p38 mitogen-activated protein kinase (MAPK) in rheumatoid arthritis.

The importance of p38 MAPK inhibitors as new drug for rheumatoid arthritis is reflected by the large number of compounds that has been developed over the last years. In this review new insights such as non-stressful activation of p38 MAPK, and the role of p38 MAPK in regulation of NF-kappaB recruitment are also discussed.

Quantitation of autoantibodies in systemic autoimmune diseases: clinically useful?

Serial assessment of levels of autoantibodies has been proposed as being clinically useful in certain systemic autoimmune diseases. In particular, attention has been given to anti-dsDNA antibodies in systemic lupus erythematosus (SLE) and ANCA in the ANCA-associated vasculitides (AAV). Much controversy exists, however, concerning the value of serial testing in these diseases.

A prospective study of anthropometric and clinical measurements associated with insulin resistance syndrome and colorectal cancer in male smokers.

Type 2 diabetes mellitus shares risk factors for and has shown a positive association with colorectal cancer. Anthropometric measures (height, weight, and body mass index (weight (kg)/height (m)(2)) and metabolic abnormalities associated with insulin resistance syndrome (IRS) (abnormalities in measured blood pressure, high density lipoprotein (HDL) cholesterol, and total cholesterol) were prospectively evaluated for associations with incident colon (n = 227), rectal (n = 183), and colorectal (n = 410) cancers diagnosed between 1985 and 2002 in 28,983 Finnish male smokers from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals.

Visceral fat analysis at CT colonography.

Rationale And Objectives: Obesity is associated with increased risks for colorectal neoplasia. Few studies have examined quantitative body fat measurements as predictors of colorectal polyps. The objective is to determine whether visceral fat is associated with colorectal polyps at computed tomography (CT) colonography.

Gene expression differences in normal esophageal mucosa associated with regression and progression of mild and moderate squamous dysplasia in a high-risk Chinese population.

A randomized, double-blinded, placebo-controlled 2 x 2 factorial chemoprevention trial was conducted in Linxian, China to assess the effects of selenomethionine and celecoxib on the natural history of esophageal squamous dysplasia. Results from this study indicated that asymptomatic adults with mild dysplasia were more likely to show an improvement when treated with selenomethionine compared with placebo (P = 0.02).

Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study.

Objectives: Patients with type 2 diabetes mellitus (DM) may be at increased colorectal cancer (CRC) risk. However, existing data are inconsistent. We investigated CRC risks, overall and by anatomic subsite, within a population-based inception cohort of clinically confirmed type 2 DM subjects.

Selenomethionine treatment does not alter gene expression in normal squamous esophageal mucosa in a high-risk Chinese population.

Selenium is a promising cancer chemoprevention agent. A recent randomized controlled chemoprevention trial found that selenomethionine (SeMet) supplementation for 10 months favorably effected a change in esophageal dysplasia grade among participants who started the trial with mild dysplasia. To further explore the role of SeMet in this trial, we compared gene expression profiles by treatment group using Affymetrix HU 133A chips in before/after supplementation paired normal esophageal biopsies from a subset of 29 trial participants, 16 who received SeMet, and 13 who received placebo.

Incidence of colorectal cancer in relation to glycemic index and load in a cohort of women.

Background: Dietary glycemic index (GI) and glycemic load (GL) affect circulating insulin concentrations. Elevated circulating insulin concentrations can increase insulin-like growth factor-1, and both of these hormones may have growth-promoting effects within the colorectum.

Methods: We examined associations of GI and GL with colorectal cancer (CRC) among participants in the Iowa Women's Health Study (n = 35,197; ages 55-69 years at baseline in 1986).

Colorectal cancer prognosis among patients with inflammatory bowel disease.

Background & Aims: Inflammatory bowel disease (IBD) is associated with an increased risk for colorectal cancer (CRC). However, the genetic, endoscopic, and histologic features of IBD-associated CRC differ from cancers that arise sporadically. The objectives of this study were to describe the clinicopathologic features of IBD-associated CRC and to compare survival rates between patients with IBD-associated CRC and patients with sporadic CRC.

Abundance of the long pentraxin PTX3 at sites of leukocytoclastic lesions in patients with small-vessel vasculitis.

Objective: The prototypical tissue pentraxin PTX3 inhibits phagocytosis of late apoptotic polymorphonuclear leukocytes (PMNs) by macrophages. Levels of PTX3 parallel disease activity in small-vessel vasculitis. Small-vessel vasculitis is often characterized by leukocytoclasia, a phenomenon of accumulation of nuclear remnants from unscavenged PMNs in or near the vessel wall.

Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers.

Context: Obesity, diabetes mellitus, and glucose intolerance have been associated with increased pancreatic cancer risk; however, prediagnostic serum insulin concentration has not been evaluated as a predictor of this malignancy.

Objective: To investigate whether prediagnostic fasting glucose and insulin concentrations and insulin resistance are associated with subsequent incidence of exocrine pancreatic cancer in a cohort of male smokers.

Design, Setting, And Participants: A case-cohort prospective study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985-1988) cohort of 29,133 male Finnish smokers ages 50 to 69 years.

Skin sensitivity to UVB irradiation in systemic lupus erythematosus is not related to the level of apoptosis induction in keratinocytes.

Objectives: Accumulation of apoptotic cells has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). As sunlight exposure is one of the factors that can trigger disease activity, we hypothesized that UV light may induce increased numbers of apoptotic cells in SLE.

Methods: Fourteen SLE patients and 16 controls were irradiated with UVB to determine their minimal erythemal dose (MED).

Prepregnancy exposure to cigarette smoking and subsequent risk of postmenopausal breast cancer.

Objective: To examine the association of cigarette smoking before first pregnancy with risk of postmenopausal breast cancer in a large population-based cohort.

Patients And Methods: The Iowa Women's Health Study is a prospective cohort study of 55- to 69-year-old women at baseline in 1986. In January 1986, a questionnaire was mailed to 99,826 postmenopausal women to Identify risk factors for cancer and other chronic diseases; 41,836 women responded (42.

Differential influence of p38 mitogen activated protein kinase (MAPK) inhibition on acute phase protein synthesis in human hepatoma cell lines.

Background: Inhibition of intracellular signal transduction is considered to be an interesting target for treatment in inflammation. p38 MAPK inhibitors, especially, have been developed and are now in phase II clinical trials for rheumatoid arthritis (RA).

Objective: To investigate the influence of p38 MAPK inhibition on acute phase protein (APP) production, which is dependent on both JAK/STAT and p38 MAPK pathways.

Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib.

Background & Aims: Esophageal squamous cell carcinoma remains a leading cause of cancer death worldwide. Squamous dysplasia, the accepted histological precursor for esophageal squamous cell carcinoma, represents a potentially modifiable intermediate end point for chemoprevention trials in high-risk populations.

Methods: We conducted a randomized, controlled trial of selenomethionine 200 microg daily and/or celecoxib 200 mg twice daily (2 x 2 factorial design) among residents of Linxian, People's Republic of China.

Apoptosis in human skin: role in pathogenesis of various diseases and relevance for therapy.

Cell death by apoptosis is a physiological process that enables the elimination of cells without causing an inflammatory response. In self-renewing tissue like the epidermal layers of the skin, cell numbers are tightly regulated by a delicate balance between proliferation, differentiation, and cell death. Besides cell death by terminal differentiation in normal skin, cell death can also be induced by exposure to sunlight.

Activation, apoptosis, and clearance of neutrophils in Wegener's granulomatosis.

Wegener's granulomatosis (WG) is strongly associated with the presence of antineutrophil cytoplasmic autoantibodies (ANCAs). Within WG these ANCAs are usually (80-90%) directed against the azurophilic enzyme proteinase 3, the so called PR3-ANCA. A pathophysiological role for these autoantibodies, supported by numerous in vitro and in vivo studies, is specifically based on their capacity to bind and activate neutrophils and potentially may damage vessels.

Human anti-neutrophil cytoplasm autoantibodies to proteinase 3 (PR3-ANCA) bind to neutrophils.

Background: Recently, the in vivo pathogenic role of anti-neutrophil cytoplasm autoantibodies (ANCA) in ANCA-associated vasculitis has been challenged by Abdel-Salam et al. In their report, they observed that ANCA directed against proteinase 3 (PR3) cannot bind to their target autoantigen PR3 on circulating neutrophils (PMN). Here we present evidence that human PR3-ANCA do specifically bind to PMN that express PR3 on their membrane.

Differential effects of NF-{kappa}B and p38 MAPK inhibitors and combinations thereof on TNF-{alpha}- and IL-1{beta}-induced proinflammatory status of endothelial cells in vitro.

Endothelial cells actively participate in inflammatory events by regulating leukocyte recruitment via the expression of inflammatory genes such as E-selectin, VCAM-1, ICAM-1, IL-6, IL-8, and cyclooxygenase (COX)-2. In this study we showed by real-time RT-PCR that activation of human umbilical vein endothelial cells (HUVEC) by TNF-alpha and IL-1beta differentially affected the expression of these inflammatory genes. Combined treatment with TNF-alpha and IL-1beta resulted in nonadditive, additive, and even synergistic induction of expression of VCAM-1, IL-8, and IL-6, respectively.

Levels of complement in sera from inactive SLE patients, although decreased, do not influence in vitro uptake of apoptotic cells.

Background: Accumulation of apoptotic cells is considered relevant in the pathogenesis of systemic lupus erythematosus (SLE). Complement factors facilitate the clearance of apoptotic cells and, when decreased, might result in an increased amount of apoptotic cells found in SLE patients.

Objective: To determine the influence of complement profiles from inactive SLE patients on the in vitro phagocytosis of apoptotic cells.

Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement.

Background: Defects in phagocytosis of apoptotic cells have a role in the pathogenesis of autoimmune diseases. Decrease of phagocytosis of apoptotic cells occurs in systemic lupus erythematosus (SLE). Factors underlying this decrease are, presently, unknown.

Chemokine production and E-selectin expression in activated endothelial cells are inhibited by p38 MAPK (mitogen activated protein kinase) inhibitor RWJ 67657.

Endothelial cells play an important role in inflammatory diseases like rheumatoid arthritis by recruitment of inflammatory cells. The cytokines TNF-alpha and IL-1beta are major inducers of endothelial cell activation and are stimulators of inflammatory signal transduction pathway involving p38 MAPK (mitogen-activated protein kinase). The present study investigated the effects of p38 MAPK inhibition on cell adhesion molecule (CAM) expression and chemokine production by endothelial cells both on mRNA and protein level.

Pathogenesis and risk factors of small bowel adenocarcinoma: a colorectal cancer sibling?

Small bowel adenocarcinoma (SBA) is a very rare entity accounting for one-fourth of the small intestine neoplasms. Usually accompanied by nonspecific symptoms occurring late in the course of the disease, they are associated with a dismal prognosis. It appears that SBA shares several genetic characteristics with large bowel tumors, but also has unique features.