Genomic Characterization of Prostatic Basal Cell Carcinoma.

Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.

Optimizing Post-Acute Coronary Syndrome Dyslipidemia Management: Insights from the North American Acute Coronary Syndrome Reflective III.

INTRODUCTION: Despite contemporary practice guidelines, a substantial number of post-acute coronary syndrome (ACS) patients fail to achieve guideline-recommended LDL-C thresholds. Our study aimed to investigate this guideline recommendations-to-practice care gap. Specifically, we aimed to identify opportunities where additional lipid-lowering therapies are indicated and explore reasons for the non-prescription of guideline-recommended therapies. METHODS: ACS patients with LDL-C ≥1.81 mmol/L (70 mg/dL) despite maximally tolerated statin ± ezetimibe therapy (including those intolerant of ≥2 statins) were enrolled 1-12 months post-event from 27 Canadian and US sites from September 2018 to October 2020 and followed up for three visits during the 12 months post-event. We determined the proportion of patients who did not achieve Canadian/US guideline-recommended LDL-C thresholds, the number of patients who would have been eligible for additional lipid-lowering therapies, and reasons behind lack of escalation in lipid-lowering therapies when indicated. Individual patient and aggregate practice feedback, including guideline-recommended intensification suggestions, were provided to each physician. RESULTS: Of the 248 patients enrolled in the pilot study (median age 64 [57, 73] years, 31.5% female and STEMI 27.4%), 75.4% were on high-intensity statins on the first visit. A total of 18.5% of those who attended all 3 visits had an LDL-C measured only at the first visit which was above the threshold. After 1 year of follow-up, 51.9% of patients achieved LDL-C thresholds at either visit 2 or 3. In the context of feedback reminding physicians about guideline-directed LDL-C-modifying therapy in their individual participating patients, we observed an increase in the use of ezetimibe and PCSK9 inhibitor therapy at 3-12 months. This was associated with a significant lowering of the mean LDL-C (from 2.93 mmol/L [baseline] to 2.09 mmol/L [3-6 months] to 1.87 mmol/L [6-12 months]) and a significantly greater proportion of patients (from 0% [baseline] to 38.6% [3-6 months] to 53.4% [6-12 months]) achieving guideline-recommended LDL-C thresholds. The most prevalent reasons behind the non-intensification of LDL-C-lowering therapy with ezetimibe and/or PCSK9i were LDL-C levels being close to target, the pre-existing use of other lipid-lowering therapies, patient refusal, and cost. CONCLUSION: Although most patients post-ACS were on high-intensity statin therapy, almost 50% failed to achieve guideline-recommended LDL-C thresholds by 1-year follow-up. Furthermore, additional lipid-lowering therapies in this high-risk group were underprescribed, and this might be linked to several factors including potential gaps in physician knowledge, treatment inertia, patient refusal, and cost.

Organizational Ethics in Healthcare: A National Survey.

Organizational ethics-defined as the alignment of an institution's practices with its mission, vision, and values-is a growing field in health care not well characterized in empirical literature. To capture the scope and context of organizational ethics work in United States healthcare institutions, we conducted a nationwide convenience survey of ethicists regarding the scope of organizational ethics work, common challenges faced, and the organizational context in which this work is done. In this article, we report substantial variability in the structure of organizational ethics programs and the settings in which it is conducted. Notable findings included disagreement about the activities that comprise organizational ethics and a lack of common metrics used to assess organizational ethics activities. A frequently cited barrier to full engagement in these activities was poor institution-wide understanding about the role and function of organizational ethics resources. These data suggest a tension in the trajectory of organizational ethics' professionalization: while some variability is appropriate to the field's relative youth, inadequate attention to definitions of organizational ethics practice and metrics for success can impede discussions about appropriate institutional support, leadership context, and training for practitioners.

Single-cell atlas of epithelial and stromal cell heterogeneity by lobe and strain in the mouse prostate.

BACKGROUND: Evaluating the complex interplay of cell types in the tissue microenvironment is critical to understanding the origin and progression of diseases in the prostate and potential opportunities for intervention. Mouse models are an essential tool to investigate the molecular and cell-type-specific contributions of prostate disease at an organismal level. While there are well-documented differences in the extent, timing, and nature of disease development in various genetically engineered and exposure-based mouse models in different mouse strains and prostate lobes within each mouse strain, the underlying molecular phenotypic differences in cell types across mouse strains and prostate lobes are incompletely understood. METHODS: In this study, we used single-cell RNA-sequencing (scRNA-seq) methods to assess the single-cell transcriptomes of 6-month-old mouse prostates from two commonly used mouse strains, friend virus B/NIH jackson (FVB/NJ) (N = 2) and C57BL/6J (N = 3). For each mouse, the lobes of the prostate were dissected (anterior, dorsal, lateral, and ventral), and individual scRNA-seq libraries were generated. In situ and pathological analyses were used to explore the spatial and anatomical distributions of novel cell types and molecular markers defining these cell types. RESULTS: Data dimensionality reduction and clustering analysis of scRNA-seq data revealed that basal and luminal cells possessed strain-specific transcriptomic differences, with luminal cells also displaying marked lobe-specific differences. Gene set enrichment analysis comparing luminal cells by strain showed enrichment of proto-Oncogene targets in FVB/NJ mice. Additionally, three rare populations of epithelial cells clustered independently of strain and lobe: one population of luminal cells expressing Foxi1 and components of the vacuolar ATPase proton pump (Atp6v0d2 and Atp6v1g3), another population expressing Psca and other stem cell-associated genes (Ly6a/Sca-1, Tacstd2/Trop-2), and a neuroendocrine population expressing Chga, Chgb, and Syp. In contrast, stromal cell clusters, including fibroblasts, smooth muscle cells, endothelial cells, pericytes, and immune cell types, were conserved across strain and lobe, clustering largely by cell type and not by strain or lobe. One notable exception to this was the identification of two distinct fibroblast populations that we term subglandular fibroblasts and interstitial fibroblasts based on their strikingly distinct spatial distribution in the mouse prostate. CONCLUSIONS: Altogether, these data provide a practical reference of the transcriptional profiles of mouse prostate from two commonly used mouse strains and across all four prostate lobes.

Drought patterns: their spatiotemporal variability and impacts on maize production in Limpopo province, South Africa.

Due to global climate change, droughts are likely to become more frequent and more severe in many regions such as in South Africa. In Limpopo, observed high climate variability and projected future climate change will likely increase future maize production risks. This paper evaluates drought patterns in Limpopo at two representative sites. We studied how drought patterns are projected to change under future climatic conditions as an important step in identifying adaptation measures (e.g., breeding maize ideotypes resilient to future conditions). Thirty-year time horizons were analyzed, considering three emission scenarios and five global climate models. We applied the WOFOST crop model to simulate maize crop growth and yield formation over South Africa's summer season. We considered three different crop emergence dates. Drought indices indicated that mainly in the scenario SSP5-8.5 (2051-2080), Univen and Syferkuil will experience worsened drought conditions (DC) in the future. Maize yield tends to decline and future changes in the emergence date seem to impact yield significantly. A possible alternative is to delay sowing date to November or December to reduce the potential yield losses. The grain filling period tends to decrease in the future, and a decrease in the duration of the growth cycle is very likely. Combinations of changed sowing time with more drought tolerant maize cultivars having a longer post-anthesis phase will likely reduce the potential negative impact of climate change on maize.

SARS-CoV-2 Delta variant isolates from vaccinated individuals.

BACKGROUND: The SARS-CoV-2 Delta variant was first identified in the U.S. in March 2021 and has rapidly become the predominant lineage across the U.S. due to increased transmissibility, immune evasion and vaccine breakthrough. The aim of this study was to better understand the genetic diversity and the potential impact of mutations observed in SARS-CoV-2 viruses circulating in the U.S. in vaccinated individuals. RESULTS: Whole genome sequencing was performed on thirty-four SARS-CoV-2 positive samples using the Oxford Nanopore MinION. Evolutionary genomic analysis revealed two novel mutations, ORF1b:V2354F and a premature stop codon, ORF7a:Q94*, identified in a cluster of SARS-CoV-2 Delta isolates collected from vaccinated individuals in Colorado. The ORF1b:V2354F mutation, corresponding to NSP15:V303F, may induce a conformational change and result in a disruption to a flanking beta-sheet structure. The premature stop codon, ORF7a:Q94*, truncates the transmembrane protein and cytosolic tail used to mediate protein transport. This may affect protein localization to the ER-Golgi. In addition to these novel mutations, the cluster of vaccinated isolates contain an additional mutation in the spike protein, at position 112, compared to the Delta variant defining mutations. This mutation, S112L, exists in isolates previously obtained in the U.S. The S112L mutation substitutes a bulky hydrophobic side chain for a polar side chain, which results in a non-conservative substitution within the protein that may affect antibody-binding affinity. Additionally, the vaccinated cluster of isolates contains non-synonymous mutations within ORF8 and NSPs which further distinguish this cluster from the respective ancestral Delta variant. CONCLUSIONS: These results show there is an emerging sub-lineage of the ancestral Delta variant circulating in the U.S. As mutations emerge in constellations, those with a potentially beneficial advantage to the virus may continue to circulate while others will cease.

Porcine Hemagglutinating Encephalomyelitis Virus Infection In Vivo and Ex Vivo.

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a betacoronavirus that causes vomiting and wasting disease and/or encephalomyelitis in suckling pigs. This study characterized PHEV infection, pathogenesis, and immune response in cesarean-derived, colostrum-deprived (CDCD) neonatal pigs. Infected animals developed mild respiratory, enteric, and neurological clinical signs between 2 to 13 days postoronasal inoculation (dpi). PHEV did not produce viremia, but virus shedding was detected in nasal secretions (1 to 10 dpi) and feces (2 to 7 dpi) by reverse transcriptase quantitative PCR (RT-qPCR). Viral RNA was detected in all tissues except liver, but the detection rate and RT-qPCR threshold cycle (CT ) values decreased over time. The highest concentration of virus was detected in inoculated piglets necropsied at 5 dpi in turbinate and trachea, followed by tonsils, lungs, tracheobronchial lymph nodes, and stomach. The most representative microscopic lesions were gastritis lymphoplasmacytic, moderate, multifocal, with perivasculitis, and neuritis with ganglia degeneration. A moderate inflammatory response, characterized by increased levels of interferon alpha (IFN-α) in plasma (5 dpi) and infiltration of T lymphocytes and macrophages were also observed. Increased plasma levels of interleukin-8 (IL-8) were detected at 10 and 15 dpi, coinciding with the progressive resolution of the infection. Moreover, a robust antibody response was detected by 10 dpi. An ex vivo air-liquid CDCD-derived porcine respiratory cells culture (ALI-PRECs) system showed virus replication in ALI-PRECs and cytopathic changes and disruption of ciliated columnar epithelia, thereby confirming the tracheal epithelia as a primary site of infection for PHEV.IMPORTANCE Among the ∼46 virus species in the family Coronaviridae, many of which are important pathogens of humans and 6 of which are commonly found in pigs, porcine hemagglutinating encephalomyelitis remains one of the least researched. The present study provided a comprehensive characterization of the PHEV infection process and immune responses using CDCD neonatal pigs. Moreover, we used an ex vivo ALI-PRECs system resembling the epithelial lining of the tracheobronchial region of the porcine respiratory tract to demonstrate that the upper respiratory tract is a primary site of PHEV infection. This study provides a platform for further multidisciplinary studies of coronavirus infections.

Hormonal patterns in men with prediabetes and diabetes in NHANES III: possible links with prostate cancer.

PURPOSE: Pathways involving sex hormones and insulin-like growth factors (IGFs) have been proposed to explain, in part, the lower risk of prostate cancer among men with diabetes. To gain insights into potential biological mechanisms we explored differences in serum concentrations of sex hormones and IGFs across the trajectory from normoglycemia to prediabetes to poorly controlled diabetes. METHODS: Using cross-sectional data from the National Health and Nutrition Examination Survey III we examined differences in levels of circulating sex hormones, sex hormone-binding globulin (SHBG), IGF-1, and IFG-binding protein 3 (IGFBP-3), according to diabetes status: no diabetes [n = 648], prediabetes [n = 578], undiagnosed diabetes [n = 106], well-controlled diabetes [n = 42], and poorly controlled diabetes [n = 56]. Adjusted geometric mean concentrations were derived using multivariable linear regression, adjusted for age, race, and other lifestyle factors. RESULTS: Total testosterone concentrations were lower among prediabetics (4.89 ng/mL, 95% confidence interval (CI) 4.95-5.21) than men without prediabetes/diabetes (5.29 ng/mL, 95% CI 5.06-5.53) but did not reduce further across diabetes groups. Concentrations of estradiol, estimated free testosterone, SHGB, IGF-1, and IGFBP-3 did not differ. While the ratio of IGF-1 to IGFBP-3 was lower among men with prediabetics and undiagnosed diabetes than men without prediabetes/diabetes, there was no trend across groups. A positive trend for the ratio of estradiol-to-testosterone levels was observed across groups (p trend = 0.045). CONCLUSION: Our findings do not provide clear support for either an androgen driven or IGF-driven pathway for the inverse association between diabetes and prostate cancer risk.

Association of Serum Carotenoids and Retinoids with Intraprostatic Inflammation in Men without Prostate Cancer or Clinical Indication for Biopsy in the Placebo Arm of the Prostate Cancer Prevention Trial.

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except ß-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P-trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.

Applying the Peter Parker Principle to Healthcare.

The role of power in healthcare can raise many ethical challenges. Power is ownership, whether given, ceded, or taken of another person's autonomy. When a person has power over someone else, they can control or strongly influence the decision-making freedom of that person. From the principalist perspective1,2 of healthcare ethics, denying a person their freedom to choose should only occur when justifying conditions related to beneficence and nonmaleficence are sufficiently satisfied. In healthcare, it is rare to be able to identify situations where paternalism is justified. However, experience suggests that abusive power in healthcare is used too frequently without justifying criteria.

Demystifying individual heterogeneity.

Among-individual variation in vital rates, such as mortality and birth rates, exists in nearly all populations. Recent studies suggest that this individual heterogeneity produces substantial life-history and fitness differences among individuals, which in turn scale up to influence population dynamics. However, our ability to understand the consequences of individual heterogeneity is limited by inconsistencies across conceptual frameworks in the field. Studies of individual heterogeneity remain filled with contradicting and ambiguous terminology that introduces risks of misunderstandings, conflicting models and unreliable conclusions. Here, we synthesise the existing literature into a single and comparatively straightforward framework with explicit terminology and definitions. This work introduces a distinction between potential vital rates and realised vital rates to develop a coherent framework that maps directly onto mathematical models of individual heterogeneity. We suggest the terms "fixed condition" and "dynamic condition" be used to distinguish potential vital rates that are permanent from those that can change throughout an individual's life. To illustrate, we connect the framework to quantitative genetics models and to common classes of statistical models used to infer individual heterogeneity. We also develop a population projection matrix model that provides an example of how our definitions are translated into precise quantitative terms.

Phenotypic characterization of two novel cell line models of castration-resistant prostate cancer.

BACKGROUND: Resistance to androgen deprivation therapies is a major driver of mortality in advanced prostate cancer. Therefore, there is a need to develop new preclinical models that allow the investigation of resistance mechanisms and the assessment of drugs for the treatment of castration-resistant prostate cancer. METHODS: We generated two novel cell line models (LAPC4-CR and VCaP-CR) which were derived by passaging LAPC4 and VCaP cells in vivo and in vitro under castrate conditions. We performed detailed transcriptomic (RNA-seq) and proteomic analyses (SWATH-MS) to delineate expression differences between castration-sensitive and castration-resistant cell lines. Furthermore, we characterized the in vivo and in vitro growth characteristics of these novel cell line models. RESULTS: The two cell line derivatives LAPC4-CR and VCaP-CR showed castration-resistant growth in vitro and in vivo which was only minimally inhibited by AR antagonists, enzalutamide, and bicalutamide. High-dose androgen treatment resulted in significant growth arrest of VCaP-CR but not in LAPC4-CR cells. Both cell lines maintained AR expression, but exhibited distinct expression changes on the mRNA and protein level. Integrated analyses including data from LNCaP and the previously described castration-resistant LNCaP-abl cells revealed an expression signature of castration resistance. CONCLUSIONS: The two novel cell line models LAPC4-CR and VCaP-CR and their comprehensive characterization on the RNA and protein level represent important resources to study the molecular mechanisms of castration resistance.

The association of sex steroid hormone concentrations with non-alcoholic fatty liver disease and liver enzymes in US men.

BACKGROUND & AIMS: This study aimed to analyse the association of sex hormone levels with liver enzyme levels and non-alcoholic fatty liver disease (NAFLD) in a nationally representative sample of men. METHODS: A total of 919 men from the US National Health and Nutrition Examination Study (NHANES) III were included in this cross-sectional analysis of data from 1988 to 1991. We used existing data on serum total and free testosterone, total and free estradiol, androstanediol glucuronide (AAG) and sex steroid-binding globulin (SHBG), and estimated their associations with aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and NAFLD, as determined using ultrasound, after adjusting for possible confounders including age, race, smoking, alcohol, physical activity, waist circumference and steroid hormones. RESULTS: Lower total testosterone (TT) and higher free estradiol were associated with higher odds of NAFLD after adjusting for confounders including the other sex hormones. Lower TT was associated with higher odds of elevated AST, but not ALT. Free testosterone, total estradiol, SHBG and AAG were not associated with NAFLD or liver enzymes. CONCLUSIONS: This study supports an inverse association between TT concentration and NAFLD in men independent of other sex hormones (SHBG, AAG and estradiol) and known risk factors, such as obesity, age and lifestyle. Exploration of whether TT might be a non-invasive marker for NAFLD diagnosis is warranted.

Understanding the Stabilization and Tunability of Divalent Europium 2.2.2B Cryptates.

Lanthanides such as europium with more accessible divalent states are useful for studying redox stability afforded by macrocyclic organic ligands. Substituted cryptands, such as 2.2.2B cryptand, that increase the oxidative stability of divalent europium also provide coordination environments that support synthetic alterations of Eu(II) cryptate complexes. Two single crystal structures were obtained containing nine-coordinate Eu(II) 2.2.2B cryptate complexes that differ by a single coordination site, the occupation of which is dictated by changes in reaction conditions. A crystal structure containing a [Eu(2.2.2B)Cl]+ complex is obtained from a methanol-THF solvent mixture, while a methanol-acetonitrile solvent mixture affords a [Eu(2.2.2B)(CH3OH)]2+ complex. While both crystals exhibit the typical blue emission observed in most Eu(II) containing compounds as a result of 4f65d1 to 4f7 transitions, computational results show that the substitution of a Cl- anion in the place of a methanol molecule causes mixing of the 5d excited states in the Eu(II) 2.2.2B cryptate complex. Additionally, magnetism studies reveal the identity of the capping ligand in the Eu(II) 2.2.2B cryptate complex may also lead to exchange between Eu(II) metal centers facilitated by π-stacking interactions within the structure, slightly altering the anticipated magnetic moment. The synthetic control present in these systems makes them interesting candidates for studying less stable divalent lanthanides and the effects of precise modifications of the electronic structures of low valent lanthanide elements.

Clinical evaluation of a multiplex real-time RT-PCR assay for detection of SARS-CoV-2 in individual and pooled upper respiratory tract samples.

The aim of this study was to identify and validate a sensitive, high-throughput, and cost-effective SARS-CoV-2 real-time RT-PCR assay to be used as a surveillance and diagnostic tool for SARS-CoV-2 in a university surveillance program. We conducted a side-by-side clinical evaluation of a newly developed SARS-CoV-2 multiplex assay (EZ-SARS-CoV-2 Real-Time RT-PCR) with the commercial TaqPath COVID-19 Combo Kit, which has an Emergency Use Authorization from the FDA. The EZ-SARS-CoV-2 RT-PCR incorporates two assays targeting the SARS-CoV-2 N gene, an internal control targeting the human RNase P gene, and a PCR inhibition control in a single reaction. Nasopharyngeal (NP) and anterior nares (AN) swabs were tested as individuals and pools with both assays and in the ABI 7500 Fast and the QuantStudio 5 detection platforms. The analytical sensitivity of the EZ-SARS-CoV-2 RT-PCR assay was 250 copies/ml or approximately 1.75 genome copy equivalents per reaction. The clinical performance of the EZ-SARS-CoV-2 assay was evaluated using NP and AN samples tested in other laboratories. The diagnostic sensitivity of the assay ranged between 94 and 96% across the detection platforms, and the diagnostic specificity was 94.06%. The positive predictive value was 94%, and the negative predictive value ranged from 94 to 96%. Pooling five NP or AN specimens yielded 93% diagnostic sensitivity. The overall agreement between these SARS-CoV-2 RT-PCR assays was high, supported by a Cohen's kappa value of 0.93. The EZ-SARS-CoV-2 RT-PCR assay performance attributes of high sensitivity and specificity with AN sample matrix and pooled upper respiratory samples support its use in a high-throughput surveillance testing program.

Sublethal concentration of insecticide amplifies interference competition in a tortrix moth.

Insecticides are extensively used worldwide to kill insect pests, yet organisms are most often exposed to insecticides at sublethal concentrations. Our understanding of sublethal effects on life histories is needed to predict the impact of insecticides on population dynamics and improve insecticide use and pest control. Sublethal concentrations can impact life histories directly and indirectly through changes in the intraspecific competition. Yet, few studies have evaluated the sublethal effects on intraspecific competition and these do not disentangle the insecticide effects on interference competition versus exploitative competition. As such, sublethal effects on the relative contribution of each pathways in shaping life histories are largely unknown, despite the fact that this can impact population dynamics. In this study, we focused on the neurotoxic insecticide spinosad and investigated its sublethal effects on interference among the aggressive larvae of the tortrix moth Adoxophyes honmai and the consequences for life histories. We conducted a set of paired experiments to disentangle the insecticide effects on interference from the ones on exploitation. Spinosad was found to amplify interference with most effects on mortality which lets us suggest that the insecticide likely increases the level of aggressive interactions resulting in more conspecific killings (e.g. cannibalism). Spinosad exposure was found to impair movement ability. Less movements may increase susceptibility to conspecific attacks and or increase aggresivity for better defence, two plausible mechanisms that could explain the increase in interference with insecticide. This study shows that insecticide at sublethal concentration can impact life histories by altering the strength of interference competition. Many organisms (pest and non-target species) compete through interference and theory predicts that a change in interference can substantially change dynamics. Our finding therefore reveals the importance of assessing the effect of insecticides on the mechanisms of competition when predicting their impact on populations.

The association between serum sex steroid hormone concentrations and intraprostatic inflammation in men without prostate cancer and irrespective of clinical indication for biopsy in the placebo arm of the Prostate Cancer Prevention Trial.

BACKGROUND: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. METHODS: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). RESULTS: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). CONCLUSIONS: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.

In utero exposure to persistent and nonpersistent endocrine-disrupting chemicals and anogenital distance. A systematic review of epidemiological studies†.

Anti-androgenic endocrine-disrupting chemicals (EDCs) can cross the placenta to modify early offspring sexual dimorphic markers. These changes are linked to anogenital distance (AGD), which is an androgen-sensitive anthropometric parameter used as a biomarker of perineal growth and caudal migration of the genital tubercle. This review aimed to summarize strength of evidence for associations of in utero exposure to EDCs with AGD and to identify gaps and limitations in the literature so as to inform future research. We performed an electronic search of English literature in September 2019 in medical literature analysis and retrieval system online (MEDLINE), Web of Science and Toxline. We included epidemiological studies that examined in utero exposure to persistent and nonpersistent EDCs and considered AGD in offspring as an outcome. Our review contained 16 investigations examining exposure to persistent EDCs (nine studies) and nonpersistent EDCs (seven studies). Some individual studies reported an inverse association between exposure to bisphenol A (BPA), dioxins, perfluoroalkyl substances, and organochlorides and AGD in both male and female offspring. Meta-analysis of three studies found a small reduction of AGD in female offspring exposed to BPA. The number of studies per chemical is small, and number of subjects examined is limited; so, replication of these results is needed. To achieve more specificity and better replication of results, future studies should establish the association of nonpersistent EDCs using multiple urine samples, evaluate the cumulative impact of exposure to a mixture of anti-androgenic chemicals, and offer adequate consideration of more maternal- and children-related confounding factors.

Activin and inhibin signaling: From regulation of physiology to involvement in the pathology of the female reproductive system.

Activins and inhibins - comprising activin A, B, AB, C and E, and inhibin A and B isoforms - belong to the transforming growth factor beta (TGFß) superfamily. They regulate several biological processes, including cellular proliferation, differentiation and invasiveness, to enhance the formation and functioning of many human tissues and organs. In this review, we have discussed the role of activin and inhibin signaling in the physiological and female-specific pathological events that occur in the female reproductive system. The up-to-date evidence indicates that these cytokines regulate germ cell development, follicular development, ovulation, uterine receptivity, decidualization and placentation through the activation of several signaling pathways; and that their dysregulated expression is involved in the pathogenesis and pathophysiology of the numerous diseases, including pregnancy complications, that disturb reproduction. Hence, some of the isoforms have been suggested as potential biomarkers and therapeutic targets for the management of some of these diseases. Tackling the research directions highlighted in this review will enhance a detailed comprehension and the clinical utility of these cytokines.

Bisphenol A-induced mechanistic impairment of decidualization.

Decidualization is a crucial precedent to embryo implantation, as its impairment is a major contributor to female infertility and pregnancy complications. Unraveling the molecular mechanisms involved in the impairment of decidualization has been a subject of interest in the field of reproductive medicine. Evidence from several experimental settings show that exposure to bisphenol A (BPA), an endocrine-disrupting chemical, affects the expression of several molecules that are involved in decidualization. Both low and high doses of BPA impair decidualization through the dysregulation of estrogen (ER) and progesterone (PR) receptors. Exposure to low doses of BPA leads to decreased levels and activities of several antioxidant enzymes, increased activity of endothelial nitric oxide synthase (eNOS), and increased production of nitric oxide (NO) via the upregulation of ER and PR. Consequently, oxidative stress is induced and decidualization becomes impaired. On the other hand, exposure to high doses of BPA downregulates ER and PR and impairs decidualization through two distinct pathways. One is through the upregulation of early growth response-1 (EGR1) via increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2; and the other is through a reduced serum glucocorticoid-induced kinase-1 (SGK1)-mediated downregulation of epithelial sodium channel-α and the induction of oxidative stress. Thus, regardless of the dose, BPA can impair decidualization to trigger infertility and pregnancy complications. This warrants the need to adopt lifestyles that will decrease the tendency of getting exposed to BPA.