Rat Model of Type 2 Diabetes Mellitus Recapitulates Human Disease in the Anterior Segment of the Eye.

Changes in the anterior segment of the eye due to type 2 diabetes mellitus (T2DM) are not well-characterized, in part due to the lack of a reliable animal model. This study evaluated changes in the anterior segment, including crystalline lens health, corneal endothelial cell density, aqueous humor metabolites, and ciliary body vasculature, in a rat model of T2DM compared with human eyes. Male Sprague-Dawley rats were fed a high-fat diet (45% fat) or normal diet, and rats fed the high-fat diet were injected with streptozotocin intraperitoneally to generate a model of T2DM. Cataract formation and corneal endothelial cell density were assessed using microscopic analysis. Diabetes-related rat aqueous humor alterations were assessed using metabolomics screening. Transmission electron microscopy was used to assess qualitative ultrastructural changes ciliary process microvessels at the site of aqueous formation in the eyes of diabetic rats and humans. Eyes from the diabetic rats demonstrated cataracts, lower corneal endothelial cell densities, altered aqueous metabolites, and ciliary body ultrastructural changes, including vascular endothelial cell activation, pericyte degeneration, perivascular edema, and basement membrane reduplication. These findings recapitulated diabetic changes in human eyes. These results support the use of this model for studying ocular manifestations of T2DM and support a hypothesis postulating blood-aqueous barrier breakdown and vascular leakage at the ciliary body as a mechanism for diabetic anterior segment pathology.

Efficacy of in-office lysis of clitoral adhesions with excision of keratin pearls on clitoral pain and sexual function: a pre-post interventional study.

BACKGROUND: Keratin pearls are foci of central keratinization within concentric layers of squamous cells that can form under the clitoral prepuce and cause pain (clitorodynia); in-office removal of keratin pearls may reduce clitoral pain and improve sexual function. AIM: This study aims to investigate clitoral pain and sexual function in women with partial clitoral phimosis and keratin pearls before and after in-office lysis of clitoral adhesions with keratin pearl excision (LCA-KPE). METHODS: A pre-post interventional study evaluated patients who underwent LCA-KPE between January 2017 and February 2023 in 2 metropolitan gynecology clinics specializing in vulvar pain. Patients presenting with keratin pearls and partial clitoral phimosis identified through retrospective chart review were asked to complete postprocedure questionnaires and provide subjective responses on clitoral discomfort, sexual function, sexual distress, and their experience with in-office LCA-KPE. Bivariate analyses with paired t tests were conducted to determine the effect of LCA-KPE. Qualitative data were analyzed with thematic coding. OUTCOMES: An 11-point pain visual analog scale was utilized to determine pre- and postprocedure clitoral discomfort and difficulty with orgasm. Female sexual dysfunction was measured with the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised. RESULTS: A total of 32 of 74 patients who met inclusion criteria completed postprocedure surveys (43% response rate). Mean clitoral pain for respondents was 6.91 at baseline and 2.50 after LCA-KPE (P < .001). Mean difficulty with orgasm was significantly decreased from 5.45 at baseline to 3.13 after LCA-KPE (P < .001). Participants had a mean FSFI total score of 17.68 after treatment compared with a mean total baseline FSFI of 12.12 (P = .017). The mean FSFI score for pain was 2.43 at follow-up compared with 1.37 at baseline (P = .049). There was no significant difference in the mean Female Sexual Distress Scale-Revised score before vs after the procedure (P = .27). Qualitative themes described the procedure as painful but worthwhile, with 77% of participants reporting the overall experience as positive. Recurrence rate overall was 28%, with a median of 2 repeat procedures. CLINICAL IMPLICATIONS: Recognizing keratin pearls as a structural cause of clitoral pain and offering in-office treatment is an important tool in addressing clitorodynia and improving sexual function. STRENGTHS AND LIMITATIONS: This is the largest study to date documenting the occurrence, identifying associated pain conditions, and evaluating procedural outcomes for clitoral keratin pearls. This study was limited by a relatively small sample size. CONCLUSION: In-office LCA-KPE significantly reduced clitoral discomfort and difficulty with orgasm.

Immunohistochemical staining with CD117 and PGP9.5 of excised vestibular tissue from patients with neuroproliferative vestibulodynia.

BACKGROUND: Neuroproliferative vestibulodynia (NPV), a provoked genital pain characterized by severe allodynia and hyperalgesia, is confirmed in excised vestibular tissue by immunohistochemical staining (>8 CD117-positive immunostained cells/100× microscopic field) rather than by hematoxylin and eosin staining. AIM: In this study we sought to assess immunostaining of tissue samples obtained during vestibulectomy surgery and to correlate results with patient outcomes. METHODS: Patients (n = 65) meeting criteria for NPV who underwent vestibulectomy during the period from June 2019 through December 2022 formed the study cohort. We performed assessment of pathology of vestibular tissues by use of immunohistochemical staining, including quantitation of mast cells by CD117 (mast cell marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments. OUTCOMES: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement. RESULTS: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments. OUTCOMES: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement. RESULTS: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the median area of CD117 immunostaining was similar in both regions (0.69% and 0.73%). The median area of PGP9.5 immunostaining was 0.47% and 0.31% in these same regions. Pain scores determined with cotton-tipped swab testing were nominally higher in lifelong vs acquired NPV patients, reaching statistical significance in the 1:00-11:00 o'clock region (P < .001). The median score for the McGill Pain Questionnaire affective subscale dimension was also significantly higher in lifelong vs acquired NPV patients (P = .011). No correlations were observed between hematoxylin and eosin results and density of mast cells or neuronal markers. Of note, 63% of the patient cohort reported having additional conditions associated with aberrant mast cell activity. CLINICAL IMPLICATIONS: The pathology of NPV is primarily localized to the vestibular epithelial basement membrane and subepithelial stroma with no visible vulvoscopic findings, making clinical diagnosis challenging. STRENGTHS AND LIMITATIONS: Strengths of this study include the large number of tissues examined with what is to our knowledge the first-ever assessment of the 12:00 vestibule. Major limitations are specimens from a single timepoint within the disease state and lack of control tissues. CONCLUSIONS: Performing immunohistochemical staining of excised vestibular tissue with CD117 and PGP9.5 led to histometric confirmation of NPV, indications that NPV is a field disease involving all vestibular regions, validation for patients whose pain had been ignored and who had experienced negative psychosocial impact, and appreciation that such staining can advance knowledge.

Prostatic proliferative inflammatory atrophy: welcome to the club†.

Single-cell RNA sequencing studies in the human prostate have defined a population of epithelial cells with transcriptional similarities to club cells in the lung. However, the localization of club-like cells in the human prostate, and their relationship to prostate cancer, is poorly understood. In a new article in The Journal of Pathology, RNA in situ hybridization was used to demonstrate that club cell markers are expressed in luminal cells adjacent to inflammation in the peripheral zone of the human prostate, where prostate cancer tends to arise. These club-like cells are commonly found in proliferative inflammatory atrophy (PIA) lesions and express markers consistent with an intermediate epithelial cell-type. Future studies will be needed to understand the functional role of club-like cells in human prostate inflammation, regeneration, and disease. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Detecting critical transition signals from single-cell transcriptomes to infer lineage-determining transcription factors.

Analyzing single-cell transcriptomes promises to decipher the plasticity, heterogeneity, and rapid switches in developmental cellular state transitions. Such analyses require the identification of gene markers for semi-stable transition states. However, there are nontrivial challenges such as unexplainable stochasticity, variable population sizes, and alternative trajectory constructions. By advancing current tipping-point theory-based models with feature selection, network decomposition, accurate estimation of correlations, and optimization, we developed BioTIP to overcome these challenges. BioTIP identifies a small group of genes, called critical transition signal (CTS), to characterize regulated stochasticity during semi-stable transitions. Although methods rooted in different theories converged at the same transition events in two benchmark datasets, BioTIP is unique in inferring lineage-determining transcription factors governing critical transition. Applying BioTIP to mouse gastrulation data, we identify multiple CTSs from one dataset and validated their significance in another independent dataset. We detect the established regulator Etv2 whose expression change drives the haemato-endothelial bifurcation, and its targets together in CTS across three datasets. After comparing to three current methods using six datasets, we show that BioTIP is accurate, user-friendly, independent of pseudo-temporal trajectory, and captures significantly interconnected and reproducible CTSs. We expect BioTIP to provide great insight into dynamic regulations of lineage-determining factors.

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

BACKGROUND: Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations. AIM: To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD. METHODS: In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software. OUTCOMES: Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations. RESULTS: The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence. CLINICAL IMPLICATIONS: Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population. STRENGTHS AND LIMITATIONS: This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States. CONCLUSION: The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

Presenting Symptoms and Diagnosis of Vulvar Lichen Sclerosus in Premenopausal Women: A Cross-Sectional Study.

OBJECTIVES/PURPOSE: Presenting symptoms of vulvar lichen sclerosus (LS) specific to premenopausal women are not well reported in the literature and may differ from those in postmenopausal women. This study aimed to characterize the presentation of vulvar LS among premenopausal women. MATERIALS AND METHODS: An observational web-based study was conducted in premenopausal women with biopsy-confirmed vulvar LS between the ages of 18-50 years. Participants completed a 28-question survey evaluating characteristics of symptoms, timing of diagnosis, alternate diagnoses, and presence of concomitant autoimmune conditions. RESULTS: Of the 956 responses received, 503 met inclusion criteria of biopsy-confirmed LS and premenopausal status. Average age of symptom onset was 27 years, and average age of diagnosis was 32 years, with a 4-year delay in diagnosis. Symptoms most present were dyspareunia (68%) and tearing with intercourse or vaginal insertion (63%). Symptoms that affect the individual most were also dyspareunia (44%) and tearing with intercourse or vaginal insertion (39%). Symptoms that most frequently prompted patients to seek medical attention were dyspareunia (35%), pruritus (31%) and tearing with intercourse or vaginal insertion (26%). Most common skin changes included hypopigmentation (81%), vulvar fissures (72%), and labial resorption (60%), with fissures affecting the individual the most (48%). Sixty-six percent of the respondents initially received an alternative diagnosis, most commonly vulvovaginal yeast infection (49%). Hypothyroidism was the most common concurrent autoimmune condition (10%). CONCLUSIONS: Vulvar LS affects premenopausal women, commonly presenting with dyspareunia and tearing with intercourse. This condition should be considered and evaluated in premenopausal women presenting with vulvar symptoms and sexual pain.

Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes.

Integration of detailed phenotype information with genetic data is well established to facilitate accurate diagnosis of hereditary disorders. As a rich source of phenotype information, electronic health records (EHRs) promise to empower diagnostic variant interpretation. However, how to accurately and efficiently extract phenotypes from heterogeneous EHR narratives remains a challenge. Here, we present EHR-Phenolyzer, a high-throughput EHR framework for extracting and analyzing phenotypes. EHR-Phenolyzer extracts and normalizes Human Phenotype Ontology (HPO) concepts from EHR narratives and then prioritizes genes with causal variants on the basis of the HPO-coded phenotype manifestations. We assessed EHR-Phenolyzer on 28 pediatric individuals with confirmed diagnoses of monogenic diseases and found that the genes with causal variants were ranked among the top 100 genes selected by EHR-Phenolyzer for 16/28 individuals (p < 2.2 × 10-16), supporting the value of phenotype-driven gene prioritization in diagnostic sequence interpretation. To assess the generalizability, we replicated this finding on an independent EHR dataset of ten individuals with a positive diagnosis from a different institution. We then assessed the broader utility by examining two additional EHR datasets, including 31 individuals who were suspected of having a Mendelian disease and underwent different types of genetic testing and 20 individuals with positive diagnoses of specific Mendelian etiologies of chronic kidney disease from exome sequencing. Finally, through several retrospective case studies, we demonstrated how combined analyses of genotype data and deep phenotype data from EHRs can expedite genetic diagnoses. In summary, EHR-Phenolyzer leverages EHR narratives to automate phenotype-driven analysis of clinical exomes or genomes, facilitating the broader implementation of genomic medicine.

International Society for the Study of Women's Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD).

BACKGROUND: Persistent genital arousal disorder (PGAD), a condition of unwanted, unremitting sensations of genital arousal, is associated with a significant, negative psychosocial impact that may include emotional lability, catastrophization, and suicidal ideation. Despite being first reported in 2001, PGAD remains poorly understood. AIM: To characterize this complex condition more accurately, review the epidemiology and pathophysiology, and provide new nomenclature and guidance for evidence-based management. METHODS: A panel of experts reviewed pertinent literature, discussed research and clinical experience, and used a modified Delphi method to reach consensus concerning nomenclature, etiology, and associated factors. Levels of evidence and grades of recommendation were assigned for diagnosis and treatment. OUTCOMES: The nomenclature of PGAD was broadened to include genito-pelvic dysesthesia (GPD), and a new biopsychosocial diagnostic and treatment algorithm for PGAD/GPD was developed. RESULTS: The panel recognized that the term PGAD does not fully characterize the constellation of GPD symptoms experienced by patients. Therefore, the more inclusive term PGAD/GPD was adopted, which maintains the primacy of the distressing arousal symptoms and acknowledges associated bothersome GPD. While there are diverse biopsychosocial contributors, there is a common underlying neurologic basis attributable to spontaneous intense activity of the genito-pelvic region represented in the somatosensory cortex and its projections. A process of care diagnostic and treatment strategy was developed to guide the clinician, whenever possible, by localizing the symptoms as originating in any of five regions: (i) end organ, (ii) pelvis/perineum, (iii) cauda equina, (iv) spinal cord, and (v) brain. Psychological treatment strategies were considered critical and should be performed in conjunction with medical strategies. Pharmaceutical interventions may be used based on their site and mechanism of action to reduce patients' symptoms and the associated bother and distress. CLINICAL IMPLICATIONS: The process of care for PGAD/GPD uses a personalized, biopsychosocial approach for diagnosis and treatment. STRENGTHS AND LIMITATIONS: Strengths and Limitations: Strengths include characterization of the condition by consensus, analysis, and recommendation of a new nomenclature and a rational basis for diagnosis and treatment. Future investigations into etiology and treatment outcomes are recommended. The main limitations are the dearth of knowledge concerning this condition and that the current literature consists primarily of case reports and expert opinion. CONCLUSION: We provide, for the first time, an expert consensus review of the epidemiology and pathophysiology and the development of a new nomenclature and rational algorithm for management of this extremely distressing sexual health condition that may be more prevalent than previously recognized. Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women's Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD). J Sex Med 2021;18:665-697.

Plasma Cell Vulvitis: A Systematic Review.

OBJECTIVE: This systematic review aimed to present the available literature on plasma cell vulvitis (PCV), a relatively uncommon form of inflammatory vulvovaginal dermatitis. MATERIALS AND METHODS: A literature search was performed in PubMed, Science Direct, and Google Scholar using the following key words: "plasma cell vulvitis," "Zoon vulvitis," and "vulvitis circumscripta plasmacellularis." Specific variables were assessed in each article, including patient age, menopausal status, comorbidities, presenting symptoms, symptom duration, histological description, treatment, and treatment response. RESULTS: Thirty-nine articles met inclusion criteria, including 38 case reports and 1 observational study, with a total of 96 cases of PCV reported. The mean age of diagnosis was 52.9 years, with an age range of 8-76 years. Most common presenting symptoms included pruritis and vaginal discomfort, with average duration of symptoms 28.2 months (range = 2 months to 10 years). All reports demonstrated subepithelial plasma cell infiltrate on histology. Five percent of PCV cases reported concomitant autoimmune conditions and 6% sexually transmitted infections. Most common treatment modalities included topical corticosteroids (n = 41), tacrolimus (n = 6), and imiquimod (n = 6). In 53 reported outcomes, 88.7% of patients had resolution of symptoms with treatment. CONCLUSIONS: Clinical research is needed to better determine the diagnostic criteria and to assess the efficacy of treatment options for PCV.

Does the microenvironment influence the cell types of origin for prostate cancer?

Despite several recent studies addressing the cells of origin for prostate cancer, there is still considerable discussion in the field regarding the most relevant target populations for transformation. Tissue regeneration studies have pointed to a basal cell origin for mouse and human prostate cancer. In contrast, genetically engineered mouse models demonstrate that cells within both the basal and luminal layers can initiate murine prostate cancer. Based on differences between these two approaches, we propose that further work should address the requirement for microenvironmental components such as immune or mesenchymal cells on epithelial cell types of origin for prostate cancer.

The Vulvodynia Experience Questionnaire: Qualitative Development of a New Patient-Reported Outcome Measure for Vulvodynia.

INTRODUCTION: Vulvodynia is defined as vulvar pain of at least 3 months duration without a clear identifiable cause. There are currently no validated questionnaires that assess the experience of women with localized vulvodynia of the vestibule (vestibulodynia, previously known as vulvar vestibulitis) that meet the requirements of the Food and Drug Administration's Patient Reported Outcome (PRO) Guidance. AIM: To develop a new content-valid PRO assessment in accordance with the Food and Drug Administration's PRO guidance to assess the symptoms and impacts of localized vulvodynia. MATERIAL AND METHODS: Participants were recruited for concept elicitation interviews (ie, interviews with open-ended questions with the goal of eliciting volunteered data about the symptoms and impacts of vulvodynia). Participants were identified as having localized vulvodynia by clinicians who were experts in treating vulvar disorders. Eligibility was confirmed by the recruiting clinician, and informed consent was obtained; participants were then scheduled for in-person interviews. 25 participants were interviewed from United States (US). After concept elicitation interviews, the draft Vulvodynia Experience Questionnaire (VEQ) was developed based on the results. Cognitive interviews were conducted with 20 participants from US sites to assess the content validity of the VEQ (eg, interpretation and clarity of the items, relevance of concepts). The VEQ was further revised after cognitive interviews. All interviews were conducted face-to-face, audio-recorded, transcribed verbatim, anonymized, and analyzed using a qualitative data analysis software program. RESULTS: 17 unique symptoms and 32 unique impacts were reported during concept elicitation interviews. Pain (n = 25, 100%) and burning (n = 24, 96%) were the most frequently reported symptoms of localized vulvodynia, and negative impact on emotional well-being (n = 25, 100%) was the most frequently reported impact. After analysis, item generation, and cognitive interviews, the resulting VEQ v2.0 contains 3 parts (part 1, pain; part 2, associated symptoms; part 3, impacts) with a total of 25 items that measure the most frequently reported symptoms and impacts of localized vulvodynia. STRENGTH AND LIMITATIONS: The VEQ is a multidimensional assessment of the core symptoms and impacts of localized vulvodynia that, after additional psychometric testing including the ability to detect change, may be used in clinical trials to characterize the benefits of novel treatments. The VEQ requires additional testing to establish its cultural relevance and linguistic validity in other countries. CONCLUSION: The VEQ is a novel method of collecting information on localized vulvodynia symptoms and impacts that may be suitable for use in clinical trials after psychometric testing. Goldstein AT, Diez PMQ, Kapanadze S, et al. The Vulvodynia Experience Questionnaire: Qualitative Development of a New Patient-Reported Outcome Measure for Vulvodynia. J Sex Med 2020;17:2055-2066.

Patient Satisfaction With Human Papillomavirus Self-Sampling in a Cohort of Ethnically Diverse and Rural Women in Yunnan Province, China.

OBJECTIVE: Rural Yunnan Province is one of the most ethnically, culturally, and religiously diverse regions in China. The majority of its women have never been screened for cervical cancer. It is not known whether women would feel comfortable and ultimately even prefer using a human papillomavirus (HPV) self-swabbing method. METHODS: In a 6-day period, 3,600 women were taught the role of HPV in cervical cancer. They were then given self-swabbing instructions. After obtaining their specimens, 600 women were interviewed about their experience with HPV self-testing. The women were of the Yi, Hui, Dai, and Han ethnicities. RESULTS: The overwhelming majority of the women surveyed understood the self-sampling instructions (588/600, 98%) and felt comfortable carrying out the self-sampling procedure (584/600, 97%). Significantly more women (389/600, 64.8%) preferred self-sampling to having the provider (211/600, 35.2%) obtain the sample (χ = 105.61, p < .05). Women who preferred self-sampling did so primarily because they felt capable of obtaining the specimens (n = 80) or that it was a more convenient way to be tested (n = 79). The medical expertise of the provider (n = 74) and concerns over the accuracy of the test (n = 88) shifted some women's preference toward a provider-obtained sample. CONCLUSIONS: There are 400+ million Chinese women who have never had a cervical cancer screening. Self-testing has the potential to significantly increase the number of women tested. Despite the diversity of the women screened, the majority felt comfortable self-sampling and preferred self-swabbing to provider testing.

Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via ß-catenin signaling.

The cell surface protein Trop2 is expressed on immature stem/progenitor-like cells and is overexpressed in many epithelial cancers. However the biological function of Trop2 in tissue maintenance and tumorigenesis remains unclear. In this study, we demonstrate that Trop2 is a regulator of self-renewal, proliferation, and transformation. Trop2 controls these processes through a mechanism of regulated intramembrane proteolysis that leads to cleavage of Trop2, creating two products: the extracellular domain and the intracellular domain. The intracellular domain of Trop2 is released from the membrane and accumulates in the nucleus. Heightened expression of the Trop2 intracellular domain promotes stem/progenitor self-renewal through signaling via ß-catenin and is sufficient to initiate precursor lesions to prostate cancer in vivo. Importantly, we demonstrate that loss of ß-catenin or Trop2 loss-of-function cleavage mutants abrogates Trop2-driven self-renewal and hyperplasia in the prostate. These findings suggest that heightened expression of Trop2 is selected for in epithelial cancers to enhance the stem-like properties of self-renewal and proliferation. Defining the mechanism of Trop2 function in self-renewal and transformation is essential to identify new therapeutic strategies to block Trop2 activation in cancer.

Dynamically decreased miR-671-5p expression is associated with oncogenic transformation and radiochemoresistance in breast cancer.

BACKGROUND: Understanding the molecular alterations associated with breast cancer (BC) progression may lead to more effective strategies for both prevention and management. The current model of BC progression suggests a linear, multistep process from normal epithelial to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Up to 20% ADH and 40% DCIS lesions progress to invasive BC if left untreated. Deciphering the molecular mechanisms during BC progression is therefore crucial to prevent over- or under-treatment. Our previous work demonstrated that miR-671-5p serves as a tumor suppressor by targeting Forkhead box protein M1 (FOXM1)-mediated epithelial-to-mesenchymal transition (EMT) in BC. Here, we aim to explore the role of miR-671-5p in the progression of BC oncogenic transformation and treatment. METHODS: The 21T series cell lines, which were originally derived from the same patient with metastatic BC, including normal epithelia (H16N2), ADH (21PT), primary DCIS (21NT), and cells derived from pleural effusion of lung metastasis (21MT), and human BC specimens were used. Microdissection, miRNA transfection, dual-luciferase, radio- and chemosensitivity, and host-cell reactivation (HCR) assays were performed. RESULTS: Expression of miR-671-5p displays a gradual dynamic decrease from ADH, to DCIS, and to IDC. Interestingly, the decreased expression of miR-671-5p detected in ADH coexisted with advanced lesions, such as DCIS and/or IDC (cADH), but not in simple ADH (sADH). Ectopic transfection of miR-671-5p significantly inhibited cell proliferation in 21NT (DCIS) and 21MT (IDC), but not in H16N2 (normal) and 21PT (ADH) cell lines. At the same time, the effect exhibited in time- and dose-dependent manner. Interestingly, miR-671-5p significantly suppressed invasion in 21PT, 21NT, and 21MT cell lines. Furthermore, miR-671-5p suppressed FOXM1-mediated EMT in all 21T cell lines. In addition, miR-671-5p sensitizes these cell lines to UV and chemotherapeutic exposure by reducing the DNA repair capability. CONCLUSIONS: miR-671-5p displays a dynamic decrease expression during the oncogenic transition of BC by suppressing FOXM1-mediated EMT and DNA repair. Therefore, miR-671-5p may serve as a novel biomarker for early BC detection as well as a therapeutic target for BC management.

Surgical management of neuroproliferative-associated vestibulodynia: a tutorial on vestibulectomy with vaginal advancement flap.

Provoked vestibulodynia is an often underdiagnosed and mismanaged medical condition that impacts the lives of many women. When symptoms are due to a dramatically increased density of pain fibers in the vestibular endoderm, the condition is referred to as neuroproliferative-associated vestibulodynia. Unfortunately, assessment of pain fiber density can only be performed after surgery during histologic examination. First-line therapies for this condition often include topical or oral medications targeting hyperalgesia and allodynia at the vulvar vestibule. However, in the setting of refractory disease, surgical treatment should be considered. The surgical video (Video 1) highlights anatomical landmarks as well as key surgical steps when performing a vulvar vestibulectomy with a vaginal advancement flap for the treatment of neuroproliferative-associated vestibulodynia. Surgeons should have a thorough understanding of pertinent vulvar anatomical landmarks before performing this procedure (Figure 1). The goal of vulvar vestibulectomy, as described in this video, is to excise the entirety of the vestibule containing the pathologic density of afferent pain fibers. This tutorial serves to identify key anatomical landmarks including Hart's line as well as outline the meticulous dissection required for successful completion of this procedure. We describe our surgical instrumentation as well as provide insight into steps that can be taken to minimize postoperative morbidity.

Spironolactone May be a Cause of Hormonally Associated Vestibulodynia and Female Sexual Arousal Disorder.

BACKGROUND: Although spironolactone is an effective treatment for androgen-mediated cutaneous disorders, the potential sexual side-effects are poorly documented in current literature. AIM: The purpose of this study was to provide clinical evidence that spironolactone may be a cause of hormonally associated vestibulodynia and female sexual arousal disorder. METHODS: A database search of a vulvar disorders clinic revealed 7 cases in which spironolactone may have caused or contributed to dyspareunia and decreased arousal. In all cases, the patients stopped taking spironolactone and used a compounded estradiol 0.01%/testosterone 0.1% gel to the vestibule twice daily. 2 cases are discussed to further illustrate these previously unreported side effects. OUTCOMES: Improvement in sexual function was determined after treatment. RESULTS: Examination of women taking spironolactone who presented with the complaints of introital dyspareunia revealed vulvar vestibular atrophy and tenderness, especially at the glandular ostia. After stopping spironolactone and applying a topical estrogen/testosterone gel to the vestibule, all women had significant improvement in their vulvar atrophy, resolution of their dyspareunia, and improved sexual arousal. CLINICAL IMPLICATIONS: Use of spironolactone may be a cause of hormonally associated vestibulodynia and female sexual arousal disorder. STRENGTHS AND LIMITATIONS: The influence of spironolactone on vulvar health and sexual function is poorly documented in the medical literature. The strength of this paper is that it examines the potential deleterious side effects of this medication on female sexual function. However, the most significant limitation of this case series is that it was not a prospective, controlled study. CONCLUSIONS: Although treatment of androgen-mediated cutaneous disorders is warranted, medical providers should be aware of the potential sexual side effects of this anti-androgenic medication. Mitchell L, Govind V, Barela K, et al. Spironolactone May be a Cause of Hormonally Associated Vestibulodynia and Female Sexual Arousal Disorder. J Sex Med 2019;16:1481-1483.

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.

Assessment of executive functions in children and adolescents with acquired brain injury (ABI) using a novel complex multi-tasking computerised task: The Jansari assessment of Executive Functions for Children (JEF-C©).

Objectives: The Jansari assessment of Executive Functions for Children (JEF-C©) is a new non-immersive computerised assessment of executive functions. The objectives of the study were to test the feasibility and validity of JEF-C© in children and adolescents with acquired brain injury (ABI). Methods: Twenty-nine patients with ABI aged 10-18 years and 30 age-and gender-matched controls were tested. Participants performed JEF-C©, Wechsler Abbreviated Scale of Intelligence (WASI) and the Behavioural Assessment of the Dysexecutive Syndrome for Children (BADS-C), while parents completed the Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire. Results: The JEF-C© task proved feasible in patients with ABI. The internal consistency was medium (Cronbach's alpha = 0.62 and significant intercorrelations between individual JEF-C© constructs). Patients performed significantly worse than controls on most of the JEF-C© subscales and total score, with 41.4% of participants with ABI classified as having severe executive dysfunction. No significant correlations were found between JEF-C© total score, the BRIEF indices, and the BADS-C. Significant correlations were found between JEF-C© and demographic characteristics of the sample and intellectual ability, but not with severity/medical variables. Conclusion: JEF-C© is a playful complex task that appears to be a sensitive and ecologically valid assessment tool, especially for relatively high-functioning individuals.

Descriptors of Vulvodynia: A Multisocietal Definition Consensus (International Society for the Study of Vulvovaginal Disease, the International Society for the Study of Women Sexual Health, and the International Pelvic Pain Society).

OBJECTIVES: Three scientific societies, the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS) developed the "2015 ISSVD, ISSWSH, and IPPS Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia" (referred to as the "2015 consensus terminology").The terminology included 11 descriptors of vulvodynia. However, the definitions of the descriptors were not included in the 2015 consensus terminology publications. The objective of this article was to provide these definitions. MATERIALS AND METHODS: The ISSVD led a discussion on the definitions for the 11 vulvodynia descriptors, with participation from the ISSWSH and IPPS. The definitions were created through a consensus process. RESULTS: The definitions are described and the rationale for their choice is elucidated. CONCLUSIONS: The definitions of vulvodynia descriptors were determined by a multistaged process of discussion among health care providers with expertise in the pathophysiology, evaluation, and treatment of vulvodynia. The definitions were approved by the ISSVD, ISSWSH, and IPPS. It is recommended that these definitions of vulvodynia descriptors as well as the 2015 consensus terminology be used for the classification of vulvodynia.