Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid.

The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.

TEAD3 inhibits the proliferation and metastasis of prostate cancer via suppressing ADRBK2.

TEAD3 acts as a transcription factor in many tumors to promote tumor occurrence and development. But in prostate cancer (PCa), it appears as a tumor suppressor gene. Recent studies have shown that this may be related to subcellular localization and posttranslational modification. We found that TEAD3 was down-expressed in PCa. Immunohistochemistry of clinical PCa specimens confirmed that TEAD3 expression was the highest in benign prostatic hyperplasia (BPH) tissues, followed by primary PCa tissues, and the lowest in metastatic PCa tissues, and its expression level was positively correlated with overall survival. MTT assay, clone formation assay, and scratch assay confirmed that overexpression of TEAD3 could significantly inhibit the proliferation and migration of PCa cells. Next-generation sequencing results indicated that Hedgehog (Hh) signaling pathway was significantly inhibited after overexpression of TEAD3. Rescue assays suggested that ADRBK2 could reverse the proliferation and migration ability caused by overexpression of TEAD3. TEAD3 is downregulated in PCa and associated with poor patient prognosis. Overexpression of TEAD3 inhibits the proliferation and migration ability of PCa cells via restraining the mRNA level of ADRBK2. These results indicate that TEAD3 was down-expressed in PCa patients and was positively correlated with a high Gleason score and poor prognosis. Mechanistically, we found that the upregulation of TEAD3 inhibits the proliferation and metastasis of prostate cancer by inhibiting the expression of ADRBK2.

Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.

BACKGROUND: Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC. METHODS: Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models. RESULTS: Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis. CONCLUSION: Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

Characteristics of and antibiotic resistance in urinary tract pathogens isolated from patients with upper urinary tract stones.

To investigate the distribution characteristics and antibiotic resistance patterns of uropathogens in patients with upper urinary calculi and urinary tract infections, data on sex, age, positive midstream urine culture results and drug sensitivity results were collected. The statistical program SPSS 26.0 was used for statistical analysis. Among the 1414 positive urine samples, the most common pathogens were Escherichia coli (36.4%), Enterococcus faecalis (13.8%), Staphylococcus epidermidis (7.5%), Klebsiella pneumoniae (5.0%), Streptococcus agalactiae (3.4%) and Enterococcus faecium (3.3%). The incidences of E. coli (48.6%), K. pneumoniae (6.3%) and Proteus mirabilis (4.2%) were higher in female patients than in male patients (23.2%, 3.5%, 0.6%, respectively; P<0.05). E. faecalis was detected more frequently in the young group (16.0%) than in the elderly group (11.2%; P<0.01). Most of the isolates were resistant to levofloxacin and ciprofloxacin, while few were resistant to imipenem, meropenem, cefoperazone/sulbactam, piperacillin/tazobactam and amikacin. The bacterial spectra in patients with urinary stones varied by sex and age, which should be taken into consideration during treatment. The proportion of E. faecium showed an upward trend, while those of S. epidermidis and S. agalactiae demonstrated downward trends in the study period. Regardless, carbapenems, cefoperazone/sulbactam, piperacillin/tazobactam and amikacin are good choices for serious cases.

DNA-repair status should be assessed in treatment-emergent neuroendocrine prostate cancer before platinum-based therapy.

OBJECTIVES: This study sought to provide contemporary data from a multi-institution with respect to DNA-repair genes (DRGs) status and its impact on effects of platinum-based chemotherapy in treatment-emergent neuroendocrine prostate cancer (t-NEPC), for which little data exist. PATIENTS AND METHODS: All patients were retrospectively collected with eligible biopsied tissues for targeted next generation sequencing (NGS). The main outcomes were radiologic progression-free survival and overall survival according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Among the 43 NEPC patients, 13/43 (30%) harbored homozygous deletions, deleterious mutations, or both in DRGs. Eleven patients (11/13, 85%) with DRGs aberrations had effective response, including 7 patients with BRCA1/2 defects and 2 with mismatch repair-deficient caused by MSH2 alterations. While significantly fewer responders (30%) were detected in patients without DRGs aberrations (odds ratio = 12.83, p = 0.003). Compared with patients without genomic DRGs aberrations, the hazard ratio (HR) for radiologic progression in those with DRGs defects was 0.42 (95% confidence interval [CI]: 0.19-0.93), and the HR for death was 0.65 (95% CI: 0.24-1.72). The most common adverse event of Grade 3 or 4 was anemia, as noted in 7 patients (16%). CONCLUSION: The DRGs status is therapeutically meaningful in t-NEPC. Given the potential responses to platinum-based chemotherapy, our findings support the clinical use of NGS in t-NEPC patients to identify DRGs aberrations.

Identification of LAT/ZAP70 characterized immune subtypes of prostate cancer.

BACKGROUND: While immunotherapy has shown potent efficacy in clinical practices, patient selection to receive checkpoint blockade is still challenging in prostate cancer (PCa). LAT and ZAP70 functions in lymphocyte activation and plays a critical role in T cell receptor (TCR) signal transduction. However, PCa genomic and clinical data regarding the role of LAT and ZAP70 are limited. We aim to identify and characterize LAT/ZAP70 defined subtypes of PCa. METHODS: We elaborated the TCGA PCa data and metastatic castration-resistant prostate cancer (mCRPC) RNA-seq data bioinformatic analysis and systematically elucidated the role of intra-tumoral expressed LAT and ZAP70 in the progression-free survival and immunotherapeutic-related signals. LAT/ZAP70-associated immune infiltration was evaluated using bioinformatic tools. Immunohistochemical staining of serial sections was used to confirm the expression and distribution of LAT, ZAP70 and androgen receptor (AR) in PCa tissues. RESULTS: Specifically, LAT and ZAP70 revealed increased expressions in PCa when compared to normal tissues and positively associated with intra-tumoral immune cells infiltration. LAT/ZAP70 defined immune-high early-stage PCa revealed higher TP53 mutation frequency and poor prognosis. Transcriptome analysis indicated immune-related signals and CTLA4 expression were highly enhanced in immune-high PCa parallel with higher protein level of MYC and lower AR expression. In mCRPC, LAT/ZAP70 defined immune-high patients also revealed upregulated immune related signals, higher CTLA4 expression and DNA repair deficiency. CONCLUSION: LAT/ZAP70 defined immune-high PCa linked to immune infiltration and predicts poor prognosis. Immune-high PCa may receive effective response from immune checkpoint inhibitor parallel with systemic treatment.

One-Stage Flexible Ureteroscopy during Single-Tract Percutaneous Nephrolithotomy in the Treatment of Parallel Calyceal Stones.

INTRODUCTION: The aim of this study was to compare the clinical safety and efficiency between one-stage flexible ureteroscopy (FURS) during single-tract percutaneous nephrolithotomy (PCNL) and multi-tract PCNL in the treatment of parallel calyceal stones. METHODS: One hundred and twenty-five patients who had calyceal stones parallel to puncture channel from March 2017 to January 2021 were enrolled and assigned into two groups. Seventy cases received the treatment of FURS combined with single-tract PCNL under the oblique supine position (the Combined group), and 55 cases had multi-tract PCNL procedure under the prone position (the Multi-tract group). Demographic characteristics, clinical information, and surgical outcomes were analyzed. RESULTS: Demographic variables and stone characteristics did not show statistical difference between the two groups. Compared with the Multi-tract group, there were longer operation time (p = 0.021), shorter postoperative hospitalization days (p = 0.003), smaller postoperative hemoglobin drop (p = 0.002), less incidence of moderate and severe postoperative pain (p = 0.001), and postoperative perirenal hematoma (p = 0.012) in the Combined group. No significant difference was found in the stone-free rate (SFR) and postoperative fever between the two groups (p = 0.880 and p = 0.324). More patients needed postoperative intervening embolization in the Multi-tract group (p = 0.048). DISCUSSION/CONCLUSIONS: For most patients with parallel calyceal stones, one-stage FURS combined with single-tract PCNL procedure was a safer procedure for the reduction of complications and could achieve a comparative SFR compared to the multi-tract PCNL.

TPX2 mediates prostate cancer epithelial-mesenchymal transition through CDK1 regulated phosphorylation of ERK/GSK3ß/SNAIL pathway.

Prostate cancer with high Gleason grade is prone to metastasis, which is one of the factors that seriously threaten the survival of patients, and it is also a treatment difficulty. In this study, we first revealed the potential connection between TPX2 and prostate cancer metastasis. We found that TPX2 is highly expressed in high-grade prostate cancer and is significantly related to poor prognosis. Depletion of TPX2 can significantly inhibit cell activity and migration, and in vivo experiments show that knockdown of TPX2 can significantly inhibit tumor growth. In terms of mechanism, we found that knocking down TPX2 can inhibit the expression of CDK1, repress the phosphorylation of ERK/GSK3ß/SNAIL signaling pathway, and thereby inhibit tumor epithelial-mesenchymal transition. Subsequently, we found that after rescuing TPX2, all related proteins and phenotype changes were restored, and this effect can be inhibited by CDK1 inhibitor, RO-3306. Our findings suggest the potential of TPX2 as an important target in anti-tumor metastasis therapy, which is conducive to precision medicine for prostate cancer.

Metformin attenuates the epithelial-mesenchymal transition of lens epithelial cells through the AMPK/TGF-ß/Smad2/3 signalling pathway.

Posterior capsule opacification (PCO) is a common ocular fibrosis disease related to the epithelial-mesenchymal transition (EMT) of human lens epithelial cells (HLECs). However, safe and effective drugs that prevent or treat PCO are lacking. Metformin (Mtf) has been used to treat fibrosis-related diseases affecting many organs and tissues, but its effect on ocular fibrosis-related diseases is unclear. We investigated whether Mtf can inhibit EMT and fibrosis in HLECs to prevent and treat PCO and elucidated the potential molecular mechanism. Here, we established an HLEC model of TGF-ß-induced EMT and found that 400 µM Mtf inhibited vertical and lateral migration and EMT-related gene and protein expression in HLECs. Smad2/3 are downstream molecules of TGF-ß that enter the nucleus to regulate EMT-related gene expression during the occurrence and development of PCO. We revealed that Mtf suppressed TGF-ß-induced Smad2/3 phosphorylation and nuclear translocation. Mtf induces AMP-activated protein kinase (AMPK) phosphorylation. In this study, we found that Mtf induced the activation of AMPK phosphorylation in HLECs. To further explore the mechanism of Mtf, we pretreated HLECs with Compound C (an AMPK inhibitor) to repeat the above experiments and found that Compound C abolished the inhibitory effect of Mtf on HLEC EMT and the TGF-ß/Smad2/3 signalling pathway. Thus, Mtf targets AMPK phosphorylation to inhibit the TGF-ß/Smad2/3 signalling pathway and prevent HLEC EMT. Notably, we first illustrated the AMPK/TGF-ß/Smad2/3 signalling pathway in HLECs, which may provide a new therapeutic strategy for PCO.

LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex.

In PTEN-deficient prostate cancers, AKT signaling may be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NF-κB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKKα. Here, we report a critical role of lncRNA PCAT1 in regulating the PHLPP/FKBP51/IKKα complex and progression of castration-resistant prostate cancer (CRPC). Using database queries, bioinformatic analyses, as well as RIP and RNA pull-down assays, we discovered and validated that the lncRNA-PCAT1 perturbs the PHLPP/FKBP51/IKKα complex and activates AKT and NF-κB signaling. Expression of lncRNA-PCAT1 is positively linked to CRPC progression. PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP1 leading to suppression of AKT signaling. Preclinical study in a mouse model of CRPC suggests therapeutic potential by targeting lncRNA PCAT1 to suppress CRPC progression. Together, the newly identified PCAT1/FKBP51/IKKα complex provides mechanistic insight in the interplay between AKT, NF-κB and AR signaling in CRPC, and the preclinical studies suggest that a novel role for PCAT1 as a therapeutic target.

Androgen deprivation therapy with chemotherapy or abiraterone for patients with metastatic hormone-naive prostate cancer: a systematic review and meta-analysis.

Patients with metastasis prostate cancer underwent androgen deprivation therapy (ADT) in the considering of the leading role of androgen receptor pathway. However, the resistance occurred within 1 year or more. The combination of cytotoxic chemotherapy and abiraterone for ADT therapy was performed in recent randomized controlled trials. The meta-analysis was focused on the treatment comparisons between additional treatment with ADT and ADT alone. A significant difference was observed that the overall survival benefit of early and active additional treatment with ADT in patients with hormone-sensitive metastatic prostate cancer. However, a great proportion of patients with metastatic disease have metastases after receiving ADT. It will be important to further improve the treatment options.

Sox5 contributes to prostate cancer metastasis and is a master regulator of TGF-ß-induced epithelial mesenchymal transition through controlling Twist1 expression.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is one of the main contributors to the death of prostate cancer patients. To date, the detailed molecular mechanisms underlying mCRPC are unclear. Given the crucial role of epithelial-mesenchymal transition (EMT) in cancer metastasis, we aimed to analyse the expression and function of Transforming growth factor-beta (TGF-ß) signal-associated protein named Sox5 in mCRPC. METHODS: The protein expression levels were analysed by western blot, immunohistochemistry and immunofluorescence. Luciferase reporter assays and chromatin immunoprecipitation were employed to validate the target of Sox5. The effect of Smad3/Sox5/Twist1 on PCa progression was investigated in vitro and in vivo. RESULTS: Here, we found that TGF-ß-induced EMT was accompanied by increased Sox5 expression. Interestingly, knockdown of Sox5 expression attenuated EMT induced by TGF-ß signalling. Furthermore, we demonstrated that Smad3 could bind to the promoter of Sox5 and regulate its expression. Mechanistically, Sox5 could bind to Twist1 promoter and active Twist1, which initiated EMT. Importantly, knockdown of Sox5 in prostate cancer cells resulted in less of the mesenchymal phenotype and cell migration ability. Furthermore, targeting Sox5 could inhibit prostate cancer progression in a xenograft mouse model. In clinic, patients with high Sox5 expression were more likely to suffer from metastases, and high Sox5 expression also has a lower progression-free survival and cancer specific-survival in clinic database. CONCLUSIONS: Therefore, we propose a new mechanism in which Smad3/Sox5/Twist1 promotes EMT and contributes to PCa progression.

High Expression of KIF22/Kinesin-Like DNA Binding Protein (Kid) as a Poor Prognostic Factor in Prostate Cancer Patients.

BACKGROUND Kid (kinesin-like DNA binding protein), a member of microtubule-dependent molecular motor proteins, also known as KIF22, is reported to be associated with carcinogenesis and cancer progression in different types of malignant tumor, but the biologic behavior and clinical outcome of KIF22 in prostate cancer (PCa) has not been well studied. This study aimed to analyze the association between KIF22 and clinical outcome in PCa patients. MATERIAL AND METHODS The expression of KIF22 in tumor specimens compared with paired paracancerous tissue from 114 patients undergoing radical prostatectomy was detected by immunohistochemistry; results were verified using The Cancer Genome Atlas (TCGA) database. Subsequently, the relationship between KIF22 expression and clinical prognosis of PCa patients was then statistically analyzed. RESULTS Both immunohistochemistry and database analysis showed that KIF22 was obviously overexpressed in PCa tissues compared with paracancerous tissue. The overexpression of KIF22 at the protein level was significantly related to higher clinical stage (P=0.025), Gleason score (P=0.002), seminal vesicle invasion (P=0.007), and lymph node metastasis (P=0.009). Furthermore, with the overexpression of KIF22 mRNA level in PCa patients, the oncological prognosis of PCa patients was much poorer. CONCLUSIONS High-level expression of KIF22 was related to both tumor progression and adverse clinical outcome. For this reason, KIF22 may become a potential prognostic factor for PCa.

Squamous differentiation in patients with superficial bladder urothelial carcinoma is associated with high risk of recurrence and poor survival.

BACKGROUND: The independent prognostic role of squamous differentiation in pT1 bladder urothelial carcinoma has not been reported in previous studies. This article describes the impact of squamous differentiation on tumor recurrence and survival, and whether this histologic variant could indeed alter definitive treatment, based on single center-based retrospective data. METHODS: Totally, we retrieved (1)1449 histologically confirmed pT1 bladder urothelial carcinoma patients without histologic variants; (2)227 pT1 bladder urothelial carcinoma patients with squamous differentiation in our institution, from May 2004 to Oct 2015. The total amount of high/low grade urothelial carcinoma patients was 991/685 respectively. Transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy were performed as initial treatments for all the patients. The clinical and pathological characteristics, treatment and survival outcomes were compared between squamous differentiation-positive and squamous differentiation-negative patients. RESULTS: In our study, 14% urothelial carcinoma patients were detected with squamous differentiation. The mean age of all the patients examined was 66.4, of whom 82% were males. The 5-year cancer specific survival rates were 69% for squamous differentiation-positive patients and 91% for squamous differentiation-negative patients (p < 0.001). Recurrence proved to be more common in squamous differentiation-positive patients than in negative patients. In the results of the univariate and multivariate Cox proportional hazard analysis, tumor size, lymphovascular invasion, recurrence and squamous differentiation were confirmed to be the prognostic factors associated with patients' survival. CONCLUSIONS: Squamous differentiation in pT1 bladder urothelial carcinoma is correlated to high risk of recurrence and poor prognosis as an independent prognostic factor. Radical cystectomy is essential for recurred high grade pT1 bladder urothelial carcinoma with squamous differentiation accompanied by lymphovascular invasion.

Targeting fatty acid synthase with ASC-J9 suppresses proliferation and invasion of prostate cancer cells.

Fatty acid synthase (FASN) is the key enzyme for the control of fatty acid synthesis that contributes significantly to the prostate cancer (PCa) progression. It was reported that androgens were able to induce FASN expression in PCa, and addition of the anti-androgen Casodex might suppress the androgen-induced FASN expression. However, here we found androgen-deprivation-therapy (ADT) with anti-androgens Bicalutamide (Casodex) or Enzalutamide (MDV3100) had little effect to suppress FASN expression and FASN-mediated cell growth and invasion during the castration resistant stage when the androgen concentration is 1 nM DHT (dihydrotestosterone). In contrast, the newly developed androgen receptor (AR) degradation enhancer ASC-J9® suppressed FASN expression and FASN-mediated cell growth and invasion in various PCa cell lines at 1 nM DHT. Mechanism dissection found ASC-J9® could suppress significantly the FASN expression and FASN-mediated PCa progression via the AR-dependent pathway involving AR→SREBP-1→FASN signaling in AR-positive C4-2 and LNCaP cells and via the AR-independent pathway involving the modulation of PI3K/AKT→SREBP-1→FASN signaling in AR-negative PC-3 and DU145 cells. Together, these results suggest that FASN is one of the important mechanism why the current ADT eventually fails. ASC-J9® might represent a new potential therapeutic approach to suppress FASN-mediated PCa progression via both AR-dependent and AR-independent pathways during the castration resistant stage of PCa. © 2016 Wiley Periodicals, Inc.

Stromal androgen receptor roles in the development of normal prostate, benign prostate hyperplasia, and prostate cancer.

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.

[Analysis of the diagnosis and treatment of desmoplastic small round cell tumor].

OBJECTIVE: To explore the clinical diagnostic features and treatment of desmoplastic small round cell tumor (DSRCT), and to improve the understanding and management of this tumor. METHODS: The clinicopathological data of nine patients treated in our hospital from October 2004 to June 2014 were retrospectively analyzed and a review of the literature was made. The clinical manifestations, pathological characteristics, diagnosis and differential diagnosis, treatment and prognosis of this tumor were summarized and analyzed. RESULTS: Nine patients with DSRCT, 5 males and 4 females, with an average age of 21 years (range 8-56 years) were included in this study. Ultrasound examination revealed irregular low-density mass shadow in the abdominal cavity. CT examination found that 6 cases had abdominal and retroperitoneal multiple solid tumor nodules, uneven density, and visible low density fluid area. Postoperative pathological examination revealed that the tumor cells were small, mostly elliptic, gathered to form clear structure of nests with clear irregular boundaries. The central portion of large tumor nests often showed necrosis. Scattered fibroblasts and large amount of hyalinization of collagen fibers were seen in the interstitial tissue around the nests. Six patients received laparotomy surgery, however, all failed to resect the tumor completely. Three patients received postoperative chemotherapy, i. e. two cases had carboplatin and paclitaxel chemotherapy, and one case of chemotherapy regimen not specified. Two patients had radiation and chemotherapy (no concrete plan was available). Another case was lost to follow-up. Two of the three patients without surgery received chemotherapy with CAP (cyclophosphamide+adriamycin+carboplatin) and total rectal lesions, pelvic and inguinal lymph nodes, ilium metastases radiation therapy. Another one patient received EP regimen (DDP+VP16) which was then changed into a TP chemotherapy alone. Eight of the nine cases died shortly after surgery, and only one patient treated with chemotherapy alone was still alive after 11 months of follow-up. CONCLUSIONS: Desmoplastic small round cell tumor is a very rare, special type of soft tissue tumor, with very poor prognosis. This tumor may be preliminarily diagnosed according to the imaging characteristics and detection of tumor markers, however, final diagnosis is made by pathology. Surgery is the priority of treatment, combined with complementary radiation and chemotherapy.

[Correlation between the expression of Pim-1 and androgen-deprivation therapy for prostate cancer].

OBJECTIVE: To investigate the expression of the Pim-1 gene in the LNCaP cells of the animal model of orthotopically implanted prostate cancer by surgical castration simulating androgen-deprivation therapy. METHODS: We equally allocated 32 male BALBc-nu mice into 4 groups, androgen-dependent prostate cancer (ADPC), androgen-deprivation therapy (ADT) , castration-resistant prostate cancer (CRPC) and blank control, and established the models of orthotopically implanted tumor using human prostate cancer LNCaP cells. We detected and ,compared the expressions of Pim-1, PSA, and androgen receptor (AR) in the tumor tissues of different groups by RT-PCR. qRT-PCR, ELSIA and immunohistochemistry. RESULTS: The relative gray scales in the ADPC and CRPC groups were 0.59 ± 0.01 and 1.14 ± 0.02, with statistically significant differences from 0.62 ± 0.03 in the ADT group (P < 0.05), and the Δ Ct values of Pim-1 were 6.15 ± 0.34 and 4.56 ± 0.23 in the former two groups, also with significant differences from 5.11 ± 0.21 in the latter (P < 0.05). The results of 2-ΔΔ Ct relative quantification analysis showed that the amplification products of Pim-1 in the ADT and CRPC groups increased 2.05 and 3.01 times respectively that of the ADPC group. The concentration of PSA was significantly higher in the ADPC ([480 ± 25] pg/ml) and CRPC ([870 ± 23] pg/ml) than in the ADT ([170 ± 32] pg/ml) and blank control groups (0 µg/L) (P < 0.01). The mean optical densities of Pim-1 and AR proteins were 0.017 ± 0.002 and 0.032 ± 0.009 in the ADPC group and 0.024 ± 0.002 and 0.040 ± 0.011 in the CRPC group, both with significant differences from those in the ADT group (0.018 ± 0.001 and 0.019 ± 0.006) (P < 0.01). CONCLUSION: Pim-1 is highly expressed in nude mice with prostate cancer receiving androgen-deprivation therapy and plays an important role in the progression and metastasis of prostate cancer.

Human kallikrein 2 (KLK2) promotes prostate cancer cell growth via function as a modulator to promote the ARA70-enhanced androgen receptor transactivation.

Recent data suggested that tissue human kallikrein 2 (KLK2) might be involved in the carcinogenesis and tumor metastasis of prostate cancer (PCa). However, the detailed pathophysiological roles of KLK2 in PCa remain unclear. We report here that KLK2 may be treated as a potential therapeutic target in castration-resistant PCa (CRPC). Histologic analyses show that the increased KLK2 expression is correlated with higher cell proliferation rate and lower cell apoptosis index in CRPC specimens. Adding functional KLK2 cDNA into high passage LNCaP cells led to increased cell growth, and knockdown of KLK2 expression with KLK2-siRNA in LNCaP cells resulted in increased cell apoptosis with cell growth arrest at the G1 phase. Results from in vitro colony formation assay and in vivo xenografted PCa tissues also demonstrated that targeting KLK2 led to suppressed growth of PCa in the castration-resistant stage. Further mechanism dissection shows that KLK2 may cooperate with the AR coregulator, ARA70, to enhance AR transactivation that may result in alteration of PCa formation. Together, these results suggested KLK2 might become a new therapeutic target to battle the CRPC and KLK2-siRNA may be developed as an alternative approach to suppress PCa growth.

Association between glutathione S-transferases M1 and T1 gene polymorphisms and prostate cancer risk: a systematic review and meta-analysis.

Genetic polymorphisms in glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) genes have been widely reported and considered to have a significant effect on prostate cancer (PCa) risk, but the results are inconsistent. To evaluate the impact of the GSTM1 and GSTT1 polymorphism on PCa risk, we conducted a comprehensive meta-analysis based on 18 eligible studies. A total of 18 studies, including 7,119 subjects for GSTM1 and 6,454 subjects for GSTT1 between 1999 and 2012 were identified through researching MEDLINE, PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature database. A meta-analysis was performed to obtain summary-estimated odd ratios and 95% confidence intervals of GSTM1 and GSTT1 polymorphisms for PCa, with attention to study quality and publication bias. Overall, there is a significant association between GSTM1 (odds ratio (OR) = 1.407, 95% confidence intervals (95% CI) = 1.147-1.727, I(2) = 73.2%, P = 0.001) genotypes and PCa susceptibility. Significant associations were also observed in subgroups of Caucasian populations (OR = 1.262, 95% CI = 1.055-1.511, I(2) = 48.7%, P = 0.011) and Asian populations (OR = 1.776, 95% CI = 1.134-2.781, I(2) = 83.4%, P = 0.012). However, no significant association was found (OR = 1.776, 95% CI = 1.134-2.781, P = 0.243) in African-American populations when stratified by ethnicity. While, there was no significant association seen between GSTT1 (OR = 1.003, 95% CI = 0.823-1.298, I(2) = 68.8%, P = 0.778) genotypes and PCa risk. However, no significant associations were observed in subgroups of Caucasian populations (OR = 1.086, 95% CI = 0.801-1.471, I(2) = 72.1%, P = 0.597) and Asian populations (OR = 0.961, 95% CI = 0.644-1.434, I(2) = 73.0%, P = 0.846), and similar result was found among African-American populations (OR = 0.802, 95% CI = 0.194-3.321, P = 0.761) when stratified by ethnicity. Our results suggest that the GSTM1 gene polymorphism contributes to PCa susceptibility, while GSTT1 gene polymorphism is not associated with PCa in our study.