality selection.

Risk factors associated with suicide among kidney cancer patients: A Surveillance, Epidemiology, and End Results analysis.

BACKGROUND: The suicide risk was higher in kidney cancer patients than in the general population. The purpose of this study was to characterize the suicide rates among kidney cancer patients and to identify the potential risk factors associated with suicide from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Kidney cancer patients were identified from the SEER database during 1973-2015. Suicide rates and standardized mortality ratios (SMRs) of this population were calculated, and the US general population during 1981-2015 was chosen as a reference. Univariable and multivariable Cox regression were performed to find out potential risk factors of suicide. RESULTS: There were 207 suicides identified among 171 819 individuals with kidney cancer observed for 948 272 person-years. The suicide rate was 21.83 per 100 000 person-years, and SMR was 1.83 (95% CI: 1.59-2.10). On Cox regression, diagnosis in early years (1973-1982 vs 2003-2015, HR: 2.03, 95% CI: 1.01-4.11, P = 0.048; 1983-1992 vs 2003-2015, HR: 1.99, 95% CI: 1.18-3.35, P = 0.010), male sex (vs female sex, HR: 4.43, 95% CI: 2.95-6.65, P < 0.001), unmarried status (vs married status, HR: 2.54, 95% CI: 1.91-3.38, P < 0.001), non-black race (white race vs black race, HR: 4.47, 95% CI: 2.09-9.58, P < 0.001; other races vs black race, HR: 3.01, 95% CI: 1.08-8.37, P = 0.035), higher histologic grade (grade IV vs grade I, HR: 3.27, 95% CI: 1.50-7.13, P = 0.003; grade III vs grade I, HR: 2.13, 95% CI: 1.19-3.81, P = 0.011) and cancer-directed surgery not performed (vs performed, HR: 2.78, 95% CI: 1.52-5.11, P < 0.001) were independent risk factors of suicide among kidney cancer patients. CONCLUSIONS: Diagnosis in early years, male sex, unmarried status, non-black race, higher histologic grade, and cancer-directed surgery not performed were significantly associated with suicide among kidney cancer patients. In order to prevent suicidal death, clinicians should pay more attention to patients with high-risk factors of suicide.

Sulfated polymannuroguluronate, a novel anti-AIDS drug candidate, inhibits HIV-1 Tat-induced angiogenesis in Kaposi's sarcoma cells.

Kaposi's sarcoma (KS), a neoplasm often associated with iatrogenic and acquired immunosuppression, is characterized by prominent angiogenesis. Angiogenic factors released from KS and host cells and HIV viral products-the protein Tat are reported to be involved in angiogenesis. Mounting evidence further suggests that multiple angiogenic activities of Tat contribute to AIDS-associated Kaposi's sarcoma (AIDS-KS). Herein, we report that sulfated polymannuroguluronate (SPMG), a novel anti-AIDS drug candidate now undergoing phase II clinical trial, significantly eliminated Tat-induced angiogenesis in SLK cells both in vitro and in vivo. SPMG significantly and dose-dependently inhibits proliferation, migration, and tube formation by SLK cells. SPMG also dramatically arrested Tat-driven KDR phosphorylation and blocked the interaction between Tat and integrin beta1, thus inhibiting the phosphorylation of the downstream kinases of FAK, paxillin and MAPKs. In addition, SPMG was noted to block the release of bFGF and VEGF from ECM. All these collectively favor an issue that SPMG functions as a promising therapeutic against Tat-induced angiogenesis and pathologic events relevant to AIDS-KS, which adds novel mechanistic profiling to the anti-AIDS action of SPMG.

Comparison of anticoagulation regimens for pregnant women with prosthetic heart valves: A meta-analysis of prospective studies.

INTRODUCTION: Pregnancy is associated with a hypercoagulable state, which makes pregnant women with prosthetic heart valves at high risk of thromboembolism. The proper anticoagulation regimen should take both the maternal protection and the fetal outcomes into consideration. However, no consensus on the present anticoagulation regimen for those women has been reached yet, especially in the first trimester of pregnancy. AIMS: The present meta-analysis is conducted to compare anticoagulation efficiency and feto-maternal complications of heparin and warfarin in the first trimester. RESULTS: Databases of MEDLINE, EMBASE, and the Cochrane Library were systematically searched (all from their inception to October 2016) for cohort studies reporting the outcome of anticoagulation in pregnant women with mechanical heart valves. Seven relevant prospective studies were identified for inclusion in the present meta-analysis. The forest plots indicated that warfarin was more effective in prevention valve thrombosis in the first trimester than heparin (OR: 14.58; 95% confidence interval [CI]: 3.94-53.94; P < .0001; I2  = 0%). The spontaneous abortion between the two regimens was not statistically different (OR: 1.42; 95% CI: 0.80-2.49; P = .23; I2  = 20%), which indicated that heparin could not provide better protection to the fetus in the early stage of pregnancy than warfarin. The incidence of warfarin embryopathy was low, and it only occurred in a twin among all the included cases. CONCLUSIONS: The present meta-analysis indicated that warfarin can provide better protection for the mother and the teratogenic effects may be overestimated. Heparin does not ensure better fetal outcomes as it is associated with severe adverse maternal outcomes, including mortality.

N-acetylglucosaminyltransferase V mediates cell migration and invasion of mouse mammary tumor cells 4TO7 via RhoA and Rac1 signaling pathway.

In tumor cells, alterations in cellular glycosylation may play a key role in their metastatic behavior. Using small interfering RNA against GnT-V, we found that the expression of GnT-V and beta1,6GlcNAc branching were significantly reduced which was particularly accompanied by the arrest in both cell migration and invasion as compared to the negative control. Moreover, the suppressed GnT-V expression by siRNA technique inactivated the signaling molecules including Rac1, cofilin, Erk and Akt, and activated RhoA levels in cells lacking GnT-V, but revealed no impact on Cdc42 activity. All these notions disclose for the first time that GnT-V and beta1, 6GlcNAc branching mediate the cell migration and invasion in Rac1-positive and RhoA-negative regulatory manners.