Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression.

The transactivation/transformation-domain associated protein (TRRAP) belongs to the Ataxia-telangiectasia mutated (ATM) super-family and has been identified as a cofactor for c-MYC-mediated oncogenic transformation. TRRAP and its yeast homolog (Tra1p) are components of histone acetyltransferase (HAT) complexes, SAGA (refs. 2,4,5), PCAF (ref. 3) and NuA4 (ref. 6), which are important for the regulation of transcription and cell cycle progression and also have a role in cell viability. Yet the biological function of this molecule and how it controls proliferation are still unclear. Here we show that null mutation of Trrap in mice results in peri-implantation lethality due to a blocked proliferation of blastocysts. We use an inducible Cre-loxP system to show that loss of Trrap blocks cell proliferation because of aberrant mitotic exit accompanied by cytokinesis failure and endoreduplication. Trrap-deficient cells fail to sustain mitotic arrest despite chromosome missegregation and disrupted spindles, and display compromised cdk1 activity. Trrap is therefore essential for early development and required for the mitotic checkpoint and normal cell cycle progression.

DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer.

BACKGROUND: Bisphenol A (BPA), an estrogen-like endocrine disruptor used in plastics, has been associated with development and promotion of breast cancer, so plastic manufacturers shifted towards less-studied analogs, BPF and BPS. Studying the associated DNA methylome-wide mechanisms of these derivatives is timely, particularly in comparison with BPA. METHODS: We assessed proliferation, cell cycle, and migration of breast cancer cells (estrogen receptor (ER)-positive: MCF-7 and ER-negative: MDA-MB-231) treated with BPF and BPS ± estrogen receptor inhibitor (ERI) in comparison to BPA ± ERI. RNA expression and activity of DNA (de)methylation enzymes and LINE-1 methylation were quantified. DNA methylome-wide analysis was evaluated in bisphenol-exposed cells and compared to clinical breast cancer data. RESULTS: The three bisphenols caused ER-dependent increased proliferation and migration of MCF-7 but not MDA-MB-231 cells, with BPS being 10 times less potent than BPA and BPF. Although they have similar chemical structures, the three bisphenols induced differential DNA methylation alterations at several genomic clusters of or single CpG sites, with the majority of these being ER-dependent. At equipotent doses, BPA had the strongest effect on the methylome, followed by BPS then BPF. No pathways were enriched for BPF while BPA- and BPS-induced methylome alterations were enriched in focal adhesion, cGMP-PKG, and cancer pathways, which were also dysregulated in methylome-wide alterations comparing ER-positive breast cancer samples to adjacent normal tissues. CONCLUSIONS: The three bisphenols have important epigenetic effects in breast cell lines, with those of BPA and BPS overlapping with cancer-related pathways in clinical breast cancer models. Hence, further investigation of their safety is warranted.

Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study.

BACKGROUND: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. RESULTS: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with qval = 0.029 and qval = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. CONCLUSIONS: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Cytology and colposcopy after loop electrosurgical excision: implications for follow-up.

OBJECTIVE: To analyze risk factors associated with residual and recurrent lesions after loop electrosurgical excision procedure and to assess the reliability of cytology and colposcopy in detection of these lesions. METHODS: Cytology and colposcopy were used to follow up 288 women after treatment by loop electrosurgical excision 3-6 months, 9-15 months, and 24-36 months after the procedure. RESULTS: The mean (+/-standard deviation) postoperative follow-up was 39+/-13 months (range 24-68 months). Treatment failure, defined as the persistence or recurrence of a cervical lesion, was observed in 20 patients (6.9%). The endocervical localization of the initial lesion (adjusted relative risk [RR] 13.7; 95% confidence interval [CI] 1.3, 150.1; P < .05) and incomplete excision (adjusted RR 9.1; 95% CI 3.0, 27.3; P < .001) were the only independent risk factors for treatment failure. In six cases, a second treatment was performed before the first cytologic and colposcopic visit because of incomplete excisions. The remaining 14 treatment failures were diagnosed by postoperative cytology and colposcopy, ten after the first visit, three after the second, and one after the third. To diagnose the treatment failures, colposcopy and cytology provided complementary information at the first (P < .001) and second postoperative visits (P < .05). Although the sensitivity of cytology was not significantly improved by the association of both methods, the latter decreased the number of residual lesions overlooked by cytology alone and contributed to the diagnosis of 95% of treatment failures in less than 2 years. CONCLUSION: The high detection rate obtained by combining cytology and colposcopy during the first 2 postoperative years may allow more leisurely follow-up schedules after that time and may reduce the consequences of subsequent loss to follow-up.

Treatment strategy for pelvic actinomycosis: case report and review of the literature.

BACKGROUND: Pelvic actinomycosis is a chronic granulomatous suppurative disease caused by an anaerobic Gram positive organism Actinomyces israelii usually associated with intra-uterine devices. Pelvic actinomycosis can mimick pelvic or intra-abdominal malignancy leading to mutilating surgical exeresis. RESULTS: We present a pelvic actinomycosis secondary to long-standing intra-uterine device use in a 50-year old European woman treated by intravenous antibiotic therapy, and then by a total abdominal hysterectomy and bilateral salpingoophorectomy to free the pelvis from abscess. We point out the difficulty in diagnosis, and the importance of high-dose intravenous antibiotic therapy to reduce the very high risk for nearby pelvic structure injuries, reported in the literature, leading to post-operative morbidity.

[Consequences and treatment of cervical stenoses after laser conization or loop electrosurgical excision]. / Conséquences et traitement des sténoses cervicales survenues aprés une conisation au laser ou une résection à l'anse diathermique.

OBJECTIVE: To assess the frequency and the consequences of cervical stenosis in patients treated by laser conization or loop electrosurgical excision procedure (LEEP) and to analyse the results of cervical enlargement plastic surgery or neostomia. METHODS: Two hundred and fifty-five women treated by laser conization and 277 by LEEP were regularly followed by postoperative colposcopy, for a mean period of 38 and 16 months, respectively. Stenosis was defined as cervical narrowing which could not admit a 2.5 mm-diameter Hegar's dilator. RESULTS: Stenosis complicated 10.2% of the laser conizations and 4.3% of the LEEP. Thus, 38 cases of cervical stenosis of which 7 were complete were diagnosed 2 to 40 months after treatment. Among the 34 non-menopaused women who developed a stenosis, 5 had a secondary amenorrhea, 6 a severe dysmenorrhea and one an infertility related to oligoamucorrhea. In the patients with stenosis, endocervical cell retrieval was possible in 21 (55%) cases and in none the squamocolumnar junction was visible at colposcopy. Seven patients underwent an enlargement plastic surgery of the cervical canal for incomplete stenosis and two a neostomia for complete stenosis. Cervical restenosis has been observed in 7 of 9 cases in a mean delay of 12 months (3 to 48 months). Nevertheless, the endocervical cell retrieval remained possible in 8 of 9 cases and after a mean follow-up of 26 months no menstrual troubles recurred. CONCLUSION: LEEP provides fewer cervical stenosis than laser conization. The enlargement plastic surgery allows to correct durably the menstrual troubles in spite of the very frequent restenosis.

[Left ventricle assist device: rehabilitation and management programmes]. / Patients sous assistance circulatoire mécanique mono-gauche en centre de réadaptation cardiaque. Retour d'une expérience de prise en charge.

Progress in the medical management of patients with heart failure with systolic dysfunction has been accompanied by a significant improvement in survival and quality of life. These strategies have also resulted in changes in the clinical profile as well as an increase in the number of patients with advanced heart failure. The technological developments in left ventricular assist devices provide real hope for these patients. This article related our experience of management and the rehabilitation program realized.

[Long term progress of low-grade intraepithelial lesions after a smear and colposcopy, directed biopsies and/or normal endocervical curettage]. / Evolution à long terme des patientes avec une lésion intra-épithéliale de bas grade au frottis et une colposcopie, des biopsies dirigées et/ou un curetage endocervical normaux.

Low-grade squamous intraepithelial lesions and atypical squamous cells of undetermined significance are the most frequent cytologic abnormalities. Their management is still highly controversial because of the many uncertainties associated with them concerning their histology and their natural history. Cervical smears HPV testing were proposed as an alternative to colposcopy. Neither have a sensitivity equivalent to that of colposcopy. The diagnosis of these abnormalities could be delayed, and a severe lesion may even remain undetected because the cytologic surveillance is frequently omitted, smear sensitivity is far from being perfect and correlation is poor between cytology and histology. The combination of smears with the detection of high risk HPV types increases the triage sensitivity before colposcopy to the detriment of specificity and predictive value, and, therefore, of cost. With colposcopy the histologic diagnosis is rapidly reached and therapeutic management becomes easier because the size and location of the lesion are precisely known. However, the long-term outcome of patients with a normal colposcopy is very poorly known. Our study including 212 patients with a mean follow-up of 79 months, showed an incidence of lesions similar to that found in a control group; 12 CIN (5.7%) were identified, but no cancer. The prevalence of CIN was significantly lower in patients whose initial colposcopy was normal or became normal within the first six months that in patients whose control smear was normal or became normal within six months (1/81 = 1.2% versus 8/143 = 5.6%; P > 0.05). No lesions were observed in patients whose colposcopy and control smear were normal. These results confirm the reliability of colposcopy in patients with minor cytologic abnormalities.

[Therapeutic results of conization with diathermy]. / Résultats thérapeutiques de la conisation à l'anse diathermique.

OBJECTIVE: To assess the frequency, histological grade and time interval of residual and recurrent lesions after loop electrosurgical excision procedure and to analyse their associated risk factors. METHODS: 288 patients treated by loop electrosurgical excision procedure between February 1991 and July 1995 were prospectively included in this study. They agreed to a postoperative cytological and colposcopic follow-up with a first visit between 3 and 6 months after excision, a second one between 9 and 15 months and a third one between 24 and 36 months. We used univariate and multivariate analyses to evaluate the association between clinical variables and residual or recurrent lesions. RESULTS: The pathologic diagnosis of the specimens included 21 normal cervices (7.3%), 35 CIN 1 (12.2%), 43 CIN 2 (14.9%), 180 CIN 3 (62.5%), 1 adenocarcinoma in situ (0.3%) and 8 microinvasive cancers (2.8%). The pathologist considered the excision complete in 244 cases (85%). Among the other 44 patients, 27 had involved endocervical margins, 17 involved exocervical margins but none had both margins involved. The mean postoperative follow-up +/- standard deviation was 39 +/- 13 months (range 24-68 months). Treatment failure, defined as the persistence or recurrence of a cervical lesion, was observed in 20 patients (6.9%) having a squamous cancer stage IB (n = 1), a CIN 3 (n = 15), an adenocarcinoma in situ (n = 1) or a CIN 1 (n = 1). In 6 cases the second treatment was performed before the first cytological and colposcopic visit because of an excision considered incomplete by the pathologist. Overall 19 out of the 20 treatment failures were diagnosed within the first two years of the follow-up. The endocervical localisation of the initial lesion (adjusted RR 13.7; 95% CI 1.3, 150.1; P < 0.05) and incomplete excision (adjusted RR 9.1; 95% CI 3.0, 27.3; P < 0.001) were the only independent risk factors for treatment failure. CONCLUSION: Residual or recurrent lesions occurs rarely after loop electrosurgical excision procedure. They are favoured by totally endocervical lesion and an incomplete excision. With the association of cytology and colposcopy, 95% of treatment failures can be detected in the first 2 postoperative years.