Inhibition of JAK1/2 can overcome EGFR-TKI resistance in human NSCLC.

Non-small lung cancer (NSCLC) is the most common cancer in the world. The epidermal growth factor receptor (EGFR) gene is mutated in approximately 10% of lung cancer cases in the US and 50% of lung cancer in Asia. The representative target therapeutic agent, erlotinib (EGFR tyrosine kinase inhibitor; EGFR TKI), is effective in inactivating EGFR in lung cancer patients. However, approximately 50-60% of patients are resistant to EGFR TKI. These populations are associated with the EGFR mutation. To overcome resistance to EGFR TKI, we discovered a JAK1 inhibitor, CJ14939. We investigated the efficacy of CJ14939 in human NSCLC cell lines in vitro and in vivo. Our results showed that CJ14939 induced the inhibition of cell growth. Moreover, we demonstrated that combination treatment with erlotinib and CJ14939 induced cell death in vitro and inhibited tumor growth in vivo. In addition, we confirmed the suppression of phosphorylated EGFR, JAK1, and Stat3 expression in erlotinib and CJ14939-treated human NSCLC cell lines. Our results provide evidence that JAK inhibition overcomes resistance to EGFR TKI in human NSCLCs.

Synthesis and biological evaluation of quinoxaline derivatives as specific c-Met kinase inhibitors.

A series of novel quinoxaline derivatives were synthesized and evaluated for their inhibitory activity against c-Met kinase enzyme. Most of the tested compounds exhibited potent inhibitory activity. All the synthesized quinoxaline compounds were further examined against c-Met overexpressed human gastric cancer cell line (MKN-45), which showed good inhibitory activity. Among the synthesized compounds, compound 4 exhibited better tumor growth inhibition in the animal model study; we also confirmed its acceptable drug property and highly selective target activity.

CJ14939, a Novel JAK Inhibitor, Increases Oxaliplatin-induced Cell Death Through JAK/STAT Pathway in Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer is reported to have the highest mortality rate among human malignancies. Although many research results for the treatment of colorectal cancer have been reported, there is no suitable treatment when resistance has developed. Therefore, it is necessary to develop new therapeutic agents. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays an essential role in cell differentiation, proliferation, and survival. Abnormal activation of the JAK/STAT signaling pathway, by gene mutation or amplification, may induce cancer development, and sustained JAK/STAT activation is involved in chemoresistance. While many therapeutic agents have been developed to treat colon cancer, there remains no drug to overcome resistance to chemotherapies. The purpose of this study was to determine the potential of CJ14939 as a novel JAK inhibitor for the treatment of colorectal cancer. MATERIALS AND METHODS: In this study, cell culture, cell death assay, 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, colony formation assay, immunoblot analysis and tumor xenograft were applied. RESULTS: CJ14939 induced cell death, and inhibited phosphorylation of JAK1 and STAT3 in colorectal cancer cells. Furthermore, CJ14939 also promoted oxaliplatin-induced cell death, up-regulated expression of cleaved caspase-3, and down-regulated expression of phospho-JAK1 and phospho-STAT3. In vivo, co-treatment with CJ14939 and oxaliplatin notably reduced tumor growth when compared with CJ14939 or oxaliplatin treatment alone. CONCLUSION: This study identifies the important potential of CJ14939 in colorectal cancer treatment and suggests that combining CJ14939 with oxaliplatin might be a novel therapeutic strategy for patients with colorectal cancer.

Analysis of an Advanced Cardiovascular Life Support Provider Course in Korea

PURPOSE: The purpose of this study was to provide direction to improvement of advanced cardiovascular life support (ACLS) training in Korea. METHODS: We conducted a retrospective analysis of the questionnaire written by 55 instructors of the 31 institutions registered in the Korean Association of Cardiopulmonary Resuscitation (KACPR) from 2009 and 2010. The contents of the questionnaire consisted of an evaluation of the ACLS curriculum, modification of the ACLS curriculum, problems of ACLS training, and other open-ended answers. RESULTS: In this questionnaire, the result for assessment of the lecture on acute coronary syndrome was intermediate, that answer was given by the majority, 40.0%. The result for assessment of the lecture on stroke was intermediate, that answer was given by the majority, 40.0%. In addition, the result for the necessity of the lecture on acute coronary syndrome was intermediate, 25.5%, which was the most common response. The result for the necessity of the lecture on stroke was intermediate, 27.3%, which was the most common response. In the ACLS curriculum, 14.5% of respondents responded that simulation curriculum should be strengthened; 20.0% of participants responded that training on equipment and medical technique should be enhanced. CONCLUSION: Lecture without practice should be avoided and simulation-oriented education should be strengthened in the ACLS course.

Effect of Public re-education in willingness to Perform bystander Cardiopulmonary Resuscitation (CPR)

PURPOSE: Effectiveness of the performance of bystander cardiopulmonary resuscitation (CPR) has a decisive impact on the outcomes for out-of-hospital cardiac arrest patients who receive it. After initial CPR education, CPR performance for those trained declines over time. Public education in CPR is commonly recommended to be repeated every 2 years. In this study, we evaluated the willingness of those who have been CPR trained to perform CPR as impacted by their training experience. METHODS: The staff of a small firm received 2 hours of primary CPR education. Two years later, their CPR training was repeated in an identical manner. Participants answered a questionnaire regarding their willingness to perform bystander CPR. Those who answered that they wouldn't perform bystander CPR were asked to select their reason. We also inquired about what they viewed as the most difficult phase of CPR performance, and collected their opinions about the overall necessity and appropriate time period for re-education. RESULTS: Those who answered 'definitely yes' to 'willingness to perform to CPR' increased from 36.6% before primary CPR education to 74.2% afterward. But 2 years later and before re-education, only 30.1% answered 'definitely yes' to 'willingness to perform CPR'. Meanwhile, 41.2% and 29.4% answered that 'fear of legal liability' and 'fear of poor knowledge/performance' were the reasons why they would not perform bystander CPR. Ventilation was the most difficult stage in CPR identified by 34% of the participants, and 18.4% answered that chest compression was the most difficult stage in CPR. 93.6% answered that they should receive CPR re-education. CONCLUSION: The willingness to perform bystander CPR declined significantly after 2 years. Therefore routine public re-education for bystander CPR is necessary.