Molecular and clinical characterization of ICOS expression in breast cancer through large-scale transcriptome data.

ICOS (Inducible T Cell Costimulator), one of the co-stimulatory B7 superfamily members, was characterized as a co-stimulatory receptor for T-cell enhancement. However, the role of ICOS in breast cancer remains largely unknown. The present study systematically investigated the expression pattern and its relation to clinical characteristics and immunotherapy by integrating multiple clinical cohorts and large-scale gene expression data. This study included 2994 breast tumor samples with transcriptome data and matched clinical data. To make our findings more reliable, we set the TCGA cohort as the discovery set and the METABRIC cohort as the validation set. The expression of ICOS in breast cancer is strongly associated with major clinical and molecular characteristics. There is an association between higher ICOS expression and malignant subtypes and grades of tumors. In addition, gene ontology analysis based on genes significantly correlated with ICOS expression indicated that the expression of ICOS is mainly associated with immune responses and inflammation. We also observed strong correlations between ICOS and other promising immune-checkpoint molecules, including PD1, PDL1, CTLA4, and IDO1. Furthermore, we found that ICOS expression is associated with the response to anti-PDL1 immunotherapy and may serve as a biomarker for immunotherapy prediction. Our results indicated higher ICOS expression is significantly associated with favorable survival in triple-negative breast cancer (TNBC) patients, but not for all subtypes of breast cancer patients. In summary, ICOS correlates with higher malignant breast cancers, and it contributes to the regulation of the immune microenvironment of breast tumors, making it a potential biomarker and immunotherapy target.

Role of Xihuang capsule combined with albumin-bound paclitaxel on the treatment of stage III breast cancer and T cell subsets, survival rate and adverse reactions.

To investigate the impact of Xihuang Capsule combined with albumin-bound paclitaxel on the treatment of stage III breast cancer and T cell subsets, survival rate and adverse reactions. Totally 200 patients with stage III breast cancer were evenly randomized into control group (albumin-bound paclitaxel for chemotherapy) and observation group (Xihuang Capsules for adjuvant therapy based on the treatment of the control group). The RR and DCR of the observation group was markedly higher as compared to the control group (66.7% vs 28.6%; 80.9% VS 47.6%) (all P <0.05). After 4 weeks of treatment, the CD8+ in the two groups decreased, while CD3+ and CD4+ increased, and the change in observation group was more significant (all P<0.05). The observation group exhibited a better half-year, 1-year, 1.5-year and 2-year survival rates compared to the control group (81.0% vs 71.4%, 71.4% vs 57.1%, 57.1% vs 33.3% and 42.9%vs 19.0%) (all P<0.05). Adding Xihuang Capsule to adjuvant therapy with albumin paclitaxel chemotherapy benefits the patient's immunity and survival rate, with good efficacy and safety profiles.

Lack of expression of miR-29a/b1 impairs bladder function in male mice.

Lower urinary tract symptoms (LUTS) refer to various urological diseases, and incomplete bladder emptying is common among affected patients. The etiology of LUTS is largely unknown, and investigations of LUTS suggest that bladder fibrosis contributes to pathogenesis of LUTS. MicroRNAs (miRNAs) are short (∼22 nucleotides), non-coding RNAs that repress target gene expression by a combination of mRNA degradation and translation inhibition. The miR-29 family is best known for its anti-fibrotic role in various organs. miR-29 was decreased in bladders of patients with outlet obstruction and a rat model of bladder outlet obstruction, suggesting that miR-29 may contribute to impaired bladder function subsequent to tissue fibrosis. We characterized bladder function in male mice lacking expression of Mir29a and Mir29b-1 (miR-29a/b1). Lack of miR-29a/b1 resulted in severe urinary retention, increased voiding duration and reduced flow rate, and these mice failed to void or voided irregularly during anesthetized cytometry. Collagens and elastin were increased in bladders of mice lacking miR-29a/b1. These findings reveal an important role for miR-29 in bladder homeostasis and suggest the therapeutic potential of miR-29 to improve symptoms in patients with LUTS.

Breast-Conserving Surgery in Triple-Negative Breast Cancer: A Retrospective Cohort Study.

Objectives: The aim of the study is to evaluate the efficacy and prognosis of neoadjuvant chemotherapy (NAC) combined with breast-conserving surgery (BCS) in treating triple-negative breast cancer (TNBC) and analyze the influencing factors and predictors of the efficiency and prognosis of NAC. Methods: A retrospective cohort study was conducted by dividing patients into two groups according to two different therapy methods. With BCS as the exposure factor, 46 cases were assigned to the exposed group and 80 cases to the nonexposed group. We compare the difference in operation-related indicators, postoperative complications, local recurrence rate, distant metastasis rate, and overall survival (OS) rate between the two groups. The factors affecting the efficiency and prognosis of NAC were analyzed by binary logistic regression, and the optimal cutoff value was determined by the area under the ROC curve (AUC). The survival curve was plotted, and the univariate log-rank test was performed to analyze the difference in OS between the two groups. The influencing factors of OS were analyzed by the Cox risk regression model. Results: NAC + BCS resulted in significantly less intraoperative blood loss, lower incidence of postoperative complications, and shorter operative time and length of hospital stay than that in NAC (P < 0.05). There was no significant difference in local recurrence, distant metastasis, or OS between the two groups (P > 0.05). Multivariate analysis showed that the clinical stage I and Ki-67 high expression were independent protective factors of the efficacy of NAC. The high expression of Ki-67 and nondecline expression of Ki-67 were independent risk factors of prognosis. Ki-67 high expression was an independent risk factor of OS (P < 0.05). The ROC curve showed that the AUC of Ki-67 for NAC efficacy, prognosis, and OS were 0.706, 0.820, and 0.687, respectively, with optimal cutoff values of 25.5%, 29.0%, and 32.5%, respectively. Survival analysis showed that the OS of patients with NAC + BCS was 73.9% and NAC + MRM was 70.0% (P > 0.05). In the low expression subgroup of Ki-67, the OS of the two groups were 100.0% and 77.8%, respectively (P=0.060). In the high expression subgroup of Ki-67, the OS of the two groups were 53.8% and 63.6%, respectively (P=0.419). Conclusions: NAC + BCS is a good method for treating TNBC, which has an obvious short-term effect and a good long-term prognosis. Clinical stage I and the high expression of Ki-67 are independent protective factors for the efficacy of NAC. The high expression of Ki-67 and nondecline expression of Ki-67 are independent risk factors of prognosis. Ki-67 is a potential predictor for the efficacy, prognosis, and OS of NAC in TNBC patients. The high expression of Ki-67 indicates better NAC efficacy, a poorer prognosis, and a lower OS.

The neoadjuvant chemotherapy responses and survival rates of patients with different molecular subtypes of breast cancer.

OBJECTIVE: The purpose of this study was to evaluate the effect of neoadjuvant chemotherapy (NAC) on the responses and survival rates of patients with different molecular subtypes of breast cancer. METHODS: A retrospective analysis was conducted on 284 breast cancer patients who underwent NAC in our hospital from January 2017 to January 2019. The patients were classified into the Luminal A (n=87), Luminal B (n=78), human epidermal growth factor receptor 2 positive (HER-2+, n=66), and triple-negative (TN, n=53) breast cancer subtypes. The Ki67 expressions and clinical prognoses were compared among the patients in the four subtypes. RESULTS: The complete response (CR) rates were significantly higher in the HER-2+ and TN patients than they were in the Luminal A and Luminal B subtype patients (P<0.05). The HER-2+ and TN breast cancer patients had significantly higher response rates (RR) than the Luminal B patients (P<0.05). The Ki67 expressions decreased significantly in the patients with the Luminal B, HER-2+, and TN subtypes after NAC (P<0.05), with a greater decrease in the Ki67 expressions in the HER-2+ and TN subtypes than in the Luminal B subtypes (P<0.05). The Ki67 levels decreased significantly in the patients with CR or PR compared to the stable disease (SD) and progressive disease (PD) patients (P<0.05). The HER-2+ patients had remarkably higher distant metastasis rates, compared to the patients with the Luminal A and B subtypes (P<0.05). CONCLUSION: Statistical differences were found in the pathological responses and survival rates in the patients with the different molecular subtypes of breast cancer after the NAC treatment. The HER-2+ or TN breast cancer patients had higher pathological response rates, which may be closely related to their decreased Ki67 expressions. Interestingly, the HER-2+ breast cancer patients also showed a higher distant metastasis rate, which warrants further analysis.

Efficacy of the Whole-Course Case Management Model on Compliance and Satisfaction of Breast Cancer Patients with Whole-Course Standardized Treatment.

Objective: To explore the influence of the whole-course case management model on the compliance and satisfaction of breast cancer patients with the whole-course standardized treatment. Methods: Eighty breast cancer patients admitted to our hospital between April 2020 and June 2021 were assigned to receive either conventional nursing (routine group, n = 40) or whole-process case management (experimental group, n = 40) according to different nursing methods. Outcome measures included self-rating anxiety scale (SAS) scores, self-rating depression scale (SDS) scores, adverse reactions, treatment compliance, and nursing satisfaction. Results: After nursing, the SAS and SDS scores of the experimental group were significantly lower than those of the routine group (P < 0.05). The whole case management mode was associated with a significantly lower incidence of adverse reactions versus routine nursing (P < 0.05). The whole case management resulted in higher compliance of patients versus routine nursing (P < 0.05). The experimental group had a significantly higher nursing satisfaction versus the routine group (P < 0.05). Conclusion: The whole-process case management mitigates patients' negative emotions, strengthens their treatment compliance, lowers the incidence of postoperative adverse reactions, and improves nursing satisfaction, which may provide a viable nursing alternative for patients with breast cancer.

Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression.

Allogeneic islet transplantation is a promising experimental therapy for poorly controlled diabetes. Despite pharmacological immunosuppression, long-term islet engraftment remains elusive. Here, we designed a synthetic fusion transgene coupling PD-L1 and indoleamine dioxygenase [hereafter PIDO] whose constitutive expression prevents immune destruction of genetically engineered islet allograft transplanted in immunocompetent mice. PIDO expressing murine islets maintain robust dynamic insulin secretion in vitro and when transplanted in allogeneic hyperglycemic murine recipients reverse pre-existing streptozotocin-induced and autoimmune diabetes in the absence of pharmacological immunosuppression for more than 50 and 8 weeks, respectively, and is dependent on host CD4 competence. Additionally, PIDO expression in allografts preserves endocrine functional viability of islets and promotes a localized tolerogenic milieu characterized by the suppression of host CD8 T cell and phagocyte recruitment and accumulation of FOXP3+ Tregs. Furthermore, in the canine model of xenogeneic islet transplantation, muscle implanted PIDO-expressing porcine islets displayed physiological glucose-responsive insulin secretion competency in euglycemic recipient for up to 20 weeks. In conclusion, the PIDO transgenic technology enables host CD4+ T cell-modulated immune evasiveness and long-term functional viability of islet allo- and xenografts in immune-competent recipients without the need for pharmacological immune suppression and would allow for improved outcomes for tissue transplantation.

Molecular and Clinical Characterization of CD80 Expression via Large-Scale Analysis in Breast Cancer.

Cancer immunotherapy is emerging as a novel promising therapy option for cancer patients. Despite the critical role of CD80 in the regulation of immune responses, the expression and biological functions of CD80 in breast cancer remain unknown. In this study, we aimed to investigate the role of CD80 both clinically and molecularly in breast cancer at a transcriptome level. Herein, we first analyzed the transcriptome profile and relevant clinical information derived from a total of 1090 breast cancer patients recorded in The Cancer Genome Atlas database and then validated this in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database (n = 1904). We revealed the associations of CD80 and the main molecular and clinical characteristics of breast cancer. The gene ontology analysis and Gene Set Variation Analysis of the CD80-related genes revealed that CD80 was closely correlated with immune responses and inflammatory activities in breast cancer. Moreover, the CD80 expression showed a remarkable positive correlation with several infiltrated immune cell populations. In summary, the CD80 expression was closely correlated with the malignancy of breast cancer, and our findings suggest that CD80 might be a promising target for immunotherapeutic strategies. To the best of our knowledge, this is the first integrative study characterizing the role of the CD80 expression in breast cancer via large-scale analyses.

Neoadjuvant Chemotherapy Combined with Breast-Conserving Surgery in the Treatment of Triple-Negative Breast Cancer.

Objective: To study the clinical efficacy and quality of life of neoadjuvant chemotherapy combined with breast-conserving surgery in the treatment of triple-negative breast cancer. Methods: A retrospective analysis of 100 patients with triple-negative breast cancer was performed from May 2012 to April 2017. The patients were divided into an observation group and a control group according to different treatment methods, with 50 cases in each group. The control group received AC-T sequential chemotherapy after breast-conserving surgery, and the observation group received AC-T sequential chemotherapy before breast-conserving surgery (neoadjuvant). The operation time, postoperative immune function, postoperative tumor markers, postoperative efficacy, and postoperative complications of the two groups of patients were statistically analyzed, and the quality of life of the two groups of patients 1 year after the operation was compared. Results: Compared with the control group, the operation time and blood loss of the observation group were significantly reduced, and the difference was statistically significant (P < 0.05). The observation group produced significantly higher total effective rate after treatment (82.00% vs. 56.00%) (P < 0.05). The observation group exhibited superior immune function indexes CD3, CD4, and CD8 after operation when compared with the control group (P < 0.05). There was no significant difference in serum tumor marker levels between the two groups before surgery and after surgery (both P > 0.05). Three days after operation, the levels of procalcitonin (PCT) and TNF-α in the observation group were lower than those in the control group (P < 0.05). There was no significant difference in the local recurrence rate, distant metastasis rate, and 3-year survival rate between the two groups (P > 0.05); however, the postoperative complication rate of the observation group was 6.00%, which was significantly lower than that of the control group (30%) (P < 0.05). The overall health, physiological function, physiological function, and body pain of the observation group were significantly higher than those of the control group (P < 0.05). Conclusion: Neoadjuvant chemotherapy combined with breast-conserving surgery for triple-negative breast cancer can not only improve the therapeutic effect of patients and reduce the incidence of postoperative adverse reactions but also significantly improve the quality of life of patients after surgery.

Clinical Observation of Zhengyuan Capsule Combined with Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer.

Objective: To study the clinical effect of Zhengyuan capsule combined with neoadjuvant chemotherapy in the treatment of triple-negative breast cancer (TNBC). Methods: From September 2014 to September 2017, 120 TNBC patients who underwent radical mastectomy in our hospital were randomly divided into control group (n = 60) and observation group (n = 60). The short-term curative effect, the incidence of toxicity and side effects, and the score of quality of life of the patients were compared. Both recurrence and metastasis rates were also analyzed. Results: The combined treatment of Zhengyuan capsule with neoadjuvant chemotherapy significantly improved the objective remission rate (70.00% in the observation group versus 40.00% in the control group) (P < 0.05). Moreover, this combined treatment significantly decreased the total incidence of side effects (35.00% versus 75.00%). Accordingly, the score of quality of life was also increased in patients treated with Zhengyuan capsule plus neoadjuvant chemotherapy (P < 0.05). Furthermore, supplementation of Zhengyuan capsule can significantly suppress both the recurrence and metastasis rate of TNBC in patients treated with neoadjuvant chemotherapy after radical mastectomy in following 3 years (30.00% versus 10.00%, P < 0.05). Conclusion: Zhengyuan capsule effectively improves the short-term curative effect, reduces the side effects of chemotherapy, and improves the quality of life of patients treated with neoadjuvant chemotherapy after radical mastectomy. More importantly, this combined treatment can also reduce the long-term recurrence and metastasis of TNBC.

Developmental polychlorinated biphenyl (PCB) exposure alters voiding physiology in young adult male and female mice.

The impact of developmental exposure to environmental chemicals on lower urinary tract function is not well understood, despite the fact that these chemicals could contribute to etiologically complex lower urinary tract symptoms (LUTS). Polychlorinated biphenyls (PCBs) are environmental toxicants known to be detrimental to the central nervous system, but their impact on voiding function in mouse models is not known. Therefore, we test whether developmental exposure to PCBs is capable of altering voiding physiology in young adult mice. C57Bl/6J female mice received a daily oral dose of the MARBLES PCB mixture for two weeks prior to mating and through gestation and lactation. The mixture mimics the profile of PCBs found in a contemporary population of pregnant women. Voiding function was then tested in young adult offspring using void spot assay, uroflowmetry and anesthetized cystometry. PCB effects were sex and dose dependent. Overall, PCBs led to increases in small size urine spots in both sexes with males producing more drop-like voids and greater peak pressure during a voiding cycle while females displayed decreases in void duration and intervoid interval. Together, these results indicate that developmental exposure to PCBs are capable of altering voiding physiology in young adult mice. Further work to identify the underlying mechanisms driving these changes may help develop more effective preventative or therapeutic strategies for LUTS.

Real-world effectiveness and sensitivity of palbociclib plus endocrine therapy in HR+/HER2- patients with metastatic breast cancer.

ABSTRACT: Palbociclib has shown satisfactory outcomes when combined with endocrine therapy (ET) in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, data in Asia are currently scarce.This retrospective study aimed to evaluate the real-world effectiveness, sensitivity, and toxicity of palbociclib plus ET in HR+/HER2- MBC in North China. We recruited patients with HR+/HER2- MBC from August 2018 to July 2020 across 7 hospitals in North China. The primary endpoint was to evaluate progression-free survival (PFS) after initial progress on palbociclib therapy. The secondary endpoints included determining predictive biomarkers of palbociclib sensitivity and toxicity of palbociclib.A total of 54 patients were analyzed in this cohort with an estimated median follow-up time of 14.3 months. Patients who received palbociclib as a first-line treatment showed significantly prolonged PFS compared with those who received palbociclib as a second-line or beyond treatment (21.8 months vs 15.9 months vs 6.8 months) (P < .001). Besides, patients with Ki67 <30% (P = .024) and PR ≥20% (P = .041) in metastatic tumors had significantly longer PFS. The Cox proportional-hazards regression analyses proved that different lines (P = .001 in multivariate analysis), Ki67 <30% (P = .035 in multivariate analysis), and PR ≥20% (P = .045 in univariate analysis) in metastatic tumors affected PFS significantly. The most common adverse events were hematologic, with 31.48% of patients having neutropenia.Palbociclib plus ET significantly prolonged PFS for patients with HR+/HER2- MBC who received first-line therapy, with manageable toxicity. The values of Ki67 and PR in metastatic tumors may be potential predictive biomarkers of palbociclib sensitivity.

Ketamine suppresses proliferation and induces ferroptosis and apoptosis of breast cancer cells by targeting KAT5/GPX4 axis.

Breast cancer (BC) serves as a prevalent and mortal malignancy among female globally. Ferroptosis, as an oxidative cell death that characterized by abnormal iron accumulation, plays critical role in cancer development. Ketamine is a rapid-acting anesthetic agent and has presented potential anti-tumor properties. However, the effect of Ketamine on breast cancer is still obscure. Here, we aimed to explore the function of Ketamine in the modulation of proliferation and ferroptosis of breast cancer cells. The cell viability of breast cancer cells was repressed by the treatment of Ketamine, while ferroptosis inhibitor ferrostatin 1 and apoptosis inhibitor ZVAD-FMK could restore the cell viability. The treatment of Ketamine significantly decreased the Edu-positive breast cancer cells and the colony formation numbers, and the treatment of ferrostatin 1 reversed the effect of Ketamine. We observed that the levels of ferroptosis markers, such as MDA, lipid ROS, and Fe2+ were increased by the treatment of Ketamine in breast cancer cells. Regarding to the mechanism, we found that Ketamine inhibited the expression of GPX4, an anti-ferroptosis factor, by attenuating KAT5 on the promoter region of GPX4, repressing the enrichment of histone H3 lysine 27 acetylation (H3K27ac) and RNA polymerase II (RNA pol II). The treatment of Ketamine reduced the cell viability and proliferation of breast cancer cells, in which the overexpression of KAT5 or GPX4 was able to restore the phenotypes. The treatment of Ketamine induced the levels of MDA, lipid ROS, and Fe2+, while KAT5 or GPX4 overexpression could reverse this effect in breast cancer cells. Thus, we concluded that Ketamine suppressed proliferation and induced ferroptosis of breast cancer cells by targeting KAT5/GPX4 axis. Ketamine may serve as a potential therapeutic strategy for breast cancer.

LncRNA MALAT1 promotes breast cancer progression by sponging miR101-3p to mediate mTOR/PKM2 signal transmission.

Breast cancer (BC) is a common malignant tumor in women and exhibits a poor prognosis. This study examined the role and underlying mechanisms of long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in BC pathogenesis. The MALAT1 expression levels in BC cells and tissues were measured using quantitative reverse transcription-polymerase chain reactions. CCK-8 kits and wound healing and transwell assays were used to evaluate the cell growth, invasion, and migration of BC. Bioinformatics and dual-luciferase reporter analyses were conducted to identify MALAT1's potential targets. The protein levels in the mTOR/PKM2 pathway were assessed using Western blot analyses. The MALAT1 overexpressions in the BC tissues and cells were considered to be a predictor of poor prognosis. Therefore, MALAT1 downregulation significantly inhibited BC progression, including cell growth, invasion, and migration. MALAT1 was anticipated to be an miR-101-3p target according to the dual-luciferase reporter gene assay results. The miR-101-3p levels were indirectly proportional to the MALAT1 expressions and the suppressed BC cells. Additionally, the mTOR/PKM2 pathway was directly targeted by miR-101-3p. MALAT1 overexpression significantly decreased the miR-101-3p gene levels and increased the mTOR/PKM2 pathway protein expressions. This miR-101-3p inhibition blocked MALAT1. These findings suggest that lncRNA MALAT1 is related to BC pathogenesis using the miR101-3p/mTOR/PKM2 pathway and is a potential therapeutic target.

In utero and lactational PCB exposure drives anatomic changes in the juvenile mouse bladder.

Bladder dysfunction, including incontinence, difficulty emptying the bladder, or urgency to urinate is a pervasive health and quality of life concern. However, risk factors for developing these symptoms are not completely understood, and the influence of exposure to environmental chemicals, especially during development, on the formation and function of the bladder is understudied. Environmental contaminants such as polychlorinated biphenyls (PCBs) are known to pose a risk to the developing brain; however, their influence on the development of peripheral target organs, such as bladder, are unknown. To address this data gap, C57Bl/6J mouse dams were exposed to an environmentally-relevant PCB mixture at 0, 0.1, 1 or 6 mg/kg daily beginning two weeks prior to mating and continuing through gestation and lactation. Bladders were collected from offspring at postnatal days (P) 28-31. PCB concentrations were detected in bladders in a dose-dependent manner. PCB effects on the bladder were sex- and dose-dependent. Overall, PCB effects were observed in male, but not female, bladders. PCBs increased bladder volume and suburothelial ßIII-tubulin-positive nerve density compared to vehicle control. A subset of these nerves were sensory peptidergic axons indicated by increased calcitonin gene-related protein (CGRP) positive nerve fibers in mice exposed to the highest PCB dose compared to the lowest PCB dose. PCB-induced increased nerve density was also positively correlated with the number of mast cells in the bladder, suggesting inflammation may be involved. There were no detectable changes in epithelial composition or apoptosis as indicated by expression of cleaved caspase 3, suggesting PCBs do not cause overt toxicity. Bladder volume changes were not accompanied by changes in bladder mass or epithelial thickness, indicating that obstruction was not likely involved. Together, these results are the first to suggest that following developmental exposure, PCBs can distribute to the bladder and alter neuroanatomic development and bladder volume in male mice.

A mechanism linking perinatal 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure to lower urinary tract dysfunction in adulthood.

Benign prostatic hyperplasia/lower urinary tract dysfunction (LUTD) affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging paradigms about when this disease process begins. We delivered a single dose of a widespread environmental contaminant present in the serum of most Americans [2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 1 µg/kg], and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues, and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood.

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms.

BACKGROUND: Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease. However, medical therapies for BPH/LUTS are not effective in many patients. The reasons for nonresponse or loss of therapeutic response in the remaining patients over time are unknown. A better understanding of why patients fail to respond to medical therapy may have a major impact on developing new approaches for the medical treatment of BPH/LUTS. Prostaglandins (PG) act on G-protein-coupled receptors (GPCRs), where PGE2 and PGF2 elicit smooth muscle contraction. Therefore, we measured PG levels in the prostate tissue of BPH/LUTS patients to assess the possibility that this signaling pathway might explain the failure of medical therapy in BPH/LUTS patients. METHOD: Surgical BPH (S-BPH) was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy and underwent surgical intervention to relieve LUTS. Control tissue was termed Incidental BPH (I-BPH). I-BPH was TZ obtained from men undergoing radical prostatectomy for low-volume, low-grade prostatic adenocarcinoma (PCa, Gleason score ≤ 7) confined to the peripheral zone. All TZ tissue was confirmed to be cancer-free. S-BPH patients divided into four subgroups: patients on α-blockers alone, 5ARI alone, combination therapy (α-blockers plus 5ARI), or no medical therapy (none) before surgical resection. I-BPH tissue was subgrouped by prior therapy (either on α-blockers or without prior medical therapy before prostatectomy). We measured prostatic tissue levels of prostaglandins (PGF2α , PGI2 , PGE2 , PGD2 , and TxA2 ), quantitative polymerase chain reaction levels of mRNAs encoding enzymes within the PG synthesis pathway, cellular distribution of COX1 (PTGS1) and COX2 (PTGS2), and tested the ability of PGs to contract bladder smooth muscle in an in vitro assay. RESULTS: All PGs were significantly elevated in TZ tissues from S-BPH patients (n = 36) compared to I-BPH patients (n = 15), regardless of the treatment subgroups. In S-BPH versus I-BPH, mRNA for PG synthetic enzymes COX1 and COX2 were significantly elevated. In addition, mRNA for enzymes that convert the precursor PGH2 to metabolite PGs were variable: PTGIS (which generates PGI2 ) and PTGDS (PGD2 ) were significantly elevated; nonsignificant increases were observed for PTGES (PGE2 ), AKR1C3 (PGF2α ), and TBxAS1 (TxA2 ). Within the I-BPH group, men responding to α-blockers for symptoms of BPH but requiring prostatectomy for PCa did not show elevated levels of COX1, COX2, or PGs. By immunohistochemistry, COX1 was predominantly observed in the prostatic stroma while COX2 was present in scattered luminal cells of isolated prostatic glands in S-BPH. PGE2 and PGF2α induced contraction of bladder smooth muscle in an in vitro assay. Furthermore, using the smooth muscle assay, we demonstrated that α-blockers that inhibit alpha-adrenergic receptors do not appear to inhibit PG stimulation of GPCRs in bladder muscle. Only patients who required surgery to relieve BPH/LUTS symptoms showed significantly increased tissue levels of PGs and the PG synthetic enzymes. CONCLUSIONS: Treatment of BPH/LUTS by inhibition of alpha-adrenergic receptors with pharmaceutical α-blockers or inhibiting androgenesis with 5ARI may fail because of elevated paracrine signaling by prostatic PGs that can cause smooth muscle contraction. In contrast to patients who fail medical therapy for BPH/LUTS, control I-BPH patients do not show the same evidence of elevated PG pathway signaling. Elevation of the PG pathway may explain, in part, why the risk of clinical progression in the MTOPS study was only reduced by 34% with α-blocker treatment.

The influence of intermittent hypoxia, obesity, and diabetes on male genitourinary anatomy and voiding physiology.

We used male BTBR mice carrying the Lepob mutation, which are subject to severe and progressive obesity and diabetes beginning at 6 wk of age, to examine the influence of one specific manifestation of sleep apnea, intermittent hypoxia (IH), on male urinary voiding physiology and genitourinary anatomy. A custom device was used to deliver continuous normoxia (control) or IH to wild-type and Lepob/ob (mutant) mice for 2 wk. IH was delivered during the 12-h inactive (light) period in the form of 90 s of 6% O2 followed by 90 s of room air. Continuous room air was delivered during the 12-h active (dark) period. We then evaluated genitourinary anatomy and physiology. As expected for the type 2 diabetes phenotype, mutant mice consumed more food and water, weighed more, and voided more frequently and in larger urine volumes. They also had larger bladder volumes but smaller prostates, seminal vesicles, and urethras than wild-type mice. IH decreased food consumption and increased bladder relative weight independent of genotype and increased urine glucose concentration in mutant mice. When evaluated based on genotype (normoxia + IH), the incidence of pathogenic bacteriuria was greater in mutant mice than in wild-type mice, and among mice exposed to IH, bacteriuria incidence was greater in mutant mice than in wild-type mice. We conclude that IH exposure and type 2 diabetes can act independently and together to modify male mouse urinary function. NEW & NOTEWORTHY Metabolic syndrome and obstructive sleep apnea are common in aging men, and both have been linked to urinary voiding dysfunction. Here, we show that metabolic syndrome and intermittent hypoxia (a manifestation of sleep apnea) have individual and combined influences on voiding function and urogenital anatomy in male mice.

Genetic background but not prostatic epithelial beta-catenin influences susceptibility of male mice to testosterone and estradiol-induced urinary dysfunction.

Urinary voiding dysfunction in aging men can cause bothersome symptoms and irreparable tissue damage. Underlying mechanisms are not fully known. We previously demonstrated that subcutaneous, slow-release testosterone and estradiol implants (T+E2) drive a pattern of urinary voiding dysfunction in male mice that resembles that of aging men. The initial goal of this study was to test the hypothesis that prostatic epithelial beta-catenin (Ctnnb1) is required for T+E2-mediated voiding dysfunction. Targeted Ctnnb1 deletion did not significantly change voiding function in control or T+E2 treated mice but led to the surprising discovery that the C57BL/6J × FVB/NJ × 129S1 mixed genetic background onto which Ctnnb1 loss of function alleles were maintained is profoundly susceptible to voiding dysfunction. The mixed background mice develop a more rapid T+E2-mediated increase in spontaneous urine spotting, are more impaired in ability to initiate bladder contraction, and develop larger and heavier bladders than T+E2 treated C57BL/6J pure bred mice. To better understand mechanisms, we separately evaluated contributions of T and E2 and found that E2 mediates voiding dysfunction. Our findings that genetic factors serve as modifiers of responsiveness to T and E2 demonstrate the need to control for genetic background in studies of male voiding dysfunction. We also show that genetic factors could control severity of voiding dysfunction. We demonstrate the importance of E2 as a key mediator of voiding impairment, and show that the concentration of E2 in subcutaneous implants determines the severity of voiding dysfunction in mice, demonstrating that the mouse model is tunable, a factor which is important for future pharmacological intervention studies.