tbuckley/cabot-search huggingface dataset:
CD40-Licensing Of Human Dendritic Cells Further Matures Tnfa-Treated Dcs But Does Not Mediate Resistance Against Inhibition Of T-Cell Proliferation By TREG
Authors: Matthias Eyrich, Johannes Rachor, Marissa Blume, Isabelle Becker, Anne Stumpf, Harald Wajant, Matthias Wolfl, Paul G. Schlegel, Manfred Lutz
Journal: Blood (2013)
Abstract 4314: Using antioxidant to enhance liver cancer preventive effect of n-3 PUFAs
Authors: Ying Fu, Angela Y. Bai, Marcin Dyba, Jing X. Kang, Fung-Lung Chung
Journal: Cancer Research (2016)

Abstract In various animal models, n-3 polyunsaturated fatty acids (PUFAs) have demonstrated cancer preventive effects. This protective effect is associated with reduced levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2). On the other hand, an endogenous DNA adduct formed from the peroxidation of ω-3 PUFAs, γ-hydroxy-1, N2-propanodeoxyguanosine (γ-OHPdG), is known to be mutagenic. In light of these observations, we hypothesized that the combination of n-3 PUFAs with an antioxidant to inhibit lipid peroxidation (e.g. α-lipoic acid) will result in an enhanced cancer preventive effect than n-3 PUFAs alone. The chemical carcinogen diethylnitrosamine (DEN) induced HCC model is employed in this study. The DEN-induced HCC model has a histology and genetic signature similar to that of human HCCs, such that it has poor prognosis and recapitulates a dependence on inflammatory signaling. It also reflects the same gender disparity seen in human HCCs. Fat-1 transgenic mice were used because they express a Caenorhabditis elegans desaturase converting n-6 to n-3 PUFAs endogenously without using dietary supplementation. This model underlies the importance of dietary control of PUFAs intake and ratios due to the inability of mammalian cells to generate anti-inflammatory n-3 PUFAs from pro-inflammatory n-6 PUFAs, which are a major component of the standard Western diets. The results showed that antioxidant can efficiently suppress the elevated level of γ-OHPdG in fat-1 mice. The tumor incidence, multiplicity, and size are monitored continuously. This work was supported by the NCI grant: RO1-CA-134892. Y.F. thanks the Prevent Cancer Foundation for his fellowship (Marcia and Frank Carlucci Charitable Foundation Award in Cancer Prevention and Early Detection) Citation Format: Ying Fu, Angela Y. Bai, Marcin Dyba, Jing X. Kang, Fung-Lung Chung. Using antioxidant to enhance liver cancer preventive effect of n-3 PUFAs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4314.
Abstract 84: Expression of the Transcription Factors PPAR Alpha and Gamma, and Their Target Genes in the Heart of Obese Mice
Authors: Andrea Ruiz-Velasco, Amelia Rios, Bruno Escalante
Journal: Circulation Research (2015)

The Peroxisome-Proliferator Activated Receptors (PPARs) have been identified as key regulators of energy metabolism by sensing fatty acid availability and activating the transcription of enzymes involved in fatty acid and glucose metabolism. In the heart, PPARs have been proven to participate in the development of diseases, such as cardiac hypertrophy and diabetic cardiomyopathy, conditions that have been associated to obesity. Furthermore, the use of PPARs activator drugs is frequent for the treatment of obesity-dependent diseases, such as hypoglycemiant (fibrates) and anti-diabetic (thiazolidinediones) drugs. Therefore, the objective of this project was to characterize the expression of PPARs and some of their target genes involved in fatty acid and glucose metabolism in the heart of obese mice. Mice (C57BL/6) were fed with either a standard chow diet (control group) or a high fat diet (obese group) for three months. Hearts were weighed prior to quantifying protein expression of two PPARs (alpha and gamma), and both mRNA and protein expression of three enzymes (phosphofructokinase (PFK), glycerol-3-phosphate dehydrogenase (GPD1) and glycerol-3-phosphate acyltransferase (GPAT)). Protein levels were measured by western blot, while mRNA levels were quantified by real-time PCR. The obese group presented 41% increase in body weight compared with control mice. However, no change was observed in obese hearts weight compared with control group, meaning that hypertrophy had not been developed yet. The expression of PPAR-alpha was increased 42% in obese mice compared with the control group, suggesting a possible activation of the fatty acid oxidation pathway. PPAR-gamma together with GPD1 and GPAT showed no differences at any level; however, PFK presented 90% increase in mRNA level and 54% increase in protein level in obese mice. Interestingly, decrease in PFK has been reported in any altered PPAR-alpha condition, contrary to our results. These results suggest that there is a dysregulation of the heart’s energetic pathways mediated by PPARs in earlier stages of obesity.
Les caractéristiques des endoscopistes qui influent sur la qualité de la coloscopie
Authors: S Lecleire
Journal: Endoscopy (2016)

Le travail de Jover et al. est l’analyse post-hoc d’une étude espagnole, appelée COLONPREV, qui visait à comparer le test immunologique de recherche de sang dans les selles tous les deux ans à une coloscopie dans la prévention de la mortalité par cancer colorectal (CCR). Quarante-huit gastroentérologues endoscopistes ont participé à cette étude pour un total de 3838 coloscopies réalisées. Les critères qualité de la coloscopie apparaissent de plus en plus importants dans la stratégie de prévention du CCR. A ce jour, les facteurs directement associés à une meilleure qualité de la coloscopie permettant d’augmenter le taux de détection des adénomes (TDA) sont le temps de retrait de l’endoscope supérieur à 7 min, la qualité de la préparation colique, l’horaire de la coloscopie qui doit être réalisé au maximum 5 heures après la dernière ingestion de préparation colique et l’anesthésie générale.
P287 Offline Fractional Exhaled Nitric Oxide and Breath Frequency: Abstract P287 Table 1
Authors: C Howard, V MacBean, A Lunt, A Greenough
Journal: Thorax (2015)

<h3>Introduction/objectives</h3> Fractional exhaled nitric oxide (FeNO) is a noninvasive method of assessing airway inflammation and recommended by NICE (2014) to aid asthma diagnosis and management. Offline measurement techniques demonstrate comparable results to online and are more practical in certain clinical settings, particularly in young children who struggle with online measurements. International guidelines (ATS/ERS 2005) recommend targets for pressure and flow but not for the number of breaths per sample. Young children may take multiple breaths to complete offline reservoir filling, but whether this influences results due to contamination of the sample with ambient gas from equipment deadspace has not been assessed. Our aims were to investigate the magnitude of such effects and form a predictive equation for how increasing breath number dilutes offline measurements. <h3>Methods</h3> A prospective observational study was undertaken recruiting 20 volunteers aged 18–42 years (13 female). FeNO was measured online (Medisoft Exp’Air 2001) and offline following exhalation into a one-litre Tedlar bag using one, five or ten breaths to complete bag filling. Airway pressure was maintained above 5 cmH<sub>2</sub>O to ensure velum closure and expiratory flow at 50 (+/-5) ml/s. Predicted percentages of offline FeNO relative to online were calculated by: 100 – ((equipment deadspace (53 mls) x no of breaths)/bag volume) *100 Predicted offline values were compared to measured. <h3>Results</h3> The median (IQR) online FeNO in parts per billion (ppb) was 24 (14–30) ppb. There was a significant reduction in offline FeNO with increasing breath number (p &lt; 0.0001). Median (IQR) offline FeNO of 1-breath (22 (15–32) ppb) was not significantly different to online FeNO (p = 0.51). Median (IQR) offline FeNO of 5-breaths was 16 (7–22) ppb and 10-breaths 13 (5–19) ppb, lower than online FeNO (p = 0.03 and p = 0.005 respectively). The predicted offline values are compared with measured offline values, expressed as a percentage of online, in Table 1. <h3>Conclusion</h3> One-breath offline collection methods had comparable results to online FeNO measurements, but higher breath number resulted in lower values likely due to sample contamination with ambient gas and dilution of nitric oxide. These results suggest that multiple breaths should not be used to obtain an offline FeNO result.
Diabetes drugs show no significant difference in risk of death
Authors: Jacqui Wise
Journal: BMJ (2016)

The nine available classes of glucose lowering drugs showed no significant difference in terms of cardiovascular or all cause mortality, in a systematic review with network meta-analysis published in JAMA . The review included 301 clinical trials and nearly 120 000 adults with type 2 diabetes.1

A large number of glucose lowering drug classes are now approved for type 2 diabetes, including metformin, insulins, sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) …
Abstract 1138: Prognostic impact of BRAF-V600E expression and correlation with mutation status in cutaneous melanoma
Authors: Emilia Hugdahl, May Britt Kalvenes, Hanne Puntervill, Rita Ladstein, Lars A. Akslen
Journal: Cancer Research (2016)

Abstract Around 50% of primary cutaneous melanomas harbour BRAF mutations, but their prognostic impact has not been clear. Recently, a BRAF-V600E mutation-specific antibody has become available for immunohistochemistry (IHC). Here, we investigated for the first time the prognostic impact of BRAF-V600E protein expression in primary melanoma. In a patient series of 248 nodular melanomas, BRAF-V600E and total BRAF expression were assessed by IHC using tissue microarray sections of paraffin-embedded archival tissue. Mutation status was assessed by real-time PCR. Positive BRAF-V600E expression was present in 86 (35%) of the cases and was significantly associated with increased tumor thickness, presence of tumor ulceration and reduced survival. Further, BRAF-V600E expression was an independent prognostic factor by multivariate survival analysis. There was 88% concordance between BRAF-V600E expression and mutation status. Our findings indicate that BRAF-V600E expression is a novel prognostic marker in primary melanoma. Citation Format: Emilia Hugdahl, May Britt Kalvenes, Hanne Puntervill, Rita Ladstein, Lars A. Akslen. Prognostic impact of BRAF-V600E expression and correlation with mutation status in cutaneous melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1138.
Hypoxia-dependent regulation of inflammatory pathways in immune cells
Authors: Cormac T. Taylor, Glen Doherty, Padraic G. Fallon, Eoin P. Cummins
Journal: Journal of Clinical Investigation (2016)

Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-κB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia-dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease.
Abstract 564: Combination therapy of chemokine receptor inhibition plus PD-L1 blockade potentiates antitumor effects in a murine model of breast cancer
Authors: Heiyoun Jung, Linda Ertl, Karen Ebsworth, Christine Janson, Penglie Zhang, Punna Sreenivas, Thomas Schall, Israel Charo
Journal: Cancer Research (2016)

Abstract Trafficking and expansion of myeloid derived suppressor cells (MDSCs) plays a major role in the immune suppression of tumors. MDSCs express chemokine receptors which likely mediate their recruitment to the tumor microenvironment. Suppression of T cells is also mediated by the interaction of programmed death-1 (PD-1) and its ligands which are abundantly expressed in cancer cells and immune infiltrates, including MDSCs. Here, we show that targeting both pathways through administration of a small molecule chemokine receptor antagonist (CCX9588, which blocks CCR1) and a PD-L1 monoclonal antibody (mAb) significantly reduced tumor burden in mice who received orthotopic transplants of 4T1 cells, a cell line used to model triple negative breast cancer. Primary tumor growth was modestly reduced by either agent (PD-L1 mAb or CCR1 inhibitor) alone, but the combination of CCR1 inhibitor plus PD-L1 mAb resulted in significantly reduced tumor progression as compared to either of the single agents. Furthermore, lung metastasis was also significantly reduced by CCR1 antagonist and combination treatment. Orthotropic 4T1 cell engraftment induced robust expansion of CD11b+Ly6Ghi Ly6Chi MDSCs, a subpopulation of which express CCR1. Analysis of the tumor infiltrating cells revealed that CCX9588 significantly reduced the number of MDSCs and increased CD8 T cells infiltration in primary tumors, suggesting that CCR1 blockade of MDSC trafficking in combination with PD-L1 mAb translates into reduced tumor burden, possibly through increased CD8 T cell response against the tumor. Analysis of human breast cancer patient samples from The Cancer Genome Atlas (TCGA) database revealed that the CCR1 ligands, MCP-7 (CCL7) and RANTES (CCL5) are present at significantly higher levels in breast cancers as compared to normal breast tissue. Interestingly, ligands for CCR1 and PD-1 are significantly higher in triple negative breast cancer samples than in the other breast cancer subtypes. These data are the first to show that CCR1 chemokine receptor antagonists can act synergistically with PDL-1 inhibitors, and suggest a novel approach for potentiating the activity of immune cell checkpoint inhibitors in one of the most aggressive forms of breast cancer. Citation Format: Heiyoun Jung, Linda Ertl, Karen Ebsworth, Christine Janson, Penglie Zhang, Punna Sreenivas, Thomas Schall, Israel Charo. Combination therapy of chemokine receptor inhibition plus PD-L1 blockade potentiates antitumor effects in a murine model of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 564.
Abstract 4420: Heparan sulfate proteoglycans mediate SW13 oncogenic potential and response to granulin
Authors: McKale Davis, Elizabeth Hull
Journal: Cancer Research (2016)

Abstract The SW13 adrenal adenocarcinoma cell line exists as two epigenetically and phenotypically distinct subtypes. One is a highly proliferative epithelial subtype lacking the expression of key tumor suppressor proteins, Brm and Brg1, the intermediate filament protein vimentin, and the cell cycle check point protein CD44 (SW13-), while the other is a slow growing, mesenchymal-like subtype which expresses all of these proteins (SW13+). Evidence strongly suggests that subtype determination is epigenetic in nature, as HDAC inhibitors can induce an SW13- to SW13+ subtype switch, but the cellular and environmental factors that regulate cellular phenotype have yet to be characterized. We performed a comprehensive microarray analysis and identified heparan sulfate proteoglycan (HSPG) binding as a primary pathway affected between these two subtypes. HSPGs are glycoproteins present in the extracellular matrix that can have tumor-promoting or tumor-suppressing activities depending on the number and sulfation status of attached sugar chains known as glycosaminoglycans (GAGs). Quantitative RT-PCR was then used to confirm the increased expression of the HSPGs, serglycin and glypican-3, as well as the HSPG-binding growth factors granulin and fibroblast growth factors-1 and -2 in SW13+ cells. Furthermore, HDAC inhibition was also shown to increase the expression of these genes in a time-dependent manner. As granulin over-production is associated with cancer progression in a number of human cancers, we were interested in examining the role of this HSPG binding growth factor further. A pro-granulin ELISA showed that SW13+ cells secrete significantly more granulin than SW13- cells. Intriguingly however, treatment with exogenous granulin increases growth rates in the already highly proliferative SW13- subtype, but had no effect on SW13+ growth. We hypothesized that the pleiotropic response of SW13 cells to growth factor treatment may be the result of HSPG post-translational modifications, so we assessed total GAG sulfation was by dimethylmethylene blue assay, and indeed the SW13+ cells were found to have significantly higher levels of total GAG sulfation than SW13- cells. Thus, transcriptional and post-translational modifications of HSPGs may contribute to SW13 phenotype control, and ultimately may affect tumorigenesis. Citation Format: McKale Davis, Elizabeth Hull. Heparan sulfate proteoglycans mediate SW13 oncogenic potential and response to granulin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4420.
Serum procalcitonin can guide antibiotic administration for respiratory tract infections in primary care
Authors: Alexander G Mathioudakis, Victoria Chatzimavridou-Grigoriadou, Efstathia Evangelopoulou, George A Mathioudakis
Journal: BMJ (2016)

In a large cohort study, Gulliford and colleagues assessed the safety of reduced antibiotic prescribing for self limiting respiratory tract infections (RTIs) in primary care and recommended avoiding antibiotics in patients lacking clinical features suggestive of bacterial infections.1

However, the study demonstrated an 11% increase in risk of pneumonia associated with …
Abstract 1636: The role of the ROR receptors in ovarian cancer progression and chemoresistance
Authors: Claire E. Henry, Estelle Llamosas, Neville F. Hacker, Viola Heinzelmann-Schwarz, Caroline E. Ford
Journal: Cancer Research (2016)

Abstract BACKGROUND: Despite recent advances in our understanding of the underlying genetic profile of distinct subtypes of ovarian cancer, overall survival remains poor. This is partly due to the absence of available targeted therapies, widespread metastatic disease at diagnosis, and the development of resistance to chemotherapy in the majority of patients. Patients with a more mesenchymal gene signature have a shorter overall survival, and are more likely to recur and develop chemoresistance. These patients also have upregulated Wnt signalling, a key developmental pathway associated with metastasis, epithelial to mesenchymal transition (EMT) and chemoresistance. AIM: To investigate the role of the novel Wnt receptors ROR1 and ROR2 in ovarian cancer progression and chemoresistance, to determine their feasibility as therapeutic targets. METHOD: Expression of ROR1 and ROR2 was measured in patient tumour (primary and metastatic) samples and ascites fluid taken at multiple time points during disease progression. In addition, the A2780 and cisplatin resistant A2780-cis cell lines were used as a model of ovarian cancer chemoresistance. Profiling of EMT and Wnt genes was undertaken alongside cell proliferation, adhesion, migration, invasion and viability assays after modulation of ROR1 and ROR2. RESULTS: Expression of ROR1 and ROR2 is increased in ovarian cancer patients compared to benign fallopian tube and ovarian surface epithelium. High ROR1 expression is associated with type I epithelial ovarian cancer, and high ROR2 expression with aggressive type II epithelial ovarian cancer. Expression of each receptor fluctuates in paired metastatic samples compared to primary tumours, depending on the site of metastasis and recurrence time. Both receptors are increased in a model of cisplatin resistant ovarian cancer, and when silenced, cell migration and invasion is significantly inhibited. Silencing ROR1 and ROR2 also sensitizes resistant cells to cisplatin, and is associated with a shift away from a mesenchymal phenotype. CONCLUSION: Upregulation of ROR1 and ROR2 drives migration, invasion and chemoresistance through regulating EMT via β-catenin independent Wnt signalling. As cell surface regulators of β-catenin independent Wnt signalling, the ROR receptors represent potential therapeutic targets for chemoresistant cancers. Citation Format: Claire E. Henry, Estelle Llamosas, Neville F. Hacker, Viola Heinzelmann-Schwarz, Caroline E. Ford. The role of the ROR receptors in ovarian cancer progression and chemoresistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1636.
Abstract 1: Opposing Roles for Endoglin and Soluble Endoglin in Cardiac Remodeling and Heart Failure
Authors: Navin K Kapur, Szuhuei Wilson, Adil A Yunis, Corey Baker, Mark J Aronovitz, Qing Lu, Ananth Karumanchi, Michelle Letarte, David A Kass, Michael E Mendelsohn, Richard H Karas
Journal: Circulation Research (2011)

Transforming growth factor beta-1 (TGFb1) promotes cardiac fibrosis. The transmembrane co-receptor Endoglin (Eng; CD105) facilitates TGFb1 signaling via SMAD effector proteins. In contrast, a circulating form of soluble endoglin (sEng) inhibits TGFb1 signaling in vascular endothelium. We recently reported that increased sEng levels in human serum correlate with clinical indices of heart failure severity. Therefore, we tested the hypothesis that Eng and sEng mediate opposing effects on cardiac fibrosis in heart failure. In male, wild-type mice (WT), Eng expression increased in the left ventricle (LV) after 2, 4, and 10 weeks of thoracic aortic constriction (TAC) accompanied by progressive LV fibrosis and hypertrophy. In contrast to WT mice, Eng haploinsufficient (Eng +/− ) mice had preserved LV function (FS%: 78±4 vs 22±16, Eng +/− vs WT, p&lt;0.01) and improved survival [88%(7/8) vs 50%(4/8), Eng +/− vs WT, p&lt;0.001) after 10 weeks of TAC. Reduced LV fibrosis was observed in Eng +/− mice, while LV mass, cardiomyocyte hypertrophy, and calcineurin, SerCA, and bMHC expression were comparable to WT after TAC. Capillary density was significantly higher in Eng +/− mice after TAC compared to WT. LV SMAD phosphorylation (pSMAD) after TAC was studied and a preferential increase was observed in pSMAD1/5/8 expression in Eng +/− mice as compared to WT mice, in which cardiac pSmad2/3 expression was increased. The dependence of TGFb1 induced collagen synthesis on Eng expression was tested in vitro using human cardiac fibroblasts (hCF). Neutralizing antibodies and siRNA against Eng each attenuated TGFb1 induced collagen synthesis. In contrast, conditioned media from cells transfected with an adenovirus over-expressing sEng attenuated pSMAD2/3 expression and TGFb1 induced collagen synthesis in hCF. Treatment of hCF with recombinant sEng blocked TGFb1 induced collagen synthesis in a dose-dependent manner, confirming an inhibitory role of sEng. These results indicate that Eng and sEng mediate opposite effects on TGFb1 induced collagen synthesis. Reduced Eng expression uncouples cardiac fibrosis from cardiomyocyte hypertrophy, promotes SMAD1/5/8-signaling, and enhances angiogenesis. Eng may represent a novel therapeutic target to improve survival in heart failure.