References of "FOIDART, Jean-Michel"
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See detailRh D foeto-maternal alloimmunization prophylaxis with anti-D immunoglobulins reviewed in the era of foetal RHD genotyping.
Minon, J. M.; Gerard, Christiane ULg; Schaaps, Jean-Pierre ULg et al

in Acta Clinica Belgica (2009), 64(3), 195-202

In Belgium, prevention of anti-D immunization is currently based on systematic postnatal prophylaxis associated with targeted antenatal injection in high-risk situations of foeto-maternal haemorrhage.The ... [more ▼]

In Belgium, prevention of anti-D immunization is currently based on systematic postnatal prophylaxis associated with targeted antenatal injection in high-risk situations of foeto-maternal haemorrhage.The failures of prevention are mainly due to the non-respect of established guidelines for RhlG prophylaxis, and to spontaneous undetected foetal-maternal haemorrhages without any obvious cause during the third trimester of pregnancy. In order to reduce the rate of residual post-pregnancy anti-D immunization, several countries decided to associate the classical prophylaxis to a routine antenatal anti-D prophylaxis (RAADP) during the 28th or 29th week of gestation. Since a few years, the foetal RHD genotyping in maternal plasma enables us to limit the antenatal prophylaxis only to those D- women carrying a D+ foetus. This paper deals with: the advantages of an antenatal prevention in the light of non-invasive foetal RHD genotyping, the rules rendering prevention protocols efficient whatever the algorithm applied, and the recommended immuno-haematology follow-up of women who received RhlG. [less ▲]

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See detailThe influence of level of care on admission to neonatal care for babies of low-risk nullipara
Le Ray, C.; Zeitlin, J.; Jarreau, P. H. et al

in European Journal of Obstetrics & Gynecology & Reproductive Biology (2009), 144

Objective To analyze the risk of admission to neonatal care for newborns of low-risk nullipara and its variation with level of care of the maternity unit. Study design The sample included infants born to ... [more ▼]

Objective To analyze the risk of admission to neonatal care for newborns of low-risk nullipara and its variation with level of care of the maternity unit. Study design The sample included infants born to low-risk nulliparas from the PREMODA study of 138 French maternity units (n = 3652). Medical records of children admitted to neonatal care were reviewed to determine the reasons for admission and the severity of morbidity. The risk factors associated with admission to neonatal care, including maternal, infant and delivery unit characteristics, were studied by univariable analysis, followed by a multivariable analysis using a multilevel logistic model. Results The newborns of 3.5% (n = 129) of the nulliparous mothers at low risk were admitted to neonatal care at birth. The two principal reasons were infections (57%) and respiratory diseases (19%). Babies born in level 2 maternity units were twice as likely to be admitted to neonatal care as those born in level 1 units (ORa = 2.0 [1.1–3.7]) and those born in level 3 units, 1.5 times more often, although this was not statistically significant (ORa = 1.5 [0.8–2.8]). Babies admitted to neonatal care after delivery in level 1 had more severe morbidity (n = 4, 26.7%) than those admitted from level 2 (n = 4, 5.7%) or level 3 (n = 3, 6.8%) facilities (p = 0.046). Conclusion In low-risk populations, the level of care could have an influence on the decision to admit babies to neonatal care at birth. These findings add to the on-going debate about the optimal organization of care for women at low obstetrical risk. [less ▲]

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See detailManifestations hémodynamiques et respiratoires de la prééclampsie
Brichant, Jean-François ULg; Brichant, Géraldine ULg; Dewandre, Pierre-Yves ULg et al

in Pottecher, Thierry; Luton, Dominique (Eds.) Prise en charge multidisciplinaire de la prééclampsie (2009)

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See detailThe impact of detailed explanatory leaflets on patient satisfaction with urodynamic consultation: A double-blind randomized controlled trial.
Hougardy, Véronique ULg; Vandeweerd, Jean-Michel ULg; Reda, A. A. et al

in Neurourology and Urodynamics (2009), 28(5), 374-9

Aims To develop and validate a scale that is applicable in Belgium to investigate the aspects of female patients' satisfaction with urodynamic consultation, and to use it to measure the impact of a ... [more ▼]

Aims To develop and validate a scale that is applicable in Belgium to investigate the aspects of female patients' satisfaction with urodynamic consultation, and to use it to measure the impact of a detailed explanatory leaflet on their satisfaction. Materials and Methods Question items were obtained from a group consensus (Delphi process). Each item was scored on a five-point Likert scale. The satisfaction scale was administered to two groups of patients attending the clinics for urodynamics. One hundred twenty-nine patients were included in the study and randomized in two groups. One group (n = 60) received a detailed explanatory leaflet about urodynamic consultation and the other did not (n = 69). Responses were subjected to a reliability and principal component analysis (PCA) to achieve data reduction and analysis, and to assess the reliability of the new scale. Relevant items were retained to compare both interventions using regression analysis. Results A 15-item scale was derived from the Delphi process. Exploratory factor analysis suggested a single factor solution with 11 meaningful items. No significant difference was noted in global scores of satisfaction between the two groups (P = 0.051). Conclusions A short-form patient satisfaction scale with acceptable validity and reliability was developed and used to measure patient satisfaction with urodynamic consultation in this population of Belgian women. This study did not provide support for the effectiveness of explanatory leaflets in improving satisfaction. [less ▲]

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See detailContrast-enhanced coded phase-inversion harmonic sonography of knee synovitis correlates with histological vessel density: 2 automated digital quantifications
Kaiser, Marie-Joëlle ULg; Hauzeur, Jean-Philippe ULg; Blacher, Silvia ULg et al

in Journal of Rheumatology (2009), 36(7), 1391-400

OBJECTIVE: To use contrast-enhanced coded phase-inversion harmonic B-mode sonography to assess the acoustic enhancement of the synovial area of the knee; and to compare the data with the histological ... [more ▼]

OBJECTIVE: To use contrast-enhanced coded phase-inversion harmonic B-mode sonography to assess the acoustic enhancement of the synovial area of the knee; and to compare the data with the histological vessel density. METHODS: Eleven patients eligible for a knee arthroscopy were studied. Acoustic quantification was carried out by a digital image analysis program that detects the time-dependent increase [intensity (time) = k x time + C] of gray-level intensity in all the pixels of a specific region of interest (ROI) following intravenous injection of the microbubble contrast agent sulfur hexafluoride. Echo-guided synovial biopsies were carried out in the same ROI. Synovial vessel areas were quantified after Factor VIII immunostaining of synovial biopsies using an automated digital image analysis. RESULTS: Significant (p < 0.05) correlations were observed between histological vessel density and percentage of the synovial area with a k value > 0.01 (r = 0.93) and k(max) values (r = 0.79), as well as between the 2 latter parameters (r = 0.72). The histological vessel density and the 2 acoustic parameters were also significantly correlated with the logarithm of erythrocyte sedimentation rate (r = 0.77, r = 0.87, r = 0.67, respectively) and with log C-reactive protein serum concentration (r = 0.69, r = 0.83, r = 0.62, respectively). CONCLUSION: Contrast-enhanced coded phase-inversion harmonic B-mode sonography coupled with an appropriate data analysis method is a new tool to identify and quantify vessel density in knee synovitis. [less ▲]

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See detailL'endométriose en 2009: place respective du traitement médical et du traitement chirurgical.
Cheruy, Charlotte ULg; Nervo, Patricia ULg; Dequesne, J. et al

in Gunaïkeia (2009), 14(3), 69-73

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See detailNouveautés en contraception d'urgence.
Pintiaux, Axelle ULg; Foidart, Jean-Michel ULg

in Gunaïkeia (2009), 14(1), 18-20

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See detailLes anomalies d'insertion placentaire
Chantraine, Frédéric ULg; Foidart, Jean-Michel ULg

in Gunaïkeia (2009), 14(4), 121-123

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See detailEffects of oral contraception with ethinylestradiol and drospirenone on oxidative stress in women 18-35 years old.
De Groote, D.; PERRIER d'HAUTERIVE, Sophie ULg; Pintiaux, Axelle ULg et al

in Contraception (2009), 80(2), 187-93

Background Oral contraceptives (OCs) with estrogens and progestins may affect oxidative stress (OS) status. Study design A group of 32 women using oral contraceptives (OCU) containing 0.03 mg ... [more ▼]

Background Oral contraceptives (OCs) with estrogens and progestins may affect oxidative stress (OS) status. Study design A group of 32 women using oral contraceptives (OCU) containing 0.03 mg ethinylestradiol and 3 mg drospirenone have been compared to a matched control group of 30 noncontraception users (NCU). Blood levels of antioxidants, trace elements and markers of lipid peroxidation were assessed by biochemical methods. A microarray analysis of whole blood mRNA levels of 200 genes involved in OS-dependant pathway was also performed. Results Levels of zinc, vitamin E and antibodies to oxidized low-density lipoproteins (LDLs) were not significantly different between the two groups. On the other hand, significant increases in the mean levels of lipid peroxides (+176%, p<.001), oxidized LDLs (+145%, p<.002), copper (+103%, p<.001), Cu/Zn ratio (+100%, p<.001) and a significant decrease in the mean level of β-carotene (−41%, p<.01) were observed in the OCU compared to NCU. There was a highly significant positive correlation between the lipid peroxide levels and the copper-to-zinc ratio. From the 200 genes tested by microarray, one coding for HSP70 was significantly up-regulated (log2 fold change=+ 0.45, p<.02) and one coding for inducible nitric oxide synthase significantly down-regulated (log2 fold change=−0.24, p<.05) in the OCU compared to the NCU. Conclusions The recently introduced combination of ethinylestradiol and drospirenone induced the heightening of lipid peroxidation correlated with high levels of copper, a situation that could be associated with increased cardiovascular risk. [less ▲]

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See detailSoluble HLA-G in IVF/ICSI embryo culture supernatants does not always predict implantation success: a multicentre study.
Tabiasco, J.; PERRIER d'HAUTERIVE, Sophie ULg; Thonon, Fabienne ULg et al

in Reproductive Biomedicine Online (2009), 18(3), 374-81

Several reports have described an association between the presence of soluble human leukocyte antigen G (sHLA-G) in human embryo culture supernatants (ES) and implantation success. However, not all ... [more ▼]

Several reports have described an association between the presence of soluble human leukocyte antigen G (sHLA-G) in human embryo culture supernatants (ES) and implantation success. However, not all studies agree with these findings. To further document this debate, a multicentre blinded study was performed to investigate, on a large number of IVF ES and ICSI ES, whether sHLA-G is a useful criterion for embryo selection before transfer. A total of 1405 ES from 355 patients were collected from three assisted reproductive technique (ART) centres and evaluated for their sHLA-G content in a single laboratory, using a chemiluminescence enzyme-linked immunosorbent assay. In only one centre was a significant association between sHLA-G-positive ES and successful implantation established (P = 0.0379), whereas no such association was observed in the other centres. It was found that the percentages and concentrations of sHLA-G-positive ES varied between centres, depending on culture media and ART conditions. The percentage of sHLA-G-positive ES was significantly higher in IVF ES than ICSI ES (P < 0.001 and P < 0.01 for two centres). These data demonstrate that substantial variations of sHLA-G content in ES occur between different ART centres, highlighting the influence of several technical parameters that differ from one centre to another. [less ▲]

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See detailDifferential elevation of matrix metalloproteinase expression in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time
Labied, Soraya ULg; Galant, C.; Nisolle, Michelle ULg et al

in Human Reproduction (2009), 24(1), 113-121

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is an effective contraceptive and has many non-contraceptive health benefits. However, it is commonly associated with irregular ... [more ▼]

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is an effective contraceptive and has many non-contraceptive health benefits. However, it is commonly associated with irregular endometrial bleeding. Metalloproteinases contribute to extracellular matrix (ECM) remodelling and regulate bleeding during the menstrual cycle. Enhanced metalloproteinase expression participates in the pathogenesis of breakthrough bleeding. Thus the objective of this study was to compare matrix metalloproteinase (MMP) expression in endometrium during luteal phase and in short-term (1 month) and long-term (> or =6 months) LNG-IUS users. METHODS: MMP expression was analysed by semi-quantitative RT-PCR and immunohistochemistry. Gelatinase activity was determined by gelatin zymography. RESULTS: MMP-1, -2, -3, -7, -9 and -12 mRNAs levels were increased, whereas that of MMP-26 was decreased in the endometrium of LNG-IUS users. MMP-1, -2, -3, -7 and -9 were localized by immunohistochemistry in all biopsies in the short-term group but in only 0-27% in the control group. The incidence of positive immunostaining for MMP-2 and -3 decreased significantly in the long-term compared with short-term LNG-IUS users. MMP-26 was localized in all biopsies from the control group but in only 14 and 25% from the short- and long-term LNG-IUS groups, respectively. In both LNG groups, the numbers of macrophages (the major source of MMP-12) was increased. CONCLUSIONS: MMP-1, active MMP-2, MMP-3, MMP-7, MMP-9 and MMP-12 are more prevalent in the short-term LNG-IUS group, suggesting their important contribution to ECM breakdown and transient bleeding. The decrease in the percentage of women expressing MMP-2 and -3 might contribute to the decreased occurrence of unwanted spotting and bleeding in long-term LNG-IUS users. [less ▲]

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See detailGynaecological uses of a new class of steroids: the selective progesterone receptor modulators
Pintiaux, Axelle ULg; Chabbert-Buffet, N.; Foidart, Jean-Michel ULg

in Gynecological Endocrinology : The Official Journal of the International Society of Gynecological Endocrinology (2009), 25(2), 67-73

Selective progesterone receptor modulators (SPRM) represent a new class of synthetic steroids, which can interact with the progesterone receptor (PR) and can exert agonist, antagonist or mixed effects on ... [more ▼]

Selective progesterone receptor modulators (SPRM) represent a new class of synthetic steroids, which can interact with the progesterone receptor (PR) and can exert agonist, antagonist or mixed effects on various progesterone target tissues in vivo. This review evaluates the actual and potential usefulness of SPRMs in gynaecology [less ▲]

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See detailSafety and efficacy of tibolone in breast cancer patients with vasomotor symptoms : a double-blind, randomised non inferiority tria
Kenemans, P.; Bundred, N. J.; Foidart, Jean-Michel ULg et al

in Lancet Oncology (2009), 10(2), 135-46

Background Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is ... [more ▼]

Background Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is unknown. The aim of this study was to show non-inferiority of tibolone to placebo regarding risk of recurrence in breast-cancer patients with climacteric complaints. Methods Between July 11, 2002, and Dec 20, 2004, women surgically treated for a histologically confirmed breast cancer (T1–3N0–2M0) with vasomotor symptoms were randomly assigned to either tibolone 2·5 mg daily or placebo at 245 centres in 31 countries. Randomisation was done by use of a centralised interactive voice response system, stratified by centre, with a block size of four. The primary endpoint was breast-cancer recurrence, including contralateral breast cancer, and was analysed in the intention-to-treat (ITT) and per-protocol populations; the margin for non-inferiority was set as a hazard ratio of 1·278. This study is registered with ClinicalTrials.gov, number NCT00408863. Findings Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52·7 years (SD 7·3) and mean time since surgery was 2·1 years (SD 1·3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6·5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6·4 (SD 5·1). After a median follow-up of 3·1 years (range 0·01–4·99), 237 of 1556 (15·2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10·7%) on placebo (HR 1·40 [95% CI 1·14–1·70]; p=0·001). Results in the per-protocol population were similar (209 of 1254 [16·7%] women in the tibolone group had a recurrence vs 138 of 1213 [11·4%] women in the placebo group; HR 1·44 [95% CI 1·16–1·79]; p=0·0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone, compared with placebo. [less ▲]

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See detailAbsence of aromatase protein and mRNA expression in endometriosis.
Colette, S.; Lousse, J. C.; Defrère, S. et al

in Human Reproduction (2009), 24(9), 2133-41

BACKGROUND: Aromatase has been reported to be involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of endometriosis patients. The objective of the present study was to ... [more ▼]

BACKGROUND: Aromatase has been reported to be involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of endometriosis patients. The objective of the present study was to investigate its expression and localization in three distinct types of endometriosis. METHODS: Human peritoneal, ovarian and rectovaginal endometriotic lesions and matched eutopic endometrium were collected from patients during laparoscopy. Aromatase protein localization (immunohistochemistry, n = 63) and mRNA expression [quantitative polymerase chain reaction (Q-PCR), n = 64] were assessed. RESULTS: No aromatase protein was detected by immunohistochemistry in either the glandular or stromal compartment of endometriotic lesions or eutopic endometrium, while it was strong in placental syncytiotrophoblasts, granulosa and internal theca cells from pre-ovulatory follicles, and luteal cells from corpus luteum. By Q-PCR, low but discernible levels of aromatase expression were found in endometriomas, probably due to follicular expression. Transcripts for aromatase were barely detectable in only a few peritoneal and rectovaginal endometriotic lesions, and a few eutopic endometrium samples, probably due to contaminating surrounding tissues (adipose tissue, intact peritoneum). CONCLUSIONS: Unlike previous studies, we observed no aromatase protein in any of the endometriosis types, and barely detectable aromatase mRNA expression, suggesting that locally produced aromatase (within endometriotic lesions) may be less implicated in endometriosis development than previously postulated. Potential factors responsible for these discrepancies are discussed. [less ▲]

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See detailLes défauts d'implantation placentaire et leurs conséquences sur la fonction endothéliale maternelle
Foidart, Jean-Michel ULg; Noël, Agnès ULg; Chantraine, Frédéric ULg et al

in Bulletin Académique National de Médecine (2009), 193(5), 1059-66

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See detailBiomarker discovery in asthma-related inflammation and remodeling.
Calvo, Florence Quesada; Fillet, Marianne ULg; De Seny, Dominique ULg et al

in Proteomics (2009), 9(8), 2163-70

Asthma is a complex inflammatory disease of airways. A network of reciprocal interactions between inflammatory cells, peptidic mediators, extracellular matrix components, and proteases is thought to be ... [more ▼]

Asthma is a complex inflammatory disease of airways. A network of reciprocal interactions between inflammatory cells, peptidic mediators, extracellular matrix components, and proteases is thought to be involved in the installation and maintenance of asthma-related airway inflammation and remodeling. To date, new proteic mediators displaying significant activity in the pathophysiology of asthma are still to be unveiled. The main objective of this study was to uncover potential target proteins by using surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) on lung samples from mouse models of allergen-induced airway inflammation and remodeling. In this model, we pointed out several protein or peptide peaks that were preferentially expressed in diseased mice as compared to controls. We report the identification of different five proteins: found inflammatory zone 1 or RELM alpha (FIZZ-1), calcyclin (S100A6), clara cell secretory protein 10 (CC10), Ubiquitin, and Histone H4. [less ▲]

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See detailA rare case of placental choriangioma associated with neonatal diffuse hemangomatosis.
Capelle, Xavier ULg; Syrios, Petros ULg; Chantraine, Frédéric ULg et al

in Journal de Gynécologie, Obstétrique et Biologie de la Reproduction (2009), 38(3), 246-249

Placental chorioangioma is a benign vascular tumor. Lesions larger than 4cm may cause fetal and maternal complications. Its association with disseminated neonatal hemangiomatosis is rarely described. We ... [more ▼]

Placental chorioangioma is a benign vascular tumor. Lesions larger than 4cm may cause fetal and maternal complications. Its association with disseminated neonatal hemangiomatosis is rarely described. We report a case of a large chorioangioma associated with an hydrops foetalis and disseminated neonatal hemangiomatosis. The relationship between placental chorioangioma and hemangioma is briefly discussed. [less ▲]

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See detailDysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia--a step forward but not the definitive answer
Foidart, Jean-Michel ULg; Schaaps, Jean-Pierre ULg; Chantraine, Frédéric ULg et al

in Journal of Reproductive Immunology (2009), 82(2), 106-11

Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, which resolves on placental delivery. It is thought to be the consequence of impaired placentation ... [more ▼]

Preeclampsia (PE) is a pregnancy-specific syndrome characterized by hypertension, proteinuria and edema, which resolves on placental delivery. It is thought to be the consequence of impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries. In PE the maternal plasma concentration of free vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) is decreased whereas the concentration of soluble fms-like tyrosine kinase-1 (sFlt-1) and of soluble endoglin (sEng) is increased. These soluble receptors may bind VEGF, PLGF and TGFβ1 and TGFβ3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Hence there is a view that the pathogenesis is more or less clarified. According to the vascular theory, poor placentation leads to poor uteroplacental perfusion and hypoxia, which stimulates sFlt-1 and sEng production causing the maternal syndrome. This assumption has been recently challenged. The role of hypoxia as the main stimulus for release of sFlt-1 has been questioned and the role of inflammatory mechanisms has been emphasized. According to this inflammatory theory, poor placentation may predispose more to placental oxidative stress than hypoxia and endothelial dysfunction may be part of a broader disorder of systemic inflammation. Finally, the recent demonstration of activating auto-antibodies to the angiotensin 1 receptor that experimentally play a major pathogenic role in PE further suggests a pleiotropism of aetiologies for this condition. The purpose of this review is to critically evaluate the recent hypotheses and their possible insights on early diagnosis, prevention and treatment. [less ▲]

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See detailThe IGF system in in-vitro human decidualization
Ganeff, Corinne ULg; Chatel, G.; Munaut, Carine ULg et al

in Molecular Human Reproduction (2009), 15(1), 27-38

Decidualization of endometrial stromal cells (ESCs) is critical for a successful pregnancy but the molecular mechanisms of the process are poorly understood. In this study, we investigated whether the ... [more ▼]

Decidualization of endometrial stromal cells (ESCs) is critical for a successful pregnancy but the molecular mechanisms of the process are poorly understood. In this study, we investigated whether the insulin-like growth factor (IGF) network is involved in this cellular process. Expression kinetics of members of the IGF system was examined at both mRNA and protein levels during in-vitro decidualization of cultured human ESCs. We found a significant up-regulation of IGF-II as well as of IGF-I receptor and the A and B insulin receptor (InsR) isoforms. In addition, levels of the key adaptor proteins insulin receptor substrate 1 (IRS-1) and IRS-2 increased, suggesting a potential involvement of the IGF signalling pathway in the decidualization process. Expression of two IGF binding proteins, IGFBP-1 and IGFBP-4, which can inhibit IGF action, also increased. In order to determine whether IGF signalling was activated during decidualization, the phosphorylation status of the receptors and the adaptor proteins was estimated. Only IRS-2 was slightly phosphorylated in decidualized cells and was further activated by the addition of exogenous IGF-II. These results suggest that the IGF signalling pathway could play a crucial role in the functions of decidualized endometrial cells [less ▲]

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See detailPAI-1 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma
Freytag, J.; Wilkins-Port, C. E.; Higgins, C. E. et al

in Journal of Oncology Management : The Official Journal of the American College of Oncology Administrators (2009)

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR ... [more ▼]

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype. In one physiologically relevant model of human cutaneous SCC progression, TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs), among the most prominent of which is MMP-10—an MMP known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC. One testable hypothesis proposes that TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies. [less ▲]

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