The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.

RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.

Gastritis - facts and doubts.

INTRODUCTION: Many clinicians consider chronic gastritis to be equivalent to Helicobacter pylori infection. However, it is known that there are numerous other causes of the condition. AIM: Determination of the incidence of gastritis in patients with dyspepsia referred for diagnostic endoscopy of the upper part of the digestive tract, identification of the parts of the stomach most frequently affected by the inflammation, as well as the impact of an insufficient number of collected samples on the correct diagnosis. MATERIAL AND METHODS: Upper gastrointestinal endoscopy due to dyspepsia was performed in 110 patients. In the course of gastroscopy two biopsy specimens were collected for histopathological examination and towards H. pylori infection from the lesser and greater curvature in the antrum 3 cm from the pyloric sphincter, in the body - 4 cm proximally to the stomach angular incisure on the lesser curvature, and in the middle of the greater curvature, as well as in the subcardiac region on the side of the lesser and greater curvature. RESULTS: In patients with dyspepsia H. pylori-negative chronic gastritis is more common than gastritis with accompanying H. pylori infection. Collection of too small a number of biopsy specimens results in failure to detect inflammatory changes and/or H. pylori infection, which may be limited to one part of the stomach. Biopsy specimens of gastric mucosa should be collected in compliance with the assumptions of the Sydney System. Helicobacter pylori infection in people with dyspepsia is now being reported more rarely than in the past (36%). CONCLUSIONS: In patients with dyspepsia chronic H. pylori-negative gastritis is more common than gastritis with an accompanying H. pylori infection. Helicobacter pylori infection is not always equivalent to the presence of chronic gastritis.

Impaired glucose metabolism in colorectal cancer.

OBJECTIVE: Some studies have found that people with type 2 diabetes mellitus are at increased risk of neoplasms, especially colorectal cancer (CRC). In other studies it is also suggested that there is a higher incidence of diabetes mellitus in patients with CRC. The aims of this study were to assess whether the incidence of type 2 diabetes mellitus and impaired glucose tolerance (IGT) are higher in subjects with CRC and to determine the difference between diabetic subjects and healthy controls regarding glucose metabolism (glycaemia, insulinaemia, serum levels of C-peptide) as well as insulin resistance and sensitivity. MATERIAL AND METHODS: The study included a total of 80 subjects: 40 enrolled patients (20 M, 20 F) with newly diagnosed sporadic colorectal cancer and 40 subjects with endoscopically excluded CRC or adenomas serving as controls. Subjects were matched for gender, age and body mass index (BMI) (age +/- 5 years BMI +/- 1 kg/m2). A 75-g oral glucose tolerance test was performed after an overnight fast. Samples for glycaemia, serum levels of C-peptide and insulin were taken at 0, 30, 60, 90, 120 and 150 min of the study. HOMA-IR, EIR, EIR/HOMA-IR indexes were calculated. RESULTS: There was a significantly higher incidence of impaired glucose metabolism (IGM-diabetes mellitus or IGT) in CRC subjects. No differences were found in levels of glucose, insulin or C-peptide. Insulinaemia and C-peptide curves showed a shift typical of diabetes, in the form of a delayed insulin release peak. The HOMA-IR, EIR as well as the EIR/HOMA-IR indexes showed no differences between groups. CONCLUSIONS: A significantly higher incidence of IGM appears to occur in CRC patients than in the healthy population. This phenomenon is not dependent on age and body-weight, which may suggest that it is cancer that predisposes to diabetes rather than the other way round. The neoplastic process in the colon is not associated with hyperinsulinaemia or insulin resistance, but in CRC patients, pancreatic B-cell dysfunction typical of the early stages of diabetes is seen.

[Gastric emptying disorders in diabetes mellitus]. / Zaburzenia oprózniania zoladka w cukrzycy.

OBJECTIVE: 1. To find out the prevalence of gastroperesis and of accelerated gastric emptying in long-standing and recently diagnosed diabetic patients. 2. and to determine the relationship between the percentage of gastric retention of the test meal to the gastric symptoms, degree of metabolic control, cardiovascular autonomic neuropathy, and late diabetic complication. RESEARCH DESIGN AND METHODS: We studied the gastric emptying of technetium labeled digestible solid test meal in 81 diabetic patients (51 long-standing and 30 recently diagnosed diabetic patients) and in 44 healthy controls. Diabetic patients were divided roto 2 groups according to the type and duration of diabetes. All patients were evaluated for gastric symptoms, glycemic control, peripheral neuropathy, retinopathy and cardiovascular autonomic neuropathy. RESULTS: Delayed gastric emptying was found in 21 long-standing diabetic patients and in 3 recently diagnosed type 2 diabetic patients. Accelerated gastric emptying was found in 10 patients mainly recently diagnosed type 2 diabetic patients. The rate of gastric emptying was related to CANP but not gastric symptoms or actual glycemic control. CONCLUSIONS: 1. Diabetics gastroparesis is a common disorder affecting both type 1 and type 2 long-standing diabetes mellitus in about 40% usually in the setting of late diabetic complications and can be manifested in recently diagnosed type 2 diabetes mellitus. 2. Accelerated gastric emptying is another gastrointestinal disorder manifested in about 20% of recently diagnosed diabetic patients (maimy type 2) but can be present in long-standing diabetic patients. 3. The rate of gastric emptying is related to cardiovascular autonomic neuropathy but not to gastric symptoms or actual metabolic control.