tbuckley/cabot-search huggingface dataset:
The role of <i>TMPRSS6</i> and <i>HFE</i> variants in iron deficiency anemia in celiac disease
Authors: Luigia De Falco, Raffaella Tortora, Nicola Imperatore, Mariasole Bruno, Mario Capasso, Domenico Girelli, Annalisa Castagna, Nicola Caporaso, Achille Iolascon, Antonio Rispo
Journal: American Journal of Hematology (2017)

We investigated the role of HFE C282Y, H63D, and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1 year of gluten-free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D, and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P = .001), whereas H63D and A736V allele frequencies were similar among patients and controls (P = .92 and .84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to nonanemic group (2% and 0.5%, P = .04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P < .0001). CD patients with H63D mutation showed higher Hb, MCV, serum iron, and ferritin levels than subjects without HFE mutations. Decreased hepcidin values were observed in anemic compared to nonanemic subjects at follow-up (1.22 ± 1.14 vs 2.08 ± 2.15, P < .001). This study suggests a protective role of HFE in IDA CD patients and confirms the role of TMPRSS6 in predicting oral iron response modulating hepcidin action on iron absorption. Iron supplementation therapeutic management in CD could depend on TMPRSS6 genotype that could predict persistent IDA despite iron supplementation and GFD.
Radiotherapy-Activated Cancer-Associated Fibroblasts Promote Tumor Progression through Paracrine IGF1R Activation
Authors: Joke Tommelein, Elly De Vlieghere, Laurine Verset, Elodie Melsens, Justine Leenders, Benedicte Descamps, Annelies Debucquoy, Christian Vanhove, Patrick Pauwels, Christian P. Gespach, Anne Vral, Astrid De Boeck, Karin Haustermans, Pascal de Tullio, Wim Ceelen, Pieter Demetter, Tom Boterberg, Marc Bracke, Olivier De Wever
Journal: Cancer Research (2017)

Abstract Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival. Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659–70. ©2017 AACR.
Ectopic expansion of engineered human liver tissue seeds using mature cell populations
Authors: Raymond D. Hickey, Willscott E. Naugler
Journal: Hepatology (2017)

1Department of Surgery, Department of Molecular MedicineMayo ClinicRochesterMN 2Department of Medicine, Division of Gastroenterology and Hepatology, Oregon Health & Science Center, Portland, OR; Oregon Stem Cell CenterOregon Health & Science CenterPortlandOR
DNA methylation profile, histone modification code and CTCF content within aberrantly silenced vs. transcriptionally active human von Hippel-Lindau disease (VHL) Locus.
Authors: Igor A. Kuzmin, Laura Geil, Dmitri I. Loukinov, Tiziana Cavinato, Lauren Gibson, Victor V. Lobanenkov, Michael I. Lerman
Journal: Cancer Research (2004)

3628  Kruppel-like transcription factors have been linked to cell growth regulation and tumorigenesis in a number of systems. In the intestinal epithelium, expression of KLF5 (IKLF/BTEB2) is limited to proliferating crypt cells, indicating a growth promoting role. However, we have found that, while KLF5 is growth promoting in non-transformed intestinal epithelial cells, it is growth inhibitory in colon tumor-derived and transformed cells, indicating that this factor has both growth promoting and tumor suppressive properties in the intestine. This idea is consistent with our previous observation that KLF5 mRNA is downregulated in APCmin mouse and human familial adenomatous polyposis adenomas. A tumor suppressive role for KLF5 is likely to be common in epithelial cancers since this factor has been implicated as a tumor suppressor in prostate and breast, where its gene locus at chromosome 13q21 is commonly deleted. While deletion of this chromosome region is found in multiple cancer types, it is not observed in colon cancer, pointing to other mechanisms for downregulation of KLF5 in intestinal tumors. One mechanism involves downregulation of KLF5 mRNA which correlates with enhanced cell growth and tumorigenicity in the HCT116/HCT116B syngeneic colon cancer cell lines. However, analysis of other colon tumor cell lines and a syngeneic model of intestinal tumor progression indicated that loss of mRNA could not fully account for the loss of KLF5 protein, pointing to post-translational mechanisms of downregulation during tumor progression. Use of the proteasome inhibitor, MG132 indicated that this involves enhanced turnover of the protein. High levels of proteasome-dependent downregulation were seen in all human colon cancer cells tested, but not in non-transformed intestinal epithelial cells, indicating that it is a common mechanism for KLF5 loss during colon cancer progression. The utilization of multiple mechanisms for downregulation of KLF5 emphasizes the importance of reduced expression of this factor in intestinal tumorigenesis and points to potential targets for therapy. This work was supported by the Roswell Park Alliance foundation and the Roswell Park CCSG core grant CA16056.
γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program
Authors: Ryunosuke Muro, Takeshi Nitta, Kenta Nakano, Tadashi Okamura, Hiroshi Takayanagi, Harumi Suzuki
Journal: Journal of Clinical Investigation (2017)

γδT cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17–producing γδT (γδT17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of αβT cells, failed to functionally substitute for Syk in the development of γδT17. Syk induced the activation of the PI3K/Akt pathway upon γδTCR stimulation. Mice deficient in PI3K signaling exhibited a complete loss of γδT17, without impaired development of IFN-γ–producing γδT cells. Moreover, γδT17-dependent skin inflammation was ameliorated in mice deficient in RhoH, an adaptor known to recruit Syk. Thus, we deciphered lineage-specific TCR signaling and identified the Syk/PI3K pathway as a critical determinant of proinflammatory γδT cell differentiation.
NHS publishes estimates of avoidable deaths in hospitals
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The NHS will publish estimates of “avoidable” deaths in hospitals as part of a drive by the health secretary, Jeremy Hunt, to improve patient safety by delivering greater transparency.

NHS trusts will publish their own quarterly estimates of the number of deaths in their organisation resulting from problems in care. The government said that 171 of the 223 NHS trusts in England had released their first estimates or would do so by the end of December.

The data will not be comparable and will not be collated centrally, as they rely on self reporting from trusts. But Hunt said that their publication would enable trusts to focus on learning …
Endocannabinoid Actions on Cortical Terminals Orchestrate Local Modulation of Dopamine Release in the Nucleus Accumbens
Authors: Yolanda Mateo, Kari A. Johnson, Dan P. Covey, Brady K. Atwood, Hui-Ling Wang, Shiliang Zhang, Iness Gildish, Roger Cachope, Luigi Bellocchio, Manuel Guzmán, Marisela Morales, Joseph F. Cheer, David M. Lovinger
Journal: Neuron (2017)
Abstract 12208: Microrna-181b Inhibits Thrombin-mediated Activation of Endothelial Cells and Arterial Thrombosis by Targeting Card10 <i>(Best of Basic Science Abstract)</i>
Authors: Xinghui Sun, Jibin Lin, Shaolin He, Gregory Franck, AKM Wara, Basak Icli, Dazhu Li, Mark W Feinberg
Journal: Circulation (2015)

Objective: Thrombogenic and inflammatory mediators such as thrombin induce NF-kB-mediated EC activation and dysfunction, which contribute to the pathogenesis of arterial thrombosis. The role of the anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Methods and Results: It has been demonstrated that miR-181b inhibits downstream NF-kB signaling in response to TNF-a. Herein, we reveal that miR-181b can inhibit upstream NF-kB signaling uniquely in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-kB signaling demonstrated by the reduction of phospho-IKK-b, -IkB-a, and p65 nuclear translocation in ECs. MiR-181b also reduced the expression of NF-kB target genes VCAM-1, ICAM-1, E-selectin, PAI-1, and tissue factor. Mechanistically, miR-181b targets Card10, an adaptor protein that participates in the activation of the IKK complex in response to signals transduced from G-protein coupled receptors such as PAR-1. MiR-181b reduced the expression of Card10 mRNA and protein, but not PAR-1. In addition, miR-181b inhibited Card10 3’-UTR luciferase reporter activity, and Argonaute-2 miRNP-IP studies revealed 4-fold enrichment of Card10 mRNA in the RNA-induced silencing complex in the presence of miR-181b, indicating that Card10 is a bona fide direct target. SiRNA-mediated knockdown of Card10 expression phenocopied miR-181b’s effects on NF-kB signaling and targets. Interestingly, knockdown of Card10 does not affect TNF-a-induced activation of NF-kB signaling and target gene expression, suggesting stimulus-specific regulation of NF-kB signaling and endothelial responses by miR-181b in ECs. Finally, in response to photochemical injury-induced arterial thrombosis, systemic delivery of miR-181b reduced thrombus formation by 73% in carotid arteries, and prolonged the time to occlusion by 1.6-fold. Conclusions: MiR-181b is an important regulator of thrombin-induced EC activation and arterial thrombosis. These studies highlight the relevance of miRNA-dependent targets in response to ligand-specific signaling in ECs. Delivery of miR-181b or Card10 inhibition may represent a new therapeutic approach to reduce arterial thrombosis by improving vascular EC function.
TGF-β signalling attenuates tumour response to PD-L1 checkpoint blockade by contributing to retention of T cells in the peritumoural stroma
Authors: S. Mariathasan, S.J. Turley, D. Nickles, A. Castiglioni, K. Yuen, Y. Wang, K. Edward E, H. Koeppen, J.L. Astarita, R. Cubas, S. Jhunjhunwala, Y. Yang, Y. Şenbabaoğlu, M. van der Heijden, Y. Loriot, I. Mellman, D. Chen, P. Hegde, R. Bourgon, T. Powles
Journal: Annals of Oncology (2017)
Une approche multiple pour comprendre la résurgence et l’évolution de la syphilis en Europe de l’ouest
Authors: K Fenton
Journal: Eurosurveillance (2004)

Pres de huit ans apres l’epidemie de syphilis survenue a Bristol, Angleterre [1], une vague d’epidemies a touche la plupart des pays de l’Europe de l’ouest [2]. Ce numero d’Eurosurveillance fait le point sur la recente resurgence et l’evolution de la syphilis dans sept pays europeens permettant d’une part une analyse crtique de notre comprehension de son epidemiologie, et d’autre part de proposer des solutions pour reorienter les interventions dans un futur proche [3-9]. Ces articles fournissent egalement un eclairage, a plusieurs niveaux et selon de multiples facteurs, sur les causes de ces epidemies de syphilis [10], et sur les mesures de prevention susceptibles de faire evoluer cette situation.
Single-cell DNA methylome sequencing of human preimplantation embryos
Authors: Ping Zhu, Hongshan Guo, Yixin Ren, Yu Hou, Ji Dong, Rong Li, Ying Lian, Xiaoying Fan, Boqiang Hu, Yun Gao, Xiaoye Wang, Yuan Wei, Ping Liu, Jie Yan, Xiulian Ren, Peng Yuan, Yifeng Yuan, Zhiqiang Yan, Lu Wen, Liying Yan, Jie Qiao, Fuchou Tang
Journal: Nature Genetics (2017)
Statin-Induced Cancer Cell Death Can Be Mechanistically Uncoupled from Prenylation of RAS Family Proteins
Authors: Rosemary Yu, Joseph Longo, Jenna E. van Leeuwen, Peter J. Mullen, Wail Ba-Alawi, Benjamin Haibe-Kains, Linda Z. Penn
Journal: Cancer Research (2017)

The statin family of drugs preferentially triggers tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for protein prenylation cannot explain increased statin sensitivity. Although ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the antiproliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity data indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anticancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.Significance: The use of statins to target cancer cell EMT may be useful as a therapy to block cancer progression. Cancer Res; 78(5); 1347-57. ©2017 AACR.
Regulation of low-density lipoprotein cholesterol by intestinal inflammation and the acute phase response
Authors: Karl E Herbert, Clett Erridge
Journal: Cardiovascular Research (2017)

Abstract Systemic inflammation, induced by disease or experimental intervention, is well established to result in elevated levels of circulating triglycerides, and reduced levels of high-density lipoprotein-cholesterol (HDL-C), in most mammalian species. However, the relationship between inflammation and low-density lipoprotein-cholesterol (LDL-C) concentrations is less clear. Most reports indicate that systemic inflammation, as observed during sepsis or following high dose experimental endotoxaemia, lowers total, and LDL-C in man. However, isolated reports have suggested that certain inflammatory conditions are associated with increased LDL-C. In this review, we summarize the emerging evidence that low-grade inflammation specifically of intestinal origin may be associated with increased serum LDL-C levels. Preliminary insights into potential mechanisms that may mediate these effects, including those connecting inflammation to trans-intestinal cholesterol efflux (TICE), are considered. We conclude that this evidence supports the potential downregulation of major mediators of TICE by inflammatory mediators in vitro and during intestinal inflammation in vivo. The TICE-inflammation axis therefore merits further study in terms of its potential to regulate serum LDL-C, and as a readily druggable target for hypercholesterolaemia.
Structural priming is not a Royal Road to representations
Authors: Antje S Meyer
Journal: Behavioral and Brain Sciences (2017)

Abstract Branigan &amp; Pickering (B&amp;P) propose that the structural priming paradigm is a Royal Road to linguistic representations of any kind, unobstructed by influences of psychological processes. In my view, however, they are too optimistic about the versatility of the paradigm and, more importantly, its ability to provide direct evidence about the nature of stored linguistic representations.
931. Specificity of gfa2 Derived Promoters in Adenoviral Vectors for Conditional Replication in Glioblastoma
Journal: Molecular Therapy (2003)

4602  The limited spread of non-replicating adenoviral vectors after injection into glial tumors may contribute to the lack of significant tumor reduction in many human gene therapy trials. To enhance viral spread in the tumor while keeping it restricted to the the brain, we designed conditionally replicating viruses in which the E1A gene is under the control of the promoter of the glia specific intermediate filament Glial Fibrillary Acidic Protein (GFAP). Because of the moderate activity of the normal GFAP promoter (gfa2) compared to the CMV promoter, we also evaluated constructs containing additional glial specific enhancers: gfa2(B)3 and gfa2(ABD)3 promoters. The gfa2 derived promoters followed by a beta galactosidase reporter gene were cloned into the pShuttle plasmid, in an orientation inverse to wildtype E1 expression . Viral vectors were produced according to the Ad-Easy protocol and viruses giving rise to blue plaques upon infection of U251 but not A549 cells were selected and grown to high titers. To check the specificity and effectivity of the promoter constructs, a panel of human cell lines (glial and non-glial) was infected with the gfa2 (triple enhancer) promoter-beta galactosidase vectors. An adenoviral vector containing a CMV-beta galactosidase cassette was included to estimate cell entry. Expression of beta galactosidase was evaluated both in situ using X-gal staining and quantitatively using ONPG staining. Results: Of 11 glial cell lines tested, four were positive for GFAP on a Western blot incubated with anti-GFAP (U251, SNB19, U373 and GOS3). Furthermore, of 12 primary cultures of glial tumors one was positive for GFAP using immunohistochemistry. This positive primary culture was also GFAP positive on Western and was added to the panel of cell lines, as were fourteen non glial cell lines (all GFAP negative on Western). Of the three gfa2 derived promoters, the gfa2 (ABD)3-LacZ construct gives rise to high beta galactosidase expression levels in the GFAP positive cell lines. Beta galactosidase expression levels in some GFAP positive lines are at a level comparable to the CMV promoter construct. The ONPG ratio of GFAP positive cell lines to GFAP negative cell lines (both glial and non-glial) is best for the gfa2-(B)3 promoter containing virus. Preliminary results indicate that conditionally replicating adenovirus in which E1A is regulated by the gfa2-B3 promoter replicate better on the GFAP positive U251 cell line than on the GFAP negative Hep2 cells. Conclusion: The gfa2 promoter constructs are highly active in an adenoviral context and have retained their specificity. Constructs for conditionally replicating viruses using these promoters have been prepared and conditionally replicating virus is being produced.
Prognostic Significance of Circumferential Resection Margin in Patients Receiving Oesophagectomy for Oesophageal Cancer
Authors: L.M. Quinn, A.C. Hollis, J. Hodson, M.A. Elshafie, M.T. Hallissey, J.L. Whiting, E.A. Griffiths
Journal: International Journal of Surgery (2017)
Eating disorders in children and young people
Authors: Helen Bould, Claudia Newbegin, Anne Stewart, Alan Stein, Mina Fazel
Journal: BMJ (2017)

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Acute Malnutrition Among Children, Mortality, and Humanitarian Interventions in Conflict-Affected Regions — Nigeria, October 2016–March 2017
Authors: Eva Leidman, Erin Tromble, Adamu Yermina, Robert Johnston, Chris Isokpunwu, Adeyemi Adeniran, Assaye Bulti
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

A public health emergency was declared by the Nigerian Federal Ministry of Health in northeastern Nigeria in June 2016 and escalated by the United Nations to a Level 3 Emergency in August 2016, after confirmation of wild poliovirus and measles outbreaks and evidence that prevalence of acute malnutrition exceeded emergency thresholds in areas newly liberated from Boko Haram control (1,2). To monitor rates of mortality, acute malnutrition among children, infectious disease morbidity, and humanitarian interventions after the emergency declaration, a series of cross-sectional household surveys were conducted in fall 2016 and winter 2017 in the northeastern states of Borno and Yobe using a cluster methodology. All-cause mortality among all age groups (crude mortality) and among children aged <5 years (under-five mortality) were above emergency thresholds in 2017 and significantly increased from 2016, despite evidence of increased preventive public health interventions, including measles vaccination. Access to treatment for common childhood illnesses remained very low, as evidenced by reports of fewer than one in six children in areas outside Borno's capital receiving any care for diarrhea. The data from these surveys provide evidence of excessively high mortality (particularly among children), highlight the impact of ongoing violence, and underscore the need for humanitarian efforts to scale up access to treatment services in conflict-affected areas.