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Abstract Background To identify novel HLA-A*2402-restricted human cytomegalovirus (HCMV) immediate early-1 (IE-1) epitopes for adoptive immunotherapy, we explored 120 overlapping 15-amino acid spanning IE-1. Methods These peptides were screened by measuring the frequency of polyclonal CD8+ T cells producing intracellular interferon-γ (IFN-γ) using flow cytometry and the epitopes were validated with a HCMV-infected target Cr release cytotoxicity assay. Results Initial screening was performed with 12 mini-pools of 10 consecutive peptides made from 120 overlapping peptides15-amino acids in length that spanned IE-1. When peripheral blood mononuclear cells (PBMCs) from HLA-A*2402 HCMV-seropositive donors were sensitized with each of the 12 mini-pools, mini-pools 1 and 2 induced the highest frequency of CD8+ cytotoxic T lymphocytes (CTLs) producing IFN-γ. When PBMCs were stimulated with each of the twenty peptides belonging to mini-pools 1 and 2, peptides IE-11–15MESSAKRKMDPDNPD and IE-15–19AKRKMDPDNPDEGPS induced the greatest quantities of IFN-γ production and cytotoxicity of HLA-matched HCMV-infected fibroblasts. To determine the exact HLA-A*2402-restricted epitopes within the two IE-1 proteins, we synthesized a total of twenty-one overlapping 9- or 10 amino acid peptides spanning IE-11–15 and IE-15–19. Peptide IE-13–12SSAKRKMDPD induced the greatest quantities of IFN-γ production and target cell killing by CD8+ CTLs. Conclusion HCMV IE-13–12SSAKRKMDPD is a HLA-A*2402-restricted HCMV IE-1 epitope that can serve as a common target for CD8+ HCMV-specific CTLs. more...

Abstract Background High mobility group box-1 (HMGB1) is a newly recognized factor regulating cancer cell tumorigenesis, expansion and invasion. We investigated the correlation between the serum HMGB1 levels and the clinical and pathologic features of gastric cancer and evaluated the validity of HMGB1 as a potential biomarker for the early diagnosis of gastric cancer. Methods A total of 227 subjects were classified into 5 disease groups according to the 'gastritis-dysplasia-carcinoma' sequence of gastric carcinogenesis and their serum levels of HMGB1 were analyzed by an enzyme-linked immunosorbent assay (ELISA) method. Clinical parameters, International Union Against Cancer (UICC) TNM stage, cancer size, differentiation or lymphatic invasion, vascular or perineural invasion and prognosis were used as analysis variables. Results The serum HMGB1 levels were significantly different among disease groups (ANOVA, p < 0.05) and HMGB1 levels tended to increase according to the progression of gastric carcinogenesis. Serum HMGB1 levels were significantly associated with depth of invasion, lymph node metastasis, tumor size, and poor prognosis (p < 0.05). However, HMGB1 levels were not associated with patient gender or age, differentiation of tumor cells, or lymphatic, vascular and perineural invasion, or the existence of distant metastasis in advanced cancer (p > 0.05). The sensitivity and specificity of serum HMGB1 was 71% and 67% (cut-off value of 5 ng/ml) for the diagnosis of early gastric cancer, and 70% and 64% (cut-off value of 4 ng/ml) for the diagnosis of high-risk lesions, respectively. These values were greater than those for carcinoembryonic antigen (CEA) (30–40% of sensitivity). Conclusion HMGB1 appears to be a useful serological biomarker for early diagnosis as well as evaluating the tumorigenesis, stage, and prognosis of gastric cancer. more...

Context: In the management of growth hormone (GH)-secreting pituitary adenomas, the oral glucose tolerance test (OGTT) has been the gold standard not only for diagnoses but also for the determination of biochemical remission. Insulin-like growth factor-1 (IGF-1) is an essential biomarker, although it should be adjusted for both age and sex.Objective: We evaluated whether IGF-1 levels could serve as a reliable alternative to an OGTT for disease monitoring after the surgical treatment of acromegaly. We retrospectively reviewed the medical records of 320 patients who underwent surgical resection of their GH-secreting pituitary tumors at the Severance hospital. Receiver operator characteristic (ROC) analyses were performed to validate the accuracy of IGF-1 levels for the assessment of remission. In addition, regression analyses were performed to identify factors associated with discrepancy between OGTT and IGF-1 levels.Results: Except for 1 week after surgery, ROC analyses showed an area under the curve of greater than 0.8 for IGF-1 at all time points. Of 320 patients, 270 achieved endocrine remission after surgery alone. Among these patients, IGF-1 levels were normalized in 250 patients. The mean duration from surgery to IGF-1 normalization was 4.7 months. Regression analyses demonstrated that risk of failed IGF-1 normalization was increased by 3.1-fold when the tumor invaded the cavernous sinus and increased by 9.0-fold in patients with incomplete tumor removal.Conclusion: IGF-1 level is a reliable alternative to OGTT and plays a valuable role in monitoring acromegaly status. [ABSTRACT FROM AUTHOR] more...

Aims Early identification of individuals with insulin resistance (IR) and metabolically unhealthy state can help prevent various diseases and improve quality of life. In this study, we investigated a possible marker of IR and metabolic health status, alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio, and aimed to confirm its feasibility in a large population study. Methods A total of 16,371 adults from Korean National Health and Examination Survey were studied. Participants were divided into four groups according to their ALT/AST ratio quartiles. The homeostatic model assessment of insulin resistance level and proportion of people with IR, impaired fasting glucose, and undiagnosed type 2 diabetes were compared for each group. Receiver-operating characteristics (ROC) curve was also used to assess the usefulness of ALT/AST ratio to identify individuals with IR and metabolically unhealthy. Results In the groups with higher ALT/AST ratio, HOMA-IR level, proportion of IR, and proportion of individuals with IFG or type 2 diabetes mellitus was higher than that in those with low ALT/AST ratio. When analyzed with other factors related to IR, the data showed that the ALT/AST ratio was an independent predictor of IR (odds ratio 1.363, 95% confidential interval 1.323–1.405, p<0.001). When ROC curve analysis was done, area under curve (AUC) for identifying individuals with IR was 0.634. In addition, metabolically unhealthy individuals showed significantly higher ALT/AST ratio than metabolically healthy individuals (0.9780 vs 0.8511, p<0.001). Conclusions ALT/AST ratio was well-correlated with IR, IR-related conditions, and metabolic health status. This easily accessible method to estimate IR may facilitate the early screening of IR, which can result in prevention of IR-related morbid conditions. [ABSTRACT FROM AUTHOR] more...

Subcutaneous (SC) insulin injection has been demonstrated to be the most effective method for treatment of diabetes mellitus but is conventionally performed by hypodermic needles, leading to poor management of diabetes because of the pain, needle phobia, and tissue trauma. Identification of a viable, safe, and pain-free alternative method has been a longstanding challenge in modern health care. Here, the thermoplastic droplet stretching technique is developed to create an ultrahigh-aspect-ratio needle mold with simple microstructure control. The optimized ultrafine needle (UN) with 4 mm length, minimized 120 µm outer diameter, and 15° sharp bevel angle is formed via electroplating of a metallic layer on the surface of a needle mold with forcing sharp tip. This novel UN enables minimally invasive 4 mm skin insertion to deliver insulin in the targeted SC layer. The similar relative areas under the curves of insulin concentration within UN and 31G needle in vivo insulin administration indicate that UN can ensure stable insulin absorption for secure blood glucose management. Additionally, the proposed fabrication method may facilitate industrialization and commercialization of the UN, holding great promise for replacement of hypodermic needles and for improvement of quality of life among patients with diabetes. [ABSTRACT FROM AUTHOR] more...