Despite its potent antitumor effect, clinical use of Doxorubicin is limited because of serious side effects including myocardial toxicity. Understanding the cellular mechanism involved in this process in a better manner is beneficial for optimizing Doxorubicin treatment. In the current study, the authors focus on the AMP-activated protein kinase (AMPK) in the said process. In this study, the authors discovered for the first time that Doxorubicin induces AMPK activation in cultured rat embryonic ventricular myocardial H9c2 cells. Reactive oxygen species (ROS)-dependent LKB1 activation serves as the upstream signal for AMPK activation by Doxorubicin. Evidence in support of the activation of AMPK contributing to Doxorubicin-induced H9c2 cell death/apoptosis--probably by modulating multiple downstream signal targets, including regulating JNK, p53, and inhibiting mTORC1--is provided in this article.

The molecular basis for induction of apoptosis in melanoma cells by vincristine remains unknown. Here we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found for the first time that vincristine induces AMPK activation (AMPKα, Thr 172) and Acetyl-CoA carboxylase (ACC, Ser 79) (a downstream molecular target of AMPK) phosphorylation in cultured melanoma cells in vitro. Reactive oxygen species (ROS) dependent LKB1 activation serves as the upstream signal for AMPK activation. AMPK inhibitor (compound C) or AMPKα siRNA knockdown inhibits vincristine induced B16 melanoma cell apoptosis, while AMPK activator 5-aminoimidazole-4-carboxamide-1-β-riboside (AICAR) enhances it. AMPK activation is involved in vincristine induced p53 phosphorylation and stabilization, the latter is known to mediate melanoma cell apoptosis. Further, activation of AMPK by vincristine inhibits mTOR Complex 1 (mTORC1) in B16 melanoma cells, which serves as another important mechanism to induce melanoma cell apoptosis. Our study provides new insights into understanding the cellular and molecular mechanisms of vincristine induced cancer cell death/apoptosis. We suggest that combining AMPK activator AICAR with vincristine may have potential to be used as a new therapeutic intervention against melanoma.

Note: The sample collection time in parentheses in the column heads is the month after osimertinib treatment. Em dash indicates that the mutation was undetectable. a Coverage depth of EGFR in patient's tumor or cell-free DNA samples normalized to the value in patient's own whole blood control sample. FFPE, formalin-fixed paraffin-embedded.

No abstract

Published data on the association between lymphocyte-specific protein 1 (LSP1) rs3817198T>C polymorphism and breast cancer risk are inconclusive. Hence, we conducted a meta-analysis of the LSP1 gene and risk of breast cancer to obtain the most reliable estimate of the association. PubMed, Embase and Web of Science databases were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of the association between the LSP1 rs3817198T>C polymorphism and risk of breast cancer. A total of seven eligible studies including 33,920 cases and 35,671 controls based on the search criteria were involved in this meta-analysis. The distributions of genotypes in the controls were all in agreement with Hardy-Weinberg equilibrium. We observed that the LSP1 rs3817198T>C polymorphism was significantly correlated with breast cancer risk when all studies were pooled into the meta-analysis (the allele contrast model: OR = 1.06, 95% CI = 1.04-1.08; the homozygote codominant: OR = 1.14, 95% CI = 1.01-1.28). In the stratified analysis by ethnicity, significant association was observed in Caucasians for CC versus TT homozygote codominant model (OR = 1.25; 95% CI = 1.03-1.52) and for the recessive model (OR = 1.22; 95% CI = 1.02-1.47). There was significant association observed in Africans for CC versus TT homozygote codominant model (OR = 0.45; 95% CI = 0.22-0.92) and for the recessive model (OR = 0.43; 95% CI=0.22-0.88). Also, significant association was observed in mixed ethnicities for CC versus TT homozygote codominant model (OR = 1.12; 95% CI = 1.05-1.19). When stratified by study design, statistically significantly elevated risk was found in nested case-control studies (CC vs. TT: OR = 1.12, 95% CI = 1.05-1.19). But no significant association was observed for all comparison models between LSP1 rs3817198T>C polymorphism and breast cancer risk in hospital-based and people-based studies. When stratified by BRCA1 mutation carriers status, statistically significantly elevated risk was found in this meta-analysis (the allele contrast model: OR = 1.07, 95% CI = 1.01-1.14; the dominant model: OR = 1.09, 95% CI = 1.00-1.18). And significant association was found in the BRCA2 mutation carriers in the allele contrast (OR = 1.11, 95% CI = 1.03-1.20), the homozygote codominant (OR = 1.23, 95% CI = 1.04-1.47), the heterozygote codominant (OR = 1.12, 95% CI = 1.00-1.25) and the dominant models (OR = 1.14, 95% CI = 1.03-1.27). There was significant association between LSP1 rs3817198T>C polymorphism and breast cancer risk in BRCA1 and BRCA2 positive cohort in all comparison models (the allele contrast model: OR = 1.08, 95% CI = 1.03-1.13; CC vs. TT: OR = 1.16, 95% CI = 1.05-1.29; TC vs. TT: OR = 1.09, 95% CI = 1.01-1.16; the dominant model: OR = 1.10, 95% CI = 1.03-1.17; the recessive model: OR = 1.12, 95% CI = 1.01-1.23). In conclusion, this meta-analysis suggests that the LSP1 rs3817198T>C polymorphism is a low-penetrant risk factor for developing breast cancer but may not be in Africans.

Background. Great success has been made in the targeting therapy of advanced non-small cell lung cancer (NSCLC). Nowadays, next generation sequencing (NGS) is acquirable and affordable in developed area of China. Using this feasible and accurate method of detecting therapeutic genes would help to select optimal treatments to extend patients survival. Here, we identified somatic mutations by NGS and analyzed the value for treatment of NSCLC in a real-world clinical setting. Methods. NGS was carried out on biopsy samples obtained from 66 advanced unresectable NSCLC patients who had not received any treatment. 23 patients received liquid biopsy after failure of first-line targeted treatment. The mutation profiling as well as associations between mutations and clinicopathological characters was analyzed. The study also assessed the values of NGS for choosing treatment options and predicting prognosis in NSCLC patients. Results. 152 somatic mutations were identified in 45 (68.18%) tissue samples. The most frequently mutated genes were EGFR (42.42%), TP53 (31.82%) and KRAS (15.15%). Specifically, the most frequent EGFR mutation subtypes were exon 19 deletion (60.71%) and L858R in exon 21 (46.43%). 83.33% mutated patients received targeted therapy. Among the adenocarcinoma cases, patients with EGFR exon 19 deletion mutation have longer overall survival (OS) than the wide-type (36.0 months versus 19.0 months p=0.046). In addition, in the smoking group, patients with EGFR exon 19 deletion mutation tended to have longer OS (38.0 months versus 16.5 months p<0.01). After the failure of first-line targeted therapy, 23 EGFR mutated patients received liquid biopsy, and the positive rate of T790M mutation in EGFR exon 20 was 47.83%. T790M positive patients have longer progression-free survival (PFS) than the others (15 months versus 9.5 months p=0.025). Conclusions. The observational study from real-world demonstrated that using NGS in routine clinical detection may be useful in guiding the therapy decisions and benefit more Chinese NSCLC patients.

Numerous studies have investigated the association between NQO1 Pro187Ser polymorphism and urinary system cancer risk, but the findings are inconsistent. To derive a more precise estimation of such association, we performed a meta-analysis based on 22 publications encompassing 5,274 cases and 6,459 controls. Overall, significant association was found between NQO1 Pro187Ser polymorphism and urinary system cancer risk. Moreover, stratified analysis observed a statistically significant association for bladder cancer, prostate cancer, renal cell carcinoma, Caucasians, Asians, and hospital-based studies. In summary, this meta-analysis indicated that NQO1 Pro187Ser polymorphism conferred genetic susceptibility to urinary system cancer.

Background: Apatinib showed promising efficacy in the treatment of advanced or metastatic gastric cancer (mGC) in previous clinical studies. However, the real-world data are limited, and this study aimed to assess the effectiveness and safety of apatinib for the treatment of advanced or mGC in this setting. Methods: In this prospective observational study, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and treatment-related adverse events (AEs) were recorded and evaluated. Univariate and multivariate analyses were conducted to explore potential biomarkers which might be related to the effectiveness. Results: A total of 321 mGC patients from 47 centers in China were enrolled between July 1, 2015, and March 1, 2018. Thirty-two patients achieved partial response, 155 patients achieved stable disease, and 115 patients had progressive disease, and no CR was achieved, illustrating an ORR of 10.60% and a DCR of 61.92%. The median PFS and OS were 4.0 and 8.2 months, respectively. Multivariate Cox analysis showed that the potential biomarkers associated with longer PFS were combination regimens plus taxel/docetaxel, and apatinib initial dosage ≥500mg, occurrence of AEs of leukopenia, and hand-foot syndrome. Main AEs were proteinuria (17.1%), hypertension (15.9%), and handfoot syndrome (8.7%). Conclusion: The present prospective observational study showed favorable effectiveness and safety of apatinib in real-world patients with advanced or metastatic GC in China. (A prospective, multi-center, non-intervention study of apatinib in the treatment of advanced gastric cancer-Trial Registry Number: ChiCTR-OPN-15006601).