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Lucien Frappart

Publications and source records attributed to Lucien Frappart.

15 recordsLinked to original sources
PubMed2006

A novel function of DNA repair molecule Nbs1 in terminal differentiation of the lens fibre cells and cataractogenesis.

The Nbs1 protein, hypomorphic mutant in Nijmegen breakage syndrome (NBS), is a component of the Mre11/Rad50/Nbs1 (M/R/N) complex that acts as a DNA double-strand break sensor and functions in cell cycle checkpoint in response to DNA damage and DNA repair. Here we report that targeted disruption of murine NBS1 gene (Nbn) in the lens alters the M/R/N complex nuclear localization and results in microphthalmia in mice due to reduced proliferation of the lens epithelial cells. Unexpectedly, all Nbn-deficient lenses develop cataracts at an early age due to altered lens fibre cell differentiation, including disruption of normal lens epithelial and fibre cell architecture and incomplete denucleation of fibre cells, and these changes are independent of the p53 pathway. In addition, Nbn-deficient lenses show dysregulated transcription of various crystallins. Thus, this study implicates a novel function of Nbs1 in terminal differentiation of the lens fibre cells and in cataractogenesis.

Animals↗
PubMed2006

p16INK4A overexpression and HPV infection in uterine cervix adenocarcinoma.

Human papillomaviruses (HPVs) are causally involved in the genesis of cervical carcinomas and their precursors, and there is a strong relationship between the cyclin-dependant kinase inhibitor p16INK4A and HPV infection. This study was carried out to assess the correlations between p16INK4A expression as an early biomarker of the endocervical adenocarcinoma and HPV infection. p16INK4A expression and HPV typing were performed on 46 samples including 5 normal endocervix, 9 benign lesions of the endocervix, 25 endocervical adenocarcinomas, and 7 endometrioid adenocarcinomas of the uterine corpus. A semiquantification of the p16INK4A immunostaining was realized (using both the staining intensity and the percentage of positive cells) and was graded from 0 to 15. All of the 25 endocervical adenocarcinomas overexpressed p16INK4A; the adjacent epithelium and the connective tissue were strictly negative. No p16INK4A was detected in nine benign endocervical lesions and in five normal endocervix. Few endometrioid adenocarcinomas of the uterine corpus that infiltrate the endocervix exhibited a low immunoreactivity (score 0/15 or 1/15). This pattern of expression is significantly associated with HPV infection (p<10(-3)), mainly high-risk HPV types (p=0.02). Our results suggest that p16INK4A is a putative molecular biomarker that consistently discriminates uterine cervix adenocarcinomas from benign lesions and from endometrioid adenocarcinomas of the uterine corpus.

Adenocarcinoma↗
PubMed2005

Human breast tumors override the antiangiogenic effect of stromal thrombospondin-1 in vivo.

The antiangiogenic extracellular matrix protein thrombospondin-1 (TSP-1) inhibits tumor growth and metastasis in animals. However, the clinical relevance of such findings are equivocal as increased stromal TSP-1 expression has been associated with either good or poor prognosis. In an effort to obtain a more integrated understanding of the role of TSP-1 in breast cancer, we first used a breast tumorigenesis model in which tumor-associated stromal fibroblasts were engineered to produce high levels of TSP-1. We demonstrate here that stromal TSP-1 delayed human MDA-MB-231/B02 breast tumor growth. However, this delay in MDA-MB-231/B02 tumor growth upon exposure to TSP-1 was associated with an increased vascular endothelial growth factor (VEGF) expression in tumor cells themselves, leading to a tumor growth rate comparable to that of tumors whose fibroblasts did not overproduce TSP-1. Clinical evidence also suggested that primary breast carcinomas have adapted to escape the effects of stromal TSP-1. TSP-1 was found to be expressed in the stroma of human breast carcinomas where, although its level correlated with decreased vascularization, it was unexpectedly associated with a reduction of relapse-free survival. In metastatic axillary lymph nodes, tumor cells expressed high levels of VEGF and TSP-1 expression were no longer associated with a decreased vascularization. Overall, these results suggest that a resistance may develop early in human breast cancers as a result of high in situ exposure to stromal TSP-1, leading to disease progression.

Animals↗
PubMed2005

A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India.

The impact of screening by visual inspection with acetic acid (VIA), cytology or HPV testing on cervical cancer incidence and mortality is investigated in a cluster randomized controlled trial in India. We report findings after the screening phase, when 52 clusters, with a total of 142,701 women aged 30-59 years in Osmanabad District, India, were randomized into 4 arms for a single round of screening by trained midwives with either VIA, cytology or HPV testing as well as a control group. All laboratory tests were done locally. Test-positive women underwent investigations (colposcopy/biopsy) and treatment in the base hospital. Data on participation, test positivity, positive predictive value and detection rates of cervical neoplasia were analyzed using cluster design methodology. Of the eligible women, 72-74% were screened. Test positivity rates were 14.0% for VIA, 7.0% for cytology and 10.3% for HPV. The detection rate of high-grade lesions was similar in all intervention arms (0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing) (p = 0.06, Mann-Whitney test). While the detection rate for VIA dropped to 0.5% with declining test positivity during the course of the study, it remained constant for cytology and HPV testing. Over 85% of women with high-grade lesions received treatment. Our results show that a high level of participation and good-quality cytology can be achieved in low-resource settings. VIA is a useful alternative but requires careful monitoring. Detection rates obtained by HPV testing were similar to cytology, despite higher investments.

Acetic Acid↗
PubMed2004

Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: results from a multicenter study in India.

The knowledge that cervical neoplasia are caused by human papillomavirus (HPV) infection has led to the evaluation of its role in screening. We evaluated the accuracy of HPV testing by Hybrid capture II (HC II) method in detecting cervical intraepithelial neoplasia grade 2 and 3 (CIN 2 and 3) lesions in 4 cross-sectional studies with common protocol and questionnaire in 3 different locations (Kolkata, Mumbai and Trivandrum) in India. These studies involved 18,085 women aged 25-65 years. The reference standard for final diagnosis was a combination of colposcopy/biopsy. All women were investigated with colposcopy and 3,116 received directed biopsy. The sensitivity of HPV testing for detecting CIN 2-3 lesions varied from 45.7% to 80.9% across the study sites; the specificity varied from 91.7% to 94.6% and the positive predictive value from 6.7% to 13.7%. Retesting of 298 randomly chosen denatured samples in France revealed an agreement rate of 85.9% and a kappa-value of 0.72. Although HPV testing seems to be a promising approach for cervical cancer prevention, a large range in sensitivity was observed in our study, possibly due to variations in the quality of specimen collection and reference standards. A higher sensitivity was associated with the center performing the test well. Further developments in terms of more reproducible, less expensive and less sophisticated testing are essential to make the test feasible and effective in low-resource settings.

Adult↗
PubMed2004

Accuracy of visual screening for cervical neoplasia: Results from an IARC multicentre study in India and Africa.

Visual inspection-based screening tests, such as visual inspection with 4% acetic acid (VIA) and with Lugol's iodine (VILI), have been proposed as alternatives to cytology in mass screening programs. To date, there is only limited information on the accuracy of these tests in detecting High-grade Squamous Intraepithelial Lesions (HSIL). Eleven cross-sectional studies involving 56,939 women aged 25-65 years were conducted in Burkina Faso, Congo, Guinea, India, Mali and Niger to evaluate the accuracy of VIA and VILI performed by health workers. A common protocol and questionnaire was used. For final diagnosis, all women were investigated with colposcopy and biopsies were taken when necessary. Data from the studies were pooled to calculate sensitivity, specificity and predictive values of the tests for the detection of HSIL. Of the screened women, 16.1% and 16.4% were positive on examination using, respectively, VIA and VILI; 1,063 were diagnosed with HSIL. The pooled sensitivity, specificity, positive and negative predictive values for VIA were 76.8% (95% CI: 74.2-79.4%), 85.5% (95% CI: 85.2-85.8%), 9.4% (95% CI:8.8-10.8%) and 99.5% (95% CI:99.4-99.6%), respectively. The values were 91.7% (95% CI: 89.7-93.4%), 85.4% (95% CI: 85.1-85.7%), 10.9% (95% CI: 10.2-11.6%) and 99.8% (95% CI:99.7-99.9%), respectively for VILI. The range of sensitivity and specificity for VIA was 56.1-93.9% and 74.2-93.8%, respectively, between studies and were 76.0-97.0 % and 73.0-91.3% for VILI. VILI had a significantly higher sensitivity than VIA in detecting HSIL, but specificity was similar. VILI appears to be a more accurate visual test for use in screening and treatment programs in low-resource settings.

Adult↗
PubMed2004

Correlation between the DNA global methylation status and progesterone receptor expression in normal endometrium, endometrioid adenocarcinoma and precursors.

Endometrial carcinomas are the most common malignancy of the female genital tract and the third most common cancer in women. Progesterone and oestrogen receptors (PRs, ERs) are the most widely documented prognostic and predictive factors in endometrioid adenocarcinoma. Besides the hormonal pathway involved in the progression of preneoplastic and neoplastic lesions, alterations of the DNA methylation status have been shown to be an early signal of tumorigenesis. In this study, we show that in normal endometrium, during the proliferative phase, DNA methylation and PR expression are high, with a significant decline towards the end of the secretory phase and a gradual increase in non-atypical and atypical endometrial hyperplasia; they reach their highest level in grade I, then decrease significantly in grade-II and grade-III endometrioid adenocarcinomas. During each stage, a significant positive correlation is observed between DNA methylation and PR (P<0.0001). The strong parallelism between DNA methylation and PR expression precludes establishing a precise determination regarding the timing of these events, clearly involved in the genesis of endometrioid adenocarcinoma.

Carcinoma, Endometrioid↗
PubMed2004

Initial results from a randomized trial of cervical visual screening in rural south India.

The impact of a single round of screening of visual inspection with acetic acid (VIA) on cervical cancer incidence and mortality was investigated in a cluster randomized trial in south India. Women 30-59 years of age in 113 clusters in Dindigul District were randomized to VIA screening (57 clusters, 48,225 women) by nurses and to a control group (56 clusters, 30,167 women). 30,577 eligible women were screened between May 2000 and April 2003; 2,939 (9.6%) screen-positive women were investigated with colposcopy by nurses and 2,777 (9.1%) women had biopsy. CIN 1 was diagnosed in 1,778 women, CIN 2-3 lesions were found in 222, and there were 69 screen detected invasive cervical cancers. The detection rates of lesions per 1,000 screened women were 58.2 for CIN 1, 7.3 for CIN 2-3, and 2.3 for invasive cancer. The detection rate of high-grade lesions in our study was 2-3-fold higher than those observed in repeatedly screened populations in developed countries. 71% of women with CIN 1 and 80% of those with CIN 2-3 lesions accepted cryotherapy provided by nurses and surgical treatment by mid-level clinicians. Overall, 97 and 34 incident cervical cancer cases were observed in the intervention and control arms, respectively. The intervention arm accrued 124,144 person years and the control arm accrued 90,172 during the study period. The age standardized cervical cancer incidence rates were 92.4/100,000 person-years in the intervention and 43.1/100,000 in the control arms. In the screened arm, 35.0% of cases were in Stage I as opposed to none in the control arm. The preliminary findings from our study indicate that not only is a VIA-based screening programme feasible, safe and acceptable to a population in rural settings, it also results in early detection of cervical neoplasia.

Acetic Acid↗
PubMed2004

Poly(ADP-ribose) polymerase-1, a novel partner of progesterone receptors in endometrial cancer and its precursors.

Endometrial carcinomas are the most common malignancy of the female genital tract. Although the downregulation of the progesterone receptor (PR) in the progression of endometrioid carcinomas (ECs) has been well documented, the mechanism of PR alteration in endometrioid carcinogenesis is poorly understood. Recently, biochemical studies have shown that the DNA strand break-sensing molecule poly(ADP-ribose) polymerase (PARP-1) was associated with the DNA binding domain of PR. In our present study, we show that in normal endometrial epithelium, the expression level of PARP-1 protein is high in the proliferative phase but markedly decreases during the secretory phase. Interestingly, PARP-1 expression gradually increases in nonatypical and atypical endometrial hyperplasia, reaching its highest level in grade I, and decreases significantly toward grade III ECs. Notably, PARP-1 and PR expressions, in each stage, are positively correlated (p < 0.0001), with the exception of nonendometrioid carcinomas. Thus, these data suggest that PARP-1 is substantially involved in the regulation of progesterone action in the development of ECs.

Adenocarcinoma, Clear Cell↗
PubMed2004

The role of low-level magnification in visual inspection with acetic acid for the early detection of cervical neoplasia.

Several studies have investigated the accuracy of naked eye visual inspection with acetic acid (VIA) in the early detection of cervical neoplasia. It is not clear whether low-level (2-4x) magnification (VIAM) can improve the sensitivity and specificity of VIA. The accuracy of both VIA and VIAM, provided by independent health workers, were evaluated in three cross-sectional studies involving 18,675 women aged 25-65 years in Kolkata and Mumbai in India. All screened women were investigated with colposcopy and biopsies were obtained based on colposcopy findings. The final disease status was based on the reference standard of histology (if biopsies had been taken) or colposcopy. Data from the studies were pooled to calculate the test characteristics for the detection of high-grade squamous intraepithelial lesions (HSIL). 14.1% and 14.2% were positive on testing with VIA and VIAM respectively. Two hundred twenty-nine were diagnosed with HSIL and 68 with invasive cancer. The pooled sensitivity, specificity, positive and negative predictive values for VIA in detecting high-grade squamous intraepithelial lesions (HSIL) were 60.3% (95% CI: 53.6-66.7), 86.8% (95% CI: 86.3-87.3), 5.9% (95% CI: 5.0-7.0), and 99.4% (95% CI: 99.2-99.5), respectively. The values were 64.2% (95% CI: 57.6-70.4), 86.8% (95% CI: 86.2-87.3), 6.3% (95% CI: 5.3-7.3) and 99.4% (95% CI: 99.3-99.6), respectively, for VIAM. Low-level magnification did not improve the test performance of naked eye visualization of acetic acid impregnated uterine cervix.

Acetic Acid↗
PubMed2002

MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland.

During the last years, a direct link between DNA methylation and repressive chromatin structure has been established. This structural modification is mediated by histone deacetylases targeted to the methylated sequences by Methyl Binding Proteins (MBD). Human cancer cells exhibit both a global hypomethylation and some localized hypermethylations suggesting that the deregulation of the methylation machinery is a central event in tumorigenesis. Therefore, we have investigated in human tissues the expression of two major MBDs, MeCP2 and MBD2, during the proliferation of normal breast and in benign and neoplasic breast tumors. Quantitation of the transcripts indicates that MBD2 mRNAs are 20-30-fold more abundant than MeCP2 transcripts in the adult and fetal human mammary gland. In pathological tissues samples MBD2 mRNA levels are significantly higher (P=0.001) in benign tumors compared with normal breast tissues, whereas MeCP2 expression is not modified in these specimens. In neoplasic samples a deregulation of the expression of both genes was found. The amounts of MBD2 and MeCP2 transcripts vary greatly between samples in cancer cells compared to normal breast tissues or benign tumors, and in invasive ductal carcinomas the amount of MBD2 mRNA is significantly (P=0.03) associated with the tumor size. Taken together these data suggest that upregulation of MBD2 might be associated with breast cell proliferation. In line with this hypothesis MBD2 is also upregulated during the prenatal development of the human mammary gland, but in contrast to that observed in tumor cells, MeCP2 is also coordinately upregulated in the fetal breast tissues, suggesting that deregulation of MeCP2 and MBD2 occurs in human breast cancers.

Blotting, Western↗
PubMed2002

Morphological alterations and DNA fragmentation in oocytes from primordial and primary follicles after freezing-thawing of ovarian cortex in sheep.

OBJECTIVE: To evaluate DNA fragmentation in the oocyte of primordial and primary follicles and morphology of these follicles after freezing and thawing of ovarian cortex in sheep using two freezing protocols. DESIGN: Fragmentation of DNA was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) technique. SETTING: Fertility clinic in a large university hospital. ANIMALS: Five- to 6-month-old lambs. INTERVENTION(S): Two-millimeter-thick slices of hemi-ovary cortex were prepared. MAIN OUTCOME MEASURE(S): Histological structure and DNA fragmentation. RESULT(S): In the frozen fragments, the percentage of morphologically normal follicles was significantly lower for both protocols compared with the case of the control group of fresh fragments. There was no significant difference between the two types of freezing protocols (60.4% +/- 13.2% vs. 68.4% +/- 13.7%). However, the distribution of abnormalities (nucleus, cytoplasm, and nucleus and cytoplasm) was dissimilar. The results of the TUNEL technique for the three groups showed no significant difference, but the percentage of the TUNEL-positive follicles was slightly lower for the frozen fragments for both protocols with respect to the control group. CONCLUSION(S): The freezing and thawing process of the ovarian cortex does not induce fragmentation of the DNA on the oocyte of primary and primordial follicles.

Animals↗
PubMed2001

Retroviral transduction of splice variant Brca1-Delta11 or mutant Brca1-W1777Stop causes mouse epithelial mammary atypical duct hyperplasia.

We have investigated the effects of the expression of wild-type and mutant Brca1 alleles on the murine mammary gland morphogenesis and carcinogenesis. Primary cultures of mammary cells from BALB/cByJIco mice were infected with recombinant Babe Puro retroviruses expressing lacZ, full-length Brca1, splice variant Brca1-Delta11, or mutant Brca1-W1777Stop alleles. Infected cells were reinjected into the mammary fat pad of a syngeneic virgin mouse whose endogenous epithelium had previously been removed. Four months after reinjection, nulliparous and postlactating mice were checked for the reconstitution of the mammary gland. Stable expression of beta-galactosidase was observed in the ducts formed by epithelial mammary cells infected with Babe Puro/ lacZ retrovirus. Epithelial mammary cells transduced with full-length Brca1 developed normally, whereas those transduced with Brca1-Delta11 or Brca1-W1777Stop formed atypical duct hyperplasia associated with reduced branching. These results suggest that ectopically expressed splice variant Brca1-Delta11 and mutant Brca1-W1777Stop have dominant negative effects.

Alternative Splicing↗