USP11 regulates proliferation and apoptosis of human spermatogonial stem cells via HOXC5-mediated canonical WNT/ß-catenin signaling pathway.

Spermatogonial stem cells (SSCs) are capable of transmitting genetic information to the next generations and they are the initial cells for spermatogenesis. Nevertheless, it remains largely unknown about key genes and signaling pathways that regulate fate determinations of human SSCs and male infertility. In this study, we explored the expression, function, and mechanism of USP11 in controlling the proliferation and apoptosis of human SSCs as well as the association between its abnormality and azoospermia. We found that USP11 was predominantly expressed in human SSCs as shown by database analysis and immunohistochemistry. USP11 silencing led to decreases in proliferation and DNA synthesis and an enhancement in apoptosis of human SSCs. RNA-sequencing identified HOXC5 as a target of USP11 in human SSCs. Double immunofluorescence, Co-immunoprecipitation (Co-IP), and molecular docking demonstrated an interaction between USP11 and HOXC5 in human SSCs. HOXC5 knockdown suppressed the growth of human SSCs and increased apoptosis via the classical WNT/ß-catenin pathway. In contrast, HOXC5 overexpression reversed the effect of proliferation and apoptosis induced by USP11 silencing. Significantly, lower levels of USP11 expression were observed in the testicular tissues of patients with spermatogenic disorders. Collectively, these results implicate that USP11 regulates the fate decisions of human SSCs through the HOXC5/WNT/ß-catenin pathway. This study thus provides novel insights into understanding molecular mechanisms underlying human spermatogenesis and the etiology of azoospermia and it offers new targets for gene therapy of male infertility.

The prognostic nutritional index predicts the biochemical recurrence of patients treated with robot-assisted laparoscopic radical prostatectomy.

OBJECTIVE: To evaluate the prognostic nutritional index (PNI) in predicting the biochemical recurrence (BCR) of patients treated with robot-assisted laparoscopic radical prostatectomy (RALP). METHODS: The clinical data of 136 patients treated with RALP in the Department of Urology, The Third Xiangya Hospital of Central South University were retrospectively analyzed. The endpoint of observation was BCR. The area under the receiver operating characteristic (ROC) curve was evaluated to determine the optimal cutoff value of PNI. The correlation of the PNI with BCR was estimated using Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: The optimal cutoff value of the PNI was 46.03 according to the ROC curve. (95% confidence interval: 0.604-0.805, Youden index = 0.401, sensitivity = 82.5%, specificity = 57.6%, p < 0.01). Multivariate Cox analysis showed that clinical staging, prostate-specific antigen, and PNI were independent prognostic factors for predicting BCR in patients treated with RALP. CONCLUSION: PNI is an independent prognostic factor for predicting BCR in patients treated with RALP. The incorporation of the PNI into risk assessments may provide additional prognostic information.

[Ductal adenocarcinoma of the prostate: Report of 45 cases and review of the literature].

OBJECTIVE: To explore the clinical features, treatment and prognosis of ductal adenocarcinoma of the prostate (DAP) and get a deeper insight into the malignancy. METHODS: We retrospectively studied the clinical data on 45 cases of confirmed DAP, 26 in the high-risk group and 19 in the medium-risk group, treated from January 2013 to September 2020. We compared the time and rate of biochemical recurrence and the rate of imaging progression between the two groups of patients, and evaluated the effect of palliative transurethral bipolar plasma resection of the prostate (pTU-PKRP) on the lower urinary tract symptoms (LUTS). RESULTS: Of the 45 cases of DAP, 4 (8.9%) were of the simple type, and 41 (91.1%) complicated by prostatic acinar carcinoma (PAA). And of the latter 41 cases, 9 (21.9%) were complicated by neuroendocrine differentiation and another 4 (9.8%) by intraductal carcinoma. The time to biochemical recurrence was longer in the medium-risk than in the high-risk group (P < 0.05). No statistically significant differences were observed in the rates of biochemical recurrence and imaging progression between the two groups (P > 0.05). The maximum urinary flow rate (Qmax), postvoid residual urine volume (PVR), IPSS and QOL of the patients were significantly improved at 6 months after pTU-PKRP compared with the baseline (P < 0.05). CONCLUSION: Radical prostatectomy can improve the prognosis of early DAP, while for advanced DAP with serious LUTS, pTU-PKRP can improve the quality of life of the patients.

[Up-regulated expression of miR-576 inhibits ALK4 expression, regulates JAK/STAT signaling pathway and promotes proliferation and migration of prostatic cancer cells].

OBJECTIVE: To explore the mechanism of the action of the miR-576/ALK4 axis on the progression of prostate cancer (PCa). METHODS: PCa cells were transfected with miR-576 mimics/inhibitor, the proliferation and migration distance of the cells were detected by MTT and scratch wound healing assay, respectively. The targeted regulation effect of miR-576 on ALK4 was verified by dual-luciferase reporter assay. The effects of miR-576 on the mRNA and protein expressions and phosphorylation levels of the ALK4 and JAK/STAT signaling pathway factors JAK2 and STAT3 were determined by qPCR and Western blot, respectively. The C4-2 cells were co-treated with sh-ALK4 and Ruxolitinib for measurement of the proliferation and migration of the PCa cells. RESULTS: Bioinformatics analysis and binding site prediction showed that miR-576 was up-regulated in the PCa cells, and dual-luciferase reporter assay revealed its targeted regulation effect on ALK4 and its impact on the phosphorylation levels of JAK2 and STAT3. Overexpressed miR-576 promoted while knocked-down miR-576 inhibited the proliferation and migration of the PCa cells. sh-ALK4 increased the proliferation and migration of the cells, while Ruxolitinib suppressed the promoting effect of sh-ALK4. CONCLUSION: The expression of miR-576 is up-regulated in PCa, inhibits the expression of ALK4, regulates the activity of the JAK and STAT signaling pathways, and promotes the proliferation and migration of PCa cells.

ZHX3 promotes the progression of urothelial carcinoma of the bladder via repressing of RGS2 and is a novel substrate of TRIM21.

Clinically, patients with urothelial carcinoma of the bladder (UCB) with tumor metastasis are incurable. To find new therapeutic strategies, the mechanisms underlying UCB invasion and metastasis should be further investigated. In this study, zinc finger and homeobox 3 (ZHX3) was first screened as a critical oncogenic factor associated with poor prognosis in a UCB dataset from The Cancer Genome Atlas (TCGA). These results were also confirmed in a large cohort of clinical UCB clinical samples. Next, we found that ZHX3 could promote the migration and invasion capacities of UCB cells both in vitro and in vivo. Mechanistically, coimmunoprecipitation (coIP) and mass spectrometry (MS) analysis indicated that ZHX3 was a target of tripartite motif 21 (TRIM21), which mediates its ubiquitination, and subsequent degradation. Notably, RNA-seq analysis showed that ZHX3 repressed the expression of regulator of G protein signaling 2 (RGS2). Generally, our results suggest that ZHX3 plays an oncogenic role in UCB pathogenesis and might serve as a novel therapeutic target for UCB.

Fe-doped chrysotile nanotubes containing siRNAs to silence SPAG5 to treat bladder cancer.

BACKGROUND: For certain human cancers, sperm associated antigen 5 (SPAG5) exerts important functions for their development and progression. However, whether RNA interference (RNAi) targeting SPAG5 has antitumor effects has not been determined clinically. RESULTS: The results indicated that Fe-doped chrysotile nanotubes (FeSiNTs) with a relatively uniform outer diameter (15-25 nm) and inner diameter (7-8 nm), and a length of several hundred nanometers, which delivered an siRNA against the SPAG5 oncogene (siSPAG5) efficiently. The nanomaterials were designed to prolong the half-life of siSPAG5 in blood, increase tumor cell-specific uptake, and maximize the efficiency of SPAG5 silencing. In vitro, FeSiNTs carrying siSPAG5 inhibited the growth, migration, and invasion of bladder cancer cells. In vivo, the FeSiNTs inhibited growth and metastasis in three models of bladder tumors (a tail vein injection lung metastatic model, an in-situ bladder cancer model, and a subcutaneous model) with no obvious toxicities. Mechanistically, we showed that FeSiNTs/siSPAG5 repressed PI3K/AKT/mTOR signaling, which suppressed the growth and progression of tumor cells. CONCLUSIONS: The results highlight that FeSiNTs/siSPAG5 caused no activation of the innate immune response nor any systemic toxicity, indicating the possible therapeutic utility of FeSiNTs/siSPAG5 to deliver siSPAG5 to treat bladder cancer.

SLC12A5 interacts and enhances SOX18 activity to promote bladder urothelial carcinoma progression via upregulating MMP7.

Solute carrier family 12 member 5 (SLC12A5) has an oncogenic role in bladder urothelial carcinoma. The present study aimed to characterize the molecular mechanisms of SLC12A5 in bladder urothelial carcinoma pathogenesis. Functional assays identified that in bladder urothelial carcinoma SLC12A5 interacts with and stabilizes SOX18, and then upregulates matrix metalloproteinase 7 (MMP7). In vivo and in vitro assays were performed to confirm the effect of SLC12A5's interaction with SOX18 on MMP7-mediated bladder urothelial carcinoma progression. SLC12A5 was upregulated in human bladder tumors, and correlated with the poor survival of patients with bladder urothelial carcinoma tumor invasion and metastasis, promoted by SLC12A5 overexpression. We demonstrated that SLC12A5 interacted with SOX18, and then upregulated MMP7, thus enhancing tumor progression. Importantly, SLC12A5 expression correlated positively with SOX18 and MMP7 expression in bladder urothelial carcinoma. Furthermore, SLC12A5 expression was suppressed by miR-133a-3p. Ectopic expression of SLC12A5 partly abolished miR-133a-3p-mediated suppression of cell migration. SLC12A5-SOX18 complex-mediated upregulation on MMP7 was important in bladder urothelial carcinoma progression. The miR-133a-3p/SLC12A5/SOX18/MMP7 signaling axis was critical for progression, and provided an effective therapeutic approach against bladder urothelial carcinoma.

Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse-Associated Cavernous Nerve Regeneration.

BACKGROUND: Neurogenic erectile dysfunction (ED) is often refractory to treatment because of insufficient functional nerve recovery after injury or insult. Noninvasive mechano-biological intervention, such as microenergy acoustic pulse (MAP), low-intensity pulsed ultrasound, and low-intensity extracorporeal shockwave treatment, is an optimal approach to stimulate nerve regeneration. AIM: To establish a new model in vitro to simulate nerve injury in neurogenic ED and to explore the mechanisms of MAP in vitro. METHODS: Sprague-Dawley rats were used to isolate Schwann cells (SCs), major pelvic ganglion (MPG), and cavernous nerve with MPG (CN/MPG). SCs were then treated with MAP (0.033 mJ/mm2, 1 Hz, 100 pulses), and SC exosomes were isolated. The MPG and CN/MPG were treated with MAP (0.033 mJ/mm2, 1 Hz) at different dosages (25, 50, 100, 200, or 300 pulses) or exosomes derived from MAP-treated SCs in vitro. OUTCOMES: Neurite growth from the MPG fragments and CN was photographed and measured. Expression of neurotropic factors (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) was checked. RESULTS: Neurite outgrowth from MPG and CN/MPG was enhanced by MAP in a dosage response manner, peaking at 100 pulses. MAP promoted SC proliferation, neurotropic factor (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) expression, and exosome secretion. SC-derived exosomes significantly enhanced neurite outgrowth from MPG in vitro. CLINICAL IMPLICATIONS: MAP may have utility in the treatment of neurogenic ED by SC-derived exosomes. STRENGTH & LIMITATIONS: We confirmed that MAP enhances penile nerve regeneration through exsomes. Limitations of this study include that our study did not explore the exact mechanisms of how MAP increases SC exosome secretion nor whether MAP modulates the content of exosomes. CONCLUSION: This study revealed that neurite outgrowth from MPG was enhanced by MAP and by SC-derived exosomes which were isolated after MAP treatment. Our findings indicate that one mechanism by which MAP induces nerve regeneration is by stimulation of SCs to secrete exosomes. Peng D, Reed-Maldonado AB, Zhou F, et al. Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse-Associated Cavernous Nerve Regeneration. J Sex Med 2020;17:1618-1628.

Primary abdominal cocoon with cryptorchidism: a case report.

BACKGROUND: We report a rare case of primary abdominal cocoon with bilateral cryptorchidism. CASE PRESENTATION: The patient had a history of laparoscopic surgery for bilateral cryptorchidism 6 years earlier. He was admitted to the hospital again due to intestinal obstruction. Surgery was performed on the patient after the failure of conservative treatment. The patient was diagnosed with primary abdominal cocoon. Instead of the greater omentum, many cocoon-like tissues surrounding the bowel were seen during operation. Abdominal surgery can increase the risk of intestinal adhesion, which is one of the main causes of intestinal obstruction, especially in patients with abdominal cocoon. We hypothesize that the surgery 6 years earlier to address transabdominal bilateral cryptorchidism accelerated the patient's intestinal obstruction. CONCLUSION: This case implies that it is important for urologists to evaluate whether their patients exhibit abdominal cocoon before cryptorchidism surgery, to choose better surgical methods and reduce the risks of poor prognosis.

[Neuroendocrine differentiated prostate adenocarcinoma: Report of 23 cases and review of the literature].

OBJECTIVE: To study the clinical features and prognosis of neuroendocrine differentiated prostate adenocarcinoma (NED/AdPC). METHODS: We retrospectively analyzed the clinical data on 23 cases of NED/AdPC treated between 2005 and 2018, among which, 18 had lower urinary tract symptoms (LUTS). RESULTS: All the 23 patients were diagnosed with NED/AdPC, including 2 cases of AdPC initially diagnosed and confirmed with neuroendocrine differentiation in a second pathological diagnosis after androgen deprivation therapy (ADT). In addition to hormonal therapy for all the cases, 3 of the patients were treated by radical prostatectomy combined with adjuvant chemo- and radiotherapy, 13 by palliative transurethral bipolar plasmakinetic resection of the prostate (pTU-PKRP), of whom 2 underwent a second pTU-PKRP and chemotherapy for castration resistance, 2 with chronic renal insufficiency by percutaneous nephrostomy because of extensive pelvic metastasis, and the other 5 by ADT alone or in combination with radiotherapy. During the follow-up of 7 to 60 months, 2 of the patients died of cancer progression and 1 of pulmonary infection, while the others survived with effective control of the tumor. CONCLUSIONS: Long-term ADT may induce neuroendocrine differentiation in AdPC patients. For early-stage NED/AdPC, radical prostatectomy combined with adjuvant therapy is a main therapeutic option, while for advanced NED/AdPC, pTU-PKRP in combination with ADT may relieve LUTS and improve the patients' quality of life.

Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro.

INTRODUCTION: Modulating tissue-resident stem and progenitor cells with a non-invasive, mechanobiological intervention is an optimal approach for tissue regeneration. Stem cell antigen-1 (Sca-1) has been identified as a stem cell marker within many organs but never within the penis. AIM: To localize and isolate penile stem/progenitor cells (PSPCs) and to evaluate cellular differentiation after exposure to induction medium and microenergy acoustic pulse (MAP) therapy. METHODS: Six male Sprague-Dawley rats were used to isolate PSPCs. Isolation was followed by stem cell characterization and differentiation assays. The PSPCs were then treated with MAP (0.033 mJ/mm2, 1 Hz) at various dosages (25, 50, 100, and 200 pulses) and for different durations (1, 2, 4, 6, or 8 hours) in vitro. MAIN OUTCOME MEASURE: The PSPCs (Sca-1-positive cells) were isolated using the magnetic-activated cell sorting system. PSPC cellular differentiation was assessed after induction with induction medium and with MAP in vitro. Wnt/ß-catenin signaling was also assayed. RESULTS: The PSPCs were successfully localized within the penile subtunic and perisinusoidal spaces, and they were successfully isolated using magnetic-activated cell sorting. The stemness of the cells was confirmed by stem cell marker characterization and by multiple differentiation into smooth muscle cells, endothelial cells, adipocytes, and neurons. MAP-induced PSPCs differentiated into smooth muscle cells by activating the Wnt/ß-catenin signaling pathway in a time- and dosage-dependent manner. CLINICAL IMPLICATIONS: By modulating resident PSPCs, MAP may have utility in the treatment of erectile dysfunction (ED). STRENGTHS & LIMITATIONS: This study provides solid evidence in support of microenergy therapies, including both MAP and low-intensity extracorporeal shock wave therapy, for the treatment of ED. Additional studies are needed and should include additional stem cells markers. Furthermore, studies exploring the underling mechanisms for PSPC activation and differentiation are required. CONCLUSION: PSPCs were successfully identified, localized, and isolated. Additionally, MAP provoked PSPCs to differentiate into smooth muscle cells via the Wnt/ß-catenin signaling pathway. As such, MAP provides a novel method for activating endogenous tissue-resident stem/progenitor cells and might facilitate stem cell regenerative therapy targeting ED. Peng D, Yuan H, Liu T, et al. Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro. J Sex Med 2019; 16:1874-1884.

Suppression of Tescalcin inhibits growth and metastasis in renal cell carcinoma via downregulating NHE1 and NF-kB signaling.

BACKGROUND: Renal cell carcinoma (RCC) is the most common form of kidney cancer. Recent studies reported that Tescalcin was overexpressed in various tumor types. However, the status of Tescalcin protein expression in RCC and its biological function is uncertain. This study was designed to investigate the expression of Tescalcin in human RCC and its biological function. METHODS: shRNA transfection was performed to abrogates the expression of Tescalcin. Quantitative real time PCR and western blotting assays were used to determine mRNA and protein expression levels, respectively. The cell viability was analyzed by MTT and colony formation. Cell flow cytometry was used to assess pHi value and cell apoptosis. Cell invasive and migratory ability was measured with modified Boyden chamber assay. Xenograft model was setup to evaluate tumor growth. RESULTS: Tescalcin was overexpressed in RCC tissues compared with matched normal tissues. It was also overexpressed in RCC cell lines relative that of normal cells. Suppression Tescalcin with specific shRNA resulted in the inhibition of cell proliferation, migration, invasion and apoptosis of RCC cells. Additionally, silencing of Tescalcin also caused the inhibition of the tumor growth in nude mice. Mechanistic study showed that Tescalcin regulated cell proliferation, migration and invasion via NHE1/pHi axis as well as AKT/NF-κB signaling pathway. CONCLUSIONS: These findings demonstrate that atopic expression of Tescalcin facilitates the survival, migration and invasion of RCC cells via NHE1/pHi axis as well as AKT/ NF-κB signaling pathway, providing new perspectives for the future study of Tescalcin as a therapeutic target for RCC.

[Early complications after robot-assisted laparoscopic radical cystectomy and their risk factors].

OBJECTIVE: To identify risk factors for early complications in patients after robot-assisted laparoscopic radical cystectomy (RARC) and a standardized reporting model to predict complications precisely and recommend reasonable prophylaxis.
 Methods: A total of 90 patients with bladder cancer, who underwent RARC in the Second Xiangya Hospital and the Third Xiangya Hospital of Central South University from January 2016 to January 2018, were enrolled for this study. Their clinical information, preoperative examination and follow-up data within 90 d after RARC were collected. Univariable and multivariable logistic regressions were performed to identify risk factors for early complications after RARC.
 Results: The overall incidence of complications within 90 d after RARC was 48.9% (44/90), including 9 cases of Clavien grade 1, 17 cases of Clavien grade 2, 4 cases of Clavien grade 3, 12 cases of Clavien grade 4, and 2 cases of Clavien grade 5. Acute renal injury (22.2%), intestinal obstruction (16.7%), urinary tract infection (14.4%) and lymphatic leakage (10.0%) were the most common complications within 90 d after the operation. Two patients (2.2%) died within 90 d after the operation. Preoperative BMI (OR=1.16, 95% CI 1.02 to 1.32), postoperative instant (≤30 min) serum creatinine (OR=1.02, 95% CI 1.00 to 1.03), and pT stage (OR=1.67, 95% CI 1.05 to 2.68) were the risk factors for early complications after RARC. 
 Conclusion: The incidence of early complications after RARC is high. Preoperative hemodialysis, correction of anemia, intraoperative protection of renal function, and early recovery after surgery are helpful to prevent early complications after RARC.

RIPK4 promotes bladder urothelial carcinoma cell aggressiveness by upregulating VEGF-A through the NF-κB pathway.

BACKGROUND: Constitutively activated nuclear factor kappa B (NF-κB) signalling plays vital roles in bladder urothelial carcinoma (BC) progression. We investigate the effect of receptor-interacting protein kinase 4 (RIPK4) on NF-κB activation and BC progression. METHODS: The expression of RIPK4 was examined in 25 cryopreserved paired bladder samples and 112 paraffin BC specimens. In vivo and in vitro assays were performed to validate effect of RIPK4 on NF-κB pathway-mediated BC progression. RESULTS: High expression of RIPK4 was observed in BC tissues and was an independent predictor for poor overall survival. Up or downregulating the expression of RIPK4 enhanced or inhibited, respectively, the migration and invasion of BC cells in vitro and in vivo. Mechanistically, RIPK4 promoted K63-linked polyubiquitination of tumour necrosis factor receptor-associated factor 2 (TRAF2), receptor-interacting protein (RIP) and NF-κB essential modulator (NEMO). RIPK4 also promoted nuclear localisation of NF-κB-p65, and maintained activation of NF-κB substantially, leading to upregulation of VEGF-A, ultimately promoting BC cell aggressiveness. CONCLUSIONS: Our data highlighted the molecular aetiology and clinical significance of RIPK4 in BC: upregulation of RIPK4 contributes to NF-κB activation, and upregulates VEGF-A, and BC progression. Targeting RIPK4 might represent a new therapeutic strategy to improve survival for patients with BC.

Triptorelin relieves lower urinary tract symptoms in Chinese advanced prostate cancer patients: a multicenter, non-interventional, prospective study.

BACKGROUND: Although triptorelin is increasingly used in China for biochemical castration, its effects on primary prostate cancer symptoms remain unclear. This study aimed to assess the prevalence of lower urinary tract symptoms (LUTS) in Chinese prostate cancer patients and the effectiveness of triptorelin on LUTS. METHODS: In this 48-week multicenter, non-interventional, prospective study, we enrolled patients with locally advanced or metastatic prostate cancer. Patients received triptorelin (15 mg) intramuscularly at baseline and at weeks 12, 24, and 36 with symptom assessment using the International Prostate Symptoms Score (IPSS). The primary endpoints were the prevalence of LUTS at baseline per IPSS categories and the percentage of patients with moderate to severe LUTS (IPSS > 7) at baseline, having at least a 3-point reduction of IPSS score at week 48. RESULTS: A total of 398 patients were included; 211 (53.0%) and 160 (40.2%) among them had severe and moderate LUTS, respectively. Of the patients with IPSS scores available at baseline and at week 48 (n = 213), 81.2% achieved a reduction in IPSS of at least 3 points. Of the patients with moderate to severe LUTS at baseline and IPSS scores available at baseline and at week 48 (n = 194), 86.6% achieved a total IPSS reduction of at least 3 points. CONCLUSIONS: The vast majority of Chinese patients with locally advanced or metastatic prostate cancer scheduled to receive triptorelin as part of their standard treatment have severe or moderate LUTS. Triptorelin therapy resulted in sustained improvement of LUTS in these patients.

Tyrosine Residues Regulate Multiple Nuclear Functions of P54nrb.

The non-POU-domain-containing octamer binding protein (NONO; also known as p54nrb) has various nuclear functions ranging from transcription, RNA splicing, DNA synthesis and repair. Although tyrosine phosphorylation has been proposed to account for the multi-functional properties of p54nrb, direct evidence on p54nrb as a phosphotyrosine protein remains unclear. To investigate the tyrosine phosphorylation status of p54nrb, we performed site-directed mutagenesis on the five tyrosine residues of p54nrb, replacing the tyrosine residues with phenylalanine or alanine, and immunoblotted for tyrosine phosphorylation. We then preceded with luciferase reporter assays, RNA splicing minigene assays, co-immunoprecipitation, and confocal microscopy to study the function of p54nrb tyrosine residues on transcription, RNA splicing, protein-protein interaction, and cellular localization. We found that p54nrb was not phosphorylated at tyrosine residues. Rather, it has non-specific binding affinity to anti-phosphotyrosine antibodies. However, replacement of tyrosine with phenylalanine altered p54nrb activities in transcription co-repression and RNA splicing in gene context-dependent fashions by means of differential regulation of p54nrb protein association with its interacting partners and co-regulators of transcription and splicing. These results demonstrate that tyrosine residues, regardless of phosphorylation status, are important for p54nrb function. J. Cell. Physiol. 232: 852-861, 2017. © 2016 Wiley Periodicals, Inc.

A novel delocalized lipophilic cation-chlorambucil conjugate inhibits P-glycoprotein in HepG2/ADM cells.

Multidrug resistance (MDR) limits the application of a large number of cancer-fighting agents in clinical therapy. One reason is that P-glycoprotein (Pgp) efflux pumps are usually overexpressed and lead to drug efflux in the cancer cells, which limits the viability of many chemotherapeutics. Current available inhibitors which block the Pgp pump efflux are usually not widely used in clinical practice, because they change other drug pharmacokinetic profiles or increase side effects. Here, through covalent linkage of cancer-targeting delocalized lipophilic cation FF and DNA-damaging drug nitrogen mustard chlorambucil (CLB), we rationally designed and synthesized a tumor-targeting anticancer agent FFCLB. And we found and proved that the FFCLB was capable of reducing the outflow of Pgp substrates efficiently. This conjugate selectively improves adriamycin uptake and toxicity through reducing MDR1 mRNA and Pgp protein expression. Based on molecular targeted strategy, this study can facilitate the discovery of superior MDR reducing agents to provide a more effective and safer way of resensitizing MDR.

Laparoscopic versus open nephroureterectomy to treat localized and/or locally advanced upper tract urothelial carcinoma: oncological outcomes from a multicenter study.

BACKGROUND: Many studies have reported the oncological outcomes between open radical nephroureterectomy (ONU) and laparoscopic radical nephroureterectomy (LNU) of upper tract urothelial carcinoma (UTUC). However, few data have focused on the oncological outcomes of LNU in the subgroup of localized and/or locally advanced UTUC (T1-4/N0-X). The purpose of this study was to compare the oncological outcomes of LNU vs. ONU for the treatment in patients with T1-4/N0-X UTUC. METHODS: We collected and analyzed the data and clinical outcomes retrospectively for 265 patients who underwent radical nephroureterectomy for T1-4/N0-X UTUC between April 2000 and April 2013 at two Chinese tertiary hospitals. Survival was estimated using the Kaplan-Meier method. Cox's proportional hazards model was used for univariate and multivariate analysis. RESULTS: The mean patient age was 62.0 years and the median follow-up was 60.0 months. Of the 265 patients, 213 (80.4%) underwent conventional ONU, and 52 (19.6%) patients underwent LNU. The groups differed significantly in their presence of previous hydronephrosis, presence of previous bladder urothelial carcinoma, and management of distal ureter (P < 0.05). The predicted 5-year intravesical recurrence- free survival (RFS) (79% vs. 88%, P = 0.204), overall RFS (47% vs. 59%, P = 0.076), cancer-specific survival (CSS) (63% vs. 70%, P = 0.186), and overall survival (OS) (61% vs. 55%, P = 0.908) rates did not differ between the ONU and LNU groups. Multivariable Cox proportional regression analysis showed that surgical approach was not significantly associated with intravesical RFS (odds ratio [OR] 1.23, 95% confidence interval [CI] 0.46-3.65, P = 0.622), Overall RFS (OR 0.99, 95% CI 0.54-1.83, P = 0.974), CSS (OR 1.38, 95% CI 0.616-3.13, P = 0.444), or OS (OR 1.61, 95% CI 0.81-3.17, P = 0.17). CONCLUSIONS: The results of this retrospective study showed no statistically significant differences in intravesical RFS, overall RFS, CSS, or OS between the laparoscopy and the open groups. Thus, LNU can be an alternative to the open procedure for T1-4/N0-X UTUC. Further studies, including a multi-institutional, prospective study are required to confirm these findings.

[Initial experience with robot-assisted laparoscopic prostatectomy for complicated cases].

OBJECTIVE: To present our initial experience with robot-assisted laparoscopic prostatectomy (RALP) for complicated cases.
 Methods: Clinical and pathological data from 4 complicated prostate cancer cases, who underwent RALP from October to November in 2015, were analyzed retrospectively. All the cases were conducted transurethral plasmakinetic enucleation of prostate and hormonal therapy before RALP.
 Results: All surgeries were done successfully. The age, baseline prostatic special antigen, clinical tumor stage, operation time and estimated blood loss were 58-70 years, 6.04-70.15 ng/mL, T2b-T3b, 210-360 min and 50-250 mL, respectively. No blood transfusion was needed. All surgical margin were negative.
 Conclusion: Although previous transurethral surgeries and hormonal therapies may increase the difficulty for operations, RALP is still appropriate for the complicated cases of prostate cancer.

[Causes of orchiectomy: An analysis of 291 cases].

OBJECTIVE: To study the causes of orchiectomy in different age groups. METHODS: We retrospectively reviewed the clinical data about 291 cases of orchiectomy performed between March 1993 and October 2014 and analyzed the causes of surgery and their distribution in different age groups. RESULTS: The main causes of orchiectomy were testicular torsion (45.8%), cryptorchidism (32.5%) and testicular tumor (16.9%) in the patients aged 0-25 years, testicular tumor (42.4%), cryptorchidism (25.9%) and tuberculosis (10.6%) in those aged 26-50 years. Prostate cancer was the leading cause in those aged 51-75 years (77.6%) or older (84.0%)), and testicular tumor was another cause in the 51-75 years old men (10.2%). Prostate cancer, testicular tumor, cryptorchidism, and testicular torsion were the first four causes of orchiectomy between 1993 and 2009. From 2010 to 2014, however, testicular tumor rose to the top while prostate cancer dropped to the fourth place. CONCLUSION: The causes of orchiectomy vary in different age groups. The proportion of castration for prostate cancer patients significantly reduced in the past five years, which might be attributed to the improvement of comprehensive health care service.