Purpose: This study aimed to analyze the association between fibrotic focus (FF) and tumor-infiltrating lymphocytes (TILs) and to determine the prognostic significance of FF and TILs in the breast according to its molecular subtypes. Methods: The study included patients who underwent surgical treatment for breast cancer, for whom tissue samples were available. FF within the tumor and TILs in breast cancer tissues were evaluated. Clinicopathological characteristics were reviewed from medical records. Results: FF and TILs were present in 31.3% and 81.7% of the patients, respectively. FF and TILs showed a positive correlation. FF were significantly associated with tumor size, lymphovascular invasion, regional lymph node metastasis, and tumor stage. TILs were significantly associated with menopausal status, histologic grade, tubule formation, nuclear grade, mitosis, human epidermal growth factor receptor 2 (HER2) overexpression, molecular subtype of breast cancer, and the number of cluster of differentiation 8+ T cells. In TIL-positive cases, FF were significantly associated with tumor size, regional lymph node metastasis, extranodal extension, lymphovascular invasion, tumor stage, recurrence-free survival, and overall survival (OS). Based on HER2 overexpression status, TILs were significantly associated with tumor size, tumor necrosis, histologic grade, estrogen receptor status, and epidermal growth factor receptor expression in HER2-negative breast cancer. Further, in HER2-negative breast cancer, OS and recurrence-free survival were significantly associated with FF. The OS of FF-positive patients was significantly shorter than that of FF-negative patients. Conclusion Our study showed an association between FF and TIL levels in breast cancer, indicating that FF are associated with poor prognostic factors for breast cancer and poor OS, and that TILs are associated with HER2 overexpression. However, further studies are needed to elucidate the interactions between FF and TILs in breast cancer.

Myxofibrosarcoma is a rare tumor, refractory to cytotoxic chemotherapy and radiotherapy. Pembrolizumab is an innovative immunotherapy drug consisting of programmed death receptor ligand 1 antibody proven to be useful for numerous types of cancer cells. A patient had been diagnosed with metastatic myxofibrosarcoma, refractory to radiotherapy and conventional cytotoxic chemotherapy. The patient achieved a partial response during palliative chemotherapy with pembrolizumab for 14 cycles. To the best of our knowledge, this is the first case report demonstrating the efficacy of pembrolizumab for refractory myxofibrosarcoma.
Drug Therapy ; Humans ; Immunotherapy ; Radiotherapy ; Sarcoma

Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration- (>50 μM) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to 500 μM. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 μM. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.
Acetylcysteine ; Cell Line ; Cytoplasm ; Fibroblasts ; GTP-Binding Proteins ; Hepatocytes ; Humans ; Hyperglycemia ; Hypoglycemia ; Larva ; Liver ; Mortality ; Reactive Oxygen Species* ; RNA, Small Interfering ; Weight Gain ; Zebrafish

BACKGROUND/AIMS: Optimized regimen has not yet been established for failures of multiple Helicobacter pylori (H. pylori) eradication. Hence, we aimed to evaluate the efficacy of rifabutin-based rescue therapy, at least after three eradication failures. METHODS: Twelve patients, who failed in the treatment for H. pylori eradication at least three times, were consecutively enrolled between 2007 and 2015 at Seoul National University Bundang Hospital. The rifabutin-based rescue regimen was consisted of proton pump inhibitor (PPI), rifabutin (150 mg b.i.d.), and amoxicillin (1 g b.i.d.), given for 7 or 14 days. MIC concentration test by the agar dilution method was performed on six patients prior to rifabutin-based rescue therapy. RESULTS: One patient did not take this regimen, and per-protocol (PP) analysis was performed in 11 patients. The overall eradication rate by intention-to-treat and PP analysis with rifabutin-based rescue therapy was 50.0% (6/12 patients) and 54.5% (6/11 patients), respectively. There was no difference of the eradication rate depending on the underlying disease, smoking, alcohol, number of previous eradication failures, and CYP2C19 genotype. All of the six patients were susceptible to rifabutin, but only three of them succeeded in eradicating with H. pylori. Side effects occurred in two patients (18.2%), and compliance was 90.9%. CONCLUSIONS: Even the eradication rate of rifabutin-based rescue therapy was not very good. Rifabutin-based rescue therapy could be considered as a rescue therapy, perhaps as the fourth or the fifth-line treatment option. No correlation of rifabutin sensitivity with eradication success rate of H. pylori suggests that frequent administration of high dose PPI and amoxicillin might be important.
Agar ; Amoxicillin ; Compliance ; Cytochrome P-450 CYP2C19 ; Genotype ; Helicobacter pylori* ; Helicobacter* ; Humans ; Methods ; Proton Pumps ; Rifabutin ; Salvage Therapy ; Seoul ; Smoke ; Smoking

PURPOSE: This study focused on the evaluation of the relation between pollen concentration and the outbreak of allergic disease (symptom index), and this outcome would be necessary to upgrade risk grade for the pollen forecasting system. METHODS: Airborne particles carrying allergens, such as pollen, were collected daily at the Seoul and Guri area by using 7-day Burkard samplers for 6 years. A total of 596 Subjects were recruited from Hanyang University Seoul Hospital (n=144 for spring, n=139 for autumn), and Hanyang University Guri Hospital (n=157 for spring, n=156 for autumn). Symptom index was evaluated and recorded by phone calling to study subjects daily or asking questionnaire when they visit outpatient clinic every week. Statistical analysis of data was performed by using correlation coefficients and regression models with time series graph. RESULTS: Two peak seasons of pollen concentration were May and September in Korea. In skin prick tests, the sensitization rate to ragweed pollen was gradually increased in children. In the same period, sensitization rates to airborne pollen, especially oak, birch for spring, and Japanese hop for autumn were increased annually. There was a significantly relationship between symptom index of allergic patients and allergic pollen concentrations in this study. Especially symptom index was significantly correlated to the concentration of oak pollen of day 1 in spring and to the concentration of Japanese hop pollen of day 0 in autumn. CONCLUSION: Sensitization rates to pollens increased annually. There is a significant relationship between allergy symptom index and pollen concentration. There remains to confirm the Korean own risk grade of pollen allergy.
Allergens ; Ambrosia ; Ambulatory Care Facilities ; Asian Continental Ancestry Group ; Betula ; Child ; Forecasting ; Humans ; Hypersensitivity ; Korea ; Pollen* ; Rhinitis, Allergic, Seasonal ; Seasons ; Seoul ; Skin

SINE-VNTR-Alu (SVA) elements are present in hominoid primates and are divided into 6 subfamilies (SVA-A to SVA-F) and active in the human population. Using a bioinformatic tool, 22 SVA element-associated genes are identified in the human genome. In an analysis of genomic structure, SVA elements are detected in the 5' untranslated region (UTR) of HGSNAT (SVA-B), MRGPRX3 (SVA-D), HYAL1 (SVA-F), TCHH (SVA-F), and ATXN2L (SVA-F) genes, while some elements are observed in the 3'UTR of SPICE1 (SVA-B), TDRKH (SVA-C), GOSR1 (SVA-D), BBS5 (SVA-D), NEK5 (SVA-D), ABHD2 (SVA-F), C1QTNF7 (SVA-F), ORC6L (SVA-F), TMEM69 (SVA-F), and CCDC137 (SVA-F) genes. They could contribute to exon extension or supplying poly A signals. LEPR (SVA-C), ALOX5 (SVA-D), PDS5B (SVA-D), and ABCA10 (SVA-F) genes also showed alternative transcripts by SVA exonization events. Dominant expression of HYAL1_SVA appeared in lung tissues, while HYAL1_noSVA showed ubiquitous expression in various human tissues. Expression of both transcripts (TDRKH_SVA and TDRKH_noSVA) of the TDRKH gene appeared to be ubiquitous. Taken together, these data suggest that SVA elements cause transcript isoforms that contribute to modulation of gene regulation in various human tissues.
3' Untranslated Regions ; 5' Untranslated Regions ; Exons ; Gene Expression Profiling ; Genome, Human ; Genomics ; Humans ; Lung ; Organ Specificity ; Poly A ; Primates ; Protein Isoforms

Increased fat intake is known to be a major cause of prostate cancer. In this study, we investigated the effect of dietary high fat on prostate intraepithelial neoplasia using transgenic adenocarcinoma mouse prostate (TRAMP) mice. Six-week-old male TRAMP mice were fed AIN93G (control group, 4.0 kcal/kg, n=6) and AIN93G-HFD (experimental group, 4.8 kcal/kg, n=7) for 10 weeks. Prostate histopathology, urogenital tract (UGT) weight, epididymal white adipose tissue weight, argyrophilic nucleolar organizer regions (AgNORs) counts, and serum leptin levels were examined. AIN93G-HFD fed group showed progressed neoplastic lesions in the prostate (P<0.05) compared to AIN93G fed group. AIN93G-HFD intake resulted in a increase in the weight of UGT (P<0.05) and epididymal white adipose tissue. The number of Ag-NOR positive dots significantly increased in each prostate lobe and final serum leptin levels in AIN93G-HFD fed group were about twice those of AIN93G fed group (P<0.05). Dietary high fat was related to the prostate cancer progression in the early stage of TRAMP mice and increased serum leptin levels, suggesting that the regulation of dietary components could delay the progression of prostate cancer.
Adenocarcinoma ; Adipose Tissue, White ; Animals ; Humans ; Leptin ; Male ; Mice ; Nucleolus Organizer Region ; Prostate ; Prostatic Neoplasms

This study was performed to investigate the differences in food choice, nutrition labeling perceptions, and prevalence of obesity due to meal skipping in Korean elementary school children. A national survey was performed in 2010 to collect data on food intake frequency, understanding of nutrition labeling, and body mass index from 2,335 fifth grade students in 118 elementary schools selected from 16 metropolitan local governments by stratified cluster sampling. The data were analyzed using the SAS 9.1 and SUDAAN 10.0 packages. Students who consumed three meals for 6-7 days during the past week were classified into the regular meal eating (RM) group (n = 1,476) and those who did not were placed into the meal skipping (MS) group (n = 859). The daily intake frequency of fruits, vegetables, kimchi, and milk was significantly lower in the MS group compared to that in the RM group (P < 0.001), whereas the daily intake frequency of soft drinks and instant noodles (ramyeon) was significantly higher in the MS group than that in the RM group (P < 0.05). The MS group demonstrated a significantly lower degree of understanding with regard to nutrition labeling and high calorie foods containing low nutritional value than that in the RM group. The distribution of obesity based on the percentile criteria using the Korean growth chart was different between the MS and RM groups. The MS group (8.97%) had a higher percentage of obese subjects than that in the RM group (5.38%). In conclusion, meal skipping was related to poor food choice, low perception of nutrition labeling, and a high prevalence of obesity in Korean fifth grade children.
Body Mass Index ; Carbonated Beverages ; Child ; Eating ; Food Labeling ; Fruit ; Growth Charts ; Humans ; Meals ; Milk ; Nutritive Value ; Obesity ; Phenothiazines ; Prevalence ; Vegetables

BACKGROUND/AIMS: The prognostic impact of empirical anti-tuberculous management according to adenosine deaminase (ADA) levels in patients exhibiting pericardial effusion (PE) has not been established. We evaluated the appropriateness of ADA-guided anti-tuberculous medication for patients with PE. METHODS: From 2001 to 2010, 47 patients with PE and who were diagnosed with either tuberculous pericarditis (TbP) or idiopathic pericarditis (IP) were enrolled. The diagnosis of definite TbP was made by the presence of Tb bacilli or caseous granuloma in pericardial tissue or effusion. The diagnosis of probable TbP was made by the presence of one or more of the following: (1) elevated ADA (> or = 40 IU/L) in pericardial fluid, (2) positive Tb interferon test, or (3) extracardiac presence of Tb. All clinical information was collected by medical record review and telephone contact. RESULTS: Among the 47 patients with PE, 12 were diagnosed with definite TbP; 17, with probable TbP; and 18, with IP. The mean ADA level was significantly higher in patients with definite TbP than in patients with IP (74.97 +/- 36.79 vs. 20.14 +/- 7.39 IU/L; p < 0.001). The optimal ADA cutoff value for diagnosis of definite TbP was 64 IU/L. The median follow-up time was 12.1 months (range, 0.17-100 months). In patients with low levels of ADA (< 40 IU/L), the incidence of death or recurrence did not different between patients who were prescribed anti-tuberculous medication and those who were not. CONCLUSIONS: The ADA level in pericardial fluid was useful for making a rapid diagnosis of tuberculous pericarditis. Even in tuberculosis-endemic areas, patients with ADA < 40 IU/L may have a good prognosis without empirical anti-tuberculous treatment.
Adenosine ; Adenosine Deaminase ; Follow-Up Studies ; Granuloma ; Humans ; Incidence ; Interferons ; Medical Records ; Organophosphates ; Pericardial Effusion ; Pericarditis ; Pericarditis, Tuberculous ; Prognosis ; Recurrence ; Telephone

The thymus is a central lymphoid organ for T cell development. Thymic epithelial cells (TECs) constitute a major component of the thymic stroma, which provides a specialized microenvironment for survival, proliferation, and differentiation of immature T cells. In this study, subsets of TECs were examined immunohistochemically to investigate their cytokeratin (CK) expression patterns during thymus regeneration following thymic involution induced by cyclophosphamide treatment. The results demonstrated that both normal and regenerating mouse thymuses showed a similar CK expression pattern. The major medullary TECs (mTEC) subset, which is stellate in appearance, exhibited CK5 and CK14 staining, and the minor mTEC subset, which is globular in appearance, exhibited CK8 staining, whereas the vast majority of cortical TECs (cTECs) expressed CK8 during thymus regeneration. Remarkably, the levels of CK5 and CK14 expression were enhanced in mTECs, and CK8 expression was upregulated in cTECs during mouse thymus regeneration after cyclophosphamide-induced acute thymic involution. Of special interest, a relatively high number of CK5+CK8+ TEC progenitors occurred in the thymic cortex during thymus regeneration. Taken together, these findings shed more light on the role of CK5, CK8, and CK14 in the physiology of TECs during mouse thymus regeneration, and on the characterization of TEC progenitors for restoration of the epithelial network and for concomitant regeneration of the adult thymus.
Adult ; Animals ; Cyclophosphamide ; Epithelial Cells ; Humans ; Keratins ; Light ; Mice ; Regeneration ; T-Lymphocytes ; Thymus Gland