Delay of insulin initiation in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycemic agents (analysis of patient‐ and physician‐related factors): A prospective observational DIPP‐FACTOR study in Korea

Kim, Sin Gon,Kim, Nam Hoon,Ku, Bon Jeong,Shon, Ho Sang,Kim, Doo Man,Park, Tae Sun,Kim, Yong&#x2010,Seong,Kim, In Joo,Choi, Dong Seop John Wiley & Sons Ltd 2017 Journal of diabetes investigation Vol.8 No.3

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>To assess the time to initiation of insulin therapy, and concurrently investigate both patient‐ and physician‐related factors associated with delaying insulin therapy in Korean patients with type 2 diabetes uncontrolled by oral hypoglycemic agents (OHAs).</P><P><B>Materials and Methods</B></P><P>This prospective, observational disease registry study was carried out across 69 centers in Korea. Type 2 diabetes patients who had received two or more OHAs within the past 5 years, had a glycated hemoglobin ≥8% in the past 6 months and had not received insulin were included. Data recorded on data collection forms during a 12‐month period were analyzed.</P><P><B>Results</B></P><P>Of 2168 patients enrolled, 1959 were evaluated and classified as the insulin‐initiated or insulin‐delayed group. Insulin was prescribed for just 20% of the patients during a 1‐year follow‐up period, and less than half (44.5%) of the patients who were taking two OHAs started insulin after 6 years. Patient‐related factors for delay in insulin initiation included older age, shorter duration of diabetes and lower glycated hemoglobin. Physician‐related factors included age (~50 to <60 years), sex (women) and number (<1000) of patients consulted per month. Patient refusal (33.6%) and physicians’ concerns of patient non‐compliance (26.5%) were the major physician‐reported reasons for delaying insulin therapy. Inconvenience of insulin therapy (51.6%) and fear of injection (48.2%) were the major reasons for patient refusal.</P><P><B>Conclusions</B></P><P>Insulin initiation is delayed in patients with type 2 diabetes uncontrolled by two or more OHAs in Korea. Patient‐ and physician‐related factors associated with this delay need to be addressed for better diabetes management.</P>

Solution‐Processable Reduced Graphene Oxide as a Novel Alternative to PEDOT:PSS Hole Transport Layers for Highly Efficient and Stable Polymer Solar Cells

Yun, Jin&#x2010,Mun,Yeo, Jun&#x2010,Seok,Kim, Juhwan,Jeong, Hyung&#x2010,Gu,Kim, Dong‐,Yu,Noh, Yong&#x2010,Jin,Kim, Seok&#x2010,Soon,Ku, Bon&#x2010,Cheol,Na, Seok&#x2010,In WILEY‐VCH Verlag 2011 Advanced Materials Vol.23 No.42

<P><B>The preparation of a reduced graphene oxide (pr‐Go) is with a novel p‐TosNHNH2 reductant</B> is demonstrated for use as an efficient anode interfacial layer for high‐performance and highstability organic solar cells (OSCs). The efficiency of the cells with pr‐GO is highly comparable to those of the PEDOT:PSSbased devices. Furthermore, the pr‐GO based OSCs show a much longer cell life time in air stability tests in comparison with PEDOT:PSS‐based cells.</P>

<i>In vivo</i> and <i>ex vivo</i> evidence for ketamine‐induced hyperglutamatergic activity in the cerebral cortex of the rat: Potential relevance to schizophrenia

Kim, Sang&#x2010,Young,Lee, Hyunseung,Kim, Hyun&#x2010,Ju,Bang, Eunjung,Lee, Sung&#x2010,Ho,Lee, Do&#x2010,Wan,Woo, Dong‐,Cheol,Choi, Chi&#x2010,Bong,Hong, Kwan Soo,Lee, Chulhyun,Choe, Bo&#x2010 John Wiley Sons, Ltd 2011 NMR in biomedicine Vol.24 No.10

<P>Subanesthetic doses of ketamine, a noncompetitive <I>N</I>‐methyl‐<SMALL>D</SMALL>‐aspartate (NMDA) receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in patients with schizophrenia. In the present study, <I>in vivo</I> <SUP>1</SUP>H‐MRS and <I>ex vivo</I> <SUP>1</SUP>H high‐resolution magic angle spinning (HR‐MAS) spectroscopy was used to examine the brain metabolism of rats treated with subanesthetic doses of ketamine (30 mg/kg) for 6 days. A single voxel localization sequence (PRESS, TR/TE = 4000/20 ms and NEX = 512) was used to acquire the spectra in a 30‐µl voxel positioned in the cerebral cortex (including mainly PFC) of the rats (ketamine group: <I>n</I> = 12; saline group: <I>n</I> = 12) anesthetized with isoflurane. After the <I>in vivo</I> <SUP>1</SUP>H‐MRS acquisition, the animals were sacrificed and the cerebral cortex tissues were extracted (ketamine group: <I>n</I> = 7; saline group: <I>n</I> = 7) for <I>ex vivo</I> <SUP>1</SUP>H HR‐MAS spectroscopy (CPMG sequence, 2.0‐s presaturation delay, 2.0‐s acquisition time, 128 transients and 4‐ms inter‐pulse delay) using a 500‐MHz NMR spectrometer. All proton metabolites were quantified using the LCModel. For the <I>in vivo</I> spectra, there was a significant increase in glutamate concentration in the cerebral cortex of the ketamine group compared with the controls (<I>p</I> < 0.05). For the <I>ex vivo</I> HR‐MAS spectra, there was a significant increase in the glutamate/total creatine ratio, and a decrease in the glutamine/total creatine and glutamine/glutamate ratios in the cerebral cortex tissue of the ketamine group compared with the controls. The results of the present study demonstrated that administration of subanesthetic doses of ketamine in the rat may exert at least part of their effect in the cerebral cortex by activation of glutamatergic neurotransmission. Copyright © 2011 John Wiley & Sons, Ltd.</P>

Patient‐specific 17‐segment myocardial modeling on a bull's‐eye map

Jung, Joonho,Kim, Young&#x2010,Hak,Kim, Namkug,Yang, Dong Hyun unknown 2016 Journal of applied clinical medical physics Vol.17 No.5

<P>The purpose of this study was to develop and validate cardiac computed tomography (CT) quantitative analysis software with a patient‐specific, 17‐segment myocardial model that uses electrocardiogram (ECG)‐gated cardiac CT images to differentiate between normal controls and severe aortic stenosis (AS) patients. ECG‐gated cardiac CT images from 35 normal controls and 144 AS patients were semiautomatically segmented to create a patient‐specific, 17‐segment myocardial model. Two experts then manually determined the anterior and posterior interventricular grooves to be boundaries between the 1st and 2nd segments and between the 3rd and 4th segments, respectively, to correct the model. Each segment was automatically identified as follows. The outer angle of two boundaries was divided to differentiate the 1st, 4th, 5th, and 6th segments in the basal plane, whereas the inner angle divided the 2nd and 3rd segments. The segments of the midplane were similarly divided. Segmental area distributions were quantitatively evaluated on the bull's‐eye map on the basis of the morphological boundaries by measuring the area of each segment. Segmental areas of severe AS patients and normal controls were significantly different (t‐test, all p‐values<0.011) in the proposed model because the septal regions of the severe AS patients were smaller than those of normal controls and the difference was enough to divide the two groups. The capabilities of the 2D segmental areas (p<0.011) may be equivalent to those of 3D segmental analysis (all p‐values<0.001) for differentiating the two groups (t‐test, all p‐values<0.001). The proposed method is superior to the conventional 17‐segment in relation to reflection of patient‐specific morphological variation and allows to obtain a more precise mapping between segments and the AHA recommended nomenclature. It can be used to differentiate severer AS patients and normal controls and also helps to understand the left ventricular morphology at a glance.</P><P>PACS number(s): 87.57.N‐, 87.57.R‐, 87.57.qp</P>

A Biodegradable Polymersome Containing Bcl‐xL siRNA and Doxorubicin as a Dual Delivery Vehicle for a Synergistic Anticancer Effect

Kim, Hyun&#x2010,Ouk,Kim, Eunjung,An, Yonghee,Choi, Jihye,Jang, Eunji,Choi, Eun Bi,Kukreja, Aastha,Kim, Myeong&#x2010,Hoon,Kang, Byunghoon,Kim, Dong‐,Joo,Suh, Jin&#x2010,Suck,Huh, Yong&#x2010,Mi WILEY‐VCH Verlag 2013 Macromolecular bioscience Vol.13 No.6

<P><B>Abstract</B></P><P>Combined cancer treatment via co‐delivery of siRNAs and an anticancer drug can be a promising strategy due to the synergistic effect of simultaneously minimizing gene/drug administration. In this study, Bcl‐xL siRNA and doxorubicin (DOX) are encapsulated into designed methoxy‐poly(ethylene glycol)‐<I>block</I>‐poly(<SMALL>D</SMALL>,<SMALL>L</SMALL>‐lactic acid) (mPEG‐<I>b</I>‐PLA) block copolymer polymersomes (PSomes). A study of the cytotoxicity of Bcl‐xL siRNA and DOX co‐encapsulated PSomes (CPSomes) shows more inhibited proliferation of MKN‐45 and MKN‐28 human gastric cancer cell lines than only gene‐ and drug‐loaded ones. Consequently, these results demonstrate that co‐delivery of genes and drugs using PSomes results in a synergistic efficacy and indicates the potential of PSomes as efficient nanocarriers for combined cancer therapy. </P>

Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors

Gambacorti&#x2010,Passerini, Carlo,Kantarjian, Hagop M.,Kim, Dong‐,Wook,Khoury, Hanna J.,Turkina, Anna G.,Brü,mmendorf, Tim H.,Matczak, Ewa,Bardy&#x2010,Bouxin, Nathalie,Shapiro, Mark,Turnbu John Wiley and Sons Inc. 2015 American journal of hematology Vol.90 No.9

<P>Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, <I>n =</I> 79] chronic myeloid leukemia [CML], blast‐phase [BP, <I>n =</I> 64] CML, acute lymphoblastic leukemia [ALL, <I>n =</I> 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (<I>n =</I> 9) for AP and pyrexia (<I>n =</I> 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.</P>

α‐Lipoic acid suppresses the development of DNFB‐induced atopic dermatitis‐like symptoms in NC/Nga mice

Kim, Gun&#x2010,Dong,Kim, Tae&#x2010,Ho,Jang, An&#x2010,Hee,Ahn, Hyun&#x2010,Jong,Park, Yong Seek,Park, Cheung&#x2010,Seog Blackwell Publishing Ltd 2011 Experimental dermatology Vol.20 No.2

<P><B>Abstract: </B> Atopic dermatitis (AD) is a common skin disease that has complex pathogenic mechanisms. Under specific pathogen‐free conditions, repeated epicutaneous treatment of 2‐4‐dinitrofluorobenzene (DNFB) evokes AD‐like clinical symptoms in NC/Nga mice. α‐Lipoic acid (α‐LA; 1, 2‐dithiolane‐3‐pentanoic acid) is a dietary component that is synthesized in bacteria, yeast, plants, and mammals. α‐LA and its reduced form, dihydrolipoic acid, are powerful antioxidants that have many physiological functions, including free radical scavenging of reactive oxygen species, generation of cellular antioxidants, chelation of metal ions, and inflammatory suppression. In this study, we investigated whether α‐LA suppresses AD‐like skin lesions induced by repeated DNFB application in NC/Nga mice. α‐LA significantly suppressed production of interferon (IFN)‐γ and interleukin (IL)‐4 by activated CD4<SUP>+</SUP> T cells. We found that the oral administration of α‐LA reduced AD‐like clinical symptoms and inhibited increases of epidermal thickness in DNFB‐induced AD‐like skin lesions of NC/Nga mice. Furthermore, total serum IgE levels were dramatically reduced by topical α‐LA treatment. Our findings suggest that oral administration of α‐LA suppresses the development of AD in DNFB‐treated NC/Nga mice and reduces IFN‐γ and IL‐4 production from activated CD4<SUP>+</SUP> T cells as well as total serum IgE levels.</P>

Development of high‐throughput phosphorylation profiling method for identification of Ser/Thr kinase specificity

Kim, Eun&#x2010,Mi,Kim, Jaehi,Kim, Yun&#x2010,Gon,Lee, Peter,Shin, Dong‐,Sik,Kim, Mira,Hahn, Ji&#x2010,Sook,Lee, Yoon&#x2010,Sik,Kim, Byung&#x2010,Gee John Wiley Sons, Ltd. 2011 Journal of peptide science Vol.17 No.5

<P><B>Abstract</B></P><P>Identification of substrate specificity of kinases is crucial to understand the roles of the kinases in cellular signal transduction pathways. Here, we present an approach applicable for the discovery of substrate specificity of Ser/Thr kinases. The method, which is named as the ‘high‐throughput phosphorylation profiling (HTPP)’ method was developed on the basis of a fully randomized one‐bead one‐compound (OBOC) combinatorial ladder type peptide library and MALDI‐TOF MS. The OBOC ladder peptide library was constructed by the ‘split and pool’ method on a HiCore resin. The peptide library sequence was Ac‐Ala‐X‐X‐X‐Ser‐X‐X‐Ala‐BEBE‐PLL resin. The substrate specificity of murine PKA (cAMP‐dependent protein kinase A) and yeast Yak1 kinase was identified using this method. On the basis of the result, we identified Ifh1, which is a co‐activator for the transcription of ribosomal protein genes, as a novel substrate of Yak1 kinase. The putative Yak1‐dependent phosphorylation site of Ifh1 was verified by <I>in vitro</I> kinase assay. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.</P>

2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation

Yoon, Yae Jin,Kim, Young&#x2010,Hwan,Lee, Yu&#x2010,Jin,Choi, Jiyeon,Kim, Cheol&#x2010,Hee,Han, Dong Cho,Kwon, Byoung&#x2010,Mog John Wiley and Sons Inc. 2019 CANCER SCIENCE Vol.110 No.1

<P>Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway is a novel therapeutic strategy to treat human cancers with constitutively active STAT3. During the screening of natural products to find STAT3 inhibitors, we identified 2′‐hydroxycinnamaldehyde (HCA) as a STAT3 inhibitor, which was isolated from the stem bark of <I>Cinnamomum cassia</I>. In this study, we found that HCA inhibited constitutive and inducible STAT3 activation in STAT3‐activated DU145 prostate cancer cells. HCA selectively inhibited the STAT3 activity by direct binding to STAT3, which was confirmed by biochemical methods, including a pull‐down assay with biotin‐conjugated HCA, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). HCA inhibited STAT3 phosphorylation at the tyrosine 705 residue, dimer formation, and nuclear translocation in DU145 cells, which led to a downregulation of STAT3 target genes. The downregulation of cell cycle progression and antiapoptosis‐related gene expression by HCA induced the accumulation of cells in the G0/G1 phase of the cell cycle and then induced apoptosis. We also found that reactive oxygen species (ROS) were involved in the HCA‐induced inhibition of STAT3 activation and cell proliferation because the suppressed p‐STAT3 level was rescued by glutathione or N‐acetyl‐L‐cysteine treatment, which are general ROS inhibitors. These results suggest that HCA could be a potent anticancer agent targeting STAT3‐activated tumor cells.</P>

Efficacy of nano‐particulated, water‐soluble erlotinib against intracranial metastases of EGFR ‐mutant lung cancer

Kim, Dong Ha,Choi, Yun Jung,Sung, Ki Jung,Yoo, Seon&#x2010,A,Sung, Young Hoon,Kim, Jeong Kon,Choi, Chang&#x2010,Min,Yun, Miyong,Lee, Eun Yong,Jin, Yong Suk,Cook, Seungho,Rho, Jin Kyung,Lee, Jae Cheol John Wiley and Sons Inc. 2018 Molecular Oncology Vol.12 No.12

<P>Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.</P>