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IntroductionSocioeconomic status (SES) is a known risk factor for gastric cancer (GC). This study seeks to examine education, income, and occupation variables separately to identify the single variable that can be best used to assess SES risk for GC.MethodsData from a case-control survey study were used. Logistic regression models were created for education, income, and occupation adjusted for age, sex, and race. Models were compared using AIC, c-statistics, and pseudo-R square to determine the model that had the highest risk predictive ability.ResultsGC cases had lower education levels and more commonly held jobs in unskilled labor. Annual household income was lower in cases compared to controls. Age, gender, race, education, and occupation were associated with increased risk of GC. The education model adjusted for age, gender, and race found < high school (HS) education to have an OR of 3.18 (95% CI 1.09–9.25) for GC compared to > HS education. The occupation model demonstrated that employment in unskilled labor had OR of 4.32 (95% CI 1.05–17.76) for GC compared to professional occupation. Model fit was best for the education model (AIC: 113.583, lower AIC is better) compared to income (117.562) or occupation (117.032). Education contributed the most to model variability (% delta pseudo-R square (4.7%)) compared to occupation (4.0%) or income (3.8%).ConclusionEducation level was the single most reliable measure of GC risk among 3 SES variables and can be employed as an ideal single indicator of SES-related GC risk when multiple SES factors cannot be obtained.

Latest data suggest that placental growth factor (PLGF), growth differentiation factor-15 (GDF-15) and hepatic growth factor (HGF) are involved in hepatic fibrogenesis. Diagnostic performance of these markers for non-invasive liver fibrosis prediction was evaluated based on liver histology and stiffness. In total 834 patients were recruited. Receiver-operating-characteristics were used to define cut-offs for markers correlating to fibrosis stages. Odds-ratios were calculated for the presence/absence of fibrosis/cirrhosis and confirmed in the sub-group of patients phenotyped by elastography only. Logistic and uni- and multivariate regression analyses were used to test for association of markers with liver fibrosis stages and for independent prediction of liver histology and stiffness. Marker concentrations correlated significantly (P<0.001) with histology and stiffness. Cut-offs for liver fibrosis (≥F2) were PLGF = 20.20 pg/ml, GDF15 = 1582.76 pg/ml and HGF = 2598.00 pg/ml. Logistic regression confirmed an increase of ORs from 3.6 over 33.0 to 108.4 with incremental (1-3) markers positive for increased liver stiffness (≥12.8kPa; all P<0.05). Subgroup analysis revealed associations with advanced fibrosis for HCV (three markers positive: OR = 59.9, CI 23.4-153.4, P<0.001) and non-HCV patients (three markers positive: OR = 144, CI 59-3383, P<0.001). Overall, serum markers identified additional 50% of patients at risk for advanced fibrosis presenting with low elastography results. In conclusion, this novel combination of markers reflects the presence of significant liver fibrosis detected by elastography and histology and may also identify patients at risk presenting with low elastography values.

Background Recently, we identified neutralizing autoantibodies against progranulin (PGRN) in a wide spectrum of rheumatic diseases including cases with enteropathic spondylarthritis. PGRN is a secreted protein with strong anti-inflammatory effects, believed to be mediated by the direct inhibition of TNF receptors 1&2. Given the central role of TNF-α as proinflammatory cytokine, a neutralizing antibody directed against its physiologic antagonist PGRN might entertain a proinflammatory environment. Objective The aim of the present study was to investigate a possible occurrence of PGRN-antibodies (PGRN-Abs) in inflammatory bowel disease (IBD), and to investigate a possible pathogenic effect. Materials and Methods Sera samples of 141 patients with Crohn’s disease (CD) and of 71 patients with ulcerative colitis (UC) were tested for PGRN-Abs by ELISA. PGRN plasma levels were detected by ELISA. Proinflammatory effects of progranulin-antibodies were analyzed by TNF-α-mediated cytotoxicity assays using HT29 cells and by examination of possible effects of PGRN and of PGRN-antibodies on TNF-α-induced downmodulation of FOXP3 expression in CD4 + CD25 hi Tregs. Results PGRN-Abs were found in sera of 23/141 (16.31 %) patients with CD, and 15/71 (21.13 %) patients with UC. PGRN-Abs were more frequent than anti-neutrophil cytoplasmic autoantibodies (ANCAs) in UC, but less frequent than anti-Saccharomyces cerevisiae antibodies (ASCAs) in CD. PGRN-Abs belonged mostly to IgG1 (71.1 %) and IgA (26.3 %). They occurred in relevant titres and had significant neutralizing effects on PGRN plasma levels. Cytotoxicity assays comparing PGRN-antibody-positive sera with negative sera from matched patients with IBD showed a proinflammatory effect of PGRN-Abs on HT29 cells. Moreover, PGRN-antibodies led to an increase of TNF-α-induced downmodulation of FOXP3 in CD4 + CD25 hi Tregs. Conclusion The results suggest that PGRN-Abs occur frequently in CD and UC, and have a proinflammatory effect.

[This corrects the article DOI: 10.1371/journal.pone.0173506.].

In November 2018, an outbreak of tularemia occurred among hare hunters in Bavaria, Germany. At least one infected hare was confirmed as the source of infection. A number of hunting dogs showed elevated antibody titers to Francisella tularensis, but the absence of titer increases in subsequent samples did not point to acute infections in dogs. Altogether, 12 persons associated with this hare hunt could be diagnosed with acute tularemia by detection of specific antibodies. In nine patients, the antibody and cytokine responses could be monitored over time. Eight out of these nine patients had developed detectable antibodies three weeks after exposure; in one individual the antibody response was delayed. All patients showed an increase in various cytokines and chemokines with a peak for most mediators in the first week after exposure. Cytokine levels showed individual variations, with high and low responders. The kinetics of seroconversion has implications on serological diagnoses of tularemia.

BackgroundThe proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined.MethodsIL-1β production in response to DSS was studied in macrophages of wild-type, caspase-1−/−, NLRP3−/−, ASC−/−, cathepsin B−/− or cathepsin L−/− mice. Colitis was induced in C57BL/6 and NLRP3−/− mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue.ResultsMacrophages incubated with DSS in vitro secreted high levels of IL-1β in a caspase-1-dependent manner. IL-1β secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1β secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3−/− mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency.ConclusionsThe NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.

Background Multiple studies have shown that dendritic cell (DC)-based vaccines can induce antitumor immunity. Previously, we reported that gemcitabine enhances the efficacy of DC vaccination in a mouse model of pancreatic carcinoma. The present study aimed at investigating the influence of gemcitabine on vaccine-induced anti-tumoral immune responses in a syngeneic pancreatic cancer model. Materials and methods Subcutaneous or orthotopic pancreatic tumors were induced in C57BL/6 mice using Panc02 cells expressing the model antigen OVA. Bone marrow-derived DC were loaded with soluble OVA protein (OVA-DC). Animals received gemcitabine twice weekly. OVA-specific CD8 + T-cells and antibody titers were monitored by FACS analysis and ELISA, respectively. Results Gemcitabine enhanced clinical efficacy of the OVA-DC vaccine. Interestingly, gemcitabine significantly suppressed the vaccine-induced frequency of antigen-specific CD8 + T-cells and antibody titers. DC migration to draining lymph nodes and antigen cross-presentation were unaffected. Despite reduced numbers of tumor-reactive T-cells in peripheral blood, in vivo cytotoxicity assays revealed that cytotoxic T-cell (CTL)-mediated killing was preserved. In vitro assays revealed sensitization of tumor cells to CTL-mediated lysis by gemcitabine. In addition, gemcitabine facilitated recruitment of CD8 + T-cells into tumors in DC-vaccinated mice. T- and B-cell suppression by gemcitabine could be avoided by starting chemotherapy after two cycles of DC vaccination. Conclusions Gemcitabine enhances therapeutic efficacy of DC vaccination despite its negative influence on vaccine-induced T-cell proliferation. Quantitative analysis of tumor-reactive T-cells in peripheral blood may thus not predict vaccination success in the setting of concomitant chemotherapy.

Background: Tumour-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by vaccination with dendritic cells (DCs). However, clinical responses to DC-based vaccination have only been observed in a minority of patients with solid cancer. Combination with other treatment modalities such as chemotherapy may overcome immunoresistance of cancer cells. It has been shown previously that gemcitabine sensitises human pancreatic carcinoma cells against CTL-mediated lysis. Here, a murine pancreatic carcinoma model was used to investigate whether combination with gemcitabine increases therapeutic efficacy of DC-based vaccination. Methods: Bone marrow-derived DCs from C57BL/6 mice were loaded with UV-irradiated, syngeneic Panc02 carcinoma cells and were administered subcutaneously. For prophylactic vaccination, mice were vaccinated three times at weekly intervals prior to tumour challenge with Panc02 cells. Therapeutic vaccination was started when tumours formed a palpable nodule. Gemcitabine was administered intraperitoneally twice weekly. Results: Prophylactic DC-based vaccination completely prevented subcutaneous and orthotopic tumour development and induced immunological memory as well as tumour antigen-specific CTLs. In the subcutaneous tumour model, therapeutic DC-based vaccination was equally effective as gemcitabine (14% vs 17% survival at day 58 after tumour challenge; controls, 0%). Combination of the two strategies significantly increased survival of tumour-bearing mice (50% at day 58 after tumour challenge). DC-based vaccination also prevented death from pulmonary metastatisation after intravenous injection of Panc02 cells. Conclusion: DC-based immunotherapy may not only be successfully combined with gemcitabine for the treatment of advanced pancreatic carcinoma, but may also be effective in preventing local recurrence or metastatisation in tumour-free patients.

Purpose The purpose of this study is to investigate the association of intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular nonaspirin NSAIDs and compare it with other risk factors for the progression of diverticulosis to diverticulitis in patients who underwent colonoscopy. Methods A total of 194 patients who underwent complete colonoscopy in our center between 2012 and 2016 were recruited: 144 with diverticulosis without prior diverticulitis (median age 71 years, 59.7% men) and 50 with diverticulitis (median age 64 years, 54.0% men). Data concerning current and previous medication as well as concomitant diseases were collected using a structured questionnaire and by revision of patients medical charts. Results Patients with diverticulitis were significantly ( p  < 0.001) younger as compared to individuals with plain diverticulosis (median age 64 versus 71 years, respectively). The intake of NSAIDs significantly ( p  = 0.002) increased the risk of prior diverticulitis (OR 3.2, 95% CI 1.5–6.9). In the multivariate model, both age ( p  < 0.001) and NSAIDs ( p  = 0.03) proved to be independent determinants of diverticulitis. When analyzing aspirin intake, it was not associated with diverticulitis. Conclusions Our study demonstrates, in line with previous reports, that intake of NSAIDs is associated with diverticulitis. We show in particular that nonaspirin NSAIDs might be selectively associated with diverticulitis. These results point to divergent role of aspirin and nonaspirin NSAIDs in the development of diverticulitis.

Background and aims Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma. Methods Tumor lysate of patients with pancreatic carcinoma was generated by repeated freeze–thaw cycles of surgically obtained tissue specimens. Patients were eligible for DC vaccination after recurrence of pancreatic carcinoma or in a primarily palliative situation. DC were generated from peripheral blood mononuclear cells (PBMC), loaded with autologous tumor lysate, stimulated with TNF-α and PGE 2 and injected intradermally. All patients received concomitant chemotherapy with gemcitabine. Disease response was the primary endpoint. Individual immunological responses to DC vaccination were analyzed by T cell-based immunoassays using pre- and post-vaccination samples of non-adherent PBMC. Results Twelve patients received DC vaccination and concomitant chemotherapy. One patient developed a partial remission, and two patients remained in stable disease. Median survival was 10.5 months. No severe side effects were observed. Tumor-reactive T cells could be detected prior to vaccination. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. To quantify the presence of tumor-reactive T cells, stimulatory indices (SI) were calculated as the ratio of proliferation-inducing capacity of lysate-loaded versus -unloaded DC. The patient with longest overall survival of 56 months had a high SI of 6.49, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more. Conclusion DC-based vaccination can stimulate an antitumoral T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment.