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BrdU cell proliferation and MTT cell viability assay for different Wnt signaling manipulators (100 µM SB216763, 50 µM XAV939, 50 nM triptolide) in A2780 and A2780cis after 72 h: a In the BrdU assay only triptolide displayed a significant impairment of proliferation in A2780 and A2780cis, whereas SB216763 revealed a significant reduction of cell proliferation in A2780cis and XAV939 showed no influence (n = 9 per column, mean, *p < 0.05/ ***p < 0.001 by Dunnett's multiple comparisons test, controls with 0‰ DMSO were set 100%). b In the MTT assay all three inhibitors in platinum-sensitive and -resistant cells reduced metabolic activity with different levels of significance (n = 9 per column, mean, **p < 0.01/ ***p < 0.001 by Dunnett's multiple comparisons test, controls with 0‰ DMSO were set 100%)
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PurposeCanonical Wnt/ β-catenin pathway is one mechanism being activated in platinum-resistant epithelial ovarian cancer (EOC). Detecting potential targets for Wnt pathway modulation as a putative future therapeutic approach was the aim of this study.Methods
Biological effects of different Wnt modulators (SB216763, XAV939 and triptolide) on the EOC...
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... While Doramapimod also showed potent anti-inflammatory effects as p38MAPK inhibitors (Schreiber et al., 2006), perhaps our study will explore a new alternative for the application of Doramapimod in ovarian cancer. Similarly, RO3306 (Yang et al., 2016), SB216763 (Kaltofen et al., 2020) were also shown to play an anti-cancer role in ovarian cancer. Moreover, the combination of JQ1 and cisplatin helped ovarian cancer-bearing mice survive (Yokoyama et al., 2016). ...
Background: Tumor pathology can assess patient prognosis based on a morphological deviation of tumor tissue from normal. Digitizing whole slide images (WSIs) of tissue enables the use of deep learning (DL) techniques in pathology, which may shed light on prognostic indicators of cancers, and avoid biases introduced by human experience.
Purpose: We aim to explore new prognostic indicators of ovarian cancer (OC) patients using the DL framework on WSIs, and provide a valuable approach for OC risk stratification.
Methods: We obtained the TCGA-OV dataset from the NIH Genomic Data Commons Data Portal database. The preprocessing of the dataset was comprised of three stages: 1) The WSIs and corresponding clinical data were paired and filtered based on a unique patient ID; 2) a weakly-supervised CLAM WSI-analysis tool was exploited to segment regions of interest; 3) the pre-trained model ResNet50 on ImageNet was employed to extract feature tensors. We proposed an attention-based network to predict a hazard score for each case. Furthermore, all cases were divided into a high-risk score group and a low-risk one according to the median as the threshold value. The multi-omics data of OC patients were used to assess the potential applications of the risk score. Finally, a nomogram based on risk scores and age features was established.
Results: A total of 90 WSIs were processed, extracted, and fed into the attention-based network. The mean value of the resulting C-index was 0.5789 (0.5096–0.6053), and the resulting p-value was 0.00845. Moreover, the risk score showed a better prediction ability in the HRD + subgroup.
Conclusion: Our deep learning framework is a promising method for searching WSIs, and providing a valuable clinical means for prognosis.
... A summary of patient characteristics is provided (Table S2). Sampling, microarray construction and immunohistochemical staining were performed as previously described [20]. Evaluation, imaging and storing were performed with an AxioScope microscope (Carl Zeiss, Jena, Germany); the immunereactivity score (IRS) was assessed semi-quantitatively by two examiners, and mean values of the three representative IHC scores of every probe were calculated. ...
Epithelial ovarian cancer (EOC) is the most lethal disease of the female reproductive tract, and although most patients respond to the initial treatment with platinum (cPt)-based compounds, relapse is very common. We investigated the role of epigenetic changes in cPt-sensitive and -resistant EOC cell lines and found distinct differences in their enhancer landscape. Clinical data revealed that two genes (JAK1 and FGF10), which gained large enhancer clusters in resistant EOC cell lines, could provide novel biomarkers for early patient stratification with statistical independence for JAK1. To modulate the enhancer remodeling process and prevent the acquisition of cPt resistance in EOC cells, we performed a chromatin-focused RNAi screen in the presence of cPt. We identified subunits of the Nucleosome Remodeling and Deacetylase (NuRD) complex as critical factors sensitizing the EOC cell line A2780 to platinum treatment. Suppression of the Methyl-CpG Binding Domain Protein 3 (MBD3) sensitized cells and prevented the establishment of resistance under prolonged cPt exposure through alterations of H3K27ac at enhancer regions, which are differentially regulated in cPt-resistant cells, leading to a less aggressive phenotype. Our work establishes JAK1 as an independent prognostic marker and the NuRD complex as a potential target for combinational therapy.
... Analysis of this large data set suggests that even subtle defects in Wnt signalling activity in the fallopian tube epithelium increase the propensity of the epithelium to transformation events. In contrast, there is evidence that active Wnt signalling plays an important role in the development of platinum resistance in advanced HGSOC [61,62]. ...
Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to highly aggressive and mostly lethal high-grade serous ovarian cancer, malignancies of the female genital tract have unique presentations and distinct cell biology features. Recent discoveries of stem cell regulatory mechanisms, development of organoid cultures, and NGS analysis have provided valuable insights into the basic biology of these cancers that could help advance new-targeted therapeutic approaches. This review revisits new findings on stemness and differentiation, considering main challenges and open questions. We focus on the role of stem cell niche and tumour microenvironment in early and metastatic stages of the disease progression and highlight the potential of patient-derived organoid models to study key events in tumour evolution, the appearance of resistance mechanisms, and as screening tools to enable personalisation of drug treatments.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and progressive joint destruction in the middle and late stages. Notably, activated rheumatoid arthritis synovial fibroblasts (RASFs) exhibit tumor-like features, including an increased proliferation rate that largely contributes to pannus formation and joint destruction. Our previous studies have demonstrated that acid-sensing ion channel 1a (ASIC1a) was highly expressed in RASFs, and acidic microenvironment of synovial fluid in patients with RA can activate ASIC1a to promote synovial inflammation, leading to the progression of RA. However, the role and possible mechanism of ASIC1a in RASF proliferation remains unclear. The present study aimed to investigate the effect of ASIC1a activation upon acidosis on RASF proliferation and its molecular mechanism in vivo and in vitro. The results of in vitro experiments showed that activation of ASIC1a upon acidosis promoted the proliferation of RASFs, which could be attenuated by the specific ASIC1a inhibitor Psalmotoxin-1 (PcTx-1) or specific siRNA for ASIC1a. Mechanistically, Wnt/β-catenin/c-Myc signaling pathway was involved in ASIC1a-induced RASF proliferation. The results of in vivo experiments indicated that intra-articular injection of PcTx-1 reduced synovial hyperplasia and ameliorated cartilage degradation in rats with adjuvant arthritis (AA). Collectively, these results suggest that activation of ASIC1a upon acidosis promotes RASF proliferation, and the mechanism may be related to Wnt/β-catenin/c-Myc pathway.
