DNA Damage Promotes TMPRSS2-ERG Oncoprotein Destruction and Prostate Cancer Suppression via Signaling Converged by GSK3ß and WEE1.

TMPRSS2-ERG gene fusion occurs in approximately 50% of cases of prostate cancer (PCa), and the fusion product is a key driver of prostate oncogenesis. However, how to leverage cellular signaling to ablate TMPRSS2-ERG oncoprotein for PCa treatment remains elusive. Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3ß and WEE1, respectively. The dual phosphorylation triggers ERG recognition and degradation by the E3 ubiquitin ligase FBW7 in a manner independent of a canonical degron. DNA damage-induced TMPRSS2-ERG degradation was abolished by cancer-associated PTEN deletion or GSK3ß inactivation. Blockade of DNA damage-induced TMPRSS2-ERG oncoprotein degradation causes chemotherapy-resistant growth of fusion-positive PCa cells in culture and in mice. Our findings uncover a previously unrecognized TMPRSS2-ERG protein destruction mechanism and demonstrate that intact PTEN and GSK3ß signaling are essential for effective targeting of ERG protein by genotoxic therapeutics in fusion-positive PCa.

Serum prolactin level as a predictive factor for abiraterone response in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. METHODS: This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI). RESULTS: The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037). CONCLUSIONS: Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

The Correlation between Severity of Overactive Bladder Symptoms with Female Sexual Dysfunction and Sexual Satisfaction of Partners.

PURPOSE: Sexual dysfunction in women with overactive bladder (OAB) syndrome has been an important topic, while the sexual satisfaction of partners has not been fully investigated. Our aim was to explore the association between the severity of OAB with female sexual dysfunction and sexual satisfaction of partners. METHODS: A total of 323 patients with OAB recruited in our hospital were included in our study from September 2017 to March 2019. Data were collected by Overactive Bladder Symptom Score (OABSS) questionnaire, self-designed questionnaire for basic characteristics; Female Sexual Function Index (FSFI); and sexual satisfaction survey for sex partners of patients. χ2 test or 1-way ANOVA was used to compare the variables among groups. Logistic regression analysis was performed to analyze the severity of OAB with female sexual dysfunction and sexual satisfaction of partners. The correlations between different OABSS domains with female sexual dysfunction and sexual satisfaction of partners were assessed. RESULTS: All the patients were classified into mild (n = 107), moderate (n = 98), severe (n = 118) OAB group based on OABSS. Most of the basic information were similar among groups, except for BMI, highest education, occupation, fertility, and history of pelvic floor surgery. After multiple factors correction, the severity of OAB, exercise frequency, and the history of pelvic floor surgery were statistically associated with the female sexual dysfunction and sexual satisfaction of partners. Urgency score was significantly correlated with female sexual dysfunction, and the urge incontinence was most significantly associated with the sexual satisfaction of partners. CONCLUSION: Severe OAB was closely associated with female sexual dysfunction and sexual satisfaction of partners. The urgency and urge incontinence should be focused for OAB management.

[Yun's optimized pelvic floor training therapy for idiopathic moderate overactive bladder with sexual dysfunction in young and middle-aged women].

OBJECTIVE: To explore the efficacy and safety of Yun's optimized pelvic floor training (OPFT) therapy for idiopathic moderate overactive bladder (OAB) with female sexual dysfunction (FSD) in young and middle-aged women. METHODS: Eighty 25－45 years old women with idiopathic moderate OAB companied by FSD were randomized into an experimental and a control group of equal number, the former treated by 6 weeks of Yun's OPFT therapy, followed by a 2-week washout period and then another 6 weeks of traditional pelvic floor muscle exercises (PFME), while the latter by 6 weeks of traditional PFME, followed by a 2-week washout period also and then another 6 weeks of Yun's OPFT. At 0, 6 and 14 weeks, we recorded the scores on overactive bladder symptoms (OABS), patient perception of bladder condition (PPBC), Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire-7 (IIQ-7), pelvic floor muscle strength, voided volume (VV), average urinary flow rate (Qavg), maximum urinary flow rate (Qmax) and postvoid residual urine volume (PVR), female sexual function index (FSFI), sexual satisfaction of the male partners and adverse events, and compared the parameters obtained between the two groups of patients. RESULTS: Thirty-eight of the patients in the experimental group and 29 controls completed the experiment. There were no statistically significant differences in the baseline data between the two groups (P > 0.05). After 6 and 14 weeks of treatment, the effectiveness rate was decreased from 71% to 58% in the experimental group, but increased from 45% to 72% in the control. Significant improvement was achieved in the experimental group in the OABS, PPBC, UDI-6 and IIQ-7 scores, pelvic floor muscle strength, VV, Qavg, Qmax, FSFI and sexual satisfaction of the male partners at 6 weeks as compared with the baseline (P < 0.05), and even more significant at 14 weeks than at 6 (P < 0.05), and so was it in the control group in the PPBC and IIQ-7 scores, VV, Qmax and sexual satisfaction of the male partners at 6 weeks (P < 0.05), and more significant in the OABS, PPBC, UDI-6 and IIQ-7 scores, pelvic floor muscle strength, FSFI and sexual satisfaction of the male partners at 14 than at 6 weeks (P < 0.05). The patients of the experimental group showed remarkably more improvement than the controls in the OABS, PPBC, UDI-6 and IIQ-7 scores, pelvic floor muscle strength, FSFI and sexual satisfaction of the male partners at 6 weeks (P < 0.05), while the control group exhibited significantly better improved OABS, PPBC, UDI-6 and IIQ-7 scores, pelvic floor muscle strength, VV, Qmax, PVR and FSFI than the experimental group at 14 weeks (P < 0.05). No serious adverse reactions were observed during the treatment. CONCLUSIONS: Yun's OPFT therapy can improve the symptoms of moderate OAB with FSD in young and middle-aged women, with significantly better effects than traditional pelvic floor muscle exercises.

Sumoylation Negatively Regulates CSR1-Dependent Prostate Cancer Cell Death.

BACKGROUND/AIMS: SUMOylation is a dynamic process and reversed by the activity of SUMO-specific proteases (SENPs) family. SENP1, a member of this family, is highly expressed and plays oncogenic roles in diverse cancers including prostate cancer. However, the SENP1-transgenic mice exhibit aberrant transformation of the mouse prostate gland but do not develop cancer. Cellular Stress Response 1 (CSR1) is a tumor suppressor gene and frequently deleted in prostate cancers. Overexpression of CSR1 in prostate cancer cells inhibits colony formation, anchorage-independent growth and induces cell death. METHODS: The relationship between CSR1 and SENP1 were determined by immunoprecipitation-based proteomics screen and verified by GST-pull down assay. In vivo SUMOylation assay was used to detect the direct effect of SENP1 in the regulation of CSR1. Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing was used to generate Senp1-/- and CSR1-/- PC3 cells. FACS assay was used to determine the apoptosis ratio of cells after transfection. RESULTS: CSR1 is SUMOylated at K582 and rapid ubiquitinated and degradated in prostate cancer cells. SENP1 interacts with and deSUMOylates CSR1 to prevent its degradation and enhances CSR1-dependent prostate cancer cell death. CONCLUSION: Thus, our data indicates that CSR1 is a critical SUMOylated substrate of SENP1 that might partially explain the controversial roles of SENP1 in prostate cancer development.

Intermediate-Term Outcomes and Complications of Long Segment Urethroplasty with Lingual Mucosa Grafts.

PURPOSE: We evaluated outcomes and donor site complications in male patients with complex urethral strictures who underwent urethroplasty using with long strip oral mucosal grafts. We also analyzed whether a lingual mucosa graft is a good substitute for repairing long segment urethral strictures. MATERIALS AND METHODS: This retrospective study was done in 81 male patients with complex urethral strictures who underwent oral mucosal graft urethroplasty. Patients with long segment (8 cm or greater) anterior urethral strictures who were considered candidates for long strip lingual mucosa graft urethroplasty were included in study. RESULTS: Oral mucosal graft urethroplasty was performed in 81 patients with complex urethral strictures between August 2006 and December 2014. Mean urethral stricture length was 12.1 cm (range 8 to 20). A single 9 to 12 cm long strip lingual mucosa graft was used in 52 patients, a lingual mucosa graft greater than 12 cm was placed in 17 and a lingual mucosa graft combined with a buccal mucosal graft was used in 12. Mean followup was 41 months (range 15 to 86) postoperatively. The overall urethroplasty success rate was 82.7%. Urethral complications developed in 14 patients (17.3%), including urethral strictures in 10 and urethrocutaneous fistulas in 4. At 12 months 5 patients (6.2%) reported minimal difficulty with fine motor movement of the tongue. CONCLUSIONS: Lingual mucosa harvested from the ventrolateral surface of the tongue can provide a wide and long graft that is an excellent urethral substitute. Donor site complications are primarily limited to postoperative year 1. Our study confirms that the lingual mucosa graft is a good substitute for urethral reconstruction and lingual mucosa graft urethroplasty is a valuable procedure to treat long anterior urethral strictures.

Specific MAPK inhibitors prevent hyperglycemia-induced renal diseases in type 1 diabetic mouse model.

Mitogen-activated protein kinase (MAPK) and renin-angiotensin system (RAS) play critical roles in the process of renal diseases, but their interaction has not been comprehensively discussed. In the present studies, we investigated the renoprotective effects of MPAK inhibitors on renal diseases in type 1 diabetic mouse model, and clarify the crosstalk among MAPK signaling. Type 1 diabetic mouse model was established in male C57BL/6 J mice, and treated with or without 10 mg/kg MAPK blockers, including ERK inhibitor PD98059, p38 inhibitor SB203850, and JNK inhibitor SP600125 for four weeks. Hyperglycemia induced renal injuries, but treating them with MAPK inhibitors significantly decreased glomerular volume and glycogen in renal tissues. Although slightly changed body weight and fasting blood glucose levels, MAPK inhibitors attenuated blood urea nitrogen, urea protein, and microalbuminuria. Administration also reduced the diabetes-induced RAS activation, including angiotensin II converting enzyme (c) and Ang II, which contributed to its renal protective effects in the diabetic mice. In addition, the anti-RAS of MAPK inhibitor treatment markedly reduced gene expression of tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase, fibrotic accumulation, and transforming growth factor-ß1 levels in renal tissues. Furthermore, chemical inhibitors and genetic siRNA results identified the crosstalk among the three MAPK signaling, and proved JNK signaling played a critical role in MAPK-mediated ACE pathway in hyperglycemia state. Collectively, these results support the therapeutic effects of MAPK-specific inhibitors, especially JNK inactivation, on hyperglycemia-induced renal damages.

A comparative study of diode laser and plasmakinetic in transurethral enucleation of the prostate for treating large volume benign prostatic hyperplasia: a randomized clinical trial with 12-month follow-up.

The objective of this study is to compare the efficacy and safety of diode laser enucleation of the prostate (DiLEP) with plasmakinetic enucleation of the prostate (PKEP) for symptomatic benign prostatic hyperplasia (BPH) patients with large prostate (volume > 80 ml). From January 2013 to June 2014, 80 consecutive patients were randomized treated with DiLEP (n = 40) or PKEP (n = 40). Perioperative and postoperative outcome data were assessed during a 1-year follow-up. There were no significant preoperative differences between the two surgical groups. The mean prostate volumes in the DiLEP and PKEP groups were 98.6 and 93.3 ml, respectively. DiLEP was equivalent to PKEP in improvement in International Prostate Symptom Score (IPSS), quality of life scores, and maximum flow rate. Compared with PKEP, patients treated with DiLEP showed a lower risk of blood loss (P < 0.01), shorter bladder irrigation and catheterization times (P < 0.01), as well as shorter hospital stays (P < 0.01). Moreover, the DiLEP group was significantly superior to bipolar plasmakinetic group in the irritative symptoms. However, the operation time of the DiLEP group was longer than that of PKEP group (P = 0.02). Both DiLEP and PKEP are safe and effective methods for the treatment of BPH in large prostates (volume > 80 ml). Compared with PKEP, DiLEP provides a decreased risk of hemorrhage, reduced bladder irrigation, and catheterization times, as well as shorter hospital stays.

Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer.

BACKGROUND: 3ß-hydroxysteroid dehydrogenase type 1 (3ßHSD1), which is a rate-limiting enzyme that catalyzes the conversion of adrenal-derived steroid dehydroepiandrosterone to dihydrotestosterone (DHT), may be a promising target for treating castration-resistant prostate cancer (CRPC). METHODS: From 2004 to 2011, a total of 103 consecutive patients presenting with advanced prostate cancer were included in this study. All patients were treated with surgical castration as androgen-deprivation therapy (ADT). Germline DNA was extracted from archived tissue from each patient and sequenced. PSA half-time (representing rate to PSA nadir after ADT), the incidence of, and time to CRPC occurrence, and cause-specific mortality rates were determined during the 3-10 years follow-up. The perioperative data and postoperative outcomes are compared. The patients were retrospectively analyzed for survival time. RESULTS: Of the 103 patient samples analyzed, 18 harbored a heterozygous variant (1245C) HSD3B1 gene, while 85 patients were homozygous wild-type (1245A) for HSD3B1. The two groups were homogenous for age, PSA, Gleason and metastases rate preoperatively. The incidence of CRPC observed in the variant group was significantly higher than that of wild-type group (100% vs. 64.7%, respectively; P = 0.003). Despite this higher incidence of CRPC, there were no significant differences in time to develop CRPC, or in cause-specific mortality. Further, neither PSA half-time, nor time to biochemical recurrence were different between the variant and wild-type groups. CONCLUSION: Prostate cancer patients who harbored the heterozygous variant HSD3B1 (1245C) are more likely to develop to CRPC, but do not have shorter time to biochemical recurrence, shorter survival time or higher mortality risk.

[Prostate cancer stem cells: advances in current research].

Prostate cancer is one of the most common malignancies threatening men's health, and the mechanisms underlying its initiation and progression are poorly understood. Last decade has witnessed encouraging progress in the studies of prostate cancer stem cells (PCSCs), which are considered to play important roles in tumor initiation, recurrence and metastasis, castration resistance, and drug resistance. Therefore, a deeper insight into PCSCs is of great significance for the successful management of prostate cancer. This article presents an overview on the location, origin, and markers of PCSCs as well as their potential correlation with tumor metastasis and castration resistance.

[Meatoplasty with pedicle flap for meatal stenosis secondary to chronic balanitis].

OBJECTIVE: To evaluate the effect of meatoplasty with the pedicle flap in the treatment of meatal stenosis secondary to chronic balanitis. METHODS: We retrospectively analyzed 32 cases of meatal stenosis secondary to chronic balanitis treated by meato- plasty with the pedicle flap. All the patients had a history of chronic balanitis and had received meatal dilatation or simple ventral mea- totomy without significant effect. Their mean maximum urinary flow rate (Qmax) was (4.3 ± 2.4) ml/s. During the operation, A "/\"-shaped incision was made in the healthy epidermis and a flap was harvested from the frenulum. After complete removal of the scar, the flap was placed into the urethral wall, followed by reconstruction of the external urethral orifice. RESULTS: The patients were fol- lowed up for 6 to 30 months, which revealed smooth urination in all the patients with Qmax of (26.7 ± 4.5) ml/s and normal erectile function and uresiesthesis. CONCLUSION: With little invasiveness and few complications, meatoplasty with the pedicle flap is an ideal surgical method for the treatment of meatal stenosis secondary to chronic balanitis. However, there might be some change in the normal appearance of the balanus postoperatively, and its long-term effect needs further observation.

PRL-mediated STAT5B/ARRB2 pathway promotes the progression of prostate cancer through the activation of MAPK signaling.

Previous study showed that higher expression of prolactin (PRL) was found in CRPC samples compared with hormone-naive prostate cancer (HNPC) and benign prostatic hyperplasia (BPH) samples. We further investigate the function of PRL in prostate cancer (PCa) and explored its downstream effects. We found heterogeneous expression of the PRLR in clinical prostate samples. The VCaP and 22Rv1 cells exhibited PRLR expression. Among the downstream proteins, STAT5B was the dominant subtype in clinical samples and cell lines. Human recombinant PRL stimulation of PCa cells with PRLR expression resulted in increased phosphorylation of STAT5B(pSTAT5B) and progression of PCa in vitro and in vivo, and STAT5B knockdown can suppress the malignant behavior of PCa. To understand the mechanism further, we performed Bioinformatic analysis, ChIP qPCR, and luciferase reporter gene assay. The results revealed that ARRB2 was the transcription target gene of STAT5B, and higher expression of ARRB2 was related to higher aggression and poorer prognosis of PCa. Additionally, Gene set enrichment analysis indicated that higher expression of ARRB2 was significantly enriched in the MAPK signaling pathway. Immunohistochemistry (IHC) demonstrated elevated pSTAT5B, ARRB2, and pERK1/2 expression levels in CRPC tissues compared to HNPC and BPH. Mechanically, ARRB2 enhanced the activation of the MAPK pathway by binding to ERK1/2, thereby promoting the phosphorylation of ERK1/2 (pERK1/2). In conclusion, our study demonstrated that PRL stimulation can promote the progression of PCa through STAT5B/ARRB2 pathway and activation of MAPK signaling, which can be suppressed by intervention targeting STAT5B. Blockade of the STAT5B can be a potential therapeutic target for PCa.

Perineural Invasion as a Risk Factor For Soft Tissue Progression in Patients With Metastatic Castration-Resistant Prostate Cancer After Abiraterone Resistance.

BACKGROUND: Prostate cancer presents with soft tissue progression (STP) is highly aggressive. We analyzed the risk factor for STP in patients with metastatic castration-resistant prostate cancer (mCRPC) who developed abiraterone acetate (AA) resistance. METHODS: This retrospective study included patients with mCRPC who received AA between February 2018 and July 2022. STP was defined as recurrent lesions in situ, multiple regional lymph node metastases (mLNM), or visceral metastases. Clinical features of patients with STP were analyzed, and risk factors for STP were further investigated. RESULTS: Sixty-three patients (mean age, 75.0 years; median follow-up time, 22.3 months) were included in this study. Twenty-three patients (36.5%) presented STP during follow up, the overall survival (OS) after STP was 4.6 months. The serum neuron-specific enolase (NSE) were significantly elevated in patients with STP. Biopsies for 8 patients with STP showed neuroendocrine prostate cancer (NEPC, n = 5) was the major pathological types. Further analysis showed that perineural invasion (PNI) in primary tumor were the independent risk factors (HR = 3.145, P = 0.020) for STP, and PNI was related to the aggressiveness of tumor. Patients with PNI showed shorter castration-resistant progression free survival (median, 23.73 months vs. 25.59 months) and STP progression free survival (median, 19.7 months vs. not reached) compared with patients without PNI. CONCLUSIONS: STP showed extremely poor prognoses in patients with mCRPC after AA resistance, NEPC is the main pathological type of STP, and PNI in primary tumor was an independent risk factor for STP and indicated poor prognosis of prostate cancer.

PRMT5 mediated FUBP1 methylation accelerates prostate cancer progression.

Strategies beyond hormone-related therapy should need to be developed to improve prostate cancer mortalityfor better disease management. Here we show that FUBP1 and its methylation are essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppresses the development of prostate cancer. FUBP1 accelerated prostate cancer development across in various pre-clinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence shorter treatment durations in our patient cohort. Suppressed prostate cancer progression was observed in different various genetic mouse models expressing FUBP1 mutants deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, successfully disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in different various pre-clinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potentially therapeutic strategy for disease prostate cancer management.

Glycolysis related lncRNA SNHG3 / miR-139-5p / PKM2 axis promotes castration-resistant prostate cancer (CRPC) development and enzalutamide resistance.

Although androgen deprivation therapy (ADT) by the anti-androgen drug enzalutamide (Enz) may improve the survival level of patients with castration-resistant prostate cancer (CRPC), most patients may eventually fail due to the acquired resistance. The reprogramming of glucose metabolism is one type of the paramount hallmarks of cancers. PKM2 (Pyruvate kinase isozyme typeM2) is a speed-limiting enzyme in the glycolytic mechanism, and has high expression in a variety of cancers. Emerging evidence has unveiled that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have impact on tumor development and therapeutic efficacy by regulating PKM2 expression. Herein, we found that lncRNA SNHG3, a highly expressed lncRNA in CRPC via bioinformatics analysis, promoted the invasive ability and the Enz resistance of the PCa cells. KEGG pathway enrichment analysis indicated that glucose metabolic process was tightly correlated with lncRNA SNHG3 level, suggesting lncRNA SNHG3 may affect glucose metabolism. Indeed, glucose uptake and lactate content determinations confirmed that lncRNA SNHG3 promoted the process of glycolysis. Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM2 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men.

BACKGROUND: A rare mutation G84E in HOXB13 was recently identified to be associated with prostate cancer (PCa) in Caucasians. The goal of this study is to test association between HOXB13 genetic variants and PCa risk in Chinese men. METHODS: All study subjects were part of the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). In the first stage, we screened for mutations by sequencing the HOXB13 coding region in 96 unrelated PCa patients. In stage 2, G84E and novel mutations found in stage 1 were genotyped in 671 PCa patients and 1,536 controls. In stage 3, mutation status in 751 additional PCa patients was imputed via haplotype. RESULTS: The G84E mutation was not detected in this study. However, a novel mutation, G135E, was identified among 96 patients in stage 1. It was also observed twice in 575 additional PCa patients but not in 1,536 control subjects of stage 2. The frequency of G135E was significantly different between cases and controls, with a P-value of 0.027, based on Fisher's exact test. Haplotype estimation showed that G135E mutation carriers shared a unique haplotype that was not observed in other subjects. In stage 3, two more PCa patients were predicted to carry the G135E mutation. CONCLUSIONS: We identified a novel rare mutation in the HOXB13 gene, G135E, which appears to be a founder mutation. This mutation is associated with increased PCa risk in Chinese men. Consistent with a previous report, our findings provide further evidence that rare mutations in HOXB13 contribute to PCa risk.

Tet1 is required for Rb phosphorylation during G1/S phase transition.

DNA methylation plays an important role in many biological processes, including regulation of gene expression, maintenance of chromatin conformation and genomic stability. TET-family proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which indicates that these enzymes may participate in DNA demethylation. The function of TET1 has not yet been well characterized in somatic cells. Here, we show that depletion of Tet1 in NIH3T3 cells inhibits cell growth. Furthermore, Tet1 knockdown blocks cyclin D1 accumulation in G1 phase, inhibits Rb phosphorylation and consequently delays entrance to G1/S phase. Taken together, this study demonstrates that Tet1 is required for cell proliferation and that this process is mediated through the Rb pathway.

[Diagnosis and treatment of yolk sac tumor of the testis with hydrocele in children: report of 7 cases].

OBJECTIVE: To study the clinical characteristics of yolk sac tumor of the testis with concomitant testicular hydrocele in children and the association between the two conditions in order to improve the diagnosis and treatment of the disease. METHODS: We retrospectively analyzed the clinical data of 7 cases of stage-I yolk sac tumor of the testis with concomitant testicular hydrocele. The patients ranged in age from 6 to 14 (mean 11) months. As treatment, we performed radical high spermatic cord orchiectomy after diagnosis established on intraoperative frozen sections, and conducted follow-up visits by medical examination, serum alpha-fetoprotein (AFP) detection, chest X-ray, ultrasonography and CT for 3-41 (mean 17) months, every month in the first year, every 3 months in the second year and every 6 months in the third year after surgery. RESULTS: Postoperative pathology confirmed yolk sac tumor in all the cases, with negative incisal margin. The level of serum AFP were decreased to normal in 6 cases within 1 month after surgery, all diagnosed as at stage I, and cured without chemotherapy. The other 1 case, with the serum AFP level of 116 microg/L at 1 month after operation, was diagnosed as at stage II and received PVC chemotherapy, but lost to follow-up at 3 months post-operatively. CONCLUSION: Yolk sac tumor of the testis with concomitant testicular hydrocele is easily misdiagnosed in children. Ultrasonography is necessitated as routine examination in its diagnosis. Radical high spermatic cord orchiectomy can be performed for patients in stage I, and chemotherapy should follow for those in stage II. Its prognosis is similar to that of other yolk sac tumors. Hitherto, there has been no evidence for a definitive correlation between yolk sac tumor of the testis and hydrocele in children.

Identification of cuproptosis-related genes for predicting the development of prostate cancer.

Copper can be toxic at very high intracellular concentrations and can inhibit prostate cancer (PCa) progression. Recently, a study reported the mechanism of cuproptosis and the potentially associated genes. However, the function of these cuproptosis-related genes in PCa remains unknown. Based on the RNA sequence and clinical data from public databases, we analyzed the clinical value of cuproptosis-related genes in PCa. DLD, DLAT, PDHA1, and CDKN2A were expressed differently between normal and PCa tissues. The FDX1, LIAS, DLAT, GLS, and CDKN2A genes can affect PCa progression, while PDHA1 and CDKN2A influence the patients' disease-free survival (DFS) status. The expression of LIAS, LIPT1, DLAT, and PDHB did not alter upon the incidence of PCa in Chinese patients. A constructed regression model showed that FDX1, PDHA1, MTF1, and CDKN2A can be risk factors leading to PCa in both Western and Chinese patients with PCa. The lasso regression model reflected that these genes can affect the patients' DFS status. Additionally, the cuproptosis-related genes were associated with immune cell infiltration. We also verified the high expression of PDHA1 and CDKN2A, in clinical samples. In conclusion, we identified a novel cuproptosis-related gene signature for predicting the development of PCa.

Study on clinical outcomes between non-transecting urethroplasty and lingual mucosal urethroplasty for iatrogenic bulbar urethral stricture treatment.

BACKGROUND: This study aimed to compare the clinical outcomes of non-transecting urethroplasty and lingual mucosal urethroplasty in the treatment of iatrogenic bulbar urethral stricture. RESULTS: A total of 25 patients with iatrogenic bulbar urethral stricture were enrolled, 12 of whom underwent lingual mucosal urethroplasty, 13 patients who underwent non-transecting urethroplasty. All patients were followed-up and evaluated at 3 postoperative months. Evaluations included urethrography, maximum urine flow rate (Qmax), nocturnal erectile function testing, International Index of Erectile Function (IIEF-5) assessment, and Anxiety Related Scale (SAS) assessment. In terms of operation time, there was a significant difference between non-transecting urethroplasty and lingual mucosal urethroplasty. However, there was no significant intergroup difference in intraoperative blood loss. Both techniques were associated with significantly improved Qmax relative to preoperative rates, but there was no significant difference between the groups in this regard over 3 months of postoperative follow-up. Nocturnal penile tumescence and rigidity results showed that there was no significant change in tip hardness after surgery in the non-transecting urethroplasty group. Moreover, IIEF-5 scores indicated that there was no significant intergroup difference in terms of subjective postoperative erectile function. According to the preliminary psychological evaluations during postoperative follow-up, the anxiety scores of patients undergoing non-transecting urethroplasty significantly improved, but there was no significant change in the mean SAS score among patients who underwent lingual mucosal urethroplasty. CONCLUSION: Both surgical methods can achieve the clinical goal of treating iatrogenic bulbar urethral stricture. Non-transecting urethroplasty has the characteristics of short operation time, relative technical simplicity, and retention of the original erectile function of most patients, and the surgical outcomes of non-transecting urethroplasty are not inferior to those of lingual mucosal urethroplasty, and it is a promising technique for widespread use to treat bulbar urethral strictures.

RéSUMé: CONTEXTE: Cette étude visait à comparer les résultats cliniques de l'urétroplastie non transectante et de l'urétroplastie avec greffe de  muqueuse linguale dans le traitement de la sténose urétrale bulbaire iatrogène. Un total de 25 patients présentant une sténose urétrale bulbaire iatrogène a été recruté, dont 12 ont subi une urétroplastie avec greffe de muqueuse buccale et 13 une urétroplastie non-transectante. Tous les patients ont été suivis et évalués à 3 mois postopératoires. Les évaluations comprenaient une uréthrographie, le débit urinaire maximal (Qmax), un test nocturne de la fonction érectile, l'évaluation de l'index international de la fonction érectile (IIEF5) et une évaluation de l'échelle d'anxiété. RéSULTATS: En termes de durée opératoire, il y avait une différence significative entre l'urétroplastie non-transectante et urétroplastie avec greffe de muqueuse buccale. Cependant, il n'y avait pas de différence significative entre les groupes en ce qui concerne la perte de sang peropératoire. Les deux techniques ont été associées à une amélioration significative du Qmax par rapport aux taux préopératoires, mais il n'y avait pas de différence significative entre les groupes à cet égard sur 3 mois de suivi postopératoire. Les résultats de la tumescence et de la rigidité nocturnes du pénis ont montré qu'il n'y avait pas de changement significatif de la dureté de l'extrémité du pénis après l'opération dans le groupe d'urétroplastie sans transsection. De plus, les scores IIEF-5 ont indiqué qu'il n'y avait pas de différence significative entre les groupes en termes de fonction érectile subjective postopératoire. Selon les évaluations psychologiques préliminaires au cours du suivi postopératoire, les scores d'anxiété des patients ayant subi une urétroplastie non-transectante se sont améliorés de manière significative, mais il n'y a pas eu de changement significatif du score moyen de l'échelle d'anxiété chez les patients ayant subi une urétroplastie avec greffe de muqueuse buccale. CONCLUSIONS: Les deux méthodes permettent d'atteindre l'objectif clinique du traitement de la sténose urétrale bulbaire iatrogène. L'urétroplastie sans transsection présente les caractéristiques suivantes: temps d'opération court, simplicité technique relative et maintien de la fonction érectile initiale chez la plupart des patients. Les résultats chirurgicaux de l'urétroplastie sans transsection ne sont pas inférieurs à ceux de l'urétroplastie avec greffe de muqueuse buccale et cette technique est prometteuse pour une utilisation généralisée dans le traitement des rétrécissements urétraux bulbaires.