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Gliomas represent the most frequent form of primary brain tumors in adults, the prognosis of which remains extremely poor. Inactivating mutations on the tumor suppressor TP53 were proposed as a key etiological trigger of glioma development. p53 has been recently identified as a transcriptional target of parkin. Interestingly, somatic mutations on parkin have also been linked to glioma genesis. We examined the possibility that a disruption of a functional interaction between p53 and parkin could contribute to glioma development in samples devoid of somatic parkin mutations or genetic allele deletion. We show here that parkin levels inversely correlate to brain tumor grade and p53 levels in oligodendrogliomas, mixed gliomas and glioblastomas. We demonstrate that p53 levels negatively and positively correlate to bax and Bcl2 respectively, underlying a loss of p53 transcriptional activity in all types of glial tumors. Using various cell models lacking p53 or harboring either transcriptionally inactive or dominant negative p53, as well as in p53 knockout mice brain, we establish that p53 controls parkin promoter transactivation, mRNA and protein levels. Furthermore, we document an increase of parkin expression in mice brain after p53-bearing viral infection. Finally, both cancer-related p53 inactivating mutations and deletion of a consensus p53 binding sequence located on parkin promoter abolish p53-mediated control of parkin transcription, demonstrating that p53 regulates parkin transcription via its DNA binding properties. In conclusion, our work delineates a functional interplay between mutated p53 and parkin in glioma genesis that is disrupted by cancer-linked pathogenic mutations. It also allows envisioning parkin as a novel biomarker of glioma biopsies enabling to follow the progression of this type of cancers.

This study sought to quantify CD8+ T cell responses to Trypanosoma cruzi and to identify potential links between these responses and the severity of disease in humans. In the majority of patients with Chagas disease, staining with class I major histocompatibility complex tetramers and analysis of interferon (IFN)-γ ELISPOT responses to a panel of known cytotoxic T lymphocyte target epitopes from T. cruzi failed to identify parasitespecific CD8+ T cells. However, the frequency of individuals with positive ELISPOT responses was higher in areas of active transmission. Analysis of IFN-γ ELISPOT responses to a parasite lysate revealed a very high frequency of responders among patients with mild clinical disease and a very low frequency of responders among those with the most severe form of the disease. These data suggest that the frequency of IFN-γ- producing T cells in patients with chronic Chagas disease is associated with the history of recent exposure and with the clinical status of the patient.

Objectives: To establish the usefulness of echocardiography for the clinical classification of patients with Chagas disease and to determine the predictors of mortality and clinical events. Methods: 849 patients with chronic Chagas disease with a mean follow up of 9.9 years were studied. On admission, ECG, chest radiograph, and two dimensional echocardiogram were obtained from all patients. Clinical events were defined as new ECG abnormalities, change in clinical status resulting in transfer to another group, and death. Morphologically characterised segmental lesions were also seen in 12 patients on a second harmonic echocardiogram with intravenous contrast agent. Univariate and multivariate analysis for clinical events and mortality were performed. Setting: Community of San Martín, Buenos Aires, Argentina. Results: Change in clinical group (68 of 833 survivors v 15 of 16 who died, p < 0.001), left ventricular systolic dimension (mean (SD) 3.06 (0.72) cm v 4.71 (0.90) cm, p < 0.0001), and ejection fraction (mean (SD) 0.67 (0.11)% v 0.42 (0.17)%, p < 0.0001) were found to be the only predictors of mortality. ECG abnormalities related to the disease (in 220 of 699 patients with no clinical event v 98 of 150 patients with a clinical event, p < 0.0001), left ventricular diastolic dimension (mean (SD) 4.88 (0.54) cm v 5.44 (0.83) cm, p < 0.0001), left ventricular systolic dimension (mean (SD) 2.98 (0.62) cm v 3.64 (1.03) cm, p < 0.0001), and ejection fraction (mean (SD) 0.68 (0.10)% v 0.60 (0.16)%, p < 0.0001) were predictors of clinical events. Segmental lesions were observed in 211 of 849 patients (25%). Segmental lesions were seen in 66 (13%) and systolic dysfunction was seen in four of 505 (0.8%) patients with normal ECG. Significant differences were found between the groups of patients (group 0: reactive serology and normal ECG and chest radiography without cardiac enlargement and no signs of heart failure; group 1: reactive serology and abnormal ECG and chest radiography without cardiac enlargement; group 2: reactive serology and abnormal ECG and chest radiography with cardiac enlargement and no signs of heart failure). Conclusion: Echocardiography was useful both to characterise and to determine the prognosis of patients with chronic Chagas disease without heart failure.

Purpose Anemia is common in oncology and negatively impacts quality of life. However, there is lack of knowledge about iron deficiency (ID) epidemiology. The aim of this study was to prospectively assess iron status in patients with locally advanced or metastatic cancer beginning chemotherapy. Methods In this prospective, multicenter cohort study, anemia and ID were evaluated in patients with locally advanced or metastatic solid tumors and lymphoma before starting chemotherapy. Blood samples were collected at inclusion (W0), 6 weeks (W6), and 12 weeks (W12). Prevalence was evaluated in the general population, according to tumor location and was correlated with tumor response. Results One hundred twenty-nine patients were enrolled between 2013 and 2015; 119 had solid tumors and 10 lymphomas. At W0, there were no significant difference between locations with a prevalence around 50–60% (range 47.2–70.4%) and only a trend for colorectal cancer (70.4%, P  = 0.069) due to a higher prevalence of absolute ID (18.5%). Prevalence of ID+ decreased between W0 and W6 and remained stable until W12 due to the proportion of patients with ID and without anemia. However, anemia prevalence increased during W0 and W6 and remained stable to W6 from W12 due to patients with anemia but without ID. A significant correlation between tumor response and ID prevalence was found ( P  = 0.036). Conclusions We confirm the high prevalence of ID and anemia in cancer patients. ID status is correlated to tumor response providing a strong rationale for iron monitoring during cancer management.

Subjects are considered infected with when tested positive by at least two out of three serological tests, whereas a positive result in only one of up to three tests is termed \"serodiscordant\" (SD). Assessment of parasite-specific T-cell responses may help discriminate the uninfected from infected individuals among SD subjects. Peripheral blood mononuclear cells from SD and seropositive (SP) subjects, who were born in areas endemic for infection but living in Buenos Aires city, Argentina, at the time of the study, and seronegative unexposed subjects were included for analysis. The function and phenotype of T cells were assessed by interferon-γ (IFN-γ) and interleukin (IL)-2 enzyme-linked immunospot assay and multiparameter flow cytometry. -specific antibodies were quantified by conventional serology and a multiplex assay format. SD subjects exhibited immunity cell responses to but in contrast to SP subjects, T cells in SD subjects more often display the simultaneous production of IFN-γ and IL-2 in response to antigens and have a resting phenotype. SD individuals also have higher IFN-γ spot counts, polyfunctional CD4 T-cells enriched in IL-2 secreting cells and low levels of antibodies specific for a set of -derived recombinant proteins compared with the SP group. Long-term follow-up of SD individuals confirmed that humoral and T-cell responses fluctuate but are sustained over time in these subjects. T cells in SD subjects for infection did not recognize antigens. Both T-cell and humoral responses in most subjects assessed by conventional tests as SD for infection indicate prior exposure to infection and the establishment of immunological memory suggestive of a resolved infection.

Background The search for biomarkers in spondyloarthritis is of great interest because of their diagnostic and prognostic role in the treatment of these diseases.In recent years cartilage has been shown to be a major target organ in spondyloarthritis. Cartilage degradation causes type II collagen fragments to be released into the bloodstream and these are then excreted in urine and can be used as biomarkers of cartilage destruction.In other diseases of the joints, elevated levels of urinary CTX-II (C-telopeptide fragments of type II collagen) have been associated with progression of radiological damage. Objectives To compare the level of urinary CTX-II in patients with early-stage spondyloarthritis with urinary levels in healthy people of similar age and gender. To analyze the association between patient variables and diagnosis at 3 years of follow up. Patients We included 68 patients aged <45 years, followed for at least 3 years by our department, and presenting at least one the following data suggestive of spondyloarthritis: inflammatory back pain, asymmetrical arthritis especially in lower limbs, enthesitis, dactylitis raquialgia or arthralgia, plus one of the following; psoriasis, IBD, anterior uveitis, family history of spondyloarthritis, radiographic sacroiliitis, HLA-B27 Methods Urine samples were taken from all patients attending for the first time with suspected early spondyloarthritis. Urinary excretion of CTX-II was determined by immunoassay (ELISA) (ng/ml).We also determined CTX-II urinary excretion in a healthy control group (n=25) of similar age and sex. Because urinary levels were not normally distributed, all data were transformed into logarithms for analysis. Association analysis was performed with the following variables at 3 years: final diagnosis, HLA-B27, spondyloarthritis axial/peripheral ASAS, early involvement of large joints (hips, knees), presence of extra-articular manifestations (anterior uveitis, psoriasis) and anti-TNF therapy. Results Urinary excretion of CTX-II in patients presenting for the first time with suspected early SA was significantly higher than in the healthy control group matched for age and sex (p<0.001). At 3 years follow up, the levels of urinary CTX-II in these patients were significantly higher in those who had predominantly peripheral involvement (spondyloarthritis peripheral ASAS) versus axial involvement, developed early large joint involvement and, due to high clinical activity and functional deficits (BASDAI and BASFI), required biological treatment. We found no association with HLA B27 or the presence of extra-articular manifestations. Conclusions Urinary excretion of CTX-II in patients with early spondyloarthritis may be a prognostic biomarker since in our series it was associated with peripheral involvement and early large joint involvement, and the need for biological treatment in the first three years of follow-up. Disclosure of Interest None Declared

Objectives Rheumatoid Arthritis (RA) patients show alterations in cholesterol and lypoproteins levels. These disturbances seem to be related to the inflammation that takes place in the disease, but the pathological mechanisms that leed to it are unknown. Cholesterol ester transfer protein (CETP) is an enzyme that allows transference of cholesterol ester from HDL to LDL-cholesterol particles. CETP has recently gained interest as therapeutic goal of new treatments developed to treat dyslipidemia. The aim of this study is to describe the role of this enzyme in a model of chronic inflammation associated dyslipidemia as it occurs in rheumatoid arthritis. Methods 101 RA patients and 115 sex and age-matched controls were included. Serum levels of CEPT were measured by an enzimelinked inmunoassay and the enzymatic activity by a specific kit (Roar CEPT activity assay kit). In both patients and controls classical lipidic profile (cholesterol, triglycerides, HDL and LDL cholesterol, apolipoprotein A1, apolipoprotein B and lipoprotein A) was defined. Also ESR and CRP were determined. In RA patients disease activity indexes like DAS28 and HAQ were collected, as well as, sociodemographic variables, comorbidility and anthropometric variables. Multivariate analysis was performed to compare results between patients and controls adjusting for corticosteroids intake and for classical dyslipidemia risk factors. Results Serum protein levels were correlated with the enzimatic activity (r=0,5, p=0,00), showing that serum levels could be enough to express the activity of this enzime. Patients show lower CETP activity levels after adjusting for sex and age (beta coefficient -0,52 pmol/l, CI95% -0,87–0,18, p=0,01). In patients, CRP levels show a negative correlation with CETP activity (r=-0.34, p=0,03); in controls this correlation did not achieve the stadistic significance. Disease activity scores like DAS28 did not show association with CETP. Conclusions CETP is underexpressed in RA patients. Differencial characteristics of dyslipIdemia in RA could be partly explained by this fact. Disclosure of Interest None Declared

Objectives The retinol binding protein 4 (RBP4) has recently been described as a protein highly related with insulin resistance (IR) states like obesity and diabetes. The chronic inflammatory states, like in rheumatoid arthritis (RA), are linked also to insulin resistance by mechanisms that are unknown. Therefore, RA is considered as an insulin resistance model related with a chronic inflammatory state, where diabetes and obesity, classical factors for IR, are absent. The objective of this study is to estimate RBP4 expression in RA patients. Methods 101 RA patients and 115 age and sex-matched controls were included. Pancreatic beta cell function was estimated by classical insulinresistance indexes like HOMA (homeostatic model assessment 2). RBP4, C peptide and insuline levels were measured in patients and controls by a specific enzyme-linked immunosorbent assay (ELISA). Multivariate analysis was performed to compare results between patients and controls and the data were adjusted for glucocorticoids intake and for IR classical risk factors. Results RBP4 levels did not show differences between controls and patients, after adjusting for sex, age, body mass index (BMI) and waist circumference (lnRBP4 2,83 mcg/dl in patients vs. 2,70 mcg/dl, p=0,33). On going steroids patients showed higher RBP4 levels (lnRBP4 3,03 vs 2,61 mcg/dl, p=0.00), after adjusting for age, sex, BMI and waist circumference. Similarly, in the univariate analysis, RBP4 levels tended to correlate with steroid average dose (r=0,20, p=0,14). In our serie, RBP4 levels were not related with the classical IR characteristics, like abdominal waist and BMI, both in controls and patients. Nor these levels showed relation with ESR, CRP, insuline levels or disease activity indexes. Conclusions The molecular mechanisms that lead to IR in RA patients appear to be different from those that ocurr in obesity and diabetes status. RBP4 does not seem to play a role in IR in patients with RA. Disclosure of Interest None Declared

Objectives To explore the influence of body composition and abdominal adiposity on endothelial dysfunction and radiological damage in Rheumatoid Arthritis (RA) patients. Methods A total of 100 patients, 54 RA patients and 46 controls, adjusted for sex, body mass index (BMI), age and comorbidity, were included. Total body composition was measured by dual energy X-ray absorptiometry; total and regional lean mass, fat mass, fat free mass index (fat free mass/m2) and fat mass index (fat mass/m2) were established. Quantification of visceral and parietal abdominal fat area was determined using magnetic resonance imaging, as well as visceral/parietal fat index. Endothelial dysfunction was assessed by brachial artery flow-mediated dilatation (FMD) as the dilator response to 5 minutes distal cuff occlusion and after sublingual nitroglycerine administration, and the Sharp Score defined radiological damage. The 28-joint DAS (DAS-28) and disability using HAQ (Health Assessment Questionnaire) scores, erythrocyte sedimentation rate (ESR) and C-reactive protein were collected. Multivariate analysis was performed to compare body composition between controls and patients and the relationship between those and endothelial dysfunction and radiological damage, everything adjusted for demographic and comorbidity variables. Results In the univariate analysis RA patients showed less flow-mediated dilatation (5.9 vs 9.8 mm, p=0.03). Similarly, fat free mass index was higher in patients than in controls (beta coefficient 0,94 (CI95% 0,08-1,80), P=0,03) after adjusting for BMI, sex and age; on the other hand fat mass index tended to be higher in patients than in controls (beta coefficient 2,51 (CI95% -0,82-5,84), p=0.13). Parietal and visceral abdominal fat values did not show differences between controls and patients. Fat mass, lean mass and abdominal fat did not correlate with DAS-28, HAQ, ESR or CRP. Parietal abdominal fat through resonance imaging in RA patients showed a negative relation with flow-mediated dilatation (beta coefficient -0.045 mm FMD/cm2 parietal area, p=0.02) after adjusting for BMI. This relation was not found with visceral abdominal fat. Radiological damage was negatively correlated with total bone mass (beta coefficient -1,13, CI95% -2,05-0,22, p=0.02) and showed a negative trend to do it also with total lean mass (beta coefficient -1.11 CI95% 2,42-0,21, p=0,09). Conclusions Changes in body composition take place in RA patients. These changes can be related to the endothelial dysfunction and radiological damage that occurs in this disease. Disclosure of Interest None Declared

Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa. : Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839). : We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab. : This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine.