Ureteral reimplantation for the management of pelvic lipomatosis.

Introduction: Pelvic lipomatosis is a rare benign disease characterized by urethral elongation, bladder deformity, and/or hydronephrosis. Conservative management is not effective, and urinary diversion is the most effective treatment option but is usually unacceptable for relatively young patients. Ureteral reimplantation seemed to be an appropriate modality under these conditions. We present one case in which pelvic lipomatosis was managed with ureteral reimplantation. Patient presentation: A 45-year-old, previously healthy man presented with right flank pain. Pelvic CT and CT urography showed excessive pelvic fat, bilateral hydronephrosis, tortuous ureters, and a pear-shaped bladder, all of which indicated a diagnosis of pelvic lipomatosis. We performed laparoscopic bilateral urinary tract infection on this patient. At follow-up, bilateral hydronephrosis and flank pain were greatly relieved. Conclusion: Pelvic lipomatosis can be managed safely and effectively by urinary tract infection, but longer follow-up periods are needed to evaluate the long-term efficacy of this approach.

Comparison of Regional Saturation Biopsy, Targeted Biopsy, and Systematic Biopsy in Patients with Prostate-specific Antigen Levels of 4-20 ng/ml: A Prospective, Single-center, Randomized Controlled Trial.

BACKGROUND: Despite the use of multiparametric magnetic resonance imaging (mpMRI)-guided targeted biopsy (TB) to identify suspicious prostate lesions, it may still miss clinically significant prostate cancer (csPCa) or result in false-negative findings. Recent evidence suggests that combining biopsies taken from within and around magnetic resonance imaging (MRI) lesions can improve the detection of csPCa. OBJECTIVE: This study aimed to compare the diagnostic performance of the regional saturation biopsy (RSB) method, involving template-based nine-core biopsies for suspected regions, with that of the MRI-directed TB and/or the systematic biopsy (SB) methods in biopsy-naïve patients with prostate-specific antigen (PSA) levels ranging from 4 to 20 ng/ml. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-center, randomized controlled trial included 434 biopsy-naïve patients with suspected lesions on mpMRI and PSA levels between 4 and 20 ng/ml (from January 2022 to July 2023). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The detection rates of csPCa for the RSB, TB, and SB methods were analyzed using the McNemar test for intrapatient comparisons. The Fisher's exact test was used for comparisons between RSB and TB. RESULTS AND LIMITATIONS: The RSB approach yielded a significantly higher detection rate of csPCa than both the TB approach (44.1% vs 31.8%, p = 0.01) and the SB approach (44.1% vs 34.1%, p = 0.03). The RSB approach exhibited a comparable detection rate of csPCa (44.1% vs. 40.7%, p = 0.3) to the combined approach (TB + SB), while requiring fewer biopsy cores and a higher positive core number to avoid sampling the entire prostate gland (32.7% vs 18.3%, p < 0.001). Upon conducting a whole-mount histopathological analysis, it was observed that the RSB approach successfully identified 97% (32 out of 33) of the prostate cancer foci as the index lesion, whereas only 59.18% (29 out of 49) were classified as index lesions using the SB approach. Furthermore, mpMRI underestimated the average diameter of histological tumor size by a median of 0.76 cm, highlighting the importance of an optimal biopsy area for the RSB procedure. CONCLUSIONS: For patients with suspected lesions on mpMRI and PSA levels between 4 and 20 ng/ml, the RSB approach has shown improved detection of clinically significant prostate cancer, accurately identifying index lesions, and minimizing biopsy cores compared with the MRI-directed TB and SB approaches. PATIENT SUMMARY: For patients with suspected lesions on multiparametric magnetic resonance imaging and prostate-specific antigen levels between 4 and 20 ng/ml, the regional saturation biopsy method provides enhanced detection of clinically significant prostate cancer, as well as precise identification of index lesions, surpassing both magnetic resonance imaging-directed targeted biopsy and the systematic biopsy method.

Exosomal lincROR Promotes Docetaxel Resistance in Prostate Cancer through a ß-catenin/HIF1α Positive Feedback Loop.

Emerging evidence has suggested that patients with metastatic prostate cancer will become resistant after receiving docetaxel (DTX) chemotherapy, but the specific regulatory mechanism is still unclear. lincROR is an important oncogenic long noncoding RNA which plays an important role in regulating tumor carcinogenesis and metastasis; however, the underlying mechanism of lincROR functioning in the DTX resistance process of prostate cancer remains largely unknown. In the current study, we found that lincROR is highly expressed in DTX-resistant prostate cancer cell lines and was associated with poor DTX response in patients with metastatic prostate cancer. By using loss- and gain-of-function experiments revealed that lincROR promotes prostate cancer cells growth and DTX resistance in vitro and in vivo. Mechanistic studies demonstrated that lincROR specifically interacts with and stabilizes MYH9 protein, which enhances ß-catenin/hypoxia-inducible factor 1-alpha (HIF1α) pathways. Besides, HIF1α could bind with the promoter region of lincROR to activate its transcription, thus forming the lincROR/MYH9/HIF1α positive feedback loop. Moreover, lincROR could be packaged into exosomes in an heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1)-dependent manner and then disseminated chemoresistance phenotype to receipt cells. Overall, our study provides evidence supporting exosome-mediated lincROR activates the ß-catenin/HIF1α positive feedback loop by targeting MYH9 protein, which may be exploited for anticancer therapy. IMPLICATIONS: Our findings suggest that targeting hypoxia stress and chemoresistance for therapeutic purposes and lincROR could promote the improvement of treatment responses in patients with DTX-resistant prostate cancer.

TFAP2C-Mediated lncRNA PCAT1 Inhibits Ferroptosis in Docetaxel-Resistant Prostate Cancer Through c-Myc/miR-25-3p/SLC7A11 Signaling.

Recent evidence has shown that the induction of ferroptosis is a new therapeutic strategy for advanced prostate cancer (PCa) when used as a monotherapy or in combination with second-generation antiandrogens. However, whether ferroptosis inducers are effective against docetaxel-resistant PCa remains unclear. In addition, the biological role and intrinsic regulatory mechanisms of long noncoding RNAs (lncRNAs) in ferroptosis and chemoresistance are not well understood. In this study, we established two acquired docetaxel-resistant PCa cell lines and found that docetaxel-resistant PCa cells developed tolerance toward ferroptosis. In addition, dysregulated lncRNAs in drug-resistant and -sensitive PCa cells were identified by RNA sequencing, and we identified that prostate cancer-associated transcript 1 (PCAT1) was highly expressed in the docetaxel-resistant PCa cell lines and clinical samples. Overexpression of PCAT1 inhibited ferroptosis and increased docetaxel resistance, which could be attenuated by PCAT1 knockdown. Furthermore, we revealed that PCAT1 inhibited ferroptosis by activating solute carrier family 7-member 11 (SLC7A11) expression via reducing iron accumulation and subsequent oxidative damage. Mechanistically, we demonstrated that PCAT1 interacted with c-Myc and increased its protein stability using nucleotides 1093-1367 of PCAT1 and 151-202 amino acids of c-Myc protein, thereby transcriptionally promoting SLC7A11 expression. In addition, PCAT1 facilitated SLC7A11 expression by competing for microRNA-25-3p. Finally, transcription factor AP-2 gamma (TFAP2C) activated PCAT1 expression at the transcriptional level to reduce ferroptosis susceptibility and enhance chemoresistance. Collectively, our findings demonstrated that TFAP2C-induced PCAT1 promotes chemoresistance by blocking ferroptotic cell death through c-Myc/miR-25-3p/SLC7A11 signaling.

EIF4A3-Induced circARHGAP29 Promotes Aerobic Glycolysis in Docetaxel-Resistant Prostate Cancer through IGF2BP2/c-Myc/LDHA Signaling.

Docetaxel-based chemotherapy is a standard-of-care treatment for metastatic prostate cancer, and chemoresistance remains a major challenge in clinical practice. Recent studies have demonstrated that circular RNAs (circRNA) play critical roles in the development and progression of prostate cancer. However, the biological roles and potential functions of circRNAs in mediating docetaxel-resistant prostate cancer have yet to be well elucidated. In this study, we analyzed the expression profiles of circRNAs in docetaxel-resistant and -sensitive prostate cancer cells through RNA sequencing and found that expression of circARHGAP29 was significantly upregulated in docetaxel-resistant cell lines and clinical samples. Ectopic expression of circARHGAP29 triggered docetaxel resistance and aerobic glycolysis in prostate cancer cells, which was reduced by silencing circARHGAP29. Moreover, eukaryotic initiation factor 4A3, which bound the back-spliced junction site and the downstream flanking sequence of circARHGAP29, induced cyclization and cytoplasmic export of circARHGAP29. circARHGAP29 increased the stability of lactate dehydrogenase A (LDHA) mRNA by strengthening its interaction with insulin-like growth factor 2 mRNA-binding protein 2, leading to enhanced glycolytic metabolism. In addition, circARHGAP29 interacted with and stabilized c-Myc mRNA and protein, which further increased LDHA expression by facilitating its transcription. These findings reveal the crucial function of circARHGAP29 in prostate cancer glycolysis by increasing and stabilizing LDHA mRNA, providing a promising therapeutic target in docetaxel-resistant prostate cancer. SIGNIFICANCE: Upregulation of a novel circRNA, circARHGAP29, promotes docetaxel resistance and glycolytic metabolism, suggesting it could be a prognostic biomarker and therapeutic target in chemoresistant prostate cancer.

LncRNA PCA3 promotes antimony-induced lipid metabolic disorder in prostate cancer by targeting MIR-132-3 P/SREBP1 signaling.

Antimony is a common environmental contaminant that causes biological toxicity in exposed populations worldwide. Previous studies have revealed that antimony promotes prostate cancer growth by stabilizing the c-Myc protein and mimicking androgen activity. However, the role of lncRNAs in the regulation of antimony-induced carcinogenesis remains unknown, and the precise mechanisms need to be explored. In the present study, we found that chronic exposure to antimony promoted cell growth and lipid metabolic disequilibrium in prostate cancer. Mechanistically, we identified a long noncoding RNA molecule, PCA3, that was substantially upregulated in LNCaP cells in response to long-term antimony exposure. Functional studies indicated that abnormal PCA3 expression modulated antimony-induced proliferation and cellular triglyceride and cholesterol levels. In addition, PCA3 levels were found to be inversely correlated with MIR-132-3 P levels by acting as a decoy for MIR-132-3P. Besides, SREBP1 directly interacted with MIR-132-3 P to increase cell growth and disrupt lipid metabolism by targeting its 3'UTR regions. Taken together, our results revealed that lncRNA PCA3 promotes antimony-induced lipid metabolic disorder in prostate cancer by targeting MIR-132-3 P/SREBP1 signaling.

LncRNA OIP5-AS1 inhibits ferroptosis in prostate cancer with long-term cadmium exposure through miR-128-3p/SLC7A11 signaling.

Previous studies suggest that cadmium (Cd) is one of the causative factors of prostate cancer (PCa), but the effect of chronic Cd exposure on PCa progression remains unclear. Besides, whether long noncoding RNAs (lncRNAs) are involved in the regulation of prolonged exposure to Cd in PCa needs to be elucidated. In the present study, we found that the serum concentration of Cd in PCa patients was positively correlated with the Gleason score and tumor-node-metastasis (TNM) classification. To simulate chronic Cd exposure in PCa, we subjected PC3 and DU145 cells to long-term, low-dose Cd exposure and further examined tumor behavior. Functional studies identified that chronic Cd exposure promoted cell growth and ferroptosis resistance in vitro and in vivo. Furthermore, we found that lncRNA OIP5-AS1 expression was greatly elevated in PC3 and DU145 cells upon chronic Cd exposure. Dysregulation of OIP5-AS1 expression mediated cell growth and Cd-induced ferroptosis. Mechanistically, we demonstrated that OIP5-AS1 served as an endogenous sponge of miR-128-3p to regulate the expression of SLC7A11, a surrogate marker of ferroptosis. Moreover, miR-128-3p decreased cell viability by enhancing ferroptosis. Taken together, our data indicate that lncRNA OIP5-AS1 promotes PCa progression and ferroptosis resistance through miR-128-3p/SLC7A11 signaling.

Astragalus Polysaccharides Inhibits Tumorigenesis and Lipid Metabolism Through miR-138-5p/SIRT1/SREBP1 Pathway in Prostate Cancer.

Astragalus polysaccharides (APS) is a traditional Chinese medicine and have been proved to involve in multiple biological processes, including inflammation, metabolism, and carcinogenics. However, the specific mechanisms by which APS on prostate cancer (PCa) remains largely unknown. In the current study, we found APS greatly inhibited the proliferation and invasion of PCa cells in a dose-dependent and time-dependent manner in vitro and in vivo. In addition, cellular triglyceride and cholesterol levels were also decreased significantly under APS treatment. Microarray data revealed the SIRT1 expression was markably suppressed under APS exposure. Mechanistic studies demonstrated that over-expression of SIRT1 inhibits the expression and nuclear translocation of SREBP1 via activating AMPK phosphorylation to suppress lipid metabolism. Otherwise, knockdown of SIRT1 significantly promotes AMPK/SREBP1 signaling and its associated target genes. Besides, we also found miR-138-5p was greatly inhibited the SIRT1 expression to regulating cell metabolism by targeting its 3'UTR region. To summarize, our findings suggested that APS inhibits tumorigenesis and lipid metabolism through miR-138-5p/SIRT1/SREBP1 pathways in PCa.

LncRNA NEAT1 promotes docetaxel resistance in prostate cancer by regulating ACSL4 via sponging miR-34a-5p and miR-204-5p.

Docetaxel resistance remains one of the main problems in clinical treatment of metastatic prostate cancer (PCa). Previous studies identified differently expressed lncRNAs in docetaxel-resistant PCa cell lines, while the potential mechanisms were still unknown. In the present study, we found NEAT1 was expressed at high levels in docetaxel-resistant PCa clinical samples and related cell lines. When knockdown NEAT1, cell proliferation and invasion in docetaxel-resistant PCa cells in vitro and in vivo were downregulated. Our further researches explained that NEAT1 exerts oncogenic function in PCa by competitively 'sponging' both miR-34a-5p and miR-204-5p. Inhibition of miR-34a-5p or miR-204-5p expression mimics the docetaxel-resistant activity of NEAT1, whereas ectopic expression of miR-34a-5p or miR-204-5p attenuates the anti-drug function of NEAT1 in PCa cells. Besides, we also found ACSL4 is a target of both miR-34a-5p and miR-204-5p, and ACSL4 was also inhibited by miR-34a-5p and miR-204-5p. Moreover, suppression of miR-34a-5p or/and miR-204-5p greatly restrained the expression of ACSL4 upon NEAT1 overexpression. Joint expression of miR-34a-5p and miR-204a-5p synergistically decreased the expression of ASCL4, indicating miR-34a-5p and miR-204a-5p collaboratively inhibit the expression of ACSL4. Innovatively, we concluded that NEAT1 contributes to the docetaxel resistance by increasing ACSL4 via sponging miR-34a-5p and miR-204-5p in PCa cells.

Laparoscopic treatment of a huge seminal vesicle calculus: A case report and review of literature.

A 67-year-old male patient had a history of repeated urinary tract infections for numerous years. X-ray examination revealed a large calcific density in the pelvic cavity, with a diameter of 10.4 cm and a CT value of ~792.9 HU. On MRI of the pelvis, the lesion displayed with extremely low signals. The inside of the stone had a concentric ring shape with a slightly higher signal and the patient was diagnosed with a large left seminal vesicle calculus. Laparoscopic surgery was selected to treat the stone. The patient recovered rapidly and the symptoms, including urgency, urinary frequency, as well as lower abdominal and perineal pain, were obviously improved. The present case study reports on the largest seminal vesicle calculus reported in the current English literature in addition to a brief literature review. Cases of seminal vesicle calculi (SVC) are rare. The present study reports on a case of SVC, which is the largest reported in current English literature, to the best of our knowledge.

The Specific Choice of Transrectal Ultrasound-Guided Prostate Biopsy Scheme Based on Prostate Specific Antigen and Prostate Specific Antigen Density.

BACKGROUND Although magnetic resonance imaging (MRI)-targeted biopsy and saturation biopsy can improve the accuracy of prostate biopsy, transrectal ultrasound (TRUS)-guided prostate biopsy is still the cornerstone for diagnosis of prostate cancer. However, it is not clear whether it is necessary to perform the same TRUS-guided biopsy scheme for patients with different prostate specific antigen (PSA) or prostate specific antigen density (PSAD) levels. The purpose of this study was to evaluate the optimal core number for specific suspected prostate cancer patients. MATERIAL AND METHODS There were 398 patients who underwent 12-core biopsy scheme, who were included in this retrospective analysis. The 12-core scheme incorporated a classic sextant scheme and 4-core biopsies from the base and middle regions bilaterally. The cancer detection rates of patients with different PSA or PSAD levels between the 12-core, sextant, 4-core, and 2-core biopsy were compared. RESULTS The differences in cancer detection rates between the 12-core biopsy scheme and the sextant biopsy scheme were significant in patients with PSA <20 ng/mL or PSAD <0.3. There were no differences in the cancer detection rates between the 12-core biopsy scheme and the 4-core biopsy scheme in patients with PSA ≤50 ng/mL or PSAD ≤1.0. There were significant differences between 12-core and 2-core scheme when PSA ≤70 ng/mL or PSAD ≤1.5. CONCLUSIONS We recommend that the 12-core biopsy should be used for patients with PSA <20 ng/mL or PSAD <0.3. The biopsy scheme in patients with PSA 20-50 ng/mL or PSAD 0.3-1.0 should be considered in combination with DRE and MRI. For patients with PSA >50 ng/mL or PSAD >1.0, we recommend 6-core or 4-core biopsy by comprehensively considering multiple factors. The 2-core biopsy is recommended for patients with PSA >70 ng/mL or PSAD >1.5.

Radical cystectomy for pT1 urothelial carcinoma of bladder not amenable to TURBT: Long-term results.

PURPOSE: This study sought to identify factors associated with survival of pT1 urothelial carcinoma of bladder (UCB) after radical cystectomy (RC). METHODS: This study consists of 114 pT1 UCB [primary 83, recurrent 31, none were amenable to transurethral resection (TUR)] treated by radical cystectomy. Survival analysis using Cox regression tests were performed to identify factors associated with survival of pT1 UCB after RC. RESULTS: Pelvic lymph node (LN) status, age and lymphovascular invasion (LVI) are associated with survival of pT1 UCB after RC; recurrent pT1 UCB of high grade origin (HGO) tends to have poorer CSS than primary pT1 UCB or recurrent pT1 UCB of low grade origin (LGO) (5-year and 10-year CSS rates was 75% and 73% for primary cases; 77% and 77% for recurrent pT1 UCB of LGO; and 56% and 37% for recurrent pT1 UCB of HGO, p = 0.078). CONCLUSIONS: LN status, age and LVI were significantly associated with survival of pT1 UCB after RC. Recurrent pT1 UCB of HGO should be managed with radical cystectomy in a timely fashion given that these cases tend to have poorer CSS than primary pT1 UCB after RC, even if they did not progress to muscle-invasive bladder cancer (MIBC).

The protective role of TET2 in erythroid iron homeostasis against oxidative stress and erythropoiesis.

Although previous studies suggested that stress erythropoiesis and iron metabolism regulate each other to increase iron availability for hemoglobin synthesis, the molecular bases determining its different traits remain elusive. In addition, global DNA demethylation has been reported during mouse erythropoiesis in vivo. However, the understanding of iron-related genes through DNA demethylation under stress erythropoiesis is largely unknown. In the current study, we found disordered iron homeostasis and misregulated hepcidin-ferroportin axis under stress erythropoiesis. Interestingly, global 5hmC content and TET2 expression were significantly induced by oxidative stress, whereas antioxidant had the opposite's effect. Mechanistic investigation manifested that TET2-mediated DNA demethylation promotes the expression of ferroportin and erythroferrone against oxidative stress. Besides, the expression of NRF2 was significantly increased by TET2-mediated DNA demethylation during stress erythropoiesis. Elevated NRF2 expression could also modulate the activation of ferroportin and erythroferrone through a canonical antioxidant response element within its promoter. These direct and indirect pathways of TET2 synergistically cooperated to mediating iron metabolism during stress erythropoiesis. Our work revealed a critical role of TET2-mediated DNA demethylation against oxidative stress, and provided the molecular mechanisms underlying the epigenetic regulation of iron homeostasis in response to stress erythropoiesis.

Genetic and epigenetic silencing of mircoRNA-506-3p enhances COTL1 oncogene expression to foster non-small lung cancer progression.

Although previous studies suggested that microRNA-506-3p (miR-506-3p) was frequently downregulated, and functioned as a tumor suppressor in several cancers, the biological role and intrinsic regulatory mechanisms of miR-506-3p in non-small cell lung cancer (NSCLC) remain elusive. The present study found miR-506-3p expression was downregulated in advanced NSCLC tissues and cell lines. The expression of miR-506-3p in NSCLC was inversely correlated with larger tumor size, advanced TNM stage and lymph node metastasis. In addition, we also found patients with lower expression of miR-506-3p had a poor prognosis than those patients with higher expression of miR-506-3p. Function studies demonstrated that aberrant miR-506-3p expression modulates tumor cell growth, cell mobility, cell migration and invasion in vitro and in vivo. Mechanistic investigations manifested that coactosin-like protein 1 (COTL1) was a direct downstream target of miR-506-3p. Knockdown of COTL1 mimicked the tumor-suppressive effects of miR-506-3p overexpression in A549 cells, whereas COTL1 overexpression enhanced the tumorigenic function in HCC827 cells. Importantly, we also found GATA3 transcriptionally actives miR-506-3p expression, and the long non-coding RNA urothelial carcinoma-associated 1 (UCA1) exerts oncogenic function in NSCLC by competitively 'sponging' miRNA-506. Together, our combined results elucidated genetic and epigenetic silencing of miR-506-3p enhances COTL1 oncogene expression to foster NSCLC progression.

Elevated expression of ZNF217 promotes prostate cancer growth by restraining ferroportin-conducted iron egress.

Although we and other studies indicated ZNF217 expression was increased in prostate cancer (PCa), the factors mediating its misregulated expression and their oncogenic activity remain largely unexplored. Recent evidence demonstrated that ferroportin (FPN) reduction lead to decreased iron export and increased intercellular iron that consequently aggravates the oncogenic effects of iron. In the present study, ZNF217 was identified as a transcriptional repressor that inhibits FPN expression. Increased of ZNF217 expression led to decreased FPN concentration, coupled with resultant intracellular iron retention, increased iron-related cellular activities and enhanced tumor cell growth. In contrast, decreased of ZNF217 expression restrained tumor cell growth by promoting FPN-driven iron egress. Mechanistic investigation manifested that ZNF217 facilitated the H3K27me3 levels of FPN promoter by interacting with EZH2. Besides, we also found that MAZ increased the transcription level of ZNF217, and subsequently inhibited the FPN expression and their iron-related activities. Strikingly, the expression of MAZ, EZH2 and ZNF217 were concurrently upregulated in PCa, leading to decreased expression of FPN, which induce disordered iron metabolism. Collectively, this study underscored that elevated expression of ZNF217 promotes prostate cancer growth by restraining FPN-conducted iron egress.

GATA3-driven expression of miR-503 inhibits prostate cancer progression by repressing ZNF217 expression.

Although increasing evidence demonstrated that deregulation of mircoRNA-503 (miRNA-503) contributes to tumorigenesis, little is known about the biological role and intrinsic regulatory mechanisms of miR-503 in prostate cancer (PCa). In present study, we found that miR-503 was significantly downregulated in advanced PCa tissues and cell lines. Downregulation of miR-503 was strongly associated with aggressive clinical-pathological features and poor prognosis in PCa patients. Ectopic expression of miR-503 significantly inhibited tumor cells growth, cell migration and invasion in vitro and in vivo. Mechanistic studies revealed that ZNF217 was a direct target downstream target of miR-503. Knockdown of ZNF217 mimicked the tumor-suppressive effects of miR-503 overexpression on PCa invasion, whereas ZNF217 overexpression attenuated the tumor-suppressive function of miR-503. Subsequently, miR-503 further modulated the activation of ZNF217-downstream epithelial-mesenchymal transition (EMT) genes. Besides, we also found that GATA3 directly increased miR-503 expression and thus decreased ZNF217 expression, indicating the involvement of GATA3/miR-503/ZNF217 signaling in EMT process. Collectively, our results demonstrated that GATA3-driven expression of miR-503 inhibits PCa progression by repressing ZNF217 expression, and also implicated the potential application of miR-503 in PCa therapy.

The protective role of Nrf2-Gadd45b against antimony-induced oxidative stress and apoptosis in HEK293 cells.

Antimony (Sb) is one of the most prevalent heavy metals and frequently causes biological toxicity. However, the specific mechanisms by which Sb elicits its toxic effects remains to be fully elucidated. In this study, we found antimony trioxide (Sb2O3) caused a dose-dependent cytotoxicity against HEK293 cells, and Sb2O3-induced excessive reactive oxygen species (ROS) was closely correlated with increased cell apoptosis. Mechanistic investigation manifested that nuclear factor NF-E2-related factor 2 (Nrf2) expression and nuclear translocation were significantly induced under Sb2O3 treatment in HEK293 cells, and Nrf2 knockdown aggregated Sb2O3-induced cell apoptosis. Moreover, elevated Gadd45b expression actives the phosphorylation of MAPKs upon Sb2O3 exposure, whereas Gadd45b knockdown diminished Sb2O3-induced activation of MAPKs and promoted cell apoptosis. In the meantime, however, the antioxidant N-acetylcysteine (NAC) was found to ameliorate Nrf2 expression and nuclear translocation as well as Gadd45b expression and MAPKs activation by repressing Sb2O3-induced ROS production. More importantly, we found Gadd45b was transcriptionally enhanced by Nrf2 through binding to three canonical antioxidant response elements (AREs) within its promoter region. Either Sb2O3 or TBHQ (a selective Nrf2 activator) treatment, Gadd45b expression was significantly increased by luciferase assay. Nrf2 inhibition greatly diminished Gadd45b expression due to reduced binding of Nrf2 in Gadd45b promoter under Sb2O3 treatment. To summarize, this study demonstrated the Nrf2-Gadd45b signaling axis exhibited a protective role in Sb-induced cell apoptosis.

EPO-dependent induction of erythroferrone drives hepcidin suppression and systematic iron absorption under phenylhydrazine-induced hemolytic anemia.

Hemolytic anemia is a common form of anemia due to hemolysis, resulting in disordered iron homeostasis. In this study, a dose of 40mg/kg phenylhydrazine (PHZ) was injected into mice to successfully establish a pronounced anemia animal model, which resulted in stress erythropoiesis and iron absorption. We found that serum erythropoietin (EPO) concentration was dramatically elevated by nearly 5000-fold for the first 2days, and then drop to the basal level on day 6 after PHZ injection. Mirrored with serum EPO concentration, the mRNA expression of erythroferrone (ERFE) was rapidly increased in the bone marrow and spleen 3days after injection of PHZ, and then gradually decreased but was still higher than baseline on day 6. In addition, we also found that the hepcidin mRNA levels were gradually reduced almost up to 8-fold on day 5, and then was ameliorated compared to the untreated control. Mechanistic investigation manifested that the increase of serum EPO essentially determined the induction of ERFE expression particular at the first 3days after PHZ treatment. Lentiviral mediated ERFE knockdown significantly restrained hepcidin suppression under PHZ treatment. Thus, our data unearthed EPO-dependent ERFE expression acts as an erythropoiesis-driven regulator of iron metabolism under PHZ-induced hemolytic anemia.

The protective effect of methylenetetrahydrofolate reductase C677T polymorphism against prostate cancer risk: Evidence from 23 case-control studies.

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were considered to have some influence on both folate metabolism and cancer risk. Previous studies on the relation between MTHFR C677T polymorphism and prostate cancer (PCa) risk remained controversial. To derive a more precise estimation of the relationship, we carried out an update comprehensive meta-analysis to assess the associations of the MTHFR C677T polymorphism with the susceptibility of PCa. Twenty-three trials with a total of 24,024 participants on the MTHFR C677T polymorphism that met inclusion criteria were analyzed in the current study. Overall, no statistical relationship was found with any MTHFR C677T genetic model associated with susceptibility to PCa (TT versus CC, OR=0.83, 95% CI 0.68-1.02, P=0.07; CT versus CC, OR=0.95, 95% CI 0.85-1.07, P=0.43; Dominant, OR=0.93, 95% CI 0.83-1.03, P=0.17; Recessive, OR=0.84, 95% CI 0.70-1.02, P=0.09.). Nevertheless, subgroup analysis found a reduced PCa risk associated with polymorphism in Asian population (TT versus CC, CT versus CC, dominant and recessive model). Moreover, the protective effect of polymorphism against PCa risk was also shown upon hospital-based studies (TT versus CC, and recessive model). When benign prostate hyperplasia was chosen as controls, both TT versus CC and recessive model showed significant difference. In addition, the protective effect of homozygote TT against high aggressive PCa was proved to have significant difference. Taken together, the existing evidence indicates the homozygote TT of MTHFR C677T should be viewed as a protective factor against PCa risk for clinical practice with the consideration of different gene background, study design as well as specific controls.

Is an initial saturation prostate biopsy scheme better than an extended scheme for detection of prostate cancer? A systematic review and meta-analysis.

CONTEXT: The optimal initial prostate biopsy core number is still an issue with many unanswered questions and significant controversy. OBJECTIVE: To compare diagnostic values of initial saturation prostate biopsy scheme and extended scheme with respect to prostate-specific antigen (PSA) levels, prostate volume (PV), and PSA density (PSAD). EVIDENCE ACQUISITION: Electronic databases including Medline, Web of Knowledge, and the Cochrane Library were searched through November 1, 2012. Experts were consulted, and references from relevant articles were scanned. The meta-analysis was conducted with RevMan 5.1, according to the PRISMA guidelines. Mantel-Haenszel estimates were calculated and pooled under a fixed or random effect model, with data expressed as risk difference (RD) and 95% confidence interval (CI). EVIDENCE SYNTHESIS: We analyzed eight trials with a total of 11997 participants who underwent transrectal ultrasound guided prostate biopsies for the first time and met inclusion criteria. Studies consisted of one paired design study, two randomized clinical trials, and five nonrandomized studies. Saturation biopsy scheme showed a significant advantage in prostate cancer (PCa) detection over an extended scheme (RD: 0.04; 95% CI, 0.01-0.08; p=0.02). In addition, subgroup analyses found a saturation protocol to be superior to an extended protocol in the detection of PCa in men with PSA <10 ng/ml (RD: 0.04; 95% CI, 0.01-0.07; p=0.002), PV >40 ml (RD: 0.05; 95%CI, 0.01-0.09; p=0.02), or PSAD <0.25 ng/ml per gram (RD: 0.04; 95% CI, 0.00-0.09; p=0.04). CONCLUSIONS: The existing evidence indicates that an initial saturation biopsy scheme is more efficient than an extended scheme for PCa detection, especially for those men with lower PSA levels, higher PV, or lower PSAD, without increasing complications and the amount of insignificant cancer.