Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
LC3; autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole
Tinea incognito (TI) is a dermatophytic infection which has lost its typical clinical appearance because of improper use of steroids or calcineurin inhibitors. The incidence of TI is increasing nowadays. We conducted retrospective review on 283 patients with TI from 25 dermatology training hospitals in Korea from 2002-2010 to investigate the demographical, clinical, and mycological characteristics of TI, and to determine the associated risk factors. More than half (59.3%) patients were previously treated by non-dermatologists or self-treated. The mean duration of TI was 15.0 ± 25.3 months. The most common clinical manifestations were eczema-like lesion, psoriasis-like, and lupus erythematosus-like lesion. The trunk and face were frequently involved, and 91 patients (32.2%) also had coexisting fungal infections. Among 67 isolated strains, Trichophyton rubrum was the most frequently detected (73.1%). This is the largest study of TI reported to date and the first investigational report concerning TI in Korea. We suggest that doctors should consider TI when a patient has intractable eczema-like lesions accompanied by tinea pedis/unguium. Furthermore, there should be a policy change, which would make over-the-counter high-potency topical steroids less accessible in some countries, including Korea.
Calcineurin Inhibitor; Dermatophytoses; Korea; Steroid; Tinea; Tinea Incognito
The prevalence of Behcet's disease is the highest in the East Asian and the Mediterranean countries. Behcet's disease is also distributed in the Asian countries, but the nationwide survey has not been performed in Korea yet. The Korean Study Group for Behcet's Disease, founded in 1999, conducted a multicenter, retrospective survey on epidemiologic and clinical features of the patients with Behcet's disease from 20 hospitals around the nation from 1997 to 1999. Of 3,497 patients, 1,527 were classified into complete or incomplete type of Behcet's disease according to the revised Shimizu's classification. The sex ratio was 1:1.75 with the female predominance. Geographical distribution showed the highest frequency in Seoul (38.5%). Clinically, 98.8% had oral ulcers, 83.2% had genital ulcers, 84.3% had skin lesions and 50.9% had ocular lesions. As for the minor clinical manifestations, articular symptoms were the most frequent. The pathergy test showed positive in 15.4% of patients and revealed a higher positive rate in males (20.2%) than in females (12.7%). In conclusion, we performed the first multicenter study on Behcet's disease in Korea and revealed the female predominance, higher frequency of ocular lesions, and lower positivity of pathergy test in the patients.
The dramatic increase in the prevalence of obesity and its accompanying comorbidities are major health concerns in Korea. Obesity is defined as a body mass index ≥25 kg/m2 in Korea. Current estimates are that 32.8% of adults are obese: 36.1% of men and 29.7% of women. The prevalence of being overweight and obese in national surveys is increasing steadily. Early detection and the proper management of obesity are urgently needed. Weight loss of 5% to 10% is the standard goal. In obese patients, control of cardiovascular risk factors deserves the same emphasis as weight-loss therapy. Since obesity is multifactorial, proper care of obesity requires a coordinated multidisciplinary treatment team, as a single intervention is unlikely to modify the incidence or natural history of obesity.
Clinical practice guidelines; Obesity; Korea
Waldenström's macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Clinical features and cytogenetics of WM in Asia including Republic of Korea remain unclear. Moreover, no study has reported treatment outcomes in patients with WM treated with novel agent combined with conventional chemotherapy. This study investigated clinical features and assessed treatment outcomes with novel agent and conventional chemotherapy in Republic of Korea. Data from all (n = 71) patients with newly diagnosed WM at 17 hospitals who received chemotherapy between January 2005 and December 2012 were collected retrospectively. The median age of patients was 66 years (range: 37–92 years) and male to female ratio was 5 : 1. Patients treated with novel agent combined chemotherapy displayed higher overall response rate (ORR) compared to conventional chemotherapy alone (92.9% versus 52.6%, P = 0.006). The 5-year overall survival rate was 62.6% (95% confidence interval: 34.73–111.07). Use of novel agents produced higher ORR but survival benefit was not apparent due to the small number of patients and short follow-up duration. Further studies are needed to confirm the efficacy of novel agents in patients with WM.
Using a simple method of mass production of green carbon nanotags (G-tags) from harmful cyanobacteria, we developed an advanced and efficient imaging platform for the purpose of anticancer therapy. Approximately 100 grams of G-tags per 100 kilograms of harmful cyanobacteria were prepared using our eco-friendly approach. The G-tags possess high solubility, excellent photostability, and low cytotoxicity (<1.5 mg/mL for 24 h). Moreover, doxorubicin-conjugated G-tags (T-tags; >0.1 mg/mL) induced death in cancer cells (HepG2 and MCF-7) in-vitro at a higher rate than that of only G-tags while in-vivo mice experiment showed enhanced anticancer efficacy by T-tags at 0.01 mg/mL, indicating that the loaded doxorubicin retains its pharmaceutical activity. The cancer cell uptake and intracellular location of the G- and T-tags were observed. The results indicate that these multifunctional T-tags can deliver doxorubicin to the targeted cancer cells and sense the delivery of doxorubicin by activating the fluorescence of G-tags.
There have been few studies of pulmonary actinomycosis, which is an uncommon anaerobic infection. Consequently, the optimal therapeutic regimen, appropriate duration of treatment, long-term prognosis, and factors predicting prognosis are not well established.
We retrospectively reviewed the medical records of histopathologically confirmed cases of pulmonary actinomycosis seen between November 2003 and December 2012.
The study included 68 patients with a mean age of 58.4 ± 11.6 years. Of the 68, initial surgery was performed in 15 patients (22.1%), while the remaining 53 (77.9%) received antibiotic therapy initially. In the initial antibiotic group, 45/53 (84.9%) were cured without relapse (median antibiotic duration 5.3 months). 5/53 (9.4%) patients were refractory medically (median antibiotic duration 9.7 months), and 3/53 (5.7%) experienced a recurrence (median time to relapse 35.3 months). In the initial surgery group, 14/15 (93.3%) were cured and treatment failure occurred in one (6.7%). In the multivariate analysis, the absence of an antibiotic response at 1 month was the only independent factor associated with a poor treatment outcome, with an adjusted odds ratio of 49.2 (95% CI, 3.34–724.30). There was no significant difference in treatment outcome based on the size of the parenchymal lesion, comorbidities, whether intravenous antibiotics were used, antibiotic therapy duration, or whether the initial treatment was surgical.
Antibiotic treatment with or without surgery was effective for treatment of pulmonary actinomycosis. Nevertheless, treatment failure or recurrence occurred in a considerable proportion of patients, especially those resistant to the initial antibiotic treatment.
Actinomycosis; Anti-bacterial agents; Treatment outcome; Prognostic factors; Pulmonary
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and responses to therapies are highly variable. The aim of this study was to identify the predictors of pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD. A total of 127 patients with stable COPD from the Korean Obstructive Lung Disease (KOLD) Cohort, which were prospectively recruited from June 2005 to September 2009, were analyzed retrospectively. The prediction models for the FEV1, FVC and IC/TLC changes after 3 months of treatment with salmeterol/fluticasone were constructed by using multiple, stepwise, linear regression analysis. The prediction model for the FEV1 change after 3 months of treatment included wheezing history, pre-bronchodilator FEV1, post-bronchodilator FEV1 change and emphysema extent on CT (R = 0.578). The prediction models for the FVC change after 3 months of treatment included pre-bronchodilator FVC, post-bronchodilator FVC change (R = 0.533), and those of IC/ TLC change after 3 months of treatment did pre-bronchodilator IC/TLC and post-bronchodilator FEV1 change (R = 0.401). Wheezing history, pre-bronchodilator pulmonary function, bronchodilator responsiveness, and emphysema extent may be used for predicting the pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD.
Pulmonary Disease, Chronic Obstructive; Emphysema; Corticosteroids; Adrenergic beta-Agonists; Respiratory Function Tests
Recent advances in sequencing technologies have initiated an era of personal genome sequences. To date, human genome sequences have been reported for individuals with ancestry in three distinct geographical regions: a Yoruba African, two individuals of north-west European origin, and a person from China1–4. Here we provide a highly annotated, whole-genome sequence for a Korean individual, known as AK1. The genome of AK1 was determined by an exacting, combined approach that included whole-genome shotgun sequencing (27.8× coverage), targeted bacterial artificial chromosome sequencing, and high-resolution comparative genomic hybridization using custom microarrays featuring more than 24 million probes. Alignment to the NCBI reference, a composite of several ethnic clades5,6, disclosed nearly 3.45 million single nucleotide polymorphisms (SNPs), including 10,162 non-synonymous SNPs, and 170,202 deletion or insertion polymorphisms (indels). SNP and indel densities were strongly correlated genome-wide. Applying very conservative criteria yielded highly reliable copy number variants for clinical considerations. Potential medical phenotypes were annotated for non-synonymous SNPs, coding domain indels, and structural variants. The integration of several human whole-genome sequences derived from several ethnic groups will assist in understanding genetic ancestry, migration patterns and population bottlenecks.
Cytoplasmic presence of Hsp60, which is principally a nuclear gene-encoded mitochondrial chaperonin, has frequently been stated, but its role in intracellular signaling is largely unknown. In this study, we demonstrate that the cytosolic Hsp60 promotes the TNF-α-mediated activation of the IKK/NF-κB survival pathway via direct interaction with IKKα/β in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-κB activation and the expression of NF-κB target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-α. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-κB activation. Mechanistically, the cytosolic Hsp60 enhanced IKK activation via upregulating the activation-dependent serine phosphorylation in a chaperone-independent manner. Furthermore, transgenic mouse study showed that the cytosolic Hsp60 suppressed hepatic cell death induced by diethylnitrosamine in vivo. The cytosolic Hsp60 is likely to be a regulatory component of IKK complex and it implicates the first mitochondrial factor that regulates cell survival via NF-κB pathway.
The aim of this study was to evaluate whether the mucosa-tracking technique is effective for improving precutting-related pancreatitis and the sustained failure of bile duct cannulation in precut papillotomy (PP) with the Iso-Tome (MTW Endoskopie).
From September 2004 to June 2006, PP was performed with the Iso-Tome if biliary cannulation failed by conventional methods for approximately 5 minutes. The pink intrapapillary mucosa (PIPM) exposed by PP was tracked and classified into four groups: fully exposed and oriented to the direction of the bile duct (group A) or the pancreatic duct (group B), partially exposed (group C), or unexposed (group D). The success rate of bile duct cannulation (SRBC), the procedure time required for successful bile duct cannulation (PTBC), and the complications in the first session were compared between the mucosa-exposed groups (MEGs; group A, B, and C) and the mucosa-unexposed group (MUEG; group D).
A total of 59 patients (25 females, 34 males) with a mean age of 65.2 years were enrolled. The MEGs and MUEG comprised 52 (88.1%) and 7 (11.9%) patients, respectively. SRBC in the first session was 86.4% (51/59) in total and 92.3% (48/52) in the MEGs, compared to only 42.9% (3/7) in the MUEG (p=0.005). The mean PTBC in the MEGs and MUEG was 8.7 minutes and 16.3 minutes, respectively (p=0.23). Complications occurred in 6.8% of the patients (4/59; all pancreatitis); there were no differences between the MEGs (5.8%, 3/52) and MUEG (14.3%, 1/7; p=0.41). All four patients with pancreatitis were managed medically.
The mucosa-tracking technique in PP with the Iso-Tome is a feasible and useful method of enhancing SRBC. PIPM is an important endoscopic landmark for successful PP.
Precut papillotomy; Iso-Tome; Mucosatracking technique; Pink intrapapillary mucosa
We prospectively conducted a multi-center, open-label, randomized phase II trial to compare the efficacy and safety of docetaxel plus cisplatin (DC) and etoposide plus cisplatin (EC) for treating advanced stage non-small cell lung cancer (NSCLC).
Materials and Methods
Seventy-eight previously untreated patients with locally advanced, recurrent or metastatic NSCLC were enrolled in this study. The patients received cisplatin 75 mg/m2 on day 1 and either docetaxel 75 mg/m2 on day 1 or etoposide 100 mg/m2 on days 1 to 3 in the DC or EC arm, respectively, every 3 weeks.
The objective response rate was 39.4% (15/38) and 18.4% (7/38) (p=0.023) in the DC and EC arms, respectively. The median time to progression (TTP) was 5.9 and 2.7 months (p=0.119), and the overall survival was 12.1 and 8.7 months (p=0.168) in the DC and EC arms, respectively. The prognostic factors for longer survival were an earlier disease stage (stage III, p=0.0095), the responders to DC (p=0.0174) and the adenocarcinoma histology (p=0.0454). The grades 3 and 4 toxicities were similar in both arms, with more febrile neutropenia (7.9% vs. 0%) and fatigue (7.9% vs. 0%) being noted in the DC arm.
DC offered a superior overall response rate than does EC, along with tolerable toxicity profiles, although the DC drug combination did not show significantly improved survival and TTP.
Docetaxel; Etoposide; Cisplatin; Non-small-cell lung carcinoma
The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients.
Pulmonary Disease, Chronic Obstructive; Forced Expiratory Volume; Disease Progression
Characteristics of stroke cases, acute stroke care, and outcomes after stroke differ according to geographical and cultural background. To provide epidemiological and clinical data on stroke care in South Korea, we analyzed a prospective multicenter clinical stroke registry, the Clinical Research Center for Stroke-Fifth Division (CRCS-5). Patients were 58% male with a mean age of 67.2±12.9 years and median National Institutes of Health Stroke Scale score of 3 [1-8] points. Over the 6 years of operation, temporal trends were documented including increasing utilization of recanalization treatment with shorter onset-to-arrival delay and decremental length of stay. Acute recanalization treatment was performed in 12.7% of cases with endovascular treatment utilized in 36%, but the proportion of endovascular recanalization varied across centers. Door-to-IV alteplase delay had a median of 45 [33-68] min. The rate of symptomatic hemorrhagic transformation (HT) was 7%, and that of any HT was 27% among recanalization-treated cases. Early neurological deterioration occurred in 15% of cases and were associated with longer length of stay and poorer 3-month outcomes. The proportion of mRS scores of 0-1 was 42% on discharge, 50% at 3 months, and 55% at 1 year after the index stroke. Recurrent stroke up to 1 year occurred in 4.5% of patients; the rate was higher among older individuals and those with neurologically severe deficits. The above findings will be compared with other Asian and US registry data in this article.
Stroke registry; South Korea; Case profile; Hyperacute treatment; Thrombolysis; Outcome; Recurrent event
Sorafenib is a standard treatment for advanced hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC] stage C). However, transarterial chemoembolization (TACE) has also been widely used as a treatment for patients with advanced HCC, even if they have extrahepatic metastases (EHM). The aim of this study was to determine the efficacy of TACE for advanced HCC patients with EHM upon initial diagnosis, as compared with those patients without EHM.
This cohort study involved consecutive patients who underwent TACE as an initial treatment for advanced HCC. One hundred seventy-seven patients with EHM (the EHM group) and 205 with portal vein invasion without EHM (the non-EHM group) were included. A survival analysis was performed to compare overall survival between the two groups.
The mean age was 54.5±9.9 years, and median follow-up duration was 13.1 months (range, 0.5–111.0). Overall survival was significantly shorter in the EHM group than the non-EHM group (median, 8.3 vs. 19.1 months; P<0.001). A multivariate analysis showed that the presence of EHM was an independent poor prognostic factor for shorter overall survival (adjusted hazard ratio, 1.74; 95% confidence interval, 1.39–2.17; P<0.001) after adjustment for Child-Pugh classification, intrahepatic tumor T classification, tumor response to TACE, and serum alpha-fetoprotein level. Patients administered TACE and systemic therapy demonstrated a better survival rate than those administered TACE alone in both the EHM (median, 13.5 vs. 7.2 months) and non-EHM groups (median, 27.9 vs. 18.2 months) (both, P<0.05).
The prognosis of advanced HCC patients with EHM is significantly worse than those without EHM administered repeated TACE treatments, even if their tumor stage was similar to BCLC stage C. These results suggest that EHM presence means aggressive tumor biology and that BCLC stage C might be subclassified according to EHM presence.
It is known that water purified by conventional TiO2 photocatalysts may not be safe enough for drinking, due to the toxicity by tiny existence of TiO2 nanoparticles after water treatment. We herein demonstrate a facile design of a three-dimensional (3D) TiO2 photocatalyst structure with which both the efficiency of purification and the safety level of the final purified water can be improved and ensured, respectively. The structure, consisting of 3D sulfur-doped TiO2 microtubes in nanotubes (eco-TiO2), is suitable for both environmental and bio-medical applications. Investigation of its formation mechanism reveals that anodic aluminum oxide (AAO), owing to a spatial constraint, causes a simple, nanoparticles-to-nanotubes structural rearrangement as a template for nanotube growth. It is found that eco-TiO2 can be activated under visible-light irradiation by non-metal (sulfur; S) doping, after which it shows visible-light photocatalytic activities over a range of solar energy. Importantly, an in vitro cytotoxicity test of well-purified water by eco-TiO2 confirms that eco-TiO2 satisfies the key human safety conditions.
Background and Purpose
In order to improve inter-rater reliability and minimize diagnosis of undetermined etiology for stroke subtype classification, using a stroke registry, we developed and implemented a magnetic resonance imaging (MRI)-based algorithm for acute ischemic stroke subtype classification (MAGIC).
We enrolled patients who experienced an acute ischemic stroke, were hospitalized in the 14 participating centers within 7 days of onset, and had relevant lesions on MR-diffusion weighted imaging (DWI). MAGIC was designed to reflect recent advances in stroke imaging and thrombolytic therapy. The inter-rater reliability was compared with and without MAGIC to classify the Trial of Org 10172 in Acute Stroke Treatment (TOAST) of each stroke patient. MAGIC was then applied to all stroke patients hospitalized since July 2011, and information about stroke subtypes, other clinical characteristics, and stroke recurrence was collected via a web-based registry database.
The overall intra-class correlation coefficient (ICC) value was 0.43 (95% CI, 0.31-0.57) for MAGIC and 0.28 (95% CI, 0.18-0.42) for TOAST. Large artery atherosclerosis (LAA) was the most common cause of acute ischemic stroke (38.3%), followed by cardioembolism (CE, 22.8%), undetermined cause (UD, 22.2%), and small-vessel occlusion (SVO, 14.6%). One-year stroke recurrence rates were the highest for two or more UDs (11.80%), followed by LAA (7.30%), CE (5.60%), and SVO (2.50%).
Despite several limitations, this study shows that the MAGIC system is feasible and may be helpful to classify stroke subtype in the clinic.
Stroke; Magnetic resonance imaging; Algorithm; Classification
Type 2 diabetes is characterized by progressive deterioration of β‐cell function. Recently, it was suggested that the C‐peptide‐to‐glucose ratio after oral glucose ingestion is a better predictor of β‐cell mass than that during fasting. We investigated whether postprandial C‐peptide‐to‐glucose ratio (PCGR) reflects β‐cell function, and its clinical application for management of type 2 diabetes.
Materials and Methods
We carried out a two‐step retrospective study of 919 Korean participants with type 2 diabetes. In the first step, we evaluated the correlation of PCGR level with various markers for β‐cell function in newly diagnosed and drug‐naïve patients after a mixed meal test. In the second step, participants with well‐controlled diabetes (glycated hemoglobin <7%) were divided into four groups according to treatment modality (group I: insulin, group II: sulfonylurea and/or dipeptityl peptidase IV inhibitor, group III: metformin and/or thiazolidinedione and group IV: diet and exercise group).
In the first step, PCGR was significantly correlated with various insulin secretory indices. Furthermore, PCGR showed better correlation with glycemic indices than homeostatic model assessment of β‐cell function (HOMA‐β). In the second step, the PCGR value significantly increased according to the following order: group I, II, III, and IV after adjusting for age, sex, body mass index and duration of diabetes. The cut‐off values of PCGR for separating each group were 1.457, 2.870 and 3.790, respectively (P < 0.001).
We suggest that PCGR might be a useful marker for β‐cell function and an ancillary parameter in the choice of antidiabetic medication in type 2 diabetes.
C‐peptide; Pancreatic β‐cell; Type 2 diabetes mellitus
Common treatment modalities for non-small cell lung cancer (NSCLC) involve the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due in large part to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non-small cell lung cancer (NSCLC).
Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model.
Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs, while having little toxicity toward normal cells. Genetic silencing of USP8 led to the down-regulation of several receptor tyrosine kinases (RTKs), including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression, while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells.
Our results demonstrate for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells.
USP8; selective killing; gefitinib-resistance; lung cancer; receptor tyrosine kinases
We postulated that palonosetron, a novel antiemetic agent, might have the effect of alleviating injection pain from propofol and rocuronium. A double-blind, controlled study was undertaken to evaluate the effect of palonosetron on injection pain during total intravenous anesthesia and postoperative nausea and vomiting (PONV) using propofol-remifentanil in breast and thyroid cancer surgery.
Sixty patients were randomly allocated to one of two groups. Before injection of propofol and rocuronium, patients in group S (n = 30) received 4 ml of saline and patients in group P (n = 30) received 75 µg (1.5 ml) of palonosetron mixed with 2.5 ml of saline (n = 30). Patients were evaluated by a blinded anesthesiologist with regard to the scoring of injection pain of propofol, withdrawal response by rocuronium, PONV, shivering, postoperative pain, recall of pain, and overall satisfaction.
The differences between groups in the incidence of injection pain due to propofol and rocuronium were insignificant. However, in group P, the severity of propofol-induced injection pain (3% vs. 33%, P = 0.003) and postoperative pain (P = 0.038) was significantly lower during the first 12 h after surgery. No differences were observed between the groups with respect to PONV, shivering, recall of pain, and overall satisfaction.
We concluded that pretreatment of palonosetron was effective to reduce the severity of propofol-induced injection pain and early postoperative pain, although it did not reduce the incidence of injection pain from propofol and rocuronium.
Pain; Palonosetron; Postoperative nausea and vomiting; Propofol
The use of synovial fluid-derived mesenchymal stem cells (SFMSCs) obtained from patients with degenerative arthropathy may serve as an alternative therapeutic strategy in osteoarthritis (OA) and rheumatoid arthritis (RA). For treatment of OA and RA patients, autologous transplantation of differentiated MSCs has several beneficial effects for cartilage regeneration including immunomodulatory activity. In this study, we induced chondrogenic differentiation of SFMSCs by inhibiting protein kinase A (PKA) with a small molecule and microRNA (miRNA). Chondrogenic differentiation was confirmed by PCR and immunocytochemistry using probes specific for aggrecan, the major cartilaginous proteoglycan gene. Absorbance of alcian blue stain to detect chondrogenic differentiation was increased in H-89 and/or miRNA-23btransfected cells. Furthermore, expression of matrix metalloproteinase (MMP)-9 and MMP-2 was decreased in treated cells. Therefore, differentiation of SFMSCs into chondrocytes through inhibition of PKA signaling may be a therapeutic option for OA or RA patients.
autologous cell transplantation; microRNAs; small molecules; synovial fluid-derived mesenchymal stem cells
The objectives of this study were to develop a coronary heart disease (CHD) risk model among the Korean Heart Study (KHS) population and compare it with the Framingham CHD risk score.
A prospective cohort study within a national insurance system.
18 health promotion centres nationwide between 1996 and 2001 in Korea.
268 315 Koreans between the ages of 30 and 74 years without CHD at baseline.
Non-fatal or fatal CHD events between 1997 and 2011. During an 11.6-year median follow-up, 2596 CHD events (1903 non-fatal and 693 fatal) occurred in the cohort. The optimal CHD model was created by adding high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides to the basic CHD model, evaluating using the area under the receiver operating characteristic curve (ROC) and continuous net reclassification index (NRI).
The optimal CHD models for men and women included HDL-cholesterol (NRI=0.284) and triglycerides (NRI=0.207) from the basic CHD model, respectively. The discrimination using the CHD model in the Korean cohort was high: the areas under ROC were 0.764 (95% CI 0.752 to 0.774) for men and 0.815 (95% CI 0.795 to 0.835) for women. The Framingham risk function predicted 3–6 times as many CHD events than observed. Recalibration of the Framingham function using the mean values of risk factors and mean CHD incidence rates of the KHS cohort substantially improved the performance of the Framingham functions in the KHS cohort.
The present study provides the first evidence that the Framingham risk function overestimates the risk of CHD in the Korean population where CHD incidence is low. The Korean CHD risk model is well-calculated alternations which can be used to predict an individual's risk of CHD and provides a useful guide to identify the groups at high risk for CHD among Koreans.
Background and Purpose
Symptomatic steno-occlusion (SYSO) in acute ischemic stroke has a significant impact on treatment options and prognosis. However, the prevalence, distribution, clinical characteristics, and outcome of SYSO are not well known.
We retrospectively identified 3,451 patients hospitalized because of ischemic stroke within 24 hours of symptom onset at 9 stroke centers in South Korea. Patients who did not undergo magnetic resonance imaging were excluded. SYSO was defined as stenosis or occlusion of cerebral arteries with relevant ischemic lesions in the corresponding arterial territory. The number, location, and severity of SYSOs and their effects on functional outcome were analyzed.
In total, 1,929 of 3,057 subjects (63.1%) had SYSO. The most frequently affected vessels were the middle cerebral artery (34.6%), extracranial internal carotid artery (14%), vertebral artery (12.4%), and basilar artery (8.7%). SYSO predicted poor outcome on the modified Rankin Scale 3-6 (odds ratio, 1.77; 95% confidence interval, 1.46-2.15) with adjustments. Involvement of 2 or more vessels was observed in 30.6% of patients with SYSO and independently increased the risk of poor outcome (odds ratio, 2.76; 95% confidence interval, 2.12-3.59). The severity of SYSO was associated with outcome and showed a significant dose-response trend (P<0.001). The effect of SYSO on outcome did not significantly differ by individual arterial location (P for contrast=0.21).
Approximately 60% of patients with acute ischemic stroke had SYSO, and the severity and number were inversely correlated with outcome. The results suggest that SYSO could predict stroke outcome.
Cerebrovascular occlusion; Stroke; Cerebral arteries; Magnetic Resonance Imaging
The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress. It has been hypothesized that BI-1 protects against neuron degenerative diseases. In this study, BI-1−/− mice showed increased vulnerability to chronic mild stress accompanied by alterations in the size and morphology of the hippocampi, enhanced ROS accumulation and an ER stress response compared with BI-1+/+ mice. BI-1−/− mice exposed to chronic mild stress showed significant activation of monoamine oxidase A (MAO-A), but not MAO-B, compared with BI-1+/+ mice. To examine the involvement of BI-1 in the Ca2+-sensitive MAO activity, thapsigargin-induced Ca2+ release and MAO activity were analyzed in neuronal cells overexpressing BI-1. The in vitro study showed that BI-1 regulates Ca2+ release and related MAO-A activity. This study indicates an endogenous protective role of BI-1 under conditions of chronic mild stress that is primarily mediated through Ca2+-associated MAO-A regulation.