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Sökning: WFRF:(Mints Miriam)

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  • Föregående 1[2]3Nästa
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  • O'Mara, Tracy A, et al. (författare)
  • Identification of nine new susceptibility loci for endometrial cancer.
  • 2018
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
  • Razumova, Z., et al. (författare)
  • The prognostic role of LRIG proteins in endometrial cancer
  • 2019
  • Ingår i: International Journal of Gynecological Cancer. - : BMJ Publishing Group Ltd. - 1048-891X .- 1525-1438. ; 29, s. A358-A358
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • Introduction/Background Endometrial cancer (EC) is the most common gynaecological malignancy in Sweden. The disease has several prognostic factors. Still, the high amount of EC develops into more aggressive forms of cancer, even though being first considered to be non-aggressive. The LRIG proteins are a family of three integral surface proteins that have a similar domain organisation. The current study evaluated the role of LRIG proteins as prognostic biomarkers in EC.Methodology The cohort included 75 women who underwent a hysterectomy and bilateral salpingo-oophorectomydue to EC at the Department of Women's and Children's Health, Karolinska University Hospital Solna between 2007 and 2012. The expression of LRIG1, LRIG2, and LRIG3 in paraffin biopsies was analysed by immunohistochemistry (IHC) with applying specific polyclonal antibodies. Evaluation of immunostainings was performed by two senior pathologists without knowledge of the disease outcome. The percentage of positive cells was divided in two groups with median percentage as cut off to have two groups of equal size included in the statistical analysis. Then the groups were assessedin connection with different tumour characteristics and clinical outcomes of EC.Results The majority of women in the cohort had >50% LRIG1-, LRIG2-, and LRIG3-positive cells. Among 6047 person-months of follow-up a total, of 14 incident cases of relapsed EC were identified. A statistically significant association between high LRIG3 expression and superior overall survival was observed in the cohort (IRR=2.559, 95 CI=1.054–6.210, p=0.038). LRIG1 and LRIG2 expression did not significantly correlate with survival.Conclusion Our results support the hypothesis that LRIG3 expression may have a prognostic role in women with EC. The significance of LRIG1 and LRIG2 expression remains to be clarified.
  • Tzortzatos, Gerasimos, et al. (författare)
  • Screening for germline phosphatase and tensin homolog-mutations in suspected Cowden syndrome and Cowden syndrome-like families among uterine cancer patients
  • 2015
  • Ingår i: Oncology Letters. - 1792-1074 .- 1792-1082. ; 9:4, s. 1782-1786
  • Tidskriftsartikel (refereegranskat)abstract
    • Cowden syndrome (CS) is an autosomal dominant disorder characterized by multiple hamartomas in the breast, thyroid and endometrium, with a prevalence of 1 per 250,000. Females with CS have a 21-28% lifetime risk of developing uterine cancer. Germline mutations in the phosphatase and tensin homolog (PTEN) gene, a tumor suppressor gene, are responsible for 30-80% of CS cases. PTEN is a nine-exon gene, located on chromosome 10q23.3, which encodes the 403 amino acid PTEN protein. It negatively regulates the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway, affecting various cellular processes and signaling pathways. The present study examined whether PTEN mutations are present in CS-like families with uterine cancer (UC). UC patients underwent surgery at Karolinska University Hospital, Stockholm, Sweden (2008-2012). Pedigrees were analyzed and 54 unrelated CS-like families were identified. CS-like families were defined as having at least one occurrence of uterine cancer and one of breast cancer, as well as at least one additional Cowden-associated tumor (uterine, breast, thyroid, colon or kidney cancer) in the same individual or in first-degree relatives. Genomic DNA was amplified using polymerase chain reaction, and DNA sequencing analysis of all nine exons of the PTEN gene was conducted. No germline PTEN mutations or polymorphisms were identified. Germline PTEN mutations are rare in CS-like families with uterine cancer, therefore, genetic screening must be restricted to patients that meet the strict National Comprehensive Cancer Network criteria. Gynecologists must be aware of the CS criteria and identify potential cases of CS in females where uterine cancer is the sentinel cancer.
  • Alder, Susanna, et al. (författare)
  • Incomplete excision of cervical intraepithelial neoplasia as a predictor of the risk of recurrent disease : a 16-year follow-up study
  • 2020
  • Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier. - 0002-9378 .- 1097-6868. ; 222:2, s. 172.e1-172.e12
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Women treated for high-grade cervical intraepithelial neoplasia (CIN, grade 2 or 3) are at elevated risk of developing cervical cancer. Suggested factors identifying women at highest risk for recurrence post-therapeutically include incomplete lesion excision, lesion location, size and severity, older age, treatment modality and presence of high-risk human papilloma virus (hrHPV) after treatment. This question has been intensively investigated over decades, but there is still substantial debate as to which of these factors or combination of factors most accurately predict treatment failure.OBJECTIVES: In this study, we examine the long-term risk of residual/recurrent CIN2+ among women previously treated for CIN2 or 3 and how this varies according to margin status (considering also location), as well as comorbidity (conditions assumed to interact with hrHPV acquisition and/or CIN progression), post-treatment presence of hrHPV and other factors.STUDY DESIGN: This prospective study included 991 women with histopathologically-confirmed CIN2/3 who underwent conization in 2000-2007. Information on the primary histopathologic finding, treatment modality, comorbidity, age and hrHPV status during follow-up and residual/recurrent CIN2+ was obtained from the Swedish National Cervical Screening Registry and medical records. Cumulative incidence of residual/recurrent CIN2+ was plotted on Kaplan-Meier curves, with determinants assessed by Cox regression.RESULTS: During a median of 10 years and maximum of 16 years follow-up, 111 patients were diagnosed with residual/recurrent CIN2+. Women with positive/uncertain margins had a higher risk of residual/recurrent CIN2+ than women with negative margins, adjusting for potential confounders (hazard ratio (HR)=2.67; 95% confidence interval (CI): 1.81-3.93). The risk of residual/recurrent CIN2+ varied by anatomical localization of the margins (endocervical: HR=2.72; 95%CI: 1.67-4.41) and both endo- and ectocervical (HR=4.98; 95%CI: 2.85-8.71). The risk did not increase significantly when only ectocervical margins were positive/uncertain. The presence of comorbidity (autoimmune disease, human immunodeficiency viral infection, hepatitis B and/or C, malignancy, diabetes, genetic disorder and/or organ transplant) was also a significant independent predictor of residual/recurrent CIN2+. In women with positive hrHPV findings during follow-up, the HR of positive/uncertain margins for recurrent/residual CIN2+ increased significantly compared to women with hrHPV positive findings but negative margins.CONCLUSIONS: Patients with incompletely excised CIN2/3 are at increased risk of residual/recurrent CIN2+. Margin status combined with hrHPV results and consideration of comorbidity may increase the accuracy for predicting treatment failure.
  • Andersson, Sonia, et al. (författare)
  • Uneven distribution of human papillomavirus 16111 cervical carcinoma in situ and squamous cell carcinoma in older females : A retrospective database study
  • 2014
  • Ingår i: Oncology Letters. - 1792-1074 .- 1792-1082. ; 8:4, s. 1528-1532
  • Tidskriftsartikel (refereegranskat)abstract
    • Human papillomavirus (HPV) 16 is the dominant cofactor in cervical cancer development. The present report investigated the age-specific prevalence of HPV16 in cervical carcinoma in situ (CIS) in females attending organised cervical cancer screening. A retrospective observational study was performed based on individual data from two databases. A total of 162 females aged between 20 and 65 years from Uppsala County, Sweden with CIS and an HPV test conducted between 2010 and 2011, preceding or concomitant to CIS diagnosis, were included. Females with cervical squamous cell carcinoma (SCC; n=35) were used for comparison. In total, 96% (n=156) of females with CIS were positive for high-risk HPV; HPV16 was the most prevalent (44.5%), followed by HPV33/52/58 (19.5%), HPV31 (13.1%) and HPV18145 (9.5%). HPV16 was most frequently detected in females with CIS aged between 20 and 29 years (73.6%) and least frequently detected in those aged between 50 and 65 years (33.3%), with a statistically significant age-specific difference (P=0.001). Among the HPV16-positive females, multiple infections were most frequent in the younger age groups. The prevalence of HPV16 in females with CIS decreased with age, whereas a high prevalence of HPV16 remained in females with SCC. These results may indicate that HPV16 has increased oncogenic potential in older females.
  • Lomnytska, Marta I, et al. (författare)
  • Diagnostic protein marker patterns in squamous cervicalcancer
  • 2010
  • Ingår i: Proteomics - Clinical Applications. - Weinheim : WILEY-VCH Verlag GmbH & Co. KGaA. - 1862-8346. ; 4:1, s. 17-31
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Cervical cancer is the second most prevalent malignancy of women. Our aim was toidentify additional marker protein patterns for objective diagnosis of squamous cervical cancer(SCC).Experimental design: Collected tissue biopsies of SCC, squamous vaginal cancer (SVC), normalcervical and vaginal mucosa were subjected to 2-DE, SameSpot analysis, MALDI-TOF-MSprotein identification, and analysis of the expression of selected proteins by immunohistochemistry.Results: In 148 protein spots selected by the difference in expression 99 proteins were identified.A differential protein pattern for SCC was, e.g. over-expressed (OE) eukaryotic translationinitiation factor 3-2b, neutrophil cytosolic factor 2, annexin A6 (ANXA6), for SVC it was OEcathepsin D, g-catenin, RAB2A, for both cancers it was OE apolipoprotein E, tropomyosin 3,HSPA8, and underexpressed cytokeratin 13, osteoglycin. In SCC nuclear expression ofneutrophil cytosolic factor 2, PRDX2, HSP27 (nine of ten cases), ANXA6 (nine of ten cases) wasobserved while tropomyosin 4 was expressed only in two of ten cases. There was 81.1% (43/53)agreement between the expression of protein spots and the immune expression of proteins(www.proteinatlas.org).Conclusions and clinical relevance: SCC is characterized by specific tissue marker proteinpatterns that allow objective detection of the disease. They can become a basis for objectiveautomated cytology-based screening and improve current diagnostics of SCC.
  • Mints, Miriam (författare)
  • Idiopathic menorrhagia : Studies of angiogenesis and surgical therapy
  • 2003
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background Excessive menstrual bleeding, menorrhagia (i.e. > 80 nil loss of blood) is a com-mon gynecological problem in women of reproductive age, accounting for over 20% of visits to gynecology outpatient clinics. The disorder may not only cause iron deficiency anemia but also considerable social discomfort and reduction in the quality of life. Although commonly associated with fibroids and carcinoma, approximately 50% of patients with menorrhagia do not show any evidence of uterine pathology. This suggests a defect in the cellular processes and regulatory mechanisms of menstruation. Historically, many women with heavy menstrual bleeding were advised to undergo hysterectomy, which was the only way of enduring a "cure". Hysterectomy is an effective treatment of menorrhagia, but it is associated with substantial postoperative morbidity and convalescence. In the early 1990s, endometrial resection or ablation became a well-established outpatient alternative for the surgical treatment of menorrhagia. The aim of this thesis This work has mainly been focused on two aspects: firstly, the analysis of transcervical resection of the endometrium (TCRE) as a surgical option for treatment of menorrhagia and, secondly, on the involvement of the vascular endothelial growth factor (VEGF) family in the regulation of anglogenesis in the human endometrium in healthy women and those with idiopathic menorrhagia. In particular, we investigated if the vessel wall anatomy was abnormal and related findings to the expression of VEGF and VEGF receptors in the blood vessels. Results The general clinical outcome in the present studies (papers I and II) showed favorable results with low peroperative and postoperative complication rates: fluid overload occurred in 4% and perforation in 1% of the patients. Most of women who underwent TCRE found this surgery acceptable and approximately 80% of these women have avoided hysterectomy. Second-look hysteroscopy in women after TCRE showed signs of regenerative endometrium. In order to determine why the endometrium regenerates and what regulates this process, we have investigated the expression and distribution of VEGF and its receptors as well as vessel morphology in normal and menorrhagic endometrium (papers III- V). Our data suggest an up-regulation of the agonist-receptor pathway of VEGF in idiopathic menorrhagia: the vascular expression of VEGF-A, VEGFR1, -2, -3 in capillaries was 1.8-, 1.8-, 2.0-, and 1. 6-fold higher, respectively, in the menorrhagia group. Since VEGF-A not only stimulates migration and survival of endothelial cells but also induces vascular permeability, we have addressed this aspect by analyzing of vessel morphology. We found that vessels in patients with menorrhagia displayed an unusual morphology with focal regions, gaps. The relative size of the gaps was significantly larger in menorrhagia samples than in controls (P=0.000002). Moreover, the sizes of the gaps correlated positively to the number of endometrial blood vessels expressing VEGF-A (P=0.0002) and VEGFR1 (P=0.03). To our knowledge, this is the first study that demonstrates the presence of endothelial gaps in menorrhagic endometrium and as a part of a specific disease process. Conclusions TCRE provides a minimally invasive technique for treatment of menorrhagia with good clinical results: about 80% of women have the possibility of avoiding hysterectomy. Therefore, endometrial resection/ablation should be offered as a surgical option to all women with idiopathic menorrhagia who have completed their families. Normal endometrial angiogenesis is perturbed in idiopathic menorrhagia with an up-regulation of the agonist-receptor pathway of VEGF-A, which leads to anatomical differences in blood vessels, manifested inter alia as gaps. Our novel observations may be of significance in order to explain some of the underlying mechanisms that contribute to idiopathic menorrhagia and will provide novel opportunities for therapeutic intervention in the future.
  • Razumova, Zoia, et al. (författare)
  • Cadmium Intake as a Prognostic Factor in Endometrial Cancer : A Swedish Cohort-Based Study
  • 2021
  • Ingår i: Nutrition and Cancer. - : Routledge. - 0163-5581 .- 1532-7914. ; , s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Metalloendocrinology is a new interdisciplinary field, which was established due to the importance of connections between inorganic chemicals and hormonal mechanisms. The role of cadmium in hormone-related tumors is an excellent example of this connection, as cadmium mimics estrogen in the human body. Since endometrial cancer (EC) is hormone-related, it is well-suited for assessing the estrogenic effects of cadmium. Therefore, the present study aims to explore the role of dietary cadmium intake in the progression-free survival (PFS) and overall survival (OS) in women with EC. Dietary cadmium intake was estimated based on a large cohort of Swedish women (n = 416) with EC. Median dietary cadmium intake was then analyzed in relation to different tumor characteristics and clinical outcomes. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Median daily dietary cadmium intake in the cohort was 13.1 μg (interquartile range 25%-75%=6.4). High dietary cadmium intake (μg/day) was associated with significantly decreased OS in the study cohort (HR = 0.956, 95% CI = 0.914-1.001, p = 0.05). Dietary cadmium intake was not associated with PFS (HR = 0.975, 95% CI = 0.924-1.028, p = 0.348). Therefore, our results indicate that high dietary cadmium intake could be associated with poor outcome in women with EC.
  • Wersäll, Ofra Castro, et al. (författare)
  • PGC1α and VDAC1 expression in endometrial cancer
  • 2021
  • Ingår i: Molecular and clinical oncology. - : Spandidos Publications. - 2049-9450 .- 2049-9469. ; 14:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Endometrial cancer (EC) is one of the ten most common gynecological cancers. As in most cancers, EC tumour progression involves alterations in cellular metabolism and can be associated with, for instance, altered levels of glycolytic enzymes. Mitochondrial functions and proteins are known to serve key roles in tumour metabolism and progression. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α) is a major regulator of mitochondrial biogenesis and function, albeit of varying prognostic value in different cancers. The voltage-dependent anion channel type 1 (VDAC1) regulates apoptosis as well as metabolite import and export over the mitochondrial outer membrane, and is often used for comparative quantification of mitochondrial content. Using immunohistochemistry, the present study examined protein expression levels of PGC1α and VDAC1 in tumour and paired benign tissue samples from 148 patients with EC, in order to examine associations with clinical data, such as stage and grade, Ki-67, p53 status, clinical resistance and overall survival. The expression levels of both PGC1α and VDAC1, as well as a PGC1α downstream effector, were significantly lower in tumor tissues than in benign tissues, suggesting altered mitochondrial function in EC. However, Kaplan-Meier, log rank and Spearman's rank correlation tests revealed that their expression was not correlated with survival and clinical data. Therefore, PGC1α and VDAC1 are not of major prognostic value in EC.
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