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Introduction: There remains a significant therapeutic need for small-cell lung cancer (SCLC). We and others have reported high frequency of copy number gains in cytogenetic bands encoding fibroblast growth factor receptor 1 (FGFR1) in SCLC tumors and cell lines. Methods: Thirteen SCLC cell lines and 68 SCLC patient tumor samples were studied for FGFR1 amplification. Growth inhibition assays were performed using PD173074, a pan-FGFR inhibitor to determine the correlation between FGFR1 expression and drug sensitivity. Results: We did not detect FGFR1 mutations in SCLC cell lines. Focal amplification of FGFR1 gene was found in five tumor samples (7%), with high-level focal amplification in only one tumor sample (1%). Amplification owing to polysomy of chromosome 8, where FGFR1 locates, was observed in 22 tumor samples (32%). There was no correlation between FGFR1 gene copy number and messenger RNA expression or protein expression in SCLC cells. FGFR inhibitor sensitivity correlated with FGFR1 copy number determined by real-time polymerase chain reaction assay ( r = −0.79; p = 0.01). Conclusion: FGFR1 gene mutations and focal amplification are rare in SCLC, but polysomy of chromosome 8 is relatively common. FGFR1 copy number gain predicts sensitivity to FGFR inhibition, and FGFR expression correlates inversely with chemosensitivity.

Objective : Therefore, we evaluated the relationship between the subclinical hypothyroidism and red cell distribution width (RDW) levels in a healthy population. Subjects and methods : The medical records of 23,343 consecutive health subjects were reviewed. Subjects were classified into four thyroid stimulating hormone (TSH) groups to determine the correlation between TSH and other variables in detail (0.3 to < 2.5 mU/L, 2.5 to < 5 mU/L, 5 to < 7.5 mU/L, and ≥ 7.5 mU/L). Results : In the multivariate linear regression analysis, RDW was associated with TSH levels, and e-GFR was inversely associated with TSH levels, respectively (standardized beta coefficient = 0.102, -0.019; p < 0.001, p < 0.001). After adjusting for age and sex, in the four groups, TSH levels were significantly correlated with RDW, estimated glomerular filtration rate (e-GFR), and free thyroxine (fT4) levels in all groups. Furthermore in the 4 th group, RDW levels were more strongly associated with TSH levels than in the other groups (p = 0.006). Conclusions : RDW levels are correlated with euthyroid and subclinical thyroid status. Notably, RDW is more correlated with subclinical hypothyroidism than the euthyroid status. This study presents the relationship between the RDW levels and thyroid function using TSH level in a large healthy population. Objetivo : Avaliamos a relação entre o hipotireoidismo subclínico e os níveis de distribuição do tamanho dos eritrócitos (RWD) em uma população saudável. Pacientes e métodos : Foram revisadas as fichas médicas de 23.343 sujeitos saudáveis consecutivos. Os sujeitos foram classificados em quatro grupos de nível de hormônio tireoestimulante (TSH) para se determinar a correlação entre o TSH e outras variáveis, em detalhe (0,3 a < 2,5 mU/L; 2,5 a < 5 mU/L; 5 a < 7,5 mU/L; e ≥ 7,5 mU/L). Resultados : Na análise de regressão linear múltipla, a distribuição do tamanho dos eritrócitos (RWD) foi associada aos níveis de TSH, e a taxa estimada de filtração glomerular (e-GFR) foi inversamente associada aos níveis de TSH, respectivamente (coeficiente betapadronizado = 0,102; -0,019; p < 0,001; p < 0,001). Depois do ajuste para idade e sexo, nos quatro grupos, os níveis de TSH se correlacionaram significativamente com os níveis de RDW, e-GFR e tiroxina livre (fT4) em todos os grupos. Além disso, no quarto grupo, os níveis de RDW estiveram mais fortemente associados aos níveis de TSH do que nos outros grupos (p = 0,006). Conclusões : Os níveis de RDW estão correlacionados com o estado eutiroide e com o hipotireoidismo subclínico. Notavelmente, a RDW é mais correlacionada com o hipotireoidismo subclínico do que com o estado eutiroide. Este estudo apresenta uma relação entre os níveis de RDW e a função tiroidiana por meio da concentração de TSH em um grande número de indivíduos saudáveis.

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 physi cians) (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. (Allergy Asthma Respir Dis 2019;7:99-105)

Purpose Adherence is a major component of successful medical treatment. However, non-adherence remains a barrier to effective delivery of healthcare worldwide. Methods Twenty healthcare facilities (secondary or tertiary hospitals) belonging to the Korean Academy of Pediatric Allergy and Respiratory Diseases (KAPARD) participated. Questionnaires were given to patients currently receiving treatment in the form of inhalant useor oral intake or transdermal patch for mild to moderate asthma. Results A total of 1,838 patients responded to the questionnaire. Mean age was 5.98 ± 3.79 years (range: 0-18 years). With help from their caregivers, the percentage of patients that answered “taking as prescribed” was 38.04% for inhalant users, 50.09% for oral medication users and 67.42% for transdermal users. Transdermal patch users had significantly greater adherence compared to the other 2 groups (P < 0.001). The 34.15% of inhalant users, 70.33% of oral medication users and 93.00% of transdermal patch users felt that their medication delivery system was “Easy” or “Very easy” to use (P < 0.001). “Method of administration” was deemed to be the most difficult part of the treatment regimen to follow, and 76.7% of patients preferred once-daily administration (i.e., “Frequency of administration”). Conclusions Asthma medication adherence in young children was found to be better in the transdermal patch group. This may be due to requiring fewer doses and easy to follow instructions. From an adherence point of view, the transdermal patch seems more useful for long-term asthma control in children compared to oral or inhaled medicine.

OBJECTIVE Type B insulin resistance due to autoantibodies against the insulin receptor is characterized by diabetes refractory to massive doses of insulin, severe hypercatabolism, hyperandrogenism, and a high mortality rate. We analyzed the efficacy of combined immunosuppressive therapy in the management of this extreme form of diabetes. RESEARCH DESIGN AND METHODS We performed a prospective cohort study including patients with confirmed insulin receptor autoantibodies, monitored for median 72 months (25th, 75th interquartile range 25, 88), and treated with rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine. Remission was defined as the amelioration of the hyperglycemia and discontinuation of insulin and/or normalization of hyperandrogenemia. RESULTS All data are given as median (25th, 75th interquartile range). Twenty-two patients aged 42 (25, 57) years, 86.4% women, fulfilled inclusion criteria. At baseline, fasting glucose was 307 (203, 398) mg/dL, HbA1c was 11.8% (9.7, 13.6), total testosterone (women) was 126 (57, 571) ng/dL (normal 8–60), and daily insulin requirement was 1,775 (863, 2,700) units. After 5 (4, 6.3) months, 86.4% (19 of 22) of patients achieved remission, documented by discontinuation of insulin in all patients, normal fasting glucose of 80 (76, 92) mg/dL, HbA1c of 5.5% (5.2, 6), and testosterone (women) of 28 (20, 47) ng/dL. During follow-up of 72 (25, 88) months, 13.6% (3 of 22) of patients developed disease recurrence, occurring 24 (22, 36) months after initial remission, which responded to repeated therapy. None of the patients died. CONCLUSIONS Combined immunosuppressive therapy has changed the natural history of this disease, from 54% mortality to a curable form of diabetes and, as such, should be recommended in patients with type B insulin resistance.

Developing proteomic biomarkers is valuable for evaluating therapeutic effects of drugs and generating better treatment strategies. However, conventional protein analysis is often challenging due to inadequate sample size of clinical specimens, lack of assay reproducibility, accuracy, and sensitivity. A novel capillary isoelectricfocusing (IEF) immunoassay system (NanoPro) was used to study the dynamic phosphorylation status of signaling molecules in non–small cell lung cancer (NSCLC) cells treated with EGFR tyrosine kinase and MEK inhibitors. NanoPro showed the same dynamic ERK phosphorylation as Western blotting with good assay reproducibility using 1,000 times less protein. The IEF separation in NanoPro system enables multiple protein phosphorylation isoforms to be resolved and detected simultaneously. With NanoPro, we identified a specific on-target mitogen-activated protein/extracellular signal–regulated kinase (MEK) response pattern to MEK inhibitor PD325901, which was not detectable by Western blot analysis. We also revealed a MEK2 signal that may be associated with NSCLC cell sensitivity to the EGF receptor inhibitor erlotinib, and distinguished erlotinib-sensitive cells from intrinsic as well as acquired resistant cells to erlotinib. Moreover, NanoPro could differentiate human ERK1 isoforms from the mouse isoforms based on their isoelectric point differences and showed that erlotinib effectively inhibited ERK phosphorylation in targeted human xenograft cancer cells but not in surrounding mouse stromal cells. With 8 μg of tumor aspirates, we precisely quantified the response of 18 signaling molecules to erlotinib and MEK1 inhibitor treatments in an NSCLC patient. NanoPro's higher sensitivity, better resolution of protein phosphorylation status, and reduced tissue requirement warrant NanoPro's investigation for future drug development and evaluation of drug effects of targeted therapies. Mol Cancer Ther; 12(11); 2601–13. ©2013 AACR.

Small cell lung cancer (SCLC) at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31 nM) was much more potent than 17-allylamino-17-demethoxygeldanamycin (17-AAG), a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of receptor-interacting serine/threonine-protein kinase 1 (RIP1), a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 small interfering RNA (siRNA) or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through the downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib+doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immunocompromised mice. We conclude that ganetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.

Aims/Introduction Recently, patient‐tailored statin therapy was proven effective for achieving target low‐density lipoprotein (LDL) cholesterol levels. It is unclear, however, whether this therapeutic modality would be effective for atherogenic lipid profiles and inflammation in patients with type 2 diabetes. Materials and Methods The present study was an 8‐week, multicenter, single‐step titration trial of patient‐tailored atorvastatin therapy (10, 20 and 40 mg) according to baseline LDL cholesterol levels in 440 patients with type 2 diabetes. We measured the LDL particle size by polyacrylamide gel electrophoresis, and used high‐sensitivity C‐reactive protein (hsCRP) and adiponectin as surrogate markers of inflammation. Results In the intention‐to‐treat analysis, 91% of the patients achieved their LDL cholesterol targets (

BACKGROUND: The identification and characterization of the gene, ERRFI1, in diabetes has not been reported. In this study, we evaluated the relationship between ERRFI1 polymorphism and characteristics of type 2 diabetes mellitus (T2DM) in Korea.SUBJECTS AND METHODS: We conduct a case-control study involving T2DM patients (n=342) and controls (n=473).RESULTS: A novel single nucleotide ERRFI1 gene polymorphism at +807(T/G) was found. G genotype frequency was 40.1% in the diabetic group and 42.7% in the control group; the difference was not significant (p=0.45). In the diabetic group, the urine albumin to creatinine ratio (ACR) was lower in the G genotype than in the T genotype (P=0.004). In males with T2DM, those with the G genotype displayed lower systolic blood pressure (P=0.01) and higher glomerular filtration rate (P=0.048) compare to those with the T genotype. In females with T2DM, urine ACR was low in those with the G genotype than in those with the T genotype (P=0.02). In the diabetic group, patients who harboring T allele had a 1.81 times higher risk of diabetic nephropathy than the G allele (95% CI 1.11–2.96, P=0.02). In females with T2DM, patients who harboring T allele had a 2.12 times higher risk of diabetic nephropathy (95% CI 1.07–4.1, P=0.03).CONCLUSIONS: We identify new loci associated with glycemic traits in diabetes and this finding indicates the potential of ERRFI1 as a novel therapeutic target of diabetic nephropathy.

Background Koreans eat rice, which is usually served in a rice bowl. We investigated the effect of a meal plan using small rice bowls on the total energy intake (TEI) and the marcronutrient intake in Korean men with type 2 diabetes. Methods A total of 62 men with type 2 diabetes were divided by body mass index (BMI) (normal weight [NW], BMI60%). The 3-day dietary records were analyzed for TEI and proportions of macronutrients, before and 2 weeks after a small-sized (300 mL) rice bowl based education was given. Results There were no significant differences in the age and BMI within the sub-groups by BMI and PCI groups. In baseline, the ratio of TEI to recommended total energy intake (RTR) of OW and OB were higher than that of NW. The PCI of HC was higher than that of LC and alcohol intake of HC was lower than that of LC. After education, the reduction of RTREI in OB was higher than that in OW and NW. The reduction of PCI in HC was higher than that of LC. Conclusion A small rice bowl based meal plan was effective for the reduction of energy intake and control of marcronutrient intake in Korean obese men with type 2 diabetes consuming a high carbohydrate diet.

Neurofibromatosis type 1 (NF-1) is a genetically inherited disorder that may cause skin abnormalities and tumors that form on nerve tissues. These tumors can be small or large and can occur anywhere in the body, including the brain, spinal cord, or other peripheral nerves. Retroperitoneal lymphangiomas are very rare benign malformations of the lymphatic system. About 95% lymphangiomas occur in the skin and the subcutaneous tissues of the head, neck and axillary region and the remaining 5% appear in other parts of the body such as lungs, pleura, pericardium, liver, gallbladder, kidney, and the mesentery. Herein, we report the case of a giant retroperitoneal lymphangioma in a patient with NF-1 with a review of the literature.

Increased levels of transglutaminase 2 (TGase 2) expression have been reported in many inflammatory diseases, as well as in drug resistant cancer cells. Previous reports have shown that TGase 2 is capable of inducing nuclear factor-kappaB (NF-kappaB) activation via depletion of inhibitor of kappaB (I-kappaB)alpha through polymerization in the absence of I-kappaBalpha kinase activation. This raises the question of whether increased expression of TGase 2 can extend NF-kappaB activation mediated by a canonical activation pathway. In the TGase 2-inducible EcR23/TG cell line, TGase 2 over-expression resulted in sustained activation of NF-kappa B in the presence of TNF-alpha, for up to 24 hrs, while in the absence of TGase 2 induction, NF-kappaB activity was restored to basal levels within 6 hrs of TNF-alpha treatment. In mice injected with an adenovirus vector expressing TGase 2, NF-kappaB was constitutively activated for up to 5 days, whereas Adeno/GFP-injected mice exhibited attenuated activation of NF-kappaB in response to TNF-alpha stress. Thus, the presence of increased levels of TGase 2 may exacerbate NF-kappa B activation in inflammatory states.

There has been considerable interest in virulence genes in the plasticity region of Helicobacter pylori , but little is known about many of these genes. JHP940, one of the virulence factors encoded by the plasticity region of H. pylori strain J99, is a proinflammatory protein that induces tumor necrosis factor-alpha and interleukin-8 secretion as well as enhanced translocation of NF-κB in cultured macrophages. Here we have characterized the structure and function of JHP940 to provide the framework for better understanding its role in inflammation by H. pylori . Our work demonstrates that JHP940 is the first example of a eukaryotic-type Ser/Thr kinase from H. pylori . We show that JHP940 is catalytically active as a protein kinase and translocates into cultured human cells. Furthermore, the kinase activity is indispensable for indirectly up-regulating phosphorylation of NF-κB p65 at Ser276. Our results, taken together, contribute significantly to understanding the molecular basis of the role of JHP940 in inflammation and subsequent pathogenesis caused by H. pylori . We propose to rename the jhp940 gene as ctkA ( c ell t ranslocating k inase A ).

e21150Background: Despite osimertinib revealed marked antitumor activity in EGFR T790M mutant lung adenocarcinoma, second tumor biopsy is inevitably required for detection of T790M mutation. We inv...

Background The Korean National Health and Nutrition Examination Surveys reported 65% of daily energy intake (EI) as carbohydrate (CHO) in the Korean population and main source of CHO was cooked rice. We used a standardized-small sized rice bowl for diet education and investigated its effectiveness on body weight, glucose and lipid, compared to the conventional food exchange system in type 2 diabetes obese women. Methods Type 2 diabetic women with body mass index ≥ 23 kg/m2 were randomly assigned to small rice bowl-based meal plan (BM) and food exchange-based meal plan (ExM) group. Both groups were asked to reduce their EI by 500 kcal/day for 12 weeks. The macronutrient composition was instructed: 55 to 60% of EI as CHO, 15 to 20% as protein, and 20 to 25% as fat. BM group received only a simple instruction for application of the rice bowl. Nutrient intake was estimated with the 3-day dietary records. Results Finally, 44 subjects finished the study. The percent reduction of body weight was significant both BM group (-5.1 ± 2.6%) and ExM group (-4.8 ± 2.8%) after 12 weeks (P < 0.001) but there was no difference between the groups. There was no difference in the proportional change of CHO, protein and fat in EI between the groups. Additionally, the change of HbA1c and low density lipoprotein-cholesterol were not significantly different between the two groups. Conclusion The BM group was as effective as ExM for body weight and glucose control in type 2 diabetes obese women.

Background The aim of this study was to explore the differences in the clinical characteristics and diagnostic rates of diabetes mellitus (DM) according to various criteria in different age groups and to evaluate the efficacy of each criterion for screening older patients. Methods We studied 515 patients and measured the fasting plasma glucose level (FPG), 2-hour plasma glucose level after the 75 g oral glucose tolerance test (2-hour postload glucose [2-h PG]), and glycosylated hemoglobin (HbA1c) for re-evaluation of hyperglycemia without a history of diabetes. Patients with newly diagnosed DM were grouped by age as younger (

Background: The serum concentrations of ferritin and adiponectin are associated with several metabolic disorders and have been used as predictors of insulin resistance and metabolic syndrome. But there have been no reports demonstrating a direct correlation between serum ferritin and adiponectin levels. We performed this study to evaluate the association between serum ferritin and adiponectin concentrations.Subjects and methods: We evaluated a total of 995 subjects from the Korea Rural Genomic Cohort Study in a population-based cross-sectional study. Extensive clinical and laboratory measurements, including adiponectin and ferritin concentrations, were recorded.Results: Univariate analysis revealed that the serum adiponectin level was correlated with age, sex, BMI, diastolic blood pressure, triglyceride, HDL-cholesterol, fasting blood glucose, fasting insulin, HOMA-IR, hs-CRP, and ferritin. Multivariate analysis demonstrated that the adiponectin concentration was correlated with age, BMI, fasting glucose, hs-CRP, and ferritin. The ferritin concentration was the most powerfully associated with serum adiponectin. In non-diabetic subgroups, the adiponectin level was correlated with BMI, triglyceride, HDL-cholesterol, fasting glucose, and ferritin level in multivariate analysis. In diabetic subgroups, the adiponectin level was correlated with BMI, triglyceride, hs-CRP, and ferritin level in multivariate analysis.Conclusions: The serum adiponectin concentration was correlated with conventional clinical variables, but the most powerfully associated factor was the serum ferritin level.

Transglutaminase 2 (TGase 2) catalyzes covalent isopeptide bond formation between glutamine and lysine residues. Recently, we reported that TGase 2 activates nuclear factor-kappa B (NF-κB) by depleting inhibitor of NF-κBα (I-κBα) levels via polymer formation. Furthermore, TGase 2 expression synergistically increases NF-κB activity with canonical pathway. The major I-κB proteins such as I-κBα and I-κBβ resemble each other in both primary sequence and tertiary structure. However, I-κBβ does not degrade fully, while I-κBα degrades immediately in response to most stimuli. We found that I-κBβ does not contain any of the previously identified TGase 2 target sites. In this study, both an in vitro cross-linking assay and a TGase 2 transfection assay revealed that I-κBβ is independent from TGase 2-mediated polymerization. Furthermore, increased I-κBβ expression reversed NF-κB activation in cancer cells, compensating for the loss of I-κBα via TGase 2 polymerization.

We recently reported that increased transglutaminase 2 (TGase 2) expression correlates with increased resistance to the cancer drug doxorubicin in breast-cancer cell lines. Interestingly, high-molecular-weight (HMW) proteins also increased with increased TGase 2 expression in the drug-resistant cell lines. TGase 2 is likely to be responsible for the formation of HMW proteins, because TGase 2 catalyzes cross-linking between proteins. Although the role of the HMW proteins is unclear, we demonstrated that TGase 2 inhibition increases drug sensitivity in breast-cancer cells. Herein we find that TGase 2 inhibition by cystamine dramatically reduces the level of HMW proteins. Identification of the HMW proteins may suggest the mechanism of cancer drug resistance associated with aberrant TGase 2 function. To explore the identities of HMW proteins, we performed in-gel tryptic digestions of unresolved HMW proteins and analyzed the resulting peptides using LC-MALDI-MS/MS. Most of the identified proteins were associated with gene regulation, such as polyadenylate-binding proteins, translation initiation factors, and ribonucleoproteins. This finding suggests that TGase 2 may participate in gene regulation, in addition to its role in cell adhesion.

Background & Objective: We aimed to analyse the risk factors of atopic dermatitis (AD) in Korean schoolchildren in 2010. Methods: A nationwide, cross-sectional study was conducted in children aged 6-7 years and adolescents aged 12-13 years who were randomly selected. Information was obtained through a Korean version of the International Study of Asthma and Allergies in Childhood questionnaire (ISAAC), and skin prick tests were performed. AD-diagnosed children were selected for risk factor analysis by using logistic regression. Results: In the univariate logistic regression analysis in 6-7 year-old children, possible risk factors were atopy, a parental history of allergic disease, the use of antibiotics during infancy, a history of having moved into a newly built house during infancy, the presence of visible mould in the house, and remodelling of house within 12 months. The statistical significance persisted after adjustment. However, antibiotic use during infancy and remodelling within 12 months showed no statistical significance as a risk factor for AD. In contrast, multivariate logistic regression analysis in adolescents demonstrated that female sex, atopy, a parental history of allergic diseases, the presence of visible mould in the house, and a history of having moved into a newly built house during infancy was associated with AD. There was no significant association between AD and other risk factors. Conclusion: In Korean schoolchildren, risk factors such as atopy, the presence of parental allergic diseases, moving into a newly built house during infancy and visible mould in the house were associated with AD.

RAS-driven tumors are often difficult to treat with conventional therapies and therefore, novel treatment strategies are necessary. The present study describes a promising targeted therapeutic strategy against non-small cell lung cancer (NSCLC) harboring KRAS mutations, which has intrinsic resistance to MEK inhibition. Results showed that intrinsic resistance to MEK inhibition occurred via high AKT expression by PI3K activation as a bypass pathway. The HSP90 inhibitor AUY922 suppressed PI3K-AKT-mTOR and RAF-MEK-ERK, and rendered cells sensitive to trametinib (GSK1120212). Synergy from the combination of the two drugs was observed in only sub-therapeutic concentrations of either drug. Dual inhibition of the HSP90 and MEK signaling pathways with sub-therapeutic doses may represent a potent therapeutic strategy to treat KRAS-mutant NSCLC with intrinsic resistance to MEK inhibition and to resolve the toxicity observed upon dual inhibition of AKT and MEK at therapeutic doses in clinical trials.

We read the paper by Sevket BALTA and cols. and thanks for your interest in our study entitled “Red Cell Distribution Width in Subclinical Hypothyroidism” (). As we mentioned in the discussion part, the RDW can be affected by some disease conditions such as recent blood transfusion, renal dysfunction, hepatic dysfunction, anemia related nutritional deficiencies (i.e. iron, vitamin B12, and folic acid), bone marrow dysfunction, inflammatory diseases, chronic or acute systemic inflammation (-) and some medications () is already well [...]

We report a case of split liver transplantation (SLT) for two adult recipients, which was the first successful case in Korea. The brain-dead donor was a 22-year-old man weighing 65 kg, but his liver volume was estimated as 2120 mL on computed tomographic volumetry. As it seemed to be too large for a 60-kg recipient candidate, SLT was planned after assessment of lobar liver volume and middle hepatic vein anatomy. The right lobe was mobilized first and the liver parenchyma transected along the right border of the middle hepatic vein. The 1240-g right lobe (segments 5 to 8) graft was implanted into a 57-year-old male patient with acute-on-chronic liver failure in the same manner as a living-donor graft. After that, routine procedures of cadaveric multiorgan procurement were performed. The 670-g left lobe (segments 1 to 4) with a retrohepatic vena cava, common bile duct, and aortic patch was implanted into another 37-year-old male recipient. These two recipients recovered uneventfully surviving 12 months to date. We integrated the surgical techniques learned from hundreds of adult-to-adult living donor liver transplants into this first trial of two adult SLT.

The non-small cell lung cancer (NSCLC) patients with EGFR-sensitive mutations can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib. Unfortunately, even though the intrinsic EGFR-TKI resistant patients harboring the EGFR-sensitizing mutation, a part of those are still resistant to EGFR-TKI. And, it has been reported that both PTEN loss and NF-kB activation contribute to intrinsic EGFR-TKI resistance in EGFR-mutant lung cancer. Transglutaminse 2 (TG2) is post-translational modification enzyme and known to induce degradation of tumor suppressors including PTEN and IκB-α with peptide cross-linking activity. Because TG2 was known as a regulator of PTEN and IκB-α (NF-κB inhibitor) level in cytosol, we have explored if TG2 can be another key regulator to the intrinsic resistance of EGFR-TKI in the intrinsic EGFR-TKI resistant NSCLC cell. In NSCLC with EGFR-sensitive mutations, we first found that higher TG2 expression level and lower PTEN and IκB-α expression levels in the intrinsic EGFR-TKI resistant NSCLC compare with EGFR-TKI sensitive NSCLC. TG2 stably expressing EGFR-TKI sensitive NSCLC cells harboring EGFR mutations showed reduction of both PTEN and IκB-α and exhibited EGFR-TKI resistance. In reverse, TG2 stably downregulated H1650, intrinsic EGFR-TKI resistant NSCLC cell harboring EGFR sensitive mutation, restored EGFR-TKI sensitivity via PTEN and IκB-α restoration by TG2 loss. Xenograft study using TG2 overexpressed and downregulated NSCLC cells also verified our in vitro results. Therefore, we have demonstrated that TG2 elicits the intrinsic EGFR-TKI resistance via PTEN loss and activation of NF-κB pathway. These results suggest that TG2 may be a useful target for overcoming the intrinsic EGFR-TKI resistance of NSCLC harboring EGFR sensitive mutations. Citation Format: Junyoung Choi, Hannah Yang, Sang-We Kim, Kyung Hae Jung, Kang-Seo Park, Dae Ho Lee. Transglutaminase 2(TG2) induces the intrinsic EGFR-TKI resistance in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2017-4096

Background: Bcl-2 family is a group of apoptosis regulators that plays an anti-apoptotic role for cell survival and is known to contribute to induce chemotherapy resistance in small cell lung cancer (SCLC). ABT-737 is an anti-cancer drug that induces apoptosis by selectively blocking the activities of Bcl-2 and Bcl-xL, but not Mcl-1. Consequently, the efficacy of ABT-737 is largely restricted in the presence of Mcl-1. Heat-shock-protein 90 (Hsp90) is highly expressed in most tumors and Hsp90 inhibitors induce the proteasomal degradation of Hsp90 client proteins. In addition, Hsp90 inhibitor can reduce Mcl-1 expression, a down-stream of Akt and Erk pathway. Furthermore, Hsp90 inhibitor inhibits activities of NF-κB by degradation of IKK. Thus, we show that downregulation of Mcl-1 and NF-κB by Hsp90 inhibitor can lead to synergistic pro-apoptotic effects with ABT-737. Materials and methods: The proliferative activity, apoptotic activities, and expression of apoptotic proteins were assessed in SCLC cell lines after treatment with ABT-737, NVP-AUY922, or both drugs. The synergy effects of ABT-737 and NVP-AUY922 were analyzed by cell viabilities with different concentrations in SCLC cell lines, and the combination index values were < 1. In addition, the synergy effects of the drugs were showed with xenograft model with human SLCL cell line in vivo. Results: Here, we show that NVP-AUY922, an Hsp90 inhibitor, can potentiate the pro-apoptotic effects of ABT-737 not only by reducing the levels of Akt but also by inhibiting pNF-κB, both of which are proteins regulating apoptosis signaling. Western blot analysis revealed that proteins associated with apoptosis such as PARP, Caspase 3 and 7 were more upregulated in SCLC cells exposed to the drug combination than in cells exposed to NVP-AUY922 or ABT-737 alone. In addition, Annexin V & dead cell assay showed dual inhibition of the Hsp90 and Bcl-2 signaling pathways more increased apoptotic cells and dead cells in SCLC. In our result, ABT-737 induced apoptosis by blocking Bcl-2 activation, and NVP-AUY922 blocked the levels of Hsp90 client proteins, Akt and pErk, ultimately leading to decreased level of Mcl-1. In addition, NVP-AUY922 induced degradation of IKK, and increased IκB-α inhibited activation of NF-κB. And this combination treatment showed higher BIM and BID expression, pro-apoptotic proteins, than single treatment. Furthermore, synergy effects of combination were verified in xenograft model with human SCLC cell line. Conclusions: Consequently, NVP-AUY922 synergizes with ABT-737 to induce apoptosis by reducing activities of Mcl-1 and NF-κB in SCLC. This study suggests that adopting an appropriate combination of drugs can lead to better outcomes compared with monotherapy in SCLC. Citation Format: Hannah Yang, Kang-Seo Park, Junyoung Choi, Sang-We Kim Kim, Dae Ho Lee. Hsp90 inhibitor (NVP-AUY922) enhances anti-cancer effect of Bcl-2 inhibitor (ABT-737) in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2022. doi:10.1158/1538-7445.AM2017-2022

Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial–mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1- and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target.

We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I β and δ isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies.

Accidental slippage of vascular clamps during living donor hepatectomy can induce brisk bleeding and even imperil the donor. After practicing more than 1000 cases of living donor hepatectomy, the investigators realized that specialized suture techniques were important to secure the vascular closure to prevent unnecessary bleeding. For secure division of intrahepatic vein branches, we devised a continuous penetration suture method in which the orders of procedures were changed to clamping-closure-cut sequence. For secure division of the main and accessory hepatic vein branches from the inferior vena cava, we applied stay sutures at each corner and midpoint of the hepatic vein stump so as not to permit its slippage. After application of these methods, we did not experience any episode of accidental clamp slippage. We are sure that these suture techniques are beneficial to prevent unnecessary bleeding during living donor hepatectomy and to make surgeons feel at ease during the living donor operation.

We analyzed the anatomy and reconstruction of the right hepatic artery (RHA) in 96 cases of adult-to-adult living donor right liver transplantations, during 2002. Most right livers had a single orifice (n = 185, 96%). Seven right livers (4%) showed multiple arteries, namely a replaced artery in five cases and accessory arteries in two cases. Three liver grafts had two separate orifices: both arterial stumps were reconstructed in one case, and accessory arteries were ligated in two cases because of sufficient back bleeding. The mean diameter of the graft RHA was 2.4 mm (1-4). More than 60% (59 of 96) of graft arteries were anastomosed with distal branches of recipient RHA for size matching. Eleven graft arteries were anastomosed to vessels other than the RHA, namely the left hepatic artery [LHA] in eight right gastroepiploic artery in three: for size matching in five and due to previous injury of RHA in six. Five cases showed significant size-mismatches of more than twofold. The median follow-up period was 270 days. In one patient, an intramural thrombus developed on postoperative day 3 requiring a revision of the anastomosis. In another patient, arterial stenosis occurred on postoperative day 16 a time when collateral arteries had developed. The overall complication rate related to arterial reconstruction was 2%. In conclusion, with precise knowledge of the anatomy, an adequate selection of recipient arterial stump, and an experienced technique, a desirable result may be achieved in right lobe transplantation.

Purpose Allergic rhinitis (AR) is a common chronic disease. Many factors could affect the development of AR. We investigated early-life factors, such as delivery mode, feeding method, and use of antibiotics during infancy, which could affect the development of AR. In addition, how interactions between these factors and innate gene polymorphisms influence the development of AR was investigated. Methods A cross-sectional study of 1,828 children aged 9-12 years was conducted. Three early-life factors and AR were assessed by a questionnaire. Skin prick tests were done. Polymorphisms of TLR4 (rs1927911) and CD14 (rs2569190) were genotyped. Results Use of antibiotics during infancy increased the risk of AR (aOR [95% CI] 1.511 [1.222-2.037]) and atopic AR (aOR [95% CI], 1.565 [1.078-2.272]). There were synergistic interactions between caesarean delivery, formula feeding, and use of antibiotics in the rate of atopic AR (aOR [95% CI], 3.038 [1.256-7.347]). Additional analyses revealed that the risk for the development of AR or atopic AR subjects with the TLR4 CC genotype were highest when all the 3 early-life factors were present (aOR [95% CI], 5.127 [1.265-20.780] for AR; 6.078 [1.499-24.649] for atopic AR). In addition, the risk for the development of AR or atopic AR in subjects with the CD14 TT genotype were highest when all the 3 early-life factors were present (aOR [95% CI], 5.960 [1.421-15.002] for AR; 6.714 [1.440-31.312] for atopic AR). Conclusions Delivery mode, feeding method, and use of antibiotics during infancy appeared to have synergistic interactions in the development of AR. Gene-environment interactions between polymorphism of innate genes and early- life risk factors might affect the development of AR.

Purpose: The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of Janus-activated kinases (JAK) inhibitor, AZD1480, for treatment of SCLC in vitro and in vivo. Experimental Design: JAK1 and JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell-cycle distribution and apoptosis induction was studied. Antitumor effects of AZD1480 in tumor xenografts were assessed. Results: AZD1480 significantly inhibited growth of six out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μmol/L. Knocking down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in an increase of 4N DNA content and histone 3 serine 10 phosphorylation, indicative of G2–M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved caspase 3, cleaved PARP, and increase of annexin-V–positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31-positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment. Conclusions: JAK inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation. Clin Cancer Res; 19(24); 6777–86. ©2013 AACR.

The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.

Due to the increased prevalence of papillary thyroid carcinoma (PTC), difficult cases and unexpected events have become more common during long-term follow-up. Herein we reported four cases that exhibited poor progress during long-term follow-up. All the cases were diagnosed with PTC and treated with total thyroidectomy before several years, and the patients had been newly diagnosed with recurrent and metastatic PTC. These four cases included recurred PTC with invasion of large blood vessels, a concomitant second malignancy, malignant transformation, and refractoriness to treatment. Physicians should closely monitor patients to promptly address unforeseen circumstances during PTC follow-up, including PTC recurrence and metastasis. Furthermore, we suggest that the development of a management protocol for refractory or terminal PTC is also warranted.

Breastfeeding is widely recommended to reduce risk of sensitization, eczema and asthma. However, the role of breastfeeding in prevention of allergic diseases is uncertain. We aimed to investigate whether the relationship between breastfeeding and sensitization to aeroallergens is modified by cluster of differentiation 14 (CD14) genotype. This study included 1,828 school children aged 9-12. We administered a detailed questionnaire and genotyped the CD14C-159T polymorphism. Skin prick tests for 12 aeroallergens were performed. School children who had been breastfed were less likely sensitized to aeroallergens (adjusted odds ratio [aOR] 0.712, 95% confidence interval [CI]: 0.555-0.914). There was no significant association between CD14C-159T genotype and atopy. Breastfeeding was associated with a decreased risk of atopic sensitization in children with CT/CC genotype (aOR 0.667, 95% CI: 0.463-0.960). Our data might identify the gene-environment interaction between the CD14C-159T polymorphism and breastfeeding in relation to aeroallergen sensitization.

Introduction: Mutant KRAS is feature of more than 25% of non-small cell lung cancers (NSCLC) and exemplifies one of the most popular oncogenic drivers. Ras-driven tumors are often hard to cure with conventional therapies and are necessary novel treatment strategies. Experiment: Using the HSP90 inhibitor NVP-AUY922, we investigated the potential of HSP90 inhibition to overcome the resistance to Trametinib, MEK inhibitor, in lung cancers harboring K-RAS mutant cell lines (H23, H358, H647, H1944, and A549). The synergistic effect of AUY-922 and trametinib was determined by analysis of the combination index (CI). After performing western blotting, we underwent following xenograft study with 6-week-old Balb/c-nu/nu female using H649 and H1944 cell lines. The mice were randomized into groups of 5, and NVP-AUY922 (5 mg/kg) was administered 3 days/week and GSK1120212 (300 μg/kg) was administered 5 days/week for up to 21 days in total. Result: NSCLC cells harboring G13D KRAS mutation showed intrinsic MEK inhibitor resistance via PI3K activation by highly expressed AKT as a bypass pathway. And then, HSP90 inhibitor AUY-922 suppresses both PI3K-AKT-mTOR and RAF-MEK-ERK reactivated by MEK inhibitor GSK1120212 and finally AUY-922 renders intrinsic MEK inhibitor resistant NSCLC cells sensitive to GSK1120212 with significant synergy. Furthermore, we showed this synergistic effect is occurred on sub-effective dose of either drug. Conclusion: The dual inhibition of HSP90 and MEK signaling pathways on sub-effective dose may constitute a potent therapeutic strategy to treat intrinsic MEK inhibitor resistant G13DKRAS mutant NSCLCs for resolving toxicity problem of dual inhibition of AKT and MEK in clinical trials. Citation Format: Dae Ho Lee, Kang-Seo Park, Bora Oh, Mi-Hee Lee, Hannah Yang. HSP90 inhibitor NVP-AUY922 sensitizes intrinsic MEK inhibitor Trametinib-resistant NSCLC cells harboring KRAS mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B90.

Background Expression of transglutaminase 2 (TGase 2) is related to invasion and resistance to chemotherapeutic agents in several cancer cells. However, there has been only limited clinical validation of TGase 2 as an independent prognostic marker in cancer. Methods The significance of TGase 2 expression as an invasive/migratory factor was addressed by in vitro assays employing down-regulation of TGase 2. TGase 2 expression as a prognostic indicator was assessed in 429 Korean patients with early-stage non-small cell lung cancer (NSCLC) by immunohistochemical staining. Results TGase 2 expression increased the invasive and migratory properties of NSCLC cells in vitro, which might be related to the induction of MMP-9. In the analysis of the immunohistochemical staining, TGase 2 expression in tumors was significantly correlated with recurrence in NSCLC (p = 0.005) or in the non-adenocarcinoma subtype (p = 0.031). Additionally, a multivariate analysis also showed a significant correlation between strong TGase 2 expression and shorter disease-free survival (DFS) in NSCLC (p = 0.029 and HR = 1.554) and in the non-adenocarcinoma subtype (p = 0.030 and HR = 2.184). However, the correlation in the adenocarcinoma subtype was not significant. Conclusions TGase 2 expression was significantly correlated with recurrence and shorter DFS in NSCLC, especially in the non-adenocarcinoma subtype including squamous cell carcinoma.

Background: Pinitol is thought to mediate insulin action and improve insulin resistance. We evaluated the effects of pinitol on glycemic control, insulin resistance and adipocytokine levels in type 2 diabetic patients. Material and Method: A total of 66 patients with type 2 diabetes who had been taking oral hypoglycemic agents for at least 3 months were enrolled and randomized to receive pinitol (n = 33) or matching placebo (n = 33). All subjects took 1,200 mg pinitol or placebo and maintained their current oral hypoglycemic agents throughout the study. Results: Mean HbA1c, fasting plasma glucose, and HOMA-IR were significantly lowered more in patients taking pinitol than in those given a placebo. Patients who had an HbA1c over 8.0% showed a greater reduction (p < 0.01) than those who had an HbA1c below 8.0% (p =0.16). In addition, in the group of patients with a HOMA-IR over 2.5, there was a significant decrease in HbA1c compared to that in the group of patients with a HOMA-IR below 2.5. There were no differences in the changes in adiponectin, FFA and CRP between the two groups. Conclusions: Pinitol can mediate insulin action to improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus, especially in patients with insulin resistance.

Background: The purpose of this study was to evaluate the usefulness of an accelerometer in predicting body weight (BW) change during a lifestyle intervention and to find out whether exercise or overall physical activity is associated with change in in sulin sensitivity and body composition. Methods: A total of 49 overweight (body mass index [BMI] ≥ 23 kg/m 2 ) women with diabetes were enrolled and performed lifestyle intervention while monitoring BW, total energy expenditure (TEE) and physical activity energy expenditure (PAEE) using an accelerometer, and energy intake (EI) using a three-day dietary record at baseline and every 2 weeks for 12 weeks. We assessed body composition using bioimpedance analysis and compared the actual BW change to the predicted BW change, which was calculated from the energy deficit (ED) between EI and TEE (ED = EI-TEE). Results: Mean age was 57.2 years, duration of diabetes was 8.0 years, and BMI was 27.8 kg/m 2 . There was no significant differ ence between EI and TEE at baseline. For 12 weeks, the ED was 474.0 kcal · day -1 , which was significantly correlated with BW change (-3.1 kg) (r = 0.725, P < 0.001). However, the actual BW change was 50% lower than the predicted BW change. Both TEE and PAEE correlated with change in KITT (r = 0.334, P = 0.019; r = 0.358, P = 0.012, respectively), BMI (r = -0.395, P = 0.005; r = -0.347, P = 0.015, respectively), and fat mass (r = -0.383, P = 0.007; r = -0.395, P = 0.005, respectively), but only TEE correlated with fat free mass change (r = -0.314, P = 0.030). Conclusion: The accelerometer appears to be a useful tool for measuring TEE under free-living conditions for both short- and long-term periods.

Face detection is required prior to various face-related applications. The objective of face detection is to determine whether or not there are any faces in an image and, if any, the location of each face is shown. Face detection in a natural scene image is challenging due to large variability of face appearances. This paper proposes a face detection algorithm using the 3×3 block rank patterns of gradient magnitude images and a geometrical face model. The 3×3 block rank patterns are used to roughly classify whether the detected face candidate region contains a face or not. Finally, the face, if any, is detected by using a geometrical face model. Experimental results show that the proposed face detection algorithm is insensitive to illumination in natural scene images.

Background The hygiene hypothesis suggests that infectious diseases in early life reduce the risk of allergic diseases. Objective To investigate the association between measles infection during early childhood and the prevalence of allergic diseases, lung function, bronchial hyperresponsiveness (BHR), and sensitization in later childhood. Methods A survey was conducted 5 years after a nationwide measles outbreak in Korea. From September 1 through November 30, 2006, we obtained information on history of measles and allergic diseases but not of measles vaccination through a questionnaire completed by 1,004 schoolchildren aged 6 to 7 years. Furthermore, we measured measles antibody titers and performed skin prick tests, pulmonary function tests, and methacholine challenge tests. Children were divided into groups based on their history of measles infection and antibody titers. Results Prevalence of measles infection was 8.2%. Children with both a positive measles history and a positive antimeasles antibody had significantly higher antimeasles antibody levels than those without a measles history. The prevalence of current rhinitis (adjusted odds ratio [aOR], 1.86; 95% confidence interval [CI], 1.02-3.40), rhinitis ever (aOR, 2.17; 95% CI, 1.19-3.94), and current BHR (aOR, 1.98; 95% CI, 1.04-3.78) was significantly higher in the group with a positive measles history compared with the group with a negative measles antibody. No differences were found among groups in the prevalence of asthma, lung function, provocation concentration that caused a decrease in forced expiratory volume of 1 second of 20%, or sensitization. Conclusion Early measles infection was associated with increased prevalence of rhinitis and BHR at the age of 7 years but has no effect on the development of asthma and allergy at the age of 7 years. This study indicates that common childhood infections such as measles in early age do not protect against later development of allergic diseases.

Transglutaminase 2 (TGase2) is a calcium-dependent, cross-linking enzyme that catalyzes iso-peptide bond formation between peptide-bound lysine and glutamine residues. TGase 2 can activate NF-kappaB through the polymerization-mediated depletion of I-kappaBalpha without IKK activation. This NF-kappaB activation mechanism is associated with drug resistance in cancer cells. However, the polymers cannot be detected in cells, while TGase 2 over-expression depletes free I-kappaBalpha, which raises the question of how the polymerized I-kappaBalpha can be metabolized in cells. Among proteasome, lysosome and calpain systems, calpain inhibition was found to effectively increase the accumulation of I-kappaBalpha polymers in MCF7 cells transfected with TGase 2, and induced high levels of I-kappaBalpha polymers as well in MDA-MB-231 breast cancer cells that naturally express a high level of TGase 2. Inhibition of calpain also boosted the level of I-kappaBalpha polymers in HEK-293 cells in case of TGase 2 transfection either with I-kappaBalpha or I-kappaBalpha mutant (S32A, S36A). Interestingly, the combined inhibition of calpain and the proteasome resulted in an increased accumulation of both I-kappaBalpha polymers and I-kappaBalpha, concurrent with an inhibition of NF-kappaB activity in MDA-MB-231 cells. This suggests that mu-calpain proteasome-dependent I-kappaBalpha polymer degradation may contribute to cancer progression through constitutive NF-kappaB activation.

Recently, it was reported that expression of transglutaminase 2 plays an important role in doxorubicin/cisplatin resistance in breast and ovarian cancer. The aims of this study were to verify the role of transglutaminase 2 in cisplatin response in non-small cell lung cancer (NSCLC) and to study if transglutaminase 2 gene (TGM2) methylation can be a molecular marker for good response to cisplatin. TGM2 promoter methylation was analyzed by sodium bisulfite sequencing. Cisplatin sensitivity was analyzed by treatment of cisplatin in NSCLC cell lines with/without TGM2 or TGM2 siRNA transfection. In one-third of NSCLC cell lines, TGase 2 gene (TGM2) was silenced by promoter methylation. The TGM2 promoter-methylated cell lines (HCC-95 and HCC-1588) showed relatively higher sensitivity to cisplatin than the TGM2-expressing cell lines (NCI-H1299 and HCC-1195). Down-regulation and over-expression of TGM2 in those NSCLC cells also suggested a positive correlation of cisplatin sensitivity and TGM2 inhibition. With doxorubicin, the relationship was quite similar. We showed that good responders of cisplatin in NSCLC could be identified by the promoter methylation of TGM2 and that TGase 2 inhibition appears to be an effective cisplatin-sensitizing modality in NSCLC.

Protein kinase C (PKC) is a complex family consisting of many types of isoenzymes, of which PKC-zeta, an atypical isoform, has been reportedly implicated in the regulation of apoptosis and NF-kappaB, as well as control of T-dependent responses. Based on the recent report that PKC-zeta controls TH2 response, the current study was aimed to evaluate PKC-zeta as a potential therapeutic target for asthma using a mouse model. Mouse allergic asthma was induced by repeated sensitization followed by intranasal challenge with OVA and PKC-zeta pseudosubstrate inhibitor (PPI) was intratracheally instilled before each OVA challenge. Airway hyperreactivity (AHR) was measured by beta-methacoline-induced airflow obstruction. Cellular and cytokine profile in bronchoalveolar lavage fluid (BALF) and level of serum IgE as well as cytokine production by draining lymph node cells were compared. AHR and numbers of eosinophils in BALF were significantly lowered by PPI, indicating that blocking of PKC-zeta activation alleviates asthmatic manifestations. Additionally, PPI instillation decreased IL-5 and IL-13 levels in BALF to approximately 20% of controls, but not IFN-gamma level. Instillation of PPI also caused a marked fall in the level of TNF-alpha, another NF-kappaB-dependent, proinflammatory cytokine. Serum OVA-specific IgE level and ex vivo IL-4, IL-5 and IL-13, but not IFN-gamma, production by peribronchial lymph node cells was also considerably lower in PPI-treated mice. In conclusion, blockade of PKC-zeta signals by intratracheal instillation of PPI alleviates allergen-specific TH2 response as well as asthmatic manifestations and hence PKC-zeta is a promising target for treatment of asthma.