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BACKGROUND: Esophageal and gastroesophageal junctional (GEJ) adenocarcinoma is one of the most fatal cancers and has the fastest rising incidence rate of all cancers. Identification of biomarkers is needed to tailor treatments to each patient's tumor biology and prognosis. METHODS: Gene expression profiling was performed in a test cohort of 80 chemoradiotherapy (CRTx) naïve patients with external validation in a separate cohort of 62 CRTx naïve patients and 169 patients with advanced stage disease treated with CRTx. RESULTS: As a novel prognostic biomarker after external validation CD151 showed promise. Patients exhibiting high levels of CD151 (=median) had a longer median overall survival than patients with low CD151 tumor levels (median not reached vs. 30.9 months; p = 0.01). This effect persisted in a multivariable Cox regression model with adjustment for tumor stage [adjusted hazard ratio (aHR) 0.33; 95 confidence interval (CI) 0.14 0.78; p = 0.01] and was further corroborated through immunohistochemical analysis (aHR 0.22; 95 CI 0.08 0.59; p = 0.003). This effect was not found in the separate cohort of CRTx exposed patients. CONCLUSION: Tumoral expression levels of CD151 may provide independent prognostic information not gained by conventional staging of patients with esophageal and GEJ adenocarcinoma treated by esophagectomy alone.

The contribution of immune cells to the inflammasome that characterises type 2 diabetes mellitus and obesity is under intense research scrutiny. We hypothesised that early changes in glucose metabolism following gastric banding surgery may relate to systemic inflammation, particularly cell-mediated immunity.Obese participants (BMI 43.4 ± 4.9 kg/m(2), n = 15) with diabetes or impaired glucose tolerance (IGT) underwent laparoscopic adjustable gastric banding surgery. Measurements taken before, and at 2 and 12 weeks after surgery included: fasting glucose, glucose levels 2 h after a 75 g oral load, glucose incremental AUC, oral glucose insulin sensitivity index (OGIS), circulating immune cell numbers and activation, and adipokine levels. Subcutaneous and visceral adipose tissue were collected at surgery, and macrophage number and activation measured.There were significant reductions in fasting and 2 h glucose, as well as improved OGIS at 2 and 12 weeks. At 12 weeks, 80% of the diabetic participants reverted to normal glucose tolerance or IGT, and all IGT participants had normalised glucose tolerance. The 12 week fall in fasting glucose was significantly related to baseline lymphocyte and T lymphocyte numbers, and to granulocyte activation, but also to the magnitude of the 12 week reduction in lymphocyte and T lymphocyte numbers and TNF-α levels. In a model that explained 75% of the variance in the change in fasting glucose, the 12 week change in T lymphocytes was independently associated with the 12 week fall in fasting glucose.Rapid improvements in glucose metabolism after gastric banding surgery are related to reductions in circulating pro-inflammatory immune cells, specifically T lymphocytes. The contribution of immune cell-mediated inflammation to glucose homeostasis in type 2 diabetes and its improvement after bariatric surgery require further investigation.

Antitumor immunity is strongly influenced by the balance of tumor antigen-specific effector T cells (Teff) and regulatory T cells (Treg). However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T-cell populations is not well understood. We found that antigen-specific Tregs were induced following subcutaneous vaccination with either OVA or melanoma-derived peptides, with a restricted expansion of Teffs. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified Teffs over Tregs, dramatically increasing the antigen-specific Teff:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase Teff:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific Teffs:Tregs in draining lymph nodes were associated with enhanced CD8+ T-cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of proinflammatory type I cytokines early after vaccination. This environment promoted CD8+ and CD4+ Teff expansion over that of antigen-specific Tregs, tipping the Teff to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T-cell populations, facilitating the rational design of more effective cancer vaccines. Cancer Res; 73(22); 6597–608. ©2013 AACR.

The origin of smooth muscle cells in developing atherosclerotic lesions is a controversial topic with accumulating evidence indicating that at least some arterial smooth muscle cells might originate from bone marrow-derived smooth muscle cell precursors circulating in the blood. The stem cell markers currently used for the identification of stem cells in the arterial intima can be expressed by a number of different cell types residing in the arterial wall, such as mast cells, endothelial cells and dendritic cells, which can make interpretation of the data obtained somewhat ambiguous. In the present study we examined whether the putative intestinal stem cell marker Musashi-1 is expressed in the arterial wall. Using a multiplexed tandem polymerase chain reaction method (MT-PCR) and immunohistochemistry, Musashi-1 expression was revealed in human coronary arterial wall tissue segments, and this finding was followed by the demonstration of significantly higher expression levels of Musashi-1 in atherosclerotic plaques compared with those in undiseased intimal sites. Double immunohistochemistry demonstrated that in the arterial wall Musashi-1 positive cells either did not display any specific markers of cells that are known to reside in the arterial intima or Musashi-1 was co-expressed by smooth muscle α-actin positive cells. Some Musashi-1 positive cells were found along the luminal surface of arteries as well as within microvessels formed in atherosclerotic plaques by neovascularization, which supports the possibility that Musashi-1 positive cells might intrude into the arterial wall from the blood and might even represent circulating smooth muscle cell precursors.

Type 2 diabetes mellitus (T2D) is predicted by central obesity and circulating adipokines regulating inflammation. We hypothesized that visceral adipose tissue (VAT) in T2D expresses greater levels of proinflammatory molecules. Paired samples of subcutaneous (SAT) and VAT were excised at elective surgery (n = 16, 6 with T2D, n = 8 age- and gender- matched controls). Metabolic parameters were measured in the fasted state: body composition by dual-energy X-ray absorptiometry and insulin action by hyperinsulinemic-euglycemic clamp. Adipose tissue mRNA gene expression was measured by quantitative reverse transcriptase-PCR. Subjects with T2D had higher VAT expression of molecules regulating inflammation (tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein (MIP), interleukin-8 (IL-8)). Fasting glucose related to VAT expression of TNFalpha, MIP, serum amyloid A (SAA), IL-1alpha, IL-1beta, IL-8, and IL-8 receptor. Abdominal fat mass was related to VAT expression of MIP, SAA, cAMP response element-binding protein (CREBP), IL-1beta, and IL-8. Insulin action related inversely to VAT complement C3 expression only. There were depot-specific differences in expression of serum T2D predictors: VAT expressed higher levels of complement C3; SAT expressed higher levels of retinol-binding protein-4 (RBP4), adiponectin, and leptin. In summary, VAT in T2D expresses higher levels of adipokines involved in inflammation. VAT expression of these molecules is related to fasting glucose and insulin action. Increased production of these proinflammatory molecules by VAT may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.

Background Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia–dysplasia–neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett’s esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27–1.26, p = 0.17). Conclusions CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues. Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-4155-y) contains supplementary material, which is available to authorized users.

Background: Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC. Methods: One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC. Results: Median tissue expression of MIC-1/GDF15 mRNA was ⩾25-fold higher in BO and LGD compared to NE (P720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73–0.96; P

Weight loss after bariatric surgery reduces cardiac risk and morbidity. We examined weight loss effects on arterial stiffness in morbidly obese subjects, in relation to cytokines, circulating and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)-based immune cells and gene expression. Obese subjects with type 2 diabetes mellitus (T2D) or impaired glucose tolerance ( n = 14, mean ± SEM body mass index 42.9 kg/m2) underwent 24 weeks’ caloric restriction, with gastric banding at 12 weeks. Measures were: arterial augmentation index (AIx), insulin resistance, circulating cytokines, immune cell activation markers, and SAT and VAT cytokine gene expression. Weight loss reduced AIx by 20% ( p = 0.007), with falls in s-selectin ( p = 0.001) and inter-cellular adhesion molecule ( p = 0.04). Improved AIx related to reduced surface expression of the interleukin (IL)-2 receptor on T-lymphocytes (TL-IL2R) and granulocyte adhesion markers ( r = 0.59, 0.64, respectively, p < 0.04). Higher VAT expression of interferon-γ and monocyte chemoattractant protein-1 associated with a blunted AIx response. A model of TL-IL2R expression, waist, weight and insulin resistance explained 73% of the variance in AIx reduction ( p = 0.005). In morbidly obese dysglycaemic subjects, modest weight loss reduces arterial stiffness, the magnitude of which relates to improved markers of inflammation.

FTO gene variants are linked to obesity. We tested for site-specific differences in FTO gene expression in subcutaneous and visceral adipose tissue (SAT and VAT, respectively) from individuals with and without type 2 diabetes mellitus (T2D) and the relationships between fasting glucose, in vivo insulin action, and measures of adiposity with FTO gene expression in adipose tissue.Paired subcutaneous and visceral fat were excised at elective surgery in n = 16 subjects (six with T2D, age-matched). Metabolic parameters were measured in fasted state; body composition by dual-energy X-ray absorptiometry; and insulin action by hyperinsulinemic euglycemic clamp. Adipose tissue mRNA gene expression was determined by quantitative RT-PCR.Subjects with T2D had SAT and VAT FTO mRNA expression similar to controls. There was no depot specificity between SAT and VAT FTO mRNA expression. Insulin action did not relate to SAT or VAT FTO mRNA expression. SAT FTO mRNA expression was related to fasting glucose and waist circumference only. SAT and VAT FTO mRNA expression was not related to direct measures of total or central abdominal adiposity. SAT FTO mRNA expression was related to SAT tumor necrosis factor-alpha and nuclear factor-kappaB mRNA expression.FTO gene expression is not increased in SAT and VAT in T2D and does not relate to insulin action. The links between FTO and metabolic complications of diabetes require further elucidation.