Case report: Sarcomatoid urothelial carcinoma of the renal pelvis masquerading as a renal abscess.

Sarcomatoid urothelial carcinoma (SUC), a rare tumor of the urinary tract epithelium, exhibits a high degree of malignancy and therefore a poor prognosis. Due to the absence of specific clinical presentations and imaging findings, SUC of the renal pelvis masquerades as a renal abscess is frequently under-recognized or misdiagnosed as benign inflammatory disease, resulting in delayed or erroneous treatment. Here, we report a patient with SUC of the renal pelvis who presented with a renal abscess. Repeated anti-inflammatory treatment was ineffective. Unexpectedly, cancerous cells were detected in subsequent exfoliative cytology of nephrostomy drainage fluid. In accordance with this, radical surgery and postoperative chemotherapy were conducted. Fortunately, neither recurrence nor metastasis occurred during a one-year follow-up.

The feasibility and safety of adopting the left lumbar vein to localize the renal artery location during left transperitoneal laparoscopic partial nephrectomy.

Background: Laparoscopic partial nephrectomy (LPN) is the standard of care for localized small renal cancer. The most critical step in this form of surgery is to localize the renal artery. In the present study, we describe a novel technique that uses the left lumbar vein (LV) to access the left renal artery during LPN. Materials and methods: This was a retrospective review of 130 cases of transperitoneal laparoscopic partial nephrectomies (TLPNs) performed on patients with renal cancer in our center between January 2018 and December 2021. Either the LV or non-lumbar vein (N-LV) technique was used to locate and manage the left renal artery. We recorded relevant clinical data from all patients, including patient characteristics, tumor data, and perioperative outcomes (artery mobilization time, operative time, estimated blood loss, and complications). Comparative analysis was then carried out between the cases using LV or N-LV vein techniques. Results: All TLPNs were successfully accomplished without conversion to open approaches. There were no complications involving the renal vessels during the entire study. The LV technique resulted in a significantly shorter time to mobilize the renal and significantly less estimated blood loss (p < 0.05). There was no significant difference between the two techniques with regard to perioperative complications. Conclusion: The left LV represents an anatomical landmark for locating the left renal artery in TLPN. This approach has numerous advantages over the transperitoneal approach including facilitating access to the left renal artery and reducing the duration of surgery.

Expression of Tripartite Motif-Containing Proteactiin 11 (TRIM11) is Associated with the Progression of Human Prostate Cancer and is Downregulated by MicroRNA-5193.

BACKGROUND Tripartite motif-containing protein 11 (TRIM11), encoded by the TRIM11 gene, has been studied in some human malignant tumors. MicroRNA-5193 (miRNA-5193) was predicted to target TRIM11, according to bioinformatics data from TargetScan. However, the roles of TRIM11 and miRNA-5193 in prostate cancer remain unknown. This study aimed to investigate the regulatory effects of miRNA-5193 on the expression of TRIM11 in prostate cancer tissues compared with adjacent normal prostate, and in human prostate cancer cell lines, PC3 and DU145 in vitro. MATERIAL AND METHODS Prostate tumor tissue and adjacent normal tissue from 137 patients with stage T1c (n=66), stage T2 (n=48), and stage T3 (n=23) prostate cancer were studied. Expression levels of the TRIM 11 protein and the TRIM11 gene in prostate cancer, normal prostate tissue, and human prostate cancer cell lines, PC3 and DU145, were measured by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Transfection with TRIM11 small interfering RNA (siRNA) resulted in gene knockdown. Transfection with a miR-5193 mimic resulted in overexpression of miR-5193. Proliferation and invasion assays were performed for PC3 and DU145 cells in vitro. RESULTS TRIM11 expression was upregulated in prostate cancer specimens compared with normal prostate tissue and was significantly correlated with reduced outcome. In human prostate cancer cell lines, PC3 and DU145, TRIM11 overexpression promoted cell proliferation. Upregulation of miR-5193 downregulated the expression of TRIM11. CONCLUSIONS TRIM11 was upregulated in prostate cancer tissue and was associated with reduced prognosis. TRIM11 expression increased cell proliferation in vitro and was downregulated by miR-5193.

Genetic risk factors for post-transplantation diabetes mellitus in Chinese Han renal allograft recipients treated with tacrolimus.

BACKGROUND: Post-transplantation diabetes mellitus (PTDM) is a serious metabolic complication after kidney transplantation. The aim of this study was to explore the association of clinical variables and five selected single nucleotide polymorphisms (SNPs) with PTDM in Chinese Han renal allograft recipients taking tacrolimus (TAC). METHODS: A total of 129 non-diabetic, primary, Chinese Han renal allograft recipients treated with TAC were enrolled. Five SNPs (CYP3A5 rs776741, rs776746, rs15524, CYP24A1 rs2296241, and PPARG rs1801282) were genotyped and analyzed. RESULTS: Among 129 recipients, 17 (13.2%) developed PTDM. Both univariate and multivariate analysis demonstrated that age over 50 years old and CYP24A1 rs2296241 A allele were independently correlated with the development of PTDM, while no significant differences was observed in TAC pharmacokinetics and CYP3A5, PPARG polymorphisms between two groups. CONCLUSIONS: Patients with advanced age and CYP24A1 rs2296241 A allele had an increased risk of PTDM after kidney transplantation.

Knockdown of ubiquitin­specific peptidase 39 inhibits the malignant progression of human renal cell carcinoma.

Ubiquitin specific peptidase 39 (USP39) serves important roles in mRNA processing and is involved in tumorigenesis of multiple solid malignancies. However, the influence and underlying mechanism of USP39 on human renal cell carcinomas (RCC) remain to be elucidated. The current study investigated the functional roles of USP39 in human RCC cell lines. siRNA­mediated RNA interference was used to downregulate USP39 in RCC cells. CCK­8, wound healing and invasion assays were performed to assess the proliferative ability and metastatic potential. The cell cycle distribution and apoptosis were evaluated by flow cytometry. The activity of signaling pathways and the expression of cell cycle­related proteins were detected by western blot analysis. The siRNA­directed RNA interference targeting USP39 could effectively downregulate the expression level of USP39 in two RCC cell lines. Depletion of USP39 by siRNA significantly suppressed cell growth and decreased invasive capacity of RCC cells. Silencing of USP39 induced cell apoptosis and cell cycle arrest at G2/M phase. Additionally, the expression levels of apoptotic and G2/M phase­related proteins were notably decreased following depletion of USP39. Mechanistically, downregulation of USP39 blocked the activation of Akt and extracellular signal regulated kinase signaling pathways in RCC cells. These findings indicate that USP39 may serve as an oncogenic factor in RCC and could be a potential therapeutic candidate for human RCCs.

Efficacy of Daily Low-dose Tadalafil for Treating Overactive Bladder: Results of a Randomized, Double-blind, Placebo-controlled Trial.

OBJECTIVE: To evaluate the efficacy of daily low-dose tadalafil therapy for overactive bladder (OAB) in women. PATIENTS AND METHODS: A total of 96 women with idiopathic OAB from 3 medical centers in the south of Zhejiang Province of China were randomly assigned to treatment with daily low-dose tadalafil (5 mg, n = 48) or placebo (n = 48) for 3 months. The Indevus Urgency Severity Scale, overactive bladder symptom score (Homma et al, 2006), and a 3-day micturition diary with frequency, incontinence, and urgency episodes were recorded and compared before the treatment, every 2 weeks following the treatment, and 3 months after the treatment. Uroflowmetry and transabdominal ultrasound were also conducted following the treatment to determine the maximum flow rate, voided volume, postvoid residual volume, total bladder capacity, and voiding efficiency. The patient's overall rating of improvement in symptoms was assessed as well. RESULTS: The overactive bladder symptom score significantly decreased, and the frequency, incontinence, and urgency episodes significantly improved in the tadalafil treatment group as compared with the placebo group and baselines at weeks 4, 6, 8, 10, and 12, as well as 3 months posttreatment (P <.05). In addition, voided volume and total bladder capacity obviously increased in the treatment group (P <.05). The Indevus Urgency Severity Scale decreased from week 4 to 3 months posttreatment in the treatment group (P <.05). No changes were found in the maximum flow rate, postvoid residual volume, and voiding efficiency. All adverse symptoms were mild to moderate. CONCLUSION: Daily low-dose tadalafil is a considerable, well-tolerated, and effective treatment for OAB in women.

Ubenimex attenuates acquired sorafenib resistance in renal cell carcinoma by inhibiting Akt signaling in a lipophagy associated mechanism.

Sorafenib is used as first line treatment of renal cell carcinoma (RCC) due to the poor sensitivity to radiotherapy and chemotherapy of this malignancy; however, acquired resistance limits the application of sorafenib and its analogues. In this study, we explored a new strategy to overcome acquired resistance to sorafenib. The RCC cell lines 786-O and ACHN were cultured in presence of increasing concentrations of sorafenib to generate sorafenib-resistant cell lines, 786-O-R and ACHN-R. Interestingly, treatment with ubenimex (0.25 mg/ml) and 3-MA (2 mM) restored the sensitivity of resistant cell lines to sorafenib, indicating the involvement of autophagy in acquired resistance. High levels of autophagy flux were observed in resistant cells, and the opposite effects of ubenimex and 3-MA suggested a complex role for autophagy. While 3-MA abolished protection in sorafenib-resistant cells, ubenimex induced uncontrolled autophagy and autophagic cell death. Lipophagy, characterized by a lipid droplet cargo, was observed in RCC tissues and cells. In sorafenib-resistant cells, ubenimex inhibited the Akt signaling pathway that regulates autophagy. In summary, lipophagy participates in sorafenib-resistance of RCC, which could be reversed by interventions targeting the Akt pathway.

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1.

Prostate cancer presents high occurrence worldwide. Medicinal plants are a major source of novel and potentially therapeutic molecules; therefore, the aim of the present study was to investigate the possible anti-prostate cancer activity of afzelin, a flavonol glycoside that was previously isolated from Nymphaea odorata. The effect of afzelin on the proliferation of androgen-sensitive LNCaP and androgen-independent PC-3 cells was evaluated by performing a water soluble tetrazolium salt-1 assay. In addition, the effect of afzelin on the cell cycle of the LNCaP and PC-3 prostate cancer cell lines was evaluated. Western blot analysis was performed to evaluate the effect of afzelin on the kinases responsible for the regulation of actin organization. Afzelin was identified to inhibit the proliferation of LNCaP and PC3 cells, and block the cell cycle in the G0 phase. The anticancer activity of afzelin in these cells was determined to be due to inhibition of LIM domain kinase 1 expression. Thus, the in vitro efficacy of afzelin against prostate cancer is promising; however, additional studies on different animal models are required to substantiate its anticancer potential.

Regulation of Th1/Th2 polarization by tissue inhibitor of metalloproteinase-3 via modulating dendritic cells.

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is one of a family of proteins inhibiting matrix metalloproteinases, which has also been identified as a mediator for checking inflammation. Meanwhile, it is well known that inflammation causes the activation of the immune response. However, it is not clear whether TIMP-3 plays a role in the immune system. In the present study, we demonstrated a novel function of TIMP-3 in Th1/Th2 polarization through its influence on the antigen-presenting cells. First, TIMP-3 was found strikingly up-regulated by IL-4 during the differentiation of human dendritic cells via the p38MAPK pathway. Second, the expression of costimulatory molecule-CD86 was repressed by TIMP-3. Besides, the induction of IL-12 in matured dendritic cells was significantly inhibited in a PI3K-dependent manner. Furthermore, dendritic cells matured in the presence of TIMP-3 could stimulate allogeneic naive T helper (Th) cells to display a prominent Th2 polarization. Importantly, in an autoimmune disorder-primary immune thrombocytopenia, TIMP-3 showed a statistically positive correlation with IL-4 and platelet count, but a negative correlation with IFN-γ in patient blood samples. Collectively, these in vitro and in vivo data clearly suggested a novel role of TIMP-3 in Th1/Th2 balance in humans.

A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells.

CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-κB) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-κB activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-κB activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFα)-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-κB transcriptional activity in RASMCs; however, did not affect the TNFα-induced NF-κB activity. Intriguingly, the TNFα-induced IκB phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of IκBα and IκBß proteins, it did not alter the kinetics of TNFα-induced IκB protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-κB activity and TNFα-induced IκB kinase activation without affecting TNFα-induced NF-κB activity in VSMCs. In addition, knocking down of Cyld suppressed TNFα-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNFα-induced RASMC migration and monocyte adhesion to RASMCs were inhibited by the Cyld knockdown. Finally, immunochemical staining revealed a dramatic augment of CYLD expression in the injured coronary artery with neointimal hyperplasia. Taken together, our results uncover an unexpected role of CYLD in promoting inflammatory responses in VSMCs via a mechanism involving MAPK activation but independent of NF-κB activity, contributing to the pathogenesis of vascular disease.

Validation of the current prognostic models for nonmetastatic renal cell carcinoma after nephrectomy in Chinese population: a 15-year single center experience.

OBJECTIVES: To explore the applicability of the current prognostic models for nonmetastatic renal cell carcinoma in the Chinese population based on a single center experience. METHODS: Clinical and pathological variables of 653 nonmetastatic renal cell carcinoma patients were retrospectively reviewed. Seven models were used to predict the prognosis, including the Yaycioglu model, the Cindolo model, the University of California Los Angeles Integrated Staging System model, the stage, size, grade, and necrosis model, the Kattan nomogram, the Sorbellini nomogram and the Karakiewicz nomogram. Three different end-points were used for validation, including overall survival, cancer-specific survival, and recurrence-free survival. Survival was estimated using the Kaplan-Meier method. Discriminating ability was assessed using the Harrell's concordance-index. RESULTS: At the last follow up, 159 patients had died due to various causes, and disease recurrence occurred in 156 patients. The discriminating ability of all models was confirmed in the Chinese population. Nomograms discriminate better than algorithms, regardless of end-points. The Kattan nomogram was the most accurate, with the highest concordance-indexes of 0.752, 0.793 and 0.841 for overall survival, cancer-specific survival, and recurrence-free survival, respectively. CONCLUSIONS: The current prognostic models were developed and validated entirely based on Caucasian populations. This study defines the general applicability of the models for Chinese patients with nonmetastatic renal cell carcinoma treated with nephrectomy. The Kattan model was found to be the most accurate. The Cindolo model performed well in some situations, although only including clinical presentation and size of tumor. Therefore, models should be chosen according to different environments and purposes.

Prognostic implication of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma: a tissue microarray study.

BACKGROUND: p27Kip1 plays a major role as a negative regulator of the cell cycle. The regulation of p27Kip1 degradation is mediated by its specific ubiquitin ligase subunits S-phase kinase protein (Skp) 2 and cyclin-dependent kinase subunit (Cks) 1. However, little is known regarding the prognostic utility of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma. METHODS: Immunohistochemistry was performed for p27Kip1, Skp2 and Cks1 in tissue microarrays of 482 renal cell carcinomas with follow-up. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. RESULTS: Immunoreactivity of p27Kip1, Skp2 and Cks1 was noted in 357, 71 and 82 patients, respectively. Skp2 and Cks1 expression were not noted in chromophobe cancers. A strong correlation was found between Skp2 and Cks1 expression (P < 0.001), both of which were inversely related to p27Kip1 levels (P = 0.006 and P < 0.001), especially in primary and clear-cell cancers. Low p27Kip1 expression and Skp2 expression were correlated with larger tumor size and higher stage, as well as tumor necrosis. Cks1 expression was only correlated with tumor size. In univariate analysis, low p27Kip1 expression, Skp2 and Cks1 expression were all associated with a poor prognosis, while in multivariate analysis, only low p27Kip1 expression were independent prognostic factors for both cancer specific survival and recurrence-free survival in patients with RCC. CONCLUSION: Our results suggest that immunohistochemical expression levels of p27Kip1, Skp2 and Cks1 may serve as markers with prognostic value in renal cell carcinoma.

Chronic administration of valproic acid inhibits PC3 cell growth by suppressing tumor angiogenesis in vivo.

AIM: Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. We investigated the mechanisms of chronic valproic acid (VPA) inhibiting PC3 cell growth in the study. METHODS: We established tumor xenografts of the PC3 cell line and investigated the effect of VPA chronic administration on tumor growth. Apoptosis in tumor tissue was measured using the TUNEL Detection Kit. We detected the effect of VPA chronic administration on histone acetylation; p21CIP1/WAF1 gene expression; vascular endothelial growth factor (VEGF) expression by reverse-transcription Polymerase Chain Reaction (PCR) analysis; immunohistochemistry; and Western Blotting. RESULT: In mouse models with established subcutaneous prostate (PC3), VPA treatment induced 70% inhibition of tumor growth without overt toxicity. Our result showed that chronic administration of VPA has an effect on tumor growth arrest and the effect was associated with increased histone acetylation, p21CIP1/WAF1 up-regulation, and VEGF down-regulation. CONCLUSION: We conclude that chronic VPA results in profound decreases in the proliferation of PC3 cells, not only by increasing histone H3 acetylation and up-regulating p21CIP1/WAF1 expression, but also by down-regulating VEGF.