Effects of short-term dietary restriction on plasma metabolites and the subcutaneous fat area according to metabolic status in obese individuals: a case-control study.

BACKGROUND: Research elucidating the metabolic mechanisms that differentiate subtypes of obesity has been increasing. We aimed to investigate the effects of a 12-week dietary intervention on the metabolomic profiles of obese subjects. METHODS: Subjects followed a 12-week dietary restriction protocol consisting of a 300 kcal/day reduction in their usual caloric intake. Twenty-nine obese subjects were included and divided into two groups: the metabolic status maintenance group (n = 17, controls) and the metabolic status improvement group (n = 12, tests). We analyzed the somatometric and biochemical parameters and performed ultra-performance liquid chromatography-mass spectrometry analysis of the plasma metabolites. RESULTS: At 12 weeks, the fat percentage, whole fat area (WFA), subcutaneous fat area (SFA) at the L1 vertebra, and the levels of triglycerides, gamma-glutamyltransferase (gamma-GT), and leptin were markedly decreased in the metabolic status improvement group, while the level of high-density lipoprotein cholesterol increased compared with that in the metabolic status maintenance group. Metabolomic profiling at 12 weeks showed substantial differences in 4-aminobutyraldehyde (p = 0.005) and 4'-apo-ß-carotenal (p = 0.024) between the two groups. Furthermore, an AUC value of 0.89 was obtained for the following seven featured biomarkers: triglycerides, gamma-GT, leptin, fat percentage, WFA, and SFA at the L1 vertebra, and 4-aminobutyraldehyde. CONCLUSIONS: We demonstrated that 4-aminobutyraldehyde and related regional fat distribution parameters were strongly associated with obesity according to metabolic status. Thus, these biomarkers are potentially valuable in confirming the efficacy of short-term interventions and predicting metabolic status in obese individuals. TRIALS REGISTRATION: This study was registered at ClinicalTrials.gov under NCT03135132 (registered 1 May 2017-retrospectively registered).

An optimized protocol for patient-derived xenograft in humanized mice to evaluate the role of IL-34 in immunotherapeutic resistance.

Previously, we identified a therapy-resistant role of IL-34 in an immune checkpoint blockade in murine models. To investigate whether a similar mechanism is applicable in human tumors as well, we used this protocol for the selection of IL-34-neutralizing antibody and transplanting human tumor tissue expressing both IL-34 and PD-L1 as a patient-derived xenograft in immunologically humanized mice. This model helps to determine the effect of IL-34 neutralization along with the immune checkpoint blockade in human tumors. For complete details on the use and execution of this protocol, please refer to Hama et al. (2020).

PDX models of human lung squamous cell carcinoma: consideration of factors in preclinical and co-clinical applications.

BACKGROUND: Treatment of human lung squamous cell carcinoma (LUSC) using current targeted therapies is limited because of their diverse somatic mutations without any specific dominant driver mutations. These mutational diversities preventing the use of common targeted therapies or the combination of available therapeutic modalities would require a preclinical animal model of this tumor to acquire improved clinical responses. Patient-derived xenograft (PDX) models have been recognized as a potentially useful preclinical model for personalized precision medicine. However, whether the use of LUSC PDX models would be appropriate enough for clinical application is still controversial. METHODS: In the process of developing PDX models from Korean patients with LUSC, the authors investigated the factors influencing the successful initial engraftment of tumors in NOD scid gamma mice and the retainability of the pathological and genomic characteristics of the parental patient tumors in PDX tumors. CONCLUSIONS: The authors have developed 62 LUSC PDX models that retained the pathological and genomic features of parental patient tumors, which could be used in preclinical and co-clinical studies. Trial registration Tumor samples were obtained from 139 patients with LUSC between November 2014 and January 2019. All the patients provided signed informed consents. This study was approved by the institutional review board (IRB) of Samsung Medical Center (2018-03-110).

[Distal Ileal Lymphoma Presenting Ileocecal Intussusception with Spontaneous Reduction].

Intussusception is a rare disease in adults. A demonstrable etiology is found in approximately 85% of all cases, and approximately 40% of them are caused by malignant tumors. A 65-year-old patient visited the outpatient department with mild abdominal pain without other symptoms. The initial laboratory test and simple X-ray showed normal findings. CT revealed intussusception in the ileocecal area. The initial colonoscopic biopsy revealed atypical cells. Follow up colonoscopy showed spontaneous reduction of the intussusception. Diffuse large B-cell lymphoma was suspected in the second colonoscopic biopsy. An elective operation was performed. This case reports a case of a spontaneous reduction of adult intussusception with a brief review of literature.

Outcomes of Acute Myocardial Infarction Patients Implanted With Biodegradable Polymer Biolimus-Eluting Stents Versus New-Generation Durable Polymer Drug-Eluting Stents: A Retrospective Analysis.

We compared outcomes between biodegradable polymer biolimus-eluting stent (BP-BES) and new-generation durable polymer drug-eluting stent (DP-DES) implantations in patients with acute myocardial infarction (MI). Among 13472 patients with acute MI in a nationwide registry, 557 (64.8%) were in the BP-BES and 303 (35.2%) in the new-generation DP-DES group following coronary reperfusion. The occurrence of major adverse cardiac events (MACE; death, MI, revascularization) and stent thrombosis was compared. Major adverse cardiac events occurred in 53 (6.2%) patients and showed similar rates between the BP-BES and new-generation DP-DES groups (all: 6.6% vs 5.9%, P = .652; propensity score [PS] matched: n = 380, 6.3% vs 5.3%, P = .623). Stent thrombosis did not differ between groups (all: 0.3% vs 0.4%, P = .892; PS matched: 0.5% vs 0.5%, P = 1.000). Major adverse cardiac event-free survival was comparable between groups (all: 93.4% vs 94.1%, log-rank P = .357; PS matched: 93.7% vs 94.7%, log-rank P = .445). Biodegradable polymer biolimus-eluting stent was not associated with MACE (all: hazard ratio [HR], 1.67; 95% confidence interval [CI], 0.75-3.74; P = 0.212; PS matched: HR, 1.05; 95% CI, 0.40-2.75; P = .915). In conclusion, in patients with acute MI, BP-BES was equivalent to the new-generation DP-DES in terms of outcomes.

Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma.

CTLA4 and CD28 are co-regulatory receptors with opposite roles in T-cell signaling. By RNA sequencing, we identified a fusion between the two genes from partial gene duplication in a case of angioimmunoblastic T-cell lymphoma. The fusion gene, which codes for the extracellular domain of CTLA4 and the cytoplasmic region of CD28, is likely capable of transforming inhibitory signals into stimulatory signals for T-cell activation. Ectopic expression of the fusion transcript in Jurkat and H9 cells resulted in enhanced proliferation and AKT and ERK phosphorylation, indicating activation of downstream oncogenic pathways. To estimate the frequency of this gene fusion in mature T-cell lymphomas, we examined 115 T-cell lymphoma samples of diverse subtypes using reverse transcriptase polymerase chain reaction analysis and Sanger sequencing. We identified the fusion in 26 of 45 cases of angioimmunoblastic T-cell lymphomas (58%), nine of 39 peripheral T-cell lymphomas, not otherwise specified (23%), and nine of 31 extranodal NK/T cell lymphomas (29%). We further investigated the mutation status of 70 lymphoma-associated genes using ultra-deep targeted resequencing for 74 mature T-cell lymphoma samples. The mutational landscape we obtained suggests that T-cell lymphoma results from diverse combinations of multiple gene mutations. The CTLA4-CD28 gene fusion is likely a major contributor to the pathogenesis of T-cell lymphomas and represents a potential target for anti-CTLA4 cancer immunotherapy.

Comparison of transradial and transfemoral coronary intervention in octogenarians with acute myocardial infarction.

BACKGROUND: The transradial (TR) approach for percutaneous coronary intervention (PCI) is challenging and associated with failure in elderly patients. We compared the TR and transfemoral (TF) approaches in patients>80 years with acute myocardial infarction (MI) undergoing PCI. METHODS: A total of 1945 (7.2%) octogenarians were enrolled from among 27,129 patients in the Korea Acute Myocardial Infarction Registry. The TR group (n=336, 17.3%) was compared with the TF group (n=1609, 82.7%) in the overall and propensity-matched cohorts with respect to procedural success, complications, in-hospital mortality, and one-year mortality and total major adverse cardiac event (MACE; death, MI, and revascularization) rate. RESULTS: In the overall cohort, the TR group had lower incidence of Killip class III or IV compared to the TF group. The disease extent and lesion severity were similar between groups, as was the procedural success rate (97.7% vs. 98.3%); however, in-hospital complications were significantly lower in the TR group (8.1% vs. 20.3%). In-hospital mortality was significantly lower in the TR group than the TF group (3.4% vs. 11.4%), as were the one-year mortality and total MACE (9.8% vs. 18.4% and 13% vs. 21.9%, respectively). These outcomes were consistent in the propensity-matched cohort. The TR approach was found to be a significant predictor of low in-hospital mortality (OR 0.355, 95% CI 0.139-0.907), but not of one-year mortality (OR 0.644, 95% CI 0.334-1.240). CONCLUSIONS: In octogenarians with acute MI undergoing PCI, the TR approach was more effective than the TF approach as it had lower complication rate and better clinical outcomes with comparable procedural success.

Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma.

PURPOSE: To better understand the complete genomic architecture of lung adenocarcinoma. EXPERIMENTAL DESIGN: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes. RESULTS: We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma. CONCLUSIONS: Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients.

Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification.

UNLABELLED: Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). CONCLUSION: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.

False-positive radioiodine uptake in a functional ovarian cyst in a patient treated with total thyroidectomy for papillary cancer.

False positive radioiodine uptake following thyroidectomy for differentiated thyroid cancer has been reported in some cases. A 42-year-old woman was referred for ablative radioiodine treatment six weeks after undergoing total thyroidectomy for papillary thyroid carcinoma. Posttherapeutic I-131 scintigraphy showed an intense hot spot in the left pelvis. Pelvic computed tomography (CT) revealed a benign left ovarian mass such as a functional cyst. After menstruation, ultrasonographic imaging demonstrated a shrunken ovarian mass. Therefore, we diagnosed the patient with a functional cyst that was influenced by hormonal fluctuation. It is believed that this is the first case of false-positive radioiodine uptake in a functional ovarian cyst.

A case of squamous metaplasia of the stomach.

Intestinal metaplasia of the stomach is a common metaplastic lesion associated with chronic gastritis and mucosal atrophy. However, squamous metaplasia is a comparatively rare condition. On endoscopy, squamous metaplasia is usually observed as a whitish mucosal lesion in the lesser curvature of the cardiac region of the stomach. When Lugol's iodine solution is applied, the lesion stains brown in the same way as normal esophageal mucosa. We report a case of 79-year-old man with a whitish flat lesion in the lesser curvature of the cardiac region on surveillance endoscopy after endoscopic treatment of gastric adenoma. The endoscopic biopsy showed stratified squamous epithelial mucosa.

Association of polymorphisms in genes encoding IL-4, IL-13 and their receptors with atopic dermatitis in a Korean population.

Th2-dominated immune responses are believed to contribute to the pathogenesis of atopic dermatitis (AD). IL-4 and IL-13 are typical pleiotropic Th2 cytokines that play a central role in IgE-dependent inflammatory reactions. Single-nucleotide polymorphisms (SNPs) in IL-4 and IL-13 have been reported in patients with allergic disease from numerous countries. Gene-gene interactions among genes have been identified in patients with asthma, although negative results have been reported. To investigate the associations of SNPs in these genes and the interactions between these genes in AD, we genotyped 23 SNPs of the IL-4, IL-13, IL-4R, IL-13Rα1 and IL-13Rα2 genes for 1089 case-control samples (631 AD patients and 458 controls) and analysed the SNPs and haplotypes in these genes. We also searched for gene-gene interactions among these five genes. Our data identified an association between rs3091307 and rs20541 in the IL-13 gene and between rs2265753 and rs2254672 in the IL-13Rα1 gene and the AD phenotype. In particular, three of the four SNPs were especially predictive of the allergic type of AD (ADe), and the haplotype TCGG in the IL-13Rα1 gene showed significant association with AD, especially ADe. Furthermore, the combination of rs3091307 GG/ rs2265753 GG (IL-13/IL-13Rα1) conveyed a significantly higher risk for developing ADe. However, we did not identify any SNPs in the IL-4, IL-4R and IL-13Rα2 genes that were associated with AD. As IL-13Rα1 is most likely expressed in Th17 cells rather than in Th2 cells, these data suggest diversity in the classification of Th cells that needs to be verified in future studies.

Carriage of the V279F null allele within the gene encoding Lp-PLA2 is protective from coronary artery disease in South Korean males.

BACKGROUND: The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA2) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA2 in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted. METHODOLOGY/PRINCIPAL FINDINGS: PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA2 activity and CAD risk. CONCLUSIONS: Natural deficiency in Lp-PLA2 activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA2 and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.

An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population.

BACKGROUND: The genes encoding IL-9 and IL-9R have recently been implicated in the genetic basis of asthma and allergy. Although studies performed on transgenic and knockout mice have shown conflicting results, no evidence of skin changes has ever been reported in these animals. OBJECTIVE: To find association of the SNPs in IL-9 and IL-9R genes and interaction of these genes in atopic dermatitis. METHOD: We genotyped 5 SNPs from the IL-9 and IL-9R genes of 1090 subject samples (631 AD patients and 459 normal controls). A luciferase assay was then performed for the rs31563 (-4091G/A) SNP located in the IL-9 gene promoter region. RESULT: The rs31563 (-4091G/A) SNP in the IL-9 gene was significantly associated with the AD phenotype, especially allergic-type AD. In the luciferase assay, the rs31563 G construct was observed to have 1.54 times higher activity than the rs31563 A construct. Although no association was found between SNPs in IL-9R gene and AD, the rs3093467 SNP showed association with non-allergic AD. In the gene-gene interaction analysis, we found that IL-9/IL-9R genotype rs31563 GG/rs3093467 TT conveyed a greater risk for AD phenotype development. CONCLUSION: Significant evidence exists to suggest that the rs31563 SNP (-4091G/A) located in the IL-9 gene is associated with an increased susceptibility to AD. Similarly, the rs3093467 SNP in IL-9R gene seems to be associated with an increased risk for developing non-allergic AD. In a subsequent gene-gene interaction analysis, the rs31563 GG/rs3093467 TT genotype combination (IL-9/IL-9R) was found to exert a synergistic effect in the development of the AD phenotype. As the classes of helper T cells are diverse and the function of IL-9 cytokine has not been fully described, the cutaneous function of IL-9 needs to be further explored in future studies.

Genome-wide association analysis and replication of coronary artery disease in South Korea suggests a causal variant common to diverse populations.

BACKGROUND: Recent genome-wide association (GWA) studies have identified and replicated several genetic loci associated with the risk of development of coronary artery disease (CAD) in samples from populations of Caucasian and Asian descent. However, only chromosome 9p21 has been confirmed as a major susceptibility locus conferring risk for development of CAD across multiple ethnic groups. The authors aimed to find evidence of further similarities and differences in genetic risk of CAD between Korean and other populations. METHODS: The authors performed a GWA study comprising 230 cases and 290 controls from a Korean population typed on 490 032 single nucleotide polymorphisms (SNPs). A total of 3148 SNPs were taken forward for genotyping in a subsequent replication study using an independent sample of 1172 cases and 1087 controls from the same population. RESULTS: The association previously observed on chromosome 9p21 was independently replicated (p=3.08e-07). Within this region, the same risk haplotype was observed in samples from both Korea and of Western European descent, suggesting that the causal mutation carried on this background occurred on a single ancestral allele. Other than 9p21, the authors were unable to replicate any of the previously reported signals for association with CAD. Furthermore, no evidence of association was found at chromosome 1q41 for risk of myocardial infarction, previously identified as conferring risk in a Japanese population. CONCLUSION: A common causal variant is likely to be responsible for risk of CAD in Korean and Western European populations at chromosome 9p21.3. Further investigations are required to confirm non-replication of any other cross-race genetic risk factors.

A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits.

To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 x 10(-9)) and 6q22 (rs12110693, P = 1.6 x 10(-9)), with the latter approximately 400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 x 10(-7)). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 x 10(-12)) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we identified two loci influencing bone mineral density at multiple sites. On chromosome 7q31, rs7776725 (within the FAM3C gene) was associated with bone density at the radius (P = 1.0 x 10(-11)), tibia (P = 1.6 x 10(-6)) and heel (P = 1.9 x 10(-10)). On chromosome 7p14, rs1721400 (mapping close to SFRP4, a frizzled protein gene) showed consistent associations at the same three sites (P = 2.2 x 10(-3), P = 1.4 x 10(-7) and P = 6.0 x 10(-4), respectively). This large-scale GWA analysis of well-characterized Korean population-based samples highlights previously unknown biological pathways.

Fine-scale map of encyclopedia of DNA elements regions in the Korean population.

The International HapMap Project aims to generate detailed human genome variation maps by densely genotyping single-nucleotide polymorphisms (SNPs) in CEPH, Chinese, Japanese, and Yoruba samples. This will undoubtedly become an important facility for genetic studies of diseases and complex traits in the four populations. To address how the genetic information contained in such variation maps is transferable to other populations, the Korean government, industries, and academics have launched the Korean HapMap project to genotype high-density Encyclopedia of DNA Elements (ENCODE) regions in 90 Korean individuals. Here we show that the LD pattern, block structure, haplotype diversity, and recombination rate are highly concordant between Korean and the two HapMap Asian samples, particularly Japanese. The availability of information from both Chinese and Japanese samples helps to predict more accurately the possible performance of HapMap markers in Korean disease-gene studies. Tagging SNPs selected from the two HapMap Asian maps, especially the Japanese map, were shown to be very effective for Korean samples. These results demonstrate that the HapMap variation maps are robust in related populations and will serve as an important resource for the studies of the Korean population in particular.