MAL2 and tumor protein D52 (TPD52) are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome

Background: The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52), which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. Methods: Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. Results: MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p < 0.001; n = 124) and was an independent predictor of survival in the overall carcinoma cohort (hazard ratio (HR), 0.498; 95% confidence interval (CI), 0.34-0.728; p < 0.001; n = 221), and in serous carcinomas (HR, 0.440; 95% CI, 0.294-0.658; p < 0.001; n = 182). Conclusions: MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients.11 page(s

High-resolution analysis of copy number alterations and associated expression changes in ovarian tumors

<p>Abstract</p> <p>Background</p> <p>DNA copy number alterations are frequently observed in ovarian cancer, but it remains a challenge to identify the most relevant alterations and the specific causal genes in those regions.</p> <p>Methods</p> <p>We obtained high-resolution 500K SNP array data for 52 ovarian tumors and identified the most statistically significant minimal genomic regions with the most prevalent and highest-level copy number alterations (recurrent CNAs). Within a region of recurrent CNA, comparison of expression levels in tumors with a given CNA to tumors lacking that CNA and to whole normal ovary samples was used to select genes with CNA-specific expression patterns. A public expression array data set of laser capture micro-dissected (LCM) non-malignant fallopian tube epithelia and LCM ovarian serous adenocarcinoma was used to evaluate the effect of cell-type mixture biases.</p> <p>Results</p> <p>Fourteen recurrent deletions were detected on chromosomes 4, 6, 9, 12, 13, 15, 16, 17, 18, 22 and most prevalently on X and 8. Copy number and expression data suggest several apoptosis mediators as candidate drivers of the 8p deletions. Sixteen recurrent gains were identified on chromosomes 1, 2, 3, 5, 8, 10, 12, 15, 17, 19, and 20, with the most prevalent gains localized to 8q and 3q. Within the 8q amplicon, <it>PVT1</it>, but not <it>MYC</it>, was strongly over-expressed relative to tumors lacking this CNA and showed over-expression relative to normal ovary. Likewise, the cell polarity regulators <it>PRKCI </it>and <it>ECT2 </it>were identified as putative drivers of two distinct amplicons on 3q. Co-occurrence analyses suggested potential synergistic or antagonistic relationships between recurrent CNAs. Genes within regions of recurrent CNA showed an enrichment of Cancer Census genes, particularly when filtered for CNA-specific expression.</p> <p>Conclusion</p> <p>These analyses provide detailed views of ovarian cancer genomic changes and highlight the benefits of using multiple reference sample types for the evaluation of CNA-specific expression changes.</p

Genome Wide DNA Copy Number Analysis of Serous Type Ovarian Carcinomas Identifies Genetic Markers Predictive of Clinical Outcome

Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups

PORTEC-4a: International randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer

Background Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with highintermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients’ risk of recurrence based on molecular tumor characteristics. Primary objectives To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecularintegrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy Study hypothesis Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant t

containing Non-electrolytes

Abstract: In this study, the antisolvent crystallization system containing sodium chloride as solute, water as primary solvent and ethanol as the antisolvent was considered. At first there was a saturated solution of water-NaCl, by gradual addition of ethanol in a specific rate, the solubility of NaCl decreases. A thermodynamic model which can predict the behavior of the aqueous salt systems containing non-electrolytes was applied in this study. This model consists of a Gibbs energy function, which combines a Debye-Hückel term with the standard UNIQUAC model. Using the Extended UNIQUAC model for the purpose of thermodynamic modeling, the solubility of NaCl in the water-ethanol mixture in different compositions with an acceptable error was calculated. The model parameters including volume, surface area and binary interaction parameters were modified by comparing the experimental and theoretical data of NaCl solubility in water-ethanol mixture. Afterwards, this thermodynamic solubility model was introduced to the kinetic modeling of antisolvent crystallization process using Population Balance Equation. Using supersaturation for the calculation of the nucleation and the crystal growth rates, crystal size distribution and the volume mean of crystals were determined by the numerical solution to the PBE implementing Discretization technique. In order to evaluate the model accuracy, antisolvent addition rates were changed and the results were compared with the experimental data, the results appeared justifiable

Highly efficient azido-Ugi multicomponent reactions for the synthesis of bioactive tetrazoles bearing sulfonamide scaffolds

Recent studies revealed that the contribution of the different bioactive scaffolds in one structure creates modern drugs/compounds with unique synergistic biological properties. In this regard, thanks to the interesting biological and medicinal properties of sulfonamide and tetrazole skeletons, this study describes the engagement of sulfonamides in the Ugi tetrazole reaction to access a library of tetrazole bearing sulfonamide. This four-component reaction was performed in a one-pot among available starting material, i.e., an isocyanide, a sulfonamide, an aldehyde and sodium azide in MeOH at 45 °C using ZnCl2 as a catalyst, for the synthesis of very versatile products with high atom economy and yields. The key point in this strategy is the formation of an intermediate Schiff base and its activation in the azido-Ugi reaction by a Lewis acid catalyst. Importantly, all products are purified through the group-assisted purification (GAP) chemistry, which can avoid traditional purification such as recrystallization and chromatography methods. Also, the docking study between the synthesized compounds and human serum albumin (HSA) was stimulated to theoretically rationalize their biological activity and potential binding interactions. © 2021 Elsevier Lt

Pre-treatment prediction of early response to chemoradiotherapy by quantitative analysis of baseline staging FDG-PET/CT and MRI in locally advanced cervical cancer

Background Early prediction of response to concurrent chemoradiotherapy (cCRT) could aid to further optimize treatment regimens for locally advanced cervical cancer (LACC) in the future. Purpose To explore whether quantitative parameters from baseline (pre-therapy) magnetic resonance imaging (MRI) and FDG-PET/computed tomography (CT) have potential as predictors of early response to cCRT. Material and Methods Forty-six patients with LACC undergoing cCRT after staging with FDG-PET/CT and MRI were retrospectively analyzed. Primary tumor volumes were delineated on FDG-PET/CT, T2-weighted (T2W)-MRI and diffusion-weighted MRI (DWI) to extract the following quantitative parameters: T2W volume; T2W signal(mean); DWI volume; ADC(mean); ADC(SD); MTV42%; and SUVmax. Outcome was the early treatment response, defined as the residual tumor volume on MRI 3-4 weeks after start of external beam radiotherapy with chemotherapy (before the start of brachytherapy): patients with a residual tumor volume <10 cm(3)were classified as early responders. Imaging parameters were analyzed together with FIGO stage to assess their performance to predict early response, using multivariable logistic regression analysis with bi-directional variable selection. Leave-one-out cross-validation with bootstrapping was used to simulate performance in a new, independent dataset. Results T2W volume (OR 0.94,P = 0.003) and SUVmax(OR 1.15,P = 0.18) were identified as independent predictors in multivariable analysis, rendering a model with an AUC of 0.82 in the original dataset, and AUC of 0.68 (95% CI 0.41-0.81) from cross-validation. Conclusion Although the predictive performance achieved in this small exploratory dataset was limited, these preliminary data suggest that parameters from baseline MRI and FDG-PET/CT (in particular pre-therapy tumor volume) may contribute to prediction of early response to cCRT in cervical cancer

The impact of image acquisition time on registration, delineation and image quality for magnetic resonance guided radiotherapy of prostate cancer patients

BACKGROUND AND PURPOSE: Magnetic resonance (MR) guided radiotherapy utilizes MR images for (online) plan adaptation and image guidance. The aim of this study was to investigate the impact of variation in MR acquisition time and scan resolution on image quality, interobserver variation in contouring and interobserver variation in registration. MATERIALS AND METHODS: Nine patients with prostate cancer were included. Four T2-weighted 3D turbo spin echo (T2w 3D TSE) sequences were acquired with different acquisition times and resolutions. Two radiologists assessed image quality, conspicuity of the capsule, peripheral zone and central gland architecture and motion artefacts on a 5 point scale. Images were delineated by two radiation oncologists and interobserver variation was assessed by the 95% Hausdorff distance. Seven observers registered the MR images on the planning CT. Registrations were compared on systematic offset and interobserver variation. RESULTS: Acquisition times ranged between 1.3 and 6.3 min. Overall image quality and capsule definition were significantly worse for the MR sequence with an acquisition time of 1.3 min compared to the other sequences. Median 95% Hausdorff distance showed no significant differences in interobserver variation of contouring. Systematic offset and interobserver variation in registration were small (<1 mm) and of no clinical significance. CONCLUSIONS: Our results can be used to effectively shorten overall fraction time for online adaptive MR guided radiotherapy by optimising the imaging sequence used for registration. From the sequences studied, a sequence of 3.1 min with anisotropic voxels of 1.2 × 1.2 × 2.4 mm(3) provided the shortest acquisition time without compromising image quality