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Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels

by Katsuhiko Sato, Hayato Hikita, Yuta Myojin, Kenji Fukumoto, Kazuhiro Murai, Sadatsugu Sakane, Takeshi Tamura, Takuo Yamai, Yasutoshi Nozaki, Teppei Yoshioka, Takahiro Kodama, Minoru Shigekawa, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara

Diabetes mellitus is a well-known risk factor for pancreatic cancer. We focused on hyperglycemia, a main feature of diabetes mellitus, and uncovered its effect on precancerous pancreatic intraepithelial neoplasia (PanIN) progression. In vivo induction of hyperglycemia with 100 mg/kg streptozotocin in KrasLSL G12DPdx1Cre (KP) mice promoted the PanIN formation and progression. Preconditioning with a high- or low-glucose medium for 28 days showed that a high-glucose environment increased cell viability and sphere formation in PANC-1, a Kras-mutant human pancreatic ductal adenocarcinoma cell line, and mPKC1, a Kras-mutant murine pancreatic cancer cell line. In contrast, no changes were observed in BxPC3, a Kras-wild-type human pancreatic cancer cell line. Orthotopic injection of mPKC1 into the pancreatic tails of BL6/J mice showed that cells maintained in high-glucose medium grew into larger tumors than did those maintained in low-glucose medium. Hyperglycemia strengthened the STAT3 phosphorylation, which was accompanied by elevated MYC expression in Kras-mutant cells. Immunohistochemistry showed stronger phosphorylated STAT3 (pSTAT3) and MYC staining in PanINs from diabetic KP mice than in those from euglycemic counterparts. STAT3 inhibition with 1 μM STAT3 inhibitor STATTIC in Kras-mutant pancreatic cell lines blocked the cell viability- and sphere formation-enhancing effects of the hyperglycemic environment and reversed the elevated pSTAT3 and MYC expression. MYC knockdown did not affect cell viability but did reduce sphere formation. No decrease in pSTAT3 expression was observed upon siMYC treatment. In conclusion, hyperglycemia, on a Kras-mutant background, aggravates the PanIN progression, which is accompanied by elevated pSTAT3 and MYC expression.

Pharmacologic and non-pharmacologic interventions to prevent hypersensitivity reactions of non-ionic iodinated contrast media: a systematic review protocol

Por: Umakoshi · H. · Nihashi · T. · Shimamoto · H. · Yamada · T. · Ishiguchi · H. · Takada · A. · Hirasawa · N. · Ishihara · S. · Takehara · Y. · Naganawa · S. · Davenport · M. · Terasawa · T.

Iodinated contrast media are commonly used in medical imaging and can cause hypersensitivity reactions, including rare but severe life-threatening reactions. Although several prophylactic approaches have been proposed for severe reactions, their effects remain unclear. Therefore, we aim to review systematically the preventive effects of pharmacologic and non-pharmacologic interventions and predictors of acute, hypersensitivity reactions.

Methods and analysis

We will search the PubMed, EMBASE and Cochrane Central Register of Controlled Trials databases from 1 January 1990 through 31 December 2019 and will examine the bibliographies of eligible studies, pertinent review articles and clinical practice guidelines. We will include prospective and retrospective studies of any design that evaluated the effects of pharmacological and non-pharmacological preventive interventions for adverse reactions of non-ionic iodinated contrast media. Two assessors will independently extract the characteristics of the study and intervention and the quantitative results. Two independent reviewers will assess the risk of bias using standard design-specific validity assessment tools. The primary outcome will be reduction in acute contrast media-induced hypersensitivity reactions. The secondary outcomes will include characteristics associated with the development of contrast media-induced acute hypersensitivity reactions, and adverse events associated with specific preventive interventions. Unique premedication regimens (eg, dose, drug and duration) and non-pharmacological strategies will be analysed separately. Average-risk and high-risk patients will be considered separately. A meta-analysis will be performed if appropriate.

Ethics and dissemination

Ethics approval is not applicable, as this will be a secondary analysis of publicly available data. The results of the analysis will be submitted for publication in a peer reviewed journal.

PROSPERO registration number