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PLoS Genetics Jun 2020Reactive oxygen species (ROS) are signalling molecules whose study in intact organisms has been hampered by their potential toxicity. This has prevented a full...
Reactive oxygen species (ROS) are signalling molecules whose study in intact organisms has been hampered by their potential toxicity. This has prevented a full understanding of their role in organismal processes such as development, aging and disease. In Caenorhabditis elegans, the development of the vulva is regulated by a signalling cascade that includes LET-60ras (homologue of mammalian Ras), MPK-1 (ERK1/2) and LIN-1 (an ETS transcription factor). We show that both mitochondrial and cytoplasmic ROS act on a gain-of-function (gf) mutant of the LET-60ras protein through a redox-sensitive cysteine (C118) previously identified in mammals. We show that the prooxidant paraquat as well as isp-1, nuo-6 and sod-2 mutants, which increase mitochondrial ROS, inhibit the activity of LET-60rasgf on vulval development. In contrast, the antioxidant NAC and loss of sod-1, both of which decrease cytoplasmic H202, enhance the activity of LET-60rasgf. CRISPR replacement of C118 with a non-oxidizable serine (C118S) stimulates LET-60rasgf activity, whereas replacement of C118 with aspartate (C118D), which mimics a strongly oxidised cysteine, inhibits LET-60rasgf. These data strongly suggest that C118 is oxidized by cytoplasmic H202 generated from dismutation of mitochondrial and/or cytoplasmic superoxide, and that this oxidation inhibits LET-60ras. This contrasts with results in cultured mammalian cells where it is mostly nitric oxide, which is not found in worms, that oxidizes C118 and activates Ras. Interestingly, PQ, NAC and the C118S mutation do not act on the phosphorylation of MPK-1, suggesting that oxidation of LET-60ras acts on an as yet uncharacterized MPK-1-independent pathway. We also show that elevated cytoplasmic superoxide promotes vulva formation independently of C118 of LET-60ras and downstream of LIN-1. Finally, we uncover a role for the NADPH oxidases (BLI-3 and DUOX-2) and their redox-sensitive activator CED-10rac in stimulating vulva development. Thus, there are at least three genetically separable pathways by which ROS regulates vulval development.
Topics: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Female; Gain of Function Mutation; Gene Expression Regulation, Developmental; Genes, Helminth; Oxidation-Reduction; Oxidoreductases; Peroxides; Signal Transduction; Transcription Factors; Vulva; rac GTP-Binding Proteins; ras Proteins
PubMed: 32544191
DOI: 10.1371/journal.pgen.1008838 -
American Journal of Obstetrics and... Aug 2023
Topics: Female; Humans; Herpes Zoster; Herpesvirus 3, Human; Vulva
PubMed: 36828295
DOI: 10.1016/j.ajog.2023.02.013 -
International Urogynecology Journal Sep 2022
Topics: Clitoris; Epidermal Cyst; Female; Humans; Postpartum Period; Vulvar Diseases
PubMed: 35380211
DOI: 10.1007/s00192-022-05177-7 -
Pathology Jun 2016Growing evidence has established two major types of vulvar intraepithelial neoplasia (VIN), which correspond to two distinct oncogenic pathways to vulvar squamous cell... (Review)
Review
Growing evidence has established two major types of vulvar intraepithelial neoplasia (VIN), which correspond to two distinct oncogenic pathways to vulvar squamous cell carcinoma (VSCC). While the incidence of VSCC has remained relatively stable over the last three decades, the incidence of VIN has increased. VIN of usual type (uVIN) is human papillomavirus (HPV)-driven, affects younger women and is a multicentric disease. In contrast, VIN of differentiated type (dVIN) occurs in post-menopausal women and develops independent of HPV infection. dVIN often arises in a background of lichen sclerosus and chronic inflammatory dermatoses. Although isolated dVIN is significantly less common than uVIN, dVIN bears a greater risk for malignant transformation to VSCC and progresses over a shorter time interval. On histological examination, uVIN displays conspicuous architectural and cytological abnormalities, while the morphological features that characterise dVIN are much more subtle and raise a wide differential diagnosis. On the molecular level, dVIN is characterised by a higher number of somatic mutations, particularly in TP53. Here we review the classification, epidemiology, clinical features, histomorphology, ancillary markers and molecular genetics of both types of VIN, and discuss the morphological challenges faced by pathologists in interpreting these lesions.
Topics: Carcinoma in Situ; Carcinoma, Squamous Cell; Female; Humans; Precancerous Conditions; Vulva; Vulvar Neoplasms
PubMed: 27113549
DOI: 10.1016/j.pathol.2016.02.015 -
Journal of the American Academy of... Oct 2023
Topics: Female; Humans; Vulvar Lichen Sclerosus; Vitiligo; Lichen Sclerosus et Atrophicus; Vulva; Hypopigmentation; Vulvar Neoplasms; Vulvar Diseases
PubMed: 37328003
DOI: 10.1016/j.jaad.2023.06.016 -
Urology Mar 2023To test the hypothesis that genital skin and male urethra affected by lichen sclerosus (LS) has increased collagen content and altered collagen structure.
OBJECTIVE
To test the hypothesis that genital skin and male urethra affected by lichen sclerosus (LS) has increased collagen content and altered collagen structure.
METHODS
We used picrosirius red to stain and image collagen in human urethral, vulvar, and foreskin specimens with and without LS. Using Image J software, we quantified and compared (1) collagen content (using 2o metrics: collagen proportionate area [CPA] and collagen fiber count), (2) collagen fiber length and width, and (3) collagen structure using the texture analysis technique gray level co-localization matrix (GLCM) with respect to LS status and tissue type.
RESULTS
We analyzed 23 LS specimens (vulva n=9, urethra n=7, foreskin n=7) and 29 non-LS specimens (vulva n=9, urethra n=7, foreskin n=13). Fiber count and CPA were significantly higher in all LS specimens compared to non-LS specimens (CPA: mean±SD 0.971±0.03 vs 0.948±0.02, P < .007; fiber count: mean±SD = 2906±127 vs 2509±78 fibers; P = .003). Collagen fiber width and length were similar with respect to LS status. GLCM analysis showed decreased inverse difference moment and increased entropy in LS tissues indicative of less homogeneous and more disorganized tissue structure (P<.001).
CONCLUSION
LS tissues have greater collagen content compared to non-LS tissues. Quantitative assessment of collagen organization, using GLCM, revealed less homogeneity and more disorganization of collagen in LS compared to non-LS tissues. Taken together, our findings suggest that alterations in physical tissue properties seen in LS may be due to both increased collagen abundance and altered structure.
Topics: Female; Male; Humans; Lichen Sclerosus et Atrophicus; Vulva; Collagen; Skin; Extracellular Matrix
PubMed: 36509210
DOI: 10.1016/j.urology.2022.11.036 -
Journal of Anatomy Feb 2021The clitoris is a leading player in female sexual arousal, if not the main protagonist. Despite this role, studies performed on this structure with specific...
The clitoris is a leading player in female sexual arousal, if not the main protagonist. Despite this role, studies performed on this structure with specific neuroanatomical techniques are few. This study focuses on glans clitoris innervation, with special emphasis on sensory corpuscles and the presence of the mechanotransducer protein PIEZO2 in these structures. Six glans clitoris samples were obtained at autopsy covering an age spectrum between 52 and 83 years old. Several types of nerve terminations including free nerve endings, genital endbulbs as well as Meissner-like corpuscles and Pacinian corpuscles, but not Ruffini corpuscles, were found. Although corpuscular morphology in the glans clitoris was subtly different from the cutaneous digital counterparts, their basic composition was comparable for both Pacinian and Meissner-like corpuscles. Genital endbulbs showed heterogeneous morphology, and the axons usually exhibited a typical "wool ball" or "yarn ball" aspect. Some of them were lobulated and variably encapsulated by endoneurial elements (65%); from the capsule originate septa that divides the genital endbulbs, suggesting that they are found in clusters rather than as single corpuscles. In addition, most corpuscles in the glans clitoris showed axonal PIEZO2 immunoreactivity, thus, suggesting a mechanical role and molecular mechanisms of mechanosensibility similar to those of digital Meissner's corpuscles. Our results demonstrate that sensory corpuscles of the glans clitoris are similar to those of other glabrous skin zones, as most genital organs are characterized by clusters of corpuscles and the occurrence of the mechanoprotein PIEZO2 in the axons. These findings strongly suggest that PIEZO2 participates in erotic and sexual mechanical sensing.
Topics: Aged; Aged, 80 and over; Clitoris; Female; Humans; Ion Channels; Mechanoreceptors; Mechanotransduction, Cellular; Middle Aged
PubMed: 32996126
DOI: 10.1111/joa.13317 -
International Journal of... Sep 2016Genital tract tuberculosis is usually secondary to extragenital tuberculosis. The upper genital tract is usually involved; involvement of cervix and vulva is very...
Genital tract tuberculosis is usually secondary to extragenital tuberculosis. The upper genital tract is usually involved; involvement of cervix and vulva is very uncommon. We present two such rare cases of vulval and cervical tuberculosis diagnosed on histopathology and treated with antitubercular chemotherapy.
Topics: Adult; Antitubercular Agents; Cervix Uteri; Female; Histocytochemistry; Humans; Microscopy; Middle Aged; Tuberculosis, Female Genital; Vulva
PubMed: 27847026
DOI: 10.1016/j.ijmyco.2016.06.017 -
Abdominal Radiology (New York) Dec 2021Primary vulvar and vaginal cancers are rare female genital tract malignancies which are staged using the 2009 International Federation of Gynecology and Obstetrics... (Review)
Review
Primary vulvar and vaginal cancers are rare female genital tract malignancies which are staged using the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging. These cancers account for approximately 2,700 deaths annually in the USA. The most common histologic subtype of both vulvar and vaginal cancers is squamous cell carcinoma, with an increasing role of the human papillomavirus (HPV) in a significant number of these tumors. Lymph node involvement is the hallmark of FIGO stage 3 vulvar cancer while pelvic sidewall involvement is the hallmark of FIGO stage 3 vaginal cancer. Imaging techniques include computed tomography (CT), positron emission tomography (PET)-CT, magnetic resonance imaging (MRI), and PET-MRI. MRI is the imaging modality of choice for preoperative clinical staging of nodal and metastatic involvement while PET-CT is helpful with assessing response to neoadjuvant treatment and for guiding patient management. Determining the pretreatment extent of disease has become more important due to modern tailored operative approaches and use of neoadjuvant chemoradiation therapy to reduce surgical morbidity. Moreover, imaging is used to determine the full extent of disease for radiation planning and for evaluating treatment response. Understanding the relevant anatomy of the vulva and vaginal regions and the associated lymphatic pathways is helpful to recognize the potential routes of spread and to correctly identify the appropriate FIGO stage. The purpose of this article is to review the clinical features, pathology, and current treatment strategies for vulvar and vaginal malignancies and to identify multimodality diagnostic imaging features of these gynecologic cancers, in conjunction with its respective 2009 FIGO staging system guidelines.
Topics: Female; Genital Neoplasms, Female; Humans; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Pregnancy; Radiologists; Vaginal Neoplasms; Vulva
PubMed: 34435227
DOI: 10.1007/s00261-021-03209-2 -
G3 (Bethesda, Md.) Sep 2022Communication between mesodermal cells and epithelial cells is fundamental to normal animal development and is frequently disrupted in cancer. However, the genes and...
Communication between mesodermal cells and epithelial cells is fundamental to normal animal development and is frequently disrupted in cancer. However, the genes and processes that mediate this communication are incompletely understood. To identify genes that mediate this communication and alter the proliferation of cells with an oncogenic Ras genotype, we carried out a tissue-specific genome-wide RNAi screen in Caenorhabditis elegans animals bearing a let-60(n1046gf) (RasG13E) allele. The screen identifies 24 genes that, when knocked down in adjacent mesodermal tissue, suppress the increased vulval epithelial cell proliferation defect associated with let-60(n1046gf). Importantly, gene knockdown reverts the mutant animals to a wild-type phenotype. Using chimeric animals, we genetically confirm that 2 of the genes function nonautonomously to revert the let-60(n1046gf) phenotype. The effect is genotype restricted, as knockdown does not alter development in a wild type (let-60(+)) or activated EGF receptor (let-23(sa62gf)) background. Although many of the genes identified encode proteins involved in essential cellular processes, including chromatin formation, ribosome function, and mitochondrial ATP metabolism, knockdown does not alter the normal development or function of targeted mesodermal tissues, indicating that the phenotype derives from specific functions performed by these cells. We show that the genes act in a manner distinct from 2 signal ligand classes (EGF and Wnt) known to influence the development of vulval epithelial cells. Altogether, the results identify genes with a novel function in mesodermal cells required for communicating with and promoting the proliferation of adjacent epithelial cells with an activated Ras genotype.
Topics: Adenosine Triphosphate; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Chromatin; Epidermal Growth Factor; ErbB Receptors; Female; Helminth Proteins; Ligands; Mutation; Signal Transduction; Vulva; ras Proteins
PubMed: 35929788
DOI: 10.1093/g3journal/jkac200