Structure-based classification predicts drug response in EGFR-mutant NSCLC.

Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)1-3. Targeted therapies are approved for patients with 'classical' mutations and a small number of other mutations4-6. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7-10. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.

Cathepsin G promotes arteriovenous fistula maturation by positively regulating the MMP2/MMP9 pathway.

BACKGROUND: Arteriovenous fistula (AVF) is currently the preferred vascular access for hemodialysis patients. However, the low maturation rate of AVF severely affects its use in patients. A more comprehensive understanding and study of the mechanisms of AVF maturation is urgently needed. METHODS AND RESULTS: In this study, we downloaded the publicly available datasets (GSE119296 and GSE220796) from the Gene Expression Omnibus (GEO) and merged them for subsequent analysis. We screened 84 differentially expressed genes (DEGs) and performed the functional enrichment analysis. Next, we integrated the results obtained from the degree algorithm provided by the Cytohubba plug-in, Molecular complex detection (MCODE) plug-in, weighted gene correlation network analysis (WGCNA), and Least absolute shrinkage and selection operator (LASSO) logistic regression. This integration allowed us to identify CTSG as a hub gene associated with AVF maturation. Through the literature search and Pearson's correlation analysis, the genes matrix metalloproteinase 2 (MMP2) and MMP9 were identified as potential downstream effectors of CTSG. We then collected three immature clinical AVF vein samples and three mature samples and validated the expression of CTSG using immunohistochemistry (IHC) and double-immunofluorescence staining. The IHC results demonstrated a significant decrease in CTSG expression levels in the immature AVF vein samples compared to the mature samples. The results of double-immunofluorescence staining revealed that CTSG was expressed in both the intima and media of AVF veins. Moreover, the expression of CTSG in vascular smooth muscle cells (VSMCs) was significantly higher in the mature samples compared to the immature samples. The results of Masson's trichrome and collagen I IHC staining demonstrated a higher extent of collagen deposition in the media of immature AVF veins compared to the mature. By constructing an in vitro CTSG overexpression model in VSMCs, we found that CTSG upregulated the expression of MMP2 and MMP9 while downregulating the expression of collagen I and collagen III. Furthermore, CTSG was found to inhibit VSMC migration. CONCLUSIONS: CTSG may promote AVF maturation by stimulating the secretion of MMP2 and MMP9 from VSMCs and reducing the extent of medial fibrosis in AVF veins by inhibiting the secretion of collagen I and collagen III.

Identification and validation of leukemia inhibitory factor as a protective factor in ischemic acute kidney injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a common pathophysiological mechanism of acute kidney injury (AKI). There is an urgent need for a more comprehensive analysis of its underlying mechanisms. MATERIALS AND METHODS: The RNA-sequencing dataset GSE153625 was used to examine differentially expressed genes (DEGs) of kidney tissues in IRI-AKI mice compared with sham mice. We used 10 algorithms provided by cytohubba plugin and four external datasets (GSE192532, GSE52004, GSE98622, and GSE185383) to screen for hub genes. The IRI-AKI mouse model with different reperfusion times was established to validate the expression of hub gene in the kidneys. HK-2 cells were cultured in vitro under hypoxia/reoxygenation (H/R) conditions, via transfection with si-LIF or supplementation with the LIF protein to explore the function of the LIF gene. RESULTS: We screened a total of 1,540 DEGs in the IRI group compared with the sham group and identified that the LIF hub gene may play potential roles in IRI-AKI. LIF was markedly upregulated in the kidney tissues of IRI-AKI mice, as well as in HK-2 cells grown under H/R conditions. The knockdown of LIF aggravated apoptosis and oxidative stress (OS) injury under H/R conditions. Administration of the LIF protein rescued the effects of si-LIF, alleviating cellular apoptosis and OS. CONCLUSION: These findings indicate an important role of the LIF gene in term of regulating apoptosis and OS in the early phases of IRI-AKI. Targeting LIF may therefore represent a promising therapeutic strategy for IRI-AKI.

Dietary lycopene is negatively associated with abdominal aortic calcification in US adults: a cross-sectional study.

BACKGROUND: Vascular calcification (VC) is one of the complications of chronic kidney disease (CKD) patients. Previous studies have confirmed that oxidative stress (OS) plays an important role in developing VC and that antioxidants have anti-VC effects. OBJECTIVES: Our study aimed to determine the relationship between the intake of antioxidants from dietary sources and the prevalence of VC, especially in the CKD population. METHODS: This cross-sectional study analyzed population-based data from the National Health and Nutrition Examination Survey (NHANES; 2013-2014). Participants were noninstitutionalized adults >40 years of age. Diet-derived antioxidants were obtained from the first 24-h dietary recall interviews. The abdominal aortic calcification (AAC) score was measured by a DXA scan. We divided the AAC scores into three groups: no calcification (AAC =0), mild to moderate calcification (0< AAC ≤6), and severe calcification (AAC >6). RESULTS: A total of 2897 participants were included in the main analysis. Our results showed that vitamin B6, α-tocopherol, and lycopene were associated with severe AAC in unadjusted models (odds ratio (OR): 0.81, 95% confidence interval (CI): 0.72-0.91, p = 0.001; OR: 0.97, 95% CI: 0.95-0.99, p = 0.008; OR: 0.98, 95% CI: 0.96-0.99, p = 0.01, respectively). However, only dietary lycopene was associated with severe AAC after adjusting covariates based on clinical and statistical significance. Per 1 mg higher intake of diet-derived lycopene per day, the odds of having severe AAC were 2% lower in the fully adjusted model (OR: 0.98, 95% CI: 0.95-0.999, p = 0.04). Moreover, in subgroup analysis, diet-derived antioxidant was not associated with AAC in patients with CKD.Our findings indicate that a higher intake of diet-derived lycopene was independently associated with lower odds of having severe AAC in humans. Therefore, a high intake of diet-derived lycopene may help prevent severe AAC.

Dietary lycopene was inversely associated with vascular calcification (VC) in adults.Patients with chronic kidney disease (CKD) have a higher chance of having severe VC.Dietary antioxidants were not significantly associated with VC in patients with CKD.

Transcriptome Analysis of Protocatechualdehyde against Listeria monocytogenes and Its Effect on Chicken Quality Characteristics.

The development of natural antimicrobial agents offers new strategies for food preservation due to the health hazards associated with the spoilage of meat products caused by microbial contamination. In this paper, the inhibitory mechanism of protocatechualdehyde (PCA) on Listeria monocytogenes was described, and its effect on the preservation of cooked chicken breast was evaluated. The results showed that the minimal inhibitory concentration (MIC) of PCA on L. monocytogenes was 0.625 mg/mL. Secondly, PCA destroyed the integrity of the L. monocytogenes cell membrane, which was manifested as a decrease in membrane hyperpolarization, intracellular ATP level, and intracellular pH value. Field emission gun scanning electron microscopy (FEG-SEM) observed a cell membrane rupture. Transcriptome analysis showed that PCA may inhibit cell growth by affecting amino acid, nucleotide metabolism, energy metabolism, and the cell membrane of L. monocytogenes. Additionally, it was discovered that PCA enhanced the color and texture of cooked chicken breast meat while decreasing the level of thiobarbituric acid active substance (TBARS). In conclusion, PCA as a natural antibacterial agent has a certain reference value in extending the shelf life of cooked chicken breast.

Prognosis value of EAS index in patients with obstructive coronary artery disease.

Background: EAS index is reported to be an adjunctive tool for risk stratification in addition to left ventricular ejection fraction (LVEF). This study aimed to verify the predictive value of EAS index among coronary artery disease (CAD) patients with different cardiac systolic function levels. Methods: A total of 477 patients with obstructive CAD were included in the exploratory analysis of a prospective cohort between October 2017 and January 2018 at Guangdong Provincial People's Hospital. EAS index, e'/(a' × s'), is a novel parameter assessed by tissue Doppler imaging (TDI) indicating combined diastolic and systolic performance. Any occurrence of major adverse cardiovascular event (MACE) was recorded, including first onset of myocardial infarction, stroke, readmission for heart failure, coronary revascularization, or cardiovascular death that occurred within 6 months of the first admission. Kaplan-Meier survival and Cox regression analyses were applied to testify the predictive value of EAS index for cardiovascular outcome. Results: A total of 415 patients (87.2%) completed the follow-up (median, 25.9 months) and experienced 101 (24.3%) MACEs, 17 (4.0%) deaths, and 139 (33.4%) composite events. Elevated EAS index was significantly associated with a higher incidence of MACE, even after adjustment for age, sex, body mass index, N-terminal pro brain natriuretic peptide, high-sensitivity troponin T, high-density lipoprotein, stenosis degree, and other TDI parameters [Model 3, hazard ratio: 1.81, 95% confidence interval (CI): 1.15-2.85]. For different levels of cardiac function, Kaplan-Meier survival analysis revealed that elevated EAS index was associated with higher MACE incidence only in patients with LVEF ≥50% (P<0.05). Conclusions: EAS index is an independent predictor of MACE in patients with obstructive CAD, which could be utilized as a tool for risk stratification in CAD patients or incorporated into a prediction model to improve efficacy.

Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.