Transcription factor Dp-1 knockdown downregulates thymidine kinase 1 expression to protect against proliferation and epithelial-mesenchymal transition in cervical cancer.

Thymidine kinase 1 (TK1) level is an independent survival prognostic factor for both premalignant and malignant cervical pathologies. Herein, this study sought to probe the impacts of TK1 on cervical cancer (CC) progression and its underlying mechanism. Transcription factor Dp-1 (TFDP1) and TK1 expression was assessed using qRT-PCR in CC cell lines. After ectopic expression and knockdown experiments, cell counting kit-8 and colony formation assays were adopted to measure cell proliferation, western blot to examine the expression of epithelial-mesenchymal transition (EMT)-related proteins, and Transwell assays to assess cell invasion and migration. The binding of TFDP1 to TK1 was predicted by bioinformatic sites and verified by chromatin immunoprecipitation and dual-luciferase reporter assays. Tumor xenograft experiments in nude mice were performed to validate the influence of TFDP1/TK1 on CC progression in vivo. CC cells had high TK1 and TFDP1 expression. TFDP1 or TK1 knockdown restrained CC cell EMT, invasion, migration, and proliferation. TFDP1 facilitated TK1 expression in CC via transcription. Overexpression of TK1 counteracted the suppressive impacts of TFDP1 knockdown on CC cell malignant behaviors. Moreover, TFDP1 knockdown depressed CC growth in vivo by downregulating TK1. TFDP1 knockdown restricted proliferation and EMT in CC by downregulating TK1 expression.

A single-centre, open-label, single-arm, fixed-sequence pharmacokinetic study of SHR3680 on repaglinide and bupropion in prostate cancer patients.

To evaluate the pharmacokinetic effects of SHR3680 on repaglinide and bupropion and its metabolite hydroxybupropion. METHODS: A single-centre, open-label, single-arm, fixed-sequence clinical trial in 18 patients with prostate cancer. RESULTS: After a single oral dose of 0.5 mg repaglinide and SHR3680, geometric mean peak plasma concentration (Cmax ) of plasma repaglinide was 14.240 and 5.887 ng/mL, geometric mean area under the concentration-time curve (AUC0-t )was 20.577 and 7.320 h ng/mL, geometric mean AUC0-∞ was 20.949 and 7.451 h ng/mL, mean half-life (t1/2 ) was 1.629 and 1.195 hours, and geometric mean oral clearance (CL/F) was 23.867 and 67.107 L/h, respectively. After a single oral administration of 150 mg bupropion and SHR3680, geometric mean Cmax of plasma bupropion was 85.430 and 33.747 ng/mL, geometric mean AUC0-t was 1003.896 and 380.158 h ng/mL, geometric mean AUC0-∞ was 1038.054 and 401.387 h ng/mL, mean t1/2 was 22.533 and 17.733 hours, and geometric mean CL/F was 144.501 and 373.705 L/h, respectively. The plasma geometric mean Cmax of its main active metabolic hydroxybupropion was 268.113 and 177.318 ng/mL, geometric mean AUC0-t was 14 283.087 and 5420.219 h ng/mL, geometric mean AUC0-∞ was 15 218.158 and 5364.625 h ng/mL, mean t1/2 were 36.069 and 16.688 hours, and geometric mean CL/F was 8.623 L/h and 27.961 L/h, respectively. CONCLUSION: Coadministration of SHR3680 with repaglinide or bupropion significantly shortened the elimination half-lives, significantly increased the apparent clearance rate, and significantly decreased the in vivo exposure of repaglinide, bupropion and hydroxybupropion compared with single administration of repaglinide or bupropion.

MRI-Based Radiomics and Urine Creatinine for the Differentiation of Renal Angiomyolipoma With Minimal Fat From Renal Cell Carcinoma: A Preliminary Study.

Objectives: Standard magnetic resonance imaging (MRI) techniques are different to distinguish minimal fat angiomyolipoma (mf-AML) with minimal fat from renal cell carcinoma (RCC). Here we aimed to evaluate the diagnostic performance of MRI-based radiomics in the differentiation of fat-poor AMLs from other renal neoplasms. Methods: A total of 69 patients with solid renal tumors without macroscopic fat and with a pathologic diagnosis of RCC (n=50) or mf-AML (n=19) who underwent conventional MRI and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) were included. Clinical data including age, sex, tumor location, urine creatinine, and urea nitrogen were collected from medical records. The apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) were measured from renal tumors. We used the ITK-SNAP software to manually delineate the regions of interest on T2-weighted imaging (T2WI) and IVIM-DWI from the largest cross-sectional area of the tumor. We extracted 396 radiomics features by the Analysis Kit software for each MR sequence. The hand-crafted features were selected by using the Pearson correlation analysis and least absolute shrinkage and selection operator (LASSO). Diagnostic models were built by logistic regression analysis. Receiver operating characteristic curve analysis was performed using five-fold cross-validation and the mean area under the curve (AUC) values were calculated and compared between the models to obtain the optimal model for the differentiation of mf-AML and RCC. Decision curve analysis (DCA) was used to evaluate the clinical utility of the models. Results: Clinical model based on urine creatinine achieved an AUC of 0.802 (95%CI: 0.761-0.843). IVIM-based model based on f value achieved an AUC of 0.692 (95%CI: 0.627-0.757). T2WI-radiomics model achieved an AUC of 0.883 (95%CI: 0.852-0.914). IVIM-radiomics model achieved an AUC of 0.874 (95%CI: 0.841-0.907). Combined radiomics model achieved an AUC of 0.919 (95%CI: 0.894-0.944). Clinical-radiomics model yielded the best performance, with an AUC of 0.931 (95%CI: 0.907-0.955). The calibration curve and DCA confirmed that the clinical-radiomics model had a good consistency and clinical usefulness. Conclusion: The clinical-radiomics model may be served as a noninvasive diagnostic tool to differentiate mf-AML with RCC, which might facilitate the clinical decision-making process.

SQLE Mediates Metabolic Reprogramming to Promote LN Metastasis in Castration-Resistant Prostate Cancer.

BACKGROUND: Almost all metastatic hormone-sensitive prostate cancers (mHSPC) will develop into metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT). The expression level of squalene monooxygenase (SQLE) is increased in CRPC cells and regulates cholesterol metabolism. This study verified the biological function and mechanisms of SQLE in CRPC. METHODS: The expression of SQLE in human prostate cancer cells was overexpressed or silenced and its efficacy on cell survival was determined by the MTS test. Energy metabolism phenotype test was evaluated by XF real-time ATP rate assay, XF cell mitochondrial stress test, XF glycolysis stress test and XF mito fuel flex test. Cell migration and invasion were evaluated by colony formation assays and transwell assays; the expression of mRNA and protein was assessed by RT-qPCR and Western blot, respectively. Moreover, BALB/c nude mice model was performed to evaluate the lymph node metastasis. RESULTS: In our study, we found that the expression level of SQLE was significantly increased in bicalutamide-resistant-C4-2B cells compared to LNCaP cells. SQLE knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and reduced lymph node metastasis by inhibiting fatty acid oxidation in mitochondria. We also found that terbinafine, the specific inhibitor of SQLE, can enhance the sensitivity of prostate cancer cells to bicalutamide. CONCLUSION: Our study revealed that SQLE is involved in the progression of castration resistance in CRPC through mediating metabolic reprogramming, presenting SQLE as a new target for the treatment of mCRPC.

Comparison of Renal Artery vs Renal Artery-Vein Clamping During Partial Nephrectomy: A System Review and Meta-Analysis.

Background: Although artery-only (AO) clamping has been proposed to minimize ischemic renal damage compared with artery-vein (AV) clamping, the benefit of AO clamping during laparoscopic partial nephrectomy (LPN) is still controversial. We performed a systematic review and meta-analysis to test the difference between AO clamping and AV clamping in partial nephrectomy (PN). Materials and Methods: A systematic review of the literature on PubMed, Web of Science, the Cochrane Library, and Embase was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement to search-related studies. Data were extracted using a reporting checklist proposed by the Meta-analysis of Observational Studies in Epidemiology Group. RevMan 5.3 software and Stata 12.0 were used to do meta-analysis. Results: The present meta-analysis included 2 retrospective and 3 prospective studies, including 242 patients who underwent AO clamping and 369 patients who underwent AV clamping, which compared AO and AV clamping in LPN for renal cell carcinoma. At baseline, no statistically significant differences were detected between AO and AV clamping groups in terms of body mass index (p = 0.23), tumor size (p = 0.95), but AO clamping group had significantly lower RENAL Score (fixed effects [FE]: weighted mean difference [WMD]: 0.36, p = 0.007). For surgical outcomes analysis, no significant difference was detected regarding to warm ischemia (p = 0.58), operating time (p = 0.40), transfusion rate (p = 0.58), and estimated blood loss (p = 0.35) between two groups. The assessment of renal function by creatinine value both at the early postoperative (p = 0.36) and at last follow-up (p = 0.38) revealed no difference. There was no significant difference in estimated glomerular filtration rate (eGFR) (p = 0.62), and at the early postoperative percentage decrease of eGFR (p = 0.79). However, a higher percentage decrease of eGFR decrease at last follow-up was demonstrated for the AV clamping group (FE: WMD: 2.42, p < 0.00001). Conclusion: These results suggest that AO clamping might be a better choice for PN in long term. Randomized controlled trial studies with larger sample numbers and long-term follow-up and split renal function assessment should be conducted in the future to confirm our conclusion.

[Low expressions of EHD2 and E-cadherin correlate with a poor prognosis for clear cell renal cell carcinoma].

OBJECTIVE: To explore roles of expressions of EHD2 and E-cadherin in clear cell renal cell carcinoma (ccRCC).
 Methods: Four couples of fresh ccRCC tissues and adjacent non-cancerous tissues were collected to evaluate the expression of EHD2 and E-cadherin protein by Western blotting. A total of 65 paraffin-embedded renal ccRCC tissues were collected, and immunohistochemical assay was used to detect the expression of EHD2 and E-cadherin in the samples. The correlation between their expression and clinical and pathological indicators of ccRCC was analyzed, and the relationship between EHD2 and E-cadherin proteins and prognosis for patients with ccRCC was also explored.
 Results: The results of Western blotting showed that the expression levels of EHD2 and E-cadherin were low in 4 ccRCC tissues compared with the adjacent noncancerous tissues. Immunohistochemical results revealed that the expressions of EHD2 and E-cadherin were higher in the localized ccRCC tissues than those in the metastatic ccRCC tissues; the expression levels of EHD2 and E-cadherin were decreased, while the TNM staging and Fuhrman grade were increased (P<0.05 or P<0.01). There was positive correlation between the expressions of EHD2 and E-cadherin in ccRCC (r=0.390, P<0.01). The progression-free survival in ccRCC patients with lower expression of both EHD2 and E-cadherin was better than that in ccRCC patients with higher expressions of EHD2 and E-cadherin (P<0.05). 
 Conclusion: The low expressions of EHD2 and E-cadherin are the potential indicators for the ccRCC patients with poor prognosis.

Three-Dimensional Physical Model-Assisted Planning and Navigation for Laparoscopic Partial Nephrectomy in Patients with Endophytic Renal Tumors.

Resection of completely endophytic renal tumors is a huge challenge for surgeons due to a lack of definite visual clues, especially in the laparoscopic approach. Three-dimensional (3D) kidney models, which can illustrate the clear relationship between renal masses and surrounding health tissues, were considered as reliable tools for understanding renal tumor characteristics in previous studies. We hypothesized that 3D kidney models can be used not only for planning but also for navigating laparoscopic partial nephrectomy (LPN) in patients with completely endophytic renal tumors. In this study, we successfully constructed five cases of 3D kidney models for assisted planning and navigation for LPN in endophytic renal tumors. The renal masses and surrounding normal parenchyma of the patient-specific 3D models were dyed by different colorants for clear illustration. All patients experienced acceptable perioperative outcomes, and no patient suffered serious relative complications. The 3D kidney models were considered as a reliable tool based on clinical outcome and postoperative questionnaire results. This study is the first report of 3D kidney models for patients with completely endophytic tumors. 3D kidney models can aid surgeons in understanding the characteristics of renal tumors and potentially support assisted planning and performance of LPN in endophytic tumor cases.

Renal metastasis from cervical carcinoma presenting as a renal cyst: A case report.

In the present study, the case of a 51-year-old female with a metastatic tumor in the left kidney originating from cervical carcinoma, is reported. The patient had undergone chemoradiotherapy for stage IIB squamous-cell carcinoma of the uterine cervix 3 years earlier. Computed tomography (CT) identified low-density left renal nodules, which were diagnosed post-operatively as renal cysts during the follow-up conducted 2 years later. The next year, the patient was admitted to the Hunan Provincial Tumor Hospital (The Affiliated Tumor Hospital of Xiangya Medical College, Central South University, Changsha, Hunan, China) with a fever of unknown origin, left-sided flank pain and hematuria. CT examination detected irregular low-density nodules in the left kidney and heterogeneous enhancement on enhanced CT. Subsequently, the patient was subjected to a nephrectomy. Post-surgical analysis of subsequent biopsies indicated kidney tumor metastasis originating from cervical carcinoma. Renal metastases are rare in patients with cervical carcinoma. The present study reported a case of renal metastasis originating from cervical carcinoma and also reviewed previous case reports on patients presenting with this unusual type of cancer.

[Expression and mechanism of osteoactivin in the kidney of SD rats after acute cyclosporine A toxicity].

OBJECTIVE: To determine the expression and mechanism of osteoactivin (OA) in the kidney by establishing SD rat model of acute cyclosporine A (CsA) toxicity. METHODS: SD rats were fed with normal diet for a week, which they were then randomly divided into 3 groups: an experimental group (gavage with cycloporin A and olive oil), a vector group (gavage with olive oil), and a control group (gavage with normal saline). SD rats were killed 2 days, 1 week, or 2 weeks after the gavage to examine the serum creatinine (SCr) and body weight. HE staining was used to detect the kidney histopathological change. Immunohistochemistry was used to observe the staining degree and area of OA. Western blot was used to detect the OA protein.The mRNA expressions of the OA, matrix metalloproteinase-13(MMP-13), and collagen type III(Col III) were examined by RT-PCR. RESULTS: The body weight and SCr of the rats in the experimental group 1 week and 2 days after the gavage had no significant difference compared with the vector group or the control group (P>0.05).On the end of 2nd week, the rats' body weight was significantly reduced, and SCr significantly increased compared with the vector group or the control group (P<0.001).The main histopathological changes in the experimental group were inflammatory cell infiltration, vacuolar degeneration of interstitial cells, or tubular epithelial cell necrosis. Intense OA expression located in the tubular epithelium and interstitial fibroblasts in the kidney of the experimental group was observed by immunohistochemistry. After CsA gavage, the relative mRNA expressions of OA, MMP-13, and Col III significantly increased with time. Western blot did not find the expression of OA protein in the control and the vector group, which increased with time in the experimental group. CONCLUSION: OA expresses in the kidney of SD rats after acute CsA toxicity and mainly expresses in the tubular epithelial cells and renal interstitium. OA is more sensitive to the damage of kidney tissue caused by CsA than by SCr. The early-phase up-regulation of OA expression in the tubular epithelium in response to renal injury caused by acute CsA toxicity might play a key role in triggering the renal interstitial fibrosis via activating expression of MMPs and collagen remodeling in SD rats.