tbuckley/cabot-search huggingface dataset:
Authors’ response to Young and Hopkins: vitamin D and lung function
Authors: Shoaib Afzal, Peter Lange, Stig E Bojesen, Jacob J Freiberg, Børge G Nordestgaard
Journal: Thorax (2014)

We agree with Dr RP Young and Ms RJ Hopkins that our analyses may suggest a threshold effect.However, we believe that more studies are needed before we firmly can assume a threshold effect.It is true that that the association between vitamin D level and FEV 1 % predicted was mirrored by a corresponding association between vitamin D and FVC% predicted.Therefore in our main analysis, the vitamin D level was not significantly associated with the FEV 1 /FVC ratio.This general reduction of lung volumes in
Gene expression profiling reveals potential prognostic biomarkers associated with the progression of heart failure
Authors: Agata Maciejak, Marek Kiliszek, Marcin Michalak, Dorota Tulacz, Grzegorz Opolski, Krzysztof Matlak, Slawomir Dobrzycki, Agnieszka Segiet, Monika Gora, Beata Burzynska
Journal: Genome Medicine (2015)
Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial
Authors: Jordi Bruix, Tadatoshi Takayama, Vincenzo Mazzaferro, Gar-Yang Chau, Jiamei Yang, Masatoshi Kudo, Jianqiang Cai, Ronnie T Poon, Kwang-Hyub Han, Won Young Tak, Han Chu Lee, Tianqiang Song, Sasan Roayaie, Luigi Bolondi, Kwan Sik Lee, Masatoshi Makuuchi, Fabricio Souza, Marie-Aude Le Berre, Gerold Meinhardt, Josep M Llovet
Journal: The Lancet Oncology (2015)
Pediatric high-grade glioma: identification of poly(ADP-ribose) polymerase as a potential therapeutic target
Authors: S. J. Smith, A. Long, J. H. Barrow, D. C. Macarthur, B. Coyle, R. G. Grundy
Journal: Neuro-Oncology (2011)

Pediatric high-grade gliomas (World Health Organization grades III and IV astrocytomas) remain tumors with a very poor prognosis for which novel therapeutic strategies are needed. Poly(ADP-ribose) polymerase (PARP) is known to have multiple functions in tumors, including single-strand DNA repair and induction of caspase-independent apoptosis. PARP has been suggested as a therapeutic target in adult malignancies, and this study examines whether it could also be a potential target in pediatric high-grade glioma. Tissue microarrays containing 150 formalin-fixed pediatric high-grade gliomas were examined by immunohistochemistry for levels of PARP and expression of apoptosis inducing factor (AIF). Full retrospective clinical and survival data were available for this cohort. Stratification and statistical analysis was performed to assess the effect of PARP status on prognosis. The level of PARP immunopositivity had a statistically significant inverse correlation (P = .019) with survival in supratentorial pediatric high-grade glioma. AIF staining was notable for its absence in the majority of tumors but with moderate levels of expression in surrounding normal brain. PARP is expressed at high levels in many pediatric high-grade gliomas, and in these tumors, the ability of PARP to activate AIF appears to have been lost. PARP may therefore represent a promising therapeutic target for these lesions and warrants evaluation in clinical trials.
Polycomb-Group Oncogenes EZH2, BMI1, and RING1 Are Overexpressed in Prostate Cancer With Adverse Pathologic and Clinical Features
Authors: Geert J.L.H. van Leenders, Danny Dukers, Daphne Hessels, Susan W.M. van den Kieboom, Christina A. Hulsbergen, J. Alfred Witjes, Arie P. Otte, Chris J. Meijer, Frank M. Raaphorst
Journal: European Urology (2006)
Early Clinical Results After Stentless Mitral Valve Implantation and Comparison With Conventional Valve Repair or Replacement
Authors: T. Walther, C. Walther, V. Falk, A. Diegeler, R. Krakor, J. Schneider, R. Autschbach, F. W. Mohr
Journal: Circulation (1999)

A new quadricusp stentless mitral bioprosthetic valve (QMV) is evaluated and compared with current standards.Since August 1997, 67 patients were prospectively evaluated: 23 patients received a QMV, 23 had mitral valve repair (MVR), and 21 received conventional mitral valve replacement (MVP). Patient age was 69+/-8, 64+/-10, and 62+/-9 years for QMV, MVR, and MVP treatment, respectively. The underlying pathology was mitral stenosis, incompetence, and mixed disease in a corresponding 8, 9, and 6 patients for QMV, 1, 22, and 0 patients for MVR, and 2, 12, and 7 patients for MVP. The papillary muscles were sufficient in all QMV cases to suspend the valve. Cross-clamp time was 59+/-19 minutes for QMV implantation. In-hospital mortality for QMV, MVR, and MVP was 1, 0, and 0 patients, respectively, and thoracotomy had to be performed again in 1, 1, and 2 patients, respectively (these outcomes were not valve related). At baseline transthoracic echocardiography, respective maximum flow velocities were 1.6, 1.4, and 1.7 m/s, and valve orifice area was 2.6, 3.5, and 3.4 cm(2). Mild transvalvular reflux was seen in 8, 7, and 2 patients; moderate reflux, in 1, 1, and 1 patients. Left ventricular ejection fraction was 52%, 54%, and 51% in the respective treatment groups. At follow-up, hemodynamic parameters had further improved in all groups.One year after clinical implantation, the QMV appears to function well and has no additional risks compared with MVR or MVP. The subvalvular apparatus is preserved by suspending the QMV at the papillary muscles; this arrangement is hemodynamically advantageous. Echocardiography reveals an excellent valve performance that resembles native mitral valve morphology and hemodynamic function. The QMV is a promising alternative for biological mitral valve replacement.
Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System
Authors: Robert Feil, Suzanne M. Lohmann, Hugo de Jonge, Ulrich Walter, Franz Hofmann
Journal: Circulation Research (2003)

Signaling cascades initiated by nitric oxide (NO) and natriuretic peptides (NPs) play an important role in the maintenance of cardiovascular homeostasis. It is currently accepted that many effects of these endogenous signaling molecules are mediated via stimulation of guanylyl cyclases and intracellular production of the second messenger cGMP. Indeed, cGMP-elevating drugs like glyceryl trinitrate have been used for more than 100 years to treat cardiovascular diseases. However, the molecular mechanisms of NO/NP signaling downstream of cGMP are not completely understood. Recent in vitro and in vivo evidence identifies cGMP-dependent protein kinases (cGKs) as major mediators of cGMP signaling in the cardiovascular system. In particular, the analysis of conventional and conditional knockout mice indicates that cGKs are critically involved in regulating vascular remodeling and thrombosis. Thus, cGKs may represent novel drug targets for the treatment of human cardiovascular disorders.
MECHANISMS OF PHAGOCYTOSIS IN MACROPHAGES
Authors: Alan Aderem, David M. Underhill
Journal: Annual Review of Immunology (1999)

▪ Abstract Phagocytosis of pathogens by macrophages initiates the innate immune response, which in turn orchestrates the adaptive response. In order to discriminate between infectious agents and self, macrophages have evolved a restricted number of phagocytic receptors, like the mannose receptor, that recognize conserved motifs on pathogens. Pathogens are also phagocytosed by complement receptors after relatively nonspecific opsonization with complement and by Fc receptors after specific opsonization with antibodies. All these receptors induce rearrangements in the actin cytoskeleton that lead to the internalization of the particle. However, important differences in the molecular mechanisms underlying phagocytosis by different receptors are now being appreciated. These include differences in the cytoskeletal elements that mediate ingestion, differences in vacuole maturation, and differences in inflammatory responses. Infectious agents, such as M. tuberculosis, Legionella pneumophila, and Salmonella typhimurium, enter macrophages via heterogeneous pathways and modify vacuolar maturation in a manner that favors their survival. Macrophages also play an important role in the recognition and clearance of apoptotic cells; a notable feature of this process is the absence of an inflammatory response.
Regulation of muscle transcription by the MyoD family. The heart of the matter.
Authors: E N Olson
Journal: Circulation Research (1993)

The two striated muscle cell types, skeletal and cardiac muscle, express overlapping sets of muscle-specific genes. Activation of muscle-specific transcription in skeletal muscle is controlled by the MyoD family of regulatory factors, which are expressed exclusively in skeletal muscle. Members of the MyoD family share homology within a basic helix-loop-helix (HLH) motif that mediates DNA binding and dimerization and form heterodimers with widely expressed HLH proteins, referred to as E proteins. Although many of the genes that are regulated by members of the MyoD family are also expressed in cardiac muscle, known members of the MyoD family have never been detected in cardiac muscle, suggesting that cardiac myocytes either express unique cell type-specific HLH proteins or rely on a distinct regulatory strategy for activation of cardiac muscle transcription. This review will summarize current knowledge of the mechanisms through which the MyoD family activates skeletal muscle transcription and will consider potential mechanisms that may regulate gene expression in the heart.
Heat injury in youth sport: Table 1
Authors: S W Marshall
Journal: British Journal of Sports Medicine (2009)

Heat injury is a potentially lethal condition that is considered to be completely preventable. Fatal heat injury is relatively rare (0.20 per 100 000 player-seasons in US high school football) and there are very limited data on non-fatal incidence. Expert recommendations for prevention include gradual acclimatisation of youth athletes to hot conditions, reductions in activity in hot and humid conditions, wearing light and light-coloured clothing, careful monitoring of athletes for signs of heat injury to facilitate immediate detection, having the resources to immediately and rapidly cool affected athletes, and education of athletes, care givers, and coaches about heat injury. Although a base of observational case data, physiological information, and expert opinion exists, the science surrounding this field is devoid of health communication and health behaviour research, and there is a pressing need for analytical studies to evaluate intervention programmes and/or identify new risk factors. There is also a need for ongoing data collection on heat injury incidence and on the knowledge, attitudes and behaviours towards heat injury among youth athletes, their care givers and their coaches.
The Turnover of Cholesterol in Human Atherosclerotic Arteries
Authors: S. N. Jagannathan, W. E. Connor, W. H. Baker, A. K. Bhattacharyya
Journal: Journal of Clinical Investigation (1974)

The equilibration of cholesterol between plasma and atherosclerotic arteries was studied in 13 patients with obstructive atherosclerosis 2-96 days after the intravenous and/or oral administration of isotopic cholesterol. Arterial specimens were obtained in 12 patients during surgery for arterial reconstruction and in a 13th patient at autopsy. Equilibration was calculated as the specific radioactivity of cholesterol in the arterial tissue relative to that in the plasma (percent).
Uncorrected Nucleotide Bias in mtDNA Can Mimic the Effects of Positive Darwinian Selection
Authors: Mihai Albu, Xiang Jia Min, Donal Hickey, Brian Golding
Journal: Molecular Biology and Evolution (2008)

The relative rates of nucleotide substitution at synonymous and nonsynonymous sites within protein-coding regions have been widely used to infer the action of natural selection from comparative sequence data. It is known, however, that mutational and repair biases can affect rates of evolution at both synonymous and nonsynonymous sites. More importantly, it is also known that synonymous sites are particularly prone to the effects of nucleotide bias. This means that nucleotide biases may affect the calculated ratio of substitution rates at synonymous and nonsynonymous sites. Using a large data set of animal mitochondrial sequences, we demonstrate that this is, in fact, the case. Highly biased nucleotide sequences are characterized by significantly elevated dN/dS ratios, but only when the nucleotide frequencies are not taken into account. When the analysis is repeated taking the nucleotide frequencies at each codon position into account, such elevated ratios disappear. These results suggest that the recently reported differences in dN/dS ratios between vertebrate and invertebrate mitochondrial sequences could be explained by variations in mitochondrial nucleotide frequencies rather than the effects of positive Darwinian selection.
Left Atrial Appendage Closure With the Watchman Device in Patients With a Contraindication for Oral Anticoagulation
Authors: Vivek Y. Reddy, Sven Möbius-Winkler, Marc A. Miller, Petr Neuzil, Gerhard Schuler, Jens Wiebe, Peter Sick, Horst Sievert
Journal: Journal of the American College of Cardiology (2013)
European health survey ranks UK performance as “mediocre”
Authors: Rory Watson
Journal: BMJ (2006)

The United Kingdom's health service is good at information for patients but performs poorly overall, particularly on waiting lists, finds a new survey of all European Union member states and Switzerland.

The Euro health consumer index 2006, compiled by the Health Consumer Powerhouse in Brussels, ranks the UK 15th out of 26 countries.

The index assessed 28 indicators grouped in five categories: patients' rights and information; waiting time for treatment; outcomes measured by certain death rates; the range of services offered by health systems; and the availability of drugs.

France …
RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations
Authors: D. Hershkovitz, D. Bercovich, E. Sprecher, M. Lapidot
Journal: British Journal of Dermatology (2008)

Capillary malformation (CM), a common vascular abnormality, is often present among family members. Recently a rare form of hereditary vascular malformation termed capillary malformation-arteriovenous malformation (CM-AVM) was shown to be caused by heterozygous mutations in RASA1, encoding RAS p21 protein activator 1. CM-AVM is characterized by multiple, small CMs associated with either AVM or arteriovenous fistula (AVF) in affected individuals or at least one of their family members.The purpose of the study was to find out whether CMs in the absence of AVM/AVF are associated with RASA1 mutations.We assessed three families comprising 14 affected individuals with CMs. Linkage to the RASA1 locus was evaluated using microsatellite markers. The RASA1 gene was scrutinized for pathogenic mutations using denaturing high-performance liquid chromatography screening and direct sequencing.AVM/AVF was identified in one of three affected families. CM without AVM/AVF was found to map in one large kindred to the RASA1 locus. Direct sequencing revealed novel heterozygous mutations segregating with CM in all three families. The mutations are predicted to result in premature termination of translation and RASA1 haplo-insufficiency.We have demonstrated that the spectrum of clinical manifestations due to mutations in RASA1 is wider than previously thought and also includes typical CMs not associated with AVM/AVF.
A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease
Authors: Maria Björkqvist, Edward J. Wild, Jenny Thiele, Aurelio Silvestroni, Ralph Andre, Nayana Lahiri, Elsa Raibon, Richard V. Lee, Caroline L. Benn, Denis Soulet, Anna Magnusson, Ben Woodman, Christian Landles, Mahmoud A. Pouladi, Michael R. Hayden, Azadeh Khalili-Shirazi, Mark W. Lowdell, Patrik Brundin, Gillian P. Bates, Blair R. Leavitt, Thomas Möller, Sarah J. Tabrizi
Journal: The Journal of Experimental Medicine (2008)

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
Shear Stress–Mediated Chromatin Remodeling Provides Molecular Basis for Flow-Dependent Regulation of Gene Expression
Authors: Barbara Illi, Simona Nanni, Alessandro Scopece, Antonella Farsetti, Paolo Biglioli, Maurizio C. Capogrossi, Carlo Gaetano
Journal: Circulation Research (2003)

Shear stress (SS), the tangential component of hemodynamic forces, modulates the expression of several genes in endothelial cells. However, no information is available about its effect on chromatin structure, which plays a key role in gene transcription. In this study, a link between SS and chromatin remodeling was established in human umbilical vein endothelial cells (HUVECs). HUVECs were exposed to SS of 10 dyne/cm2 per second, in the presence or absence of the histone deacetylase inhibitor trichostatin A, and assayed for histone H3 and histone H4 modifications. SS induced histone H3 serine phosphorylation at position 10 (S10) and lysine acetylation at position 14 (K14) but required trichostatin A to induce H3 phosphoacetylation and H4 acetylation. The phosphatidylinositol 3-kinase inhibitor wortmannin and the mitogen-activated protein kinase inhibitor PD98059 decreased SS-dependent histone H3 phosphorylation, without affecting its acetylation; the p38 inhibitor SB203580 reduced both H3 phosphorylation and acetylation, whereas the protein kinase A inhibitor PKI-tide reduced histone H3 acetylation. Remarkably, the abrogation of histone acetylation inhibited SS-dependent c-fos expression. SS also activated ribosomal S6 kinase-2 and mitogen- and stress-activated kinase-1 protein kinases and promoted the formation of a cAMP-responsive element-binding protein (CREB)/CREB-binding protein complex, providing the molecular basis for the increase in histone acetyltransferase activity observed in HUVECs exposed to SS. Finally, the effect of SS on chromatin remodeling was examined. In HUVECs exposed to SS, chromatin within c-fos and c-jun promoters was specifically immunoprecipitated by an antibody against acetylated histone H3 on K14. These results indicate that SS induces posttransduction modifications of histones; this is an early step toward the flow-dependent regulation of gene expression.
Epidermal HLA-DR and the enhancement of cutaneous reactivity to superantigenic toxins in psoriasis
Authors: Jeffrey B. Travers, Qutayba A. Hamid, David A. Norris, Christine Kuhn, Ralph C. Giorno, Patrick M. Schlievert, Evan R. Farmer, Donald Y.M. Leung
Journal: Journal of Clinical Investigation (1999)

Streptococcal and staphylococcal superantigens (SAg’s) have been implicated in the pathogenesis of inflammatory skin diseases, but the mechanisms by which these toxins act are unknown. The present study assessed the ability of nanogram quantities of topically applied purified toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin type B, and streptococcal pyrogenic enterotoxin types A and C to induce inflammatory reactions in clinically uninvolved skin of normal controls and subjects with psoriasis, atopic dermatitis, and lichen planus. These SAg’s triggered a significantly greater inflammatory skin response in psoriatics than in normal control subjects or in subjects with atopic dermatitis or lichen planus. Surprisingly, skin biopsies did not exhibit the T-cell receptor Vβ stimulatory properties predicted for SAg-induced skin reactions. By 6 hours after patch testing with SAg’s, TNF-α mRNA had increased in the epidermis (but not the dermis) in biopsies from psoriatics, compared with controls. Immunohistochemical studies revealed significantly higher HLA-DR expression in keratinocytes from psoriatics than from controls. However, a mutant TSST-1 protein that fails to bind HLA-DR did not elicit an inflammatory skin reaction. These results indicate that keratinocyte expression of HLA-DR enhances inflammatory skin responses to SAg’s. They may also account for previous studies failing to demonstrate selective expansion of T-cell receptor Vβs in psoriatics colonized with SAg-producing Staphylococcus aureus, and they identify a novel T cell–independent mechanism by which SAg’s contribute to the pathogenesis of inflammatory skin diseases.
Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling
Authors: Hatem A. Azim, Stefan Michiels, Philippe L. Bedard, Sandeep K. Singhal, Carmen Criscitiello, Michail Ignatiadis, Benjamin Haibe-Kains, Martine J. Piccart, Christos Sotiriou, Sherene Loi
Journal: Clinical Cancer Research (2012)

Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age.Patients were assigned to molecular subtypes [estrogen receptor (ER)(+)/HER2(-); HER2(+), ER(-)/HER2(-))] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model.A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER(-)/HER2(-) tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI = 1.10-1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER(+)/HER2(-) tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334).Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed.