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BACKGROUND AND OBJECTIVE Global Lung Function Initiative (GLI) 2012 equations were developed to resolve the age-related disparity in interpreting spirometry results. Local validation of the equation is needed, especially in Northeast Asian children. This study evaluated the GLI equation in Korean children. METHODS Spirometry indices (FEV1, FVC, FEV1/FVC, and FEF25%-75%) and clinical information were gathered from three population-based birth cohorts. Predicted GLI reference values and z scores of spirometry results were calculated for 1239 healthy children. The mean, standard deviation of z scores were compared with the expected 0 and 1. Probabilities of falling below the lower limit of normal (LLN) (z score: -1.64) were compared with the expected value 5%. GLI z scores were assessed according to low ( 2) BMI z score groups. RESULTS Mean z scores significantly differed from 0 for FEV1/FVC in males (mean [95% confidence interval]: 0.18 [0.08, 0.27]) and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in females (-0.23 [-0.31, -0.15] and -0.26 [-0.36, -0.16], respectively). The standard deviation was larger than 1 for all variables in males and FVC and FEV1/FVC in females. The probability of falling below the LLN was significantly larger than 5% for FEV1 (12.13% [9.64, 14.77]), FVC (15.86% [13.06, 18.81]), and forced expiratory flow at 25%-75% of forced vital capacity (FEF25%-75%) (7.31% [5.29, 9.49]) in males and FVC (11.91% [9.40, 14.60]) in females. FEV1 and FVC z scores increased across low to high body mass index (BMI) groups, and FEV1/FVC decreased from low to high BMI groups. CONCLUSION GLI equations marginally differ from real-world values, which should be considered by pulmonologists in practice or research.

Nonalcoholic fatty liver disease (NAFLD) refers to a series of diseases, including simple steatosis, caused by the excessive accumulation of fat in hepatocytes, nonalcoholic steatohepatitis with inflammation and fibrosis, and more advanced forms of cirrhosis. The pathogenic mechanisms underlying fatty liver and the progression from simple fatty liver to hepatitis and cirrhosis remain unclear. One potentially unifying mechanism may be a dysregulation of free fatty acid oxidation. The oversupply of fatty acids to the liver can result in mitochondrial dysfunction leading to the accumulation of lipids in the liver. Interestingly, there have been several reports showing that inhibitors of phosphodiesterase 5 (PDE5) can increase mitochondrial biogenesis, preserve mitochondrial function in vitro. And, we have recently demonstrated that the phosphodiesterase type 5 inhibitor udenafil improves insulin sensitivity by increasing mitochondrial function in adipocytes. In this study, we aimed to examine the effects of the PDE5 inhibitor udenafil on NAFLD in the ob/ob mouse model. Treatment of ob/ob mice for 6 weeks with udenafil reduced fat mass and fasting glucose. Importantly, udenafil caused a reduction in lipid accumulation in the liver of these mice, including hepatic triglyceride (TG) and cholesterol levels. Mechanistically, udenafil decreased the proinflammatory cytokines in the liver. Also, udenafil increased the levels in the liver of the important lipolytic enzymes and the levels of several mitochondrial β-oxidation related genes. Similar effects were seen in udenafil treated primary hepatocytes. We believe that our study makes a significant contribution to the literature because the results from our study suggest that udenafil may be an effective treatment for NAFLD by improving mitochondrial function.

Background Diabetes leads to severe complications and imposes health and financial burdens on the society. However, currently existing domestic public health studies of diabetes in South Korea mainly focus on prevalence, and data on the nationwide burden of diabetes in South Korea are lacking. The study aimed to estimate the prevalence and economic burden of diabetes imposed on the South Korean society. Methods A prevalence-based cost-of-illness study was conducted using the Korean national claims database. Adult diabetic patients were defined as those aged ≥20 years with claim records containing diagnostic codes for diabetes (E10-E14) during at least two outpatient visits or one hospitalization. Direct costs included medical costs for the diagnosis and treatment of diabetes and transportation costs. Indirect costs included productivity loss costs due to morbidity and premature death and caregivers’ costs. Subgroup analyses were conducted according to the type of diabetes, age ( Results A total of 4,472,133 patients were diagnosed with diabetes in Korea in 2017. The average annual prevalence of diabetes was estimated at 10.7%. The diabetes-related economic burden was USD 18,293 million, with an average per capita cost of USD 4090 in 2019. Medical costs accounted for the biggest portion of the total cost (69.5%), followed by productivity loss costs (17.9%), caregivers’ costs (10.2%), and transportation costs (2.4%). According to subgroup analyses, type 2 diabetes, presence of diabetic complications or related comorbidities, diabetes medication, and hospitalization represented the biggest portion of the economic burden for diabetes. As the number of complications increased from one to three or more, the per capita cost increased from USD 3991 to USD 11,965. In inpatient settings, the per capita cost was ~ 10.8 times higher than that of outpatient settings. Conclusions South Korea has a slightly high prevalence and economic burden of diabetes. These findings highlight the need for effective strategies to manage diabetic patients and suggest that policy makers allocate more health care resources to diabetes. This is the first study on this topic, conducted using a nationally representative claims database in South Korea.

Resistance of glioblastoma to the chemotherapeutic compound temozolomide is associated with the presence of glioblastoma stem cells in glioblastoma and is a key obstacle for the poor prognosis of glioblastoma. Here, we show that phospholipase D1 is elevated in CD44High glioblastoma stem cells and in glioblastoma, especially recurring glioblastoma. Phospholipase D1 elevation positively correlated with the level of CD44 and poor prognosis in glioblastoma patients. Temozolomide significantly upregulated the expression of phospholipase D1 in the low and moderate CD44 populations of glioblastoma stem cells, but not in the CD44High population in which phospholipase D1 is highly expressed. Phospholipase D1 conferred resistance to temozolomide in CD44High glioblastoma stem cells and increased their self‐renewal capacity and maintenance. Phospholipase D1 expression significantly correlated with levels of temozolomide resistance factors, which were suppressed by microRNA‐320a and ‐4496 induced by phospholipase D1 inhibition. Genetic and pharmacological targeting of phospholipase D1 attenuated glioblastoma stem cell‐derived intracranial tumors of glioblastoma using the microRNAs, and improved survival. Treatment solely with temozolomide produced no benefits on the glioblastoma, whereas in combination, phospholipase D1 inhibition sensitized glioblastoma stem cells to temozolomide and reduced glioblastoma tumorigenesis. Together, these findings indicate that phospholipase D1 inhibition might overcome resistance to temozolomide and represents a potential treatment strategy for glioblastoma. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Background This study was conducted to compare glycaemic control with insulin detemir administered according to two titration algorithms (3-0-3 and 2-4-6-8) after 20 weeks of treatment in subjects with type 2 diabetes mellitus inadequately controlled on metformin. Methods This was a 20-week, randomised, multicentre, open-labelled, treat-to-target trial. Forty-six patients were randomised in a 1:1 manner to either the 3-0-3 (G3, n=23) or 2-4-6-8 (G2, n=23) algorithm. The primary endpoint was change of haemoglobin A1c (HbA1c), and the secondary safety endpoint included hypoglycaemic events. Results After 20 weeks, HbA1c decreased similarly in the G3 and G2 groups, with a mean change of -0.9% from baseline. The mean change in fasting plasma glucose was numerically similar in both groups. The hypoglycaemia event rate per 100-patient-years of exposure (r) in the G2 group (r=1,427) was higher than that in the G3 group (r=807). Conclusion Both treatment groups had numerically similar HbA1c reductions. A trend towards fewer hypoglycaemia episodes after dose stabilisation was seen with the simpler G3. Clinically, this may be an important observation, as a simpler titration algorithm may support self-management and maintenance of insulin therapy.

Although early diagnosis and treatment of cancers in women are achievable through continuous diagnostic tests, cervical cancer (CVC) still has a high mortality rate. In the present study, we investigated whether certain nanoparticles (NPs), comprising aspirin conjugated 2′-hydroxy-2,3,5′-trimethoxychalcone chemicals, could induce the apoptosis of cancer cells. HeLa cells were treated with NPs and the cell viability was evaluated using WST-1 assay. Protein expression of Ki-67 was measured using immunocytochemistry. In addition, the apoptotic effect of NPs was determined using TUNEL assay. To investigate the apoptosis signaling pathways, reverse transcription quantitative PCR was performed and lipid accumulation was observed via holotomographic microscopy. The IC50 value of the NPs was 4.172 µM in HeLa cells. Furthermore, 10 µM NPs significantly inhibited the cell proliferation and stimulated the apoptosis of HeLa cells. In addition, apoptosis and mitochondrial dysfunction were induced by the NPs through lipid accumulation in HeLa cells, leading to apoptotic signaling cascades. Taken together, the results from the present study demonstrated that the NPs developed promoted apoptosis though efficient lipid accumulation in HeLa cells, suggesting that they may provide a novel way to improve the efficacy of CVC anticancer treatment.

Mucosal-associated invariant T (MAIT) cells exhibit different characteristics from those of TCRα7.2− conventional T cells. They play important roles in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. MAIT cells express a single T cell receptor alpha chain, TCRα7.2 segment associated with Jα33 and CDR3 with fixed length, which recognizes bacteria-derived vitamin B metabolites. However, the characteristics of MAIT cells and TCRα7.2+ CD161− T cells have never been compared. Here, we performed RNA sequencing to compare the properties of MAIT cells, TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells. Genome-wide transcriptomes of MAIT cells, TCRα7.2− conventional T cells, and TCRα7.2+ CD161− T cells were compared and analyzed using causal network analysis. This is the first report comparing the transcriptomes of MAIT cells, TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells. We also identified the predominant signaling pathways of MAIT cells, which differed from those of TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells, through a gene set enrichment test and upstream regulator analysis and identified the genes responsible for the characteristic MAIT cell phenotypes. Our study advances the complete understanding of MAIT biology.

Although bronchial responsiveness (BR) is usually categorized as normal or hyperresponsive to aid the diagnosis of asthma, it exists on a continuous spectrum, not in a dichotomous manner. We aimed to evaluate the distribution profile of BR in a general population of 7-year-olds.In 2015, 7-year-old Korean children from a nationwide birth cohort study visited regional study hospitals for skin prick test, standard spirometry, and bronchial provocation to establish reference values for the general population. Their BR degrees were categorized into five ordered groups: hyperresponsive BRs were classified into group 1 (provocative concentration (PC) of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV1], PC20 of4 mg/mL) and group 2 (PC20 of ≥4 mg/mL and16 mg/mL), and nonresponsive BRs were categorized into group 3 (final FEV1 percentage fall after inhaling 16 mg/mL of methacholine [FEV1%fall] of15% and ≤20%), group 4 (FEV1%fall of10% and ≤15%), and group 5 (FEV1%fall of ≤10%).In total, 559 subjects finished all tests reliably. Groups 1 and 2 comprised 10.0% and 15.7% of the total population, respectively. Groups 3, 4, and 5 comprised 14.7%, 18.4%, and 41.1%, respectively. As the group number increased, the proportion of those with recent wheezing and those with indoor allergen sensitization decreased (P for trend = 0.001 and P for trend 0.001, respectively), and the baseline FEV1/FVC increased (P for trend 0.001) CONCLUSION: BR of the 7-year-olds in the general population, while showing a wide distribution across phenotypes, is associated with allergic symptoms, negatively correlated with baseline lung function and positively correlated with indoor allergen sensitization.

PurposeHeat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.Materials and MethodsWe established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.ResultsWe identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.ConclusionThe synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

Background The effect of diet on allergic rhinitis (AR), its severity in children, and whether it modifies AR depending on genetic susceptibility are unknown. We investigated the association between dietary patterns and AR in school children and the influence of diet on AR according to a genetic risk score (GRS). Methods Totally, 435 7-year-old school children were recruited from the Panel Study on Korean Children. We used dietary patterns (vegetable, sugar, and meat) and dietary inflammatory index (DII) as dietary parameters. AR and its severity were defined by questionnaires about treatment in the previous 12 months and the Allergic Rhinitis and its Impact on Asthma (ARIA) guideline, respectively. A GRS was calculated using 6 single nucleotide polymorphisms for allergic diseases. Results A vegetable diet containing a lot of anti-inflammatory nutrients and higher vitamin D level in blood were negatively correlated, while DII was positively correlated with triglyceride level and triglyceride/HDL cholesterol. Vegetable diet (aOR, 95% CI = 0.73, 0.58-0.94) and DII (1.13, 1.01-1.28) were associated with AR risk. In particular, a high-vegetable diet resulted in a lower risk of mild and persistent AR (aOR, 95% CI = 0.24, 0.10-0.56) while a high DII represented a higher risk (2.33, 1.06-5.10). The protective effect of vegetable diet on AR appeared only among children with a lower GRS (adjusted P = .018). Conclusions A vegetable dietary pattern characterized by high intake of anti-inflammatory nutrients and higher vitamin D level in blood might be associated with a lower risk of mild and persistent AR. This beneficial effect is modified by a genetic factor.

Aim To investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes. Materials and Methods In this 12‐week, multicentre, randomized, double‐blind, active‐controlled, and 12‐week open‐label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%‐10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92). Results After 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was −0.85% and −0.75%, respectively. The between‐group difference was −0.10% (95% CI: −0.32 to 0.11), showing non‐inferiority based on a non‐inferiority margin of 0.4%. The change in MAGE was −24.6 mg/dL in the evogliptin group and −16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by −0.94%, with HbA1c values of

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.

Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function. To study the mechanism underlying the insulin sensitizing action of PDE5 inhibitors, we evaluated quantitative changes in protein or mRNA levels of mitochondrial oxidative phosphorylation (OxPhos) complex, oxygen consumption rate (OCR), and fatty acid oxidation with varying udenafil concentrations in 3T3-L1 cells. Our cell study suggested that udenafil enhanced the insulin signaling pathway in 3T3-L1 cells. Following udenafil treatment, basal mitochondrial OCR, maximal OxPhos capacity, and OxPhos gene expression significantly increased. Finally, we examined whether udenafil can affect the fatty acid oxidation process. Treatment of 3T3-L1 cells with udenafil (10 and 20 μM) significantly increased fatty acid oxidation rate in a dose-dependent manner. In addition, the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) significantly increased. We demonstrated that the PDE5 inhibitor udenafil enhances insulin sensitivity by improving mitochondrial function in 3T3-L1 cells. This might be the mechanism underlying the PDE5 inhibitor-enhanced insulin signaling in adipocytes. This also suggests that udenafil may provide benefit in the treatment of type 2 diabetes and other related cardiovascular diseases.

Background Sensitization is associated with the exacerbation, severity, and prognosis of allergic diseases in children OBJECTIVE: We characterized the association between sensitization patterns and allergic diseases. Methods A cohort of 548 children was enrolled from Panel Study of Korean Children (PSKC) study. Skin prick tests (SPTs) for 18 common allergens, blood tests, and methacholine bronchial challenge tests were performed at age 7. The Korean version of International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used. Results The sensitization rate on SPTs was 46.4%. Sensitization to indoor allergens showed an association with symptoms of asthma (adjusted odds ratio [aOR], 2.39; 95% confidence intervals [95% CIs], 1.10-5.23), allergic rhinitis (AR, aOR 2.08, 95% CIs 1.42-3.06), and atopic dermatitis (AD, aOR 2.36, 95% CIs 1.24-4.50) in the preceding 12 months. In contrast, sensitization to outdoor allergens was associated with AR diagnosis only (aOR 2.40, 95% CIs 1.30-4.41). The number of sensitized allergens was associated with a lifetime diagnosis and symptoms in the preceding 12 months of AR and asthma, but not with AD or BHR. A higher degree of sensitization to indoor allergens was associated with symptoms in the preceding 12 months of asthma, AR, AD, and that for outdoor allergens was associated with symptoms in the prior 12 months of asthma and AR. Conclusion The sensitization patterns including allergen type, number, and degree of sensitization are helpful for interpreting the association between sensitization and allergic diseases and identifying the pathophysiologies and diverse phenotypes of allergic diseases.

Background and Aims: Evogliptin is a new dipeptidyl peptidase-4 (DPP-4) inhibitor. We investigated the efficacy and safety of Evogliptin compared with linagliptin in patients with type 2 diabetes (T2D). Materials and Methods: A total of 207 untreated patients with T2D (mean age, 56.1±10.4 years; body mass index, 26.1±3.4 kg/m2) who had HbA1c 7.0-10.0%, prior to the screening were randomized 1:1 for 5 mg Evogliptin (n=102) or 5 mg linagliptin (n=105) once daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint included the change in mean amplitude of glycemic excursion (MAGE) assessed by 72-hour continuous glucose monitoring. In the extended study for another 12 weeks, open-label treatment with Evogliptin 5 mg qd was conducted in both groups; Evogliptin/Evogliptin group (n=95) and Linagliptin/Evogliptin group (n=92). Results: After 12 weeks of treatment, the mean changes in HbA1c of Evogliptin group and linagliptin group were −0.85% and −0.75%, respectively; the between-group difference was -0.10% (95% confidence interval, −0.32-0.11%), demonstrating non-inferiority, meeting the pre-specified margin of 0.40%. The changes in MAGE were −24.6 mg/dL in the Evogliptin group and −16.7 mg/dL in the linagliptin group, which were significantly lower compared with baseline values in both groups. In the Evogliptin/Evogliptin group at week 24, the mean changes from baseline in HbA1c was −0.94%, achieving HbA1c Conclusion: In this study, once-daily evoglipitin 5 mg treatment significantly decreased HbA1c levels by 0.94% at week 24 and improved glycemic variability without any serious adverse events in Korean patients with T2D (ClinicalTrials.gov Identifier: NCT02974504). Disclosure S. Lim: None. G. Kim: None. H. Kwon: None. I. Park: None. K. Ahn: None. C. Park: None. S. Kwon: None. H. Kim: None. S. Park: None. S. Kim: None. M. Moon: None. E. Kim: None. C.H. Chung: None. K. Won: None. K. Park: None. M. Kim: None. D. Chung: None. C. Lee: None. T. Kim: None. M. Lee: None.

Background: Although non-small cell lung cancer (NSCLC) patients with EGFR sensitizing mutations shows dramatic responsiveness to EGFR-TKI, some of them still showed primary resistance. The loss of PTEN and NF-κB activation have known to contribute to intrinsic EGFR-TKI resistance in EGFR mutant lung cancer. Interestingly, Transglutaminase 2 (TG2) was well known to down-regulate PTEN and IκBα (NF-kB inhibitor) levels in tumor cells. Therefore, we investigated whether TG2 plays a role in the resistance and what kind of mechanisms involves in that resistance. Methods: We have established de novo and ectopic TG2 over-expressing EGFR mutant NSCLC cell lines. Subsequently, we have elaborated the resistance to EGFR-TKI therapy in these TG2-over-expressing cells. We have tried to investigate whether TG2 inhibitor could restore EGFR-TKI sensitivity with EGFR inhibitors in vitro and in vivo. Then, we evaluated TG2 expression in two intrinsic and eight sensitive clinical cases. Findings: The higher TG2 expression and lower PTEN and IκBα expression were evident in the intrinsic EGFR-TKI resistant NSCLC. EGFR-TKI sensitive NSCLC cells, harboring EGFR mutations, that stably expressed TG2 had reduced PTEN and IκBα and exhibited EGFR-TKI resistance. TG2 inhibition alone or co-treatment with TG2 inhibitor and EGFR-TKI in intrinsic EGFR-TKI resistant NSCLC cells harboring EGFR mutations overcame EGFR-TKI resistance via PTEN and IκBα restoration. Interpretation: TG2 elicits intrinsic EGFR-TKI resistance via PTEN loss and activation of the NF-κB pathway in NSCLC harboring EGFR sensitizing mutation. Therefore, TG2 may be a useful predictive marker and also be a target for overcoming the resistance. Funding Statement: This manuscript was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1520220) and the PostGenome Technology Development Program [10067758, Business model development driven by clinico-genomic database for precision immuno-oncology] funded by the Ministry of Trade, Industry and Energy (MOTIE, Korea). Declaration of Interests: D.H.L. declares honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, ChongKunDang, Eli Lilly, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm and ST Cube. The other authors declare that they have no conflict of interest. Ethics Approval Statement: Animal procedures were approved by the institutional review board of Asan Medical Center

Background Bilateral adrenal hemorrhage is a serious condition that can result in adrenal insufficiency, shock, acute adrenal crisis, and mortality if it is not managed with adequate treatment. We report a rare case of idiopathic bilateral adrenal hemorrhage. Case presentation A 50-year-old woman visited our hospital with complaints of right upper abdominal pain. A computed tomography (CT) revealed unilateral left adrenal gland hemorrhage. However, the results of rapid adrenocorticotropic hormone (ACTH) stimulation test and adrenomedullary hormone function test were normal. Since the patient did not show signs of adrenal insufficiency, corticosteroid therapy was postponed and only supportive management therapy was started. After 1 week, a follow- up CT showed a previously unseen adrenal hemorrhage on the right adrenal gland, but the rapid ACTH stimulation test result was normal. One year later, no hemorrhagic signs were observed on the follow-up CT. Conclusion In most cases of idiopathic bilateral adrenal hemorrhage, patients are treated with steroid replacement therapy due to adrenal insufficiency. In some other cases, patients are treated with steroids despite the absence of adrenal insufficiency. Here we reported a very rare case of idiopathic bilateral adrenal hemorrhage sequentially to emphasize that before initiation of adrenal hormone replacement therapy, it is important to determine whether adrenal insufficiency is present. If there is no evidence of adrenal insufficiency, adrenal replacement therapy should be postponed until the presence of adrenal insufficiency is confirmed.

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.

Aim The aim of this study was to analyze the efficacy, insulin sensitivity and safety in the event of administering sulfonylurea-based drugs and metformin in combination with basal insulin. Methods A randomized, open-label, parallel, 16-week trial was conducted across four study centers. The 97 type 2 diabetic patients were selected and randomized into two groups, the insulin glargine plus fixed-dose combination glimepiride 1 mg and metformin 500 mg twice daily group (the G/M group) and the insulin glargine plus glimepiride 4 mg once daily group (the G group). The primary endpoint evaluated was change in HbA1c. The secondary endpoints evaluated were changes in fasting blood glucose (FPG), 2-h post prandial glucose (PPG 2 h), insulin, and C-peptide levels. Results The G/M group was found to have experienced a significantly greater decrease in HbA1c, as well as PPG 2 h compared to the G group. While no significant intergroup difference was found regarding FPG in the ITT, the G/M group in the PP set experienced a significantly greater decrease in FPG. Conclusion Comparison of combined therapy consisting of either the G/M group or the G group indicated that both forms of therapy are relatively safe but that the former more effectively decreases blood glucose levels.

Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib. [BMB Reports 2018; 51(12): 660-665].

Despite advances in the clinical management of hepatocellular carcinoma (HCC), this form of cancer remains the second leading cause of cancer-related death worldwide. Currently, there are few treatment options for advanced HCC. Therefore, novel treatment strategies for HCC are required. Here, we described the promising antitumour effects of anisomycin, which exerts both direct killing effects and natural killer cell (NK)-mediated immunotherapeutic effects in HCC. To better elucidate the mechanisms through which anisomycin mediates its antitumour effects, we performed a genome-scale transcriptional analysis. We found that anisomycin treatment of HCC differentially modulated a broad range of immune regulation-associated genes. Among these immune regulation-associated genes, we found that lymphocyte function-associated antigen-3 (LFA-3, also called CD58), whose expression was significantly increased in anisomycin-treated HCC cells, was a critical player in NK-mediated immunotherapeutic effects. Furthermore major histocompatibility complex molecules class I (MHC-I) on HCC cells were also significantly regulated by treatment of anisomycin. Those adhesion molecules like CD58, MHC-I, and ICAM4 should be important for immune synapse formation between NK cells and HCC cells to boost NK-mediated immunotherapeutic effects. Notably, this is the first report of NK-dependent immunomodulatory effects of anisomycin suggesting anisomycin as a novel therapeutic drug for treatment of HCC.

BACKGROUND Arterial stiffness is an important factor in atherosclerosis. Thus we examined whether aerobic exercise could reduce arterial stiffness in obese women with type 2 diabetes without diabetic complication. METHODS A total of 35 women with type 2 diabetes (body mass index, 26.6±2.8 kg/m(2); age, 56.4±1.9 years; duration of diabetes, 4.7±4.8 years) were assigned to aerobic exercise group (AEG) or control group (CG). AEG completed a 12-week exercise program (3.6 to 5.2 metabolic equivalents, 3 day/week, 60 min/day), with their exercise activities monitored by accelerometers. We measured abdominal total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) by computed tomography, insulin sensitivity by insulin tolerance test (KITT), and augmentation index (AIx) by SphygmoCor at baseline and at the end of the 12-week program. RESULTS The AIx was improved in the AEG compared with the CG (P

Background/aim Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The ability of HCC to avoid immune detection is considered one of the main factors making it difficult to cure. Abnormal histone deacetylation is thought to be one of the mechanisms for HCC immune escape, making histone deacetylases (HDACs) attractive targets for HCC treatment. Here, we investigated the effect of trichostatin A (TSA), a highly potent HDAC inhibitor, on HCC (HepG2) gene expression and function. Materials and methods A genome wide-transcriptional microarray was used to identify genes regulated by TSA in HepG2 cells. Gene Ontology was used to identify pathways regulated by TSA, and these changes were confirmed by qPCR. The effect of TSA on natural killer (NK) cell-mediated killing of HCC cell lines were analyzed by both flow cytometry and LDH cytotoxicity assay. A study was also conducted in a Balb/c nude mice xenograft model to assess the anti-tumor activity of TSA. Results TSA regulated the transcription of numerous innate immunity & tumor antigen recognition-associated genes, such as ULBP1 and RAET1G, in HCC cells. In vivo, TSA reduced tumor cell growth in an NK cell-dependent manner. In vitro, TSA treatment of HepG2 cells rendered them more susceptible to NK cell-mediated killing while increasing the expression of NKGD2 ligands, including ULBP1/2/3 and MICA/B. TSA also induced direct killing of HCC cells by stimulating apoptosis. Conclusion TSA likely increases killing of HCC cells indirectly by increasing NK cell-directed killing and directly by increasing apoptosis.

Small cell lung cancer (SCLC) cannot be efficiently controlled using existing chemotherapy and radiotherapy approaches, indicating the need for new therapeutic strategies. Although ABT-737, a B-cell lymphoma-2 (BCL-2) inhibitor, exerts anticancer effects against BCL-2-expressing SCLC, monotherapy with ABT-737 is associated with limited clinical activity because of the development of resistance and toxicity. Here, we examined whether combination therapy with ABT-737 and heat shock protein 90 (HSP90) inhibitor NVP-AUY922 exerted synergistic anticancer effects on SCLC. We found that the combination of ABT-737 and NVP-AUY922 synergistically induced the apoptosis of BCL-2-expressing SCLC cells. NVP-AUY922 downregulated the expression of AKT and ERK, which activate MCL-1 to induce resistance against ABT-737. The synergistic effect was also partly due to blocking NF-κB activation, which induces anti-apoptosis protein expressions. However, interestingly, targeting BCL-2 and MCL-1 or BCL2 and NF-κB did not induce the cytotoxicity. In conclusion, our study showed that combination of BCL2 inhibitor with HSP90 inhibitor increased activity in in vitro and in vivo study in only BCL-2 expressing SCLC compared to either single BCL2 inhibitor or HSP inhibitor. The enhanced activity might be led by blocking several apoptotic pathways simultaneously rather than a specific pathway.

More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway. The HSP90 inhibitor AUY922 suppressed both PI3K/AKT/mTOR and RAF/MEK/ERK signaling, rendering cells sensitive to a PI3K inhibitor (omipalisib, GSK458). Combining these two drugs achieved a synergistic effect, even using only sub-therapeutic concentrations. Dual inhibition of the HSP90 and PI3K signaling pathways with sub-therapeutic doses of these combined anticancer drugs may represent a potent treatment strategy for KRAS-mutant NSCLC with intrinsic resistance to PI3K inhibition.

OBJECTIVES: Cripto-1 (CR-1) plays a critical role in the activation of SMAD, SRC, and epithelial-to-mesenchymal transition (EMT) pathways and has been shown to be prognostic in several cancer types. In addition, we showed that CR-1 renders EGFR-mutated NSCLC cells resistant to EGFR-TKI through the activation of SRC and EMT via miR-205 downregulation. This study aimed to investigate the correlation between expression of CR-1 and miR-205 and prognosis of NSCLC patients with or without EGFR mutations. MATERIALS AND METHODS: A total of 265 patients with stage I (AJCC 6th edition) radically resected NSCLC were tested for CR-1 expression and EGFR mutations by immunohistochemistry and miR-205 expression via qPCR assay. RESULTS: CR-1 expression was evaluated with immunohistochemistry using a tissue microarray on 265 T1-2N0 surgical NSCLC samples. Of the 265 tumors, 250 (94%) expressed various levels of CR-1. A significant inverse correlation was identified between expression of miR-205 and CR-1. NSCLC patients (T1N0, n = 106) with high CR-1 expression had worse prognosis (shorter recurrence-free survival, p = .045) than those with low CR-1 expression. A similar trend was observed in NSCLC patients with normal preoperative carcinoembryonic antigen (CEA) levels (serum CEA levels < 5ng/ml; n = 179; p = .085); however, no significant correlation was found between CR-1 expression and survival rate in the T2N0 or high CEA groups. In addition, NSCLC patients with low miR-205 expression (n = 126) had poorer prognosis in terms of recurrence than those with high miR-205 expression (n = 127; p = .001). CONCLUSION: High CR-1 expression is correlated with poor prognosis in NSCLC with low tumor burden and may be used to select high-risk patients for adjuvant chemotherapy in early NSCLC. Moreover, low miR-205 expression likely related to high CR-1 expression could be a prognostic marker for patients with NSCLC.

The risk of asthma has been increasing in parallel with use of acetaminophen, which is a potential source of oxidative stress. Toll-like receptor 4 (TLR4) plays a critical role not only in innate immunity, but also in mediating reactive oxygen species induced inflammation. Therefore, we investigated associations between acetaminophen usage and TLR4 polymorphism on asthma and bronchial hyperresponsiveness (BHR). The number of 2,428 elementary school children in Seoul and Jeongeup cities was recruited. Subjects who used acetaminophen with a family history of asthma had an increased risk of both asthma diagnosis ever and current asthma. Individuals with CT+TT genotypes at the TLR4 polymorphism, in combination with acetaminophen usage, also demonstrated an increased risk of asthma diagnosis ever (aOR, 2.08; 95% confidence interval [CI], 1.10-3.92). Family history of asthma and acetaminophen usage were risk factors for BHR. Although TLR4 was not an independent risk factor for BHR, individuals with CT+TT genotypes at the TLR4 polymorphism had an increased risk of BHR when combined with acetaminophen usage (aOR, 1.74; 95% CI, 1.03-2.94). In conclusion, acetaminophen usage may be associated with asthma and BHR in genetically susceptible subjects. This effect may be modified by polymorphism at TLR4. Graphical Abstract

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 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.

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 (

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.