CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway.

Systemic therapy for muscle-invasive bladder cancer (BC) remains dominated by cisplatin-based chemotherapy. However, resistance to cisplatin therapy greatly limits long-term survival. Resistance to cisplatin-based chemotherapy still needs to be addressed. In this study, we established three cisplatin-resistant BC cell lines by multiple cisplatin pulse treatments. Interestingly, after exposure to cisplatin, all cisplatin-resistant cell lines showed lower reactive oxygen species (ROS) levels than the corresponding parental cell lines. Using proteomic analysis, we identified 35 proteins that were upregulated in cisplatin-resistant BC cells. By knocking down eleven of these genes, we found that after CAB39 knockdown, BC cisplatin-resistant cells were more sensitive to cisplatin. Overexpression of CAB39 had the opposite effect. Then, the knockdown of six genes downstream of CAB39 revealed that CAB39 promoted cisplatin resistance in BC through LKB1. Moreover, a key cause of cisplatin-induced cell death is damage to mitochondria and increased ROS levels. In our study, cisplatin-resistant cells exhibited higher autophagic flux and healthier mitochondrial status after cisplatin exposure. We demonstrated that the CAB39-LKB1-AMPK-LC3 pathway plays a critical role in enhancing autophagy to maintain the health of mitochondria and reduce ROS levels. In addition, the autophagy inhibitor chloroquine (CQ) can significantly enhance the killing effect of cisplatin on BC cells. Compared with gemcitabine plus cisplatin (GC), GC plus CQ significantly reduced tumor burden in vivo. In conclusion, our study shows that CAB39 counteracts the killing of cisplatin by enhancing the autophagy of BC cells to damaged mitochondria and other organelles to alleviate the damage of cells caused by harmful substances such as ROS.

ADAM12 promotes gemcitabine resistance by activating EGFR signaling pathway and induces EMT in bladder cancer

Background Gemcitabine (GEM)-based chemotherapy regimens is widely used in bladder cancer (BC) patients. However, GEM resistance may occur and result in treatment failure and disease progression. A disintegrin and metalloprotease 12 (ADAM12) plays a critical role in many cancers. However, the role of ADAM12 in GEM resistance of BC remains unclear. Methods We analyzed the relationship between ADAM12 expression and tumor characteristics using the data downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Then, we established GEM resistant BC cell lines and used quantitative real-time PCR, western blot, cell counting kit-8, immunohistochemistry, and xenograft mouse model to investigate the role of ADAM12 in GEM resistance. Results In general, ADAM12 was found to be upregulated in GEM resistant BC cells. ADAM12 knockdown increased the chemosensitivity of BC cells. We further proved that ADAM12 could promote GEM resistance by activating the epidermal growth factor receptor (EGFR) signaling pathway in BC. Furthermore, the epithelial–mesenchymal transition (EMT) phenotype was observed in GEM resistant BC cells. ADAM12 induced EMT process and promotes tumor progression in BC. Conclusion Our findings suggested that ADAM12 was a key gene for GEM resistance and positively correlated with malignancy of BC. It might serve as a novel and valuable therapeutic target for BC (AU)

ADAM12 promotes gemcitabine resistance by activating EGFR signaling pathway and induces EMT in bladder cancer.

BACKGROUND: Gemcitabine (GEM)-based chemotherapy regimens is widely used in bladder cancer (BC) patients. However, GEM resistance may occur and result in treatment failure and disease progression. A disintegrin and metalloprotease 12 (ADAM12) plays a critical role in many cancers. However, the role of ADAM12 in GEM resistance of BC remains unclear. METHODS: We analyzed the relationship between ADAM12 expression and tumor characteristics using the data downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. Then, we established GEM resistant BC cell lines and used quantitative real-time PCR, western blot, cell counting kit-8, immunohistochemistry, and xenograft mouse model to investigate the role of ADAM12 in GEM resistance. RESULTS: In general, ADAM12 was found to be upregulated in GEM resistant BC cells. ADAM12 knockdown increased the chemosensitivity of BC cells. We further proved that ADAM12 could promote GEM resistance by activating the epidermal growth factor receptor (EGFR) signaling pathway in BC. Furthermore, the epithelial-mesenchymal transition (EMT) phenotype was observed in GEM resistant BC cells. ADAM12 induced EMT process and promotes tumor progression in BC. CONCLUSION: Our findings suggested that ADAM12 was a key gene for GEM resistance and positively correlated with malignancy of BC. It might serve as a novel and valuable therapeutic target for BC.

The relationship between Chlamydia pneumoniae infection and CD4/CD8 ratio, lymphocyte subsets in middle-aged and elderly individuals.

Chlamydia pneumoniae (C. pneumoniae) is a common respiratory pathogen associated with many inflammatory diseases. There are few data concerning the lymphocyte subsets in middle-aged and elderly individuals with C. pneumoniae infection. A total of 191 patients were included in this study. The study population was categorized into the middle-aged group (40-64 years old) and the elderly group (65-89 years old). Lymphocyte subsets in peripheral blood were examined with multi-colored flow cytometry. Immunological monitoring included lymphocyte subsets, C. pneumoniae IgG and IgM serology. In the middle-aged group, 69.83% individuals presented IgG positivity, which was associated with the inverted CD4/CD8 ratio. Individuals with C. pneumoniae IgG positivity also presented an increased percentage of CD8+CD28- cells and a decreased CD4/CD8 ratio when compared to weakly-positive individuals. In the elderly group, C. pneumoniae IgG positivity was associated with a significant increase in the percentage of CD3+CD56+CD45+ (NKT) cells. In conclusion, altered lymphocyte homeostasis was shown in middle-aged individuals with C. pneumoniae IgG positivity. The senescent phenotypes of T cells might be associated with C. pneumoniae infection in middle-aged individuals.

ATM mutations as an independent prognostic factor and potential biomarker for immune checkpoint therapy in endometrial cancer.

The morbidity and mortality of endometrial cancer has been increasing over years. Ataxia telangiectasia mutated (ATM) gene, encoding a protein kinase participated in the response to DNA damage, is frequently mutated in endometrial cancer patients. However, the potential relationship between ATM mutations and the progression of endometrial cancer remains unclear. We performed an integrative bioinformatics analysis to investigate the relationship between ATM mutational status with clinical outcomes and tumor microenvironment in endometrial cancer patients. The whole exome sequencing data, RNA sequencing data and clinical information were collected from The Cancer Genome Atlas (TCGA) dataset. We found that mutation in the ATM gene was an independent prognostic factor for endometrial cancer. Antitumor immune pathways were enriched in endometrial tumors with ATM mutations. The tumor-infiltrating T lymphocytes, especially cytotoxic lymphocytes, were generally more abundant in tumors with ATM mutations. Furthermore, patients with ATM mutations exhibited higher tumor mutational burden, higher neoantigen load and increased expression levels of some immune checkpoints. In conclusion, the present study indicated that ATM mutations were linked to longer overall survival of endometrial cancer. Our findings may add better understanding for potential immunotherapy of endometrial cancer.

The predictive value of lymphocyte-to-monocyte ratio in the prognosis of acute coronary syndrome patients: a systematic review and meta-analysis.

BACKGROUND: The association between the lymphocyte-to-monocyte ratio (LMR) and prognosis in the patients with acute coronary syndrome (ACS) is not fully understood. We performed this systematic review and meta-analysis to evaluate the correlation between LMR and mortality or major adverse cardiac events (MACE) in patients with ACS. METHODS: A systematic search was performed in PubMed, MEDLINE, EMBASE, the Cochrane Library, Scopus, and Web of science. The association between LMR and mortality/MACE was analyzed in patients with ACS. The search was updated to April 15, 2020. RESULTS: A total of 5 studies comprising 4343 patients were included in this meta-analysis. The results showed that lower LMR predicted higher short-term mortality/MACE (hazard ratio [HR] = 3.44, 95% confidence interval [CI]: 1.46-8.14, P <  0.05) and long-term mortality/MACE (HR = 1.70, 95% CI: 1.36-2.13, P <  0.05). In the subgroup analysis, there was still statistical significance of long-term mortality/MACE in all subgroups. CONCLUSIONS: This study suggested that lower LMR value might be associated with higher short-term and long-term mortality/MACE in ACS patients. Especially for younger ACS patients, low LMR was more closely associated with poor prognosis.

Systemic Immune-Inflammatory Index Predicts Clinical Outcomes for Elderly Patients with Acute Myocardial Infarction Receiving Percutaneous Coronary Intervention.

BACKGROUND We assessed the utility of the systemic immune-inflammatory index (SII) in estimating the in-hospital and long-term prognosis of elderly patients with acute myocardial infarction (AMI) who received percutaneous coronary intervention (PCI). MATERIAL AND METHODS Our study evaluated 711 consecutive elderly patients (age 65-85 years) from January 2015 to December 2017. The correlation between clinical outcomes and SII was analyzed through the stepwise Cox regression analysis and the Kaplan-Meier approach. The clinical endpoints were all-cause mortality and major adverse cardiovascular and cerebrovascular events (MACCE) in-hospital and during 3-year follow-up. RESULTS The study enrolled 711 elderly patients with AMI (66.95% male, 71.99±0.19 years). Kaplan-Meier analysis showed a lower survival rate in patients with higher SII scores, which also predicted in-hospital and long-term (≤3 years) outcomes. In multivariate analyses, SII showed an independent predictive value for in-hospital mortality (hazard ratio (HR), 3.32; 95% confidence interval (CI), 1.55-7.10; p<0.01), in-hospital MACCE (HR, 1.43; 95%CI, 1.02-2.00; p=0.04), long-term mortality (HR, 1.95; 95%CI, 1.23-3.09; p<0.01), along with long-term MACCE (HR, 1.72; 95%CI, 1.23-2.40; p<0.01). Moreover, SII showed a weak but significant positive relationship with the Gensini score among patients developing non-ST-segment elevation myocardial infarction (r=0.18; p<0.01). CONCLUSIONS SII, a readily available laboratory marker, is a potential indicator to predict the clinical endpoints for elderly patients with AMI undergoing PCI.