Background: Digital pathology (DP) using whole slide imaging is a recently emerging game changer technology that can fundamentally change the way of working in pathology. The Digital Pathology Study ...Group (DPSG) of the Korean Society of Pathologists (KSP) published a consensus report on the recommendations for pathologic practice using DP. Accordingly, the need for the development and implementation of a quality assurance program (QAP) for DP has been raised.Methods: To provide a standard baseline reference for internal and external QAP for DP, the members of the Committee of Quality Assurance of the KSP developed a checklist for the Redbook and a QAP trial for DP based on the prior DPSG consensus report. Four leading institutes participated in the QAP trial in the first year, and we gathered feedback from these institutes afterwards.Results: The newly developed checklists of QAP for DP contain 39 items (216 score): eight items for quality control of DP systems; three for DP personnel; nine for hardware and software requirements for DP systems; 15 for validation, operation, and management of DP systems; and four for data security and personal information protection. Most participants in the QAP trial replied that continuous education on unfamiliar terminology and more practical experience is demanding.Conclusions: The QAP for DP is essential for the safe implementation of DP in pathologic practice. Each laboratory should prepare an institutional QAP according to this checklist, and consecutive revision of the checklist with feedback from the QAP trial for DP needs to follow.
Aims/Introduction
The benefits of once‐daily insulin degludec/aspart (IDegAsp) compared with basal insulin in type 2 diabetes patients have not been established.
Materials and Methods
This was a ...retrospective observational study. From a basal insulin cohort from three referral hospitals, patients were enrolled who initiated once‐daily IDegAsp. A control group maintaining basal insulin was selected by propensity score matching. Glycated hemoglobin (HbA1c) changes over a period of 6 months and associated clinical factors were evaluated.
Results
The IDegAsp group and the control group comprised of 87 patients, respectively. Baseline HbA1c was comparable between the two groups (8.7 ± 0.9 vs 8.6 ± 0.9%, mean and standard deviation). After 6 months with matched insulin doses, HbA1c in the IDegAsp group was lower than that in the control group (8.1 ± 1.0 vs 8.4 ± 1.1%, P = 0.029). Among baseline variables, fasting plasma glucose (FPG) and fasting C‐peptide in the IDegAsp were lower than that in the control (FPG 124.2 ± 38.4 vs 148.0 ± 50.6 mg/dL, P < 0.001). Considering that the lower FPG despite the comparable HbA1c could be related with the efficacy of IDegAsp, subgroup analysis was carried out according to a ratio of FPG‐to‐estimated average glucose, which is calculated from HbA1c. When compared with each control group, the superiority of IDegAsp in the reduction of HbA1c was significant only in the patients with a lower FPG‐to‐estimated average glucose ratio (0.49 ± 0.09), but not in those with a higher FPG‐to‐estimated average glucose ratio (0.79 ± 0.20).
Conclusions
We observed that IDegAsp was more effective than basal insulin in patients with an FPG lower than predicted by HbA1c, which might be related with insulin deficiency and postprandial hyperglycemia in patients on basal insulin therapy.
Once‐daily insulin degludec/aspart was more effective in glycated hemoglobin reduction than basal insulin, especially in patients showing a lower ratio of fasting plasma glucose‐to‐estimated average glucose. This indicates that marked postprandial hyperglycemia was tied to the efficacy of once‐daily insulin degludec/aspart compared with basal insulin.
Background & Aims Hepatocellular carcinomas (HCCs) expressing “stemness”-related markers have been associated with aggressive biological behavior and poor prognosis. We examined the relationship ...between “stemness”-related protein expression and telomere length, hTERT and shelterin complex protein expression and chromosomal instability. Methods Quantitative fluorescent in situ hybridization for telomere length, immunohistochemistry for K19, EpCAM, CD133, c-kit, HepPar1, hTERT, TRF1, TRF2, POT1, RAP1 and TPP1, and TUNEL assay were performed in 137 HCCs, and array comparative genomic hybridization was performed with 24 HCCs. Results Telomeres were significantly longer in HCCs expressing “stemness”-related proteins (K19: p <0.001, EpCAM: p = 0.002, CD133: p = 0.002). On analyzing different tumor cells within EpCAM-expressing HCCs, EpCAM-positive tumor cells showed longer telomeres (1.329 ± 0.246) compared to EpCAM-negative tumor cells (0.996 ± 0.381) within the same HCCs ( p = 0.031). Telomeres were significantly longer in HCCs expressing hTERT ( p = 0.048) and RAP1 proteins ( p = 0.031). K19-expressing HCCs expressed hTERT ( p = 0.002), TRF2 ( p = 0.001) and TPP1 ( p = 0.013) more frequently compared to K19-negative HCCs. EpCAM-positivity was associated with more frequent hTERT ( p = 0.028), TPP1 ( p = 0.017), TRF2 ( p = 0.027) and POT1 ( p = 0.004) expression. Copy number alterations were more frequent in K19 and EpCAM-expressing HCCs compared to HCCs without these markers (K19: p = 0.038, EpCAM: p = 0.009). HCCs with longer telomeres were associated with a shorter overall ( p = 0.019) and disease-free survivals ( p = 0.049), and decreased disease-free survivals were seen in TRF2-positive HCCs ( p = 0.018). Conclusions HCCs expressing “stemness”-related proteins are characterized by increased telomere length, increased expression of hTERT and shelterin complex proteins, and increased chromosomal instability compared to conventional HCCs. Longer telomeres and TRF2 expression in HCCs are associated with poor patient outcomes.
Background A paucity of information exists regarding colorectal neoplasm in asymptomatic, average-risk individuals 40 to 49 years of age. Objective To evaluate the prevalence and risk factors of ...colorectal neoplasms in those in their 40s. Design Cross-sectional study. Setting Results offered to subjects of a health care provider that offers screening services as part of an employer-provided wellness program. Patients A consecutive series of 1761 asymptomatic, average-risk screenees 40 to 59 years of age. Intervention First screening colonoscopy. Results The prevalence of overall colorectal neoplasm in subjects of ages 40 to 44 years, 45 to 49 years, 50 to 54 years, and 55 to 59 years increased significantly with increasing age (13.7%, 20.2%, 21.0%, and 23.8%, respectively; P < .001). The prevalence of advanced adenomas in subjects of ages 40 to 44 years, 45 to 49 years, 50 to 54 years, and 55 to 59 years increased significantly with age (1.9%, 3.0%, 3.2%, and 5.9%, respectively; P = .004). Multivariate analysis of data from the 40- to 49-year age group identified an increased risk of colorectal neoplasm associated with ages 45 years and older (odds ratio OR, 1.68; 95% CI, 1.20-2.35), male sex (OR, 1.76; 95% CI, 1.15-2.69), presence of abdominal obesity (OR, 1.57; 95% CI, 1.12-2.21), and metabolic syndrome (OR, 1.56; 95% CI, 1.03-2.35), whereas for advanced adenomas, abdominal obesity (OR, 2.37; 95% CI, 1.06-5.27) and metabolic syndrome (OR, 2.83; 95% CI, 1.23-6.53) were the independent risk factors. Limitations Single-center study and the cohort composed of ethnic Korean subjects who lived in the same geographic region. Conclusion In average-risk individuals 40 to 49 years of age, men with abdominal obesity or metabolic syndrome might benefit from screening colonoscopy starting at 45 years of age to detect colorectal neoplasm.
Administration of pancreatic endoplasmic reticulum kinase inhibitor (PERKi) improved insulin secretion and hyperglycemia in obese diabetic mice. In this study, autophagic balance was studied whether ...to mediate it.
Human islets were isolated from living patients without diabetes. PERKi GSK2606414 effects were evaluated in the islets under glucolipotoxicity by palmitate. Islet insulin contents and secretion were measured. Autophagic flux was assessed by microtubule associated protein 1 light chain 3 (LC3) conversion, a red fluorescent protein (RFP)-green fluorescent protein (GFP)- LC3 tandem assay, and P62 levels. For mechanical analyses, autophagy was suppressed using 3-methyladenine in mouse islets. Small interfering RNA for an autophagy-related gene autophagy related 7 (Atg7) was transfected to interfere autophagy.
PERKi administration to mice decreased diabetes-induced P62 levels in the islets. Glucolipotoxicity significantly increased PERK phosphorylation by 70% and decreased insulin contents by 50% in human islets, and addition of PERKi (40 to 80 nM) recovered both. PERKi also enhanced glucose-stimulated insulin secretion (6-fold). PERKi up-regulated LC3 conversion suppressed by glucolipotoxicity, and down-regulated P62 contents without changes in P62 transcription, indicating enhanced autophagic flux. Increased autophagosome-lysosome fusion by PERKi was visualized in mouse islets, where PERKi enhanced ATG7 bound to LC3. Suppression of Atg7 eliminated PERKi-induced insulin contents and secretion.
This study provided functional changes of human islets with regard to autophagy under glucolipotoxicity, and suggested modulation of autophagy as an anti-diabetic mechanism of PERKi.
Recent studies have demonstrated that an inflammatory mechanism contributes to the pathogenesis of diabetic nephropathy (DN). It is also known that colchicine (Col) can prevent various renal injuries ...via its anti-inflammatory action. However, the effect of colchicine on DN has never been explored. This study was undertaken to elucidate the effect of colchicine on inflammation and extracellular matrix accumulation in DN. In vivo, 64 rats were injected with diluent (C; n = 32) or streptozotocin intraperitoneally (DM, n = 32). Sixteen rats from each group were treated with Col. In vitro, rat mesangial cells and NRK-52E cells were cultured in media with 5.6 mM glucose (NG) or 30 mM glucose (HG) with or without 10(-8) M Col. Monocyte chemotactic protein-1 (MCP-1) mRNA expression was determined by real-time PCR (RT-PCR), and the levels of MCP-1 in renal tissue and culture media were measured by ELISA. RT-PCR and Western blotting were also performed for intercellular adhesion molecule-1 (ICAM-1) and fibronectin (FN) mRNA and protein expression, respectively, and immunohistochemical staining (IHC) for ICAM-1, FN, and ED-1 with renal tissue. Twenty-four-hour urinary albumin excretion at 6 wk and 3 mo were significantly higher in DM compared with C rats (P < 0.05), and colchicine treatment significantly reduced albuminuria in DM rats (P < 0.05). Col significantly inhibited the increase in MCP-1 mRNA expression and protein levels under diabetic conditions both in vivo and in vitro. ICAM-1 and FN expression showed a similar pattern to the expression of MCP-1. IHC revealed that the number of ED-1(+) cells were significantly higher in DM compared with C kidney (P < 0.005), and this increase was significantly attenuated by Col treatment (P < 0.01). In conclusion, Col prevents not only inflammatory cell infiltration via inhibition of enhanced MCP-1 and ICAM-1 expression but also ECM accumulation in DN. These findings provide a new perspective on the renoprotective effects of Col in DN.
Aims: Epithelial–mesenchymal transition (EMT) is defined as switching of polarized epithelial cells to a migratory fibroblastoid phenotype. EMT is known to be involved in the progression and ...metastasis of various cancers. The aim was to evaluate the expression of EMT‐related proteins in gastric carcinoma (GC).
Methods and results: The expression of nine EMT‐related proteins in the GC tissues of 598 patients was evaluated by immunohistochemistry using a tissue array method. In addition, clinicopathological characteristics and survival were compared with the expression of EMT‐related proteins. Loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins were observed in GC. These protein alterations were associated with diffuse type histology, advanced stage and poor patient outcome, respectively. Subjects were divided into three groups according to degree of EMT‐related protein alteration. Increases in alteration of EMT‐related protein were found to be significantly associated with poorly differentiated histology, higher pTNM stage and unfavourable outcome. Multivariate analysis showed that alterations in the expression of EMT‐related proteins were independently associated with poor prognosis.
Conclusions: Loss of epithelial proteins and/or the acquisition of mesenchymal proteins are associated with poorly differentiated histology, advanced stage and poor outcome in GC. The awareness and inhibition of EMT offer a promising target for prevention of metastatic progression and invasion.
Summary HER-2 gene amplification and the overexpression of HER-2 protein have been observed in various solid tumors, including gastric carcinomas. HER-2 gene amplification has attracted research ...attention since the development of the new therapeutic agent trastuzumab. Here, we evaluated HER-2 status in the surgically resected tissues of 248 gastric carcinoma cases using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and real-time quantitative polymerase chain reaction (q-PCR) and compared the results. In addition, we compared clinicopathologic characteristics with the presence of HER-2 gene amplification and with protein overexpression. Among the 248 cases, 56 (22.6%) cases showed HER-2 overexpression (2+ or 3+) by IHC and 19 cases (7.7%) showed HER-2 gene amplification by FISH. Four (2.1%) of the 192 cases negative (0 or 1+) by IHC showed amplification by FISH, whereas 15 (26.8%) of the 56 cases with HER-2 protein overexpression showed HER-2 amplification by FISH. The correlation between IHC and FISH results was statistically significant ( P < .001). HER-2 protein overexpression and HER-2 gene amplification were common in cases with a well- or moderately differentiated histology according to the World Health Organization classification ( P < .001) and in cases of intestinal type by the Lauren classification ( P < .001). Real-time q-PCR results showed that calculated HER-2 / GAPDH ratios were higher in amplified cases with 100.0% sensitivity and 96.9% specificity using FISH results as the standard. Measurements of HER-2 expression by FISH and real-time q-PCR and of HER-2 protein by IHC were found to be highly concordant at determining HER-2 status in gastric carcinoma.
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