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Fucosylated haptoglobin is a well-established glyco-biomarker of pancreatic cancer. We recently established a novel anti-glycan antibody (10-7G mAb) that specifically recognizes fucosylated haptoglobins, including prohaptoglobin (proHpt). Serum concentrations of the 10-7G value, as measured by ELISA, were increased in patients with pancreatic cancer relative to the healthy controls. However, it is currently unknown which specific tissue or cell type produces fucosylated haptoglobins or proHpt. In the present study, we performed immunohistochemical (IHC) and ELISA analyses of pancreatic cancer tissue samples using 10-7G mAb. Among 21 pancreatic tissue sections, only 1 showed direct staining of pancreatic cells with the 10-7G mAb. However, 12 of the 21 sections stained positively for immune cells. Although there was no significant difference in the 10-7G expression between the positive and negative staining IHC groups, the median value of serum 10-7G was slightly higher in IHC-positive cases. Among many assayed leukemic cell lines, differentiated THP-1 cells (a human acute monocytic leukemia cell line) were found to have the highest levels of proHpt, per Western blot using 10-7G mAb. Interestingly, production of proHpt in vitro was dramatically increased under either hypoxic conditions or after IL-6 treatment. These results suggest that immune cells, including macrophages, in the pancreatic tissue microenvironment produce fucosylated haptoglobin and proHpt. Thus, fucosylated haptoglobins can be detected by the 10-7G mAb and may be a promising biomarker for pancreatic cancer.

BACKGROUND Inflammatory bowel disease (IBD) is a chronic, relapsing inflammation of the digestive tract. Although fecal and serum biomarkers have been extremely important and supportive for monitoring of IBD, their low sensitivity and high variability characteristics limit clinical efficacy. Thus, the establishment of better biomarkers is expected. Fucosylation is one of the most important glycosylation modifications of proteins. Fucosylated haptoglobin (Fuc-Hpt) is used as a biomarker for several cancers and inflammation-related diseases. We recently established a novel glycan monoclonal antibody (mAb), designated 10-7G, which recognizes Fuc-Hpt. We developed an enzyme-linked immunosorbent assay (ELISA) to measure serum levels of Fuc-Hpt (10-7G values). AIM To investigate the usefulness of the serum 10-7G values as a potential biomarker for monitoring disease activity in IBD. METHODS This was a case control study. Intestinal tissues of IBD patients (n = 10) were examined immunohistochemically using the 10-7G mAb. We determined 10-7G values using serum from patients with ulcerative colitis (UC, n = 110), Crohn’s disease (n = 45), acute enteritis (AE, n = 11), and healthy volunteers (HVs) who exhibited normal (n = 20) or high (n = 79) C-reactive protein (CRP) levels at medical check-up. We investigated the correlation between the 10-7G value and various clinical parameters of IBD patients by correlation analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the usefulness of the 10-7G values as a biomarker for clinical and endoscopic remission of UC compared to conventional serum biomarkers. RESULTS In the immunohistochemical analysis, positive 10-7G mAb staining was observed in lymphocytes infiltrating into inflammatory sites of the mucosal layer and lymphoid follicles. The 10-7G values were significantly higher in patients with IBD (P < 0.001) and AE (P < 0.05) compared with HVs. In addition, 10-7G values were correlated with clinical examination parameters related to inflammation in patients with UC, particularly the CRP level (rs = 0.525, P = 0.003) and clinical activity index score (rs = 0.435, P = 0.038). However, there was no correlation between 10-7G values and CRP in HVs with high CRP levels, suggesting that the 10-7G values is not the same as a general inflammation biomarker. ROC curve analysis showed that area under the curve (AUC) value of 10-7G values for the diagnosis of endoscopic remission was higher than other biomarkers (AUC value = 0.699). CONCLUSION The serum 10-7G value is a novel biomarker for evaluating intestinal inflammation and endoscopic mucosal healing in UC.

Metformin is the first-line drug in the treatment of type 2 diabetes. In addition to its hypoglycemic effect, metformin has an anti-inflammatory function, but the precise mechanism promoting this activity remains unclear. High mobility group box 1 (HMGB1) is an alarmin that is released from necrotic cells and induces inflammatory responses by its cytokine-like activity and is, therefore, a target of anti-inflammatory therapies. Here we identified HMGB1 as a novel metformin-binding protein by affinity purification using a biotinylated metformin analogue. Metformin directly bound to the C-terminal acidic tail of HMGB1. Both in vitro and in vivo, metformin inhibited inflammatory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail. In an acetaminophen-induced acute liver injury model in which HMGB1 released from injured cells exacerbates the initial injury, metformin effectively reduced liver injury and had no additional inhibitory effects when the extracellular HMGB1 was blocked by anti-HMGB1-neutralizing antibody. In summary, we report for the first time that metformin suppresses inflammation by inhibiting the extracellular activity of HMGB1. Because HMGB1 plays a major role in inflammation, our results suggest possible new ways to manage HMGB1-induced inflammation.

M. Iseki , M. Mizuma , H. Yoshida , T. Okada , K. Nakagawa, H. Hayashi , T. Morikawa , S. Ottomo, N. Sakata , H. Ohtsuka , K. Fukase , T. Aoki , F. Motoi , T. Naitoh , Y. Katayose , S. Egawa , M. Unno . Division of Hepato-Biliary-Pancretic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Japan Division of Integrated Surgery and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, Japan Introduction: A solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm of low malignant potential. It typically afflicts in young women, but uncommon in men. We report giant solid pseudopapillary neoplasm of the pancreas in a middle-aged man. Case report: A 47-year-old manwas admitted to the previous hospital for continuous epigastric pain and bodyweight loss. A giantmasswas palpated in the upper abdominal area. The abdominal CT scan revealed 21 cmmass with central necrosis and peripheral calcification in the pancreas. This tumor showed enhanced solid component in the marginal area. The patient underwent total pancreatectomy with portal vein resection and reconstruction. In the resected specimen, 26 cm tumor of the pancreas, surrounded by a fibrous pseudocapsule, gave rise to central necrosis and intratumoral hemorrhage. Histological examination revealed that the tumor cells with enlarged nucleus and granular eosinophillic cytoplasm were arranged in sheets and nests, forming pseudopapilla formation. They were immunohistologically positive for CD10 and vimentin. Since nuclear accumulation of beta-catenin protein was shown, this tumor was pathologically diagnosed with SPN. This had malignant potential, indicated by venous invasion. Discussion: This case show atypical clinical feature (age, gender) and typical radiographical feature, including the enhancement of solid component and peripheral calcification. Giant SPN with central necrosis and intratumoral hemorrhage is similar to other giant pancreatic tumors, such as neuroendcrine tumor. Giant SPN is difficult to diagnose by imaging modalities preoperatively, especially in men.