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1.  AMG 479, a Novel IGF-1-R Antibody, Inhibits Endometrial Cancer Cell Proliferation Through Disruption of the PI3K/Akt and MAPK Pathways 
Reproductive Sciences  2011;18(9):832-841.
Our goal was to evaluate the therapeutic potential of a novel antibody to the insulin growth factor-1 receptor (IGF-1-R; AMG 479) in endometrial cancer cells. The endometrial cancer cell lines, ECC-1/PRAB72 and RL-95-2, were used. Treatment with AMG 479 (0.02-200 nmol/L) resulted in inhibition of cell proliferation at 72 to 120 hours. Insulin growth factor-1 (0.15-7.5 nmol/L) stimulated growth in both cell lines (range of 15%-42%, P = .0025-.0445), which could be blocked by pretreatment with AMG 479 (mean of 29% for ECC-1/PRAB72, P = .006-.007; mean of 36% for RL-95-2, P = .0002-.0045). AMG 479 suppressed IGF-1-R kinase activity in a dose-dependent manner. Cells treated with AMG 479 underwent either G1 (ECC-1/PRAB72) or G2 (RL-95-2) arrest. AMG 479 decreased human telomerase reverse transcriptase (hTERT) mRNA expression in both endometrial cancer cell lines. Treatment with AMG 479 rapidly blocked IGF-1-induced phosphorylation of IFG-1-R, Akt, and p44/42. Thus, manipulation of the IGF-1-R pathway may serve as a promising therapeutic strategy for the treatment of endometrial cancer.
PMCID: PMC4046305  PMID: 21846689
endometrial cancer; insulin growth factor-1; insulin growth factor-1 receptor; phosphatidylinositol 3-kinase/Akt pathway; mitogen-activated protein kinase pathway; telomerase
2.  Identification of Quiescent, Stem-Like Cells in the Distal Female Reproductive Tract 
PLoS ONE  2012;7(7):e40691.
In fertile women, the endometrium undergoes regular cycles of tissue build-up and regression. It is likely that uterine stem cells are involved in this remarkable turn over. The main goal of our current investigations was to identify slow-cycling (quiescent) endometrial stem cells by means of a pulse-chase approach to selectively earmark, prospectively isolate, and characterize label-retaining cells (LRCs). To this aim, transgenic mice expressing histone2B-GFP (H2B-GFP) in a Tet-inducible fashion were administered doxycycline (pulse) which was thereafter withdrawn from the drinking water (chase). Over time, dividing cells progressively loose GFP signal whereas infrequently dividing cells retain H2B-GFP expression. We evaluated H2B-GFP retaining cells at different chase time points and identified long-term (LT; >12 weeks) LRCs. The LT-LRCs are negative for estrogen receptor-α and express low levels of progesterone receptors. LRCs sorted by FACS are able to form spheroids capable of self-renewal and differentiation. Upon serum stimulation spheroid cells are induced to differentiate and form glandular structures which express markers of mature Műllerian epithelial cells. Overall, the results indicate that quiescent cells located in the distal oviduct have stem-like properties and can differentiate into distinct cell lineages specific of endometrium, proximal and distal oviduct. Future lineage-tracing studies will elucidate the role played by these cells in homeostasis, tissue injury and cancer of the female reproductive tract in the mouse and eventually in man.
PMCID: PMC3404087  PMID: 22848396
3.  Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer 
PLoS ONE  2012;7(1):e30840.
Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).
Methodology and Principal Findings
Paraffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa(IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB(IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.
Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.
PMCID: PMC3266274  PMID: 22295114
4.  The prevalence and risk factors of overactive bladder symptoms and its relation to pelvic organ prolapse symptoms in a general female population 
Introduction and hypothesis
To study the prevalence and risk factors of overactive bladder (OAB) symptoms and its relationship with symptoms of pelvic organ prolapse (POP).
This is a cross-sectional study including women aged between 45 and 85 years, registered in eight general practices. All women were asked to self complete the validated Dutch translated questionnaires. All symptoms were dichotomized as present or absent based on responses to each symptom and degree of bother.
Forty-seven percent of the women filled out the questionnaire. Prevalence of urgency was 34% and the prevalence of any OAB symptoms 49%. Prevalence of OAB symptoms increased with advancing age. Symptoms of POP were an independent risk factor for symptomatic OAB. Other risk factors were continence and prolapse surgery in the past, age above 75, overweight, postmenopausal status and smoking.
The prevalence of any OAB symptoms was 49%. POP symptoms were an independent risk factor for symptomatic OAB.
PMCID: PMC3072516  PMID: 21104400
Overactive bladder; Urgency; Urge incontinence; Frequency; Pelvic organ prolapse; Prevalence
5.  Prevalence of major levator abnormalities in symptomatic patients with an underactive pelvic floor contraction 
Introduction and hypothesis
Major levator ani abnormalities (LAA) may lead to abnormal pelvic floor muscle contraction (pfmC) and secondarily to stress urinary incontinence (SUI), prolapse, or fecal incontinence (FI).
A retrospective observational study included 352 symptomatic patients to determine prevalence of LAA in underactive pfmC and the relationship with symptoms. On 2D/3D transperineal ultrasound, PfmC was subjectively assessed as underactive (UpfmC) or normal (NpfmC) and quantified. LAA, defined as a complete avulsion of the pubic bone, was analyzed using tomographic ultrasound imaging.
LAA were found in 53.8% of women with UpfmC versus 16.1% in NpfmC (P < 0.001). Patients with UpfmC were less likely to reduce hiatal area on pfmC (mean 7% reduction vs 25% in NpfmC (P < 0.001)). An UpfmC was associated with FI (P = 0.002), not with SUI or prolapse of the anterior and central compartment.
An underactive pfmC is associated with increased prevalence of LAA and FI.
PMCID: PMC2876255  PMID: 20204327
Fecal incontinence; Levator ani abnormalities; Pelvic floor muscle contraction; Stress urinary incontinence; Prolapse; Transperineal ultrasound
6.  Pelvic floor muscle function in a general female population in relation with age and parity and the relation between voluntary and involuntary contractions of the pelvic floor musculature 
Introduction and hypothesis
The objective of this study is to describe pelvic floor muscle function (PFMF) in relation to age and parity in a general female population and to test whether strength/endurance measurements represent all functions of the pelvic floor musculature.
A cross-sectional study was performed on 95% of the women aged 45–85 years from a small Dutch town. Validated questionnaires were used to obtain general information, and vaginal examination to test PFMF was performed on 649 women. Chi-square tests were used to analyse the relation between PFMF versus age and parity. Analysis of variance was used to compare muscle strength and endurance to the other PFMF items.
Response rate to the questionnaire was 62.7% (1,869/2,979). PFM strength and endurance are not positively associated with the effective involuntary muscle contractions during coughing.
Voluntary muscle contractions decreased with age, but there was no relation with parity. Muscle strength and endurance measurements alone are not sensitive enough to determine PFMF.
PMCID: PMC2834770  PMID: 19756345
Female; Function; Pelvic floor musculature; Prevalence; Involuntary muscle contraction
7.  The prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female population 
Introduction and hypothesis
In selected populations, pelvic organ prolapse (POP) was associated with bladder/bowel symptoms, but data on the general female population are lacking. Our aim was to obtain normative data on the prevalence of POP and pelvic floor dysfunction (PFD) symptoms and signs and to identify associations.
Validated questionnaires on POP and PFD (urogenital distress inventory, (UDI) and defaecation distress inventory (DDI)) were sent to a general population of 2,979 women (aged 45–85 years). Data were analysed using the Kruskal–Wallis test, chi square test and Spearman’s rank correlation coefficient.
Response rate was 62.7%. Associations between POP stage and parity (0.002) and vaginal bulging (<0.001) are significant. Anatomical locations of POP and PFD symptoms correlated significantly with incontinence of flatus, feeling anal prolapse, manual evacuation of stool, vaginal bulging, constipation and pain during faecal urge (p ≤ 0.005).
Strategies should be developed to alleviate obstructive bowel disorders associated with POP.
PMCID: PMC2721135  PMID: 19444368
Prevalence; Incontinence; Bladder; Bowel; Pelvic floor disorders; POPQ
8.  Prediction model and prognostic index to estimate clinically relevant pelvic organ prolapse in a general female population 
Introduction and hypothesis
Estimation on prevalence and distribution of pelvic organ prolapse (POP) signs in a general female population is difficult. We therefore developed and validated a prediction model and prognostic instrument.
Questionnaires were sent to a general female population (45–85 years). A random sample underwent vaginal examination for POP (POPQ). A prediction model was developed using multivariate analysis and validated in a subgroup of participants.
Positive questionnaire-response rate was 46.8% (1,397 of 2,979). From the questionnaire group, 649 women were vaginally examined (46.5%). Prevalence of clinically relevant POP was 21%. Multivariate analysis demonstrated significantly higher odds ratios on the report of vaginal bulging, parity ≥2 and a mother with POP. The receiver operating characteristic curve showed areas under the curve of 0.672 and 0.640.
The prevalence of POP at or beyond the hymen could be estimated in a general female population using our prediction model with 17 questions and our POP score chart with eight questions.
PMCID: PMC2721134  PMID: 19444367
Pelvic organ prolapse; POPQ; Prediction model; Prevalence; Vaginal bulging
9.  Vaginal noise: prevalence, bother and risk factors in a general female population aged 45–85 years 
Introduction and hypothesis
Vaginal noise (VN) is a symptom of pelvic floor (PF) dysfunction and has been described in a few studies. No other risk factors have been described besides parity and pelvic organ prolapse (POP). Underlying mechanisms of VN are unclear. Aims of this study were to describe prevalence, bother and relation between VN and PF (muscle)(dys)function.
A cross-sectional study was performed on a general population of 2,921 women (aged 45–85 years). Questionnaires were filled in by 1,397 women, and 800 were selected at random to undergo vaginal examination for POP Quantification and PF muscle function assessment. Chi-square tests, Student's t test and multivariate logistic regression were performed (P < 0.05).
Response rate was 62.7%. Prevalence of VN was 12.8%; 72.1% reported only a little bother. Odds ratios for parity and solid stool were high.
VN was strongly related to many symptoms of pelvic floor dysfunction, but it was only causing a little bother.
PMCID: PMC2706384  PMID: 19582382
Pelvic floor dysfunction; Pelvic floor musculature; Risk factors; Vaginal noise

Results 1-9 (9)