Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy.

HER2-positive gastric cancer (GC) makes up 15-20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.

Factors influencing tourists' shared bicycle loyalty in Hangzhou, China.

Focusing on Hangzhou, a famous tourist city in China, in this study, four regression models were constructed through four items of tourist loyalty to investigate the influence of tourist perceptions and characteristics on male and female tourist loyalty to shared bicycles. A questionnaire survey and ordered logistic regression model techniques were used. Survey data from 467 tourists indicated that there were significant differences between male and female tourists. For male tourists, their willingness to reuse shared bicycles (Models 1 and 2) was positively correlated with ease of access to cycles, environmental awareness, psychological benefit, and management provision; however, their willingness to recommend shared bicycles (Models 3 and 4) was only affected by environmental awareness, psychological benefit, and management provision. Among female tourists, willingness to reuse shared bicycles (Models 1 and 2) was affected by ease of access to cycles, environmental awareness, and rule adherence, while their willingness to recommend shared bicycles (Models 3 and 4) was affected by ease of access to cycles, environmental awareness, psychological benefit, and managerial provision. In addition, female tourists' socio-demographic and behavioral characteristics had a significant impact on their loyalty, among which length of stay in Hangzhou and education were significant in the four regression models, and number of visits to Hangzhou had a positive impact on female tourists' willingness to reuse (Models 1 and 2). In addition, female tourists who used Hellobike had higher willingness to reuse and recommend than those who used Mobike. For male tourists, only length of stay in Hangzhou had a significant impact on their reuse intention (Model 2). The current study extends the theory of attribution to explore the factors which may affect tourist's loyalty to bicycle-sharing from the perspectives of tourists' perceptions. It will provide further support to decision makers in the development of new shared-bicycle systems at Chinese tourist destinations, with the aim of strengthening tourist loyalty to shared-bicycle programs.

Hsa_hsa_circ_0081069 promotes the progression of colorectal cancer through sponging miR-665 and regulating E2F3 expression.

BACKGROUND: Circular RNAs (circRNAs) have been implicated in the initiation and development of various cancers. This study explored the potential contribution of hsa_hsa_circ_0081069 in the progression of colorectal cancer (CRC). METHODS: The gene expression was analyzed by qRT-PCR. Functional roles of hsa_circ_0081069 were examined by shRNA-mediated silencing using CCK-8 proliferation assay, Transwell migration and invasion assay, tube formation assay. The tumorigenesis and metastasis of CRC cells were assess in a xenograft mouse model. RESULTS: Hsa_circ_0081069 was significantly upregulated in CRC tissues and cells. Hsa_circ_0081069 knockdown suppressed the proliferation, migration and invasion in CRC cells, as well as the angiogenesis. Silencing hsa_circ_0081069 also impaired the tumorigenesis of CRC cells in a xenograft mouse model. Furthermore, miR-665 was identified as an interacting partner of hsa_circ_0081069, which was negatively regulated by hsa_circ_0081069. miR-665 targeted the mRNA of E2F3 to suppress its expression. We further demonsatred that miR-665/E2F3 axis mediated the functional role of hsa_circ_0081069 in regulating the malignant phenotype of CRC cells. CONCLUSIONS: Collectively, our study suggests that hsa_circ_0081069 could serve as a prognostic marker in progression of CRC. Targeting hsa_circ_0081069 and miR-665/E2F3 axis could serve as potential therapeutic strategies for CRC treatment.

SP1-mediated overexpression of lncRNA LINC01234 as a ceRNA facilitates non-small-cell lung cancer progression via regulating OTUB1.

Long noncoding RNAs (lncRNAs) have been confirmed to be strongly associated with the progression of various types of cancer. LncRNA LINC01234 (LINC01234) is a newly identified tumor-related lncRNA whose upregulation has been confirmed in some tumors. However, its potential expressions and possible functions in non-small-cell lung cancer (NSCLC) have not been explored. In this study, we first found that LINC01234 expressions were distinctly upregulated in both NSCLC samples and cell lines using RT-PCR. Our group also showed that LINC01234 upregulations were modulated by nuclear transcription factor SP1. The results form clinical investigations indicated that high LINC01234 expressions were associated with positively lymph node metastasis and advanced tumor-metastasis-node (TMN) stage. Kaplan-Meier assays indicated that patients with NSCLC having high LINC01234 expressions tend to have unfavorable clinical prognosis. Using multivariate assays, it was confirmed that LINC01234 was an independent prognostic factor for patients with NSCLC. In vitro assays showed that inhibition of LINC01234 suppressed NSCLC cell proliferation, cell colony formation and metastasis, and greatly promoted apoptosis. Mechanistic investigations revealed LINC01234 promotes the progression of NSCLC cells by the modulation of miR-140 to positively regulate OTUB1 expression. Taken together our findings, they provided an exhaustive assay of LINC01234 in NSCLC and imperative clues for insights into the potential effects of lncRNAs-miRNAs regulatory network in NSCLC.

Combination of MEK Inhibitor and the JAK2-STAT3 Pathway Inhibition for the Therapy of Colon Cancer.

The study aimed to investigate the reason of HCT116 cell resistance to MEK inhibitor, and the combination treatment effects of MEK inhibitor AZD6244 and JAK2/STAT3 inhibitor AG490 on colon cancer in vitro and in vivo, including cell viability, apoptosis, and explore the partial mechanisms focused on AZD6244 promoted the activation of JAK2-STAT3 pathways. In vitro, we examined the HCT116 cell viability by CCK8, cell apoptosis by flow cytometry; Western blot measured p-ERK, p-JAK2, p-STAT3 and STAT3 expression. In vivo, nude mice were subcutaneously injected by HCT116 cells. The tumor volume and weight were detected. HCT116 cell resistance to MEK inhibitor AZD6244, which inhibited the activation of ERK and promoted the activation of JAK2-STAT3 signaling. The combination treatment of AZD6244 and AG490 significantly inhibited cell viability and induced cell apoptosis, and completely inhibited the activation of ERK and JAK2-STAT3 signaling. Combination treatment of AZD6244 and AG490 had a stronger effect than that of AZD6244 as a monotherapy in vitro and in vivo. The treatment of AZD6244 on K-Ras mutations HCT116 cells promoted the activation of JAK2/STAT3 signaling. JAK2/STAT3 inhibitor AG490 synergistically increases effects of AZD6244 on colon cancer in vitro and in vivo. Collectively, these results provide a rationale for combining inhibitors of the JAK/STAT pathway and MEK inhibitors to reduce the potential impact of drug resistance.

WITHDRAWN: Survivin, Caspase-3 and Caspase-9-activated proteins kinases in apoptosis.

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