A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Colonic epithelial cells, which express high levels of PPAR-gamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report here that PPAR-gamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-kappaB via an IkappaB-alpha-dependent mechanism. Moreover, thiazolidinedione ligands for PPAR-gamma markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-gamma may be a therapeutic target in humans suffering from IBD.     

Understanding the mechanisms of action of antiangiogenic agents in metastatic colorectal cancer: A clinician’s perspective

Multiple clinical trials using bevacizumab, ziv-aflibercept, and regorafenib have recently demonstrated efficacy for patients with metastatic colorectal cancer. While the net clinical benefit of each of these therapies in the second-line and refractory disease setting appears to be similar, important distinctions exist between the agents at the pharmacodynamic, tumor microenvironment, and clinical levels. The purpose of this review is to survey the preclinical evidence regarding the mechanisms of action of these novel antiangiogenic agents and provide an overview of their respective clinical activity, while highlighting distinctions between therapies. Fundamental understanding of these distinctions may aid in clinical decisions and choice of antiangiogenic therapies.     

Silicone lymphadenopathy with concomitant malignant lymphoma

Six cases of axillary lymphadenopathy induced by silicone elastomer following silastic finger joint arthroplasty have been reported; 2 cases had associated malignant lymphoma. This is the 3rd reported case of malignant lymphoma with concomitant silicone lymphadenopathy discovered 8 years after insertion of silastic finger joint arthroplasty for longstanding rheumatoid arthritis. Histology revealed a partially replaced reactive lymph node with immunoblastic lymphoma. Both sides contained single and clusters of multinucleated giant cells with silastic particles, as well as formed asteroid bodies. Malignant lymphoma is associated with rheumatoid disease, but to date, silicone particles have not been linked to malignant lymphoma.     

Increased production of sonic hedgehog by ballooned hepatocytes

Ballooned hepatocytes distinguish non-alcoholic steatohepatitis (NASH) from steatosis. Such cells contain dilated endoplasmic reticulum and ubiquitin aggregates, characteristics of endoplasmic reticulum stress. Hepatocyte ballooning increases the risk for fibrosis in NASH, suggesting that ballooned hepatocytes release pro-fibrogenic factors. Hedgehog ligands function as pro-fibrogenic factors in liver diseases, but mechanisms for hedgehog ligand production remain poorly understood. We evaluated the hypothesis that endoplasmic reticulum stress induces hepatocyte production of hedgehog ligands that provide paracrine pro-fibrogenic signals to neighbouring cells. In livers from NASH patients, keratin 8/18 and ubiquitin staining demonstrated enlarged, keratin 8/18-negative/ubiquitin-positive hepatocytes (ballooned hepatocytes) that were positive for Sonic hedgehog. In order to model endoplasmic reticulum stress in vitro, primary mouse hepatocytes were treated with tunicamycin. Compared to vehicle, tunicamycin significantly increased Sonic hedgehog and Indian hedgehog expression. Furthermore, conditioned medium from tunicamycin-treated hepatocytes increased Gli-luciferase reporter activity 14-fold more than conditioned medium from vehicle-treated hepatocytes. Cyclopamine (hedgehog signalling inhibitor) abrogated the effect of conditioned medium from tunicamycin-treated hepatocytes, verifying that soluble hepatocyte-derived factors activate hedgehog signalling. Ballooned hepatocytes in NASH patients did not express the hedgehog target gene, Gli2, α-smooth muscle actin or vimentin, but were surrounded by Gli2-positive stromal cells expressing these myofibroblast markers. Trichrome staining demonstrated the accumulation of ballooned hepatocytes in areas of matrix deposition, and numbers of Sonic hedgehog-positive hepatocytes correlated with the degree of ballooning and fibrosis stage. Hepatocytes undergoing endoplasmic reticiulum stress generate hedgehog ligands which act as paracrine pro-fibrogenic factors for hedgehog-responsive stromal cells. These results help to explain why fibrosis stage correlates with hepatocyte ballooning in NASH.     

Partially polyurethane-covered stent for cerebral aneurysm treatment

Partially polyurethane-covered stent (PPCS) is proposed for the treatment of cerebral aneurysms. The PPCSs were observed to substantially modify the flow entering the aneurysm in a patient-specific aneurysm phantom (PSAP). These stents can act as flow modulators and the polyurethane (PU) membrane can provide a smooth scaffold for restoring the structural integrity of the diseased vessel. Partial coating of the stent aids in sealing only the entrance to the aneurysm while keeping the perforators around the aneurysm open and patent. Biocompatibility of the PU membrane was monitored using contact angle measurements to show that critical surface tension (CST) values remained in the thromboresistant range of 20-30 mN/m. Stent flexibility, stiffness, and pressure-diameter relationship showed no significant change after asymmetric PU film application. No delamination of the PU membrane from the stent was observed within the working strains of the stent. The flow modulating capability of the PPCS was monitored by intentionally orienting the stent to cover either the proximal or the distal regions along the neck of the PSAP. Time density curves (TDCs) compared the relative metrics of input rate, washout rate, residence time, and influx in the aneurysm before and after the stent placement.     

Chromatic properties of the colour-shading effect

The 'colour-shading effect' describes the phenomenon whereby chromatic variations affect the magnitude of perceived shape-from-shading in luminance patterns. A previous study showed that in mixed colour-plus-luminance sine-wave plaids, impressions of depth in the luminance component were enhanced by non-aligned chromatic components, and suppressed by aligned chromatic components [Nature Neuroscience 6 (2003) 641-644]. Here we examine the chromatic determinants of these effects. Colour contrast was defined along the cardinal axes of colour space in order to isolate the L-M and S-(L+M) post-receptoral chromatic mechanisms. We found no difference in the potency of L-M-only and S-(L+M)-only gratings, either for enhancing or suppressing perceived depth. Moreover, the magnitude of depth-suppression was no different for any combination of depth-enhancing and depth-suppressing cardinal directions. Finally we tested whether the visual system carried the assumption that natural shading is tinged with blue, by measuring perceived depth in a colour-plus-luminance grating that was made to appear either bright-yellow/dark-blue or bright-blue/dark-yellow. However there was no difference in the magnitude of depth-suppression between conditions, suggesting that the visual system does not make any assumption about the colour of natural shading. Taken together, the results suggest that while the colour-shading effect is highly sensitive to colour contrast, it is agnostic with respect to colour direction.     

Diagnostic yield from 231 autopsies in a community hospital

Autopsy reports of 231 adult autopsies were examined for clinically unexpected diagnoses. Analysis of data showed that 97 of 188 autopsy diagnoses were clinically unexpected. The diagnosis of pulmonary embolism was clinically the most frequently missed diagnosis relative to its actual occurrence. Also noted was that the proportion of cases with unexpected diagnoses increased from 1983 to 1987.