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Caveolin-1 (Cav-1) expression has been shown to be associated with tumor growth and resistance to chemotherapy in pancreatic cancer. The primary aim of this study was to explore the significance of Cav-1 expression in pancreatic cancer cells as compared to fibroblasts in relation to cancer cell proliferation and chemoresistance, both in vitro and in vivo, in an immunodeficient mouse model. We also aimed to evaluate the immunohistochemical expression of Cav-1 in the epithelial and stromal component of pancreatic cancer tissue specimens. The immunohistochemical staining of poorly differentiated tissue sections revealed a strong and weak Cav-1 expression in the epithelial tumor cells and stromal fibroblasts, respectively. Conversely, the well-differentiated areas were characterized by a weak epithelial Cav-1 expression. Cav-1 downregulation in cancer cells resulted in an increased proliferation in vitro; however, it had no effect on chemoresistance and growth gain in vivo. By contrast, the decreased expression of Cav-1 in fibroblasts resulted in a growth advantage and the chemo-resistance of cancer cells when they were co-injected into immunodeficient mice to develop mixed fibroblast/cancer cell xenografts. On the whole, the findings of this study suggest that the downregulation of Cav-1 in fibroblasts is associated with an increased tumor proliferation rate in vivo and chemoresistance. Further studies are warranted to explore whether the targeting of Cav-1 in the stroma may represent a novel therapeutic approach in pancreatic cancer.

Background Since their discovery, S100 proteins have been associated with diverse diseases of inflammatory, degenerative, or malignant nature. Due to their participation in inflammation, they have also been studied with regard to inflammatory bowel disease (IBD). Method To provide a review of available literature, a PubMed, MEDLINE, and Embase-based literature search was performed, using all available nomenclature for each member of the S100 protein family, along with the terms inflammatory bowel disease, ulcerative colitis, Crohn’s disease, or indeterminate colitis. Result S100A8/A9, also known as calprotectin, S100A12, or calgranulin C and in a lesser extent S100P, are involved in the pathogenesis, activity, diagnosis, and therapeutic management of IBD. The majority of available literature is focused primarily on S100A8/9, although there is growing evidence on the significance of S100A12. Most studies emphasize the potential merit of S100A8/A9 and S100A12, as markers for differential diagnosis, monitoring of activity, or disease relapse, in IBD. Limitations, regarding the diagnostic utility of these markers, seem to exist and are mainly related to the publication of conflicting results, i.e., for IBD activity, and to the fact that S100A8/A9 and S100A12 are not disease-specific. Conclusions Although the existing data link specific S100 proteins with IBD, there are still several drawbacks in the use of these markers for diagnostic purposes. Thus, it seems that further research is mandatory in order to eliminate the impact of confounding factors but also to detect additional associations between S100 proteins and IBD or novel S100 proteins with a closer correlation with IBD.

Background S100A12, a calcium-binding proinflammatory protein secreted by granulocytes, has been associated with different diseases of inflammatory origin, including inflammatory bowel disease (IBD). In this study, the utility of serum S100A12, in discriminating IBD from irritable bowel syndrome (IBS), was tested. Methods S100A12 serum levels were determined in 64 patients with ulcerative colitis (UC), 64 with Crohn's disease (CD) and 73 with IBS, by means of an enzyme-linked immunosorbent assay. S100A12 serum levels were evaluated with respect to the levels of known inflammatory markers and patients' characteristics. Results The median values of serum S100A12 levels were 68.2 ng/mL (range: 43.4-147.4) in UC, 70 ng/mL (41.4-169.8) in CD and 43.4 ng/mL (34.4-74.4) in IBS patients. UC and CD patients had significantly higher serum S100A12 levels compared to IBS patients ( P = 0.001 for both comparisons). Moreover, a cut-off for serum S100A12 levels of 54.4 ng/mL could predict both UC and CD with a 66.7% sensitivity and a 64.4% specificity. The area under curve was estimated at 0.67 with a 95% confidence interval of 0.60-0.75 ( P < 0.001). Considering standard activity indices, higher serum S100A12 levels in active compared to inactive IBD were observed, although the recorded difference did not reach statistical significance. C-reactive protein (CRP) and serum amyloid A (SAA) levels, showed a statistically significant positive correlation with S100A12 (r = 0.39, P = 0.001 and r = 0.23, P = 0.02 respectively). Conclusions Increased levels of circulating S100A12 are found in IBD, compared to IBS. When used to distinguish IBD from IBS adult patients, serum S100A12 levels exhibit moderate performance. On the other hand, serum S100A12 may serve as an inflammatory marker in IBD, since it is well correlated with CRP and SAA.

Conservative management of inflammatory bowel disease (IBD) is based on a combination of drugs, including aminosalicylates (ASAs), steroids, antibiotics, immunosuppressives and biologic agents. Although various side effects have been related to treatment regimens, drug-induced nephrotoxicity is rather uncommon. Furthermore, it is often underestimated since renal function deterioration may be attributed to the underlying disease. The nephrotoxicity of ASAs and cyclosporine A seems well established, but recent data have suggested a possible role of biologic agents such as infliximab and adalimubab in renal impairment. The aim of this review is to summarize the nephrotoxic effects of medical treatment as well as to express possible caveats in the administration of novel agents in IBD. Copyright © 2011 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Background: Biologic agents used in patients with inflammatory bowel diseases (IBD) may influence the pathophysiology of coexistent metabolic-dysfunction associated steatotic liver disease (MASLD). This study primarily aimed to evaluate the six-month effect of infliximab or vedolizumab vs. no biologics on presumed hepatic steatosis in patients with IBD. Secondary endpoints were their effect on hepatic fibrosis and parameters related to hepatic metabolism. Methods: This prospective, non-randomized, controlled trial assigned adult bio-naïve patients with IBD into three groups: infliximab, vedolizumab, or controls (receiving no biologic). The baseline was the time of the initiation of biologic agents and the endpoint six months later. Hepatic steatosis was evaluated with transabdominal ultrasonography (Hamaguchi score), whereas controlled attenuation parameter (CAP), fatty liver index (FLI), and hepatic steatosis index (HSI) were used as surrogates. Hepatic fibrosis was evaluated with liver stiffness (LS), fibrosis-4 index (FIB-4), and nonalcoholic fatty liver disease (NAFLD) fibrosis score. Results: Sixty-six patients were assigned to infliximab (n = 26), vedolizumab (n = 14), or control (n = 26); At the endpoint, the Hamaguchi score, CAP, FLI, and HSI were not different between groups. LS was not different between groups; however, FIB-4 was increased within all groups, and NAFLD fibrosis score was increased within infliximab and control groups, without significant biologic × time interactions. Conclusions: No positive or adverse effect of infliximab or vedolizumab vs. no biologic agents was shown on presumed hepatic steatosis in patients with IBD, who have not been previously exposed to biologic agents. Although no effect of both biologic agent on LS, a slight but significant increase in FIB-4 and NAFLD fibrosis score warrants further studying.

Laparoscopic sleeve gastrectomy (LSG) modifies the upper gastrointestinal tract motility. Controversial data currently exist. The aim of the study was to evaluate esophageal motility before and after LSG. Morbid obese patients scheduled for LSG underwent reflux symptoms evaluation and manometry preoperatively and postoperatively. The preoperative and postoperative results were compared and analyzed. Eighteen patients were enrolled. Heartburn and regurgitation improved in 38.9% and 11.1% of the patients, but deteriorated in 11.1% and 27.8% of the patients, respectively. Lower esophageal sphincter (LES) total length decreased postoperatively ( =0.002). Resting and residual pressures tended to decrease postoperatively (mean difference [95% confidence interval]: -4 [-8.3/0.2] mmHg, =0.060; -1.4 [-3/0.1] mmHg, =0.071, respectively). Amplitude pressure decreased from 95.7±37.3 to 69.8±26.3 mmHg at the upper border of LES ( =0.014), and tended to decrease at the distal esophagus from 128.5±30.1 to 112.1±35.4 mmHg ( =0.06) and mid-esophagus from 72.7±34.5 to 49.4±16.7 mmHg ( =0.006). Peristaltic normal swallow percentage increased from 47.2±36.8 to 82.8±28% ( =0.003). Postoperative regurgitation was strongly negatively correlated with LES total length (Spearman's =-0.670). When groups were compared according to heartburn status, statistical significance was observed between the groups of improvement and deterioration regarding postoperative residual pressure and postoperative relaxation ( <0.002, <0.002, respectively). With regard to regurgitation status, there was statistically significant difference between groups regarding preoperative amplitude pressure at the upper border of LES ( <0.056). Patients developed decreased LES length and weakened LES pressure after LSG. Esophageal body peristalsis was also affected in terms of decreased amplitude pressure, especially at the upper border of LES. Nevertheless, body peristalsis was normalized postoperatively. LSG might not deteriorate heartburn. Regurgitation might increase following LSG due to shortening of LES length, particularly in patients with range of preoperative amplitude pressure at the upper border of LES of 38.9-92.6 mmHg.

Background Toll-like receptor ( TLR ) polymorphisms, and especially TLR - 4 Asp299Gly and TLR - 4 Thr399Ile , have been linked with Crohn’s disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. Aims To address these issues, the distribution of TLR - 4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. Methods TLR - 4 Asp299Gly and TLR - 4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti- Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. Results UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents ( P  = 0.002 and P  < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR - 4 compared to those with wild-type alleles ( P  = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 <  P  < 0.05). Despite the mutant TLR - 4 predisposition for UC pancolitis, smoking was associated with more limited disease ( P  < 0.001). Conclusions The presence of TLR - 4 Asp299Gly and TLR - 4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

Systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, autoantibodies, and extensive fibrosis. Intestinal involvement is frequent in SSc and represents a significant cause of morbidity. The pathogenesis of intestinal involvement includes vascular damage, nerve dysfunction, smooth muscle atrophy, and fibrosis, causing hypomotility, which leads to small intestinal bacterial overgrowth (SIBO), malabsorption, malnutrition, diarrhea, pseudo-obstruction, constipation, pneumatosis intestinalis, and fecal incontinence. Manifestations are often troublesome and reduce quality of life and life expectancy. Assessment of intestinal involvement includes screening for small intestine hypomotility, malnutrition, SIBO, and anorectal dysfunction. Current management of intestinal manifestations is largely inadequate. Patients with diarrhea are managed with low-fat diet, medium-chain triglycerides, avoidance of lactulose and fructose, and control of bacterial overgrowth with antibiotics for SIBO. In diarrhea/malabsorption, bile acid sequestrant and pancreatic enzyme supplementation may help, and nutritional support is needed. General measures are applied for constipation, and intestine rest plus antibiotics for pseudo-obstruction. Fecal incontinence is managed with measures for associated SIBO, or constipation, and with behavioral therapies. Pneumatosis intestinalis is usually an incidental finding that does not require any specific treatment. Immunomoduation should be considered early in intestinal involvement. Multidisciplinary approach of intestinal manifestations in SSc by gastroenterologists and rheumatologists is required for optimum management.