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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs., Objective: Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion., Methods and Results: Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells., Conclusion: Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hormone secretion from pancreatic islets is essential for glucose homeostasis, and loss or dysfunction of islet cells is a hallmark of type 2 diabetes. Maf transcription factors are crucial for establishing and maintaining adult endocrine cell function. However, during pancreas development, MafB is not only expressed in insulin- and glucagon-producing cells, but also in Neurog3+ endocrine progenitor cells, suggesting additional functions in cell differentiation and islet formation. Here, we report that MafB deficiency impairs β cell clustering and islet formation, but also coincides with loss of neurotransmitter and axon guidance receptor gene expression. Moreover, the observed loss of nicotinic receptor gene expression in human and mouse β cells implied that signaling through these receptors contributes to islet cell migration/formation. Inhibition of nicotinic receptor activity resulted in reduced β cell migration towards autonomic nerves and impaired β cell clustering. These findings highlight a novel function of MafB in controlling neuronal-directed signaling events required for islet formation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Aims: Reduced expression of exocytotic genes is associated with functional defects in insulin exocytosis contributing to impaired insulin secretion and type 2 diabetes (T2D) development. MAFA and MAFB transcription factors regulate β-cell physiology, and their gene expression is reduced in T2D β cells. We investigate if loss of MAFA and MAFB in human β cells contributes to T2D progression by regulating genes required for insulin exocytosis., Methods: Three approaches were performed: (1) RNAseq analysis with the focus on exocytosis-related genes in MafA -/- mouse islets, (2) correlational analysis between MAFA, MAFB and exocytosis-related genes in human islets and (3) MAFA and MAFB silencing in human islets and EndoC-βH1 cells followed by functional in vitro studies., Results: The expression of 30 exocytosis-related genes was significantly downregulated in MafA -/- mouse islets. In human islets, the expression of 29 exocytosis-related genes correlated positively with MAFA and MAFB. Eight exocytosis-related genes were downregulated in MafA -/- mouse islets and positively correlated with MAFA and MAFB in human islets. From this analysis, the expression of RAB3A, STXBP1, UNC13A, VAMP2, NAPA, NSF, STX1A and SYT7 was quantified after acute MAFA or MAFB silencing in EndoC-βH1 cells and human islets. MAFA and MAFB silencing resulted in impaired insulin secretion and reduced STX1A, SYT7 and STXBP1 (EndoC-βH1) and STX1A (human islets) mRNA expression. STX1A and STXBP1 protein expression was also impaired in islets from T2D donors which lack MAFA expression., Conclusion: Our data indicate that STXBP1 and STX1A are important MAFA/B-regulated exocytosis genes which may contribute to insulin exocytosis defects observed in MAFA-deficient human T2D β cells., (© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target of type 2 diabetes drugs aiming to enhance insulin secretion. Here we show that the protein phosphatase 1 inhibitor protein 1A (PPP1R1A), is expressed in β-cells and that its expression is reduced in dysfunctional β-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and β-cell function. We observed a strong correlation of MAFA and PPP1R1A mRNA levels in human islets, moreover, PPP1R1A mRNA levels were reduced in type 2 diabetic islets and positively correlated with GLP1-mediated GSIS amplification. PPP1R1A silencing in INS1 (832/13) β-cells impaired GSIS amplification, PKA-target protein phosphorylation, mitochondrial coupling efficiency and also the expression of critical β-cell marker genes like MafA, Pdx1, NeuroD1 and Pax6. Our results demonstrate that the β-cell transcription factor MafA is required for PPP1R1A expression and that reduced β-cell PPP1R1A levels impaired β-cell function and contributed to β-cell dedifferentiation during type 2 diabetes. Loss of PPP1R1A in type 2 diabetic β-cells may explains the unresponsiveness of type 2 diabetic patients to GLP1R-based treatments., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Maf transcription factors are critical regulators of beta-cell function. We have previously shown that reduced MafA expression in human and mouse islets is associated with a pro-inflammatory gene signature. Here, we investigate if the loss of Maf transcription factors induced autoimmune processes in the pancreas. Transcriptomics analysis showed expression of pro-inflammatory as well as immune cell marker genes. However, clusters of CD4+ T and B220+ B cells were associated primarily with adult MafA -/- MafB +/- , but not MafA -/- islets. MafA expression was detected in the thymus, lymph nodes and bone marrow suggesting a novel role of MafA in regulating immune-cell function. Analysis of pancreatic lymph node cells showed activation of CD4+ T cells, but lack of CD8+ T cell activation which also coincided with an enrichment of naïve CD8+ T cells. Further analysis of T cell marker genes revealed a reduction of T cell receptor signaling gene expression in CD8, but not in CD4+ T cells, which was accompanied with a defect in early T cell receptor signaling in mutant CD8+ T cells. These results suggest that loss of MafA impairs both beta- and T cell function affecting the balance of peripheral immune responses against islet autoantigens, resulting in local inflammation in pancreatic islets.

Aim: To understand how attribution processes (control and stability), which the nurse attributes to parental involvement in maintaining child safety, determine the nurse's response to a safety alert., Background: Participation of parents in maintaining their child's safety is shown to reduce the incidence of and risk of clinical errors. Unless nurses respond appropriately to parents' safety alerts, this potential source of support could diminish., Design: A 2 (controllability: high vs. low) × 2 (consistency: high vs. low) factorial design., Methods: Data were collected during the period 2013-2014 in paediatric wards. Four variants of scenarios were created corresponding to the different combinations of these variables. A total of 126 nurses read a scenario and completed self-report questionnaires measuring their response to the parent's safety alert. Additional data were collected about the manipulation check, safety norms in the ward and demographic variables. Data were analysed using analysis of variance., Findings: Results showed a main effect of stability and a significant two-way interaction effect of stability and controllability, on a nurse's tendency to help the parent and fix the safety problem. Furthermore, safety norms were significantly related to nurses' response., Conclusion: These findings contribute to the understanding of antecedents that affect nurses' responses to parents' speaking-up initiatives: whether nurses will reject or heed the alert. Theoretical and practical implications for promoting parents' engagement in their safety are discussed., (© 2017 John Wiley & Sons Ltd.)