Transplantation of spermatogonial stem cells (SSCs) in experimental animal models has been used to study germ line stem cell biology and to produce transgenic animals. The species-specific recipient model preparation is important for the characterization of SSCs and the production of offspring. Here, we investigated the effects of surgically induced cryptorchidism in dog as a new recipient model for spermatogonial stem cell transplantation. Artificially unilateral or bilateral cryptorchidism was induced in ten mature male dogs by surgically returning the testis and epididymis to the abdominal cavity. The testes and epididymides were collected every week after the induction of artificial cryptorchidism (surgery) for one month. To determine the effect of surgical cryptorchidism, the seminiferous tubule diameter was measured and immunohistochemistry using PGP9.5 and GATA4 antibodies was analyzed. The diameters of the seminiferous tubules of abdominal testes were significantly reduced compared to those of the scrotal testes. Immunohistochemistry results showed that PGP9.5 positive undifferentiated spermatogonia were significantly reduced after surgical cryptorchidism induction, but there were no significant changes in GATA-4 positive sertoli cells. To evaluate the testis function recovery rate, orchiopexy was performed on two dogs after 30 days of bilateral cryptorchidism. In the orchiopexy group, SCP3 positive spermatocytes were detected, and spermatogenesis was recovered 8 weeks after orchiopexy. In this study, we provided optimum experimental conditions and time for surgical preparation of a recipient canine model for SSC transplantation. Additionally, our data will contribute to recipient preparation by using surgically induced cryptorchidism in non-rodent species.
Abdominal Cavity ; Animals ; Animals, Genetically Modified ; Antibodies ; Biology ; Cryptorchidism* ; Dogs ; Epididymis ; Germ Cells ; Humans ; Immunohistochemistry ; Male ; Models, Animal ; Orchiopexy ; Recovery of Function ; Seminiferous Tubules ; Sertoli Cells ; Spermatocytes ; Spermatogenesis ; Spermatogonia ; Stem Cell Transplantation* ; Stem Cells* ; Testis

BACKGROUND/OBJECTIVES: This study investigates correlations between circulating microRNAs (miRNAs) and obesity-related parameters among young women (aged 20–30 years old) in Korea. SUBJECTS/METHODS: We analyzed TaqMan low density arrays (TLDAs) of circulating miRNAs in 9 lean (body mass index [BMI] < 25 kg/m2) and 15 obese (BMI > 25 kg/m2) women. We also performed gene ontology (GO) analyses of the biological functions of predicted miRNA target genes, and clustered the results using the database for annotation, visualization and integrated discovery. RESULTS: The TLDA cards contain 754 human miRNAs; of these, the levels of 8 circulating miRNAs significantly declined (> 2-fold) in obese subjects compared with those in lean subjects, including miR-1227, miR-144-5p, miR-192, miR-320, miR-320b, miR-484, miR-324- 3p, and miR-378. Among them, miR-484 and miR-378 displayed the most significant inverse correlations with BMI (miR-484, r = −0.5484, P = 0.0056; miR-378, r = −0.5538, P = 0.0050) and visceral fat content (miR-484, r = −0.6141, P = 0.0014; miR-378, r = −0.6090, P = 0.0017). GO analysis indicated that genes targeted by miR-484 and miR-378 had major roles in carbohydrate and lipid metabolism. CONCLUSION Our result showed the differentially expressed circulating miRNAs in obese subjects compared to lean subjects. Although the mechanistic study to reveal the causal role of miRNAs remains, these miRNAs may be novel biomarkers for obesity.

Purpose: YoungPEARL (KCSG-BR15-10) trial demonstrated a significant progression-free survival (PFS) benefit for premenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (MBC) for palbociclib plus exemestane with ovarian function suppression compared to capecitabine. However, the number of tamoxifen-sensitive premenopausal patients was small because most recurrences occurred early during adjuvant endocrine therapy (ET), with tamoxifen being the only drug used; hence, the data for these patients were limited. Here we present a subgroup analysis according to tamoxifen sensitivity from the YoungPEARL study. Materials and Methods Patients were randomized 1:1 to receive palbociclib+ET (oral exemestane 25 mg/day for 28 days, palbociclib 125 mg/day for 21 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks). Tamoxifen resistance was defined as: relapse while on adjuvant tamoxifen, relapse within 12 months of completing adjuvant tamoxifen, or progression while on first-line tamoxifen within 6 months for MBC. Results In total, 184 patients were randomized and 178 were included in the modified intention-to-treat population. PFS improvement in the palbociclib+ET group was observed in tamoxifen-sensitive patients (hazard ratio, 0.38; 95% confidence interval, 0.12 to 1.19). Furthermore, palbociclib+ET prolonged median PFS compared with capecitabine in tamoxifen-sensitive (20.5 months vs. 12.6 months) and tamoxifen-resistant (20.1 months vs. 14.5 months) patients. Palbociclib+ET demonstrated a higher rate of objective response, disease control, and clinical benefit in tamoxifen-sensitive patients. Conclusion This post hoc exploratory analysis suggests that palbociclib+ET is a promising therapeutic option for premenopausal HR+/HER2– MBC patients irrespective of tamoxifen sensitivity.

Purpose: The aim of this study was to evaluate the association between the severity of hyperechoic pancreas (HP) on ultrasonography (US) and glycemic progression. Methods: In total, 1,386 participants who underwent abdominal US as part of health examinations between December 2008 and May 2014 were included in this retrospective study. We classified pancreatic echogenicity on a 4-point scale, and compared it using two distinct criteria: fatty pancreas (FP) 1 criterion (normal vs. ≥mild HP) and FP2 criterion (normal/mild HP vs. ≥moderate HP). According to the presence of nonalcoholic fatty liver disease (NAFLD), participants were subdivided into four groups: non-NAFLD and non-HP, isolated NAFLD, isolated HP, and HP with NAFLD. Glycemic progression was defined as progression from normoglycemia to prediabetes or diabetes or progression from prediabetes to diabetes. Results: During the follow-up (median, 5.9 years), 262 of the 1,386 participants developed glycemic progression. Using FP2, the probability of glycemic progression across the four subgroups showed cumulative aggravation for NAFLD and HP (all P<0.05). Isolated HP showed a higher probability of glycemic progression than isolated NAFLD according to FP2 (P<0.001). The highest probability of glycemic progression was observed in patients with both NAFLD and HP (P<0.001). The hazard ratio for glycemic progression increased with the severity of HP. Conclusion Increasing severity of HP on US was found to be significantly correlated with glycemic progression. Moreover, isolated HP of moderate or greater severity predicted glycemic progression independent of NAFLD.

BACKGROUND/OBJECTIVES: In Oriental medicine, certain foods may be beneficial or detrimental based on an individual's constitution; however, the scientific basis for this theory is insufficient. The purpose of this study was to investigate the effect of body constitution, based on the Sasang type of Korean traditional medical classification system, on the bioavailability of soy isoflavones of Cheonggukjang, a quick-fermented soybean paste.SUBJECTS/METHODS: A pilot study was conducted on 48 healthy Korean men to evaluate the bioavailability of isoflavone after ingestion of food based on constitution types classified by the Sasang typology. The participants were classified into the Taeeumin (TE; n = 15), Soyangin (SY; n = 15), and Soeumin (SE; n = 18) groups. Each participant ingested 50 g of Cheonggukjang per 60 kg body weight. Thereafter, blood was collected, and the soy isoflavone metabolites were analyzed by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. Ntrikinetic analysis of individual isoflavone-derived metabolites was performed.RESULTS: Our nutrikinetic analysis identified 21 metabolites derived from isoflavones in the blood samples from 48 healthy Korean men (age range, 21-29 years). Significant differences were observed in the time to maximum concentration (T(max)) and elimination half-life (t(1/2)) for nine metabolites among the three groups. The T(max) and t(1/2) of the nine metabolites were higher in the SE group than in the other groups. Moreover, the absorption rates, as determined by the area under the plasma-level curve (AUC) values of intact isoflavone, were 5.3 and 9.4 times higher in the TE group than in the SY and SE groups, respectively. Additionally, the highest AUC values for phase I and II metabolites were observed in the TE group.CONCLUSIONS: These findings indicate that isoflavone bioavailability, following Cheonggukjang insgestion, is high in individuals with the TE constitution, and relatively lower in those with the SE and SY constitutions.

Purpose: YoungPEARL (KCSG-BR15-10) trial demonstrated a significant progression-free survival (PFS) benefit for premenopausal patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) metastatic breast cancer (MBC) for palbociclib plus exemestane with ovarian function suppression compared to capecitabine. However, the number of tamoxifen-sensitive premenopausal patients was small because most recurrences occurred early during adjuvant endocrine therapy (ET), with tamoxifen being the only drug used; hence, the data for these patients were limited. Here we present a subgroup analysis according to tamoxifen sensitivity from the YoungPEARL study. Materials and Methods Patients were randomized 1:1 to receive palbociclib+ET (oral exemestane 25 mg/day for 28 days, palbociclib 125 mg/day for 21 days, plus leuprolide 3.75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1,250 mg/m2 twice daily for 14 days every 3 weeks). Tamoxifen resistance was defined as: relapse while on adjuvant tamoxifen, relapse within 12 months of completing adjuvant tamoxifen, or progression while on first-line tamoxifen within 6 months for MBC. Results In total, 184 patients were randomized and 178 were included in the modified intention-to-treat population. PFS improvement in the palbociclib+ET group was observed in tamoxifen-sensitive patients (hazard ratio, 0.38; 95% confidence interval, 0.12 to 1.19). Furthermore, palbociclib+ET prolonged median PFS compared with capecitabine in tamoxifen-sensitive (20.5 months vs. 12.6 months) and tamoxifen-resistant (20.1 months vs. 14.5 months) patients. Palbociclib+ET demonstrated a higher rate of objective response, disease control, and clinical benefit in tamoxifen-sensitive patients. Conclusion This post hoc exploratory analysis suggests that palbociclib+ET is a promising therapeutic option for premenopausal HR+/HER2– MBC patients irrespective of tamoxifen sensitivity.

PURPOSE: Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established. MATERIALS AND METHODS: Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy. RESULTS: Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advancedNSCLC patients. The 22 patientswho received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progression-free survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The othertwo patients had an exon 20 insertion and another EGFR mutation and achieved a partial response. CONCLUSION: The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to first- or second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.
Carcinoma, Non-Small-Cell Lung ; Disease-Free Survival ; Drug Therapy ; Exons ; Humans ; Incidence ; Korea ; Mutagenesis, Insertional ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Retrospective Studies

Epidermal growth factor receptor (EGFR)‒tyrosine kinase inhibitors (TKIs) are effective clinical therapeutics for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib, a thirdgeneration EGFR TKI, has proven effective against T790M mutations. However, the vast majority of patients acquire resistance following successful treatment. A 59-year-old female patient with metastatic NSCLC developed resistance after 43 weeks of osimertinib. CancerSCAN of the metastatic liver lesion revealed a EGFR C797G mutation at an allele frequency of 72%, a preexisting T790M mutation (73%) in cis and an exon 19 deletion (87%). Another 53-year-old female patient developed systemic progression after 10 months of osimertinib. CancerSCAN of the lung biopsy identified an EGFR L718Q mutation at an allele frequency of 7%, concomitant PIK3CA E545K (12.90%) and preexisting EGFR L858R (38%), but loss of the T790M mutation. The heterogeneity of osimertinib resistance mechanisms warrants further investigation into novel or combination agents to overcome the rare acquired resistances.
Biopsy ; Carcinoma, Non-Small-Cell Lung* ; Exons ; Female ; Gene Frequency ; Humans ; Liver ; Lung ; Middle Aged ; Phosphotransferases ; Population Characteristics ; Receptor, Epidermal Growth Factor

Background: Subclinical left ventricular diastolic dysfunction (LVDD) is an emerging consequence of increased insulin resistance, and dyslipidemia is one of the few correctable risk factors of LVDD. This study evaluated the role of mean and visit-to-visit variability of lipid measurements in risk of LVDD in a healthy population. Methods: This was a 3.7-year (interquartile range, 2.1 to 4.9) longitudinal cohort study including 2,817 adults (median age 55 years) with left ventricular ejection fraction >50% who underwent an annual or biannual health screening between January 2008 and July 2016. The mean, standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM), and average real variability of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB), non-HDL-C, and triglycerides were obtained from three to six measurements during the 5 years preceding the first echocardiogram. Results: Among the 2,817 patients, 560 (19.9%) developed LVDD. The mean of no component of lipid measurements was associated with risk of LVDD. CV (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.10 to 1.67), SD (HR, 1.27; 95% CI, 1.03 to 1.57), and VIM (HR, 1.26; 95% CI, 1.03 to 1.55) of LDL-C and all the variability parameters of apoB were significantly associated with development of LVDD. The association between CV-LDL and risk of LVDD did not have significant interaction with sex, increasing/decreasing trend at baseline, or use of stain and/or lipid-modifying agents. Conclusion The variability of LDL-C and apoB, rather than their mean, was associated with risk for LVDD.