Epithelial-mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer.

BACKGROUND: We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy. METHODS: PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed. RESULTS: RNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-ß (TGFß). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFß production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration. CONCLUSIONS: Tumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.

Advancing COVID-19 Diagnosis: Enhancement in SERS-PCR with 30-nm Au Nanoparticle-Internalized Nanodimpled Substrates.

Real-time polymerase chain reaction (RT-PCR) with fluorescence detection is the gold standard for diagnosing coronavirus disease 2019 (COVID-19) However, the fluorescence detection in RT-PCR requires multiple amplification steps when the initial deoxyribonucleic acid (DNA) concentration is low. Therefore, this study has developed a highly sensitive surface-enhanced Raman scattering-based PCR (SERS-PCR) assay platform using the gold nanoparticle (AuNP)-internalized gold nanodimpled substrate (AuNDS) plasmonic platform. By comparing different sizes of AuNPs, it is observed that using 30 nm AuNPs improves the detection limit by approximately ten times compared to 70 nm AuNPs. Finite-difference time-domain (FDTD) simulations show that multiple hotspots are formed between AuNPs and the cavity surface and between AuNPs when 30 nm AuNPs are internalized in the cavity, generating a strong electric field. With this 30 nm AuNPs-AuNDS SERS platform, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA)-dependent RNA polymerase (RdRp) can be detected in only six amplification cycles, significantly improving over the 25 cycles required for RT-PCR. These findings pave the way for an amplification-free molecular diagnostic system based on SERS.

A randomized Phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation.

BACKGROUND: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: This is an open-label, multicenter, randomized Phase 2 study in South Korea. Chemonaïve patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. RESULTS: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty-nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression-free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51-1.08; p = .119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31-0.95; p = .032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. CONCLUSIONS: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. PLAIN LANGUAGE SUMMARY: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression-free survival compared with the erlotinib alone. However, the progression-free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects.

Immune microenvironment and lymph node yield in colorectal cancer.

BACKGROUND: Lymph node (LN) harvesting is associated with outcomes in colonic cancer. We sought to interrogate whether a distinctive immune milieu of the primary tumour is associated with LN yield. METHODS: A total of 926 treatment-naive patients with colorectal adenocarcinoma with more than 12 LNs (LN-high) were compared with patients with 12 or fewer LNs (LN-low). We performed immunohistochemistry and quantification on tissue microarrays for HLA class I/II proteins, beta-2-microglobulin (B2MG), CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. RESULTS: The LN-high group was comprised of younger patients, longer resections, larger tumours, right-sided location, and tumours with deficient mismatch repair (dMMR). The tumour microenvironment showed higher CD8+ cells infiltration and B2MG expression on tumour cells in the LN-high group compared to the LN-low group. The estimated mean disease-specific survival was higher in the LN-high group than LN-low group. On multivariate analysis for prognosis, LN yield, CD8+ cells, extramural venous invasion, perineural invasion, and AJCC stage were independent prognostic factors. CONCLUSION: Our findings corroborate that higher LN yield is associated with a survival benefit. LN yield is associated with an immune high microenvironment, suggesting that tumour immune milieu influences the LN yield.

COVID-19 vaccine refusal associated with health literacy: findings from a population-based survey in Korea.

BACKGROUND: Poor health literacy is associated with lower utilization of preventable services. However, the relationship between health literacy and COVID-19 vaccine hesitancy remains controvertible. METHODS: This study used data from 229,242 individuals who completed the Community Health Survey in Korea from August 16 to October 31 in 2021. To operationalize COVID-19 vaccine hesitancy, we measured vaccine refusal, which is defined as not having been vaccinated and not intending to get vaccinated against COVID-19. Health literacy is operationalized in two dimensions; the ability to understand spoken directions from health professionals and the ability to understand written information regarding health. Covariates include sex, age, educational level, marital status, employment status, basic living security pension status, and subjective health status. Two multivariable logistic regression models were run to determine factors associated with COVID-19 vaccine refusal. Model 1 included sociodemographic characteristics and subjective health status. Model 2 added two health literacy variables. Odds ratio (OR) and 95% confidence intervals (CI) were calculated. RESULTS: Only 3.9% of the Korean adult population were estimated to refuse COVID-19 vaccine. The most commonly cited reasons for COVID-19 vaccine refusal were concerns about vaccine adverse events (47.6%), followed by the assessment of one's own health status (29.5%). Individuals who found spoken directions very difficult to understand were more likely to refuse COVID-19 vaccine than those who found spoken directions very easy (OR = 1.55, 95% CI: 1.28-1.87, p < 0.001). People who did not pay attention to written information were more likely to refuse COVID-19 vaccine than those who reported it to be very easy to understand (OR = 1.28, 95% CI: 1.13-1.45, p < 0.001). People in all other categories of the literacy spectrum for either spoken or written information did not have an increased risk of COVID-19 vaccine refusal. CONCLUSION: Health literacy was significantly associated with COVID-19 vaccine refusal. Health literacy programs could be beneficial to reduce vaccine refusal, particularly for the people who find spoken directions from health professionals very difficult to understand and those who do not pay attention to written information.

Clinical, pathological genetics and intratumoral immune milieu of serrated adenocarcinoma of the colon.

BACKGROUND: Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end-product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations. MATERIALS AND METHODS: We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD-L1 and BRAF V600E. RESULTS: We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8-positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD-L1 expression on tumour cells and no difference in PD-L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease-specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non-mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04). CONCLUSION: SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu.

Interior Hotspot Engineering in Ag-Au Bimetallic Nanocomposites by In Situ Galvanic Replacement Reaction for Rapid and Sensitive Surface-Enhanced Raman Spectroscopy Detection.

Engineering of interior hotspots provides a paradigm shift from traditional surface-enhanced Raman spectroscopy (SERS), in which the detection sensitivity depends on the positioning of adsorbed molecules. In the present work, we developed an Ag-Au bimetallic nanocomposite (SGBMNC) SERS platform with interior hotspots through facile chemical syntheses. Ag nanoparticles replaced by Au via the galvanic replacement reaction (GRR) provided hotspot regions inside the SGBMNC that remarkably enhanced the plasmonic activity compared to the conventional SERS platforms without the internal hotspots. The diffusion of analytes into the proposed interior hotspots during the GRR process enabled sensitive detections within 10 s. The SERS behaviors of the SGBMNC platform were investigated using methylene blue (MB) as a Raman probe dye. A quantitative study revealed excellent detection performance, with a limit of detection (LOD) of 42 pM for MB dye and a highly linear correlation between peak intensity and concentration (R2 ≥ 0.91). The SGBMNC platform also enabled the detection of toxic benzyl butyl phthalate with a sufficient LOD of 0.09 ppb (i.e., 280 pM). Therefore, we believe that the proposed methodology can be used for SERS assays of hazardous materials in practical fields.

Hydrogel-Assisted 3D Volumetric Hotspot for Sensitive Detection by Surface-Enhanced Raman Spectroscopy.

Effective hotspot engineering with facile and cost-effective fabrication procedures is critical for the practical application of surface-enhanced Raman spectroscopy (SERS). We propose a SERS substrate composed of a metal film over polyimide nanopillars (MFPNs) with three-dimensional (3D) volumetric hotspots for this purpose. The 3D MFPNs were fabricated through a two-step process of maskless plasma etching and hydrogel encapsulation. The probe molecules dispersed in solution were highly concentrated in the 3D hydrogel networks, which provided a further enhancement of the SERS signals. SERS performance parameters such as the SERS enhancement factor, limit-of-detection, and signal reproducibility were investigated with Cyanine5 (Cy5) acid Raman dye solutions and were compared with those of hydrogel-free MFPNs with two-dimensional hotspots. The hydrogel-coated MFPNs enabled the reliable detection of Cy5 acid, even when the Cy5 concentration was as low as 100 pM. We believe that the 3D volumetric hotspots created by introducing a hydrogel layer onto plasmonic nanostructures demonstrate excellent potential for the sensitive and reproducible detection of toxic and hazardous molecules.

Direct comparison with terahertz metamaterials and surface-enhanced Raman scattering in a molecular-specific sensing performance.

Signal enhancement of spectroscopies including terahertz time-domain spectroscopy (THz-TDS) and surface-enhanced Raman scattering (SERS) is a critical issue for effective molecular detection and identification. In this study, the sensing performance between THz-TDS and SERS individually accompanied by the proper plasmonic subwavelength structures was compared. For the precisely quantitative study on the optical properties of rhodamine 6G (R6G) dyes, SERS incorporates with the non-linearly enhanced Raman emissions at the molecular characteristic peaks while THz-TDS refers to the transmittance change and the shift of the spectral resonance. The local molecular density-dependent trade-off relationship between limit-of-detection and quenching was observed from both measurements. The specificity for two samples, R6G and methylene blue, is determined by the discriminations in spectral features such as the intensity ratio of assigned peaks in SERS and transmittance difference in THz-TDS. The comprehension of field enhancement by the specific nanostructures was supported by the finite-element method-based numerical computations. As a result, both spectroscopic techniques with the well-tailored nanostructures show great potential for highly sensitive, reproducible, label-free, and cost-effective diagnosis tools in the biomedical fields.

Sensitive and non-invasive cholesterol determination in saliva via optimization of enzyme loading and platinum nano-cluster composition.

An excessive cholesterol level can lead to cardiovascular diseases, such as stroke, hypertension, and myocardial infarction. A non-invasive, painless method of determining the cholesterol level in blood would improve the user's convenience. To provide rapid and accurate determination of cholesterol, we have developed a simple, disposable, enzyme-based electrochemical biosensor that can detect salivary cholesterol. It is possible to detect low concentrations of cholesterol in saliva using the optimized vertical structure of the platinum nano-cluster (Pt-NC) and the immobilization of a proper volume of an enzyme. The biosensor exhibited a linear range from 2 to 486 µM, the limit of detection was about 2 µM, and the sensitivity of the sensor was calculated to be 132 µA mM-1 cm-2. It also showed good specificity for ascorbic acid, uric acid, dopamine, glucose, and lactate. In a test with an actual sample, the performance of the biosensor was confirmed by measuring total cholesterol in the saliva of a patient with hyperlipidemia. The cholesterol levels measured in the saliva of three patients with hyperlipidemia were 520, 460, and 290 µM. Therefore, the Pt-NC based enzyme sensor is a promising candidate for the detection of cholesterol in human saliva.

Incident cardiovascular disease and particulate matter air pollution in South Korea using a population-based and nationwide cohort of 0.2 million adults.

BACKGROUND: While many studies reported the association between long-term exposure to particulate matter air pollution (PM) and cardiovascular disease (CVD), few studies focused on incidence with relatively high-dose exposure using a nationwide cohort. This study aimed to investigate the association between long-term exposure to PM10 and PM2.5 and incidence of CVD in a nationwide and population-based cohort in South Korea where the annual average concentration of PM2.5 is above 20 µg/m3. METHODS: We selected 196,167 adults in the National Health Insurance Service-National Sample Cohort (NHIS-NSC) constructed based on the entire South Korean population. Incidence of four CVD subtypes including ischemic heart disease (IHD), myocardial infarction, heart failure, and stroke, and total CVD including all four was identified as the first diagnosis for 2007-2015. To assess individual exposures, we used annually-updated district-level residential addresses and district-specific PM concentrations predicted by a previously developed universal kriging prediction model. We computed individual-level long-term PM concentrations for four exposure windows: previous 1, 3, and 5 year(s) and 5 years before baseline. We applied time-dependent Cox proportional hazards models to estimate hazard ratios (HRs) of incident CVDs per 10 µg/m3 increase in PM10 and PM2.5 after adjusting for individual- and area-level characteristics. RESULTS: During 1,578,846 person-year, there were 33,580 cases of total incident CVD. Average PM10 and PM2.5 concentrations for the previous 5 years were 52.3 and 28.1 µg/m3, respectively. A 10 µg/m3 increase in PM2.5 exposed for the previous 5 years was associated with 4 and 10% increases in the incidence of total CVD (95% confidence interval: 0-9%) and IHD (4-16%), respectively. HRs tended to be higher with earlier exposure for IHD and more recent exposure for stroke. The estimated shape of the concentration-response relationship showed non-linear patterns. We did not find evidence of the association for PM10. CONCLUSIONS: Using a population-based nationwide cohort exposed to relatively high PM concentration, this study confirmed the association between PM2.5 and CVD incidence that was reported in previous studies mostly with low-dose environments. The magnitude and the shape of the association were generally consistent with previous findings.

TumorFusions: an integrative resource for cancer-associated transcript fusions.

Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as a means of validation. We observed that 65% of transcript fusions were associated with a chromosomal alteration, which is annotated in the portal. Other features of the portal include links to SNP array-based copy number levels and mutational patterns, exon and transcript level expressions of the partner genes, and a network-based centrality score for prioritizing functional fusions. Our portal aims to be a broadly applicable and user friendly resource for cancer gene annotation and is publicly available at http://www.tumorfusions.org.

Characteristics of metabolic factors related to arterial stiffness in young and old adults.

It has not been adequately studied which biomarkers for cardiovascular risk indicate changes of atherosclerosis by aging process. The current study aimed to investigate the characteristics of metabolic factors related to arterial stiffness in young and old adults. Our cross-sectional study enrolled 851 healthy young adults and 719 old adults. Metabolic biomarkers included glucose, lipid profiles, and liver enzymes. In young adults, additional biomarkers such as C-reactive protein, apolipoproteins, lipoprotein(a), ferritin, and 25-hydroxycholecalciferol were measured. Arterial stiffness was evaluated by measuring brachial-ankle pulse wave velocity (baPWV). The mean age was 37.8 and 65.1 years old in the young and old groups, respectively. Without adjustment, most parameters were significantly correlated with baPWV in both young and old groups. Mean baPWV was significantly different according to metabolic syndrome (MetS) in both groups (13.1 and 12.1 m/s in the young subjects with and without MetS, respectively; 17.4 and 15.8 m/s, respectively, in the old group). After adjusting for age, sex, and hemodynamic factors, the difference in baPWV according to MetS was significant only in the old group. The relationship between most biomarkers and baPWV was influenced by metabolic disorders such as hypertension and diabetes in old adults. Total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and apolipoprotein B were significant in young group. In conclusion, the metabolic biomarkers related to arterial stiffness were different between young and old adults. Contrary to old adults, TC, LDLC, and apolipoprotein B were independent biomarkers for arterial stiffness in healthy young adults.

Genomic partitioning of growth traits using a high-density single nucleotide polymorphism array in Hanwoo (Korean cattle).

OBJECTIVE: The objective of this study was to characterize the number of loci affecting growth traits and the distribution of single nucleotide polymorphism (SNP) effects on growth traits, and to understand the genetic architecture for growth traits in Hanwoo (Korean cattle) using genome-wide association study (GWAS), genomic partitioning, and hierarchical Bayesian mixture models. METHODS: GWAS: A single-marker regression-based mixed model was used to test the association between SNPs and causal variants. A genotype relationship matrix was fitted as a random effect in this linear mixed model to correct the genetic structure of a sire family. Genomic restricted maximum likelihood and BayesR: A priori information included setting the fixed additive genetic variance to a pre-specified value; the first mixture component was set to zero, the second to 0.0001×σ_g^2, the third 0.001 × σ_g^2, d the fourth to 0.01 × σ_g^2. BayesR fixed a priori information was not more than 1% of the genetic variance for each of the SNPs affecting the mixed distribution. RESULTS: The GWAS revealed common genomic regions of 2 Mb on bovine chromosome 14 (BTA14) and 3 had a moderate effect that may contain causal variants for body weight at 6, 12, 18, and 24 months. This genomic region explained approximately 10% of the variance against total additive genetic variance and body weight heritability at 12, 18, and 24 months. BayesR identified the exact genomic region containing causal SNPs on BTA14, 3, and 22. However, the genetic variance explained by each chromosome or SNP was estimated to be very small compared to the total additive genetic variance. Causal SNPs for growth trait on BTA14 explained only 0.04% to 0.5% of the genetic variance. CONCLUSION: Segregating mutations have a moderate effect on BTA14, 3, and 19; many other loci with small effects on growth traits at different ages were also identified.

Comparison of the Diagnostic Performance of Synthetic Versus Acquired High b-Value (1500 s/mm2 ) Diffusion-Weighted MRI in Women With Breast Cancers.

BACKGROUND: Acquired high b-value (>1000 s/mm2 ) diffusion-weighted imaging (DWI) has its strength in lesion detection. However, it is not easily used, due to a lower signal-to-noise ratio, eddy current distortions, and prolonged acquisition times. Synthetic DWI does not have these disadvantages because it is based on indirect acquisition, calculated in a voxel-wise manner. PURPOSE: To compare the diagnostic performance of synthetic and acquired high b-value (1500 s/mm2 ) DWI in women with breast cancer. STUDY TYPE: Retrospective. POPULATION: A total of 108 patients (median age 49 years [range 32-77]) with 133 breast cancers. FIELD STRENGTH/SEQUENCE: 3T, echo-planar imaging. ASSESSMENT: Three radiologists independently reviewed image sets of both synthetic (S-b1500) and acquired (A-b1500) high b-value DWI. Malignancy confidence of the lesion was scored using a 6-point Likert-type scale. STATISTICAL TEST: Jack-knife alternative free-response receiver-operating characteristic 1 (JAFROC1) analysis was used. Sensitivity and positive predictive value (PPV) were compared using generalized estimating equations. An independent t-test was used to compare the confidence. An intraclass correlation coefficient was calculated to compare interobserver agreement. RESULTS: The JAFROC1 figures of merit values were 0.816 and 0.808 in S-b1500 and A-b1500, respectively, with no statistically significant difference (P = 0.637). Sensitivity was higher in synthetic than in A-b1500 for readers 2 (P = 0.015) and 3 (P = 0.037). Although sensitivity was higher in S-b1500 than in A-b1500 for reader 1, the difference was not significant (P = 0.487). The PPV of S-b1500 was not significantly different from that of A-b1500 (P = 0.397). The malignancy confidence of true-positive tumors was higher in S-b1500 than in A-b1500 (P = 0.013). Interobserver agreement was good for both sequences. DATA CONCLUSIONS: The synthetic high b-value DWI may improve the diagnostic sensitivity for breast cancer detection without affecting PPV compared with acquired high b-value DWI. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:857-863.

Genetic diversity and population structure of the Sapsaree, a native Korean dog breed.

BACKGROUND: The Sapsaree is a breed of dog (Canis familiaris) native to Korea, which became perilously close to extinction in the mid-1980s. However, with systematic genetic conservation and restoration efforts, this breed was rescued from extinction and population sizes have been gradually increasing over the past few decades. The aim of this study was to ascertain novel information about the genetic diversity, population structure, and demographic history of the Sapsaree breed using genome-wide single nucleotide polymorphism data. We characterized the genetic profile of the Sapsaree breed by comparison with seven foreign dog breeds with similar morphologies to estimate genetic differentiation within and among these breeds. RESULTS: The results suggest that Sapsarees have higher genetic variance compared with the other breeds analyzed. The majority of the Sapsarees in this study share a discrete genetic pattern, although some individuals were slightly different, possibly as a consequence of the recent restoration process. Concordant results from analyses of linkage disequilibrium, effective population size, genetic diversity, and population structural analyses illustrate a relationship among the Sapsaree and the Tibetan breeds Tibetan terrier and Lhasa Apso, and a small genetic introgression from European breeds. The effective population size of the Sapsaree has contracted dramatically over the past generations, and is currently insufficient to maintain long-term viability of the breed's genetic diversity. CONCLUSIONS: This study provides novel insights regarding the genetic diversity and population structure of the native Korean dog breed Sapsaree. Our results suggest the importance of a strategic and systematic approach to ensure the genetic diversity and the authenticity of the Sapsaree breed.

THICKNESSES OF CENTRAL MACULAR, RETINAL NERVE FIBER, AND GANGLION CELL INNER PLEXIFORM LAYERS IN PATIENTS WITH HYPERTENSION.

PURPOSE: To compare retinal thickness between patients with chronic hypertension without retinopathy, hypertensive retinopathy, Keith-Wagener-Barker Grade IV status, and normal controls using spectral domain optical coherence tomography. METHODS: In this retrospective study, we analyzed patients who visited our retinal clinic from January 2013 to February 2016. Of those included, 58 eyes of 58 patients were in the healthy control group (Group A), 37 eyes of 37 patients were in the chronic hypertension without retinopathy group (disease duration of at least 10 years; Group B), and 31 eyes of 31 patients with relieved hypertensive retinopathy (Grade IV hypertensive retinopathy a year or more ago but no longer had hypertensive retinopathy at the time of the study; Group C). The thicknesses of the central macula, retinal nerve fiber layer (RNFL), and ganglion cell inner plexiform layer (GCIPL) were measured by spectral domain optical coherence tomography in each group. RESULTS: The average thicknesses of the central macula, RNFL, and GCIPL layers were lower in Group B than in Group A (P < 0.001, 0.001, and <0.001, respectively). The thicknesses of the three layers were lower in Group C than in Group B (P < 0.001, <0.001, and <0.001, respectively). Of the three groups, the average thicknesses of the central macula, RNFL, and GCIPL were lowest in the Group C (P < 0.001, <0.001, and <0.001, respectively). CONCLUSION: The central macula, RNFL, and GCIPL in Group B were significantly thinner than those of healthy eyes, and these retinal changes were more prominent in Group C. Thus, the effects of retinal changes associated with hypertension should be considered when analyzing the thicknesses of the central macular, RNFL, and GCIPL layers in patients with ocular disorders, including retinal, glaucoma, and neuro-ophthalmological diseases.

Predictors of Invasive Breast Cancer in Patients With Ductal Carcinoma In Situ in Ultrasound-Guided Core Needle Biopsy.

OBJECTIVES: To determine predictors of invasiveness of lesions with US-guided biopsy-confirmed ductal carcinoma in situ (DCIS), focusing on US features, including shear wave elastography (SWE). METHODS: From January 2015 to September 2016, a total of 80 lesions with US-guided biopsy-confirmed DCIS were detected in patients who underwent preoperative mammography, B-mode US, and SWE. Data were retrospectively reviewed from clinical records, pathologic reports, and imaging assessments. Imaging data included mammographic findings, B-mode US findings based on the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS), and the mean and maximum elasticity values on SWE. The final BI-RADS assessment, including the degree of elasticity of the mass, was evaluated. Continuous variables were examined by an independent t test, and categorical variables were examined by the Fisher exact test. The independent factors for predicting a histologic upgrade were evaluated by a multivariate logistic regression analysis. RESULTS: Among the 80 lesions, 27 (33.8%) showed an invasive component after surgical excision. None of the BI-RADS US descriptors, which include shape, orientation, margin, and echogenicity, showed a significant correlation with the rate of a histologic upgrade to invasive cancer. However, the BI-RADS assessment category (P = .015) and nuclear grade (P = .005) were significantly correlated with invasiveness of the mass. The maximum stiffness value was lower in the pure DCIS group (119.04 vs 85.33 kPa; P = .041). CONCLUSIONS: The BI-RADS category based on US findings, maximum stiffness value on SWE, and nuclear grade of DCIS are predictive of invasive components in DCIS.

Differential Clinical Significance of Neurotrophin-3 Expression according to MYCN Amplification and TrkC Expression in Neuroblastoma.

BACKGROUND: Neurotrophin-3 (NT-3), a member of the NT family, has only been considered an ancillary compound that provides anti-apoptotic benefits by inactivating tropomyosin receptor kinase C (TrkC)-induced apoptotic signals. However, little is known about the clinical relevance of NT-3 expression itself in neuroblastoma. The purpose of this study was to assess NT-3 expression in patients with neuroblastoma and its relevance to clinicopathologic findings and treatment outcomes. METHODS: In this study, expression of NT-3 and TrkC was analyzed using immunohistochemistry in 240 patients with newly diagnosed neuroblastoma. RESULTS: The results of the study revealed that NT-3 expression was associated with older age at diagnosis, localized tumors, and more differentiated tumors but was not associated with early treatment response (degree of residual tumor volume after three cycles of chemotherapy) and progression-free survival (PFS). However, when analysis was confined to patients with MYCN amplified tumors, NT-3 expression was associated with better early treatment response with borderline significance (P = 0.092) and higher PFS (86.9% vs. 58.2%; P = 0.044). In multivariate analysis in patients with MYCN amplified tumors, NT-3 was independent prognostic factor (hazard ratio, 0.246; 95% confidence interval, 0.061-0.997; P = 0.050). In another subgroup analysis, the early treatment response was better if NT-3 was expressed in patients without TrkC expression (P = 0.053) while it was poorer in patients with TrkC expression (P = 0.023). CONCLUSION: This study suggests that NT-3 expression in neuroblastoma has its own clinical significance independent of TrkC expression, and its prognostic significance differs depending on the status of MYCN amplification and/or TrkC expression.

Usefulness of preoperative breast magnetic resonance imaging with a dedicated axillary sequence for the detection of axillary lymph node metastasis in patients with early ductal breast cancer.

OBJECTIVE: Axillary staging of primary breast cancer is important; however, axillary staging using advanced magnetic resonance imaging (MRI) techniques is very difficult to use. Therefore, we want to evaluate the diagnostic performance of preoperative MRI with a dedicated axillary sequence for axillary lymph node (ALN) metastasis in patients with early ductal breast cancer and determine potential predictors of axillary nodal positivity. MATERIALS AND METHODS: We retrospectively reviewed the MRI findings for 74 consecutive patients diagnosed with invasive breast cancer. The diagnostic performances of axial images alone and axial + reconstructed coronal images for the detection of ALN metastasis were evaluated. The clinicopathological and MRI features of the primary breast cancer lesions were determined. RESULTS: The sensitivity (52.9% vs. 47.1%), specificity (89.5% vs. 71.9%), positive predictive value (60% vs. 33.3%), and negative predictive value (86.4% vs. 82%) for the preoperative detection of ALN metastasis were higher for axial + coronal images than for axial images. In addition, the area under the receiver operating characteristic curve value was higher for axial + coronal images than for axial images (0.595 vs. 0.712, p = 0.043). Peritumoral high signal intensity on T2-weighted images (p = 0.015) of the primary tumor was significantly associated with ALN metastasis. CONCLUSION: Our findings suggest that preoperative axial + reconstructed coronal MR images exhibit good diagnostic performance for ALN metastasis in patients with early ductal breast cancer. In addition, peritumoral high signal intensity on T2-weighted images of the primary tumor can be used as a predictor of ALN metastasis in these patients.