Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Serum Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor-binding Protein 2 as a Novel Biomarker in the Detection of Pancreatic Adenocarcinoma.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) are proteins that belong to the IGF axis, which is involved in glucose and lipid metabolism and may as well promote carcinogenesis. GOALS: The aim of this study was to evaluate the serum concentration levels of IGF-1 and IGFBP-2 in patients with newly diagnosed pancreatic adenocarcinoma (PDAC) to verify their possible role in the diagnosis of the disease. STUDY: The study included 69 patients with PDAC and 20 healthy controls. The concentrations of IGF-1 and IGFBP-2 were estimated by means of ELISA. The study protocol was approved by the Bioethics Committee at the Medical University of Lodz in Poland. RESULTS: PDAC patients compared with controls have a significantly lower mean serum IGF-1 level (45.83±30.03 vs. 70.66±60.57 ng/mL; P<0.0001). In contrast, in PDAC patients, the mean IGFBP-2 level was significantly higher compared with the control group (225.06±86.37 vs. 51.92±29.40 ng/mL; P<0.0001). The results show that, at the 0.01 sensitivity level, the IGF-1/IGFBP-2 ratio <0.85 points indicates PDAC presence. At this level of sensitivity, the test has a specificity of 0.097 (α=0.01; ß=0.097; IGF-1/IGFBP-2≤0.85). CONCLUSIONS: Our results show that IGF-1 to IGFBP-2 ratio ≤0.85 may be a powerful PDAC indicator. Further studies in this area in a larger patient group are necessary to confirm our findings.

The Role of Insulin-like Growth Factor (IGF) Axis in Early Diagnosis of Pancreatic Adenocarcinoma (PDAC).

New-onset diabetes mellitus (DM) is one of the first symptoms of pancreatic adenocarcinoma (PDAC). The frequency of endocrine disorders is estimated between 40% and 80% in patients with pancreatic cancer. DM is a risk factor for cancer development but it may also be a consequence of the tumor growth. Data confirming the existence of a relationship between long standing type 2 DM and an increased risk of PDAC comes from numerous clinical studies. Insulin resistance phenomenon and hyperinsulinemia may result in the increased proliferation of pancreatic islets which in turn may cause a predisposition to cancer development. In contrast, it is proved that new-onset DM among patients over 50 years old significantly increases the risk of PDAC recognition. Insulin-like growth factor 1 (IGF-1) and their complex proteins, IGF binding proteins, which comprise the IGF axis play a crucial role in carbohydrate metabolism disorders and, studies have shown that they may contribute to PDAC growth. Some studies confirm that IGF-1 is connected with early carcinogenesis in animals and humans. Assessing the levels of these proteins may thus be helpful in early recognition of PDAC in patients with recently detected endocrine disorders, especially pancreatic DM.

Evaluation of insulin-like growth factor (IGF-1) and retinol binding protein (RBP-4) levels in patients with newly diagnosed pancreatic adenocarcinoma (PDAC).

BACKGROUND/OBJECTIVES: The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP). METHODS: The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz. RESULTS: In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other. CONCLUSIONS: Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

[Application of double balloon enteroscopy in diagnosis of small bowel diseases]. / Zastosowanie enteroskopii dwubalonowej w diagnostyce chorób jelita cienkiego.

INTRODUCTION: Double balloon enteroscopy (DBE) is one of the newest among endoscopic techniques used in diagnosis of the digestive tract diseases--particularly in small bowel's lesions. MATERIALS AND METHODS: The retrospective analysis of patients' data from 2008 to 2012 in the Department of Digestive Tract Diseases, UM was made. Case histories were analised and evaluated for sex, age, clinical symptoms, results of additional examinations and indications. The course of the examination, its result, complications and role in final diagnosis were also checked. RESULTS: During the analysed period DBE was attempted 71 times DBE among 42 patients (17 women and 25 men; the age was 44.5 years ± 17.5 years). The most frequent indication for DBE was occult gastrointestinal bleeding--34 patients (80.9%). Among the other patients, the clinical image suggested Crohn's disease (4 cases--9.5%), suspicion of small bowel's neoplasm (2 patients--4.8%), familiar adenomatous polyposis with a need to make polypectomy (1 case--2.4%) and state after bariatric surgery to extract moved gastric balloon (1 patient--2.4%). Small bowel's lesions were detected in 21 patients (50%)--8 polyps, 8--aphthaes and inflammatory changes, 3--vascular lesions, 2--smoothing villi. In four cases the polypectomy was made. The anaesthetic complications appeared with two patients (4,8%). Complications being a result of performed DBE was observed in one case (2.4%). CONCLUSIONS: Double balloon enteroscopy is safe endoscopic procedure and it plays a key role in diagnosis of patients with gastrointestinal bleeding.

Microscopic Colitis: An Underestimated Disease of Growing Importance.

The aim of this paper is to raise awareness of MC as a clinically significant condition and to highlight its under-recognition, risk factors, diagnosis, management, and complications. This paper underlines the diagnostic and therapeutic challenges associated with the often nonspecific symptoms of MC. In order to create this article, we reviewed available articles found in the PubMed database and searched for articles using the Google Scholar platform. Microscopic colitis (MC) is a chronic inflammatory bowel disease, classified into three types: lymphocytic, collagenous, and unspecified. The average age of onset of MC is around 62-65 years and the disease is more common in women than men (nine times more common). The main symptom of MC is watery diarrhoea without blood, other symptoms include defecatory urgency, faecal incontinence, abdominal pain, nocturnal bowel movements, and weight loss. Once considered a rare disease, MC is now being diagnosed with increasing frequency, but diagnosis remains difficult. To date, a number of causative factors for MC have been identified, including smoking, alcohol consumption, medications (including NSAIDs, PPIs, SSRIs, and ICPIs), genetic factors, autoimmune diseases, bile acid malabsorption, obesity, appendicitis, and intestinal dysbiosis. It may be difficult to recognize and should be differentiated from inflammatory bowel diseases (Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), coeliac disease, infectious bowel disease, and others. Diagnosis involves biopsy at colonoscopy and histopathological evaluation of the samples. Treatment consists of budesonide oral (the gold standard) or enema. Alternatives include bile acid sequestrants (cholestyramine, colesevelam, and colestipol), biologics (infliximab, adalimumab, and vedolizumab), thiopurines, methotrexate, and rarely, surgery.

CA 19-9 but Not IGF-1/IGFBP-2 Is a Useful Biomarker for Pancreatic Ductal Adenocarcinoma (PDAC) and Chronic Pancreatitis (CP) Differentiation.

INTRODUCTION: There are still no effective diagnostic and prognostic biomarkers in pancreatic ductal adenocarcinoma (PDAC). The differentiation between PDAC and chronic pancreatitis (CP) is often challenging. The inflammatory mass in the course of CP causes diagnostic difficulties in differentiating them from neoplastic lesions and, thus, delays the initiation of radical treatment. Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) form a network involved in PDAC development. The role of IGFs in promoting pancreatic cancer cell proliferation, survival, and migration is well established, and their ability to stimulate tumor growth and metastasis is well documented. The aim of the study was to evaluate the usability of IGF-1, IGFBP-2, and IGF-1/IGFBP-2 ratio in PDAC and CP differentiation. MATERIAL AND METHODS: The study included 137 patients: 89 patients with PDAC and 48 patients with CP. All subjects were tested for the levels of IGF-1 and IGFBP-2 using the ELISA method (Corgenix UK Ltd. R&D Systems), along with the level of CA 19-9 in serum. Additionally, the IGF-1/IGFBP-2 ratio was calculated. Further analyses used logit and probit models with varying determinants in order to discern between PDAC and CP patients. The models served as a basis for AUROC calculation. RESULTS: The mean IGF-1 serum level was equal to 52.12 ± 33.13 ng/mL in PDAC vs. 74.23 ± 48.98 ng/mL in CP (p = 0.0053). The mean level of IGFBP-2 was equal to 305.95 ± 194.58 ng/mL in PDAC vs. 485.43 ± 299 ng/mL in CP (p = 0.0002). The mean CA 19-9 serum concentration was 434.95 ± 419.98 U/mL in PDAC vs. 78.07 ± 182.36 U/mL in CP (p = 0.0000). The mean IGF-1/IGFBP-2 ratio was 0.213 ± 0.14 in PDAC vs. 0.277 ± 0.33 in CP (p = 0.1914). The diagnostic usefulness of indicators for the purpose of PDAC and CP differentiation was assessed by means of AUROC comparison. The AUROCs of IGF-1, IGFBP-2, and IGF-1/IGFBP-2 ratio ranged below 0.7, being lower than the AUROC of CA 19-9 (0.7953; 0.719 within 95% CI). Together, the CA 19-9 and IGFBP-2 AUROCs also ranged below 0.8. When age was included, the AUROC increased to 0.8632, and its 95% confidence interval held above the 0.8 limit. The sensitivity of the used markers was not correlated to the stage of pancreatic PDAC. CONCLUSIONS: The presented results indicate that CA 19-9 is a marker demonstrating high potential for PDAC and CP differentiation. The inclusion of additional variables into the model, such as the serum level of IGF-1 or IGFBP-2, slightly increased the sensitivity in differentiating CP from PDAC. The IGF-1/IGFBP-2 ratio turned out to be a good marker of pancreatic diseases, but insufficient for the purpose of CP and PDAC differentiation.

Insulin-like growth factor 1 and insulin-like growth factor binding protein 2 serum levels as potential biomarkers in differential diagnosis between chronic pancreatitis and pancreatic adenocarcinoma in reference to pancreatic diabetes.

INTRODUCTION: Insulin-like growth factor 1 (IGF-1) has been connected with development of pancreatic ductal adenocarcinoma (PDAC). AIM: To evaluate the serum concentration levels of IGF-1 and insulin-like growth factor binding protein 2 (IGFBP-2) in patients with chronic pancreatitis (CP) and PDAC. Their values in diabetes mellitus (DM) were also assessed. MATERIAL AND METHODS: The study included 83 patients with CP, 92 patients with PDAC, and 20 subjects as a control group. The concentrations of IGF-1 and IGFBP-2 were estimated with ELISA (Corgenix UK Ltd, R&D Systems). RESULTS: The IGF-1 was higher in CP compared with PDAC (81.11 ±57.18 ng/ml vs. 53.18 ±36.05 ng/ml, p < 0.001), and both CP and PDAC were different from controls (81.11 ±57.18 ng/ml vs. 70.66 ±16.57 ng/ml, p < 0.001 and 53.18 ±36.05 ng/ml vs. 70.66 ±16.57 ng/ml, p < 0.001). CP without cysts have lower IGF-1 compared to those with CP and cysts (60.35 ±34.68 ng/ml vs. 93.55 ±64.78 ng/ml, p < 0.05). IGF-1 in CP without DM was higher compared to IGF-1 in PDAC without DM (91.13 ±65.48 ng/ml vs. 54.75 ±40.41 ng/ml, p < 0.001). In CP and DM the IGF-1 was elevated in comparison to PDAC and DM (62.20 ±32.38 ng/ml vs. 48.45 ±24.88 ng/ml, p < 0.05). IGFBP-2 was higher in CP compared to PDAC (512.42 ±299.77 ng/ml vs 301.59 ±190.36 ng/ml, p < 0.001). In CP and PDAC the IGFBP-2 level was elevated compared to the control group (512.42 ±299.77 ng/ml vs. 51.92 ±29.40 ng/ml, p < 0.001 and 301.59 ±190.36 ng/ml vs. 51.92 ±29.40 ng/ml, p < 0.001). IGFBP-2 in CP without DM was higher compared to PDAC without DM (559.39 ±281.43 vs. 296.53 ±196.93, p < 0.001). CONCLUSIONS: IGF-1 and IGFBP-2 may be biomarkers of CP and PDAC. IGF-1 may be an indicator that signals whether pancreatic diabetes is from CP or PDAC.

Effect of Hydrogen and Absence of Passive Layer on Corrosive Properties of Aluminum Alloys.

This paper reports the results of research on the effect of hydrogen permeation and the absence of passive layers on the variations in the corrosive properties of aluminum alloys. The study demonstrated that such variations contribute to the deterioration of corrosive properties, which in turn contributes to shortening the reliability time associated with the operation of aluminum alloy structures. The analysis involved structural aluminum alloys: EN AW-1050A, EN AW-5754, and EN AW-6060. It was demonstrated that the absorption of hydrogen by the analyzed alloys led to the shift of the electrode potential to the negative side. The built hydrogen corrosion cells demonstrate in each case the formation of electromotive force (EMF) cells. The initial EMF value of the cell and its duration depends on the duration of hydrogenation. As a result of removing the passive layers, the electrode potential also changes to the negative side. Following the removal of the passive layer from one of the electrodes, the cells also generated a galvanic (metal) cell. The duration of such a cell is equivalent to the time of restoration of the passive layer. The formation of such hydrogen and metal galvanic cells changes the electrochemical properties of aluminum alloys, therefore deteriorates the corrosive properties of aluminum alloys.