Pan-Cancer Pharmacogenomic Analysis of Patient-Derived Tumor Cells Using Clinically Relevant Drug Exposures.

As a result of tumor heterogeneity and solid cancers harboring multiple molecular defects, precision medicine platforms in oncology are most effective when both genetic and pharmacologic determinants of a tumor are evaluated. Expandable patient-derived xenograft (PDX) mouse tumor and corresponding PDX culture (PDXC) models recapitulate many of the biological and genetic characteristics of the original patient tumor, allowing for a comprehensive pharmacogenomic analysis. Here, the somatic mutations of 23 matched patient tumor and PDX samples encompassing four cancers were first evaluated using next-generation sequencing (NGS). 19 antitumor agents were evaluated across 78 patient-derived tumor cultures using clinically relevant drug exposures. A binarization threshold sensitivity classification determined in culture (PDXC) was used to identify tumors that best respond to drug in vivo (PDX). Using this sensitivity classification, logic models of DNA mutations were developed for 19 antitumor agents to predict drug response. We determined that the concordance of somatic mutations across patient and corresponding PDX samples increased as variant allele frequency increased. Notable individual PDXC responses to specific drugs, as well as lineage-specific drug responses were identified. Robust responses identified in PDXC were recapitulated in vivo in PDX-bearing mice and logic modeling determined somatic gene mutation(s) defining response to specific antitumor agents. In conclusion, combining NGS of primary patient tumors, high-throughput drug screen using clinically relevant doses, and logic modeling, can provide a platform for understanding response to therapeutic drugs targeting cancer.

Current treatments for endometriosis in South Korea: an analysis of nationwide data from 2010 to 2019.

While a wide range of treatments, including medical therapies and surgery, are used to manage endometriosis, the characteristics and treatment status of patients who received these treatments have not been investigated in Korea. This study analyzed the Korean Health Insurance Review & Assessment Service-National Patient Sample (HIRA-NPS) data from 2010 to 2019 with 7530 patients diagnosed with endometriosis. Annual trends in the types of visit and surgery, medication prescriptions and associated costs were investigated. The analysis showed that surgery slightly decreased among the types of utilized healthcare services (2010: 16.3, 2019: 12.7), dienogest prescription rapidly increased due to national health insurance coverage from 2013 (2013: 12.1, 2019: 36.0), and the use of gonadotrophin-releasing hormone analogues decreased (2010: 33.6, 2019: 16.4). There was no significant change in total and outpatient costs per person over time. Regarding endometriosis treatment, conservative treatment mainly based on prescribed medications has been gradually replacing surgery. Particularly, the listing of dienogest for national health insurance coverage might have affected the trend. However, there were no significant changes in terms of total and medication costs per person.

Gene-environment interaction explains a part of missing heritability in human body mass index.

Gene-environment (G×E) interaction could partially explain missing heritability in traits; however, the magnitudes of G×E interaction effects remain unclear. Here, we estimate the heritability of G×E interaction for body mass index (BMI) by subjecting genome-wide interaction study data of 331,282 participants in the UK Biobank to linkage disequilibrium score regression (LDSC) and linkage disequilibrium adjusted kinships-software for estimating SNP heritability from summary statistics (LDAK-SumHer) analyses. Among 14 obesity-related lifestyle factors, MET score, pack years of smoking, and alcohol intake frequency significantly interact with genetic factors in both analyses, accounting for the partial variance of BMI. The G×E interaction heritability (%) and standard error of these factors by LDSC and LDAK-SumHer are as follows: MET score, 0.45% (0.12) and 0.65% (0.24); pack years of smoking, 0.52% (0.13) and 0.93% (0.26); and alcohol intake frequency, 0.32% (0.10) and 0.80% (0.17), respectively. Moreover, these three factors are partially validated for their interactions with genetic factors in other obesity-related traits, including waist circumference, hip circumference, waist-to-hip ratio adjusted with BMI, and body fat percentage. Our results suggest that G×E interaction may partly explain the missing heritability in BMI, and two G×E interaction loci identified could help in understanding the genetic architecture of obesity.

Smoking-Interaction Loci Affect Obesity Traits: A Gene-Smoking Stratified Meta-Analysis of 545,131 Europeans.

INTRODUCTION: Although many studies have investigated the association between smoking and obesity, very few have analyzed how obesity traits are affected by interactions between genetic factors and smoking. Here, we aimed to identify the loci that affect obesity traits via smoking status-related interactions in European samples. METHODS: We performed stratified analysis based on the smoking status using both the UK Biobank (UKB) data (N = 334,808) and the Genetic Investigation of ANthropometric Traits (GIANT) data (N = 210,323) to identify gene-smoking interaction for obesity traits. We divided the UKB subjects into two groups, current smokers and nonsmokers, based on the smoking status, and performed genome-wide association study (GWAS) for body mass index (BMI), waist circumference adjusted for BMI (WCadjBMI), and waist-hip ratio adjusted for BMI (WHRadjBMI) in each group. And then we carried out the meta-analysis using both GWAS summary statistics of UKB and GIANT for BMI, WCadjBMI, and WHRadjBMI and computed the stratified p values (pstratified) based on the differences between meta-analyzed estimated beta coefficients with standard errors in each group. RESULTS: We identified four genome-wide significant loci in interactions with the smoking status (pstratified < 5 × 10-8): rs336396 (INPP4B) and rs12899135 (near CHRNB4) for BMI, and rs998584 (near VEGFA) and rs6916318 (near RSPO3) for WHRadjBMI. Moreover, we annotated the biological functions of the SNPs using expression quantitative trait loci (eQTL) and GWAS databases, along with publications, which revealed possible mechanisms underlying the association between the smoking status-related genetic variants and obesity. CONCLUSIONS: Our findings suggest that obesity traits can be modified by the smoking status via interactions with genetic variants through various biological pathways.

Association of BUD13-ZNF259-APOA5-APOA1-SIK3 cluster polymorphism in 11q23.3 and structure of APOA5 with increased plasma triglyceride levels in a Korean population.

In this association study on chromosome 11, the data from 12,537 Korean individuals within the Health Examinee (HEXA) and the Korea Association Resource (KARE) projects were analysed to identify genetic loci correlating with increased and decreased plasma triglyceride (TG) levels. We identified a locus in chromosomal region 11q23.3 that harbours genes BUD13, ZNF259, APOA5, APOA1, and SIK3, which may be associated with plasma TG levels. In this locus, 13 relevant single-nucleotide polymorphisms (SNPs) were found: rs184616707, rs118175510, rs60954647, rs79408961, and rs180373 (near BUD13); rs11604424 (in ZNF259); rs2075291, rs651821, and rs7123666 (in or near APOA5); rs525028 (near APOA1), and rs645258, rs10160754, and rs142395187 (in or near SIK3). All 13 SNPs satisfied the genome-wide significance level (P < 5.0 × 10-8) in both meta-analysis and conditional analysis. Haplotype analysis of six SNPs (rs79408961, rs180373, rs2075291, rs651821, rs525028, and rs10160754) that were selected based on the ß coefficient and conditional P values, revealed nine common haplotypes (with frequency 0.02-0.34) associated with both increased and reduced TG levels. Furthermore, to shed light on possible structural implications, we modelled and simulated the G185C variant of APOA5 (corresponding to rs2075291), which showed the strongest association. Molecular dynamics simulation results showed that this polymorphic variant of APOA5 has a different hydrogen bond network, increased average distance between chains, and an ability to form distinct clusters. Owing to the orientation of cysteine, the possibility of disulphide bond formation with other proteins is evident. In summary, our association and modelling analyses provided evidence that genetic variations in chromosomal region 11q23.3 are associated with elevated TG levels.

Colloid Adenocarcinoma of the Lung: CT and PET/CT Findings in Seven Patients.

OBJECTIVE: We aimed to assess CT and 18F-FDG PET/CT findings of colloid adenocarcinoma of the lung in seven patients. MATERIALS AND METHODS: From 2010 to 2017, seven patients with surgically proven colloid adenocarcinoma of the lung were identified. CT (both enhanced and unenhanced) and PET/CT findings were analyzed, and the imaging features were compared with histopathologic reports. Clinical and demographic features were also analyzed. RESULTS: In all cases except one, tumors showed low attenuation on unenhanced CT scans, ranging in attenuation from -16.5 to 20.7 HU (median, 9.2 HU). After contrast medium injection, enhancement was scant, so net enhancement ranged from 0.4 to 29.0 HU (median, 4.1 HU). All tumors had a lobulated contour. Stippled calcifications within the tumor were seen in one patient. The maximum standardized uptake value of tumors on PET/CT ranged from 1.5 to 4.5 (median, 3.5). In six of seven patients, FDG accumulation was seen in the tumor walls (n = 3, curvilinear uptake) or in both the tumor walls and tumor septa (n = 3, crisscross uptake). Six patients were alive without recurrence after a median follow-up period of 2.3 years (range, 2 months to 5 years). In one patient, who was alive at follow-up 4 years after imaging and had received adjuvant concurrent chemoradiation therapy after lobectomy, recurrent disease was detected 6 months after completion of the therapy. CONCLUSION: On CT, pulmonary colloid adenocarcinomas present as lobulated homogeneously low-attenuation tumors. At PET, curvilinear or crisscross FDG uptake is seen within the tumor where tumor cells are lining the walls or septal structures.

Lower diastolic wall strain is associated with coronary revascularization in patients with stable angina.

BACKGROUND: Left ventricular (LV) diastolic dysfunction occurs earlier in the ischemic cascade than LV systolic dysfunction and electrocardiographic changes. Diastolic wall strain (DWS) has been proposed as a marker of LV diastolic stiffness. Therefore, the objectives of this study were to define the relationship between DWS and coronary revascularization and to evaluate other echocardiographic parameters in patients with stable angina who were undergoing coronary angiography (CAG). METHODS: Four hundred forty patients [mean age: 61 ± 10; 249 (57%) men] undergoing CAG and with normal left ventricular systolic function without regional wall motion abnormalities were enrolled. Among them, 128 (29%) patients underwent revascularization (percutaneous intervention: 117, bypass surgery: 11). All patients underwent echocardiography before CAG and the DWS was defined using posterior wall thickness (PWT) measurements from standard echocardiographic images [DWS = PWT(systole)-PWT(diastole)/PWT(systole)]. RESULTS: Patients who underwent revascularization had a significantly lower DWS than those who did not (0.26 ± 0.08 vs. 0.38 ± 0.09, p < 0.001). Age was comparable between the two groups (61 ± 9 vs. 60 ± 11, p = 0.337), but the proportion of males was significantly higher among patients who underwent revascularization (69 vs. 52%, p = 0.001). The LV ejection fraction was similar but slightly decreased (60.9 ± 5.7 vs. 62.4 ± 6.2%, p = 0.019) and the E/E' ratio was elevated (10.3 ± 4.0 vs. 9.0 ± 3.1, p < 0.001) among patients who underwent revascularization. In multiple regression analysis, lower DWS was an independent predictor of revascularization (cut-off value: 0.34; sensitivity: 89%; AUC: 0.870; SE: 0.025; p < 0.001). CONCLUSION: DWS, a simple parameter that can be calculated from routine 2D echocardiography, is inversely associated with the presence of coronary artery disease and the need for revascularization.

Mechanism of Cisplatin-Induced Cytotoxicity Is Correlated to Impaired Metabolism Due to Mitochondrial ROS Generation.

The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS) that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player.

Higher levels of adiponectin in vascular endothelial cells are associated with greater brachial artery flow-mediated dilation in older adults.

Adiponectin, an adipocyte-derived protein, exerts anti-atherosclerotic effects on the vascular endothelium. Recently adiponectin protein has been reported in murine vascular endothelial cells, however, whether adiponectin is present in human vascular endothelial cells remains unexplored. We sought to examine 1) adiponectin protein in vascular endothelial cells collected from older adults free of overt cardiovascular disease; 2) the relation between endothelial cell adiponectin and in vivo vascular endothelial function; and 3) the relation between endothelial cell adiponectin, circulating (plasma) adiponectin and related factors. We measured vascular endothelial function (brachial artery flow-mediated dilation using ultrasonography), vascular endothelial cell adiponectin (biopsy coupled with quantitative immunofluorescence) and circulating adiponectin (Mercodia, ELISA) in older, sedentary, non-smoking, men and women (55-79 years). We found that higher endothelial cell adiponectin was related with greater flow-mediated dilation (r = 0.43, P < 0.05) and greater flow-mediated dilation normalized for shear stress (r = 0.56, P < 0.01), but was not related with vascular smooth muscle responsiveness to nitric oxide (r = 0.04, P = 0.9). Vascular endothelial cell adiponectin was not related with circulating adiponectin (r = -0.14, P = 0.6). Endothelial cell and circulating adiponectin were differentially associated with adiposity, metabolic and other factors, but both were inversely associated with renal function (r = 0.44 to 0.62, P ≤ 0.04). In conclusion, higher endothelial cell adiponectin levels are associated with higher vascular endothelial function, independent of circulating adiponectin levels in older adults.

Gonadotropin-releasing hormone stimulation test for precocious puberty.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard to identify central precocious puberty (CPP). This test requires multiple blood samples at different time points to measure gonadotropin levels, and is therefore expensive, time-consuming, and uncomfortable for patients. We aimed to simplify the GnRH stimulation test to require fewer blood samples. METHODS: A study of 166 girls with precocious puberty was undertaken. Blood samples were obtained at 0, 15, 30, 45, 60, 90, and 120 min after GnRH administration, and the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. For each parameter, the sensitivities and specificities were estimated and ROC curves were constructed. RESULTS: One hundred and twenty-eight patients (77.1%) were diagnosed for CPP. Peak LH levels were achieved 30 min after GnRH stimulation in patients with CPP. Further, 98.4% of the 45-min samples were diagnostic for CPP, and the cumulative frequency of LH values of ≥5 IU/L was 100% at 45 min. Using this cut-off value for LH, the ROC curve for LH at 45 min showed the highest sensitivity (98.4%) and specificity (100%) in the diagnosis of CPP. CONCLUSIONS: Values of LH measured from a single blood sample obtained at 45 min in the GnRH stimulation test may be adequate for the diagnosis of CPP. Two samples, taken at 30 and 45 min after stimulation, were able to accurately diagnose CPP in 100% of the patients in this study.