tbuckley/cabot-search huggingface dataset:
Lung Cancer Prognosis Before and After Recurrence in a Population-Based Setting
Authors: Dario Consonni, Mariaelena Pierobon, Mitchell H. Gail, Maurizia Rubagotti, Melissa Rotunno, Alisa Goldstein, Lynn Goldin, Jay Lubin, Sholom Wacholder, Neil E. Caporaso, Pier Alberto Bertazzi, Margaret A. Tucker, Angela C. Pesatori, Maria Teresa Landi
Journal: JNCI Journal of the National Cancer Institute (2015)

Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management.We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non-surgically treated patients.Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non-small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients.This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events.
Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes
Authors: Bing He, Lwaki Ebarasi, Zhe Zhao, Jing Guo, Juha R.M. Ojala, Kjell Hultenby, Sarah De Val, Christer Betsholtz, Karl Tryggvason
Journal: Journal of the American Society of Nephrology (2014)

Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G0 transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lmx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Co-overexpression of the two genes potently induced endogenous nphs2 expression in zebrafish podocytes. We found that the NPHS2 promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of CCNC and MEIS2 was functionally analyzed in vivo. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions.
Adrenomedullin
Authors: Toshihiro Tsuruda, John C. Burnett
Journal: Circulation Research (2002)

ince 1993, with the discovery of adrenomedullin (AM) by Kitamura and coworkers, 1 we have gained many insights into the biology of this new peptide.3][4] While this ubiquitous AM distribution has prompted many investigators to clarify the role of AM, we advance the concept that the role of endogenous AM is especially important in cardiovascular and renal homeostasis.We now know that AM circulates in plasma and is present in organs and tissues with increases in AM activity in heart failure, hypertension, and renal dysfunction. 5,6][9][10][11][12] It is also accepted that AM has multiple functional properties linked to intracellular cyclic adenosine monophosphate (cAMP) elevation.Indeed, exogenous AM administration induces vasodilation and natriuresis with cAMP elevation, resulting in beneficial cardiorenal response in humans with heart failure. 13Although AM was originally found by monitoring cAMP elevation in platelets, 1 supporting a key role for cAMP, it has been reported that the nitric oxide (NO)-cGMP pathway also contributes to actions of AM. 14 In addition, a third pathway might mediate the AM signal.
Lipid lowering drugs in diabetes: Abstract was misleading
Authors: Mieke L van Driel, Pierre Chevalier
Journal: BMJ (2006)

EDITOR—The meta-analysis by Costa et al tackles clinically relevant issues by evaluating the effect of lipid lowering treatment in primary compared with secondary prevention and diabetic patients compared with non-diabetic patients.1 The authors' conclusions as reported in the abstract may have important implications for guide-line recommendations and marketing of …
A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation
Authors: Steffen Massberg, Korbinian Brand, Sabine Grüner, Sharon Page, Elke Müller, Iris Müller, Wolfgang Bergmeier, Thomas Richter, Michael Lorenz, Ildiko Konrad, Bernhard Nieswandt, Meinrad Gawaz
Journal: The Journal of Experimental Medicine (2002)

The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE−/− mice before the development of manifest atherosclerotic lesions. Platelet–endothelial cell interaction involved both platelet glycoprotein (GP)Ibα and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE−/− mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process.
OC-040 Regular nutritional blood test monitoring in children on home enteral tube feeding—is this necessary?
Authors: Y Lim, C Paxton, D Wilson
Journal: Gut (2012)

<h3>Introduction</h3> The use of home enteral tube feeding (HETF) in children with chronic illness is increasing. 6-monthly nutritional blood test monitoring (NBTM) while on HETF is recommended by BAPEN for adults; there is minimal evidence to inform guidelines regarding the biochemical monitoring of children on long-term HETF. <h3>Aim</h3> To provide evidence for or against the practice of 6-monthly NBTM in children receiving HETF. <h3>Methods</h3> We performed a retrospective review of all children age &lt;18 years, who were started on HETF from 01 January 2005 to 30 June 2010 by the nutrition support team (NST) in the Royal Hospital for Sick Children, Edinburgh. Patients who received &lt;2 months of HETF, or failed to receive more than one set of NBTM within the 1st year of starting HETF were excluded. Comparison of baseline NBTM results with results at 6–12 months after the start of HETF were made. Our NBTM profile includes full blood count, renal profile, bone profile, liver function tests, folate, ferritin, vitamin B<sub>12</sub>, fat-soluble vitamins and trace elements (Se, Cu, Zn). <h3>Results</h3> 42 children were included in the study; none developed refeeding syndrome. 37 (88%) had NBTM performed within 6 months of commencing HETF, 19 (45%) at 6 months after commencing HETF, and 21 (50%) at 1 year after commencing HETF. Significant abnormal parameters identified prior to commencing HETF included low Hb levels (32%), low ferritin levels (31%) and low folate levels (25%). Small groups of between 8% and 10% had low levels of trace elements (Se and Cu) and vitamin D levels. At 6 months and 1 year after start of HETF, there was a small increase of children with low Hb levels (40%) but an improvement in those with low ferritin (14%) and low folate levels (6%). 4% of the study had low vitamin D, and/or trace element (Zn, Cu, Se) levels. There were no toxic levels of vitamins or trace elements within 12 months of start of HETF. Trend comparison was performed in 25 children who had NBTM both before and within a year of commencing HETF. None of the children developed toxic levels of trace elements, one child developed high trace element levels (Se) and another continued to have high Se levels after starting HETF. None of the children developed toxic or high levels of fat soluble vitamins. There were no worryingly low micronutrient levels in any of the 25 children after the start of HETF. <h3>Conclusion</h3> Children on HETF in our study maintain and had improvement of their micronutrient status after start of HETF. Six monthly blood test monitoring may only be necessary in special circumstances (refeeding syndrome, frankly deficient or toxic micronutrient levels at start of HETF) and may not significantly enhance the overall nutritional monitoring and management of all children on HETF. <h3>Competing interests</h3> None declared.
Postrepolarization Refractoriness Versus Conduction Slowing Caused by Class I Antiarrhythmic Drugs
Authors: Paulus F. Kirchhof, C. Larissa Fabritz, Michael R. Franz
Journal: Circulation (1998)

Background —Conduction block may be both antiarrhythmic and proarrhythmic. Drug-induced postrepolarization refractoriness (PRR) may prevent premature excitation and tachyarrhythmia induction. The effects of propafenone and procainamide on these parameters, and their antiarrhythmic or proarrhythmic consequences, were investigated. Methods and Results —In 11 isolated Langendorff-perfused rabbit hearts, monophasic action potentials (MAPs) were recorded simultaneously from six to seven different right and left ventricular sites, along with a volume-conducted ECG. All recordings were used to discern ventricular tachycardia (VT) or ventricular fibrillation (VF) induced by repetitive extrastimulation (S2-S5) or 10-second burst stimulation at 25 to 200 Hz at baseline and after addition of procainamide (20 μmol/L) or propafenone (1 μmol/L) to the perfusate. MAPs were analyzed for action potential duration at 90% repolarization (APD 90 ), conduction times (CT) between the pacing site and the other MAPs, and PRR (effective refractory period−APD 90 =PRR) and related to the induction of VT or VF. During steady-state pacing, procainamide and propafenone prolonged APD 90 by 12% and 14%, respectively. Procainamide slowed mean CT by 40% during S2-S5 pacing, whereas propafenone slowed mean CT by up to 400% ( P &lt;0.001 versus baseline and procainamide). Wavelength was not changed significantly by procainamide but was shortened fourfold by propafenone at S5. Both drugs produced PRR, which was associated with a 70% decrease in VF inducibility with procainamide and elimination of VF with propafenone. Despite this protection from VF, monomorphic VT was induced with propafenone in 57% of burst stimulations. Conclusions —Drug-induced PRR protects against VF induction. Propafenone promotes slow monomorphic VT, probably by use-dependent conduction slowing and wavelength shortening.
Recent Advances in Molecular Genetics of Hereditary Magnesium-Losing Disorders
Authors: Martin Konrad, Stefanie Weber
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Recent advances in molecular genetics in hereditary hypomagnesemia substantiated the role of a variety of genes and their encoded proteins in human magnesium transport mechanisms. This knowledge on underlying genetic defects helps to distinguish different clinical subtypes and gives first insight into molecular components involved in magnesium transport. By mutation analysis and functional protein studies, novel pathophysiologic aspects were elucidated. For some of these disorders, transgenic animal models were generated to study genotype-phenotype relations and disease pathology. This review will discuss genetic and clinical aspects of familial disorders associated with magnesium wasting and focuses on the recent progress that has been made in molecular genetics. Besides isolated renal forms of hereditary hypomagnesemia, the following disorders will also be presented: familial hypomagnesemia with hypercalciuria and nephrocalcinosis, hypomagnesemia with secondary hypocalcemia, Ca2+/Mg2+-sensing receptor–associated disorders, and disorders associated with renal salt-wasting and hypokalemic metabolic alkalosis, comprising the Gitelman syndrome and the Bartter-like syndromes. E-mail: [email protected]
A metagenomic study of diet-dependent interaction between gut microbiota and host in infants reveals differences in immune response
Authors: Scott Schwartz, Iddo Friedberg, Ivan V Ivanov, Laurie A Davidson, Jennifer S Goldsby, David B Dahl, Damir Herman, Mei Wang, Sharon M Donovan, Robert S Chapkin
Journal: Genome biology (2012)

Gut microbiota and the host exist in a mutualistic relationship, with the functional composition of the microbiota strongly affecting the health and well-being of the host. Thus, it is important to develop a synthetic approach to study the host transcriptome and the microbiome simultaneously. Early microbial colonization in infants is critically important for directing neonatal intestinal and immune development, and is especially attractive for studying the development of human-commensal interactions. Here we report the results from a simultaneous study of the gut microbiome and host epithelial transcriptome of three-month-old exclusively breast- and formula-fed infants.Variation in both host mRNA expression and the microbiome phylogenetic and functional profiles was observed between breast- and formula-fed infants. To examine the interdependent relationship between host epithelial cell gene expression and bacterial metagenomic-based profiles, the host transcriptome and functionally profiled microbiome data were subjected to novel multivariate statistical analyses. Gut microbiota metagenome virulence characteristics concurrently varied with immunity-related gene expression in epithelial cells between the formula-fed and the breast-fed infants.Our data provide insight into the integrated responses of the host transcriptome and microbiome to dietary substrates in the early neonatal period. We demonstrate that differences in diet can affect, via gut colonization, host expression of genes associated with the innate immune system. Furthermore, the methodology presented in this study can be adapted to assess other host-commensal and host-pathogen interactions using genomic and transcriptomic data, providing a synthetic genomics-based picture of host-commensal relationships.
Major histocompatibility complex susceptibility genes for dermatitis herpetiformis compared with those for gluten-sensitive enteropathy.
Authors: A R Ahmed, J J Yunis, D Marcus-Bagley, E J Yunis, M Salazar, A J Katz, Z Awdeh, C A Alper
Journal: The Journal of Experimental Medicine (1993)

Dermatitis herpetiformis (DH) shares some clinical features and major histocompatibility complex (MHC) markers with gluten-sensitive enteropathy (GSE). We compared MHC haplotypes in 27 patients with DH, 35 patients with GSE, and normal controls. As in GSE, the frequencies of two extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were increased in patients with DH. Distributions of fragments of extended haplotypes, consisting of some but not all of the elements of complete extended haplotypes, were analyzed to attempt to localize a susceptibility gene. Besides complete extended susceptibility haplotypes, (DR3, DQ2) and (DR7, DQ2) fragments were most common in GSE. In contrast, DH showed only a few such fragments but many instances of the fragment (SC01). The differences in distribution of these fragments in the two diseases were highly significant (P &amp;lt; 0.002). HLA-DQ2 and DR3 had the highest odds ratios for GSE, but the highest odds ratio for DH was for the complotype SC01. These findings suggest that the MHC susceptibility gene for DH is between class II and complotype regions, closest to the complotype, whereas that for GSE is in the class II region.
Using ontologies to describe mouse phenotypes.
Authors: Georgios V Gkoutos, Eain CJ Green, Ann-Marie Mallon, John M Hancock, Duncan Davidson
Journal: Genome biology (2004)

Abstract The mouse is an important model of human genetic disease. Describing phenotypes of mutant mice in a standard, structured manner that will facilitate data mining is a major challenge for bioinformatics. Here we describe a novel, compositional approach to this problem which combines core ontologies from a variety of sources. This produces a framework with greater flexibility, power and economy than previous approaches. We discuss some of the issues this approach raises.
An<i>Arabidopsis</i>Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors
Authors: Jinpu Jin, Kun He, Xing Tang, Zhe Li, Le Lv, Yi Zhao, Jingchu Luo, Ge Gao
Journal: Molecular Biology and Evolution (2015)

Transcription factors (TFs) play key roles in both development and stress responses. By integrating into and rewiring original systems, novel TFs contribute significantly to the evolution of transcriptional regulatory networks. Here, we report a high-confidence transcriptional regulatory map covering 388 TFs from 47 families in Arabidopsis. Systematic analysis of this map revealed the architectural heterogeneity of developmental and stress response subnetworks and identified three types of novel network motifs that are absent from unicellular organisms and essential for multicellular development. Moreover, TFs of novel families that emerged during plant landing present higher binding specificities and are preferentially wired into developmental processes and these novel network motifs. Further unveiled connection between the binding specificity and wiring preference of TFs explains the wiring preferences of novel-family TFs. These results reveal distinct functional and evolutionary features of novel TFs, suggesting a plausible mechanism for their contribution to the evolution of multicellular organisms.
New Soft Alkylating Agents with Enhanced Cytotoxicity against Cancer Cells Resistant to Chemotherapeutics and Hypoxia
Authors: Alexandre Patenaude, Réna G. Deschesnes, Jean L.C. Rousseau, Éric Petitclerc, Jacques Lacroix, Marie-France Côté, René C.-Gaudreault
Journal: Cancer Research (2007)

Abstract Chloroethylureas (CEU) are soft alkylating agents that covalently bind to β-tubulin (βTAC) and affect microtubule polymerization dynamics. Herein, we report the identification of a CEU subset and its corresponding oxazolines, which induce cell growth inhibition, apoptosis, and microtubule disruption without alkylating β-tubulin (N-βTAC). Both βTAC and N-βTAC trigger the collapse of mitochondrial potential (ΔΨm) and modulate reactive oxygen species levels, following activation of intrinsic caspase-8 and caspase-9. Experiments using human fibrosarcoma HT1080 respiratory-deficient cells (ρ0) and uncoupler of the mitochondrial respiratory chain (MRC) showed that βTAC and N-βTAC impaired the MRC. ρ0 cells displayed an increased sensitivity toward N-βTAC as compared with ρ+ cells but, in contrast, were resistant to βTAC or classic chemotherapeutics, such as paclitaxel. Oxazoline-195 (OXA-195), an N-βTAC derivative, triggered massive swelling of isolated mitochondria. This effect was insensitive to cyclosporin A and to Bcl-2 addition. In contrast, adenine nucleotide translocator (ANT) antagonists, bongkrekic acid or atractyloside, diminished swelling induced by OXA-195. The antiproliferative activities of the N-βTACs CEU-025 and OXA-152 were markedly decreased in the presence of atractyloside. Conversely, pretreatment with cyclosporin A enhanced growth inhibition induced by βTAC and N-βTAC. One of the proteins alkylated by N-βTAC was identified as the voltage-dependent anion channel isoform-1, an ANT partner. Our results suggest that βTAC and N-βTAC, despite their common ability to affect the microtubule network, trigger different cytotoxic mechanisms in cancer cells. The role of mitochondria in these mechanisms and the potential of N-βTAC as a new therapeutic approach for targeting hypoxia-resistant cells are discussed. [Cancer Res 2007;67(5):2306–16]
Color Fluorescence Ratio for Detection of Bronchial Dysplasia and Carcinoma <i>In situ</i>
Authors: Pyng Lee, Remco M. van den Berg, Stephen Lam, Adi F. Gazdar, Katrien Grunberg, Annette McWilliams, Jean LeRiche, Pieter E. Postmus, Tom G. Sutedja
Journal: Clinical Cancer Research (2009)

Abstract Background: Autofluorescence bronchoscopy is more sensitive than conventional bronchoscopy for detecting early airway mucosal lesions. Decreased specificity can lead to excessive biopsy and increased procedural time. Onco-LIFE, a device that combines fluorescence and reflectance imaging, allows numeric representation by expressing red-to-green ratio (R/G ratio) within the region of interest. The aim of the study was to determine if color fluorescence ratio (R/G ratio) added to autofluorescence bronchoscopy could provide an objective means to guide biopsy. Methods: Subjects at risk for lung cancer were recruited at two centers: VU University Medical Centre (Amsterdam) and BC Cancer Agency (Canada). R/G ratio for each site appearing normal or abnormal was measured before biopsy. R/G ratios were correlated with pathology, and a receiver operating characteristic curve of R/G ratio for high-grade and moderate dysplasia was done. Following analysis of the training data set obtained from two centers, a prospective validation study was done. Results: Three thousand three hundred sixty-two adequate biopsies from 738 subjects with their corresponding R/G ratios were analyzed. R/G ratio 0.54 conferred 85% sensitivity and 80% specificity for the detection of high-grade and moderate dysplasia, area under the curve was 0.90, and 95% confidence interval was 0.88 to 0.92. In another 70 different sites that were assessed, κ measurements of agreement of R/G ratios with visual scores and pathology were 0.66 (P &amp;lt; 0.0001) and 0.61 (P &amp;lt; 0.0001), respectively. R/G ratio combined with visual score improved specificity to 88% (95% confidence interval, 0.73-0.96) for high-grade and moderate dysplasia. Conclusion: Color fluorescence ratio can objectively guide the bronchoscopist in selecting sites for biopsy with good pathologic correlation.
Combinatorial Gene Therapy Accelerates Bone Regeneration: Non‐Viral Dual Delivery of VEGF and BMP2 in a Collagen‐Nanohydroxyapatite Scaffold
Authors: Caroline M. Curtin, Erica G. Tierney, Kevin McSorley, Sally‐Ann Cryan, Garry P. Duffy, Fergal J. O'Brien
Journal: Advanced Healthcare Materials (2014)

Vascularization and bone repair are accelerated by a series of gene-activated scaffolds delivering both an angiogenic and an osteogenic gene. Stem cell-mediated osteogenesis in vitro, in addition to increased vascularization and bone repair by host cells in vivo, is enhanced using all systems while the use of the nanohydroxyapatite vector to deliver both genes markedly enhances bone healing.