Purpose: New technologies like gamification are continuously integrated into medical education during the last years. However, the benefit and implementation of such gaming platforms are not clearly studied. This analysis assesses the feasibility of Kahoot! regarding simplicity and low-cost performance as a learning/teaching tool for medical education in (histo-)pathology. Materials and Methods: In this feasibility pilot study, we developed 36 modules for different benign and malignant tumors, covering four major topics: gastrointestinal tract, dermatology, urogenital tract, and hematology. Each module included histomorphological text-based questions for education of 2nd-year medical students. The online gaming-platform Kahoot! was anonymously implemented before and after "classical" medical education which included discussions of histological slides for each tumor entity using Microsoft PowerPoint-based presentations in combination with microscopical demonstrations. Participating students were invited to a seven-questions evaluation about the online educational approach. Results: Overall, 23 of 51 students of the study class completed the pre-and the postevaluation of Kahoot! in one or more organ systems. The percentage of correct answers increased from the initial mean/median of 47.2/45% to 77.2/76.3%. Simultaneously, the time for answering questions decreased by roughly 50% (from mean/median time of 9.1/8.3 seconds to 5.1/4.3 seconds) from pre-to post-assessment. The results were independent of gender; however, there were scoring differences between the different organ systems. Students positively evaluated the routine implementation of the gaming-platform Kahoot! within medical education. Conclusion: Kahoot! is as a simple, direct, and low-cost application in medical teaching improving learning outcomes of pathomorphological topics with high acceptance by students. Kahoot!-based evaluations should be also performed in more advanced topics in the field of histopathology.
Inhibition of histone deacetylases (HDACs) is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. Therefore, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition into a panel of eight established BTC cell lines. The screening results indicate a heterogeneous expression of HDACs across the studied cell lines. We next tested the effect of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect (i) is dose- and cell-line-dependent, (ii) does not correlate with HDAC isoform expression, and (iii) is most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses demonstrated that romidepsin induces apoptosis in BTC cells, reduces HDAC activity, and increases acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. In conclusion, HDAC class I inhibition in BTC cells by romidepsin is highly effective in vitro and encourages further in vivo evaluation in BTC. In situ assessment of HDAC 2 expression in BTC specimens indicates its importance for oncogenesis and/or progression of BTC as well as for the prognosis of BTC patients.
Introduction Biliary tract cancer (BTC) is a fatal disease with limited therapeutic options. Inhibition of histone deacetylases (HDACs) represents an effective anti‐cancer approach. Data regarding HDAC and BTC are sparse but promising. There, we performed a comprehensive investigation of HDAC expression and pharmacological HDAC inhibition in a BTC in vitro model. Methods Expression of HDACs in BTC cells was measured via quantitative real‐time PCR and immunohistochemistry. Cytotoxicity of HDAC pan‐inhibitors (belinostat, vorinostat) and HDAC inhibitors targeting different HDAC classes (mocetinostat, romidepsin, LMK‐235, tubastatin A) was analyzed using the resazurin assay. HDAC1/2 activity was measured via the HDAC‐Glo I/II Assay and Screening System (Promega). Mode of cytotoxicity of romidepsin was evaluated via a time‐resolved resazurin assay and the RealTime‐Glo Annexin V Apoptosis and Necrosis Assay (Promega). Changes in H3K9Ac levels were measured to investigate the epigenetic effect of romidepsin. Combinatory treatment of romidepsin and cisplatin was evaluated via the resazurin assay and changes of IC50‐values. Expression of HDAC1/2 in n = 78 BTC patient samples was done via immunohistochemistry. Appropriate statistical tests were used to correlate HDAC1/2 expression with clinicopathological data. Results HDAC profiling revealed a heterogeneous expression of HDACs across the studied cell lines (n = 8). Furthermore, we found that BTC cells show different sensitivities towards the used HDAC inhibitors. The HDAC class I inhibitor romidepsin showed significant cytotoxicity in the (low) nM‐range and was therefore chosen for further investigation. We found that romidepsin causes apoptosis and secondary necrosis and significantly reduces HDAC activity in BTC cells. Furthermore, we observed that sub‐lethal concentrations of romidepsin augmented the toxic effect of the standard chemotherapeutic cisplatin. We also measured HDAC1 and 2 expression in BTC patients. HDAC1 expression correlated with tumor localization and tumor grading. Moreover, patients with high expression of HDAC2 had a significant shorter overall survival time. Conclusions Our results demonstrate that the HDAC class I inhibitor romidepsin is a promising anti‐BTC substance. In addition, we show that HDAC1 and 2 are expressed in BTC patient samples and associate with clinical parameters.
Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN.
Endoscopic submucosal dissection (ESD) is an effective treatment of early esophageal adenocarcinomas (EACs). The decision of ESD over esophagectomy is based on clinical evaluation of tumor depth and invasion. On a molecular level, tumor invasion is strongly associated with epithelial-to-mesenchymal transition (EMT). Here, we investigated whether localized ESD-resected and surgically resected EAC samples displayed different expression profiles of EMT protein and microRNA markers and whether these different expression profiles were able to retrospectively discriminate localized and surgically resected samples. By doing this, we aimed to evaluate whether preoperative measurement of EMT marker expression might support the decision regarding ESD over surgery. The results showed that ESD-resected samples displayed an epithelial expression profile, i.e., high expression of epithelial protein markers, whereas surgically resected samples displayed high expression of mesenchymal markers. In addition, the anti-EMT microRNA-205 was significantly more expressed in ESD-resected samples, whereas we found no significant differences in the expression levels of microRNA-200 family members. Furthermore, in our retrospective approach, we have demonstrated that measurement of selected EMT markers and microRNA-205 has significant discrimination power to distinguish ESD-resected and surgically resected samples. We suggest that the assessment of EMT status of EAC samples on a molecular level may support clinical evaluation regarding the applicability of ESD.
Introduction:Although molecular insights about biliary tract cancer (BTC) increased in the last decade, new therapeutic strategy like inhibition of histone deacetylases (HDACs) could additionally improve the still dismal outcome of this tumor entity. Methods: Therefore, we performed comprehensive investigation of HDAC expression and pharmacological inhibition in a panel of eight established BTC cell lines and in a cohort resected native BTC specimens (n = 78). Results: HDAC profiling revealed a heterogeneous expression of HDACs across the studied cell lines and the BTC cancer specimen. Cytotoxicity of six established HDAC inhibitors (HDACi) covering pan-and class-specific HDACis was dose-as well as cell line-dependent and did not show a statistical correlation with HDAC isoform expression. Romidepsin (a class II HDACi), induced the highest reduction of cell viability and apoptosis in BTC cells which was paralleled by reducing HDAC1/2 activity and increasing histone 3 lysine 9 acetylation. Furthermore, non-toxic concentrations of romidepsin could augment the cytotoxic effect of the standard chemotherapeutic cisplatin. Related to the clinical tumor specimen, HDAC expression pattern correlated with the tumor grading and the survival of BTC patients. Conclusions: In conclusion, in-vitro-experiments provide clear evidence that the HDAC class I inhibitor romidepsin is effective for BTC alone and acts supportively in combination with standard chemotherapeutics. Additionally, the observed HDAC expression in BTC specimens could serve as a predictive and prognostic biomarker for BTC patients.
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