The mechanistic functions of 3-deoxysappanchalcone (3-DSC), a chalcone compound known to have many pharmacological effects on lung cancer, have not yet been elucidated. In this study, we identified the comprehensive anti-cancer mechanism of 3-DSC, which targets EGFR and MET kinase in drug-resistant lung cancer cells. 3-DSC directly targets both EGFR and MET, thereby inhibiting the growth of drug-resistant lung cancer cells. Mechanistically, 3-DSC induced cell cycle arrest by modulating cell cycle regulatory proteins, including cyclin B1, cdc2, and p27. In addition, concomitant EGFR downstream signaling proteins such as MET, AKT, and ERK were affected by 3-DSC and contributed to the inhibition of cancer cell growth. Furthermore, our results show that 3-DSC increased redox homeostasis disruption, ER stress, mitochondrial depolarization, and caspase activation in gefitinib-resistant lung cancer cells, thereby abrogating cancer cell growth. 3-DSC induced apoptotic cell death which is regulated by Mcl-1, Bax, Apaf-1, and PARP in gefitinib-resistant lung cancer cells. 3-DSC also initiated the activation of caspases, and the pan-caspase inhibitor, Z-VAD-FMK, abrogated 3-DSC induced-apoptosis in lung cancer cells. These data imply that 3-DSC mainly increased mitochondria-associated intrinsic apoptosis in lung cancer cells to reduce lung cancer cell growth. Overall, 3-DSC inhibited the growth of drug-resistant lung cancer cells by simultaneously targeting EGFR and MET, which exerted anti-cancer effects through cell cycle arrest, mitochondrial homeostasis collapse, and increased ROS generation, eventually triggering anticancer mechanisms. 3-DSC could potentially be used as an effective anti-cancer strategy to overcome EGFR and MET target drug-resistant lung cancer.

Health systems science (HSS) is recognized as the third pillar of medical education. alongside basic and clinical sciences. Today’s physicians must also be systems thinkers who are able to discern how social, economic, environmental, and technological forces influence clinical decision-making. This study aimed to propose strategies for structuring an HSS curriculum that is tailored to the Korean healthcare and medical education context. First, the authors of this study conducted a survey to identify the present curricular contents of HSS related education at Korean medical schools. Second, a needs assessment was performed to determine the necessity of HSS competencies, as well as the prerequisites for the seamless integration of HSS into the existing curriculum. Third, literature reviews on HSS education at 14 US medical schools and expert consultations was conducted. We would like to propose a set of strategic approaches, classified into two levels: comprehensive and partial restructuring of the current medical curriculum to incorporate HSS. The partial restructuring approach entails a gradual, incremental incorporation of HSS content, while maintaining the current curricular structure. In contrast, a complete overhaul of the curriculum may be ideal to build HSS as the third pillar of medical education, but its feasibility remains relatively limited. The partial reorganization approach, however, has the advantage of being highly feasible. Collaborative efforts between professors and students are imperative to collectively devise effective methods for the seamless integration of HSS into the existing curriculum.

Licochalcone H (LCH) is a phenolic compound synthetically derived from licochalcone C (LCC) that exerts anticancer activity. In this study, we investigated the anticancer activity of LCH in human skin cancer A375 and A431 cells. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell viability assay was used to evaluate the antiproliferative activity of LCH. Cell cycle distribution and the induction of apoptosis were analyzed by flow cytometry. Western blotting assays were performed to detect the levels of proteins involved in cell cycle progression, apoptosis, and the JAK2/STAT3 signaling pathway. LCH inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay revealed that LCH induced apoptosis, and the LCH-induced apoptosis was accompanied by cell cycle arrest in the G1 phase. Western blot analysis showed that the phosphorylation of JAK2 and STAT3 was decreased by treatment with LCH. The inhibition of the JAK2/STAT3 signaling pathway by pharmacological inhibitors against JAK2/STAT3 (cryptotanshinone (CTS) and S3I-201) simulated the antiproliferative effect of LCH suggesting that LCH induced apoptosis by modulating JAK2/STAT3 signaling.

Sperm function and male fertility are closely related to pH dependent K⁺ current (KSper) in human sperm, which is most likely composed of Slo3 and its auxiliary subunit leucine-rich repeat-containing protein 52 (LRRC52). Onion peel extract (OPE) and its major active ingredient quercetin are widely used as fertility enhancers; however, the effect of OPE and quercetin on Slo3 has not been elucidated. The purpose of this study is to investigate the effect of quercetin on human Slo3 channels. Human Slo3 and LRRC52 were co-transfected into HEK293 cells and pharmacological properties were studied with the whole cell patch clamp technique. We successfully expressed and measured pH sensitive and calcium insensitive Slo3 currents in HEK293 cells. We found that OPE and its key ingredient quercetin inhibit Slo3 currents. Inhibition by quercetin is dose dependent and this degree of inhibition decreases with elevating internal alkalization and internal free calcium concentrations. Functional moieties in the quercetin polyphenolic ring govern the degree of inhibition of Slo3 by quercetin, and the composition of such functional moieties are sensitive to the pH of the medium. These results suggest that quercetin inhibits Slo3 in a pH and calcium dependent manner. Therefore, we surmise that quercetin induced depolarization in spermatozoa may enhance the voltage gated proton channel (Hv1), and activate non-selective cation channels of sperm (CatSper) dependent calcium influx to trigger sperm capacitation and acrosome reaction.
Acrosome Reaction ; Calcium ; Fertility ; HEK293 Cells ; Humans ; Hydrogen-Ion Concentration ; Male ; Onions ; Phosphatidylinositols ; Protons ; Quercetin ; Sperm Capacitation ; Spermatozoa

PURPOSE: The diagnostic criteria of gastric intraepithelial neoplasia (IEN) are controversial across the world. We investigated how many discrepancies occur in the pathologic diagnosis of IEN and early gastric carcinoma in endoscopic submucosal dissection (ESD) specimens, and evaluated the reasons of the discordance. MATERIALS AND METHODS: We retrospectively reviewed 1,202 ESD specimens that were originally diagnosed as gastric IEN and early carcinoma at 12 institutions. RESULTS: The final consensus diagnosis of carcinoma were 756 cases, which were originally 692 carcinomas (91.5%), 43 high-grade dysplasias (5.7%), 20 low-grade dysplasias (2.6%), and 1 others (0.1%), respectively. High- and low-grade dysplasia were finally made in 63 and 342 cases, respectively. The diagnostic concordance with the consensus diagnosis was the highest for carcinoma (91.5%), followed by low-grade dysplasia (86.3%), others (63.4%) and high-grade dysplasia (50.8%). The general kappa value was 0.83, indicating excellent concordance. The kappa values of individual institutions ranged from 0.74 to 1 and correlated with the proportion of carcinoma cases. The cases revised to a final diagnosis of carcinoma exhibited both architectural abnormalities and cytologic atypia. The main differential points between low- and high-grade dysplasias were the glandular distribution and glandular shape. Additional features such as the glandular axis, surface maturation, nuclear stratification and nuclear polarity were also important. CONCLUSION: The overall concordance of the diagnosis of gastric IEN and early carcinoma in ESD specimens was excellent. It correlated with the proportion of carcinoma cases, demonstrating that the diagnostic criteria for carcinoma are more reproducible than those for dysplasia.
Consensus ; Diagnosis ; Retrospective Studies ; Stomach Neoplasms

PURPOSE: This study investigated medical students' attitudes toward academic misconduct that occurs in the learning environment during the pre-clinical and clinical periods. METHODS: Third-year medical students from seven medical schools were invited to participate in this study. A total of 337 of the 557 (60.5%) students completed an inventory assessing their attitudes toward academic misconduct. The inventory covered seven factors: scientific misconduct (eight items), irresponsibility in class (six items), disrespectful behavior in patient care (five items), dishonesty in clerkship tasks (four items), free riding on group assignments (four items), irresponsibility during clerkship (two items), and cheating on examinations (one item). RESULTS: Medical students showed a strict attitude toward academic misconduct such as cheating on examinations and disrespectful behavior in patient care, but they showed a less rigorous attitude toward dishonesty in clerkship tasks and irresponsibility in class. There was no difference in students' attitudes toward unprofessional behaviors by gender. The graduate medical school students showed a stricter attitude toward some factors of academic misconduct than the medical college students. This difference was significant for irresponsibility in class, disrespectful behavior in patient care, and free riding on group assignments. CONCLUSION: This study indicates a critical vulnerability in medical students' professionalism toward academic integrity and responsibility. Further study evidence is needed to confirm whether this professionalism lapse is confined only to this population or is pervasive in other medical schools as well.
Ethics ; Humans ; Learning ; Patient Care ; Professional Misconduct ; Professionalism ; Schools, Medical ; Scientific Misconduct ; Students, Medical

PURPOSE: This study investigated medical students' attitudes toward academic misconduct that occurs in the learning environment during the pre-clinical and clinical periods. METHODS: Third-year medical students from seven medical schools were invited to participate in this study. A total of 337 of the 557 (60.5%) students completed an inventory assessing their attitudes toward academic misconduct. The inventory covered seven factors: scientific misconduct (eight items), irresponsibility in class (six items), disrespectful behavior in patient care (five items), dishonesty in clerkship tasks (four items), free riding on group assignments (four items), irresponsibility during clerkship (two items), and cheating on examinations (one item). RESULTS: Medical students showed a strict attitude toward academic misconduct such as cheating on examinations and disrespectful behavior in patient care, but they showed a less rigorous attitude toward dishonesty in clerkship tasks and irresponsibility in class. There was no difference in students' attitudes toward unprofessional behaviors by gender. The graduate medical school students showed a stricter attitude toward some factors of academic misconduct than the medical college students. This difference was significant for irresponsibility in class, disrespectful behavior in patient care, and free riding on group assignments. CONCLUSION This study indicates a critical vulnerability in medical students' professionalism toward academic integrity and responsibility. Further study evidence is needed to confirm whether this professionalism lapse is confined only to this population or is pervasive in other medical schools as well.

OBJECTIVE: To investigate the feasibility of ex vivo multispectral photoacoustic (PA) imaging in differentiating cholesterol versus neoplastic polyps, and benign versus malignant polyps, of the gallbladder. MATERIALS AND METHODS: A total of 38 surgically confirmed gallbladder polyps (24 cholesterol polyps, 4 adenomas, and 10 adenocarcinomas) from 38 patients were prospectively included in this study. The surgical specimens were set on a gel pad immersed in a saline-filled container. The PA intensities of polyps were then measured, using two separate wavelength intervals (421–647 nm and 692–917 nm). Mann-Whitney U test was performed for the comparison of normalized PA intensities between the cholesterol and neoplastic polyps, and between the benign and malignant polyps. Kruskal-Wallis test was conducted for the comparison of normalized PA intensities among the cholesterol polyps, adenomas, and adenocarcinomas. RESULTS: A significant difference was observed in the normalized PA intensities between the cholesterol and neoplastic polyps at 459 nm (median, 1.00 vs. 0.73; p = 0.032). Comparing the benign and malignant polyps, there were significant differences in the normalized PA intensities at 765 nm (median, 0.67 vs. 0.78; p = 0.013), 787 nm (median, 0.65 vs. 0.77; p = 0.034), and 853 nm (median, 0.59 vs. 0.85; p = 0.028). The comparison of the normalized PA intensities among cholesterol polyps, adenomas, and adenocarcinomas demonstrated marginally significant differences at 765 nm (median, 0.67 vs. 0.66 vs. 0.78, respectively; p = 0.049). CONCLUSION: These preliminary results indicate that benign versus malignant gallbladder polyps might exhibit different spectral patterns on multispectral PA imaging.
Adenocarcinoma ; Adenoma ; Cholesterol ; Diagnosis, Differential* ; Gallbladder Neoplasms ; Gallbladder* ; Humans ; Photoacoustic Techniques ; Polyps* ; Prospective Studies

BACKGROUND/AIMS: ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been used for preoperative staging of colorectal cancer (CRC). However, the diagnostic accuracy of FDG-PET/CT for detection of lymph node or distant metastasis and its prognostic role have not been well established. We therefore evaluated the diagnostic and prognostic value of FDG-PET/CT in comparison with conventional CT for CRC. METHODS: We investigated 220 patients who underwent preoperative FDG-PET/CT and CT, followed by curative surgery for CRC. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of FDG-PET/CT and CT for detection of lymph node metastasis and distant metastasis were evaluated. In addition, we assessed the findings of FDG-PET/CT and CT according to outcomes, including cancer recurrence and cancer-related death, for evaluation of prognostic value. RESULTS: For detection of lymph node metastasis, FDG-PET/CT had a sensitivity of 44%, a specificity of 84%, and an accuracy of 67%, compared with 59%, 65%, and 62%, respectively, for CT (P=0.029, P=0.000, and P=0.022). For distant metastasis, FDG-PET/CT had a sensitivity of 79%, a specificity of 94%, and an accuracy of 93%, compared with 79%, 87%, and 86%, respectively, for CT (P=1.000, P=0.004, and P=0.037). In addition, positive findings of lymph node metastasis and distant metastasis on FDG-PET/CT were associated significantly with cancer recurrence or cancer-related death (P=0.009, P=0.001, respectively). CONCLUSIONS: Preoperative FDG-PET/CT had a higher specificity and accuracy compared to CT for detection of lymph node metastasis and distant metastasis of CRC. In addition, FDG-PET/CT could be a valuable prognostic tool for CRC.
Colorectal Neoplasms* ; Diagnosis ; Electrons* ; Humans ; Lymph Nodes ; Neoplasm Metastasis ; Positron-Emission Tomography ; Prognosis ; Recurrence ; Sensitivity and Specificity

BACKGROUND: Immunohistochemical demonstration of CD20 in diffuse large B-cell lymphoma (DLBCL) is prerequisite not only for the diagnosis but also for assigning patients to rituximab-containing chemotherapy. However, little is known about the impact of abundance of CD20 expression assessed by immunohistochemistry on the clinical outcome of DLBCL. We performed a semi-quantitative immunohistochemical analysis of CD20 expression in DLBCL to examine the prognostic implication of the level of CD20 expression. METHODS: Pre-treatment diagnostic tissue samples from 48 DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen were represented in a tissue microarray and immunostained for CD20. The relative abundance of CD20 expression was semi-quantitatively scored using a web-based ImmunoMembrane plug-in. Receiver operating characteristic curve analysis was used to determine a prognostically relevant cut-off score in order to dichotomize the patients into CD20-high versus CD20-low groups. RESULTS: The levels of CD20 expression were heterogeneous among the patients, with a wide and linear distribution of scores. Patients in CD20-low group showed significantly poor clinical outcome. CONCLUSIONS: The levels of CD20 expression in DLBCL are heterogeneous among the patients with DLBCL. A subgroup of the patients with CD20 expression levels below the cut-off score showed poor clinical outcome.
Antigens, CD20 ; B-Lymphocytes* ; Cyclophosphamide ; Diagnosis ; Doxorubicin ; Drug Therapy ; Humans ; Immunohistochemistry ; Lymphoma, B-Cell* ; Prednisone ; ROC Curve ; Tissue Array Analysis ; Vincristine ; Rituximab