Reduced Risk Of Prostate Cancer Research Articles

A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The ‘Thr’ PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Effect of GLP-1 receptor agonists on prostate cancer risk reduction: a systematic review and meta-analysis.

Prostate cancer is one of the most prevalent malignancies among men globally. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), primarily used for type 2 diabetes mellitus (T2DM) management, have been investigated for their potential effects on cancer risks. This systematic review and meta-analysis aimed to assess the association between GLP-1 RA use and risk reduction of prostate cancer. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science up to July 30, 2024. Studies that met the inclusion criteria randomized controlled trials, cohort studies, case-control studies, and observational studies assessing the incidence of prostate cancer in GLP-1 RA-treated patients were included. The quality of studies was evaluated using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool. Meta-analysis was performed using a random effects model. A total of five studies were included, analyzing data from diverse international contexts. The included studies showed a reduced risk of prostate cancer with both adjusted and unadjusted effect estimates with GLP-1 RAs. The meta-analysis revealed an RR of 0.72 (95% CI: 0.610 to 0.832), indicating a statistically significant 28% reduction in prostate cancer risk associated with GLP-1 RA use compared to placebo or other antidiabetic drugs. Moderate heterogeneity was observed (I2 = 51%). Sensitivity analysis confirmed the results. The findings suggest a significant protective association between GLP-1 RA use and reduced prostate cancer risk in men, particularly those with T2DM. This supports the potential of GLP-1 RAs not only in diabetes management but also as a strategy to mitigate cancer risk. Further research is required to confirm these findings and explore the underlying mechanisms, considering different dosages, durations of therapy, and patient subgroups based on demographic and metabolic characteristics.

The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data

We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio= 0.56, 95% confidence interval [CI]= 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data (nSGLT2i= 24,155; nDPP4i= 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio= 0.77, 95% CI= 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n4C= 57,779; nUK_Biobank= 165,430), we found little evidence to support the association of HbA1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.

Does metformin really reduce prostate cancer risk: an up-to-date comprehensive genome-wide analysis

BackgroundThe relationship between metformin use and prostate cancer (PCa) risk has yet to be clear despite more than a decade of debate on this topic. Hence, we aimed to investigate the causal role of metformin in reducing PCa risk through an up-to-date comprehensive genome-wide analysis.MethodsWe employed validated instrument variables of metformin use derived from a prior high-quality study, including five potential targets (AMPK, GCG, GDF15, MCI and MG3). Mendelian randomization (MR) analysis was performed to harmonize genetically predicted metformin use and PCa phenotypes. PCa phenotypes were from two large genome-wide association studies (GWAS), the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) and the FinnGen cohort. Seven methods were applied to generate MR results: the inverse variance weighted (IVW), IVW with multiplicative random effects, MR-Egger, MR-Egger (bootstrap), weighted median, simple mode and weighted mode. Strict sensitivity analysis was conducted to satisfy core assumptions of MR design.ResultsWe enrolled 32 significant single nucleotide polymorphisms (SNPs) that involved with metformin use. Nearly all targets yielded insignificant primary results (IVW with multiplicative random effects), except that AMPK target posed a positive effect on PCa risk from FinnGen cohort [odds ratio (OR): 6.09, 95% confidence interval (CI): 1.10-33.53, P value: 0.038]. The general effect of metformin use, comprising all 5 targets, also yielded negative results (random-effect meta-analysis with OR: 1.09, 95% CI: 0.76–1.58, P value: 0.637 for PRACTICAL; OR: 2.55, 95% CI: 0.58–11.16, P value: 0.215 for FinnGen). None of the sensitivity analyses provided support for a causal association between metformin use and PCa risk.ConclusionThis up-to-date study did not support the protective role of metformin in reducing PCa risk, considering each target, overall effect, and sensitivity analysis. It is imperative to reflect on the presumed “almighty medicine” and ongoing phase III trials are anticipated to assess the anti-neoplasm effect of metformin.

Salbutamol, a Short Acting Beta-2 Agonist, Reduces Risk and Improves Prognosis of Prostate Cancer.

Beta-blockers, a class of drugs commonly used to manage blood pressure, have been the subject of research regarding their relationship to prostate cancer (PC) risk, prognosis, and treatment. Beta-blockers reduce risk and improve the prognosis of PC. Perioperative use of a nonselective beta-blocker improves outcomes after radical prostatectomy. However, a related class of drugs, beta-2 adrenergic agonists, has received little attention in PC. We studied the relationship of the beta-2 adrenergic agonist salbutamol to PC risk and survival. We analyzed Food and Drug Administration MedWatch data to determine whether salbutamol could influence the risk of PC. We used UK Biobank data to assess the effect of salbutamol on PC survival. Salbutamol significantly reduces PC risk, proportional reporting ratio, and 95% CI (lower bound; upper bound): 0.131 (0.11; 0.155) and improves prognosis. Mean survival was 7.35 years for subjects not taking salbutamol, and 10.5 years for subjects taking salbutamol (P = 0.041, log-rank test. To adjust for the effect of age, we performed proportional hazards regression, survival time-dependent variable, age, and salbutamol use independent variables. Salbutamol use was significantly related to survival time (P = 0.016) and independent of the significant effect of age (P < 0.001). We found a lower proportion of PCs in salbutamol-treated people, but we have not demonstrated that PC risk is reduced (there is no proof of causality). There is no causality relationship between salbutamol and the survival of patients with PC treated with salbutamol versus those not treated with the drug. Yet, there is a trend in favor of salbutamol-treated patient survival. Therefore, salbutamol and other beta-adrenergic agonists might represent a new class of drugs for the treatment of PC.

Investigating the role of Vitamins in Prostate cancer risk among African Americans

Background &amp; Aims: Previous studies have shown certain vitamins and minerals are associated with a reduced risk of prostate cancer. In this study, we assess whether vitamins will have an effect on prostate cancer risk among African Americans. Methods: A case-control study was conducted in Washington, District of Columbia and Nashville, Tennessee. There were 264 participants involved in the study. The participants were divided into 3 groups: prostate cancer (n=56), elevated PSA (n=377) and control (n=163). Dietary intake was measured by using a validated food frequency questionnaire. Food items rich in vitamin D, vitamin E, selenium, and lycopene were identified. Chi square tests were performed to evaluate the association between vitamins and prostate cancer risk. Results: There is a statistically significant association between the consumption of certain food items such as beef, pork, eggs and decreased prostate cancer risk (p&lt;.05). There is also a statistically significant association between the consumption of salmon, cod liver oil, peanuts, mushrooms, orange juice and prostate cancer risk increase (p&lt;.05). When aggregated, there was no significant correlation between the consumption of vitamin D, vitamin E, lycopene, selenium and decreased prostate cancer risk. Conclusions: Results of our case-control study suggest dietary restriction of certain meats as prostate cancer risk reduction strategy cannot be suggested. Increasing annual intake of food high in vitamin D, vitamin E, selenium, and lycopene cannot be suggested as a way to decrease prostate cancer risk. Diet modification interventions should focus on dietary moderations. Center of Excellence COE/Offce of Dean, Meharry Medical College School of Medicine, Grant Number: D34HP16299. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 6276: In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation

Abstract Recent studies have shown that adrenergic fibers from the sympathetic nervous system (SNS), acting through stromal β2-adrenergic receptors, play an important role in the initial phases of cancer development by promoting tumor cell survival. Recent epidemiological data suggest that β-blocker intake is associated with improved survival of prostate cancer patients. Hypertension and high blood pressure have been suggested to increase prostate cancer development suggesting that the use of β-blockers in these patients could also reduce prostate cancer risk. β-adrenoceptors signal through the cAMP/PKA pathway that is known to promote neuroendocrine differentiation (NED) in LNCaP prostate cancer cell line. While neuroendocrine (NE) cells expressing synaptophysin (SYN) represent a minor cell population in the epithelial compartment of normal prostate glands, the population of NE-like cells, exhibiting NE phenotypes and expressing NE markers, is increased in, and correlates with, cancer progression, androgen-independent state and poor prognosis. Expression of the routine tissue biomarker of prostate cancer AMACR in NE-like cells discriminates them from NE cells. Our aim was to investigate whether NED could also be associated with benign prostatic hyperplasia (BPH) as recent studies showed that an increase in neuroendocrine cell density occurred before development of BPH in hypertensive rats. Our results showed that a 10-day treatment with 100µM IBMX (blocking cAMP degradation) and 10µM forskolin (FSK, adenylate cyclase activator) to trigger sustained activation of the cAMP/PKA pathway led to an increase in SYN and AMACR expression in BPH-1 cells (qPCR and WB). Similar results were observed by combining the effect of the β-adrenoceptor agonist isoproterenol (1µM) and FSK. The same treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively, as expected for NED. Effects on AMACR and SYN expression and cell proliferation were fully reversed by the β-blocker carvedilol (5µM). This data suggests that β-adrenoceptors could be linked to the development of NE-like cells in BPH, a non-lethal disease affecting the transition zone (TZ). As 20% of the prostate cancer occur in this TZ, this observation may need further investigation. Citation Format: Natascha Pigat, Laura N. Garrido, Coline Lefevre, Manon Baures, Vincent Goffin, Anne-Sophie Armand, Thierry Capiod. In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6276.

Abstract 6670: Could immunotherapy offer potential in managing bacterial dysbiosis in prostate cancer

Abstract Background: Since 2006 three studies, involving 289,089 adolescents, demonstrated a significant association (1.67(0.79-3.55),1.7(1.03-2.70),2.37(1.19-4.73)) between pubertal acne and poor outcome prostate cancer(PC) 30+ years later. This suggested Cutibacterium acnes, amicroaerophylic bacterium, might be contributing to PC bacterial dysbiosis analogous to the role of H. pylori in stomach cancer and explain why circumcision reduces PC risk. Six years ago, using MALDI-TOF, we demonstrated that the presence of seven obligate anaerobe species in addition to C. acnes were increased in PC and linked to increased PSA. This presentation studies stored samples from the PROVENT chemoprevention randomised PC active surveillance phase 2 trial analysed using 16S rDNA sequencing, and comparing obligate anaerobe frequency with those detected by culture and MALDI-TOF identification and their influence on PSA expression. Methods: 89 urines of PROVENT trial patients were studied using 16S rDNA sequencing and followed for 24 months. In addition, 39 previously reported MALDI-TOF screened cohort patients (21 PCs and 18 BPHs) followed for 43 months. The frequency of 7 obligate bacterial genera (Actinobaculum, Finegoldia, Prevotella, Peptoniphilus, Peptostreptococcus &amp; Viellonella) was studied. Results: Twenty six of 89 (29%) PROVENT urine samples had a majority of bacteria detected as obligate anaerobes (mean=68%), while it was 12 of the 39 (31%) in PC tested in MALDI-TOF. In the combined series, those patients (n=38) with obligate anaerobes had mean PSA of 9.59 ug/L, while those without obligate anaerobes had a mean PSA of 6.29 ug/L (n=90), (t=-2.925, p = 0.0058). In the MALDI-TOF series, statistically increased urological intervention rate was associated with the presence of anaerobes (p=0.045, Fisher’s exact test). Discussion: These findings suggest that obligate anaerobe bacterial dysbiosis could be contributing to raised PSA through prostate cell damage, and possibly participating in the chronic inflammation and hypervascular changes that are seen in precancerous lesions. Checkpoint inhibitors have shown little benefit in prostate cancer. Recent reports from animal model studies of BCG resistance have suggested a short course combination of anti PDLI and anti NKG2a could break immune tolerance associated with expression of HLA-E and this approach could be of use to break tolerance to bacterial dysbiosis in the future. Citation Format: Tim Oliver, Belinda Nedjai, Emily Lane, Frank Chinegwundoh, Prabhakar Rajan, Jack Cuzick. Could immunotherapy offer potential in managing bacterial dysbiosis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6670.

Association between 19 medication use and risk of common cancers: A cross-sectional and Mendelian randomisation study.

Previous studies have yielded inconsistent results concerning drug use and the risk of cancers. We conducted a large-scale cross-sectional study and a two-sample Mendelian randomisation (MR) study to reveal the causal effect between the use of 19 medications and the risk of four common cancers (breast, lung, colorectal, and prostate). We obtained information on medication use and cancer diagnosis from National Health and Nutrition Examination Survey participants. After propensity score matching, we conducted survey-weighted multivariate logistic regression and restricted cubic spline analysis to assess the observed correlation between medication use and cancer while adjusting for multiple covariates. We also performed MR analysis to investigate causality based on summary data from genome-wide association studies on medication use and cancers. We performed sensitivity analyses, replication analysis, genetic correlation analysis, and reverse MR analysis to improve the reliability of MR findings. We found that the use of agents acting on the renin-angiotensin system was associated with reduced risk of prostate cancer (odds ratio (OR) = 0.42; 95% confidence interval (CI) = 0.27-0.63, P < 0.001), and there was a nonlinear association of 'decrease-to-increase-to-decrease' (P < 0.0001). The random-effects inverse variance weighted (IVW) model-based primary MR analysis (OR = 0.94, 95% CI = 0.91-0.97, P = 0.0007) and replication MR analysis (OR = 0.90, 95% CI = 0.85-0.96, P = 0.0006) both provided robust evidence of the causality of genetic liability for the use of agents acting on the renin-angiotensin system on a decreased risk of prostate cancer. Our study provides robust evidence that the use of drugs acting on the renin-angiotensin system can reduce prostate cancer risk. Given the high prevalence of prostate cancer, these findings have important implications for drug selection and prostate cancer prevention in patients with cardiovascular disease.

Do Obesity-Related Traits Affect Prostate Cancer Risk through Serum Testosterone? A Mendelian Randomization Study.

This study aimed to investigate whether testosterone mediates or confounds the effect of obesity-related traits on prostate cancer (PCa) using Mendelian randomization (MR) analysis. Data of obesity-related traits (body mass index [BMI], waist-to-hip ratio [WHR], and waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) were obtained from up to 806,834 people of European ancestry; data of testosterone (bioavailable testosterone [BT], total testosterone [TT], and sex hormone-binding globulin [SHBG]) were extracted from up to 194,453 participants in the UK Biobank; and the summary-level data of PCa (79,194 cases and 61,112 controls) were obtained from the PRACTICAL consortium. The results supported the causal relationship between higher BMI and a reduced risk of PCa (OR = 0.91, 95% confidence interval [CI]: 0.86-0.96). Furthermore, increased BT levels were associated with an elevated risk of PCa (OR = 1.15, 95% CI: 1.06-1.24). Importantly, our analysis revealed a unidirectional causal effect-higher BMI was linked to lower BT levels (beta = -0.27, 95% CI: -0.3--0.24), but not the other way around. This suggests that BT may mediate the effect of BMI on PCa rather than confound it. Our multivariable MR results further demonstrated that considering BT as a mediator led to the weakening of BMI's effect on PCa risk (OR = 0.97, 95% CI: 0.90-1.05), while the impact of BT on PCa remained unchanged when accounting for BMI. Moreover, we identified a significant indirect effect of BMI on PCa risk (OR = 0.96, 95% CI: 0.94-0.98). Our study provided genetic evidence that serum BT can mediate the effect of BMI on the risk of PCa, indicating the possible mechanism by which obesity reduces PCa risk.

Five-alpha reductase inhibitors and risk of prostate cancer among men with benign prostatic hyperplasia: A historical cohort study using primary care data

Background: Five-alpha reductase inhibitors (5ARIs) are used in the management of benign prostatic hyperplasia (BPH). 5ARIs prevent the conversion of testosterone to dihydrotestosterone, which is important in prostate development. It has been suggested that 5ARIs can be used a chemopreventative agent for prostate cancer. The aim of this study was to assess the risk of prostate cancer associated with 5ARI use among men with BPH. Methods: Using Clinical Practice Research Datalink (CPRD) from 1992 to 2011 in UK, prostate cancer risk was retrospectively compared in men with a new diagnosis of BPH, with no history of prostate cancer who were treated with 5ARIs, to men treated with alpha blockers (ABs) and those given no pharmacological treatment. Incidence rate of prostate cancer was calculated by treatment group; the association between BPH treatment group and prostate cancer was estimated by a multivariate Cox model. Results: 77,494 men with newly diagnosed BPH were included. The crude incidence rate of prostate cancer was 892.4 cases per 100,000 person-years amongst those treated with 5ARIs, compared with 1209.0 and 1542.9 in those treated with ABs and untreated individuals, respectively. The HR adjusted for potential confounders was 0.79 (0.72-0.86) for 5ARI vs ABs and 0.72 (0.66-0.79) for 5ARI vs untreated. After excluding the first year after BPH diagnosis, adjusted HRs attenuated to 0.87 (0.79-0.97) for 5ARI vs ABs and 0.97 (0.87-1.08) for 5ARI vs untreated. Conclusion: Among men diagnosed with BPH, we found evidence of lower risks of subsequent prostate cancer in those treated with 5ARIs, but this appeared to be driven by cases diagnosed within a year of BPH, possibly reflecting prevalent prostate cancers that were initially misdiagnosed. After excluding the first year after BPH diagnosis, there was little evidence of a reduced prostate cancer risk in those taking 5ARIs.

Cruciferous Vegetable Intake and Risk of Prostate Cancer: A Systematic Review and Meta-Analysis

Introduction: The relationship between cruciferous vegetables and prostate cancer (PCa) risk remains contentious. This study aimed to assess the association between consuming cruciferous vegetables and PCa risk. Methods: We carried out a systematic search through PubMed, Embase, Web of Science, and the Cochrane Library until September 20, 2022. The results of the article will be analyzed using the Stata 14 software. This meta-analysis was reported as directed by the PRISMA guidance, and the study protocol was recorded in PROSPERO (CRD42022361556). Results: 7 case-control studies and 9 cohort studies were eventually included, including 70,201 PCa cases and 1,264,437 members. The higher the intake of cruciferous vegetables, the lower the risk of PCa. In comparison to the lowest dose of cruciferous vegetables, the overall relative risk (RR) of cruciferous vegetables having the highest dose was 0.87 (95% confidence interval [CI]: 0.80–0.95; I2 = 59.2%). A significant linear trend (p = 0.002) was observed for the association, with a combined RR of 0.955 (95% CI: 0.928–0.982) for every 15 g of cruciferous vegetables per day. Conclusions: The study revealed that consumption of cruciferous vegetables may be linked to reduced PCa risk.

Nucleoredoxin gene SINRX1 negatively regulates tomato immunity by activating SA signaling pathway

The tomato (Solanum lycopersicum) is widely consumed globally and renowned for its health benefits, including the reduction of cardiovascular disease and prostate cancer risk. However, tomato production faces significant challenges, particularly due to various biotic stresses such as fungi, bacteria, and viruses. To address this challenges, we employed the CRISPR/Cas9 system to modify the tomato NUCLEOREDOXIN (SlNRX) genes (SlNRX1 and SlNRX2) belonging to the nucleocytoplasmic THIOREDOXIN subfamily. CRISPR/Cas9-mediated mutations in SlNRX1 (slnrx1) plants exhibited resistance against bacterial leaf pathogen Pseudomonas syringae pv. maculicola (Psm) ES4326, as well as the fungal pathogen Alternaria brassicicola. However, the slnrx2 plants did not display resistance. Notably, the slnrx1 demonstrated elevated levels of endogenous salicylic acid (SA) and reduced levels of jasmonic acid after Psm infection, in comparison to both wild-type (WT) and slnrx2 plants. Furthermore, transcriptional analysis revealed that genes involved in SA biosynthesis, such as ISOCHORISMATE SYNTHASE 1 (SlICS1) and ENHANCED DISEASE SUSCEPTIBILITY 5 (SlEDS5), were upregulated in slnrx1 compared to WT plants. In addition, a key regulator of systemic acquired resistance, PATHOGENESIS-RELATED 1 (PR1), exhibited increased expression in slnrx1 compared to WT. These findings suggest that SlNRX1 acts as a negative regulator of plant immunity, facilitating infection by the Psm pathogen through interference with the phytohormone SA signaling pathway. Thus, targeted mutagenesis of SlNRX1 is a promising genetic means to enhance biotic stress resistance in crop breeding.

Systemic lupus erythematosus and prostate cancer risk: a pool of cohort studies and Mendelian randomization analysis

BackgroundCurrent observational studies suggest that there may be a causal relationship between systemic lupus erythematosus (SLE) and prostate cancer (PC). However, there is contradictory evidence. This study aimed to investigate and clarify the association between SLE and PC.MethodsWe searched PubMed, Embase, Web of Science, and Scopus until May 2022. A meta-analysis was conducted on the standard incidence rate (SIR) and 95% CI. Subgroup analysis was performed based on the follow-up duration, study quality, and appropriate SLE diagnosis. Mendelian randomization (MR) of the two samples was used to determine whether genetically elevated SLE was causal for PC. Summary MR data were obtained from published GWASs, which included 1,959,032 individuals. The results were subjected to sensitivity analysis to verify their reliability.ResultsIn a meta-analysis of 79,316 participants from 14 trials, we discovered that patients with SLE had decreased PC risk (SIR, 0.78; 95% CI, 0.70–0.87) significantly. The MR results showed that a one-SD increase in genetic susceptibility to SLE significantly reduced PC risk (OR, 0.9829; 95% CI, 0.9715–0.9943; P = 0.003). Additional MR analyses suggested that the use of immunosuppressants (ISs) (OR, 1.1073; 95% CI, 1.0538–1.1634; P < 0.001), but not glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs), which were associated with increased PC risk. The results of the sensitivity analyses were stable, and there was no evidence of directional pleiotropy.ConclusionsOur results suggest that patients with SLE have a lower risk of developing PC. Additional MR analyses indicated that genetic susceptibility to the use of ISs, but not GCs or NSAIDs, was associated with increased PC risk. This finding enriches our understanding of the potential risk factors for PC in patients with SLE. Further study is required to reach more definitive conclusions regarding these mechanisms.

Vitamin E Intake and Risk of Prostate Cancer: A Meta-Analysis.

Vitamin E is a group of antioxidative tocopherols and tocotrienols that play a potential role in chemoprevention. Studies investigating the association between vitamin E and prostate cancer risk have been conflicting. We identified observational and interventional studies examining the association between vitamin E intake and prostate cancer risk from PubMed, EMBASE and the Cochrane Library. A random-effects model was used to perform a meta-analysis and estimate relative risks (RRs) and the corresponding 95% confidence intervals (CIs) of prostate cancer risk according to vitamin E intake. Subgroup analyses were conducted by study design, sample size, study population characteristics, geographical region, and dose of vitamin E intake. The association between dietary (RR = 0.97; 95% CI = 0.92-1.02) and supplemental (RR = 0.99; 95% CI = 0.94-1.04) vitamin E intake on prostate cancer risk was non-significant. In subgroup analyses, supplemental vitamin E was significantly associated with reduced prostate cancer risk in studies in Europe (RR = 0.81, 95% CI = 0.69-0.97). Overall, this meta-analysis demonstrates little evidence for a beneficial effect of vitamin E intake on prostate cancer risk but suggests that there may be some conditions in which supplements could confer a protective effect on prostate cancer risk.

Recognizing the True Value of Testosterone Therapy in Health Care.

There has been little recognition within the medical community of the health impact of testosterone (T) deficiency (TD), also known as hypogonadism, and the substantial benefits of testosterone therapy (TTh) on health and quality of life despite high-level clinical evidence. In a roundtable symposium, investigators summarized the contemporary evidence in several key clinical areas. TD negatively impacts human health and quality of life and is associated with increased mortality. Several studies have demonstrated that TTh in men with TD reduced all-cause and cardiovascular mortality. The longstanding belief that TTh is associated with increased prostate cancer (PCa) risk is contradicted by recent evidence, including multiple studies showing that TTh is associated with reduced PCa risk. Similarly, the weight of current evidence indicates the purported concern that TTh is associated with increased cardiovascular risk is incorrect. Normalization of physiological T reduces myocardial infarction, stroke, and deaths compared with men whose testosterone levels failed to normalize. In diabetic men TTh improves insulin resistance, and a large 2-year controlled study in men with abnormal glucose tolerance showed a substantially reduced rate of diabetes among men treated with TTh compared with untreated controls. Long-term TTh in diabetic men resulted in progressive improvements in obesity and insulin requirements, including a substantial number who experienced complete remission of diabetes. Finally, TTh has been shown to reduce severe outcomes with Covid-19 infection. These lines of evidence argue strongly for the need for greater awareness in the medical community of the impact of TD on health, and of the health benefits of TTh.

Phytoene Is More Efficiently Absorbed Than Lycopene by In Vitro Intestinal Cells but Is Absorbed and Cleared Similarly to Lycopene by In Vitro Prostate Cancer Cells

ObjectivesConsuming tomatoes and the tomato carotenoid lycopene (LYC) is epidemiologically associated with reduced prostate cancer risk. Tomato carotenoids, including LYC, phytoene (PE), and beta-carotene (BC), are found in human prostate tissue, with greater PE: LYC ratios found in the blood and prostate tissue relative to the diet. We tested the hypothesis that PE is more efficiently absorbed by prostate cells and by absorptive intestinal cells than LYC, explaining the enrichment of PE in blood and prostate tissue. MethodsIn vitro prostate cancer (LNCaP, PC-3) and non-cancerous prostate epithelial (RWPE-1) cells were treated with human serum enriched with PE, LYC, BC, or control (final media concentration 1 uM) for 6 hours. Clearance of PE, LYC, and BC from LNCaP cells was monitored for 48 hours after a 16 hour pre-incubation with carotenoids (n = 5 trials). Differentiated in vitroabsorptive intestinal cells (Caco-2 HTB-37 cultured 21 d on a permeable support) were treated with mixed lipid micelles and either PE, LYC, BC, or no carotenoid (final media carotenoid concentration 2 uM) for 4 or 24 h (n = 5 trials). Cell and media carotenoid concentrations were measured by HPLC-PDA. ResultsPC-3s absorbed 3.8%, 1.9%, and 2.5% (not significantly different, ns) and LNCaP cells absorbed 1.5%, 2.6%, and 2.0% of the LYC, PE, and BC (ns) doses, respectively, while RWPE-1 cells absorbed more of the BC dose (8.7%) than the PE dose (0.4%, P < 0.05), and LYC dose absorption was intermediate and similar to both PE and BC (2.5%). LNCaP cells cleared PE at the same rate as BC and LYC over 48 h. Intestinal Caco-2 cells absorbed more PE dose at 4 and 24 h (16.3%, 10.8%) than LYC (0.6%, 0.9%, respectively) or BC (5.8%, 7.5% respectively) (P < 0.05), while the amount of carotenoid recovered in the basolateral media showed a similar, though non-significantly different, pattern. ConclusionsThese results align with whole body pharmacokinetic findings suggesting that differences in intestinal absorption may be a key determinant in relative tissue carotenoid accumulation, and reveal that cancer versus non-cancer cell types may differ in carotenoid absorption characteristics. Funding SourcesNIH NCCIH/ODS R01 AT008576.

A 28-year prospective analysis of serum vitamin E, vitamin E-related genetic variation and risk of prostate cancer.

Objective:Investigate the relationship between serum α-tocopherol concentration and long-term risk of prostate cancer, and evaluate the interaction with vitamin E–related genetic variants and their polygenic risk score (PRS).Methods:We conducted a biochemical analysis of 29 102 male Finnish smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and 2 724 prostate cancer cases were identified during 28 years of follow-up. Cox proportional hazards models examined whether serum α-tocopherol concentrations were associated with prostate cancer risk. Among 8 383 participants, three SNPs related to vitamin E status (rs964184, rs2108622, and rs11057830) were examined to determine whether they modified the relationship between serum α-tocopherol concentrations and prostate cancer risk, both individually and as a PRS using logistic regression models.Results:No association was observed between serum α-tocopherol and prostate cancer risk (fifth quintile (Q5) versus Q1 hazard ratio (HR)=0.87, 95% confidence interval (95% CI) 0.75, 1.02; p-trend=0.57). Though no interactions were seen by population characteristics, high α-tocopherol concentration was associated with reduced prostate cancer risk among the trial α-tocopherol supplementation group (Q5 quintile versus Q1 HR=0.79, 95% CI 0.64, 0.99). Finally, no associated interaction between the three SNPs or their PRS and prostate cancer risk was observed.Conclusion:Although there was a weak inverse association between α-tocopherol concentration and prostate cancer risk over nearly three decades, our findings suggest that men receiving the trial α-tocopherol supplementation who had higher baseline serum α-tocopherol concentration experienced reduced prostate cancer risk. Vitamin E–related genotypes did not modify the serum α-tocopherol-prostate cancer risk association.

Zinc Intakes and Health Outcomes: An Umbrella Review.

It is widely accepted that the zinc element is crucial in human beings. Zinc has gained more attention during the COVID-19 pandemic due to its utilization for the treatment and prevention of respiratory tract infections. However, some studies also pointed out that zinc intake might cause unwanted side effects and even be dangerous when overdosed. To reveal the relationship between zinc intake and health outcomes, we performed an umbrella review from human studies. In total, the umbrella review included 43 articles and identified 11 outcomes for dietary zinc intake and 86 outcomes for supplementary zinc intake. Dietary zinc intake in the highest dose would decrease the risk of overall and specific digestive tract cancers, depression, and type 2 diabetes mellitus (T2DM) in adults. Supplementary zinc consumption in adults was linked to an improvement of depression, antioxidant capacity and sperm quality, higher serum zinc concentration, and lower concentration of inflammatory markers. Zinc supplementation in children would reduce the incidence of diarrhea and pneumonia, improve zinc deficiency and boost growth. However, zinc might not decrease all-cause mortality in adults or the in-hospital mortality of COVID-19. And better maternal and neonatal outcomes may not derive from pregnant women who consumed higher or lower doses of zinc supplementation (>20 mg/day and <20 mg/day, respectively). Dose-response analyses revealed that a daily 5 mg increment of zinc would lower the risk of colorectal and esophageal cancer, whereas a large dose of zinc supplementation (daily 100 mg) showed no benefit in reducing prostate cancer risk.

Evidence on Statins, Omega-3, and Prostate Cancer: A Narrative Review.

Dietary intake selections might play a crucial role in prostate cancer (PCa) occurrence and progression. Several studies have investigated whether statin use could reduce PCa risk but with conflicting results. Nevertheless, a significantly decreased incidence of advanced PCa has been consistently noted. Statins may also reduce the risk of biochemical recurrence (BCR) in men with PCa after receiving active treatment. However, the influence of statin usage on BCR and PCa progression in men with high prostate-specific antigen levels has been found to be insignificant. In contrast, the combined use of a statin and metformin was significantly related to the survival status of PCa patients. However, some studies have revealed that the intake of long-chain omega-3 fatty acid (ω-3) from fish or fish oil supplements may elevate PCa risk. Several meta-analyses on ω-3 consumption and PCa have shown controversial results for the relationship between PCa and ω-3 consumption. However, studies with positive results for various genotypes, fatty acid intake or levels, and PCA risk are emerging. This review highlights the association among statins, ω-3, and PCa. The findings summarized here may be helpful for clinicians counseling patients related to PCa.