ResearchPad - gynecological-tumors https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers]]> https://www.researchpad.co/article/elastic_article_14755 The transcription factor Oct4 with well-known roles in embryogenesis, pluripotency and cellular reprogramming has recently been found to be expressed in several types of somatic tumors. Even though its role in cancer remains controversial, we provide evidence that Oct4 is expressed in cervical cancer tissues and cancer cell lines. The viral oncogenes of the Human Papillomavirus significantly elevate Oct4 expression both in normal and cancer cells, likely through transcriptional upregulation. While the expression levels of Oct4 in cancer are low compared to those seen in stem cells, our results suggest that they are still consequential to cell proliferation, self-renewal, and migration. We demonstrate a physical interaction of the E7 oncoprotein with Oct4, mapping to the CR3 region of E7, which correlates to a distinct Oct4 transcriptional output. Introduction of E7 into HPV(-) cells and immortalised human keratinocytes led to transcriptional and phenotypic changes, which mimicked results in HPV(+) cells. These insights provide a plausible mechanism and consequences for a long-suspected interaction.

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<![CDATA[The association between cervical cancer screening participation and the deprivation index of the location of the family doctor’s office]]> https://www.researchpad.co/article/elastic_article_14737 Cervical cancer screening rates are known to be strongly associated with socioeconomic status. Our objective was to assess whether the rate is also associated with an aggregated deprivation marker, defined by the location of family doctors’ offices.MethodsTo access this association, we 1) collected data from the claim database of the French Health Insurance Fund about the registered family doctors and their enlisted female patients eligible for cervical screening; 2) carried out a telephone survey with all registered doctors to establish if they were carrying out Pap-smears in their practices; 3) geotracked all the doctors’ offices in the smallest existing blocks of socioeconomic homogenous populations (IRIS census units) that were assigned a census derived marker of deprivation, the European Deprivation Index (EDI), and a binary variable of urbanization; and 4) we used a multivariable linear mixed model with IRIS as a random effect.ResultsOf 348 eligible doctors, 343 responded to the telephone survey (98.6%) and were included in the analysis, encompassing 88,152 female enlisted patients aged 25–65 years old. In the multivariable analysis (adjusted by the gender of the family doctor, the practice of Pap-smears by the doctor and the urbanization of the office location), the EDI of the doctor’s office was strongly associated with the cervical cancer screening participation rate of eligible patients (p<0.001).ConclusionThe EDI linked to the location of the family doctor’s office seems to be a robust marker to predict female patients’ participation in cervical cancer screening. ]]> <![CDATA[Preoperative risk stratification in endometrial cancer (ENDORISK) by a Bayesian network model: A development and validation study]]> https://www.researchpad.co/article/elastic_article_14690 Bayesian networks are graphical networks that are based on machine learning and can be used for prediction purposes without the need to have values for all predictor variables available for each patient.Approximately 10% of patients with endometrial cancer have lymph node metastasis.The risk of lymph node metastasis and poor outcome differs substantially between individuals.Preoperative identification of patients at risk for lymph node metastasis and poor outcome allows tailoring of individualized treatment.What did the researched do and find?A Bayesian network to predict the risk of lymph node metastasis and survival was constructed with data from a retrospective multicenter development cohort from 10 centers across Europe (n = 763).The predictive capability of the final network was tested in 2 external cohorts from the Netherlands (PIpelle Prospective ENDOmetrial carcinoma [PIPENDO], n = 384) and from Norway (Molecular Markers in Treatment in Endometrial Cancer [MoMaTEC], n = 446).What do these findings mean?The Bayesian network we propose allows refined risk stratification before surgery and is easily usable.Because of its graphical character, the interactions between the different variables included into the network are directly visualized.A prospective feasibility study will be needed prior to implementation in the clinic. ]]> <![CDATA[Prevalence of endosalpingiosis and other benign gynecologic lesions]]> https://www.researchpad.co/article/elastic_article_14492 Endosalpingiosis, traditionally regarded as an incidental pathological finding, was recently reported to have an association with gynecologic malignancies. To determine the prevalence of endosalpingiosis, we evaluated all benign appearing adnexal lesions using the Sectioning and Extensively Examining-Fimbria (SEE-Fim) protocol, and queried the pathology database for the presence of endosalpingiosis, gynecologic malignancy, endometriosis, Walthard nests, and paratubal cysts. Using the SEE-Fim protocol, the prevalence of endosalpingiosis, endometriosis, Walthard nests, and paratubal cysts were 22%, 45%, 33%, and 42% respectively, substantially higher than previously reported. All lesions were observed to increase with age except endometriosis which increased until menopause then decreased dramatically. Among specimens including ovarian tissue, the prevalence of implantation of at least one lesion type was ubiquitous in patients age 51 and older (93%). The clinical significance of endosalpingiosis should be a continued area of research with larger trials assessing prevalence, factors affecting incidence, and association with malignancy. Our findings contribute to elucidating the origin of ectopic lesions and gynecologic disease risk.

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<![CDATA[Clinicopathological and prognostic significance of caveolin-1 and ATG4C expression in the epithelial ovarian cancer]]> https://www.researchpad.co/article/elastic_article_14473 Altered expression of caveolin-1 (CAV1) and autophagy marker ATG4C is observed in various types of human cancers. However, the clinical significance of CAV1 and ATG4C expression in epithelial ovarian cancer (EOC) remains largely unknown. The present study aims to explore the clinicopathological value and prognostic significance of CAV1 and ATG4C expression in EOC.MethodsThe expression pattern and prognostic value of CAV1 and ATG4C mRNA in EOC were analyzed using data from the Cancer Genome Atlas (TCGA) database (N = 373). In addition, immunohistochemistry analysis was performed to detect and assay the expression of CAV1 and ATG4C proteins in tissue microarray of EOC.ResultsBased on TCGA data, Kaplan-Meier analysis indicated that patients with low CAV1 mRNA (p = 0.021) and high ATG4C mRNA (p = 0.018) expression had a significantly shorter overall survival (OS). Cox regression analysis demonstrated that the expression levels of CAV1 (p = 0.023) and ATG4C mRNA (p = 0.040) were independent prognostic factors for OS in EOC. In addition, the Concordance Index of the nomogram for OS prediction was 0.660. Immunohistochemical analysis showed the expression levels of stromal CAV1 and cancerous ATG4C proteins, and high expression of both CAV1 and ATG4C protein in the stroma were found to significantly correlate with the histologic subtypes of EOC, especially with serous subtype.ConclusionsDecreased expression of CAV1 mRNA and increased expression of ATG4C mRNA in EOC can predict poor overall survival. The expression levels of CAV1 protein in stromal cells and ATG4C protein in cancer cells are significantly associated with histologic subtypes of EOC. These findings suggest that CAV1 and ATG4C serve as useful prognostic biomarkers and candidate therapeutic targets in EOC. ]]> <![CDATA[Swainsonine, an alpha-mannosidase inhibitor, may worsen cervical cancer progression through the increase in myeloid derived suppressor cells population]]> https://www.researchpad.co/article/5c897787d5eed0c4847d2ef3

Cervical cancer, caused by high oncogenic risk Human Papillomavirus (HPV) infection, continues to be a public health problem, mainly in developing countries. Using peptide phage display as a tool to identify potential molecular targets in HPV associated tumors, we identified α-mannosidase, among other enriched sequences. This enzyme is expressed in both tumor and inflammatory compartment of the tumor microenvironment. Several studies in experimental models have shown that its inhibition by swainsonine (SW) led to inhibition of tumor growth and metastasis directly and indirectly, through activation of macrophages and NK cells, promoting anti-tumor activity. Therefore, the aim of this work was to test if swainsonine treatment could modulate anti-tumor immune responses and therefore interfere in HPV associated tumor growth. Validation of our biopanning results showed that cervical tumors, both tumor cells and leukocytes, expressed α-mannosidase. Ex vivo experiments with tumor associated macrophages showed that SW could partially modulate macrophage phenotype, decreasing CCL2 secretion and impairing IL-10 and IL-6 upregulation, which prompted us to proceed to in vivo tests. However, in vivo, SW treatment increased tumor growth. Investigation of the mechanisms leading to this result showed that SW treatment significantly induced the accumulation of myeloid derived suppressor cells in the spleen of tumor bearing mice, which inhibited T cell activation. Our results suggested that SW contributes to cervical cancer progression by favoring proliferation and accumulation of myeloid cells in the spleen, thus exacerbating these tumors systemic effects on the immune system, therefore facilitating tumor growth.

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<![CDATA[Integrated structural variation and point mutation signatures in cancer genomes using correlated topic models]]> https://www.researchpad.co/article/5c99020ad5eed0c484b97533

Mutation signatures in cancer genomes reflect endogenous and exogenous mutational processes, offering insights into tumour etiology, features for prognostic and biologic stratification and vulnerabilities to be exploited therapeutically. We present a novel machine learning formalism for improved signature inference, based on multi-modal correlated topic models (MMCTM) which can at once infer signatures from both single nucleotide and structural variation counts derived from cancer genome sequencing data. We exemplify the utility of our approach on two hormone driven, DNA repair deficient cancers: breast and ovary (n = 755 samples total). We show how introducing correlated structure both within and between modes of mutation can increase accuracy of signature discovery, particularly in the context of sparse data. Our study emphasizes the importance of integrating multiple mutation modes for signature discovery and patient stratification, and provides a statistical modeling framework to incorporate additional features of interest for future studies.

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<![CDATA[Perceptions of cervical cancer prevention on Twitter uncovered by different sampling strategies]]> https://www.researchpad.co/article/5c6b269dd5eed0c484289d78

Introduction

Cervical cancer prevention is possible through use of the HPV vaccine and Pap tests, yet the vaccine remains underutilized.

Methods

We obtained publicly-available Twitter data from 2014 using three sampling strategies (top-ranked, simple random sample, and topic model) based on key words related to cervical cancer prevention. We conducted a content analysis of 100 tweets from each of the three samples and examined the extent to which the narratives and frequency of themes differed across samples.

Results

Advocacy-related tweets constituted the most prevalent theme to emerge across all three sample types, and were most frequently found in the top-ranked sample. A random sample detected the same themes as topic modeling, but the relative frequency of themes identified from topic modeling fell in-between top-ranked and random samples.

Discussion

Variations in themes uncovered by different sampling methods suggest it is useful to qualitatively assess the relative frequency of themes to better understand the breadth and depth of social media conversations about health.

Conclusions

Future studies using social media data should consider sampling methods to uncover a wider breadth of conversations about health on social media.

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<![CDATA[A mobile-phone based high-resolution microendoscope to image cervical precancer]]> https://www.researchpad.co/article/5c648ce0d5eed0c484c819d1

Nearly 90% of cervical cancer cases and deaths occur in low- and middle-income countries that lack comprehensive national HPV immunization and cervical cancer screening programs. In these settings, it is difficult to implement screening programs due to a lack of infrastructure and shortage of trained personnel. Screening programs based on visual inspection with acetic acid (VIA) have been successfully implemented in some low-resource settings. However, VIA has poor specificity and up to 90% of patients receiving treatment based on a positive VIA exam are over-treated. A number of studies have suggested that high-resolution cervical imaging to visualize nuclear morphology in vivo can improve specificity by better distinguishing precancerous and benign lesions. To enable high-resolution imaging in low-resource settings, we developed a portable, low-cost, high-resolution microendoscope that uses a mobile phone to detect and display images of cervical epithelium in vivo with subcellular resolution. The device was fabricated for less than $2,000 using commercially available optical components including filters, an LED and triplet lenses assembled in a 3D-printed opto-mechanical mount. We show that the mobile high-resolution microendoscope achieves similar resolution and signal-to-background ratio as previously reported high-resolution microendoscope systems using traditional cameras and computers to detect and display images. Finally, we demonstrate the ability of the mobile high-resolution microendoscope to image normal and precancerous squamous epithelium of the cervix in vivo in a gynecological referral clinic in Barretos, Brazil.

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<![CDATA[Prevalence of high-risk human papilloma virus in women with high-grade squamous cell intraepithelial lesions in Botswana using Abbott RealTime HPV assay]]> https://www.researchpad.co/article/5c5b52a6d5eed0c4842bcd6b

Background

High-risk human papillomavirus (HR-HPV) has been demonstrated to be the necessary cause of cervical carcinoma. High-risk HPV detection has a prognostic significance for the women who are at increased risk of disease progression. HPV genotyping in cervical cancer precursor lesions is crucial for prevention and management of cervical cancer. This study was designed to investigate the distribution of HR-HPV genotypes among a group of patients with high-grade squamous intraepithelial lesions and higher, of the cervix, in Botswana.

Materials and methods

185-archived residual formalin-fixed paraffin-embedded cervical biopsies collected between the years, 2006 and 2008 were studied. These tissues were diagnosed with HSIL (n = 146) and squamous cell carcinoma (n = 39). DNA was extracted using the Abbott m2000 analyser (Abbott Laboratories, Illinois) using reagents provided by the manufacturer. HPV genotyping was done using the Abbott RealTime HR-HPV PCR, which qualitatively detects 14 HR-HPV (reported as HPV 16, 18 & Other HR-HPV).

Results

DNA was successfully extracted from 162/185 (87.6%) tissues as indicated by a positive β-globin test. 132/162 (82%) tested positive for HR-HPV The HPV 16 prevalence was 50% (66/132), HPV 18 at 15.2% (20/132) and other Group 1 HR-HPV plus HPV 66 and 68 had a prevalence of 56.1% (74/132). Other HR-HPV types were common in HSIL than in carcinoma, while HPV 16 was more prevalent in carcinomas than other HR-HPV genotypes.

Conclusion

In this study, HPV 16 and other HR-HPV genotypes were commonly associated with HSIL but HPV 18 was uncommon among Botswana women. Our data highlights the need for multivalent HPV vaccines with cross coverage for other high risk HPV other than HPV 16 and 18.

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<![CDATA[Synthetic lethality guiding selection of drug combinations in ovarian cancer]]> https://www.researchpad.co/article/5c57e6d4d5eed0c484ef3f0b

Background

Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy.

Materials and methods

We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.

Results

Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies.

Conclusion

A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.

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<![CDATA[Current management of cervical cancer in Poland—Analysis of the questionnaire trial for the years 2002-2014 in relation to ASCO 2016 recommendations]]> https://www.researchpad.co/article/5c5ca28fd5eed0c48441e638

Objectives

To assess the survival of patients with cervical cancer (CC). Since the recommendations concerning cervical cancer management adopted by Polish medical societies do not differ significantly from the ESGO or non-European guidelines, and the fact that evaluation of the system for CC treatment in Poland, as well as the mortality rate of Polish women with CC, which is 70% higher than the average for European Union (EU) countries, justifies the hypothesis that treatment of CC in Poland deviates from the Polish and international recommendations. This article puts forward the current management of cervical cancer in Poland and discusses it in the context of ASCO guidelines.

Material and methods

A survey retrospective multicenter analysis of the medical records of 1247 patients with cervical cancer who underwent treatment for disease and who had completed at least two years of follow-up.

Results

Although concurrent radiotherapy and chemotherapy is a standard treatment of FIGO IB to IVA cervical cancer patients in enhanced- and maximum-resources settings, in our analysis, we found that the percentage of women subjected to chemotherapy was lower than in countries where total survival rates were lower.

Conclusion

Within the IA to II A cervical cancer patients studied group, the methods of treatment remained in line with ASCO guidelines for countries with the highest standard of care.

Although concurrent radiotherapy and chemotherapy is a standard treatment of FIGO IB to IVA cervical cancer patients in enhanced- and maximum-resources settings, in our analysis, we found that the percentage of women subjected to chemotherapy was lower than in countries where total survival rates were lower.

Our findings, together with the inconsistencies within the cervical cancer screening program, may be one of the explanations of poorer survival rate of women with cervical cancer in Poland.

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<![CDATA[Clinical performance of Anyplex II HPV28 by human papillomavirus type and viral load in a referral population]]> https://www.researchpad.co/article/5c5217cad5eed0c4847945b2

Anyplex II HPV28 (`Anyplex`) is a semi-quantitative DNA PCR assay divided into set A, comprising 14 high risk (hr)HPV types; and set B, comprising 5 possibly hrHPV types and 9 low risk (lr)HPV types. We compared the ability of Anyplex to that of Hybrid Capture 2 (HC2) and PreTect HPV-Proofer (`Proofer`) to detect cervical intraepithelial neoplasia grade two or worse (CIN2+) by HPV types and viral load. This cross-sectional study included 296 women referred to colposcopy with abnormal cervical cytology and/or persistent HPV infection. CIN2+ was identified in 175/296 women. Liquid based cytology samples were used to perform HPV testing. The sensitivity of Anyplex to detect CIN2+ was 98.9% (95% CI 95.9–99.9) and specificity 43.0% (95% CI 34.0–52.3). Restricting to medium and high viral loads in Anyplex set A, sensitivity and specificity were 97.1% (95% CI 93.5–99.1) and 59.5% (95% CI 50.2–68.3) with positive (PPV) and negative predictive value (NPV) 77.6% and 93.5%, respectively, comparable to HC2. Restricting Anyplex to the hrHPV types in Proofer, HPV16, 18, 31, 33 and 45, sensitivity and specificity for CIN2+ were 85.1% (95% CI 79.0–90.1) and 71.1% (95% CI 62.1–79.0), comparable to Proofer`s. When adding HPV52 and 58, the sensitivity for CIN2+ was 92.6% (95% CI 87.6–96.0) and CIN3+ 96.5% (95% CI 92.0–98.8). No value of Anyplex set B was found in detecting CIN2+. In conclusion, the clinical performance of medium and high viral loads in Anyplex set A was comparable to HC2. Restricting the test to the 7 hrHPV types included in the 9-valent HPV-vaccine, HPV16, 18, 31, 33, 45, 52 and 58, satisfies the international criteria for cervical cancer screening with relative sensitivity compared to HC2 for CIN2+ and CIN3+ of 0.98 and 1.01, respectively. Detecting all 28 Anyplex HPV types adds no benefit in a referral population.

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<![CDATA[The Syk inhibitor R406 is a modulator of P-glycoprotein (ABCB1)-mediated multidrug resistance]]> https://www.researchpad.co/article/5c50c48ed5eed0c4845e88f0

In a previously published study, higher levels of spleen tyrosine kinase (Syk) were observed in recurrent post-chemotherapy ovarian cancers compared to primary tumors. Syk inhibition was found to stabilize microtubules and potentiate paclitaxel activity in cellular models of taxane-resistant ovarian cancers. We further studied the effects of Syk inhibition on paclitaxel activity in Syk(+) ovarian cancer cell models and in variants selected for taxane resistance. Syk inhibition was accomplished using RNAi and by exposure to the small molecule competitive inhibitor R406, the active metabolite of fostamatinib. Exposure to R406 or to a SYK-specific pool of siRNAs did not alter taxane activity in the OVCAR-3 cell line, which has the most Syk content in our panel of nine human ovarian cancer cell lines. However, treatment with R406 sensitised the multidrug resistant (MDR) variants MES-SA/Dx5 and SK-OV-3/TR to paclitaxel in a dose-dependent manner resulting from the inhibition of the ABCB1/P-glycoprotein (P-gp) drug transporter. These observations are Syk-independent since both MDR cell models are Syk negative. R406 modulated resistance to other known P-gp substrates, and we observed orthovanadate-sensitive ATPase stimulation resulting from treatment with R406. These data indicate that the chemo-sensitizing effect of R406 in taxane-resistant cells previously reported was not associated with Syk but resulted from the modulation of P-gp-mediated MDR.

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<![CDATA[Plasma growth differentiation factor-15 is an independent marker for aggressive disease in endometrial cancer]]> https://www.researchpad.co/article/5c478c52d5eed0c484bd1926

Objective

Better biomarkers are needed in order to identify patients with endometrial carcinoma at risk of recurrence and who may profit from a more aggressive treatment regimen. Our objective was to explore the applicability of plasma growth differentiation factor 15 (GDF-15) as a marker for recurrent disease, as well as a marker for poor prognosis and lymph node metastases.

Methods

EDTA-blood samples were obtained from 235 patients with endometrial cancer before primary surgery. For 36 of these patients, matching blood samples were collected at time of recurrence. Blood samples were also collected from 78 patients with endometrial hyperplasia. Plasma GDF-15 was measured by an enzyme-linked immunosorbent assay (ELISA). Preoperative pelvic MRI scans for 141 patients were investigated in parallel for imaging variables.

Results

Preoperative plasma level of GDF-15 was significantly higher for patients who experienced recurrence (1780 ng/L; 95% CI; 518–9475 ng/L) than for patients who did not develop recurrent disease (1236 ng/L; 95% CI; 307–7030 ng/L) (p<0.001). Plasma levels of GDF-15 at recurrence (2818 ng/L, 95% CI 2088–3548 ng/L) were significantly higher than plasma levels of GDF-15 measured at time of primary diagnosis (1857 ng/L, 95% CI; 1317–2398 ng/L) (p = 0.001). High plasma level GDF-15 independently predicts recurrent disease (OR = 3.14; 95% CI 2.10–4.76) and lymph node metastases (OR = 2.64; 95% CI 1.52–4.61). Patients with high plasma level of GDF-15 had significantly larger tumor volume (p = 0.008).

Conclusion

Elevated plasma level of GDF-15 is associated with aggressive disease and lymph node metastasis in endometrial carcinoma. GDF-15 may be helpful in indicating recurrent disease.

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<![CDATA[The effect of sodium butyrate and cisplatin on expression of EMT markers]]> https://www.researchpad.co/article/5c605a62d5eed0c4847ccf46

Histone modifications play a key role in the epigenetic regulation of gene transcription in cancer cells. Histone acetylations are regulated by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are increased in ovarian carcinomas and they are involved in carcinogenesis and resistance to chemotherapeutic agents. In our study we investigated anticancer effect of HDAC inhibitor sodium butyrate (NaBu) on cisplatin-sensitive and cisplatin-resistant ovarian cell lines A2780 and A2780cis. A2780 and A2780cis were treated with NaBu alone or in combination with cisplatin (CP). NaBu inhibited the growth of both cell lines and enhanced cytotoxic effect of CP. Exposure to NaBu for 24 h induced cell cycle arrest. The expressions of EMT-related genes and proteins were further investigated by qPCR and western blot analysis. Loss of E-cadherin has been shown to be crucial in ovarian cancer development. We found that NaBu dramatically induce expression of E-cadherin gene (CDH1) and protein levels in A2780 and A2780cis. We investigated correlation between transcription and methylation of CDH1gene. Methylation level analysis in 32 CpG sites in CDH1 gene (promoter/exon1 regions) was performed using bisulfite NGS (Next Generation Sequencing). We found that cisplatin-resistant cell line A2780cis cells differ from their cisplatin-sensitive counterparts in the CDH1 methylation. Methylation in A2780cis cells is elevated compared to A2780. However, NaBu-induced expression of CDH1 was not accompanied by CDH1 demethylation. NaBu treatment induced changes in expression of EMT-related genes and proteins. Interestingly E-cadherin zinc finger transcriptional repressor SNAIL1 was upregulated in both cell lines. Mesenchymal marker vimentin was downregulated. Matrix metalloproteases (MMPs) are necessary for pericellular proteolysis and facilitate migration and invasion of tumour cells. NaBu induced mRNA expression of MMPs, mild changes in activities of gelatinases MMP2 and MMP9 were detected. Our data demonstrate that NaBu sensitizes cisplatin-resistant ovarian cancer cells, re-established E-cadherin expression, but it was not able to reverse the EMT phenotype completely.

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<![CDATA[Profile of treatment-related complications in women with clinical stage IB-IIB cervical cancer: A nationwide cohort study in Japan]]> https://www.researchpad.co/article/5c3d00fed5eed0c4840375f7

Objective

To examine clinico-pathological factors associated with surgical complications and postoperative therapy for clinical stage IB-IIB cervical cancer.

Methods

This nationwide multicenter retrospective study examined women with clinical stage IB-IIB cervical cancer who underwent radical hysterectomy plus pelvic and/or para-aortic lymphadenectomy between 2008–2009 at 87 institutions of the Japanese Gynecologic Oncology Group (n = 693). Multivariate models were used to identify independent predictors of perioperative grade 3–4 complications and bladder dysfunction.

Results

The overall intraoperative and postoperative complication rates were 3.3% and 9.8%, respectively. Clinical stage was not associated with perioperative complications (P = 0.15). Radiotherapy-based adjuvant therapy was significantly associated with an increased risk of postoperative complications (radiotherapy alone: adjusted-odds ratio [OR] 3.19, 95% confidence interval [CI] 1.46–6.99, P = 0.004; radiotherapy plus chemotherapy: adjusted-OR 3.26, 95%CI 1.66–6.41, P = 0.001), whereas chemotherapy was not (P = 0.45). Nerve-sparing surgery significantly reduced the risk of postoperative bladder dysfunction (adjusted-OR 0.57, 95%CI 0.37–0.90, P = 0.02) whereas adjuvant chemotherapy increased the risk of bladder dysfunction (adjusted-OR 2.06, 95%CI 1.16–3.67, P = 0.01). Among women receiving adjuvant chemotherapy, nerve-sparing radical hysterectomy significantly reduced the risk of bladder dysfunction (15.0% versus 32.9%, OR 0.31, 95%CI 0.14–0.68, P = 0.004). After propensity score matching, survival outcomes were similar with both types of adjuvant therapy (radiotherapy-based versus chemotherapy, P>0.05).

Conclusion

Our study highlighted two distinct complication profiles of adjuvant therapy after radical hysterectomy for clinical stage IB-IIB cervical cancer, with radiotherapy increasing grade 3–4 adverse events and chemotherapy increasing bladder dysfunction. In this setting, nerve-sparing surgery may be useful if chemotherapy is being considered for adjuvant therapy.

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<![CDATA[Robust estimation of hemo-dynamic parameters in traditional DCE-MRI models]]> https://www.researchpad.co/article/5c37b79fd5eed0c4844906c1

Purpose

In dynamic contrast enhanced (DCE) MRI, separation of signal contributions from perfusion and leakage requires robust estimation of parameters in a pharmacokinetic model. We present and quantify the performance of a method to compute tissue hemodynamic parameters from DCE data using established pharmacokinetic models.

Methods

We propose a Bayesian scheme to obtain perfusion metrics from DCE MRI data. Initial performance is assessed through digital phantoms of the extended Tofts model (ETM) and the two-compartment exchange model (2CXM), comparing the Bayesian scheme to the standard Levenberg-Marquardt (LM) algorithm. Digital phantoms are also invoked to identify limitations in the pharmacokinetic models related to measurement conditions. Using computed maps of the extra vascular volume (ve) from 19 glioma patients, we analyze differences in the number of un-physiological high-intensity ve values for both ETM and 2CXM, using a one-tailed paired t-test assuming un-equal variance.

Results

The Bayesian parameter estimation scheme demonstrated superior performance over the LM technique in the digital phantom simulations. In addition, we identified limitations in parameter reliability in relation to scan duration for the 2CXM. DCE data for glioma and cervical cancer patients was analyzed with both algorithms and demonstrated improvement in image readability for the Bayesian method. The Bayesian method demonstrated significantly fewer non-physiological high-intensity ve values for the ETM (p<0.0001) and the 2CXM (p<0.0001).

Conclusion

We have demonstrated substantial improvement of the perceptive quality of pharmacokinetic parameters from advanced compartment models using the Bayesian parameter estimation scheme as compared to the LM technique.

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<![CDATA[Role of genomic DNA methylation in detection of cytologic and histologic abnormalities in high risk HPV-infected women]]> https://www.researchpad.co/article/5c390b8ed5eed0c48491d389

Cervical cancer is the fourth most common malignancy affecting women worldwide. The development of disease is related to high-risk human papillomavirus (hrHPV) infection. Cytology has been the most recommended triage for primary cervical (pre)cancer screening despite relatively low sensitivity. Recently, genomic DNA methylation has been proposed as an additional marker to increase sensitivity for detecting cervical precancerous lesion. This study aimed to evaluate the performance of methylation status of three tumor suppressor genes (CADM1, FAM19A4, and MAL) and HPV genotyping in detection of cytologic and histologic abnormalities in cervical cancer screening. Two hundred and sixty samples with available frozen cell pellets including 70 randomly selected cases of negative for intraepithelial lesion or malignancy (NILM)&HPV-negative, 70 randomly selected cases of NILM&HPV-positive, and 120 cytologic abnormalities & HPV-positive from a population-based cervical cancer screening program (n = 7,604) were investigated for the DNA methylation pattern of CADM1, FAM19A4, and MAL. Of 120 cytologic abnormalities & HPV-positive cases, there were 115 available histologic results. HPV52 and HPV58 were most commonly found in histologic HSIL+. The methylation levels of CADM1, FAM19A4, and MAL were elevated with the severity of cytologic abnormality which significantly increased by 3.37, 6.65 and 2 folds, respectively, in cytologic HSIL comparing with NILM. A significant increase in methylation levels of these three genes was also observed in histologic HSIL+ compared with negative histology but only CADM1 showed a significant higher methylation level than histologic LSIL. Using the ROC curve analysis, DNA methylation levels of FAM19A4 performed best in differentiating high-grade cytology (ASC-H+ from NILM/ASC-US/LSIL), followed by CADM1 and MAL. Whilst the CADM1 methylation performed best in distinguishing histologic HSIL+ from negative/LSIL with an area under the ROC curve of 0.684, followed by MAL (0.663) and FAM19A4 (0.642). Interestingly, after combining high DNA methylation levels to HPV16/18 genotypes, rates of histologic HSIL+ detection were substantially increased from 25% to 79.55% for CADM1, 77.27% for FAM19A4, and 72.73% for MAL, respectively. The rate further increased up to 95.45% when at least one of three genes had a high methylation level. This suggests a possible role of genomic DNA methylation, especially CADM1, in detecting histologic HSIL+ lesions in combination with hrHPV testing.

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<![CDATA[Lower circulating levels of CTRP12 and CTRP13 in polycystic ovarian syndrome: Irrespective of obesity]]> https://www.researchpad.co/article/5c1ab85fd5eed0c484027c9a

Altered production of adipokines is suggested to play a pivotal role in the pathogenesis of polycystic ovarian syndrome (PCOS). C1q/TNF-related proteins (CTRPs) play diverse roles in regulation of metabolism in physiologic and pathologic conditions. In the present study, we assessed serum concentrations of adiponectin, CTRP12, and CTRP13 in individuals with PCOS and those without PCOS. We also evaluated the possible association of these adipokines with metabolic and hormonal variables. A total of 171 premenopausal women (86 with PCOS and 85 without PCOS) enrolled in this study. Serum levels of adiponectin, CTRP12, and CTRP13 were measured. The results showed significantly lower serum concentrations of adiponectin, CTRP12, and CTRP13 in PCOS women compared to non-PCOS women. This difference remained significant after controlling for age, body mass index (BMI), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). However, we did not observe any significant differences in serum levels of adiponectin, CTRP12, and CTRP13 between the overweight/obese and normal weight subgroups in PCOS and non-PCOS women. Multiple linear regression analysis showed associations of CTRP12 with adiponectin and BMI with CTRP13 in both the PCOS and non-PCOS groups. CTRP12 was significantly associated with BMI and adiponectin in the non-PCOS group, and fasting blood glucose (FBG) and CTRP13 in the PCOS group. Our results indicated that decreased adiponectin, CTRP12, and CTRP13 levels, regardless of obesity, could independently predict PCOS. This finding suggested a novel link between adipokines and PCOS.

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