STUDY QUESTION How does exposure to a testosterone rich environment affect the function and gene expression of human fallopian tube epithelium (hFTE)? SUMMARY ANSWER Elevated testosterone level alters several gene transcripts that regulate cilia expression and negatively impacts the rate of cilia beating. WHAT IS KNOWN ALREADY The presence of estrogen in the follicular phase of the menstrual cycle increases the human fallopian tube ciliary beating frequency. The luteal phase, triggered by ovulation and increasing progesterone, is marked by a decrease in ciliary beating. Women with polycystic ovarian syndrome (PCOS) may have twice the serum level of testosterone than ovulatory women. To date, the effect of elevated androgens on the function of the human fallopian tube is not well-understood. We chose to examine the impact of elevated testosterone on hFTE. STUDY DESIGN, SIZE, DURATION A prospective basic science study of human fallopian tube specimens from reproductive-aged women undergoing benign gynecologic surgery was performed. Fallopian tube removal at a large US academic center was collected and provided to us to continue with epithelium isolation and culturing. A total of 12 patients were analyzed in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS Fallopian tube epithelium was isolated and exposed to two different conditions: normal with low testosterone concentration of 0.8 nM and PCOS-like, with high testosterone concentration of 2 nM. The study was conducted in both static and dynamic conditions in microfluidic devices for a total of 14 days, after which the tissue was collected for processing including RNA extraction, quantitative PCR and immunohistochemistry. After the first 7 days of each experiment, a sample of tissue from each condition was imaged to quantify cilia beating frequency. MAIN RESULTS AND THE ROLE OF CHANCE hFTE exposed to the 2 nM testosterone displayed slower cilia beating, inhibited estrogen signaling and decreased expression of the ciliary marker FOXJ1 when compared to stimulation with 0.8 nM testosterone. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The in vivo response to elevated testosterone may differ from in vitro studies. RNA amount was limited from tissue cultured in the microfluidic devices as compared to static culture. WIDER IMPLICATIONS OF THE FINDINGS Understanding elevated testosterone in tubal function may explain an additional contribution to subfertility in women with PCOS and other hyper-androgen disorders, aside from oligo-ovulation. Furthermore, this adds to the body of literature of fallopian tube function using a microfluidic device. STUDY FUNDING/COMPETING INTEREST(S) NIH grants: UH3 ES029073 and R01 CA240301. There are no competing interests.

with neuropathological features common to both chordoma and ecchordosis physaliphora. 1999; 19, 336-340 An unusual case of a 54-year-old woman who presented with a one-and-a-half year history of dizziness and in whom neuroimaging studies revealed an intradural prepontine growth without radiological evidence of bone involvement, is reported. A marked histological resemblance to both ecchordosis physaliphora and chordoma was observed. The medical literature concerning similar lesions is reviewed. Neuropathology

The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.

Abstract High-grade serous ovarian cancer (HGSOC) is thought to progress from a series of precursor lesions in the fallopian tube epithelium (FTE). One of the preneoplastic lesions found in the FTE is called a secretory cell outgrowth (SCOUT), which is partially defined by a loss of paired box 2 (PAX2). In the present study, we developed PAX2-deficient murine cell lines in order to model a SCOUT and to explore the role of PAX2 loss in the etiology of HGSOC. Loss of PAX2 alone in the murine oviductal epithelium (MOE) did not induce changes in proliferation, migration and survival in hypoxia or contribute to resistance to first line therapies, such as cisplatin or paclitaxel. RNA sequencing of MOE PAX2shRNA cells revealed significant alterations in the transcriptome. Silencing of PAX2 in MOE cells produced a messenger RNA expression pattern that recapitulated several aspects of the transcriptome of previously characterized human SCOUTs. RNA-seq analysis and subsequent qPCR validation of this SCOUT model revealed an enrichment of genes involved in estrogen signaling and an increase in expression of estrogen receptor α. MOE PAX2shRNA cells had higher estrogen signaling activity and higher expression of putative estrogen responsive genes both in the presence and absence of exogenous estrogen. In summary, loss of PAX2 in MOE cells is sufficient to transcriptionally recapitulate a human SCOUT, and this model revealed an enrichment of estrogen signaling as a possible route for tumor progression of precursor lesions in the fallopian tube.

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy that is primarily detected at the metastatic stage. Most HGSOC originates from the fallopian tube epithelium (FTE) and metastasizes to the ovary before invading the peritoneum; therefore, it is crucial to study disease initiation and progression using FTE-derived models. We previously demonstrated that loss of PTEN from the FTE leads to ovarian cancer. In the present study, loss of PTEN in FTE led to the enrichment of cancer stem cell markers such as LGR5, WNT4, ALDH1, CD44. Interestingly, loss of the transcription factor PAX2, which is a common and early alteration in HGSOC, played a pivotal role in the expression of cancer stem-like cells (CSC) markers and cell function. In addition, loss of PTEN led to the generation of two distinct subpopulations of cells with different CSC marker expression, tumorigenicity, and chemoresistance profiles. Taken together, these data suggest that loss of PTEN induces reprogramming of the FTE cells into a more stem-like phenotype due to loss of PAX2 and provides a model to study early events during the FTE-driven ovarian cancer tumor formation.

High-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, ~30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in Patient-Derived HGSC cells and Xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56,B56 and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlate with worse overall patient survival. We show that SMAP-061 stabilization of PP2A inhibits the homologous recombination (HR) output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient cells and in PDX models. Our studies identifies PP2A as a novel regulator of HR and indicates PP2A modulators as a therapeutic therapy for HGSC. In sum, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi-resistance driven by BRCA1/2 mutation reversions.

A todas luces, la metodología transdisciplinaria no remplaza la metodología de cada disciplina, que sigue siendo lo que es. Pero la metodología transdisciplinariafecunda estas disciplinas, aportando nuevas e indispensables claridades, que no pueden producirse con la metodología disciplinaria. La metodología transdisciplinaria podría conducir a verdaderos descubrimientos en el seno de las disciplinas, lo cual es natural puesto que uno de los objetivos de la transdisciplinariedad es la búsqueda de lo que atraviesa las disciplinas” (Tomado del libro de Basarab Nicolescu, 1996: p. 89). Basado en las corrientes del filósofo Edgar Morín, se cita lo que a mi parecer es la interpretación más realista y simple de la ciencia transdisciplinaria, dada la complejidad del tema. En honor a este “dogma”, “corolario”, “postulado”….Se abren las puertas a esta edición del Diario del Monte Scopus, con las investigaciones de científicos que no solohacen ciencia pura, sino ciencia humana; es decir, difunden el conocimiento para el multiverso cultural de los lectores. Invitados quedan todos ustedes, a conocer sobre los aportes de estos humanos transdisciplinarios

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