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Nature Nov 2023Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with...
Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11bHLA-DRCD15CD14 myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
Topics: Humans; Male; Chemotaxis; Disease Progression; Drug Resistance, Neoplasm; Inflammation; Lewis X Antigen; Myeloid Cells; Neoplasm Metastasis; Prostate; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Androgen Receptor Antagonists; Antineoplastic Agents
PubMed: 37844613
DOI: 10.1038/s41586-023-06696-z -
American Journal of Therapeutics
Topics: Male; Humans; Prostatism; Mirtazapine
PubMed: 35104061
DOI: 10.1097/MJT.0000000000001473 -
Frontiers in Cellular and Infection... 2023To explore whether type III prostatitis is related to bacterial infection by detecting the composition and function of microorganisms in expressed prostatic secretion...
OBJECTIVE
To explore whether type III prostatitis is related to bacterial infection by detecting the composition and function of microorganisms in expressed prostatic secretion (EPS) of patients with chronic prostatitis (CP) and healthy people.
METHODS
According to the inclusion and exclusion criteria, 57 subjects were included in our study, divided into the healthy group, type II prostatitis group, and type III prostatitis group. 16s rRNA sequencing technique was used to detect and analyze the microbial composition of EPS in each group. Additionally, the metagenomics sequencing technique was used to further explore the function of different bacteria in the type III prostatitis group. Data analysis was performed by bioinformatics software, and the results were statistically significant when P<0.05.
RESULTS
Many microorganisms exist in EPS in both CP patients and healthy populations. However, the relative abundance of , , , , and in CP patients (including type II and III) were significantly different. Still, the relative abundance of different bacteria in type II prostatitis patients was much higher than in type III. The metagenomics sequencing results for the type III prostatitis group showed that the different bacteria had certain biological functions.
CONCLUSION
Based on our sequencing results and previous studies, we suggest that type III prostatitis may also be caused by bacterial infection.
Topics: Male; Humans; Prostatitis; RNA, Ribosomal, 16S; Chronic Disease; Bacterial Infections; Bacteria
PubMed: 37465760
DOI: 10.3389/fcimb.2023.1189081 -
Radiologic Clinics of North America Jan 2024Prostate cancer is the most common malignancy diagnosed in men. MR imaging-guided therapies for prostate cancer have become an increasingly common treatment alternative... (Review)
Review
Prostate cancer is the most common malignancy diagnosed in men. MR imaging-guided therapies for prostate cancer have become an increasingly common treatment alternative to traditional whole-gland therapies, such as radical prostatectomy or radiation therapy. This is especially true in men with localized, low- to intermediate-risk prostate cancer. Although long-term oncologic data remain limited, the authors describe several MR imaging-guided therapeutic options for the treatment of prostate cancer, including cryoablation, laser ablation, transrectal high-intensity focused ultrasound, and transurethral ultrasound ablation.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Magnetic Resonance Imaging; Treatment Outcome
PubMed: 37973238
DOI: 10.1016/j.rcl.2023.06.012 -
The Journal of Clinical Investigation Dec 2023Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting...
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
Topics: Animals; Humans; Male; Mice; Cell Line, Tumor; Epigenesis, Genetic; Lung Neoplasms; Proline; Prostate; Prostatic Neoplasms; Sirtuins
PubMed: 38099497
DOI: 10.1172/JCI168670 -
BMJ (Clinical Research Ed.) Nov 2023
Topics: Male; Humans; Prostatitis; Chronic Disease; Pelvic Pain; Chronic Pain
PubMed: 37977592
DOI: 10.1136/bmj-2023-073908 -
Revista Internacional de Andrologia Mar 2024It is estimated that microorganisms colonize 90% of the body surface. In some tracts, such as the genitourinary tract, the microbiota varies throughout life, influenced...
It is estimated that microorganisms colonize 90% of the body surface. In some tracts, such as the genitourinary tract, the microbiota varies throughout life, influenced by hormonal stimulation and sexual practices. This study evaluated the semen differences and presence of , , and in semen samples from patients with symptoms of chronic prostatitis and men asymptomatic for urogenital infections. Fifty-three semen samples were included: 22 samples from men with symptoms of chronic prostatitis and 31 asymptomatic men (control group). In addition to the presence of , , and , semen parameters, total antioxidant capacity of seminal plasma, prostatic antigen and some proinflammatory cytokines were evaluated in each semen sample. Volunteers with symptoms of chronic prostatitis presented a lower percentage of sperm morphology (4.3% control group 6.0%, = 0.004); in the semen samples of volunteers in the group asymptomatic for urogenital infections, microorganisms associated with the vaginal microbiota were detected more frequently. The presence of bacteria in the vaginal microbiota can also benefit male reproductive health, which undergoes various modifications related to lifestyle habits that are susceptible to modification. Microorganisms associated with the vaginal microbiota, such as , , and , may have a protective role against the development of male genitourinary diseases such as prostatitis.
Topics: Humans; Male; Prostatitis; Semen; Adult; Microbiota; Coitus; Gardnerella vaginalis; Lactobacillus; Vagina; Middle Aged; Actinobacteria; Female; Young Adult; Chronic Disease; Case-Control Studies; Semen Analysis; Cytokines
PubMed: 38735876
DOI: 10.22514/j.androl.2024.006 -
Scientific Reports Feb 2024According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut...
According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut microbiota and prostate disorders is still uncertain. We first identified groups of gut microbiota based on the phylum, class, order, family, and genus levels from consortium MiBioGen. And we acquired prostate diseases statistics from the FINNGEN study and PRACTICAL consortium. Next, two-sample Mendelian randomization was used to investigate the potential associations between three prevalent prostate disease and gut microbiota. In addition, we performed a reverse MR analysis and Benjamini-Hochberg (BH) test for further research. We investigated the connection between 196 gut microbiota and three prevalent prostate diseases. We identified 42 nominally significant associations and 2 robust causative links. Upon correction for multiple comparisons using the Benjamini-Hochberg procedure, our analysis revealed a positive correlation between the risk of prostatitis and the presence of the taxonomic order Gastranaerophilales. Conversely, the risk of prostate cancer exhibited an inverse correlation with the presence of the taxonomic class Alphaproteobacteria. Our study revealed the potential association between gut microbiota and prostate diseases. The results may be useful in providing new insights for further mechanistic and clinical studies of prostate diseases.
Topics: Male; Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Prostate; Prostatic Diseases; Prostatic Neoplasms; Alphaproteobacteria; Genome-Wide Association Study
PubMed: 38369514
DOI: 10.1038/s41598-024-54293-5 -
The Prostate Oct 2023Observational studies have shown an association between major depressive disorder (MDD), anxiety, and prostatitis. However, the causal relationship between MDD, anxiety,...
BACKGROUND
Observational studies have shown an association between major depressive disorder (MDD), anxiety, and prostatitis. However, the causal relationship between MDD, anxiety, and prostatitis remains controversial. Therefore, we aimed to use two-sample Mendelian randomization (MR) to assess the causal effects of MDD and anxiety on prostatitis.
METHODS
We conducted univariable and multivariable MR analyses using summary statistics from publicly available genome-wide association studies to estimate the causal relationships between MDD, anxiety, and prostatitis risk. In the main MR analysis, the inverse-variance weighted (IVW) method was used, while secondary methods included the weighted median, weighted mode, MR-Egger regression, and MR pleiotropy residual and outlier (MR-PRESSO) tests to detect and correct for the presence of pleiotropy.
RESULTS
MDD had 97 independent instrumental variables (IVs) and anxiety had 15 IVs. Univariable MR analysis showed that genetically determined MDD had a detrimental causal effect on prostatitis (IVW: odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.12-1.92, p = 0.005), while no causal relationship was found between anxiety and prostatitis (IVW: OR = 0.25, 95% CI = 0.02-2.82, p = 0.26). More convincingly, after adjusting for confounding factors such as body mass index, alcohol consumption, and smoking, the genetic liability for MDD remained associated with prostatitis risk, with no strong evidence of anxiety affecting prostatitis incidence.
CONCLUSION
This study supports the notion that MDD has a detrimental effect on prostatitis risk, and strategies focused on addressing MDD may be one of the cornerstones for treating prostatitis. The potential preventive value of treating MDD for prostatitis should be further investigated in future research.
Topics: Male; Humans; Depressive Disorder, Major; Genome-Wide Association Study; Mendelian Randomization Analysis; Prostatitis; Anxiety; Polymorphism, Single Nucleotide
PubMed: 37504798
DOI: 10.1002/pros.24601 -
The Prostate Sep 2023The expression of programmed cell death ligand protein (PD-L1) is weakly investigated in non-tumoral and inflammatory prostatic pathology. The diagnosis of granulomatous...
BACKGROUND
The expression of programmed cell death ligand protein (PD-L1) is weakly investigated in non-tumoral and inflammatory prostatic pathology. The diagnosis of granulomatous prostatitis (GP) rests on the recognition of localized or diffuse epithelioid granulomatous inflammation in prostatic tissue which is frequently difficult by conventional histological observation alone. PD-L1 expression in GP is not well studied so far.
METHODS
We studied PD-L1 expression in 17 GP cases (9 nonspecific GP, 5 Bacillus Calmette-Guérin induced prostatitis, 1 prostatic tuberculosis, and 3 cases of postsurgical prostatic granulomas). The control group included 10 radical prostatectomies of patients with high Gleason score prostate adenocarcinoma (PCa) and National Institutes of Health-category IV prostatitis (high-grade histologic prostatitis; HG-HP).
RESULTS
All of the GP cases showed easily visible strong membranous PD-L1 expression (high levels of combined positive score) in localized and diffuse epithelioid granulomatous prostatic inflammation. None of the control cases showed the presence of significant PD-L1 expression in inflammatory infiltrates in HG-HP, tumor parenchyma, and stroma in PCa.
CONCLUSIONS
The study presents the first attempt to examine PD-L1 expression in GP. Granulomatous inflammation in GP is easily identified when stained with PD-L1.
Topics: Male; Humans; Prostatitis; B7-H1 Antigen; Diagnosis, Differential; Prostatic Neoplasms; Granuloma; Inflammation
PubMed: 37357498
DOI: 10.1002/pros.24590