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Longitudinal bone growth is mediated through several mechanisms including macro- and micronutrients, and endocrine and paracrine hormones. These mechanisms can be affected by childhood obesity as excess adiposity may affect signaling pathways, place undue stress on the body, and affect normal physiology. This review describes the physiology of the epiphyseal growth plate, its regulation under healthy weight and obesity parameters, and bone pathology following obesity. A literature review was performed utilizing PubMed, PMC, NIH, and the Cochrane Database of Systematic Reviews pertinent to hormonal and nutritional effects on bone development, child obesity, and pathologic bone development related to weight. The review indicates a complex network of nutrients, hormones, and multi-system interactions mediates long bone growth. As growth of long bones occurs during childhood and the pubertal growth spurt, pediatric bones require adequate levels of minerals, vitamins, amino acids, and a base caloric supply for energy. Recommendations should focus on a nutrient-dense dietary approach rather than restrictive caloric diets to maintain optimal health. In conclusion, childhood obesity has profound multifaceted effects on the developing musculoskeletal system, ultimately causing poor nutritional status during development. Weight loss, under medical supervision, with proper nutritional guidelines, can help counteract the ill effects of childhood obesity. [ABSTRACT FROM AUTHOR]

Despite aggressive multimodal treatment that typically includes definitive or adjuvant radiation therapy (RT), locoregional recurrence rates approach 50% for patients with locally advanced human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC). Thus, more effective therapeutics are needed to improve patient outcomes. We evaluated the radiosensitizing effects of ataxia telangiectasia and RAD3-related (ATR) inhibitor (ATRi) BAY 1895344 in preclinical models of HNSCC. Murine and human HPV-negative HNSCC cells (MOC2, MOC1, JHU-012) were treated with vehicle or ATRi with or without 4 Gy. Checkpoint kinase 1 phosphorylation and DNA damage (γH2AX) were evaluated by Western blot, and ATRi half-maximal inhibitory concentration was determined by MTT assay for HNSCC cells and immortalized murine oral keratinocytes. In vitro radiosensitization was tested by clonogenic assay. Cell cycle distribution and mitotic catastrophe were evaluated by flow cytometry. Mitotic aberrations were quantified by fluorescent microscopy. Tumor growth delay and survival were assessed in mice bearing MOC2 or JHU-012 transplant tumors treated with vehicle, ATRi, RT (10 Gy × 1 or 8 Gy × 3), or combined ATRi + RT. ATRi caused dose-dependent reduction in checkpoint kinase 1 phosphorylation at 1 hour post-RT (4 Gy) and dose-dependent increase in γH2AX at 18 hours post-RT. Addition of RT to ATRi led to decreased BAY 1895344 half-maximal inhibitory concentration in HNSCC cell lines but not in normal tissue surrogate immortalized murine oral keratinocytes. Clonogenic assays demonstrated radiosensitization in the HNSCC cell lines. ATRi abrogated the RT-induced G2/M checkpoint, leading to mitosis with unrepaired DNA damage and increased mitotic aberrations (multinucleated cells, micronuclei, nuclear buds, nucleoplasmic bridges). ATRi and RT significantly delayed tumor growth in MOC2 and JHU-012 in vivo models, with improved overall survival in the MOC2 model. These findings demonstrated that BAY 1895344 increased in vitro and in vivo radiosensitivity in HPV-negative HNSCC preclinical models, suggesting therapeutic potential warranting evaluation in clinical trials for patients with locally advanced or recurrent HPV-negative HNSCC. [ABSTRACT FROM AUTHOR]

The integral role of the hypothalamic-pituitary-gonadal axis in reproductive processes makes it a prime therapeutic target. By inhibiting sex steroid synthesis, gonadotropin-releasing hormone (GnRH) analogues are used in the management of cancers, benign neoplasms, infertility and gender dysphoria. However, the wide application of these therapeutics raises concerns regarding the unintended effects upon the cardiovascular system. In males with prostate cancer, GnRH analogues when used as an androgen deprivation therapy appear to increase the risk of cardiovascular disease, which is the leading cause of death in this population. Therefore, due to the utilisation of GnRH analogues across the lifespan and gender spectrum, this relationship merits discussion. Existing data suggest an association between GnRH analogues and major adverse cardiovascular events in males. Conversely, females receiving GnRH analogues for breast cancer treatment appear to be at an increased risk of developing hypertension. In this narrative review, we describe the uses of GnRH analogues in adults, adolescents and children. We discuss whether sex plays a role in the cardiovascular effects of GnRH analogues and explore the significance of sex hormone receptors in the vasculature. We also consider confounding factors such as malignancy, advanced age and infertility. [ABSTRACT FROM AUTHOR]

Background: Advanced prostate cancer (PC) is characterized by insensitivity to androgen deprivation therapy and chemotherapy, resulting in poor outcome for most patients. Thus, advanced PC urgently needs novel therapeutic strategies. Mounting evidence points to splicing dysregulation as a hallmark of advanced PC. Moreover, pharmacologic inhibition of the splicing process is emerging as a promising option for this disease. Method: By using a representative androgen-insensitive PC cell line (22Rv1), we have investigated the genome-wide transcriptomic effects underlying the cytotoxic effects exerted by three splicing-targeting drugs: Pladienolide B, indisulam and THZ531. Bioinformatic analyses were performed to uncover the gene structural features underlying sensitivity to transcriptional and splicing regulation by these treatments. Biological pathways altered by these treatments were annotated by gene ontology analyses and validated by functional experiments in cell models. Results: Although eliciting similar cytotoxic effects on advanced PC cells, Pladienolide B, indisulam and THZ531 modulate specific transcriptional and splicing signatures. Drug sensitivity is associated with distinct gene structural features, expression levels and cis-acting sequence elements in the regulated exons and introns. Importantly, we identified PC-relevant genes (i.e. EZH2, MDM4) whose drug-induced splicing alteration exerts an impact on cell survival. Moreover, computational analyses uncovered a widespread impact of splicing-targeting drugs on intron retention, with enrichment in genes implicated in pre-mRNA 3'-end processing (i.e. CSTF3, PCF11). Coherently, advanced PC cells displayed high sensitivity to a specific inhibitor of the cleavage and polyadenylation complex, which enhances the effects of chemotherapeutic drugs that are already in use for this cancer. Conclusions: Our study uncovers intron retention as an actionable vulnerability for advanced PC, which may be exploited to improve therapeutic management of this currently incurable disease. [ABSTRACT FROM AUTHOR]

Background: Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. Methods: We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. Results: After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. Conclusion: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted. [ABSTRACT FROM AUTHOR]

Purpose: To review the evidence for radiotherapy in the management of primary penile cancer, either as brachytherapy or external beam radiation, and the role of external beam radiotherapy in node positive penile cancer. Methods: English language literature was reviewed for the past 3 decades. As penile cancer is uncommon in developed nations, high quality evidence to guide management is limited. Single institution reports often span decades during which time staging systems and treatments have evolved, reducing their relevance to current practice. Successful clinical trials require collaboration not only among disciplines but also among multiple institutions and nations. Results: Radiotherapy is a definitive organ-preserving option for T1-T2 penile cancers. Interstitial brachytherapy is associated with penile preservation in 85% of men at 5 years, maintained in 70% by 10 years. Results of external radiotherapy are not quite as promising but nonetheless 60% of men will have an intact penis at 5 years. Inguino-pelvic external radiotherapy has been reported to increase overall survival when delivered as adjuvant treatment for men with pN3 groin but pN0 pelvic nodes, and improve disease specific survival for those with involved pelvic nodes. InPACT (ECOG-ACRIN_8134) is investigating the role of inguino-pelvic chemo-radiotherapy for men with pN3 inguinal nodes but imaging negative pelvic nodes. Conclusions: Radiotherapy has a well-defined role to play in treatment of squamous cell cancers of other sites, such as vulva, anal canal, uterine cervix and head and neck malignancies. Emerging data support the incorporation of radiotherapy into treatment paradigms for penile cancer. [ABSTRACT FROM AUTHOR]

Objectives: Our study aimed to compare the efficacy of transdermal dihydrotestosterone and testosterone enanthate in treating idiopathic micropenis. Patients and methods: It's a comparative randomized study of 49 patients with idiopathic micropenis who are followed up in the Endocrinology-Diabetology and Nutrition Department of Mohammed VI University Hospital Center of Oujda, Morocco. The study was conducted from December 2019 to April 2021. All patients received a clinical examination including measurement of penis size before and after hormonal treatment. The patients were divided into two random groups, each group received a different drug, the first arm was treated with transdermal dihydrotestosterone (27 patients) and the second arm was treated with testosterone enanthate (22 patients). The Trial registration number was researchregistry7745. Results: The majority of the patients were children. The mean age was 9.7 ± 4.4 years. In the first arm, the mean penile size increased from −2.42 SD to −0.7 SD with a gain of 2.37 cm on average. In the second arm, the mean size increased from −2.48 SD to −0.69 SD, with a gain of 1.82 cm on average. The increase in penile size in the first arm was significantly greater than in the second arm (P =.008). No side effects were detected in both arms. Discussion and conclusion: In the present study, we demonstrated the superiority of transdermal DHT compared to injectable exogenous testosterone in the treatment of idiopathic micropenis. According to the age subgroups, there was no significant difference between the 2 treatments in each age group. [ABSTRACT FROM AUTHOR]

Our previous publication found an increased risk of higher‐grade (Gleason sum ≥7) prostate cancer for men with high total cholesterol concentration (≥200 mg/dl) in the Health Professionals Follow‐up Study (HPFS). With additional 568 prostate cancer cases, we are now able to investigate this association in more detail. For the nested case‐control study, we included 1260 men newly diagnosed with prostate cancer between 1993 and 2004, and 1328 controls. For the meta‐analyses, 23 articles studied the relationship between total cholesterol level and prostate cancer incidence were included. Logistic regression models and dose‐response meta‐analysis were performed. An increased risk of higher‐grade (Gleason sum ≥4 + 3) prostate cancer for high vs low quartile of total cholesterol level was observed in the HPFS (ORmultivariable = 1.56; 95% CI = 1.01‐2.40). This finding was compatible with the association noted in the meta‐analysis of highest vs lowest group of total cholesterol level, which suggested a moderately increased risk of higher‐grade prostate cancer (Pooled RR =1.21; 95%CI: 1.11‐1.32). Moreover, the dose‐response meta‐analysis indicated that an increased risk of higher‐grade prostate cancer occurred primarily at total cholesterol levels ≥200 mg/dl, where the RR was 1.04 (95%CI: 1.01‐1.08) per 20 mg/dl increase in total cholesterol level. However, total cholesterol concentration was not associated with the risk of prostate cancer overall either in the HPFS or in the meta‐analysis. Our primary finding, as well as the result of the meta‐analysis suggested a modest increased risk of higher‐grade prostate cancer, at total cholesterol concentrations exceeding 200 mg/dl. [ABSTRACT FROM AUTHOR]

Prostate cancer (CaP) remains the second leading cause of cancer-related mortality in American men. Systemic treatments for metastatic CaP, which causes the majority of deaths, include androgen deprivation therapy and chemotherapy. These treatments induce remissions but do not cure CaP. Novel and functionally diverse therapeutic targets that control the cell biology that drives aggressive CaP progression are needed to overcome treatment resistance. Because signal transduction that mediates CaP cell behavior is tightly regulated by phosphorylation, kinases have attracted interest as alternative targets for CaP treatments. Here, we examine emerging evidence from recent NextGen sequencing and (phospho) proteomics analyses on clinical CaP specimens that were obtained during lethal disease progression to determine the role of deregulated kinase action in CaP growth, treatment resistance, and recurrence. We provide an overview of kinases that are impacted by gene amplification, gene deletion or somatic mutations during the progression from localized treatment-naïve CaP to metastatic castration-resistant CaP or neuroendocrine CaP, and the potential impact of such alterations on aggressive CaP behavior and treatment efficacy. Furthermore, we review knowledge on alterations in the phosphoproteome that occur during the progression to treatment-resistant CaP, the molecular mechanisms in the control of these changes, and the signal transduction associated with them. Finally, we discuss kinase inhibitors under evaluation in CaP clinical trials and the potential, challenges, and limitations to moving knowledge on the CaP kinome forward to new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Bone metastasis is a principal cause of mortality in patients with prostate cancer (PCa). Increasing evidence indicates that high expression of stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE) significantly activates the calcium (Ca2+) signaling pathway and is involved in multiple steps of bone metastasis in PCa. However, the regulatory mechanism and target therapy of STIM1 is poorly defined. Methods: Liquid chromatography-mass spectrometry analysis was performed to identify tetraspanin 18 (TSPAN18) as a binding protein of STIM1. Co-IP assay was carried out to explore the mechanism by which TSPAN18 inhibits STIM1 degradation. The biological function of TSPAN18 in bone metastasis of PCa was further investigated in vitro and in vivo models. Result: We identified that STIM1 directly interacted with TSPAN18, and TSPAN18 competitively inhibited E3 ligase tripartite motif containing 32 (TRIM32)-mediated STIM1 ubiquitination and degradation, leading to increasing STIM1 protein stability. Furthermore, TSPAN18 significantly stimulated Ca2+ influx in an STIM1-dependent manner, and then markedly accelerated PCa cells migration and invasion in vitro and bone metastasis in vivo. Clinically, overexpression of TSPAN18 was positively associated with STIM1 protein expression, bone metastasis and poor prognosis in PCa. Conclusion: Taken together, this work discovers a novel STIM1 regulative mechanism that TSPAN18 protects STIM1 from TRIM32-mediated ubiquitination, and enhances bone metastasis of PCa by activating the STIM1-Ca2+ signaling axis, suggesting that TSPAN18 may be an attractive therapeutic target for blocking bone metastasis in PCa. [ABSTRACT FROM AUTHOR]

In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma. Editor's summary: Lung and prostate adenocarcinomas can undergo neuroendocrine (NE) transformation, which results in a more aggressive tumor and worst prognosis for patients. Here, Quintanal-Villalonga et al. explored the role of exportin 1 in this NE transformation and saw that it was elevated after inactivation of TP53 and RB1. This increase resulted in an increased sensitivity to an exportin 1 inhibitor, selinexor, which additionally sensitized NE-transformed mouse models to standard chemotherapy. This suggests exportin 1 as a potential therapeutic target to both prevent and treat NE-transformed lung and prostate adenocarcinomas that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that immunotherapy, especially immune checkpoint inhibitors (ICIs), has the potential to facilitate long-term survival in various cancer besides prostate cancer. Emerging evidence indicated that pyroptosis, an immunogenic form of cell death, could trigger an anti-tumor immune microenvironment and enhance the effectiveness of immunotherapy. Nevertheless, the mechanism underlying the regulation of pyroptosis signaling in prostate cancer remains unclear. Methods: The differential expression of human E3 ligases in prostate cancer was integratedly analyzed from five independent public datasets. Moreover, the immunohistochemistry analysis of a tissue microarray derived from prostate cancer patients confirmed the results from the bioinformatic analysis. Furthermore, prostate cancer cell lines were evaluated via the next-generation RNA sequencing to assess transcriptomic profile upon CDC20 depletion. Next, qRT-PCR, Western blotting, cycloheximide assay, immunoprecipitation, and ubiquitination assay were employed to explore the correlation and interaction between CDC20 and GSDME. Both immune-deficient and immune-competent murine models were utilized to examine the anti-tumor efficacy of CDC20 inhibition with or without the anti-PD1 antibodies, respectively. To analyze the immune microenvironment of the xenografts, the tumor tissues were examined by immunohistochemistry and flow cytometry. Results: The analysis of multiple prostate cancer cohorts suggested that CDC20 was the most significantly over-expressed E3 ligase. In addition, CDC20 exerted a negative regulatory effect on the pyroptosis pathway by targeting GSDME for ubiquitination-mediated proteolysis in a degron-dependent manner. Knockdown of CDC20 leads to increased GSDME abundance and a transition from apoptosis to pyroptosis in response to death signals. Furthermore, in our syngeneic murine models, we found that depletion of CDC20 significantly enhances the anti-tumor immunity by promoting the infiltration of CD8+ T lymphocytes dependent on the existence of GSDME, as well as reducing myeloid immune cells. More importantly, Apcin, a small molecular inhibitor that targets CDC20, exhibited synergistic effects with anti-PD1-based immunotherapy in murine models of prostate cancer. Conclusions: Overall, these findings provide new insights into the upstream regulation of GSDME-mediated pyroptosis by CDC20, which specifically interacts with GSDME and facilitates its ubiquitination in a degron-dependent manner. Importantly, our data highlight novel molecular pathways for targeting cellular pyroptosis and enhancing the effectiveness of anti-PD1-based immunotherapy. [ABSTRACT FROM AUTHOR]

According to existing studies, sedentary behavior contributes to male infertility. Both preclinical and clinical studies have investigated the association between physical exercise, semen quality, and pregnancy rates with heterogeneous results. The current review sought to examine the relationship between physical activity (PA) and male infertility, semen characteristics, and pregnancy rates. Pre-clinical studies demonstrated mixed benefits from exercise, with diet being an important consideration. Some forms of PA showed an improvement in pregnancy rates, while others did not consistently improve semen quality. Data also suggests that more intense exercise and certain types of exercise may impair male fertility. Given the limited number of randomized trials, future research is required to examine the relationship between specific forms of exercise and semen parameters along with reproductive outcomes. [ABSTRACT FROM AUTHOR]

Since the beginning of the coronavirus disease 19 (COVID-19) pandemic, efforts in defining risk factors and associations between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinical, and molecular features have initiated. After three years of pandemic, it became evident that men have higher risk of adverse outcomes. Such evidence provided the impetus for defining the biological fundaments of such a gender disparity. Our objective was to analyze the most recent literature with the aim of defining the relationship between COVID-19 and fertility, in particular, we assessed the interplay between SARSCoV-2 and testosterone in a systematic review of literature from December 2019 (first evidence of a novel coronavirus in the Hubei province) until March 2022. As a fundamental basis for understanding, articles pertaining preclinical aspects explaining the gender disparity (n=9) were included. The main review categories analyzed the risk of being infected with SARS-CoV-2 according to testosterone levels (n=5), the impact of serum testosterone on outcomes of COVID-19 (n=23), and the impact SARSCoV-2 on testosterone levels after infection (n=19). Preclinical studies mainly evaluated the relation between angiotensinconverting enzyme 2 (ACE2) and its androgen-mediated regulation, articles exploring the risk of COVID-19 according to testosterone levels were few. Although most publications evaluating the effect of COVID-19 on fertility found low testosterone levels after the infection, follow-up was short, with some also suggesting no alterations during recovery. More conclusive findings were observed in men with low testosterone levels, that were generally at higher risk of experiencing worse outcomes (i.e., admission to intensive care units, longer hospitalization, and death). Interestingly, an inverse relationship was observed in women, where higher levels of testosterone were associated to worse outcomes. Our finding may provide meaningful insights to better patient counselling and individualization of care pathways in men with testosterone levels suggesting hypogonadism. [ABSTRACT FROM AUTHOR]

Background: KLK4::KLKP1 fusion is a recently described pseudogene that is enriched in prostate cancer (PCa). This new biomarker has not been characterized in the Middle Eastern population. Objective: To establish the incidence and prognostic value of KLK4::KLKP1 fusion in a cohort of Middle Eastern men with PCa and explore the relationship of this marker to other relevant biomarkers (PTEN, ERG, SPINK1). Design, setting, and participants: We interrogated a cohort of 340 Middle Eastern men with localized PCa treated by radical prostatectomy between 2005 and 2015. KLK4::KLKP1 fusion status was assessed by RNA Chromogenic in situ hybridization (CISH) and correlated to pathological and clinical parameters. Outcome measurements and statistical analysis: RNA-CISH expression of KLK4::KLKP1 was correlated with prognostic factors, ERG, PTEN, and SPINK1 expression, and biochemical recurrence (BCR) following prostatectomy. Results and limitations: 51.7% of patient samples showed positive KLK4::KLKP1 expression; more commonly in cores of PCa (38%) versus non-cancer (20.6%) (p < 0.0001) and in lower Gleason Grade Group tumors (1–3) vs (4–5). KLK4::KLKP1 expression positively correlated with ERG positivity and inversely associated with PTEN loss. No significant association was found with SPINK1 expression, seminal vesicle invasion, positive surgical margin, pathological stage, or patient age (< 50 or ≥ 50). The association between PTEN loss and BCR increased when combined with KLK4::KLKP1 negativity (HR 2.31, CI 1.03–5.20, p = 0.042). Conclusions: KLK4::KLKP1 expression is more common in this cohort of Middle Eastern men than has been reported in North American men. It is associated with ERG positivity and inversely correlated with PTEN loss. In isolation, KLK4::KLKP1 expression was not significantly associated with clinical outcome or pathological parameters. However, its expression is associated with certain molecular subtypes (ERG-positive, PTEN-intact) and as we demonstrate may help further stratify the risk of recurrence within these groups. [ABSTRACT FROM AUTHOR]

The incidence rate of prostate cancer (PCa) in many Western countries is high, contributing greatly to the cancer disease burden. In most cases, patients progress to metastatic disease defined as castration-resistant prostate cancer after androgen deprivation (mCRPC) following primary treatment where the majority of patients receive first-line new-generation oral hormonal therapies (HT) such as Abiraterone Acetate (AA) and Enzalutamide (ENZ). Despite the importance of correct intake of these drugs, adherence in patients with mCRPC is still poorly investigated and managed with measures not specific to this population. A self-report questionnaire was developed and validated with women with breast cancer treated with oral HT (ABET). Therefore, this study aims to test the psychometric properties of this instrument on patients with mCRPC treated with AA or ENZ. A prospective observational validation study. The questionnaire was completed by all participants and again after 7/10 days by a randomized subsample to assess stability. Sixty-six patients completed the study (mean age of 72.8 years) and 31 completed the re-test (mean age of 72.7 years). Content validity reported excellent results. Cronbach's alpha of each item showed a strong correlation. Validation of an instrument to measure adherence to HT in patients with mCRPC can be a valuable tool for health professionals involved in patient care. In addition, having a population-specific validated instrument allows to make comparisons between results from different observations. [ABSTRACT FROM AUTHOR]

Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with restoration of sensitivity to subsequent AR inhibitor therapies. [ABSTRACT FROM AUTHOR]

Prostate cancer is considered as poorly immunogenic. In a phase I/II study on de novo metastatic prostate cancer we found that a human telomerase reverse transcriptase (hTERT) vaccine induced an early immune response in most of the patients. Here we present the results from the long‐term monitoring of the immune responses and clinical outcomes. Twenty‐two men with ISUP 4 to 5 and lymph node and/or bone metastases were treated with androgen deprivation therapy (ADT), radiotherapy and the hTERT vaccine UV1 between January 2013 and July 2014. Immune response was monitored before, during and after vaccination and continued every 6 months until PSA progression. All patients had magnetic resonance imaging (MRI) at baseline, and after 6 months, 1 and 2 years, and at progression. The clinical outcome was time to progression, overall survival and prostate cancer‐specific survival. The median follow‐up was 62 months (range: 19‐101). At the last observation, nine of the 22 patients were still alive. Six have no progression, two have castration‐resistant disease treated with second‐line ADT and one has castration‐refractory disease. Median time to PSA progression was 21 months, median overall survival was 62 months and median prostate cancer‐specific survival was 84 months. Lack of immune response was an independent marker of prostate cancer death. The long‐term monitoring showed that some patients had unanticipated subsequent high immune responses without developing recurrence. This association indicates that there might be a clinical benefit of hTERT vaccination in a subgroup of men with primary metastatic hormone‐sensitive prostate cancer treated with ADT and radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Thyroid cancer is the most common endocrine malignancy and occurs three times more frequently in women than in men. Further, androgen receptor expression is decreased in thyroid cancer cells. These observations suggest that male hormones may play a role in the prevention of thyroid cancer. We show that androgen stimulation of the androgen receptor inhibits the growth of thyroid cancer cells by inducing a state of senescence, in which cells are not killed, but are unable to multiply. Further work will investigate the ability to use androgens to treat thyroid cancer cells, as well as the possibility of treating and eliminating senescent cells using specific drugs. Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated β-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is a major cause of cancer morbidity and mortality for men globally, and androgen signaling clearly drives its onset and progression. Androgen receptor (AR) regulation is complex and remains elusive, despite several studies tackling these issues. Therefore, elucidating the mechanism(s) underlying AR regulation is a potentially promising approach to suppressing PCa. Methods: We report that Par14, one isoform of the prolyl isomerases homologous to Pin1, is a critical regulator of AR transcriptional activity and is essential for PCa cell growth. Results: Par14 was shown to be overexpressed in PCa, based on analyses of deposited data. Importantly, overexpression of Par14 significantly enhanced androgen‐sensitive LNCap cell growth. In contrast, silencing of Par14 dramatically decreased cell growth in LNCap cells by causing cell cycle arrest. Mechanistically, silencing of the Par14 gene dramatically induced cyclin‐dependent kinase inhibitor p21 at both the mRNA and the protein level through modulating the localization of p53. In addition, suppression of Par14 in LNCap cells was shown to downregulate the expressions of androgen response genes, at both the mRNA and the protein level, induced by dihydrotestosterone. Par14 was shown to directly associate with AR in nuclei via its DNA‐binding domain and augment AR transcriptional activity. Conclusion: Thus, Par14 plays a critical role in PCa progression, and its enhancing effects on AR signaling are likely to be involved in the underlying molecular mechanisms. These findings suggest Par14 to be a promising therapeutic target for PCa. [ABSTRACT FROM AUTHOR]

To investigate the prevalence and cause of early discontinuation (DC) of androgen receptor inhibitor (ARi) in advanced prostate cancer (PCa) patients. Additionally, to study the effect of changing ARi vs dose reduction on duration of treatment (DOT). A retrospective cohort study of 333 patients with advanced PCa who started ARi between 2016 and 2020 was performed. ARi medication, treatment duration, reason for DC, stage of PCa, prostate specific antigen, Gleason score, and prior PCa treatments were collected. The cohort was divided into 2 subgroups, patients that stayed on one medication (Group A) vs patients who changed ARi medication (Group B). Student's t test, chi-square test, and Kaplan-Meier survival analysis were performed. At 1 year 28.8% of patient's had discontinued ARi. Reasons for DC were side effects (34.4%), death (34.4%), and cancer progression (18.8%). DOT was 13 months for enzalutamide, 13.7 months for abiraterone, 7.6 months for darolutamide, and 12.1 months for apalutamide. Average DOT for patients with a dose change was 13.4 months, similar to those without dose change at 13.9 months (P =.630). DOT was 12.7 months in Group A vs 19.8 months in Group B (P =.001). In our study population DC of ARi is higher than reported in the published trials. Providing patients with an alternative ARi is associated with an increase in DOT while dose reduction is not. It is important for clinicians to understand the causes of early DC to develop strategies to maximize duration of therapy for management of advanced PCa patients. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa. Methods and findings: Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10−8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N = 201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI), and testosterone). Applying two-sample MR using the inverse-variance weighted approach provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10−3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 95% CI = 0.86 to 0.95, P = 5.50 × 10−5) and circulating plasma levels of PCSK9 (OR = 0.93 per SD reduction in PCSK9 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = −0.08, 95% CI = −0.12 to −0.05, P = 1.00 × 10−5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging. Conclusions: Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a). Si Fang and colleagues use drug target Mendelian randomization to examine the association between lipid lowering drug targets and the risk of prostate cancer. Author summary: Why was this study done?: Prostate cancer is the second most diagnosed malignancy in men globally. Previous studies have provided conflicting evidence regarding a relationship between elevated low-density lipoprotein (LDL) cholesterol and prostate cancer risk. The aim of this study was to examine the association between genetically proxied inhibition of lipid-lowering drug targets (i.e., PCSK9, NPC1L1, HMGCR) and prostate cancer using evidence from multiple datasets and analytical methods. What did the researchers do and find?: Using genetic variants associated with LDL cholesterol, liver-derived gene expression, and plasma protein levels, the researchers applied drug target Mendelian randomisation (MR) and colocalization to examine the association between lipid-lowering drug targets and the risk of overall, early-onset, and advanced prostate cancer. Additional MR analyses were conducted to explore putative mediators of drug effects. This study provided evidence of an association between genetically proxied PCSK9 inhibition and lower risk of overall and early-onset prostate cancer supported by both MR and colocalization approaches. Follow-up analyses of genetically proxied PCSK9 inhibition highlighted a potential mediatory role for Lp(a) along the causal pathway to lower prostate cancer risk. What do these findings mean?: PCSK9 inhibition may be involved in biological mechanisms that reduce the risk of overall and early-onset prostate cancer, potentially through the regulation of Lp(a). However, functional validation is necessary to confirm these findings, as well as future research to further evaluate the relationship between lipid-lowering drug targets and advanced prostate cancer risk. [ABSTRACT FROM AUTHOR]

Objective: Congenital defects of androgen synthesis or action in 46,XY individuals can result in impaired virilisation, despite the apparent testicular development. In a recent case, report of a young adult with complete androgen insensitivity syndrome (CAIS), tumourous gonadal tissue was shown to express HSD17B3 in Sertoli cells (SCs) and not in Leydig cells (LCs). This expression pattern differs from the typical adult human testis and resembles a foetal mouse testis, suggesting an underlying testicular development and function defect. Here, we investigate the effect of altered androgen signalling in gonads from five 46,XY individuals with defects in androgen synthesis or action. Methods: Gonadal tissue sections from four patients with CAIS, one with CYP17A1 deficiency, and one control were immunostained for LC developmental and steroidogenic markers. The expression of some of these markers during development was investigated by reanalysing previously published single-cell RNA sequencing (scRNA-seq) data from normal human testicular tissues. Results: All gonadal tissues from the patients show an exclusive expression of HSD17B3 in SCs and an expression of the foetal/immature LC marker DLK1 in a subset of LCs, suggesting an androgen-dependent differentiation defect of adult SCs and LCs. Furthermore, reanalysis of scRNA-seq data reveals an expression of HSD17B3 in foetal and neonatal SCs that is downregulated in adult SCs. Conclusions: Androgen signalling may affect the differentiation of adults, but possibly not foetal SCs or LCs, and may induce a shift of testosterone production from the tubular compartment in the foetal phase to the interstitial compartment in the adult phase. [ABSTRACT FROM AUTHOR]

Prostate cancer is a common form of cancer in men, and androgen-deprivation therapy (ADT) is often used as a first-line treatment. However, some patients develop resistance to ADT, and their disease is called castration-resistant prostate cancer (CRPC). Identifying potential therapeutic targets for this aggressive subtype of prostate cancer is crucial. In this study, we show that statins can selectively inhibit the growth of these CRPC tumors that have lost their androgen receptor (AR) and have overexpressed the RNA-binding protein QKI. We found that the repression of microRNA-200 by QKI overexpression promotes the rise of AR-low mesenchymal-like CRPC cells. Using in silico drug/gene perturbation combined screening, we discovered that QKI-overexpressing cancer cells are selectively vulnerable to CDC42-PAK7 inhibition by statins. We also confirmed that PAK7 overexpression is present in prostate cancer that coexists with hyperlipidemia. Our results demonstrate a previously unseen mechanism of action for statins in these QKI-expressing AR-lost CRPCs. This may explain the clinical benefits of the drug and support the development of a biology-driven drug-repurposing clinical trial. This is an important finding that could help improve treatment options for patients with this aggressive form of prostate cancer. [ABSTRACT FROM AUTHOR]

Introduction: AKR1C3, as a crucial androgenic enzyme, implicates the androgen biosynthesis and promoting prostate cancer cell growth in vitro. This study provides a new gene therapy strategy for targeting AKR1C3 to treat castration-resistant prostate cancer. Methods: siAKR1C3@PPA is assembled from PEG3500, PAMAM, Aptamer-PSMA, and siRNA for AKR1C3. We analyzed the relationship between AKR1C3 expression and the survival rate of prostate cancer patients based on the GEPIA online database to perform disease-free survival, and found that AKR1C3 may be an important factor leading to poor prognosis in prostate cancer. Considering AKR1C3 as a therapeutic target for castration-resistant prostate cancer, we constructed a complex nucleic acid nanoparticle, siAKR1C3@PPA to investigate the inhibitory effect on castration-resistant prostate cancer. Results: Aptamer-PSMA acts as a target to guide siAKR1C3@PPA into PSMApositive prostate cancer cells and specifically down regulate AKR1C3. Cyclin D1 was decreased as a result of siAKR1C3@PPA treatment. Changes in Cyclin D1 were consistent with decreased expression of AKR1C3 in LNCaP-AKR1C3 cells and 22RV1 cells. Furthermore, in the LNCaP-AKR1C3 group, 1070 proteins were upregulated and 1015 proteins were downregulated compared to the LNCaP group according to quantitative 4D label-free proteomics. We found 42 proteins involved in cell cycle regulation. In a validated experiment, we demonstrated that PCNP and CINP were up-regulated, and TERF2 and TP53 were down-regulated by western blotting. Conclusion: We concluded that siAKR1C3@PPA may arrest the cell cycle and affect cell proliferation. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema (HAE) leads to significant morbidity and mortality from unpredictable intermittent peripheral, abdominal and laryngeal swelling. Access to appropriate healthcare and effective therapies, which can prevent and treat attacks, reduce the suffering and greatly improve quality of life. Although treatments such as C1 inhibitor (Berinert), and Icatibant are available in New Zealand (Aotearoa), there are no published data available on their use. Aim: To present a national audit of HAE and acquired angioedema (AAE) in 2019. Methods: Patients were identfied and demographical and clinical data on HAE were collected retrospectively by interview and notes review. Results: The total number of known adult (48) and children (3) HAE and AAE (3) patients is 54. Of these, 41/54 (75%) of HAE and AAE patients were recruited to the audit. Icatibant has been available for the treatment of acute HAE attacks since 2016, and is now used in 73% of HAE patients. Icatibant is also used by patients for laryngeal attacks in the community, who may not then present to hospital. Androgens are used in half of the patients as prophylaxis, but 33% of the latter were identified as not having regular liver ultrasound screening. Tranexamic acid is used as prophylaxis in one-fifth of patients. Participants have had 40 children, half of whom may be affected. Three have been diagnosed with HAE, suggesting that the majority have not yet been tested. Conclusions: Corrective actions arising from this audit will improve our capacity to provide long-term care for HAE patients and their families. [ABSTRACT FROM AUTHOR]

Objective: The aim of the meta-analysis was to explore effects of resistance exercise (RE) on body composition and physical function in patients with prostate cancer (PCa).Data Sources: We searched the electronic databases of Pubmed, Embase, Cochrane, and web of science. Published studies have been collected from these databases. Search terms include resistance training, strength training, RE, androgen suppression therapy, androgen deprivation therapy and PCa, with a deadline of 31 March 2022.Main Results: These studies showed significant improvements of body composition(Lean body mass MD: 1.12 95% CI [0.48, 1.76], p < 0.01; Body fat rate MD: -1.12 95% CI [-1.99,-0.24], p < 0.05; Appendicular skeletal mass MD: 0.74 95% CI [0.45, 1.03], p < 0.01) and physical function (leg press MD: 77.95 95% CI [38.90, 117.00], p < 0.01; stair climb MD:-0.30 95% CI [-0.49, -0.12], p < 0.01). In addition, the improvement of Body fat mass (MD: -0.21 95% CI [-0.79, 0.37], p > 0.05), 400 m walk (MD: -21.74 95% CI [-45.53, 2.05], p > 0.05) and times up and go (MD: -0.50 95% CI [-1.03, 0.03], p > 0.05) were not obvious. Subgroup analyses showed that RE for ≥ 6 months (compared with RE intervention for < 6 months) and starting exercise immediately after androgen deprivation therapy (ADT) (compared with delayed exercise after ADT) resulted in more significant improvements in body composition. Furthermore, the results showed that the exercise intensity of 8-12 RM significantly improved body composition.Conclusions: RE seems to be a promising approach in order to improve body composition and physical function in PCa patients to offset their treatment-related side effects. RE should be used as a means of rehabilitation and care for PCa. Starting exercise immediately after ADT and extending exercise time while choosing the right intensity can better improve the patients' body composition and function.Registration Number: INPLASY202280019. [ABSTRACT FROM AUTHOR]

Objective(s): Patients with poor ovarian response who have reduced ovarian reserve sometimes despite the maximum dose of gonadotropins do not respond properly. Androgens have been shown to play an important role in the early follicular development and proliferation of granulosa cells. This study aimed to evaluate the effect of androgen administration on IVF outcome in poor responders.Study Design: In this randomized clinical trial, 60 poor responder women candidate for controlled ovarian stimulation were randomly enrolled in two groups (n = 30/each). In the intervention group testosterone gel added to the interrupted microdose flare protocol. The control group received the conventional microdose flare protocol.Results: The main outcome was clinical and chemical pregnancy; and the second outcomes were the number of mature oocytes, duration of cycle and total dose of gonadotropins. Basic clinical and demographic features were comparable between the groups. The total gonadotropin consumption were significantly higher in the control group than the intervention group (p = 0.047). In addition, the number of MII oocytes was higher (but not significant) in the intervention group than the control group (p = 0.16). The mean total duration of the cycle was equal in both groups. There were no significant differences in chemical and clinical pregnancy rates between the two groups (p = 0.41, p = 0.67).Conclusion(s): The results of the current study showed that androgen administration in poor responders in in vitro fertilization reduces the total dose of gonadotropin, but it does not improve the pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Objective: Follicle-stimulating hormone (FSH) level changes may be another reason for increasing the risk of cardiovascular disease. In this study, we aimed to investigate the role of FSH in atherosclerosis and its underlying mechanism. Methods: ApoE−/− mice were divided into 4 groups, namely, the sham group, bilaterally orchidectomized group, FSH group, and testosterone-only group. Blood lipid and hormone levels were tested, aorta Oil Red O staining; the levels of NF-κB, Akt, eNOS, and FSH receptors in the aorta were measured by Western blotting. Expression of VCAM-1 was detected via Western blotting and immunohistochemical staining. Human umbilical vein endothelial cells (HUVECs) were used to induce endothelial injury model by adding FSH, and the levels of NF-κB, Akt, eNOS, and FSHR were tested in HUVECs. Results: FSH treatment exacerbated atherosclerotic lesions in ApoE−/− mice. Moreover, FSH could promote the expression of VCAM-1 protein in HUVECs, and this effect was possibly mediated by the activation of NF-κB, while NF-κB activation was further enhanced by the activation of the PI3K/Akt/eNOS pathway. FSH failed to activate Akt and NF-κB in the presence of the PI3K inhibitor LY294002 in HUVECs. Conclusion: FSH promoted the development of atherosclerosis by increasing VCAM-1 protein expression via activating PI3K/Akt/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common malignancy in men of middle and older age. The standard treatment strategy for PCa ranges from active surveillance in low-grade, localized PCa to radical prostatectomy, external beam radiation therapy, hormonal treatment and chemotherapy. Recently, the use of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) for metastatic castration-resistant PCa has been approved. PSMA is predominantly, but not exclusively, expressed on PCa cells. Because of its high expression in PCa, PSMA is a promising target for diagnostics and therapy. To understand the currently used RLT, knowledge about pharmacokinetics (PK) and pharmacodynamics (PD) of the PSMA ligand and the PSMA protein itself is crucial. PK and PD properties of the ligand and its target determine the duration and extent of the effect. Knowledge on the concentration–time profile, the target affinity and target abundance may help to predict the effect of RLT. Increased specific binding of radioligands to PSMA on PCa cells may be associated with better treatment response, where nonspecific binding may increase the risk of toxicity in healthy organs. Optimization of the radioligand, as well as synergistic effects of concomitant agents and an improved dosing strategy, may lead to more individualized treatment and better overall survival. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the leading causes of death among men worldwide; Some data suggest that ribosomal S6 p90 kinase (RSK 1-4), which belongs to the group of highly conserved Ser/Thr kinases, has been related to an increase in prostate cancer levels. For this reason, the aim of this study was to evaluate the theoretical interaction of some quinolone derivatives (compounds 1-19) with RSK-4 using 6rv2 protein and RSK-14 inhibitor (LJH685) in a docking model. The results showed that some quinolone derivatives (12, 15, 17, and 18) could interact with the 6rv2 protein surface in a different manner than LJH685. This phenomenon could be translated as greater RSK-14 inhibition, resulting in a decrease in prostate cancer levels. Analyzing these data, these quinolone derivatives could be considered good compounds to treat prostate cancer. [ABSTRACT FROM AUTHOR]

Descriptive data on late effects associated with castrate-resistant prostate cancer (CRPC) are sparse. We aimed to define the timing and incidence of cardiovascular disease (CVD), fractures, and diabetes in a patient population with CRPC. In the population-based STHLM0 cohort 1464 men with CRPC were identified and matched with three men free from prostate cancer (PC) in the Stockholm region of Sweden. Kaplan–Meier estimates of net survival were used to describe time to CVD, fracture, and diabetes. Cox regression was used to compare incidence rates (IRRs) for the respective late effects. Cumulative incidence analyses of late effects in the presence of the competing risk of death were performed to estimate absolute risks. The Kaplan Meier estimates demonstrated a higher net probability for CVD, fracture, and diabetes among men diagnosed with CRPC compared to the matched comparators. The IRRs were 1.94 (95% CI: 1.79–2.12) for CVD, 2.08 (95% CI: 1.70–2.53) for fracture, and 2.00 (95% CI: 1.31–3.05) for diabetes, respectively, comparing men diagnosed with CRPC to men free from PC. The cumulative incidence of CVD at 12 months of follow-up was higher in men diagnosed with CRPC compared to healthy controls regardless of age with a difference in cumulative incidence being 0.20 for men aged <65 and 0.11 for men aged >84. In this cohort, the incidence of CVD was significantly higher among men with CRPC compared to healthy controls. Despite having this end-stage disease this finding proves that clinicians must recognize this late effect in men diagnosed with CRPC to improve preventive actions. These men did not have a higher absolute risk of fractures and diabetes after accounting for deaths due to any cause compared to healthy controls. [ABSTRACT FROM AUTHOR]

Spindle and kinetochore-associated complex subunit 3 (SKA3) is a microtubule-binding subcomplex of the outer kinetochore that is required for proper chromosomal segregation and cell division. However, little is known regarding the probable mechanism of SKA3, particularly in terms of prostate cancer (PCA) progression. Multiple databases, including TCGA and GTEx, were utilized to examine the expression of SKA3 in PCA patients and to shed light on the clinical significance and potential mechanism of SKA3 in the onset and progression of PCA. The biological function of SKA3 was evaluated in vitro using RT–qPCR and the CCK8 assay. For statistical analysis, the R 3.6.3 software and its associated packages were utilized. SKA3 was shown to be considerably elevated in PCA patients and was linked to a shorter progress free interval (PFI). Furthermore, we discovered that SKA3 mRNA expression was higher in PCA cells than in normal cells, and inhibition of SKA3 could clearly reduce PCA cell proliferation using the CCK8 assay. Finally, SKA3 could be used as a predictive biomarker in PCA patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ascertainment of fetal sex is important in the equine industry for economic reasons. As a result, various methods have been developed for the sex determination of a fetus in a horse; however, the current techniques have some limitations. Recently, evaluation of maternal testosterone concentration has been suggested as an easy and inexpensive method for diagnosing fetal sex, but the findings are discrepant in different species. OBJECTIVES: The aim of the present study was to measure the concentration of circulating testosterone in mares carrying male and female fetuses in order to assess the diagnostic value of maternal testosterone concentration for sex determination of equine fetus. METHODS: Blood samples were collected from mares (n=20) at months three, six, and nine of pregnancy. The samples were centrifuged and stored at -20°C until hormonal analysis of testosterone concentration using an ELIZA kit. The gender of foals was determined at birth based on observation of external genitalia. RESULTS: Neither testosterone concentration in the third, sixth and ninth months of pregnancy nor the cumulative concentration of testosterone differ between mares with male and female fetuses (P>0.05). However, testosterone concentration changed during pregnancy in all mares regardless of the gender of their fetus, and it was higher at month six than at months three and nine (P<0.0001). CONCLUSIONS: In conclusion, the present study showed that maternal testosterone concentration could not be used for the sex determination of a fetus in a horse. Yet the current study revealed testosterone concentration dynamics over various gestation stages in mares. [ABSTRACT FROM AUTHOR]

Alanine-serine-cysteine transporter 2 (ASCT2) has been associated with increased levels of metabolism in various malignant tumors. However, its biological significance in the proliferation of prostate cancer (PCa) cells remains under investigation. We used the cBioPortal database to assess the effect of ASCT2 expression on the oncological outcomes of 108 PCa patients. To evaluate the function of ASCT2 in castration-sensitive PCa (CSPC) and castration-resistant PCa (CRPC), LNCaP cells and the ARV7-positive PCa cell line, 22Rv1, were assessed using cell proliferation assays and Western blot analyses. The ASCT2 expression level was associated with biochemical recurrence-free survival after prostatectomy in patients with a Gleason score ≥ 7. In vitro experiments indicated that the growth of LNCaP cells after combination therapy of ASCT2 siRNA and enzalutamide treatment was significantly reduced, compared to that following treatment with enzalutamide alone or ASCT2 siRNA transfection alone (p < 0.01, 0.01, respectively). After ASCT2 inhibition by siRNA transfection, the growth of 22Rv1 cells was significantly suppressed as compared with negative control siRNA via downregulation of ARV7 both in fetal bovine serum and androgen-deprivation conditions (p < 0.01, 0.01, respectively). We demonstrated that ASCT2 inhibition significantly reduced the proliferation rates of both CSPC and CRPC cells in vitro. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most frequently diagnosed cancers in men. The medical treatment of metastatic prostate cancer relies heavily on androgen deprivation. The present study aimed to explore the inhibitory effect of anlotinib on androgen receptor (AR)-negative prostate cancer cell lines in vitro and investigate its mechanism of action. Two prostate cancer cell lines, DU145 and PC-3, were treated with different concentrations (0-80 µM) of anlotinib. Cell proliferation was accessed by CCK-8 assay and EdU staining. Cell nuclear morphology was observed after DAPI staining, cell apoptosis level was evaluated by Annexin-V-FITC/PI staining, and western blot was used to detect the proliferation- and apoptosis-related proteins. The potential interaction between anlotinib and AKT was revealed by molecular docking. After treatment with anlotinib, the cell proliferation rate was significantly inhibited in a dose-dependent manner. The DAPI staining showed that anlotinib could induce apoptosis. Further, Annexin V/PI double staining confirmed the occurrence of apoptosis, accompanied by the increase of cleaved caspase-3 and activated PARP. Moreover, anlotinib significantly decreased the phosphorylation of protein kinase B (AKT) and its downstream pathway proteins in prostate cells (p<0.05). Experiments further confirmed that the activation of the AKT pathway reversed the inhibitory effect of anlotinib on DU145 and PC-3 cell proliferation. In addition, molecular docking analysis revealed potential interactions between anlotinib and AKT1 at multiple sites. Overall, the present study suggested that anlotinib could inhibit the proliferation and induce apoptosis in the AR-negative prostate cancer cell lines, possibly via the inactivation of the AKT pathway. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the biological function and molecular mechanism of ARPC1A (actin related protein 2/3 complex subunit 1A) in prostate cancer progression. RT–qPCR and IHC results showed that the level of ARPC1A in prostate cancer tissues was significantly higher than that in adjacent tissues. The results of TCGA (the cancer genome atlas) database analysis showed that high expression of ARPC1A indicates poor prognosis in prostate cancer patients. In vitro functional experiments confirmed that downregulation of ARPC1A expression resulted in decreased cell viability and invasive ability of prostate cancer cells, as ARPC1A knockdown promoted ferroptosis. The transcriptional regulation mechanism of STAT3 (signal transduction and activators of transcription 3) on ARPC1A was elucidated by Co-IP, ChIP and luciferase reporter assays. In vivo experiments also supported the in vitro results. We propose that reduced ARPC1A expression inhibits prostate cancer cell viability and invasion in a ferroptotic manner. The ARPC1A level may serve as an independent predictor of prognosis in prostate cancer patients. [ABSTRACT FROM AUTHOR]

Background STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival. Methods Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression). Results Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P  = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P  = .002) and PFS (nonproportional P  = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P  = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P  = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity. Conclusions There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the most common malignant tumors in men. Initially, it is androgen-dependent, but it eventually develops into castration-resistant prostate cancer (CRPC), which is incurable with current androgen receptor signaling target therapy and chemotherapy. Immunotherapy, specifically with immune checkpoint inhibitors, has brought hope for the treatment of this type of prostate cancer. Approaches such as vaccines, adoptive chimeric antigen receptor-T (CAR-T) cells, and immune checkpoint inhibitors have been employed to activate innate and adaptive immune responses to treat prostate cancer, but with limited success. Only Sipuleucel-T and the immune checkpoint inhibitor pembrolizumab are approved by the US FDA for the treatment of limited prostate cancer patients. Prostate cancer has a complex tumor microenvironment (TME) in which various immunosuppressive molecules and mechanisms coexist and interact. Additionally, prostate cancer is considered a "cold" tumor with low levels of tumor mutational burden, low amounts of antigen-presenting and cytotoxic T-cell activation, and high levels of immunosuppressive molecules including cytokines/chemokines. Thus, understanding the mechanisms of immunosuppressive signaling activation and immune evasion will help develop more effective treatments for prostate cancer. The purpose of this review is to summarize emerging advances in prostate cancer immunotherapy, with a particular focus on the molecular mechanisms that lead to immune evasion in prostate cancer. At the same time, we also highlight some potential therapeutic targets to provide a theoretical basis for the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: As local recurrence remains a challenge and the advantages of the simultaneous integrated boost (SIB) technique have been validated in photon radiotherapy, we applied the SIB technique to CIRT. The aim was to investigate the metabolomic changes of the CIRT with concurrent androgen deprivation therapy (ADT) in localized prostate cancer (PCa) and the unique metabolic effect of the SIB technique. Material and methods: This study enrolled 24 pathologically confirmed PCa patients. All patients went through CIRT with concurrent ADT. The gross target volume (GTV) boost was defined as positive lesions on both 68Ga-PSMA PET/CT and mpMRI images. Urine samples collected before and after CIRT were analyzed by the Q-TOF UPLC-MS/MS system. R platform and MetDNA were used for peak detection and identification. Statistical analysis and metabolic pathway analysis were performed on Metaboanalyst. Results: The metabolite profiles were significantly altered after CIRT. The most significantly altered metabolic pathway is PSMA participated alanine, aspartate and glutamate metabolism. Metabolites in this pathway showed a trend to be better suppressed in the SIB group. A total of 11 identified metabolites were significantly discriminative between two groups and all of them were better down-regulated in the SIB group. Meanwhile, among these metabolites, three metabolites in DNA damage and repair related purine metabolism were down-regulated to a greater extent in the SIB group. Conclusion: Metabolic dysfunction was one of the typical characteristics of PCa. CIRT with ADT showed a powerful inhibition of PCa metabolism, especially in PSMA participated metabolic pathway. The SIB CIRT showed even better performance on down-regulation of most metabolism than uniform-dose-distribution CIRT. Meanwhile, the SIB CIRT also showed its unique superiority to inhibit purine metabolism. PSMA PET/CT guided SIB CIRT showed its potentials to further benefit PCa patients. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study is to evaluate the efficacy of dienogest versus levonorgestrel-releasing intrauterine system (LNG-IUS) for the treatment of adenomyosis. Methods. In this retrospective study, 85 patients with adenomyosis treated in The First Affiliated Hospital of Zhengzhou University from May 2019 to May 2021 were recruited and assigned, via the random number table method at a ratio of 1 : 1, to receive either dienogest (observation group, n = 41) or LNG-IUS (control group, n = 44). The patients presented with dysmenorrhea, menorrhagia, and infertility. The treatment outcome was evaluated using visual analogue scale (VAS) scores, menstrual volume, uterine volume, endometrial thickness, and adverse reactions. Results. After treatment, the VAS score, menstrual volume, and endometrial thickness were significantly decreased in both groups (P < 0.05). After 3, 6, and 12 months of treatment, patients receiving dienogest showed significantly lower VAS scores compared to those treated with LNG-IUS (P < 0.05). After 6 and 12 months of treatment, patients receiving dienogest were also found to have a significantly better control of menstrual volume compared to those receiving LNG-IUS (P < 0.05). Irregular vaginal bleeding was mainly seen in the first 3 months of treatment with dienogest. The incidence of irregular vaginal bleeding lasting more than 6 months was lower with LNG-IUS treatment than with dienogest (P < 0.05), and it decreased in both groups as the duration of treatment increased. Conclusion. Dienogest effectively alleviates dysmenorrhea, relieves pelvic pain, dyspareunia, and reduces menstrual flow in patients with adenomyosis, with few adverse effects and a high safety profile. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is one of the most common malignant tumors in the male urinary system. In recent years, the morbidity and mortality of PCa have been increasing due to the limited effects of existing treatment strategies. Long non-coding RNA (lncRNA) LINC00893 was reported to inhibit the proliferation and metastasis of papillary thyroid cancer cells, but its role in PCa has not been reported. This study aims to investigate the role and underlying mechanism of LINC00893 in regulating the progression of PCa cells. Methods: We first compared LINC00893 expression levels between PCa tissues and normal prostate tissues through TCGA database. The relative LINC00893 expression levels were further validated in 66 pairs of PCa tissues and para-cancerous normal tissues, as well as in PCa cell lines. Gain-of-function experiment was performed by transfecting PCa cell with LINC00893 expression vector, and CCK (Cell count kit)-8, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, colony information and transwell assays were conducted to assess the functional phenotypes. Dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP) and RNA pull-down assays were performed to evaluate the molecular interactions. Results: LINC00893 was downregulated in PCa tissues and cell lines, and patients with low expression of LINC00893 were associated with a poorer overall survival rate. LINC00893 overexpression hindered the proliferation, epithelial-mesenchymal transition (EMT) as well as the migratory ability of PCa cells, and suppressed the tumorigenesis of PCa cells in nude mice. We further demonstrated that LINC00893 acted as a sponge for miR-3173-5p and inhibited its activity, which in turn regulated the suppressor of cytokine signaling 3 (SOCS3)/Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. Conclusions: Our study demonstrated that LINC00893 suppresses the progression of PCa cells through targeting miR-3173-5p/SOCS3/JAK2/STAT3 axis. Our data uncovers a novel tumor-suppressor role of LINC00893 in PCa, which may serve as a potential strategy for targeted therapy in PCa. [ABSTRACT FROM AUTHOR]

Objective: Androgen deprivation therapy (ADT) is still the principal treatment option for prostate cancer (PCa). In addition to reactivation of androgen receptor signaling, the resistance of PCa to apoptosis during ADT also contributes to castration resistant PCa (CRPC). A previous study reported that gene transfer of IL-13Ra2 into PCa cells sensitized the cells to the IL-13R-targeted cytotoxin IL13Ra1, leading to apoptosis. Compared with IL-13Rα2, IL13Rα1 is more constitutively expressed in PCa cells, but its function in PCa remains to be established. Methods: We determined the role and expression of IL13Rα1 in PCa cancer cells using western blotting, flow cytometry, and cell proliferation assays. Co-immunoprecipitation and mass spectrometry were used to identify the proteins that interacted with IL13Rα1, to elucidate its function. Results: In this study, we showed that IL13Rα1 was selectively suppressed in androgen-deprived PCa cells and that its suppression tended to be associated with poor prognoses of PCa patients. IL13Rα1 overexpression promoted apoptosis and inhibited tumor growth under androgen-deprived or castrated conditions (P < 0.01). Mechanistically, IL13Rα1 recruited and facilitated ubiquitin protein ligase E3C-mediated ubiquitination and degradation of hexokinase 2 (HK2), resulting in glycolytic inhibition and eventually leading to PCa cell apoptosis. Furthermore, our data revealed that mutated ataxia-telangiectasia kinase phosphorylated and facilitated the selective ubiquitin proteasome-mediated degradation of HK2. Notably, IL13Rα1-overexpressing PCa cells were more susceptible to apoptosis and exhibited reduced tumor growth after exposure to the HK2 inhibitor, 2-deoxy-D-glucose (P < 0.01). Conclusions: Our data identified a tumor suppressor role for IL13Rα1 in preventing the resistance of PCa cells to apoptosis during androgen deprivation by inhibiting glycolysis. IL13Rα1-mediated signaling involving HK2 may therefore provide a novel treatment target and strategy for CRPC. [ABSTRACT FROM AUTHOR]

Background: One of the most malignant tumors in men is prostate cancer that is still incurable due to its heterogenous and progressive natures. Genetic and epigenetic changes play significant roles in its development. The RNA molecules with more than 200 nucleotides in length are known as lncRNAs and these epigenetic factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional and epigenetic levels. LncRNAs play vital biological functions in cells and in pathological events, hence their expression undergoes dysregulation. Aim of review: The role of epigenetic alterations in prostate cancer development are emphasized here. Therefore, lncRNAs were chosen for this purpose and their expression level and interaction with other signaling networks in prostate cancer progression were examined. Key scientific concepts of review: The aberrant expression of lncRNAs in prostate cancer has been well-documented and progression rate of tumor cells are regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt and PTEN, among other molecular pathways. Furthermore, lncRNAs regulate radio-resistance and chemo-resistance features of prostate tumor cells. Overexpression of tumor-promoting lncRNAs such as HOXD-AS1 and CCAT1 can result in drug resistance. Besides, lncRNAs can induce immune evasion of prostate cancer via upregulating PD-1. Pharmacological compounds such as quercetin and curcumin have been applied for targeting lncRNAs. Furthermore, siRNA tool can reduce expression of lncRNAs thereby suppressing prostate cancer progression. Prognosis and diagnosis of prostate tumor at clinical course can be evaluated by lncRNAs. The expression level of exosomal lncRNAs such as lncRNA-p21 can be investigated in serum of prostate cancer patients as a reliable biomarker. [ABSTRACT FROM AUTHOR]

Phosphodiesterase-5 inhibitors (PDE5Is) represent a group of drugs that are registered for the treatment of erectile dysfunctions predominantly, but recently also for treatment of pulmonary hypertension and benign prostatic hypertrophy. However, more and more research deals with possible antitumor potential of PDE5Is in different types of cancers, including prostate cancer. Prostate cancer represents the one of the most common carcinoma in the male population, whose incidence is continuously increasing. Early detection combined with radical prostatectomy increases the survival rate, but also it is necessary to keep in mind the quality of life of patients undergoing prostatectomy in light of bladder control and erectile function. Authors of various clinical studies presented the results that often lead to totally opposing conclusions. For example, Chavez and colleagues have shown that use of PDE5Is in men with erectile dysfunction decreases the risk of developing prostate cancer, while, on the other hand, Michl and colleagues pointed out the adversely effect of PDE5Is on biochemical recurrence after bilateral nerve sparing radical prostatectomy. In that sense, the aim of this review was to present as many as possible of existing results dealing with of action of PDE5Is in the field of prostatic carcinoma. Taking into account all presented data, it can be concluded that eff ect of PDE5Is on formation, development and outcome of treatment in patients with prostate carcinoma is very intriguing question, whose response requires additional both experimental and clinical research. [ABSTRACT FROM AUTHOR]

Background: To evaluate the effects of a combined oral contraceptive containing 1.5 mg 17b-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) or 2 mg/daily dienogest (DNG) oral progestin on endometriosis-associated chronic pelvic pain (CPP) and on the quality of life (QoL) and sexual function, by a randomized study design.Methods: The E2/NOMAC group and DNG group included 99 and 98 women, respectively. The levels of CPP were measured by the visual analogic scale (VAS). The QoL scores were investigated by the Short Form-36 questionnaire (SF-36). Finally, sexual function was studied using the Female Sexual Function Index (FSFI), while sexual distress was studied by the Female Sexual Distress Scale (FSDS). The study had 3, 6 and 12-month follow-ups.Results: The intra-group analysis showed an improvement of the VAS score from baseline to the 12-month follow-up in the women of both groups (p < 0.001). The inter-group comparison showed a similar improvement of CPP (p = 0.06). Women on DNG had better SF-36 somatic (p < 0.01) and FSFI scores (p < 0.006) than women on E2/NOMAC at the 6- and 12-month follow-ups.Conclusions: The results support the efficacy of both hormonal treatments, even if DNG was more effective than E2/NOMAC in a limited intergroup comparison. [ABSTRACT FROM AUTHOR]

Infertility, which is defined as the inability to conceive despite one year of unprotected sexual intercourse, affects 15% of couples. Any patient with infertility by definition or at high risk of infertility may be offered an infertility evaluation. In women older than 35 years, this waiting period can be limited to 6 months, and then infertility evaluation can be started. In women older than 40 years, more urgent evaluation and initiation of treatment is the most important option. Evaluation of infertility must be done by experienced and trained physicians and necessary treatments must be followed by these physicians. Alternative treatment methods can be used in patients who do not respond after standard evaluation steps and generally accepted treatment options. Various supportive treatments come to the fore here. These options are used both to obtain better quality oocytes before treatment and to ensure that more follicles participate in stimulation. Antioxidants and metformin are the most commonly used agents before treatment in women who are thought to have insulin resistance, especially considering that oocyte mitochondrial DNA damage increases in advanced female age. On the other hand, agents such as growth hormone that should be used in a controlled manner by experienced specialists have been found effective in many publications. In the presented article, nonconventional treatment options for infertility are explained. [ABSTRACT FROM AUTHOR]