Low-dose abiraterone plus Olaparib as a late-line treatment for mCRPC patients without BRCA1/2 mutations: a multicenter retrospective pilot study.

Although overall survival data are still premature, the PROpel study found radiological progression-free survival (PFS) benefits of abiraterone and olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). However, for patients who have not been genetically tested or lack BRCA1/2 mutations (BRCAm), this combination therapy has been questioned as a first-line conventional treatment for mCRPC, mainly due to significant health economics and side effects. In our retrospective study, we found that treatment with low-dose abiraterone plus olaparib as a late-line treatment for mCRPC could lead to prostate-specific antigen (PSA) and symptom PFS in selective cases even without BRCAm. The median PSA-PFS was 8 months (IQR: 6.5-11.5), with a median follow-up duration of 39.0 months (IQR: 27.5-64.5). Gene tests were conducted in all patients, identifying non-BRCA mutations through ctDNA testing (24%), tumor tissue testing (12%), or both (64%). Adverse events occurred in 72% of patients, with 16% experiencing Grade ≥ 3 events. Common adverse events included anemia (64%), decreased appetite (48%), and fatigue (25%). Our findings support low-dose abiraterone plus olaparib as a potential option for mCRPC patients without BRCAm, offering manageable safety and efficacy profiles.

Knockdown of growth differentiation factor-15 restrains prostate cancer through regulating MAPK/ERK signaling pathway.

Prostate cancer, prevalent among males, is influenced by various molecular factors, including Growth Differentiation Factor 15 (GDF15). Despite its recognized role in multiple tumor types, GDF15's specific involvement in prostate cancer remains insufficiently explored. This study investigates the regulatory function of GDF15 in prostate cancer. To explore GDF15's impact, we established GDF15 knockdown and overexpression models in prostate cancer cells. We quantified mRNA and protein levels using RT-PCR and Western blotting. Functional assays, including CCK8, Transwell, wound healing, and flow cytometry, were employed to evaluate cell proliferation, invasion, migration, and apoptosis. Additionally, the effect of GDF15 on tumor growth was assessed using a metastatic tumor model in nude mice. Elevated GDF15 expression was identified in prostate cancer tissues and cells. The knockdown of GDF15 led to the activation of the MAPK/ERK signaling pathway. C16PAF was found to counteract the inhibitory effects of sh-GDF15 on cell proliferation, invasion, migration, and apoptosis in LNCaP cells. It also reversed the sh-GDF15-induced alterations in the epithelial-mesenchymal transition (EMT) process. In vivo, C16PAF notably mitigated the sh-GDF15-induced suppression of tumor growth. The study demonstrated that sh-GDF15 inhibits cell proliferation, invasion, migration, EMT process, and tumor growth, while it promotes apoptosis. However, these effects were significantly reversed by C16PAF. The study underscores the potential of GDF15 as a target for novel therapeutic interventions in prostate cancer treatment and prevention. These findings illuminate GDF15's multifaceted role in prostate cancer pathogenesis and suggest its viability as a therapeutic target.

Androgen deprivation therapy plus apalutamide as neoadjuvant therapy prior radical prostatectomy for patients with unresectable prostate cancer.

Whether neoadjuvant therapy confers a survival benefit in advanced prostate cancer (PCa) remains uncertain. The primary endpoints of previous retrospective and phase II clinical studies that used neoadjuvant therapy, including androgen deprivation therapy combined with new-generation androgen receptor signaling inhibitors or chemotherapy, were pathological downstaging, progression-free survival, prostate-specific antigen relief, and local symptom improvement. To the best of our knowledge, no studies have explored the efficacy and safety of neoadjuvant therapy in improving the surgical resection rate in cases of unresectable primary tumors of PCa. We first designed this retrospective study to evaluate the potential value of apalutamide as neoadjuvant therapy in improving the resectability rate of radical prostatectomy (RP). We initially reported 7 patients with unresectable primary lesions who underwent neoadjuvant apalutamide treatment for a median of 4 months, and all of them successfully underwent RP treatment. Our study supported apalutamide as neoadjuvant therapy, which helped improve RP's success rate and did not significantly increase perioperative complications, and the neoadjuvant therapy was controllable. Our findings' clinical value and benefit for survival still need further clinical research to confirm.

[Influence of different treatments of unilateral testicular torsion on the long-term fertility of the patient].

OBJECTIVE: To evaluate the effects of different treatments of unilateral testicular torsion on the long-term fertility of the patient. METHODS: We reviewed the clinical and fertility-related follow-up data on 92 cases of unilateral testicular torsion treated by orchiectomy (the OE group, n = 49) or orchiopexy (the OP group, n = 43) between January 2000 and December 2014. We compared the testis volume, semen parameters, reproductive hormone indexes, natural pregnancy rate (NPR) and time to pregnancy (TTP) between the two groups, and analyzed the influence of orchiectomy and orchiopexy on the fertility of the patients. RESULTS: Totally, 77 of the men met the inclusion criteria and included in this study, 40 in the OE and 37 in the OP group. Follow-up data exhibited no statistically significant difference between the two groups of patients in the age of marriage, mean frequency of intercourse or sexual function. The men in the OE group, compared with those in the OP group, showed a larger volume of the opposite testis (ï¼»17.62 ± 2.15ï¼½ vs ï¼»16.86 ± 2.05ï¼½ ml, P > 0.05), but lower semen volume (ï¼»4.09 ± 0.89ï¼½ vs ï¼»4.11 ± 0.76ï¼½ ml, P > 0.05), sperm concentration (ï¼»27.60 ± 7.58ï¼½ vs ï¼»27.74 ± 6.80ï¼½ ×106/ml, P > 0.05), sperm motility (ï¼»60.14 ± 14.50ï¼½% vs ï¼»60.29 ± 16.36ï¼½%, P > 0.05), and percentages of progressively motile sperm (PMS) (ï¼»38.37 ± 10.88ï¼½% vs ï¼»38.82 ± 9.73ï¼½%, P > 0.05) and morphologically abnormal sperm (MAS) (ï¼»29.80 ± 7.29ï¼½% vs ï¼»29.55 ± 7.03ï¼½%, P > 0.05), lower levels of FSH (ï¼»8.01 ± 2.31ï¼½ vs ï¼»8.12 ± 2.63ï¼½ IU/L, P > 0.05), LH (ï¼»15.05 ± 4.20ï¼½ vs ï¼»15.46 ± 4.76ï¼½ IU/L,P > 0.05) and T (ï¼»19.06 ± 3.60ï¼½ vs ï¼»19.46 ± 4.02ï¼½ nmol/L, P > 0.05), lower NPR (75.0% ï¼»30/40ï¼½ vs 83.8% ï¼»31/37ï¼½, P > 0.05) and longer TTP (ï¼»18.0 ± 5.7ï¼½ vs ï¼»14.6 ± 3.8ï¼½ mo, P > 0.05). CONCLUSIONS: For patients with unilateral testicular torsion, orchiectomy achieved a lower semen quality and NPR and a longer TTP than orchiopexy, but induced no significant fertility decrease. Detorsion of the torsioned testis little affects the fertility of the patient.

[Significance of atypical small acinar proliferation and high-grade prostatic intraepithelial neoplasia in prostate biopsy in China].

OBJECTIVE: To assess the rates of atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) detected in prostate biopsy in China and the risk of PCa found in subsequent repeat biopsy. METHODS: A total of 2,456 patients underwent TRUS-guided prostate biopsy with the samples of ASAP and/or HGPIN tissues in our hospital at least twice between July 2014 and June 2019. We analyzed the findings of digital rectal examination, prostate volumes, PSA levels, and the results of prostate biopsies. RESULTS: Initial prostate biopsies revealed 737 cases of PCa (30.0%), 215 cases of ASAP (8.8%), 98 cases of HGPIN (4.0%), and 18 cases of ASAP+HGPIN (0.7%). Totally, 313 of the patients met the inclusion criteria and included in this study. Of the 215 cases of ASAP confirmed in the first biopsy, 72 and 25 were diagnosed with PCa in the second and third biopsies, respectively, 83 with Gleason score (GS) 6, 14 with GS7, 57 with T1c and 40 with T2a tumors. Of the 98 cases of HGPIN confirmed in the first biopsy, 1 was diagnosed with PCa in the second and another 1 in the third biopsy, both with GS6 and T1c tumors. Of the 18 cases of ASAP+HGPIN confirmed in the first biopsy, 7 and 3 were diagnosed with PCa in the second and third biopsies, respectively, 7 with GS6, 3 with GS7, 6 with T1c and 4 with T2a tumors. CONCLUSIONS: ASAP is a significant risk factor for PCa and repeat prostate biopsy should be performed for patients diagnosed with ASAP in the first biopsy. Whether repeat biopsy is necessary for those diagnosed with HGPIN depends on other related clinical parameters./.

[Impact of immune inflammation on the proliferation and apoptosis of benign prostatic hyperplasia cells].

Objective: To investigate the impact of macrophage-induced immune inflammation on the proliferation and apoptosis of BPH cells and its possible mechanism. METHODS: Macrophages were stimulated with phorbol myristate acetate, co-cultured with BPH-1 cells, and then treated with the androgen receptor (AR) inhibitor or anti-CD40L antibody. The immunohistochemical biomarkers of the T lymphocytes (CD4 and CD8), B lymphocyte (CD20) and macrophages (CD68), AR, CD40/CD40L, and inflammatory factors IL-1, IL-6 and TNF-α were measured before and after treatment. The proliferation and apoptosis of the cells were observed by MTT assay, colony-forming assay and flow cytometry, and the expressions of cell apoptosis- and MAPK signaling pathway-related proteins were determined by qRT-PCR and Western blot. RESULTS: Significantly increased proliferation and decreased apoptosis of the cells, up-regulated expressions of Bcl-2, IL-1, IL-6, TNF-α, AR, CD40 and CD40L, and down-regulated expression of Bax were observed in the BPH-1 cells co-cultured with macrophages (the M-BPH-1 group) compared with those in the blank control (B-BPH-1) group (P < 0.01). In comparison with the BPH-1 cells treated with normal saline, those treated with either low-dose CD40L (L-CD40L) or high-dose CD40L (H-CD40L) showed markedly inhibited proliferation, increased apoptosis, up-regulated expression of Bax, and down-regulated expressions of Bcl-2, IL-1, IL-6 and TNF-α (P < 0.01), and those in the low- and high-dose AR (L-AR and H-AR) inhibitor groups exhibited remarkably reduced proliferation, increased apoptosis, down-regulated expressions of Bcl-2, IL-1, IL-6 and TNF-α, and up-regulated expression of Bax (P < 0.01). The phosphorylation levels of JNK, ERK and P38 were significantly elevated in the M-BPH-1 group, but declined in the H-CD40L and the H-AR inhibitor groups compared with those in the B-BPH-1 group, all in a concentration-dependent manner (P < 0.01). CONCLUSIONS: Macrophage-induced immune inflammation regulates AR and CD40/CD40L expressions and promotes the proliferation and inhibits the apoptosis of BPH-1 cells by activating the MAPK signaling pathway. /.

Influence of Androgen Receptor Antagonist MDV3100 Therapy on Rats With Benign Prostatic Hyperplasia.

PURPOSE: To probe the effect and mechanism of androgen receptor antagonist MDV3100 on benign prostatic hyperplasia (BPH) of rats. METHODS: BPH rat model was induced by testosterone propionate. Then antagomir-miR-21-3p or agomir-miR-21-3p was injected into rats before MDV3100 treatment. The prostate index was measured by weighing the wet weight of the rat prostate. The structural morphology of rat prostate was observed after hematoxylin & eosin staining. Immunohistochemistry was applied to evaluate the expression levels of Ki-6 and inflammatory cytokines (interleukin [IL]-6, IL-18, and tumor necrosis factor-α) in rat prostate tissues. Quantitative reverse transcription polymerase chain reaction was utilized for assessment of miR-21-3p expression, and Western blot for the performance of the phosphorylation levels of IKKα and p65. RESULTS: Injection of testosterone propionate caused increased prostate gland hyperplasia, heightened miR-21-3p level, and activated nuclear factor-kappa B (NF-κB) signaling pathway. Additionally, BPH was accompanied by inflammatory response, as evidenced by enhanced expressions of Ki-67 and inflammatory cytokines. MDV3100 exposure ameliorated BPH and suppressed miR-21-3p expression. Overexpression of miR-21-3p intensified BPH and inflammation level, while knockdown of miR-21-3p relieved BPH. The coeffect of miR-21-3p upregulation and MDV3100 subjection led to higher inflammatory response, elevated phosphorylation levels of IKKα and p65 than MDV3100 treatment alone. CONCLUSION: Androgen receptor antagonist MDV3100 alleviates BPH and inflammatory response through miR-21-3p downregulation and NF-κB signaling pathway blockade.

Macrophages affect immune inflammation and proliferation in benign prostatic hyperplasia via androgen receptor and CD40/CD40L signaling pathway.

OBJECTIVE: Considering the association of macrophage migration inhibitory factor with development of prostate diseases, this study aims to explore the effect and mechanism of macrophages (MAs) in inflammation and proliferation of benign prostate hyperplasia (BPH) cells. METHODS: Totally 85 prostate tissues (75 from BPH patients and 10 from brain death patients) were collected for determination of biomarkers of T lymphocyte (CD4 and CD8), B lymphocyte (CD20) and MAs (CD68), as well as androgen receptor (AR) and CD40/CD40L. MAs stimulated by phorbol myristate acetate (PMA) were cultured with BPH cells (BPH-1), followed by AR inhibitor or anti-CD40 L antibody treatment. Proliferation and cell apoptosis were observed by MTT assay, colony formation assay and flow cytometer. Expressions of apoptotic related proteins and MAPK signaling pathway-related proteins were determined by qRT-PCR and Western blot. RESULTS: BPH tissues had increased expressions of AR, CD40 and CD40 L, as well as elevated expressions of inflammation biomarkers (CD4, CD8, CD20 and CD68) in comparison to normal prostate tissues. MAs could increase the expressions of lymphocytes and inflammation biomarkers, in addition to promoting cell proliferation and inhibiting cell apoptosis. Cell proliferation and inflammation reaction could be attenuated by anti-CD40 L antibody and AR inhibitor in a concentration dependent manner through inhibiting the phosphorylation of JNK, ERK1/2 and p38. CONCLUSION: MAs regulate AR and CD40/CD40L expression to promote the inflammation and proliferation as well as inhibiting apoptosis of BPH-1 cells through activation of the MAPK signaling pathway. This conclusion may provide a therapeutic strategy for BPH patients.

Upregulation of GRIM-19 augments the sensitivity of prostate cancer cells to docetaxel by targeting Rad23b.

The gene associated with retinoid-interferon mortality (GRIM-19) has been reported to be correlated with drug resistance, whereas its functional role in prostate cancer (PC) is not fully understood. This study aims to clarify the potential role and molecular mechanisms of GRIM-19 on the response of PC cells to chemical drug docetaxel. mRNA and protein level of GRIM-19 expression in cells and tissues of PC were measured by quantitative real-time PCR and western blot, respectively. Knock-down of GRIM-19 in PC cells was performed using siRNA. Cell apoptosis was determined by flow cytometric analysis. DNA damage in PC cells was detected by γ-H2AX staining. GRIM-19 was downregulated in PC tissues and cell lines. Knock-down of GRIM-19 increased the resistance of PC cells to docetaxel, and overexpression of GRIM-19 promoted docetaxel-induced apoptotic death in PC cells. Mechanistically, GRIM-19 downregulated the expression of the survival gene Rad23b, which promoted DNA damage repair. Overexpression of Rad23b reversed GRIM-19-mediated response to docetaxel in PC cells. GRIM-19 promoted the sensitivity of PC cells to docetaxel by downregulating Rad23b, which may serve as a promising target to develop a better strategy of chemotherapy for PC.

Inhibition of miR-423-5p suppressed prostate cancer through targeting GRIM-19.

OBJECTIVE: To determine the effect of miR-423-5p on the progression of prostate cancer (PC). METHODS: miR-423-5p and GRIM-19 expressions were detected by qRT-PCR and western blot. PC cell proliferation was measured by MTT assay. PC cell apoptosis was detected by flow cytometry. Dual luciferase reporter assay was used to confirm the interaction between miR-423-5p and GRIM-19. RESULTS: Compared with normal prostate tissues and prostate epithelial cell HPrEC, miR-423-5p was up-regulated in human PC tissues and PC3 cells, whereas GRIM-19 expression was decreased. Inhibition of miR-423-5p suppressed PC3 cell proliferation, promoted PC3 cell apoptosis, and decreased anti-apoptosis protein BCL-2 expression. GRIM-19 was a target of miR-423-5p, and GRIM-19 was negatively regulated by miR-423-5p in PC3 cells. In addition, miR-423-5p knockdown inhibited the proliferation and promoted the apoptosis of PC3 cells through GRIM-19. In vivo experiments showed that miR-423-5p inhibitor administration reduced tumor volume, down-regulated miR-423-5p and GRIM-19 expressions in PC tissues of nude mice. CONCLUSION: Inhibition of miR-423-5p suppressed PC through targeting GRIM-19.