Copy number signatures for early diagnosis of high-grade serous ovarian carcinoma

BackgroundThe detection of ovarian carcinoma-derived somatic mutations in cervical samples and uterine lavages in several studies since 2013, has brought hope for the development of new biomarkers for early detection. High-grade serous ovarian carcinoma (HGSC) is strongly dominated by copy number alterations (CNAs). These CNAs are the consequence of underlying mutational processes in HGSC. We interrogated CNAs from low coverage whole-genome sequencing (WGS) data in HGSC tumors, plasma, endometrial biopsies, and cervical samples to explore if copy number signatures can be used as a biomarker for early detection of HGSC.Methods A total of 204 samples were included from 18 patients with HGSC, four BRCA mutation carriers and seven benign controls. Estimations of ploidy and cellularity, and thus calculation of absolute copy number, were optimized through a combination of the ACE, Rascal, and ichorCNA bioinformatic tools. Mixture modelling was used to subgroup the six fundamental copy number features and non-negative matrix factorization was used to generate the signatures and cluster the samples.ResultsWe extracted six fundamental copy number features from 69 diagnostic and pre-diagnostic cervical samples from patients diagnosed with HGSC and generated six CN signatures. We found different distributions of features in benign samples compared to tumors and cervical samples from HGSC patients. We also observed different exposures to the six signatures in different patient groups.ConclusionsFurther understanding of the components and cell types contributing to each signature, and inclusion of more cervical samples into the approach, will hopefully identify a novel tumorigenic signature for early detection of HGSC in cervical samples

A Wireless Future: performance art, interaction and the brain-computer interfaces

Although the use of Brain-Computer Interfaces (BCIs) in the arts originates in the 1960s, there is a limited number of known applications in the context of real-time audio-visual and mixed-media performances and accordingly the knowledge base of this area has not been developed sufficiently. Among the reasons are the difficulties and the unknown parameters involved in the design and implementation of the BCIs. However today, with the dissemination of the new wireless devices, the field is rapidly growing and changing. In this frame, we examine a selection of representative works and artists, in comparison to the current scientific evidence. We identify important performative and neuroscientific aspects, issues and challenges. A model of possible interactions between the performers and the audience is discussed and future trends regarding liveness and interconnectivity are suggested

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Prejunctional alpha 2-adrenoreceptors modulate the stimulated release of noradrenaline in isolated follicle strips from bovine ovaries

1. Strips from the follicle wall of bovine ovaries were incubated in Krebs-Ringer solution containing 3H-noradrenaline for measurement of transmitter liberation during electrical field stimulation (5 Hz frequency, 1 ms pulse duration, 10 V between the electrodes). The effects of noradrenaline as well as selective alpha-adrenoreceptor agonists and antagonists were studied on the electrically induced efflux of radioactivity. 2. Noradrenaline (1 microM) inhibited the stimulated release of radioactivity. The alpha 2-adrenoreceptor agonist, oxymetazoline, significantly reduced the release of radioactivity in concentrations as low as 0.01 microM. The alpha 1-adrenoreceptor agonist, phenylephrine (0.01-1 microM), was without significant effect. 3. Phentolamine (0.01-1 microM) and the selective alpha 2-adrenoreceptor antagonist, idazoxan (0.01-1 microM) significantly enhanced the electrically evoked release. The alpha 1-adrenoreceptor antagonist, prazosin (0.01-1 microM), was without effect. Idazoxan (0.1 microM) reversed the inhibitory effect of oxymetazoline (0.1 microM). 4. It is concluded that administration of noradrenaline or the alpha 2-adrenoreceptor agonists reduces the release of labelled noradrenaline by acting on prejunctional alpha 2-adrenoreceptors in the noradrenergic nerves distributed in the wall of the bovine ovarian follicle. This is one of several prejunctional receptor mechanisms that modulate the activity of the sympathetic nerves innervating the smooth musculature of the follicle wall

Histaminergic effects on the isolated rat ovarian artery during the estrous cycle

Histamine may play a role in many of the events occurring in the ovarian tissue and leading to ovulation. To elucidate the histaminergic influence on the ovarian vasculature, the mechanical response of the isolated rat ovarian artery to histamine and histamine agonists was investigated. Histamine relaxed the precontracted vessel segments in a concentration-dependent way, amounting to 82.7 +/- 4.3% of the papaverine-induced relaxation. This relaxant effect was counteracted by both the H1 antagonist, pyrilamine, and the H2 antagonist, cimetidine. That the effect of histamine was mediated by both histamine receptor subtypes was further confirmed by the relaxant effect produced in the presence of either of the H1-specific agonists, 2-pyridylethylamine and 2-methylhistamine on the one hand, and the H2-specific agonists, impromidine and 4-methylhistamine on the other. The H1 receptor-induced relaxation was mediated via an effect on the endothelium, whereas the H2 receptor-mediated relaxation was mostly a direct effect on the smooth musculature in the vessel wall. No major differences in the mechanical response of the rat ovarian artery were seen during the different stages of the estrous cycle, although at late proestrus, just before ovulation, the maximum relaxation induced by histamine was particularly high, in spite of a low sensitivity of the receptors for the amine

Robot-assisted abdominal laparoscopic radical trachelectomy.

BACKGROUND: Radical trachelectomy in conjunction with pelvic lymphadenectomy is an established method to preserve fertility in early cases of cervical cancer. The radical trachelectomy is usually performed vaginally despite the initial use of laparoscopy for the lymphadenectomy. The complexity of a laparoscopic abdominal trachelectomy may explain this dual approach. Here we describe the surgical technique of a robot-assisted laparoscopic radical trachelectomy with lymphatic mapping using a radiotracer and without a vaginal approach. CASES AND SURGICAL TECHNIQUE: Two nulliparous women with early cervical cancer underwent a laparoscopic radical trachelectomy and pelvic lymphadenectomy with the assistance of the da Vinci robot (Intuitive Surgical Inc, Sunnyvale, CA). After the sentinel lymph nodes were found negative on frozen section, the parametria, paracolpia and sacrouterine ligaments were dissected sparing the main branches of the uterine arteries. Following ligation of the descending branches of the uterine arteries the cervix and the vagina were transsected using monopolar diathermia and the vagina was sutured to the remaining cervix. Finally, a permanent cerclage was placed. Time for surgery was 387 and 358 min respectively. No perioperative complications were noted and the postoperative period was uneventful in both cases. CONCLUSIONS: Robot-assisted laparoscopic abdominal trachelectomy is a feasible alternative to a combined laparoscopic and vaginal approach

Outcomes Following Exenteration for Gynecological Neoplasms

The primary treatment of gynecological malignancies has considerably evolved over the last century, with a move to less aggressive procedures when appropriate. However, gynecological malignancies comprise a heterogeneous group, with varying treatment options. The choice of reconstructive method for urinary and fecal diversion is crucial, as most patients have been irradiated with high doses or had prior surgery for their primary neoplasm. Patient characteristics, such as age and comorbidity, also affect the choice of urinary diversion, especially when opting for a continent reconstruction in the setting of an anterior exenteration for a gynecological cancer. For patients with advanced gynecological tumors requiring both urinary and fecal diversion, that is, two stomas, a double-barreled colostomy has been popularized. The optimal localization of the urinary stoma is an integral part of the preoperative preparation and of critical importance to avoid postoperative difficulties with stoma accessories or emptying a continent cutaneous diversion

Elderly women above screening age diagnosed with cervical cancer have a worse prognosis.

To analyze the cervical screening history in women with cervical cancer and their outcome

Extracellular and intracellular calcium sources mediating contractile responses of smooth muscle in bovine ovarian follicle and ovarian artery

The relative importance of extracellular and intracellular calcium sources mediating smooth muscle contraction in ovarian follicle and ovarian artery was assessed in experiments on the influence of nifedipine, D-600, amrinone, diethylstilbestrol (DES), lanthanum and/or calcium removal on contractions induced by K+ depolarization, by noradrenaline, histamine and acetylcholine. The K+-induced response was biphasic in the ovarian artery but not in the ovarian follicle. The K+-induced contraction in both preparations was greatly inhibited by nifedipine (1 μM), D-600 (10 μM) and lanthanum (2 mM). Although both phases of the responses in the ovarian artery appeared to be completely dependent on extracellular calcium, phase I was significantly more sensitive to nifedipine than phase II. Incubation in calcium-free medium for 15 min almost abolished the K+-induced contraction. Noradrenaline- and histamine-induced contractions of ovarian follicle were essentially unaffected by nifedipine (1 μM) and D-600 (10 μM) whereas the noradrenaline-induced contraction in ovarian artery was inhibited significantly by D-600 (1 and 10 μM) but not nifedipine (1 μM). In calcium-free medium containing EGTA (1 mM) the responses of ovarian follicle to noradrenaline and histamine were reduced by 26 and 22% respectively. When preparations were stimulated with noradrenaline more than one in calcium-free medium, the contraction decreased progressively compared to time-matched controls. The response was 34% of the control after 50 min in calcium-free medium containing EGTA. In the ovarian artery the response obtained (6% of control) was significantly smaller (P < 0.05) than that in the follicle. Amrinone (100 μM) inhibited both noradrenaline- and K+-induced contractions to a similar degree (about 40%) in the follicle wall. The results indicate that agonist-induced responses of ovarian follicle and artery are mediated by the release of calcium from intracellular stores in addition to influx of extracellular calcium. In contrast, the K+-induced contraction seems to be totally dependent on extracellular calcium. The difference in sensitivity to nifedipine of the two phases of the K+ response in ovarian artery strongly suggests the presence of two different types of K+-activated calcium channels in this smooth muscle