tbuckley/cabot-search huggingface dataset:
Mildly Oxidized LDL Induces Activation of Platelet-Derived Growth Factor β-Receptor Pathway
Authors: Isabelle Escargueil-Blanc, Robert Salvayre, Nathalie Vacaresse, Günther Jürgens, Benoit Darblade, Jean-François Arnal, Sampath Parthasarathy, Anne Nègre-Salvayre
Journal: Circulation (2001)

Background Mildly oxidized LDL (moxLDL) is thought to play a role in atherogenesis. MoxLDL induces derivatization of cell proteins and triggers a variety of intracellular signaling. We aimed to investigate whether moxLDL-induced protein derivatization may influence the activity of platelet-derived growth factor receptor β (PDGFRβ), a tyrosine kinase receptor of major importance in vascular biology and atherogenesis. Methods and Results In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFRβ signaling pathway, as shown by PDGFRβ tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFRβ activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFRβ activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFRβ (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which induces PDGFRβ adduct formation and subsequent PDGFRβ activation (antioxidant-insensitive step); (2) the second phase involves ceramide-mediated generation of H 2 O 2 (these steps being inhibited by tosylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal–PDGFRβ adducts are also detected in atherosclerotic aortas, it is suggested that this novel mechanism of moxLDL-induced PDGFRβ activation may occur during atherogenesis. Conclusions MoxLDL acts as a local autoparacrine mediator in the vascular wall, and PDGFRβ acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFRβ activation in atherosclerotic areas.
Metabolomics Reveals Broad-Scale Metabolic Perturbations in Hyperglycemic Mothers During Pregnancy
Authors: Denise M. Scholtens, Michael J. Muehlbauer, Natalie R. Daya, Robert D. Stevens, Alan R. Dyer, Lynn P. Lowe, Boyd E. Metzger, Christopher B. Newgard, James R. Bain, William L. Lowe
Journal: Diabetes Care (2013)

OBJECTIVE To characterize metabolites across the range of maternal glucose by comparing metabolomic profiles of mothers with high and low fasting plasma glucose (FPG). RESEARCH DESIGN AND METHODS We compared fasting serum from an oral glucose tolerance test at ∼28 weeks' gestation from 67 Northern European ancestry mothers from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study with high (>90th percentile) FPG with 50 mothers with low (<10th percentile) FPG but comparable BMI. Metabolic data from biochemical analyses of conventional clinical metabolites, targeted mass spectrometry (MS)-based measurement of amino acids, and nontargeted gas chromatography/MS were subjected to per-metabolite analyses and collective pathway analyses using Unipathway annotation. RESULTS High-FPG mothers had a metabolic profile consistent with insulin resistance including higher triglycerides, 3-hydroxybutyrate, and amino acids including alanine, proline, and branched-chain amino acids (false discovery rate [FDR]-adjusted P < 0.05). Lower 1,5-anhydroglucitol in high-FPG mothers suggested recent hyperglycemic excursions (FDR-adjusted P < 0.05). Pathway analyses indicated differences in amino acid degradation pathways for the two groups (FDR-adjusted P < 0.05), consistent with population-based findings in nonpregnant populations. Exploratory analyses with newborn outcomes indicated positive associations for maternal triglycerides with neonatal sum of skinfolds and cord C-peptide and a negative association between maternal glycine and cord C-peptide (P < 0.05). CONCLUSIONS Metabolomics reveals perturbations in metabolism of major macronutrients and amino acid degradation pathways in high- versus low-FPG mothers.
Protein Kinase Cϵ Is Required for Macrophage Activation and Defense Against Bacterial Infection
Authors: Antonio Castrillo, Daniel J. Pennington, Florian Otto, Peter J. Parker, Michael J. Owen, Lisardo Boscá
Journal: The Journal of Experimental Medicine (2001)

To assess directly the role of protein kinase C (PKC)ϵ in the immune system, we generated mice that carried a homozygous disruption of the PKCϵ locus. PKCϵ−/− animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCϵ−/− animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)γ, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Further analysis revealed that LPS-stimulated macrophages from PKCϵ−/− mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IκB kinase, a reduction in IκB degradation, and a decrease in nuclear factor (NF)κB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCϵ−/− mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCϵ is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCϵ, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.
High concordance of BRAF status between primary colorectal tumours and related metastatic sites: implications for clinical practice
Authors: D. Santini, C. Spoto, F. Loupakis, B. Vincenzi, N. Silvestris, C. Cremolini, E. Canestrari, F. Graziano, N. Galluccio, L. Salvatore, M. Caraglia, F.A. Zito, G. Colucci, A. Falcone, G. Tonini, A. Ruzzo
Journal: Annals of Oncology (2010)
Diffusion tensor imaging of sport related concussion in adolescents
Authors: Naznin Virji-Babul, Michael Borich, Nadia Makan, Tiffany Moore, Kira Frew, Carolyn A Emery, Lara Boyd
Journal: British Journal of Sports Medicine (2013)

Objectives To establish the short-term changes in white matter integrity following sport related concussion in adolescents and to examine the association between changes in white matter integrity and a clinical measure of concussion. Design Cross-sectional within cohort study. Setting University hospital and community ice hockey arenas. Subjects Twelve adolescents with sport related concussion (ages 14–17 years) within 2 months of injury and 10, active adolescents with no previous history of concussion. Assessment of Risk Factors Adolescents within 2 months of sport-related concussion and healthy adolescents with no history of concussion were assessed using the Sport Concussion Assessment Tool 2 (SCAT2) and total SCAT2 score (/100) was considered. Outcome Measures Two measures of diffusion tensor imaging (DTI): fractional anisotropy (FA) and mean diffusivity (MD). Results Whole brain FA values were significantly increased (F (1,40)=6.29, p=0.01) and MD values decreased (F(1,40)=4.75, p=0.036) in concussed athletes compared with control participants. SCAT2 total scores were associated with whole brain FA and MD values with lower scores associated with higher FA (R 2 =0.25, p=0.017) and lower MD (R 2 =0.2, p=0.038). Conclusion This preliminary study provides evidence of microstructural changes in the integrity of the white matter in adolescent athletes following a sport related concussion. In addition, we found a relationship between measures of white matter integrity and the SCAT2 up to 16–61 days following concussion, which may indicate persistent structural change in the adolescent brain after injury. Further study should chart the trajectory of brain injury and recovery in this population. Acknowledgements Martha Piper Research Fund, University of British Columbia and the Brain Research Centre, University of British Columbia. Competing interests None.
Patient-Reported Outcomes After Hepatic Resection of Colorectal Cancer Metastases
Authors: Jonathan R. Rees, Jane M. Blazeby, Peter Fayers, Elizabeth A. Friend, Fenella K.S. Welsh, Timothy G. John, Myrddin Rees
Journal: Journal of Clinical Oncology (2012)

Hepatic resection of colorectal carcinoma (CRC) liver metastases is increasing, but evidence for the impact of surgery on patient-reported outcomes (PROs) is limited. This study aimed to describe comprehensively the impact of liver surgery for CRC hepatic metastases on PROs.Consecutive patients selected for hepatic resection completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and Quality of Life Questionnaire-Liver Metastases C21 before and 3, 6, and 12 months after surgery. For functional scales, mean scores with 95% CIs were calculated at each time point, with differences in scores of at least 10 points considered clinically significant. Responses to symptom scales and items were categorized as minimal or severe. Proportions and 95% CIs for each symptom category were calculated.Hepatic surgery was planned in 241 patients but abandoned in nine because of unresectable disease. There were two postoperative deaths, 58 complications (25.2%), and 32 patients (14.9%) with disease recurrence. Questionnaire compliance was excellent (> 95% at all time points). After surgery, most functional aspects of health decreased, and the proportions of patients with severe symptoms increased; role function deteriorated significantly, and 30% of patients reported severe activity/vigor problems. Functional scales recovered by 6 months and were maintained at 1 year. Postoperative symptoms returned to baseline levels at 12 months, but 32.1% of patients reported severe problems with sexual dysfunction and 11.9% with abdominal pain.These findings provide new evidence regarding outcomes of liver resection for CRC metastases. It is recommended that patients be reassured that surgery has a minimal and short-lived detrimental impact on health.
Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease
Authors: Nicola Giuliani, Simona Colla, Roberto Sala, Matteo Moroni, Mirca Lazzaretti, Silvia La Monica, Sabrina Bonomini, Magda Hojden, Gabriella Sammarelli, Sophie Barillè, Regis Bataille, Vittorio Rizzoli
Journal: Blood (2002)
Joint effects of birth outcomes and childhood body mass index on respiratory symptoms
Authors: Wen-Hua Wang, Pau-Chung Chen, Wu-Shiun Hsieh, Yungling Leo Lee
Journal: European Respiratory Journal (2012)

Thinness in infancy and higher childhood body mass index (BMI) are risk factors for poor respiratory health. However, few studies have examined the joint effects of birth outcomes and childhood BMI on the occurrence of respiratory symptoms. A total of 78,011 Taiwanese middle-school children were investigated between 1995 and 1996 in a nationwide International Study of Asthma and Allergies in Childhood (ISAAC) survey, with standardised height/weight measurement. Their survey data was compared successfully with the birth registration dataset. Childhood BMI was positively associated with all respiratory symptoms, with greater effects and significant risks associated with serious phenotypes in the video questionnaire. Children with a history of low birth weight (LBW), those who were born prematurely (pre-term), or those who were small for gestational age (SGA) were also more likely to have allergic respiratory symptoms. As birthweight and gestational age were not positively associated with childhood BMI, we proposed that LBW, pre-term birth and childhood BMI were independent factors for respiratory symptoms. LBW, pre-term birth and childhood BMI are all independent risk factors for respiratory symptoms in children. Children with a history of LBW, pre-term birth or SGA and a higher current BMI might have larger respiratory burden.
The voluntary drive to breathe is not decreased in hypercapnic patients with severe COPD
Authors: A. Topeli, F. Laghi, M.J. Tobin
Journal: European Respiratory Journal (2001)

How do the respiratory centres of patients with chronic obstructive pulmonary disease (COPD) and hypercapnia respond to acute increases in inspiratory load? A depressed respiratory motor output has long been postulated, but studies on this issue have yielded inconsistent results, partly due to limitations of investigative techniques. Many of these limitations can be overcome by the twitch interpolation technique, which is capable of accurately quantifying the degree of diaphragmatic activation, termed the voluntary drive to breathe. The hypothesis that patients with COPD and hypercapnia compensate for an acute increase in mechanical load on the inspiratory muscles with a lower voluntary drive to breathe than is the case with normocapnic patients was tested. Measurements were obtained in 15 patients with COPD, six of whom displayed hypercapnia and nine normocapnia. The maximum degree of diaphragmatic activation, expressed as a voluntary activation index (mean±sem), was higher in hypercapnic than in normocapnic patients (98.7±0.7 versus 94.5±0.9% (p=0.006)), as was the mean value (94.5±0.7 versus 88.5±1.9% (p=0.01)). Within-patient values of the index were also less variable in the hypercapnic patients (coefficients of variation, 3.4±0.3 versus 6.1±0.9%, p=0.01). Multiple regression analysis revealed the ratio of dynamic elastance to maximum transdiaphragmatic pressure, an index of inspiratory muscle loading, and pH as the only variables that correlated with maximum voluntary activation index (r 2 =0.69, p=0.02 for each variable). Contrary to the hypothesis, it was concluded that voluntary activation of the diaphragm was greater and less variable in hypercapnic patients than normocapnic patients with severe chronic obstructive pulmonary disease during an acute increase in inspiratory mechanical load. Whether greater diaphragmatic recruitment during episodes of a severe exacerbation of chronic obstructive pulmonary disease provides a survival advantage for hypercapnic patients with chronic obstructive pulmonary disease remains to be determined.
Association of anxiety with perception of histamine induced bronchoconstriction in patients with asthma
Authors: P. Spinhoven, A. S. van Peski-Oosterbaan, A. J. Van der Does, L. N. Willems, P. J. Sterk
Journal: Thorax (1997)

The perception of bronchoconstriction varies among patients with asthma and this perception may be related to the covariation of sensory and affective aspects of dyspnoea. A study was performed to evaluate whether there are differences in the perception of histamine induced bronchoconstriction between anxious and non-anxious perceivers and whether anxious perception of bronchoconstriction can be predicted by higher levels of baseline anxiety.Seventy eight asthmatic subjects referred for a histamine challenge test undertook baseline measures for anxiety symptomatology and forced expiratory volume in one second (FEV1) followed by perceived breathlessness (Borg scale), anxiety (SUDS), and FEV1 measurement before and during induced bronchoconstriction. Based on the correlation between Borg and SUDS scores, the patients were divided into anxious and non-anxious perceivers.Forty one patients reported no anxiety during the challenge test. The anxious perceivers (n = 20) had higher levels of perceived breathlessness and anxiety at 20% fall in FEV1 and were more accurate in their perception of airways obstruction than non-anxious perceivers (n = 58). However, they did not report higher baseline levels of anxiety symptomatology.Anxiety experienced during bronchial challenge testing may result from the accurate perception of physiological changes and further direct attention to airways obstruction.
Looking closely at infants' performance and experimental procedures in the A-not-B task
Authors: Adele Diamond
Journal: Behavioral and Brain Sciences (2001)

Thelen et al.'s model of A-not-B performance is based on behavioral observations obtained with a paradigm markedly different from A-not-B. Central components of the model are not central to A-not-B performance. All data presented fit a simpler model, which specifies that the key abilities for success on A-not-B are working memory and inhibition. Intention and action can be dissociated in infants and adults.
Estrogen and Different Aspects of Vascular Disease in Women and Men
Authors: Carl J. Pepine, Wilmer W. Nichols, Daniel F. Pauly
Journal: Circulation Research (2006)

onsiderable evidence indicates that sex hormones have an important influence on cardiovascular physiology and pathology. 1,2Recent work suggests that a mechanism based on estrogen receptor-alpha (ESR1) contributes to a range of structural and functional responses that relate to vascular disease.Most of this work focuses on ESR1 activity within the endothelium and yields variable findings due, at least in part, to differences in the vascular bed or species studied, as well as other experimental conditions such as age, estrogen status, degree of preconstriction, etc.But many findings in conduit arteries (eg, more frequent plaque erosion, increased wall stiffness, spasm, etc) and microvessels (eg, reduced coronary flow reserve, hot flashes, etc) implicate smooth muscle cells (SMCs) in gender differences in vascular disease.These cells are directly responsible for extracellular matrix production and assure the integrity of the artery wall.They may be decreased, apoptotic, or dysfunctional in terms of synthesis and repair of extracellular matrix, which is destroyed in vulnerable plaque by macrophages.In this issue of Circulation Research Montague and colleagues 3 report that activation of ESR1 decreases human aorta SMC differentiation (Figure).Importantly, they found that SMCs of men, compared with women, had reduced ESR1 expression associated with increased differentiation markers.Their work suggests that ESR1 activation switches SMC to a form that may promote plaque vulnerability.Could different activational states of ESR1 be responsible for shifting the functional characteristics of SMCs toward a phenotype that explains some complexities of gender-related differences in vascular disease?
The change of tuberculosis features through decades in immune-competent patients
Authors: Islam Mejri, Soumaya Ben Saad, Hafaoua Daghfous, Mouna Ben Khlifa, Hela Cherif
Journal: European Respiratory Journal (2014)

Introduction:  Tuberculosis (TB) reemerged as a major health problem. Today, this disease remain endemic all over the world. In common with other countries, Tunisia faces a resurgence of TB.   Aim:  Overview changes in clinical features and management of TB in Tunisia through decades.   Method:  There is a comparative study including 3 groups of TB cases registered between 1980-1983(G1: n=522 ), 1990-1993 (G2: n=200) and 2010-2013 (G3: n=100).   Results:  Mean age was 35 years in all groups. The incidence rate in elderly patients was 10% (G3) vs 2% (G1, 2). Low socio-economic status interested 34% (G3) vs 90% (G1). More than half of cases were smokers. Chronic alcohol consumers were 35% (G3) vs20% (G2) and drug users are 3% (G3) vs0% (G1,2). BCG vaccine was done in 82 % of patients (G3) vs 30% (G1).More than 17% had diabetes (G3) vs13% (G2) vs 7% (G1). Family transmission was 21% (G3) vs 15% (G1). Extra pulmonary symptoms was noted in 16 % (G3) vs 2% (G1).There was more extra pulmonary localization of TB 14 % (G3) vs 4,5% (G1). Thus, severe forms with bilateral localization and lung destruction decreased from 34% (G1) to 13% (G3). Microscopic sputum smear was positive in 67% (G3) vs 73% (G1) with positive culture as well in half of cases .Unfortunately, positive diagnosis was delayed by 10 days (G3) vs 3 days (G1). All patients were treated under DOTS with less success 80% (G3) vs 97% (G1) and more side effects 48% (G3) vs 34% (G1). Consequently, clearing sputum smear was differed to 90 days in 9% (G3) vs 1.5% (G1).   Conclusion:  There is still a lot to be done to control TB, especially in high burden countries where fast identification and early treatment represents the cornerstone for the best outcomes.
Prediction of Tumor Recurrence and Therapy Monitoring Using Ultrasound-Guided Photoacoustic Imaging
Authors: Srivalleesha Mallidi, Kohei Watanabe, Dmitriy Timerman, David Schoenfeld, Tayyaba Hasan
Journal: Theranostics (2015)

Selection and design of individualized treatments remains a key goal in cancer therapeutics; prediction of response and tumor recurrence following a given therapy provides a basis for subsequent personalized treatment design.We demonstrate an approach towards this goal with the example of photodynamic therapy (PDT) as the treatment modality and photoacoustic imaging (PAI) as a non-invasive, response and disease recurrence monitor in a murine model of glioblastoma (GBM).PDT is a photochemistry-based, clinically-used technique that consumes oxygen to generate cytotoxic species, thus causing changes in blood oxygen saturation (StO 2 ).We hypothesize that this change in StO 2 can be a surrogate marker for predicting treatment efficacy and tumor recurrence.PAI is a technique that can provide a 3D atlas of tumor StO 2 by measuring oxygenated and deoxygenated hemoglobin.We demonstrate that tumors responding to PDT undergo approximately 85% change in StO 2 by 24-hrs post-therapy while there is no significant change in StO 2 values in the non-responding group.Furthermore, the 3D tumor StO 2 maps predicted whether a tumor was likely to regrow at a later time point post-therapy.Information on the likelihood of tumor regrowth that normally would have been available only upon actual regrowth (10-30 days post treatment) in a xenograft tumor model, was available within 24-hrs of treatment using PAI, thus making early intervention a possibility.Given the advances and push towards availability of PAI in the clinical settings, the results of this study encourage applicability of PAI as an important step to guide and monitor therapies (e.g.PDT, radiation, anti-angiogenic) involving a change in StO 2 .
Tipping the Balance: Cdk2 Enables Myc to Suppress Senescence
Authors: Per Hydbring, Lars-Gunnar Larsson
Journal: Cancer Research (2010)

Intrinsic tumor-suppressor pathways protect healthy cells from transformation by activated oncogenes like MYC or RAS through induction of apoptosis or cellular senescence, respectively. However, when expressed together, MYC and RAS evade these barriers and initiate tumorigenesis. Although Ras suppresses Myc-induced apoptosis, the role of Myc in this cooperation has remained undefined. In a recent report, we showed that Myc represses Ras-induced senescence, thereby overcoming the second major barrier of tumorigenesis. Inhibition of Ras-induced senescence required specific phosphorylation of Myc by cyclin-dependent kinase 2 (Cdk2) and was abrogated by pharmacologic Cdk2 inhibitors, urging a reevaluation of this kinase as a therapeutic target in Myc- or Ras-driven tumors.