The effect of PLK1 inhibitor in osimertinib resistant non-small cell lung carcinoma cells / 浙江大学学报·医学版

OBJECTIVES@#To investigate the effects of PLK1 inhibitors on osimertinib-resistant non-small cell lung carcinoma (NSCLC) cells and the anti-tumor effect combined with osimertinib.@*METHODS@#An osimertinib resistant NCI-H1975 cell line was induced by exposure to gradually increasing drug concentrations. Osimertinib-resistant cells were co-treated with compounds from classical tumor pathway inhibitor library and osimertinib to screen for compounds with synergistic effects with osimertinib. The Gene Set Enrichment Analysis (GSEA) was used to investigate the activated signaling pathways in osimertinib-resistant cells; sulforhodamine B (SRB) staining was used to investigate the effect of PLK1 inhibitors on osimertinib-resistant cells and the synergistic effect of PLK1 inhibitors combined with osimertinib.@*RESULTS@#Osimertinib-resistance in NCI-H1975 cell (resistance index=43.45) was successfully established. The PLK1 inhibitors GSK 461364 and BI 2536 had synergistic effect with osimertinib. Compared with osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in osimertinib-resistant cells. In NSCLC patients with epidermal growth factor receptor mutations treated with osimertinib, PLK1 mRNA levels were negatively correlated with progression free survival of patients (R=－0.62, P<0.05), indicating that excessive activation of PLK1 in NSCLC cells may cause cell resistant to osimertinib. Further in vitro experiments showed that IC50 of PLK1 inhibitors BI 6727 and GSK 461364 in osimertinib-resistant cells were lower than those in sensitive ones. Compared with the mono treatment of osimertinib, PLK1 inhibitors combined with osimertinib behaved significantly stronger effect on the proliferation of osimertinib-resistant cells.@*CONCLUSIONS@#PLK1 inhibitors have a synergistic effect with osimertinib on osimertinib-resistant NSCLC cells which indicates that they may have potential clinical value in the treatment of NSCLC patients with osimertinib resistance.

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation

Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding motif (TAZ): a nexus between hypoxia and cancer

Hypoxia is a common feature of solid tumors. As transcription factors, hypoxia-inducible factors (HIFs) are the master regulators of the hypoxic microenvironment; their target genes function in tumorigenesis and tumor development. Intriguingly, both yes-associated protein (YAP) and its paralog transcriptional coactivator with a PDZ-binding motif (TAZ) play fundamental roles in the malignant progression of hypoxic tumors. As downstream effectors of the mammalian Hippo pathway, YAP and/or TAZ (YAP/TAZ) are phosphorylated and sequestered in the cytoplasm by the large tumor suppressor kinase 1/2 (LATS1/2)-MOB kinase activator 1 (MOB1) complex, which restricts the transcriptional activity of YAP/TAZ. However, dephosphorylated YAP/TAZ have the ability to translocate to the nucleus where they induce transcription of target genes, most of which are closely related to cancer. Herein we review the tumor-related signaling crosstalk between YAP/TAZ and hypoxia, describe current agents and therapeutic strategies targeting the hypoxia-YAP/TAZ axis, and highlight questions that might have a potential impact in the future.

Targeting slug-mediated non-canonical activation of c-Met to overcome chemo-resistance in metastatic ovarian cancer cells

Metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastatic-associated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-Met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin V function, which was confirmed by the significant correlation of slug and p-Met levels in 121 ovarian cancer patient samples. Intriguingly, c-Met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both and . Additionally, IHC analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-Met in slug-positive ovarian cancer patients with poor prognosis.

Psychometric properties of the PTSD checklist-civilian version among junior school students from earthquake-hit region / 中华行为医学与脑科学杂志

Objective To test psychometric properties of the PTSD checklist-civilian version(PCL-C) among junior school students from earthquake-hit region.Methods PC L-C Chinese Version, Rosenberg self-esteem scale and SCL-90 were utilized to assess 560 junior school students from earthquake-hit region.Results Firstly,the internal consistency of the total scale and three subscales were qualified, the coefficient alphas were 0.890,0.734,0.789 and 0.722, respectively; 307 participants, from the first samples, engaged in the second test two months after the first assessment.The test-retest stability was re-experiencing 0.40(P ＜ 0.01 ) ,avoidance 0.45 (P＜ 0.01 ), hyper-arousal 0.448 (P ＜ 0.01 ), total scale 0.535 (P ＜ 0.01 ), respectively.Secondly, the results of criteria validity showed PCL-C and its three subscales had negative correlation with self-esteem (r =-0.192 ～-0.299, P ＜ 0.01 ), and had positive-related with SCL-90 and its subscales of depression, anxiety, and psychotic (r=0.563 ～0.775, P＜0.01 ).Finally,the results of empirical validity revealed that based on the score on PCL-Ccould differentiate those people who have significant different scores on SCL-90.Conclusions The PCL-C hadgood reliabilities and validities,which could be used to assess the severity of PTSD.

Relationship Between Delay Behavior and Time Perspective of College Students / 中国临床心理学杂志

Objective: The purpose of the current research was to explore the relationship between delay behavior and time perspective of college students. Methods: 456 college students (including 135 graduate students), from four Chinese universities, were surveyed with Aitken Procrastination Inventory (API) and Time Perspective Scale for Adolescent. Results: Firstly, there didn’t exist significant difference between different genders and grades; secondly, the scores of API were significantly correlated with length factor of Future Time Perspective (r=0.55, P

Development of Social Support Scale for University Students / 中国临床心理学杂志

Objective: To develop a social support scale for university students. Methods: Based on Xiao Shuiyuan’s social support theory (subjective support, objective support and support utilization),the Social Support Scale for University Students, including 17 items, had been developed and its reliabilities and validities had been studied. Results: The discrimination index of the items were 0.26-0.52, and the ? coefficients of the total and three subscales was 0.81-0.91. Three factor model had been founded by exploratory factor analysis based on the first sample(N=212) and demonstrated by confirmatory factor analysis on the second sample (N=211). The scores of this scale had significant correlations with Xiao Shuiyuan’s social support rating scale and SCL-90 scale. Conclusion: A good psychometric feature of the scale had been demonstrated.

Chinese Meaning in Life Questionnaire Revised in College Students and Its Reliability and Validity Test / 中国临床心理学杂志

Objective: The aim of the research was to test the applicability of Chinese Meaning in Life Questionnaire (C-MLQ) and its reliability and validity in college students. Methods: C-MLQ and a parcel of scales were administered to 531 college students from three universities in China. Exploratory Factor Analysis (EFA) and confirmatory factor analysis (CFA) were employed to check the construct validity. Results: Firstly, the internal consistency of the two subscales were qualified, the coefficient alpha of two subscales were 0.85 and 0.82 respectively; test-retest reliability were 0.74 and 0.76 respectively; secondly, compared with original scales, the construct of C-MLQ also had two factors, the item factor loadings ranging from 0.61 to 0.78 on the factor it belonged to. Thirdly, the correlations of C-MLQ and criterion measurement were 0.025 to 0.637. Finally, there were no gender difference in the scores of two subscales. Conclusion: The CMILQ has good reliability and validity and it can be used to assess individual meaning in life.

The Adaptation of Intelligence Scale for Chinese Young Children / 中国心理卫生杂志

Objective: To investigate whether the ISCYC (Intelligence Scale for Chinese Young Children) is suitable for children aged 7 to 15. Method: The ISCYC used in this study consisted of 9 subtests. Some more difficult new items were added into 8 of the 9 subtests. The subjects were divided into 5 age groups, each had 20 male and 20 female. Results: The difficulty of 50% items ranged from 0.3 to 0.7. The average difficulty was 0.5. In more than 50％ items, thediscriminate index was above 0.2. The split- half reliability of these subtests were from 0.76 to 0.95, most of them higher than 0.80.The means of raw score for subtasts increased with the age of subjects. Some items in Pattern Rotation were less difficult than needed. Conclusion: This study has fulfill the theoretical construction of ISCYC, whjch is applicable for children aged 7 to 15.

Personality of Recovered Bipolar Patients in NEO-PI-R / 中国临床心理学杂志

Objective:To examine differences among recovered Bipolar Ⅰ, Bipolar Ⅱ patients and controls. Methods: Using NEO-PI-R, HAMD and BRMS, we investigated 59 recovered bipolar patients and 59 normal controls matched for age, gender and education. Results: Compared with controls, Bipolar Ⅱ patients showed significant differences in personality traits of Neuroticism, Extraversion, and Openness to Experience. While Bipolar Ⅰ patients obtained higher scores on Gregariousness, Bipolar Ⅱ patients scored higher on traits of Depression, Impulsiveness and Aesthetics. Scores on Warmth were higher in Bipolar Ⅰ patients than in Bipolar Ⅱ patients. Conclusion: Personality traits of recovered bipolar patients were markedly different from matched controls, whereas the differences between Bipolar Ⅰ and Bipolar Ⅱ patients were small.

Factor Structure of PTSD Checklist:A Confirmatory Factor Analysis Study in Adolescents from Earthquake Region / 中国临床心理学杂志

Objective: To investigate the factor structure of the PTSD through analyzing the factor structure of the PTSD Checklist in adolescents from earthquake disaster region. Methods: Chinese PTSD Checklist-Civilian Version was used to assess 560 adolescents, and technique of Confirmatory Factor Analysis (CFA) was employed to comparing seven competitive models. Results: The intercorrelated four-factor model was the best fit one. Conclusion: The Chinese PTSD Checklist-Civilian has an intercorrelated four-factor model; intercorrelated four-factor model of the PTSD may fit the Chinese people, however, which needs further confirmation.

The Adaptability of Factor Structure of Intelligence Scale for Chinese Young Children (ISCYC) / 中国心理卫生杂志

Objective: To investigate the adaptability of the factor structure of ISCYC to children aged 7 to 15. Method: A simultaneous confirmatory maximum likelihood factor analysis was conducted in 200 students. The 2-factor model of ISCYC and 3-factor model provided by Kaufman were fitted to the data and compared. Results: Both of the oblique 2-factor mode and 3-factor model fit the data quite well, but the latter had better fitness than former. Conclusion: The 2-factor model of ISCYC is applicable for children aged 7 to 15.