Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.

Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1ß to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Risk and protective factors for the occurrence of sporadic pancreatic endocrine neoplasms.

Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence.

Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis.

OBJECTIVES: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors for SI-NET and to further assess these by meta-analysis. MATERIAL AND METHODS: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015. Eligible studies were selected according to the PRISMA statement. RESULTS: Seven studies evaluating six individual populations were included (study accrual period 1980-2012) in the meta-analysis, involving 765 (range 17-325) cases and 502,282 (range 52-498,376) controls. All studies were case-control by design. The following risk factors were reported in ≥2 studies: family history of any cancer, family history of colorectal cancer, ever alcohol use and ever smoking. The pooled OR was 1.34 (95% CI: 1.12-1.60; p < .01; I2 = 0.0%) for family history of any cancer, 1.43 (95% CI: 1.15-1.79; p < .01; I2 = 0.0%) for family history of colorectal cancer, 1.04 (95% CI: 0.63-1.72; p = .87; I2 = 65.0%) for ever alcohol use and 1.40 (95% CI: 1.06-1.86; p < .05; I2 = 49.3%) for ever smoking. CONCLUSIONS: Family history of any cancer, family history of colorectal cancer and history of ever smoking were associated with an increased risk of SI-NET by meta-analysis. Alcohol consumption was not a significant risk factor for SI-NET. However, the studies reporting smoking and alcohol had a high degree of heterogeneity. Therefore, further studies are needed for clarification of smoking and alcohol as risk factors for the occurrence of SI-NET.

Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis.

Inhibition of kynurenine 3-monooxygenase (KMO) protects against multiple organ dysfunction (MODS) in experimental acute pancreatitis (AP). We aimed to precisely define the kynurenine pathway activation in relation to AP and AP-MODS in humans, by carrying out a prospective observational study of all persons presenting with a potential diagnosis of AP for 90 days. We sampled peripheral venous blood at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. We measured tryptophan metabolite concentrations and analysed these in the context of clinical data and disease severity indices, cytokine profiles and C-reactive protein (CRP) concentrations. 79 individuals were recruited (median age: 59.6 years; 47 males, 59.5%). 57 met the revised Atlanta definition of AP: 25 had mild, 23 moderate, and 9 severe AP. Plasma 3-hydroxykynurenine concentrations correlated with contemporaneous APACHE II scores (R2 = 0.273; Spearman rho = 0.581; P < 0.001) and CRP (R2 = 0.132; Spearman rho = 0.455, P < 0.001). Temporal profiling showed early tryptophan depletion and contemporaneous 3-hydroxykynurenine elevation. Furthermore, plasma concentrations of 3-hydroxykynurenine paralleled systemic inflammation and AP severity. These findings support the rationale for investigating early intervention with a KMO inhibitor, with the aim of reducing the incidence and severity of AP-associated organ dysfunction.

Keap1-Nrf2 signalling in pancreatic cancer.

Transcription factor NF-E2 p45-related factor 2 (Nrf2, also called Nfe2l2), a master regulator of redox homeostasis, and its dominant negative regulator, Kelch-like ECH-associated protein 1 (Keap1), together tightly control the expression of numerous detoxifying and antioxidant genes. Nrf2 and the 'antioxidant response element' (ARE)-driven genes it controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Upregulation of Nrf2 is, at least in part, K-Ras oncogene-driven and contributes to pancreatic cancer proliferation and chemoresistance. In this review, we aim to provide an overview of Keap1-Nrf2 signalling as it relates to pancreatic cancer, discussing the effects of inhibiting Nrf2 or Nrf2/ARE effector proteins to increase chemosensitivity.

Early organ dysfunction affects long-term survival in acute pancreatitis patients.

BACKGROUND: The effect of early organ dysfunction on long-term survival in acute pancreatitis (AP) patients is unknown. OBJECTIVE: The aim of this study was to ascertain whether early organ dysfunction impacts on long-term survival after an episode of AP. METHODS: A retrospective analysis was performed using survival data sourced from a prospectively maintained database of patients with AP admitted to the Royal Infirmary of Edinburgh during a 5-year period commencing January 2000. A multiple organ dysfunction syndrome (MODS) score of ≥ 2 during the first week of admission was used to define early organ dysfunction. After accounting for in-hospital deaths, long-term survival probabilities were estimated using the Kaplan-Meier test. The prognostic significance of patient characteristics was assessed by univariate and multivariate analyses using Cox's proportional hazards methods. RESULTS: A total of 694 patients were studied (median follow-up: 8.8 years). Patients with early organ dysfunction (MODS group) were found to have died prematurely [mean survival: 10.0 years, 95% confidence interval (CI) 9.4-10.6 years] in comparison with the non-MODS group (mean survival: 11.6 years, 95% CI 11.2-11.9 years) (log-rank test, P = 0.001) after the exclusion of in-hospital deaths. Multivariate analysis confirmed MODS as an independent predictor of long-term survival [hazard ratio (HR): 1.528, 95% CI 1.72-2.176; P = 0.019] along with age (HR: 1.062; P < 0.001), alcohol-related aetiology (HR: 2.027; P = 0.001) and idiopathic aetiology (HR: 1.548; P = 0.048). CONCLUSIONS: Early organ dysfunction in AP is an independent predictor of long-term survival even when in-hospital deaths are accounted for. Negative predictors also include age, and idiopathic and alcohol-related aetiologies.