Fimasartan Ameliorates Deteriorations in Glucose Metabolism in a High Glucose State by Regulating Skeletal Muscle and Liver Cells

PurposeSince diabetes and hypertension frequently occur together, it is thought that these conditions may have a common pathogenesis. This study was designed to evaluate the anti-diabetic function of the anti-hypertensive drug fimasartan on C2C12 mouse skeletal muscle and HepG2 human liver cells in a high glucose state.Materials and MethodsThe anti-diabetic effects and mechanism of fimasartan were identified using Western blot, glucose uptake tests, oxygen consumption rate (OCR) analysis, adenosine 5′-triphosphate (ATP) enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining for diabetic biomarkers in C2C12 cells. Protein biomarkers for glycogenolysis and glycogenesis were evaluated by Western blotting and ELISA in HepG2 cells.ResultsThe protein levels of phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK), p-AKT, insulin receptor substrate-1 (IRS-1), and glucose transporter type 4 (Glut4) were elevated in C2C12 cells treated with fimasartan. These increases were reversed by peroxisome proliferator-activated receptor delta (PPARδ) antagonist. ATP, OCR, and glucose uptake were increased in cells treated with 200 µM fimasartan. Protein levels of glycogen phosphorylase, glucose synthase, phosphorylated glycogen synthase, and glycogen synthase kinase-3 (GSK-3) were decreased in HepG2 cells treated with fimasartan. However, these effects were reversed following the addition of the PPARδ antagonist GSK0660.ConclusionIn conclusion, fimasartan ameliorates deteriorations in glucose metabolism as a result of a high glucose state by regulating PPARδ in skeletal muscle and liver cells.     

乙型肝炎疫苗免疫效果影响因素分析

目的探讨乙肝疫苗免疫效果的影响因素。方法选择正定县乙肝疫苗效果考核试点乡1986-2004年出生的人群为研究对象,以固相放射免疫(RIA)法检测血清HBsAg、抗-HBs和抗-HBc,用EpiInfo和SAS软件进行统计处理。结果1994年及以后出生的1～11岁组人群HBsAg、抗-HBc分别为0.41%、2.29%,显著低于1994年前出生的12～19岁组人群的2.18%和8.44%;乙肝疫苗3针全程免疫组人群HBsAg阳性率最低,为0.35%;44例HBsAg阳性者中,母亲HBsAg阳性者21例,占47.73%。结论母亲HBsAg携带状况和乙肝疫苗接种史是影响乙肝疫苗免疫效果的关键因素。     

Mutational Analysis of Triple-Negative Breast Cancer Using Targeted Kinome Sequencing

PurposeTriple-negative breast cancer (TNBC) does not have defined therapeutic targets and is currently treated with chemotherapy only. Kinase dysregulation triggers cancer cell proliferation and metastasis and is a crucial therapeutic target for cancer. In this study, targeted kinome sequencing of TNBC tumors was performed to assess the association between kinome gene alterations and disease outcomes in TNBC.MethodsA kinome gene panel consisting of 612 genes was used for the targeted sequencing of 166 TNBC samples and matched normal tissues. Analyses of the significantly mutated genes were performed. Genomic differences between Asian and non-Asian patients with TNBC were evaluated using two Asian TNBC datasets (from Seoul National University Hospital [SNUH] and Fudan University Shanghai Cancer Center [FUSCC]) and three non-Asian TNBC datasets (The Cancer Genome Atlas [TCGA], METABRIC, and Gustave Roussy). The prognostic value of kinome gene mutations was evaluated using tumor mutational burden (TMB) and oncogenic pathway analyses. Mutational profiles from the TCGA were used for validation.ResultsThe significantly mutated genes included TP53 (60% of patients), PIK3CA (21%), BRCA2 (8%), and ATM (8%). Compared with data from non-Asian public databases, the mutation rates of PIK3CA p.H1047R/Q were significantly higher in the SNUH cohort (p = 0.003, 0.048, and 0.032, respectively). This was verified using the FUSCC dataset (p = 0.003, 0.078, and 0.05, respectively). The TMB-high group showed a trend toward longer progression-free survival in our cohort and the TCGA TNBC cohort (p = 0.041 and 0.195, respectively). Kinome gene alterations in the Wnt pathway in patients with TNBC were associated with poor survival in both datasets (p = 0.002 and 0.003, respectively).ConclusionComprehensive analyses of kinome gene alterations in TNBC revealed genomic alterations that offer therapeutic targets and should help identify high-risk patients more precisely in future studies.     

Feasibility of Single-Shot Whole Thoracic Time-Resolved MR Angiography to Evaluate Patients with Multiple Pulmonary Arteriovenous Malformations

ObjectiveTo evaluate the feasibility of single-shot whole thoracic time-resolved MR angiography (TR-MRA) to identify the feeding arteries of pulmonary arteriovenous malformations (PAVMs) and reperfusion of the lesion after embolization in patients with multiple PAVMs.Materials and MethodsNine patients (8 females and 1 male; age range, 23–65 years) with a total of 62 PAVMs who underwent percutaneous embolization for multiple PAVMs and were subsequently followed up using TR-MRA and CT obtained within 6 months from each other were retrospectively reviewed. All imaging analyses were performed by two independent readers blinded to clinical information. The visibility of the feeding arteries on maximum intensity projection (MIP) reconstruction and multiplanar reconstruction (MPR) TR-MRA images was evaluated by comparing them to CT as a reference. The accuracy of TR-MRA for diagnosing reperfusion of the PAVM after embolization was assessed in a subgroup with angiographic confirmation. The reliability between the readers in interpreting the TR-MRA results was analyzed using kappa (κ) statistics.ResultsFeeding arteries were visible on the original MIP images of TR-MRA in 82.3% (51/62) and 85.5% (53/62) of readers 1 and 2, respectively. Using the MPR, the rates increased to 93.5% (58/62) and 95.2% (59/62), respectively (κ = 0.760 and 0.792, respectively). Factors for invisibility were the course of feeding arteries in the anteroposterior plane, proximity to large enhancing vessels, adjacency to the chest wall, pulsation of the heart, and small feeding arteries. Thirty-seven PAVMs in five patients had angiographic confirmation of reperfusion status after embolization (32 occlusions and 5 reperfusions). TR-MRA showed 100% (5/5) sensitivity and 100% (32/32, including three cases in which the feeding arteries were not visible on TR-MRA) specificity for both readers.ConclusionSingle-shot whole thoracic TR-MRA with MPR showed good visibility of the feeding arteries of PAVMs and high accuracy in diagnosing reperfusion after embolization. Single-shot whole thoracic TR-MRA may be a feasible method for the follow-up of patients with multiple PAVMs.     

Determinants of Short-Term Weight Gain Following Surgical Treatment for Craniopharyngioma in Adults

ObjectiveCraniopharyngiomas (CPs) are associated with hypothalamic damage that causes hypothalamic obesity, however, the mechanisms underlying CP-related postoperative weight gain remain debatable. This study aimed to elucidate whether the major determinant of postoperative weight gain in patients with CP is hypothalamic injury or steroid replacement therapy. MethodsWe included 48 adult patients with CP (age ≥18 years) who underwent transsphenoidal surgery between 2010 and 2018 in a single tertiary center, and whose body weight was measured pre- and postoperatively (<120 days after the surgery). We recruited 144 age- and body mass index-matched patients with non-functioning pituitary adenoma (NFPA) as controls. ResultsPatients with CP experienced greater postoperative weight gain than patients with NFPA (3.0±5.1 vs. 0.1±3.6 kg, p<0.001). The prevalence of postoperative steroid use was significantly higher in patients with CP than in those with NFPA (89.6% vs. 34.0%, p<0.001). Steroid replacement therapy and CP were associated with postoperative weight gain after adjusting for covariates in overall patients (p=0.032 and 0.007, respectively). In subgroup analysis with postoperative steroid users, weight gain was significantly greater in patients with CP (n=43, 0.96±0.25 kg/month) than in patients with NFPA (n=49, 0.26±0.23 kg/month) even after adjusting for the daily steroid dose (p=0.048). ConclusionPatients with CP experience greater postoperative weight gain than those with NFPA. Hypothalamic damage itself as well as steroid replacement may contribute to the postoperative weight gain in patients with CP.     

The Influence of Face Shields on the Quality of Colonoscopy in the Era of the COVID-19 Pandemic

Background/AimsThe worldwide coronavirus disease 2019 pandemic has led endoscopists to use personal protective equipment (PPE) for infection prevention. This study aimed to investigate whether wearing a face shield as PPE affects the quality of colonoscopy.MethodsWe reviewed the medical records and colonoscopy findings of patients who underwent colonoscopies at Asan Medical Center, Korea from March 10 to May 31, 2020. The colonoscopies in this study were performed by five gastroenterology fellows and four expert endoscopists. We compared colonoscopy quality indicators, such as withdrawal time, adenoma detection rate (ADR), mean number of adenomas per colonoscopy (APC), polypectomy time, and polypectomy adverse events, both before and after face shields were added as PPE on April 13, 2020.ResultsOf the 1,344 colonoscopies analyzed, 715 and 629 were performed before and after the introduction of face shields, respectively. The median withdrawal time was similar between the face shield and no-face shield groups (8.72 minutes vs 8.68 minutes, p=0.816), as was the ADR (41.5% vs 39.8%, p=0.605) and APC (0.72 vs 0.77, p=0.510). Polypectomy-associated quality indicators, such as polypectomy time and polypectomy adverse events were also not different between the groups. Quality indicators were not different between the face shield and no-face shield groups of gastroenterology fellows, or of expert endoscopists.ConclusionsColonoscopy performance was not unfavorably affected by the use of a face shield. PPE, including face shields, can be recommended without a concern about colonoscopy quality deterioration.     

Differences in autophagy-related activity by molecular subtype in triple-negative breast cancer

The aim of this study was to assess the expression of significant components of autophagy including beclin-1, light chain (LC) 3A, LC3B, and p62 in the molecular subtypes of triple-negative breast cancer (TNBC) and to evaluate the implications of the results. Tissues from 119 cases of TNBC were used for a tissue microarray. Expression of cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR), claudin 3, claudin 4, claudin7, E-cadherin, androgen receptor (AR), and gamma-glutamyltransferase 1 (GGT-1) was detected by immunohistochemical staining of the tissue microarrays. According to the results, the 119 cases of TNBC were subclassified into basal-like type (CK5/6-positive and/or EGFR-positive group), molecular apocrine type (AR-positive and/or GGT-1-positive group), claudin low type (claudin 3-, claudin 4-, or claudin 7-negative and/or E-cadherin-negative group), mixed type (having the features of more than two types), or null type (none of the above). Immunohistochemical staining for autophagy-related markers including beclin-1, LC3A, LC3B, and p62 was performed to evaluate the difference between clinicopathological parameters. TNBCs were categorized as basal-like type (36 patients, 30.3?%), molecular apocrine type (8 patients, 6.7?%), claudin low type (16 patients, 13.4?%), mixed type (37 patients, 31.1?%), and null type (22 patients, 18.5?%). Expression of nuclear p62 was higher in the molecular apocrine type and claudin low type than in other types of TNBC (p?=?0.008). Expression of beclin-1 was higher in molecular apocrine type than in other TNBC types (p?=?0.039). Expression of LC3A and LC3B showed no difference between the molecular subtypes. Multivariate Cox analysis revealed that the negative expression of p62 was associated with shorter disease-free survival [p?=?0.012; odds ratio, 3.192; 95?% confidence interval (CI), 1.293?C7.882] and shorter overall survival (p?=?0.009; odds ratio, 3.895; 95?% CI, 1.409?C10.771). Among the subtypes of TNBC, molecular apocrine breast cancer showed a higher expression of nuclear p62 and beclin-1 than others, which reflected higher autophagy activity.     

Anaphase-promoting complex/cyclosome protein Cdc27 is a target for curcumin-induced cell cycle arrest and apoptosis

Background  

Curcumin (diferuloylmethane), the yellow pigment in the Asian spice turmeric, is a hydrophobic polyphenol from the rhizome of Curcuma longa. Because of its chemopreventive and chemotherapeutic potential with no discernable side effects, it has become one of the major natural agents being developed for cancer therapy. Accumulating evidence suggests that curcumin induces cell death through activation of apoptotic pathways and inhibition of cell growth and proliferation. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell cycle control mechanism to delay the onset of anaphase during mitosis. One of the key regulators of the SAC is the anaphase promoting complex/cyclosome (APC/C) which ubiquitinates cyclin B and securin and targets them for proteolysis. Because APC/C not only ensures cell cycle arrest upon spindle disruption but also promotes cell death in response to prolonged mitotic arrest, it has become an attractive drug target in cancer therapy.