Network-Based Integration of Multi-Omics Data Identifies the Determinants of miR-491-5p Effects.

The identification of miRNAs' targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA's effects. Based on this assumption we devised a multi-omics approach to precisely characterize miRNAs' effects. We combined miR-491-5p target affinity purification, RNA microarray, and mass spectrometry to perform an integrated analysis in ovarian cancer cell lines. We thus constructed an interaction network that highlighted highly connected hubs being either direct or indirect targets of miR-491-5p effects: the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases. By using different combinations of specific inhibitors of these hubs, we could greatly enhance their respective cytotoxicity and mimic the miR-491-5p-induced phenotype. Our methodology thus constitutes an interesting strategy to comprehensively study the effects of a given miRNA. Moreover, we identified targets for which pharmacological inhibitors are already available for a clinical use or in clinical trials. This study might thus enable innovative therapeutic options for ovarian cancer, which remains the leading cause of death from gynecological malignancies in developed countries.

The lncRNA 'UCA1' modulates the response to chemotherapy of ovarian cancer through direct binding to miR-27a-5p and control of UBE2N levels.

Ovarian cancer (OC) is the leading cause of death in patients with gynecologic cancers. Due to late diagnosis and resistance to chemotherapy, the 5-year survival rate in patients with OC is below 40%. We observed that UCA1, a lncRNA previously reported to play an oncogenic role in several malignancies, is overexpressed in the chemoresistant OC cell line OAW42-R compared to their chemotherapy-sensitive counterpart OAW42. Additionally, UCA1 overexpression was related to poor prognosis in two independent patient cohorts. Currently, the molecular mechanisms through which UCA1 acts in OC are poorly understood. We demonstrated that downregulation of the short isoform of UCA1 sensitized OC cells to cisplatin and that UCA1 acted as competing endogenous RNA to miR-27a-5p. Upon UCA1 downregulation, miR-27a-5p downregulated its direct target UBE2N leading to the upregulation of BIM, a proapoptotic protein of the Bcl2 family. The upregulation of BIM is the event responsible for the sensitization of OC cells to cisplatin. In order to model response to therapy in patients with OC, we used several patient-derived organoid cultures, a model faithfully mimicking patient's response to therapy. Inhibition of UBE2N sensitized patient-derived organoids to platinum salts. In conclusion, response to treatment in patients with OC is regulated by the UCA1/miR-27a-5p/UBE2N axis, where UBE2N inhibition could potentially represent a novel therapeutic strategy to counter chemoresistance in OC.

Identifying patients eligible for PARP inhibitor treatment: from NGS-based tests to 3D functional assays.

Within the past few years, poly (ADP-ribose) polymerase inhibitors (PARPi) have been added to the standard of care for cancer patients, mainly for those exhibiting specific genomic alterations in the homologous recombination (HR) pathway. Until now, patients who are eligible to receive PARPi have been identified using next-generation sequencing (NGS) of gene panels. However, NGS analyses do have some limitations, with a subset of patients with negative NGS-based results can exhibit a clinical benefit, responding positively to PARPi, despite the failure to detect dynamic and predictive biomarkers such as mutated BRCA1/2 genes. Furthermore, the sequencing of initial tumour does not allow to detect reversions or secondary mutations that can restore proficient HR and lead to PARPi resistance. Therefore, it is crucial to better identify patients who are likely to benefit from PARPi treatment. In this context, tumour models such as patient-derived xenografts or tumour-derived organoids could help to guide clinicians in their decision making as these models accurately mimic phenotypic and genetic tumour heterogeneity, and could reflect treatment response in an integrative manner. In this Perspective article, we provide an overview of the currently available NGS-based tests that enable the identification of patients who might benefit from PARPi, and outline breakthroughs and discoveries to expand this selection using 3D functional assays. Combining NGS with functional assays could facilitate the efficient identification of patients, thereby improving patient survival.

Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib.

Ovarian cancer represents the first cause of mortality from gynecologic malignancies due to frequent chemoresistance occurrence. Increasing the [BH3-only Bim, Puma, Noxa proapoptotic]/[Bcl-xL, Mcl-1 antiapoptotic] proteins ratio was proven to efficiently kill ovarian carcinoma cells and development of new molecules to imbalance Bcl-2 member equilibrium are strongly required. Drug repurposing constitutes an innovative approach to rapidly develop therapeutic strategies through exploitation of established drugs already approved for the treatment of noncancerous diseases. This strategy allowed a renewed interest for Naftopidil, an α1-adrenergic receptor antagonist commercialized in Japan for benign prostatic hyperplasia. Naftopidil was reported to decrease the incidence of prostate cancer and its derivative was described to increase BH3-only protein expression in some cancer models. Based on these arguments, we evaluated the effects of Naftopidil on ovarian carcinoma and showed that Naftopidil reduced cell growth and increased the expression of the BH3-only proteins Bim, Puma and Noxa. This effect was independent of α1-adrenergic receptors blocking and involved ATF4 or JNK pathway depending on cellular context. Finally, Naftopidil-induced BH3-only members sensitized our models to ABT-737 and Trametinib treatments, in vitro as well as ex vivo, in patient-derived organoid models.

Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids.

Novel therapeutic strategies are urgently required for the clinical management of chemoresistant ovarian carcinoma, which is the most lethal of the gynecologic malignancies. miRNAs hold promise because they play a critical role in determining the cell phenotype by regulating several hundreds of targets, which could constitute vulnerabilities of cancer cells. A combination of gain-of-function miRNA screening and real-time continuous cell monitoring allows the identification of miRNAs with robust cytotoxic effects in chemoresistant ovarian cancer cells. Focusing on miR-3622b-5p, we show that it induces apoptosis in several ovarian cancer cell lines by both directly targeting Bcl-xL and EGFR-mediating BIM upregulation. miR-3622b-5p also sensitizes cells to cisplatin by inhibiting Bcl-xL in ovarian cancer cell lines escaping BIM induction. miR-3622b-5p also exerts antimigratory capacities by targeting both LIMK1 and NOTCH1. These wide-ranging antitumor properties of miR-3622b-5p in ovarian cancer cells are mimicked by the associations of pharmacologic inhibitors targeting these proteins. The combination of an EGFR inhibitor together with a BH3-mimetic molecule induced a large decrease in cell viability in a panel of ovarian cancer cell lines and several ovarian patient-derived tumor organoids, suggesting the value of pursuing such a combination therapy in ovarian carcinoma. Altogether, our work highlights the potential of phenotype-based miRNA screening approaches to identify lethal interactions which might lead to new drug combinations and clinically applicable strategies.

Predictive Relevance of Circulating miR-622 in Patients with Newly Diagnosed and Recurrent High-Grade Serous Ovarian Carcinoma.

BACKGROUND: Identifying patients with high-grade serous ovarian cancer (HGSOC) who will respond to treatment remains a clinical challenge. We focused on miR-622, a miRNA involved in the homologous recombination repair (HRR) pathway, and we assessed its predictive value in serum prior to first-line chemotherapy and at relapse. METHODS: Serum miR-622 expression was assessed in serum prior to first-line platinum-based chemotherapy in a prospective multicenter study (miRNA Serum Analysis, miRSA, NCT01391351) and a retrospective cohort (Biological Resource Center, BRC), and was also studied at relapse. Progression-free survival (PFS) and overall survival (OS) were used as primary and secondary endpoints prior to first-line chemotherapy and OS as a primary endpoint at relapse. RESULTS: The group with high serum miR-622 expression was associated with a significantly lower PFS (15.4 versus 24.4 months; adjusted HR 2.11, 95% CI 1.2 3.8, P = 0.015) and OS (29.7 versus 40.6 months; adjusted HR 7.68, 95% CI 2.2-26.2, P = 0.0011) in the miRSA cohort. In the BRC cohort, a high expression of miR-622 was also associated with a significantly lower OS (22.8 versus 35.9 months; adjusted HR 1.98, 95% CI 1.1-3.6, P = 0.026). At relapse, high serum miR-622 was associated with a significantly lower OS (7.9 versus 20.6 months; adjusted HR 3.15, 95% CI 1.4-7.2, P = 0.0062). Serum miR-622 expression is a predictive independent biomarker of response to platinum-based chemotherapy for newly diagnosed and recurrent HGSOC. CONCLUSIONS: These results may open new perspectives for HGSOC patient stratification and monitoring of resistance to platinum-based and poly(ADP-ribose)-polymerase-inhibitor-maintenance therapies, facilitating better and personalized treatment decisions.

The influence of long non-coding RNAs on the response to chemotherapy in ovarian cancer.

With 240,000 new cases and 152,000 deaths per year, ovarian cancer is the leading cause of death from gynecologic malignancies. Late diagnosis because of asymptomatic development in early stages and resistance to existing treatments are the major causes of therapeutic failure in ovarian cancer. The recent discovery of tens of thousands of long non-coding RNAs and their action as oncogenes or tumor suppressors in pathways matching all the hallmarks of cancer in most - if not all - malignancies have attracted attention of the scientific community. A growing number of studies have implicated lncRNAs in diverse aspects of ovarian carcinoma biology. We present lncRNAs which have been involved in response to the different drugs currently used for the treatment of ovarian cancers, from first-line platinum salts and taxanes to the newly available PARP inhibitors. The data already available supports the potential use of several lncRNAs, alone or in combination with other molecules, as potential biomarkers for the prediction of response to treatment. Understanding the determinants of their action might reveal new potential therapeutic targets.

Inhibition of store-operated channels by carboxyamidotriazole sensitizes ovarian carcinoma cells to anti-BclxL strategies through Mcl-1 down-regulation.

The anti-apoptotic proteins Bcl-xL and Mcl-1 have been identified to play a pivotal role in apoptosis resistance in ovarian cancer and constitute key targets for innovative therapeutic strategies. Although BH3-mimetics (i.e. ABT-737) potently inhibit Bcl-xL activity, targeting Mcl-1 remains a hurdle to the success of these strategies. Calcium signaling is profoundly remodeled during carcinogenesis and was reported to activate the signaling pathway controlling Mcl-1 expression. In this context, we investigated the effect of carboxyamidotriazole (CAI), a calcium channel inhibitor used in clinical trials, on Mcl-1 expression. CAI had an anti-proliferative effect on ovarian carcinoma cell lines and strongly down-regulated Mcl-1 expression. It inhibited store-operated calcium entry (SOCE) and Mcl-1 translation through mTORC1 deactivation. Moreover, it sensitized ovarian carcinoma cells to anti-Bcl-xL strategies as their combination elicited massive apoptosis. Its effect on mTORC1 and Mcl-1 was mimicked by the potent SOCE inhibitor, YM58483, which also triggered apoptosis when combined with ABT-737. As a whole, this study suggests that CAI sensitizes to anti-Bcl-xL strategies via its action on Mcl-1 translation and that modulation of SOCE could extend the therapeutic arsenal for treatment of ovarian carcinoma.

Updates and current challenges in microRNA research for personalized medicine in ovarian cancer.

INTRODUCTION: Ovarian cancer (OC) is the second most common and the most lethal of the gynecological malignancies. Currently, there exists no effective screening tool for OC. MicroRNAs (miRNAs) are endogenous 18-23 nucleotide non-coding RNAs that refine gene expression. MiRNAs have been found to be aberrantly expressed in OC tumor tissue as well as detectable in biological fluids such as the blood, urine, and ascites and have been proposed as biomarkers and therapeutic targets for OC. Areas covered: This review summarizes the current knowledge regarding the application of miRNAs as diagnostic, prognostic, and predictive biomarkers in OC. It describes the various tissues allowing for the analysis of miRNAs such as tumor tissue, blood, ascites and urine. It also highlights the potential of miRNAs as a therapy in other cancers and how these therapies may be applied to ovarian cancer. Expert opinion: The study of miRNAs is an innovative and promising field for the diagnosis and treatment of ovarian cancer. Methodological issues surrounding their detection and application therapeutically remain, such as the study of various OC histotypes within the same cohort, the choice of 'normal tissue' for comparison and the difficulties surrounding the choice of a normalization miRNA.

Towards a new standardized method for circulating miRNAs profiling in clinical studies: Interest of the exogenous normalization to improve miRNA signature accuracy.

Circulating miRNAs are promising biomarkers in oncology but have not yet been implemented in the clinic given the lack of concordance across studies. In order to increase the cross-studies reliability, we attempted to reduce and to control the circulating miRNA expression variability between patients. First, to maximize profiling signals and to reduce miRNA expression variability, three isolation kits were compared and the NucleoSpin(®) kit provided higher miRNA concentrations than the other widely used kits. Second, to control inter-sample variability during the profiling step, the exogenous miRNAs normalization method commonly used for RT-qPCR validation step was adapted to microarray experiments. Importantly, exogenous miRNAs presented two-fold lower inter-sample variability than the widely used endogenous miR-16-5p reflecting that the latter is subject to both biological and technical variability. Although Caenorhabditis elegans miRNAs isolation yields were heterogeneous, they correlated to each other and to their geometrical mean across samples. The normalization based on the geometrical mean of three exogenous miRNAs increased the correlation up-to 0.97 between the microarrays and individual RT-qPCR steps of circulating miRNAs expression. Overall, this new strategy open new avenue to identify reliable circulating miRNA signatures for translation into clinical practice.

An overview of long non-coding RNAs in ovarian cancers.

As with miRNAs a decade ago, the scientific community recently understood that lncRNAs represent a new layer of complexity in the regulation of gene expression. Although only a subset of lncRNAs has been functionally characterized, it is clear that they are deeply involved in the most critical physiological and pathological biological processes. This review shows that in ovarian carcinoma, data already available testify to the importance of lncRNAs and that the demonstration of an ever-growing role of lncRNAs in the biology of this malignancy can be expected from future studies. We also underline the importance of their relationship with associated protein partners and miRNAs. Together, the available information suggests that the emerging field of lncRNAs will pave the way for a better understanding of ovarian cancer biology and might lead to the development of innovative therapeutic approaches. Moreover, lncRNAs expression signatures either alone or in combination with other types of markers (miRNAs, mRNAs, proteins) could prove useful to predict outcome or treatment follow-up in order to improve the therapeutic care of ovarian carcinoma patients.

Calcium signals inhibition sensitizes ovarian carcinoma cells to anti-Bcl-xL strategies through Mcl-1 down-regulation.

Ovarian carcinoma is the leading cause of death from gynecologic cancer in the developed world and is characterized by acquired chemoresistance leading to an overall 5-year survival rate of about 30 %. We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Despite BH3-mimetics represent promising drugs to target Bcl-xL, anti-Mcl-1 strategies are still in pre-clinical studies and required new investigations. Calcium is a universal second messenger and dysregulation of calcium signal is often observed during carcinogenesis. As change in cytosolic free calcium concentration [Ca(2+)]i is known to control the fate of the cell by regulating Bcl-2 family members, we wonder if calcium signal could impact on Mcl-1 expression and if its pharmacological inhibition could be useful to sensitize ovarian carcinoma cells to anti-Bcl-xL strategies. We therefore studied the effect of different calcium signals inhibitors in ovarian carcinoma cell lines SKOV3 and IGROV1-R10 and analysed their effects on proliferation and Mcl-1 expression. We also exposed these cells to these inhibitors in combination with anti-Bcl-xL strategies (siRNA or BH3-mimetic: ABT-737). We found that calcium signaling regulates Mcl-1 through translational events and a calmodulin-mediated pathway. BAPTA-AM and calmodulin inhibitor combination with ABT-737 leads to apoptosis, a process that is reversed by Mcl-1 enforced expression. As Mcl-1 represents a crucial hurdle to the success of chemotherapy, these results could open to new area of investigation using calcium modulators to directly or indirectly target Mcl-1 and thus efficiently sensitize ovarian carcinoma cells to anti-Bcl-xL strategies.

First evidence that oligopyridines, α-helix foldamers, inhibit Mcl-1 and sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies.

Apoptosis control defects such as the deregulation of Bcl-2 family member expression are frequently involved in chemoresistance. In ovarian carcinoma, we previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect cancer cells against apoptosis and their concomitant inhibition leads to massive apoptosis even in the absence of chemotherapy. Whereas Bcl-xL inhibitors are now available, Mcl-1 inhibition, required to sensitize cells to Bcl-xL-targeting strategies, remains problematic. In this context, we designed and synthesized oligopyridines potentially targeting the Mcl-1 hydrophobic pocket, evaluated their capacity to inhibit Mcl-1 in live cells, and implemented a functional screening assay to evaluate their ability to sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies. We established structure-activity relationships and focused our attention on MR29072, named Pyridoclax. Surface plasmon resonance assay demonstrated that pyridoclax directly binds to Mcl-1. Without cytotoxic activity when administered as a single agent, pyridoclax induced apoptosis in combination with Bcl-xL-targeting siRNA or with ABT-737 in ovarian, lung, and mesothelioma cancer cells.

Body image in women with primary and secondary provoked vestibulodynia: a controlled study.

INTRODUCTION: Provoked vestibulodynia (PVD) is a women's genito-pelvic pain condition associated with psychosexual impairments, including depression. Body image (BI) has been found to be different in women with primary (PVD1) and secondary (PVD2) PVD. No controlled study has compared BI in women with PVD1 and PVD2 and investigated its associations with sexual satisfaction, sexual function, and pain. AIMS: The aims of this study were to (i) compare BI in women with PVD1, PVD2, and asymptomatic controls and (ii) to examine associations between BI and sexual satisfaction, sexual function, and pain during intercourse in women with PVD. METHODS: Fifty-seven women (20 with PVD1, 19 with PVD2, and 18 controls) completed measures of BI, sexual satisfaction, sexual function, pain during intercourse, and depression. MAIN OUTCOME MEASURES: The main outcome measures were (i) Global Measure of Sexual Satisfaction Scale, (ii) Female Sexual Function Index, and (iii) pain numerical rating scale. RESULTS: Controlling for depression, women with PVD1 reported more body exposure anxiety during sexual activities than women with PVD2 and controls F(2,51)=4.23, P=0.02. For women with PVD, more negative BI during sexual activities was associated with lower sexual satisfaction (ß=-0.45, P=0.02) and function (ß=-0.39, P=0.04) and higher pain during intercourse (ß=0.59, P=0.004). More positive body esteem was associated with higher sexual function (ß=0.34, P=0.05). CONCLUSIONS: Findings suggest that women with PVD1 present more body exposure anxiety during sexual activities than women with PVD2 and asymptomatic women. Body esteem and general attitudes toward women's genitalia were not significantly different between groups. Higher body exposure anxiety during sexual activities was associated with poorer sexual outcomes in women with PVD. Further studies assessing interventions targeting BI during sexual activities in this population are needed, as improving BI during sexual interactions may enhance sexual outcomes in women with PVD.

Attachment, Sexual Assertiveness, and Sexual Outcomes in Women with Provoked Vestibulodynia and Their Partners: A Mediation Model.

Provoked vestibulodynia (PVD) is a prevalent women's sexual pain disorder, which is associated with sexual function difficulties. Attachment theory has been used to understand adult sexual outcomes, providing a useful framework for examining sexual adaptation in couples confronted with PVD. Research to date indicates that anxious and avoidant attachment dimensions correlate with worse sexual outcomes in community and clinical samples. The present study examined the association between attachment, pain, sexual function, and sexual satisfaction in a sample of 101 couples in which the women presented with PVD. The actor-partner interdependence model was used in order to investigate both actor and partner effects. This study also examined the role of sexual assertiveness as a mediator of these associations via structural equation modeling. Women completed measures of pain intensity and both members of the couple completed measures of romantic attachment, sexual assertiveness, sexual function, and satisfaction. Results indicated that attachment dimensions did not predict pain intensity. Both anxious and avoidant attachment were associated with lower sexual satisfaction. Only attachment avoidance predicted lower sexual function in women. Partner effects indicated that higher sexual assertiveness in women predicted higher sexual satisfaction in men. Finally, women's sexual assertiveness was found to be a significant mediator of the relationship between their attachment dimensions, sexual function, and satisfaction. Findings highlight the importance of examining how anxious and avoidant attachment may lead to difficulties in sexual assertiveness and to less satisfying sexual interactions in couples where women suffer from PVD.

Women with provoked vestibulodynia experience clinically significant reductions in pain regardless of treatment: results from a 2-year follow-up study.

INTRODUCTION: Provoked vestibulodynia (PVD) is a prevalent genital pain syndrome that has been assumed to be chronic, with little spontaneous remission. Despite this assumption, there is a dearth of empirical evidence regarding the progression of PVD in a natural setting. Although many treatments are available, there is no single treatment that has demonstrated efficacy above others. AIMS: The aims of this secondary analysis of a prospective study were to (i) assess changes over a 2-year period in pain, depressive symptoms, and sexual outcomes in women with PVD; and (ii) examine changes based on treatment(s) type. METHODS: Participants completed questionnaire packages at Time 1 and a follow-up package 2 years later. MAIN OUTCOME MEASURES: Visual analog scale of genital pain, Global Measure of Sexual Satisfaction, Female Sexual Function Index, Beck Depression Inventory, Dyadic Adjustment Scale, and sexual intercourse attempts over the past month. RESULTS: Two hundred thirty-nine women with PVD completed both time one and two questionnaires. For the sample as a whole, there was significant improvement over 2 years on pain ratings, sexual satisfaction, sexual function, and depressive symptoms. The most commonly received treatments were physical therapy, sex/psychotherapy, and medical treatment, although 41.0% did not undergo any treatment. Women receiving no treatment also improved significantly on pain ratings. No single treatment type predicted better outcome for any variable except depressive symptoms, in which women who underwent surgery were more likely to improve. DISCUSSION: These results suggest that PVD may significantly reduce in severity over time. Participants demonstrated clinically significant pain improvement, even when they did not receive treatment. Furthermore, the only single treatment type predicting better outcomes was surgery, and only for depressive symptoms, accounting for only 2.3% of the variance. These data do not demonstrate the superiority of any one treatment and underscore the need to have control groups in PVD treatment trials, otherwise improvements may simply be the result of natural progression.

Do romantic partners' responses to entry dyspareunia affect women's experience of pain? The roles of catastrophizing and self-efficacy.

INTRODUCTION: Entry dyspareunia is a sexual health concern which affects about 21% of women in the general population. Characterized by pain provoked during vaginal penetration, introital dyspareunia has been shown by controlled studies to have a negative impact on the psychological well-being, sexual function, sexual satisfaction, and quality of life of afflicted women. Many cognitive and affective variables may influence the experience of pain and associated psychosexual problems. However, the role of the partner's cognitive responses has been studied very little. AIM: The aim of the present study was to examine the associations between partners' catastrophizing and their perceptions of women's self-efficacy at managing pain on one side and women's pain intensity, sexual function, and sexual satisfaction on the other. METHODS: One hundred seventy-nine heterosexual couples (mean age for women = 31, SD = 10.0; mean age for men = 33, SD = 10.6) in which the woman suffered from entry dyspareunia participated in the study. Both partners completed quantitative measures. Women completed the Pain Catastrophizing Scale and the Painful Intercourse Self-Efficacy Scale. Men completed the significant-other versions of these measures. MAIN OUTCOME MEASURES: Dependent measures were women's responses to (i) the Pain Numeric Visual Analog Scale; (ii) the Female Sexual Function Index; and (iii) the Global Measure of Sexual Satisfaction scale. RESULTS: Controlled for women's pain catastrophizing and self-efficacy, results indicate that higher levels of partner-perceived self-efficacy and lower levels of partner catastrophizing are associated with decreased pain intensity in women with entry dyspareunia, although only partner catastrophizing contributed unique variance. Partner-perceived self-efficacy and catastrophizing were not significantly associated with sexual function or satisfaction in women. CONCLUSIONS: The findings suggest that partners' cognitive responses may influence the experience of entry dyspareunia for women, pointing toward the importance of considering the partner when treating this sexual health problem.

Provoked vestibulodynia: mediators of the associations between partner responses, pain, and sexual satisfaction.

Provoked vestibulodynia (PVD) is a chronic, recurrent vulvo-vaginal pain condition affecting 12% of the general population, and is associated with sexual dysfunction, psychological distress, and reduced quality of life. There is growing interest in the role of interpersonal variables in PVD, which have been widely neglected. In a sample of 175 couples, the present study examined the mediating roles of partner and participant catastrophizing and self-efficacy in the association between solicitous partner responses and pain intensity, and that of dyadic adjustment in the association between solicitous and negative partner responses and sexual satisfaction. Couples completed measures of partner responses, catastrophizing, self-efficacy, dyadic adjustment, and depression. Women also completed measures of pain, sexual satisfaction, and sexual function. Controlling for depression and solicitousness perceived by the other member of the couple, catastrophizing and self-efficacy partially mediated the association between higher solicitous responses and higher pain during intercourse, accounting for 26 and 25% of the variance in this association for participant and partner-perceived responses, respectively. For both participant and partners, only pain catastrophizing was a unique mediator. Controlling for depression, sexual function and partner-perceived responses, dyadic adjustment partially mediated the association between higher participant-perceived solicitous responses and higher sexual satisfaction, and between higher participant-perceived negative responses and lower sexual satisfaction, accounting for 26% of the variance in each association. The current findings suggest that catastrophizing and dyadic adjustment may constitute a route by which partner responses exacerbate pain and increase or decrease sexual satisfaction in PVD couples.

Epidermoid cyst of the clitoris: a case report.

We report a rare case of spontaneous clitoral epidermal cyst without any declared previous female genital mutilation. This patient was successfully and surgically resected with good local and cosmetic results.

Two novel variants in the 3'UTR of the BRCA1 gene in familial breast and/or ovarian cancer.

For the majority of breast and/or ovarian cancer patients tested for BRCA1/2 genes, mutation screening of the coding regions remains negative. MicroRNAs which negatively regulate mRNA translation by binding to 3' untranslated region (3'UTR) are implicated in cancer. Genetic changes in the 3'UTR of several genes were reported to be associated with higher susceptibility to particular tumor types. The aim of this study was to analyze the BRCA1 3'UTR in patients tested negative for BRCA1/2 deleterious mutations, in order to find variants implicated in the decrease of BRCA1 expression through modification of miRNA binding. Genotyping analyses were performed on genomic DNA of 70 BRCA negatives index cases, selected among patients with breast or ovarian cancer, less than 50 years old, with a strong family history. The co-occurrence of the identified variants with deleterious BRCA1 mutations was then determined in a control population of 210 patients. A luciferase gene reporter assay was used to investigate the impact of the variants on the BRCA1 gene expression. Two novel variants, c.*750A>G and c.*1286C>A, were identified in the 3'UTR of BRCA1 gene, in two patients. The former was found three times in the control population, whereas the latter was absent. The used functional assay did not reveal any effect on the luciferase expression. This study reveals a weak genomic variability in the 3'UTR of the BRCA1 gene. All together, the results led us to classify the variant c.*750A>G as probably neutral, the variant c.*1286C>A remaining unclassified.