CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway.

Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a primary cause of treatment failure in non-small cell lung cancer (NSCLC) patients. Chemokine (C-C motif) ligand 2 (CCL2) is recently found to play a pivotal role in determining anti-cancer treatment response. However, the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated. In the present study, we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells. Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs. Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance. CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition (EMT) markers in EGFR-TKI-resistant NSCLC cells, which could also be rescued by CCL2 knockdown or inhibition. Furthermore, our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway; inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression. In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.

Development and validation of a novel nomogram to predict the overall survival of patients with large cell lung cancer: A surveillance, epidemiology, and end results population-based study.

Background: Large cell lung cancer (LCLC) is a rare subtype of non-small cell lung carcinoma (NSCLC), and little is known about its clinical and biological characteristics. Methods: LCLC patient data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. All patients were randomly divided into a training group and a validation group at a ratio of 7:3. The independent prognostic factors that were identified (P < 0.01) by stepwise multivariate Cox analysis were incorporated into an overall survival (OS) prediction nomogram, and risk-stratification systems, C-index, time-ROC, calibration curve, and decision curve analysis (DCA) were applied to evaluate the quality of the model. Results: Nine factors were incorporated into the nomogram: age, sex, race, marital status, 6th AJCC stage, chemotherapy, radiation, surgery and tumor size. The C-index of the predicting OS model in the training dataset and in the test dataset was 0.757 ± 0.006 and 0.764 ± 0.009, respectively. The time-AUCs exceeded 0.8. The DCA curve showed that the nomogram has better clinical value than the TNM staging system. Conclusions: Our study summarized the clinical characteristics and survival probability of LCLC patients, and a visual nomogram was developed to predict the 1-year, 3-year and 5-year OS of LCLC patients. This provides more accurate OS assessments for LCLC patients and helps clinicians make personal management decisions.

Development and performance evaluations of an HER-2 kit.

Objective To develop a kit for detecting human epidermal growth factor receptor 2 (HER-2) in the human body. Methods The HER-2 kit was evaluated based on an automated magnetic particle chemiluminescence platform. The kit was developed using the double antibody sandwich-complexation method. Results The kit showed a linear range of 0.01-800 ng/mL, with a linear R2 of >0.999. The limit of the blank was 0.0039 ng/mL, and the precision at 1.00 ng/mL was 9.4%. The recovery rate at 10.00 ng/mL was 97.81-101.81%. The negative serum reference range was 0-8.23 ng/mL. Conclusions The kit had a wide linear range, high accuracy, good precision, and high sensitivity, indicating that it has good application prospects.

Pentacyclic triterpene oleanolic acid protects against cardiac aging through regulation of mitophagy and mitochondrial integrity.

Advanced aging exhibits altered cardiac geometry and function involving mitochondrial anomaly. Natural compounds display promises in the regulation of cardiac homeostasis via governance of mitochondrial integrity in aging. This study examined the effect of oleanolic acid (OA), a natural pentacyclic triterpenoid with free radical scavenging and P450 cyclooxygenase-regulating properties, on cardiac aging and mechanisms involved with a focus on mitophagy. Young (4-5 month-old) and old (22-24 month-old) mice were treated with OA for 6 weeks prior to assessment of cardiac function, morphology, ultrastructure, mitochondrial integrity, cell death and autophagy. Our data revealed that OA treatment alleviated aging-induced changes in myocardial remodeling (increased heart weight, chamber size, cardiomyocyte area and interstitial fibrosis), contractile function and intracellular Ca2+ handling, apoptosis, necroptosis, inflammation, autophagy and mitophagy (LC3B, p62, TOM20 and FUNDC1 but not BNIP3 and Parkin). OA treatment rescued aging-induced anomalies in mitochondrial ultrastructure (loss of myofilament alignment, swollen mitochondria, increased circularity), mitochondrial biogenesis and O2- production without any notable effect at young age. Interestingly, OA-offered benefit against cardiomyocyte aging was nullified by deletion of the mitophagy receptor FUNDC1 using FUNDC1 knockout mice, denoting an obligatory role for FUNDC1 in OA-elicited preservation of mitophagy. OA reconciled aging-induced changes in E3 ligase MARCH5 but not FBXL2, and failed to affect aging-induced rises in IP3R3. Taken together, our data indicated a beneficial role for OA in attenuating cardiac remodeling and contractile dysfunction in aging through a FUNDC1-mediated mechanism.

Beclin1 Haploinsufficiency accentuates second-hand smoke exposure -induced myocardial Remodeling and contractile dysfunction through a STING-mediated mechanism.

Second-hand smoking evokes inflammation and cardiovascular diseases. Recent evidence has revealed a pivotal role for deranged autophagy in smoke exposure-induced cardiac anomalies. This study evaluated the impact of haploinsufficiency of the mTOR-independent autophagy protein Beclin1 on side-stream smoke exposure-induced cardiac anomalies and mechanism(s) involved. Adult WT and Beclin1 haploinsufficiency (Becn+/-) mice were exposed to cigarette smoke for 1 h daily for 90 days. Echocardiographic, cardiomyocyte function, intracellular Ca2+, autophagy, mitophagy, apoptosis and inflammation were examined. DHE staining was employed to evaluate O2- level. Our data revealed that Beclin1 deficiency exacerbated smoke exposure-induced myocardial anomalies in geometry, fractional shortening, cardiomyocyte function, intracellular Ca2+ handling, TEM ultrastructure, and inflammation along with pronounced apoptosis and O2- production. Side-stream smoke provoked excessive autophagy/mitophagy, mtDNA release, and activation of innate immune response signals cyclic GMP-AMP synthase (cGAS) and its effector - stimulator of interferon genes (STING), the effect was abolished or unaffected by Becn haploinsufficiency. STING phosphorylation was overtly promoted by smoke exposure in Becn+/- mice. Smoke exposure also suppressed phosphorylation of mTOR although it facilitated that of ULK1 in both groups. In vitro data revealed that inhibition of cGAS or STING failed to affect smoke extract-induced mitophagy although they abrogated smoke extract-induced cardiomyocyte dysfunction except cGAS inhibition in Becn+/- mice. These data suggest that Beclin1 is integral in the maintenance of cardiac homeostasis under side-stream smoke exposure via a STING-mediated mechanism.

Distribution of integrons and phylogenetic groups among highly virulent serotypes of Klebsiella pneumoniae in a Chinese tertiary hospital.

OBJECTIVES: This study describes the distribution of integrons and phylogenetic groups among clinical highly virulent serotype (HVS) Klebsiella pneumoniae isolates in a Chinese tertiary hospital. METHODS: Class 1, 2 and 3 integrases were identified by PCR in 90 clinical isolates of HVS K. pneumoniae. Antimicrobial susceptibility was determined by the disk diffusion method. Multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were used to analyse the genotypes of the HVS K. pneumoniae isolates. RESULTS: Serotypes K1, K2, K20, K54 and K57 accounted for 54.5%, 21.1%, 1.1%, 18.9% and 4.4% of the 90 isolates. Among the 50 integron-positive isolates, 48 (96%) and 2 (4%) were classified as having class 1 (intI1) and class 2 (intI2) integrons, respectively. Gene cassettes encoding resistance to trimethoprim (dfr) and aminoglycosides (aac, aad) were found to be predominant in class 1 integrons. In addition, the most prevalent sequence type (ST) among the HVS K. pneumoniae isolates was ST23 (49/90; 54.4%), followed by ST29 (11/90; 12.2%), ST86 (10/90; 11.1%), ST65 (9/90; 10.0%), ST15 (6/90; 6.7%), ST412 (4/90; 4.4%) and ST34 (1/90; 1.1%). CONCLUSION: In summary, a high prevalence of integrons (55.6%) was found among HVS K. pneumoniae isolates in a Chinese tertiary hospital. Class 1 integrons were the most predominant and their variable regions were polymorphic. The presence of integrons in HVS K. pneumoniae isolates results in increased antimicrobial resistance.

The Distribution Pattern of Sediment Archaea Community of the Poyang Lake, the Largest Freshwater Lake in China.

Archaea plays an important role in the global geobiochemical circulation of various environments. However, much less is known about the ecological role of archaea in freshwater lake sediments. Thus, investigating the structure and diversity of archaea community is vital to understand the metabolic processes in freshwater lake ecosystems. In this study, sediment physicochemical properties were combined with the results from 16S rRNA clone library-sequencing to examine the sediment archaea diversity and the environmental factors driving the sediment archaea community structures. Seven sites were chosen from Poyang Lake, including two sites from the main lake body and five sites from the inflow river estuaries. Our results revealed high diverse archaea community in the sediment of Poyang Lake, including Bathyarchaeota (45.5%), Euryarchaeota (43.1%), Woesearchaeota (3.6%), Pacearchaeota (1.7%), Thaumarchaeota (1.4%), suspended Lokiarchaeota (0.7%), Aigarchaeota (0.2%), and Unclassified Archaea (3.8%). The archaea community compositions differed among sites, and sediment property had considerable influence on archaea community structures and distribution, especially total organic carbon (TOC) and metal lead (Pb) (p < 0.05). This study provides primary profile of sediment archaea distribution in freshwater lakes and helps to deepen our understanding of lake sediment microbes.

Cardiac peroxisome proliferator-activated receptor-γ expression is modulated by oxidative stress in acutely infrasound-exposed cardiomyocytes.

The aim of the present study was to examine the effects of acute infrasound exposure on oxidative damage and investigate the underlying mechanisms in rat cardiomyocytes. Neonatal rat cardiomyocytes were cultured and exposed to infrasound for several days. In the study, the expression of CAT, GPx, SOD1, and SOD2 and their activities in rat cardiomyocytes in infrasound exposure groups were significantly decreased compared to those in the various time controls, along with significantly higher levels of O2 (-) and H2O2. Decreased cardiac cell viability was not observed in various time controls. A significant reduction in cardiac cell viability was observed in the infrasound group compared to the control, while significantly increased cardiac cell viability was observed in the infrasound exposure and rosiglitazone pretreatment group. Compared to the control, rosiglitazone significantly upregulated CAT, GPx, SOD1, and SOD2 expression and their activities in rat cardiomyocytes exposed to infrasound, while the levels of O2 (-) or H2O2 were significantly decreased. A potential link between a significant downregulation of PPAR-γ expression in rat cardiomyocytes in the infrasound group was compared to the control and infrasound-induced oxidative stress. These findings indicate that infrasound can induce oxidative damage in rat cardiomyocytes by inactivating PPAR-γ.