Dependency of Cholangiocarcinoma on Cyclin D-Dependent Kinase Activity.

Cholangiocarcinoma (CCA) is a bile duct cancer with a very poor prognosis. Currently, there is no effective pharmacological treatment available for it. We showed that CCA ubiquitously relies on cyclin-dependent kinases 4 and 6 (CDK4/6) activity to proliferate. Primary CCA tissues express high levels of cyclin D1 and the specific marker of CDK4/6 activity, phospho-RB Ser780. Treatment of a 15-CCA cell line collection by pharmacological CDK4/6 inhibitors leads to reduced numbers of cells in the S-phase and senescence in most of the CCA cell lines. We found that expression of retinoblastoma protein (pRB) is required for activity of the CDK4/6 inhibitor, and that loss of pRB conferred CDK4/6 inhibitor-drug resistance. We also identified that sensitivity of CCA to CDK4/6 inhibition is associated with the activated KRAS signature. Effectiveness of CDK4/6 inhibition for CCA was confirmed in the three-dimensional spheroid-, xenograft-, and patient-derived xenograft models. Last, we identified a list of genes whose expressions can be used to predict response to the CDK4/6 inhibitor. Conclusion: We investigated a ubiquitous dependency of CCA on CDK4/6 activity and the universal response to CDK4/6 inhibition. We propose that the CDK4/6-pRB pathway is a suitable therapeutic target for CCA treatment.

A WEIGHT-LOSS PROGRAM FOR MEDICAL STUDENTS IN THAILAND: AN EVALUATION OF RELATED KNOWLEDGE, PREVAILING ATTITUDES, AND PROGRAM OUTCOMES FOR WEIGHT LOSS.

Millions of people, worldwide, struggle with being overweight or obese. Medical students, who will eventually become physicians, should be good role models for patients; however, some medical students are themselves overweight or obese. The aim of this study was to evaluate the efficacy of a weight-loss program for medical students in Thailand. A six-month weight reduction program was designed consisted of three full-day sections that were scheduled, as follows: Day One, End of Week One, and End of Week Eight. The interventions incorporated various behavior modification strategies. Participant anthropometric measurements were recorded. Obesity-related knowledge, perception, attitude, and inappropriate weight-loss behaviors were obtained by validated questionnaire. At the end of the study, statistically significant weight loss was demonstrated (median 2.70 kg, p<0.05) compared to baseline. Moreover, participant knowledge significantly increased and inappropriate weight-loss behaviors significantly decreased (p<0.05 and p<0.05, respectively) compared to baseline. Given the demonstrated modest effectiveness of this low-intensity weight reduction program, this intervention should be considered as an effective education tool for medical students.

Comprehensive drug response profiling and pan-omic analysis identified therapeutic candidates and prognostic biomarkers for Asian cholangiocarcinoma.

Cholangiocarcinoma (CCA) is rare cancer with the highest incidence in Eastern and Southeast Asian countries. Advanced CCA patients rely on chemotherapeutic regimens that offer unsatisfied clinical outcomes. We developed a comprehensive drug response profiling to investigate potential new drugs using CCA cell lines from Thai and Japanese patients against 100 approved anti-cancer drugs. We identified two major CCA subgroups that displayed unique molecular pathways from our integrative pan-omic and ligand-induced pathway activation analyses. MEK and Src inhibitors specifically killed the CCA1 subgroup without causing cytotoxicity to the normal cholangiocyte. Next, we developed the CCA45 signature to classify CCA patients based on their transcriptomic data. Our CCA45 signature could accurately predict prognosis, especially for Asian CCA patients. Our study provides a comprehensive public resource for drug repurposing in CCA and introduces analytical strategies for prioritizing cancer therapeutic agents for other rare cancer.

The Tip of the Iceberg-Concealing of Advanced Conduction Abnormality.

This case report describes a patient in their 80s who presented with dyspnea and syncope during exercise and a history of essential hypertension and Parkinson disease.