BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is a limited factor in the treatment of non-small-cell lung cancer (NSCLC) patients. Therefore, ongoing studies are trying to identify EGFR-TKIs-resistant mechanisms and to discover novel therapeutic strategies and targets for NSCLC treatment.METHODS: In the present study, the possibility of overcoming intrinsic gefitinib-resistance was examined by regulating the expression of AXL. A natural product-derived antitumor agent, yuanhuadine (YD) was employed to modulate the expression of AXL in the cells.RESULTS: Treatment with YD effectively downregulated AXL expression in AXL-overexpressed gefitinib-resistant H1299 cells. The combination of gefitinib and YD exhibited a synergistic grwoth-inhibitory activity in H1299 cells by downregulation of AXL expression.CONCLUSIONS: Based on these findings, AXL was found to be a promising therapeutic target to overcome the intrinsic resistance to gefitinib in NSCLC. Furthermore, YD is able to effectively regulate the expression of AXL and thus it may be applicable as a potential lead compound for the treatment of gefitinib-resistant NSCLC.
Carcinoma, Non-Small-Cell Lung ; Down-Regulation ; Drug Resistance ; Humans ; Lung Neoplasms ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor

OBJECTIVE: Gestational diabetes mellitus (GDM) is defined as glucose intolerance first detected during pregnancy. It can result in pregnancy complications such as birth injury, stillbirth. Fatty acid-binding protein 4 (FABP4), found in adipose tissue, is associated with insulin resistance, and type 2 diabetes. The aim of this study was to investigate whether FABP4 in the placenta and decidua of pregnant women with GDM is higher than that in normal pregnant women, and whether serum from pregnant women with GDM may cause adipocytes to secrete more FABP4 than does serum from a normal pregnant group. METHODS: We obtained placentas, deciduas, and serum from 12 pregnant women with GDM and 12 normal pregnant women and performed enzyme-linked immunosorbent assay, real time quantitative-polymerase chain reaction. We cultured human pre-adipocytes for 17 days with GDM and non-GDM serum and performed western blot, real time quantitative-polymerase chain reaction, and oil red O staining. RESULTS: Expression of FABP4 in serum, placenta and decidua of pregnant women with GDM was significantly higher than that in normal pregnant women. Serum from pregnant women with GDM increased the expression of FABP4 mRNA and decreased the expression of adiponectin mRNA in human pre-adipocytes significantly. Adipocyte cultured in GDM serum showed significantly greater lipid accumulation than those cultured in normal serum. CONCLUSION: Our results suggest that FABP4 is higher in placenta and decidua from pregnant women with GDM. Increased circulating FABP4 in maternal serum from pregnant women with GDM may originate from adipocytes and the placenta. Circulating FABP4 can induce increased insulin resistance and decreased insulin sensitivity.
Adipocytes ; Adiponectin ; Adipose Tissue ; Birth Injuries ; Blotting, Western ; Decidua ; Diabetes, Gestational* ; Enzyme-Linked Immunosorbent Assay ; Female ; Glucose Intolerance ; Humans ; Humans* ; Insulin Resistance ; Placenta ; Pregnancy ; Pregnancy Complications ; Pregnancy in Diabetics ; Pregnant Women* ; RNA, Messenger* ; Stillbirth

Dyskeratosis congenita (DC) is a rare genetic disorder encompassing abnormal skin pigmentation, dystrophic nails, leukoplakia of mucous membranes and others. Bone marrow failure is the cause of early mortality. Moreover, DC is known for its predisposition to malignancy. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. We describe here a rare case of DC in a 4-year-old girl showing dark skin, dystrophic toe nails, and mild bone marrow failure. Autosomal recessive disease was suggested as the patient is female, and tests for DKC1 and hTR mutations were negative. Intermittent treatment with oxymetholone and prednisolone for about 26 months resulted in stable hemoglobin and platelet response.
Blood Platelets ; Bone Marrow ; Child, Preschool ; Dyskeratosis Congenita* ; Female* ; Humans ; Leukoplakia ; Mortality ; Mucous Membrane ; Oxymetholone ; Prednisolone ; Skin ; Skin Pigmentation ; Toes

Attenuated functional exercise capacity in elderly and diseased populations is a common problem, and stems primarily from physical inactivity. Decreased function and exercise capacity can be restored by maintaining muscular strength and mass, which are key factors in an independent and healthy life. Resistance exercise has been used to prevent muscle loss and improve muscular strength and mass. However, the intensities necessary for traditional resistance training to increase muscular strength and mass may be contraindicated for some at risk populations, such as diseased populations and the elderly. Therefore, an alternative exercise modality is required. Recently, blood flow restriction (BFR) with low intensity resistance exercise (LIRE) has been used for such special populations to improve their function and exercise capacity. Although BFR+LIRE has been intensively studied for a decade, a comprehensive review detailing the effects of BFR+LIRE on both skeletal muscle and vascular function is not available. Therefore, the purpose of this review is to discuss previous studies documenting the effects of BFR+LIRE on hormonal and transcriptional factors in muscle hypertrophy and vascular function, including changes in hemodynamics, and endothelial function.
Aged ; Hemodynamics ; Humans ; Hypertrophy* ; Muscle, Skeletal* ; Resistance Training

BACKGROUND: We aimed to estimate whether elevated levels of complement C3a and C5a in amniotic fluid (AF) are independently associated with increased risks of intra-amniotic infection and/or inflammation (IAI) and spontaneous preterm delivery (SPTD) in women with cervical insufficiency or a short cervix (≤ 25 mm). METHODS: We conducted a retrospective cohort study of 96 consecutive women with cervical insufficiency (n = 62) or a short cervix (n = 34) at 17 to 27 weeks, and who underwent an amniocentesis. AF was cultured and analyzed for C3a and C5a by enzyme-linked immunosorbent assay kits. The primary outcome measures were IAI (defined as a positive AF culture and/or an elevated AF interleukin-6 level [≥ 7.6 ng/mL]) and SPTD at < 32 weeks. RESULTS: In multivariable analysis, AF level of C3a was the only variable significantly associated with IAI, whereas C5a level in AF and serum C-reactive protein level were not associated with IAI. Using SPTD at < 32 weeks as the outcome variable in logistic regression, elevated AF levels of C3a were associated with increased risk of SPTD at < 32 weeks after adjusting for other baseline confounders, whereas elevated AF levels of C5a were not. CONCLUSION: In women with cervical insufficiency or a short cervix, elevated AF level of C3a, but not C5a, is independently associated with increased risks of IAI and SPTD at < 32 weeks. These findings suggest that subclinical IAI or SPTD in the context of cervical insufficiency is related to activation of complement system in AF.
Amniocentesis ; Amniotic Fluid* ; C-Reactive Protein ; Cervix Uteri* ; Cohort Studies ; Complement C3a* ; Complement System Proteins* ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Inflammation* ; Interleukin-6 ; Logistic Models ; Outcome Assessment (Health Care) ; Retrospective Studies

BACKGROUND: Postremission therapy is critical for achieving long-term survival in the patients with acute myelogenous leukemia (AML). Allogeneic bone marrow transplantation during the first complete remission (CR) with using a HLA-identical sibling donor may offer the best chance for long-term leukemia-free survival. The patients without matched siblings have several treatment options. The aim of this study was to compare the clinical outcomes after matched sibling transplantation (MST), unrelated stem cell transplantation (non-MST), or autologous peripheral blood stem cell transplantation (APBSCT) as a postremission therapy for children with AML. METHODS: Thirty four hematopoietic stem cell transplantations (SCT) in 32 children with AML were performed between June, 1996 and December, 2004. Two patients who failed at prior APBSCT underwent a 2nd unrelated transplantations. The disease status at the time of transplantation, the conditioning regimen, prophylaxis for graft-versus-host disease (GVHD), the incidence of GVHD, complications, the cause of death, the over-all survival and the event-free survival were retrospectively compared in relation to the stem cell sources. RESULTS: There were 19 males and 13 females with a median age of 8 yr 10 mo. The median follow-up was 17 mo. Twenty-eight cases were transplanted during CR1. Most (5/6) of patients other than the patients who were in CR1 were allocated in the non-MST group. APBSCT was done in 17 cases, and allo-transplants were done in 17 cases, which included MSTs in 10, matched-unrelated BM transplants in 5, haploidentical CD34+selected peripheral blood transplant in 1, and 1-antigen mismatch unrelated cord blood transplantation in 1. Acute GvHD > or = than Grade 2 was found in 20% of the MST cases vs. 85.7% in the non-MST cases (P<.01). The two-year cumulative relapse risks were 46.4% in the APBSCT cases, 20% in the MST cases and 31.5% in the non-MST cases. The Kaplan-Meier 2-year EFS in all cases was 55.7%: 46.3% in the APBMT cases, 80.0% in the MST cases and 68.6% in the non-MST cases, despite the higher proportion of high risk patients in the non-MST group. CONCLUSION: This study indicated that MST was the best option for pediatric AML. For patients without matched siblings, the patients with unrelated transplants fared better, had better survival and a lower relapse rate than the APBSCT patients. However, a further prospective, randomized study that incorporates a larger number of patients and a cord blood transplant arm is necessary to definitely determine the best option for pediatric AML.
Arm ; Bone Marrow Transplantation ; Cause of Death ; Child ; Disease-Free Survival ; Female ; Fetal Blood ; Follow-Up Studies ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation* ; Hematopoietic Stem Cells* ; Humans ; Incidence ; Leukemia, Myeloid, Acute* ; Male ; Peripheral Blood Stem Cell Transplantation ; Recurrence ; Retrospective Studies ; Siblings ; Stem Cell Transplantation ; Stem Cells* ; Tissue Donors

BACKGROUND: A US Food and Drug Administration (FDA)-approved drug methacholine chloride (Provocholine®) was recently introduced to Korea where it is now widely used in clinical practice. We aimed to evaluate the prevalence, risk factors and cutoff value of bronchial hyperresponsiveness (BHR) to Provocholine in 7-year-old children. METHODS: Six hundred and thirty-three children from the Panel Study on Korean Children who visited 16 regional hospitals were evaluated. Skin prick tests, spirometry and bronchial provocation tests for Provocholine as well as a detailed history and physical examinations were performed. The bronchial provocation test was reliably performed on 559 of these children. RESULTS: The prevalence of ever-diagnosed asthma via medical records was 7.7%, and that of current asthma (wheezy episode in the last 12 months + diagnosed asthma by physicians) was 3.2%. The prevalence of BHR to Provocholine was 17.2% and 25.8%, respectively, for a PC20 < 8 and < 16 mg/mL. The risk factors for BHR (PC20 < 16 mg/mL) were atopic dermatitis diagnosis and current dog ownership, whereas those for current asthma were allergy rhinitis diagnosis, a history of bronchiolitis before the age of 3, recent use of analgesics/antipyretics and maternal history of asthma. The BHR prevalence trend showed an increase along with the increased immunoglobulin E (IgE) quartile. The cutoff value of PC20 for the diagnosis of current asthma in children at age 7 was 5.8 mg/mL (sensitivity: 47.1%, specificity: 87.4%). CONCLUSIONS: BHR to Provocholine (PC20 < 8 mg/mL) was observed in 17.2% of 7-year-olds children from the general population and the cutoff value of PC20 for the diagnosis of current asthma was 5.8 mg/mL in this age group. The risk factors for BHR and current asthma showed discrepancies suggesting different underlying mechanisms. Bronchial provocation testing with Provocholine will be a useful clinical tool in the future.
Animals ; Asthma ; Bronchial Hyperreactivity ; Bronchial Provocation Tests ; Bronchiolitis ; Child* ; Dermatitis, Atopic ; Diagnosis ; Dogs ; Humans ; Hypersensitivity ; Immunoglobulin E ; Immunoglobulins ; Korea ; Medical Records ; Methacholine Chloride* ; Ownership ; Physical Examination ; Prevalence* ; Rhinitis ; Risk Factors* ; ROC Curve ; Sensitivity and Specificity ; Skin ; Spirometry ; United States Food and Drug Administration

PURPOSE: It is controversial whether indoor pet exposure is either a risk or protective factor developing sensitization to pet allergens or asthma. Therefore, we investigated whether indoor pet ownership entails a risk for the development of asthma and sensitization in childhood. METHODS: The Panel Study of Korean Children (PSKC) is a general-population-based birth cohort study that recruited 2,078 mother-baby dyads in Korea between April and July of 2008. Among 1,577 children who were followed up in 2015, 559 underwent skin prick tests, spirometry and bronchial provocation tests using Provocholine. Having a cat or a dog and the prevalence of asthma were evaluated by using self-reported questionnaires and physicians’ medical records. RESULTS: During infancy, the rate of dog ownership was 4.5% (71 of 1,574) and that of cat ownership was 0.5% (8 of 1,574). Of the subjects, 7.9% (n=109) currently had at least 1 dog and 2.5% (n=34) had at least 1 cat. Pet ownership during infancy was associated with sensitization to cats or dogs (adjusted odds ratio [aOR], 4.24; 95% confidence interval [CI], 1.29–13.98), wheezing within 12 months (aOR, 5.56; 95% CI, 1.65–18.75) and current asthma (wheezing episode in the last 12 months+diagnosed asthma by physicians) (aOR, 6.36; 95% CI, 1.54–26.28). In contrast, pet ownership during the last 12 months was not associated with sensitization to cats or dogs or current asthma. CONCLUSION: Indoor pet exposure during infancy can be critical for developing sensitization to cats or dogs and asthma in childhood. Avoidance of pet exposure in early life may reduce sensitization to cats or dogs and development of asthma.
Allergens ; Animals ; Asthma ; Bronchial Provocation Tests ; Cats ; Child ; Cohort Studies ; Dogs ; Humans ; Infant ; Korea ; Medical Records ; Methacholine Chloride ; Odds Ratio ; Ownership ; Parturition ; Pets ; Prevalence ; Protective Factors ; Respiratory Sounds ; Risk Factors ; Skin ; Spirometry

PURPOSE: Data are lacking on the association between the allergic rhinitis (AR) phenotype and sensitization to specific allergens or bronchial hyperresponsiveness (BHR) in children. We here investigated risk factors and comorbidities, including sensitization to specific allergens and BHR, for the AR phenotype by AR and its Impact on Asthma (ARIA) classification in a general population-based birth cohort study. METHODS: We enrolled 606 children aged 7 years from the Panel Study of Korean Children. The AR phenotype was assigned in accordance with the ARIA classification in children. Skin prick tests and Provocholine provocation test were performed. Risk factors and comorbidities for AR phenotypes were then analyzed. RESULTS: The prevalence of mild and moderate to severe AR in our study cohort was 37.2% and 8.8%, respectively. Recent use of analgesics or antipyretics and current cat ownership were associated with the risk of mild persistent AR. Sensitizations to Dermatophagoides Pteronyssinus (Der p), Japanese hop and cat were associated with moderate to severe persistent AR. Children with moderate to severe AR had a higher risk of current asthma and BHR compared to mild AR cases (adjusted odds ratio [aOR], 5.26; 95% confidence interval [CI], 1.77–15.62). Moderate to severe AR with allergic sensitization was associated with the highest risk of BHR (aOR, 11.77; 95% CI, 3.40–40.74). CONCLUSIONS: Moderate to severe-persistent AR is more closely related to respiratory comorbidities and sensitizations than mild AR. Stratifying the AR phenotype by ARIA classification may assist in disease management.
Allergens ; Analgesics ; Animals ; Antipyretics ; Asian Continental Ancestry Group ; Asthma ; Bronchial Hyperreactivity ; Cats ; Child ; Classification ; Cohort Studies ; Comorbidity ; Dermatophagoides pteronyssinus ; Disease Management ; Humans ; Methacholine Chloride ; Odds Ratio ; Ownership ; Parturition ; Phenotype ; Prevalence ; Rhinitis, Allergic ; Risk Factors ; Skin