tbuckley/cabot-search huggingface dataset:
Identification of Novel Modifier Loci of <i>ApcMin</i> Affecting Mammary Tumor Development
Authors: Hua Wang, Douglas Teske, Alyssa Tess, Rebecca Kohlhepp, YounJeong Choi, Christina Kendziorski, Amy Rapaich Moser
Journal: Cancer Research (2007)

Genetic background affects the susceptibility to mammary tumor development in Apc(Min/+) mice. Here we report the identification of four novel modifier loci that influence different aspects of mammary tumor development in Apc(Min/+) mice. Analysis of tumor development in a backcross of (FVBB6 Apc(Min/+)) x B6 Apc(Min/+) mice has identified a modifier on chromosome 9 that significantly affects tumor multiplicity, and a modifier on chromosome 4 that significantly affects tumor latency and affects tumor number with suggestive significance. This modifier was also identified in a backcross involving 129X1/SvJ and B6 Apc(Min/+) mice. A modifier on chromosome 18 specifically affects tumor latency but not tumor number. Kaplan-Meier analysis suggests there is at least an additive interaction affecting tumor latency between the loci on chromosomes 4 and 18. We also identified a modifier locus on chromosome 6 that interacts with the loci on chromosome 4 and chromosome 9 to affect tumor number. These results suggest that multiple genetic loci control different aspects of mammary tumor development. None of these modifiers is associated with intestinal tumor susceptibility, which indicates that these modifiers act on tumor development in a tissue-specific manner.
Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB
Authors: Stephen R. Daley, Daniel Y. Hu, Christopher C. Goodnow
Journal: The Journal of Experimental Medicine (2013)

Acquisition of self-tolerance in the thymus requires T cells to discriminate strong versus weak T cell receptor binding by self-peptide–MHC complexes. We find this discrimination is reported by expression of the transcription factor Helios, which is induced during negative selection but decreases during positive selection. Helios and the proapoptotic protein Bim were coinduced in 55% of nascent CCR7− CD4+ CD69+ thymocytes. These were short-lived cells that up-regulated PD-1 and down-regulated CD4 and CD8 during Bim-dependent apoptosis. Helios and Bim were also coinduced at the subsequent CCR7+ CD4+ CD69+ CD8− stage, and this second wave of Bim-dependent negative selection involved 20% of nascent cells. Unlike CCR7− counterparts, Helios+ CCR7+ CD4+ cells mount a concurrent Card11- and c-Rel–dependent activation response that opposes Bim-mediated apoptosis. This “hollow” activation response consists of many NF-κB target genes but lacks key growth mediators like IL-2 and Myc, and the thymocytes were not induced to proliferate. These findings identify Helios as the first marker known to diverge during positive and negative selection of thymocytes and reveal the extent, stage, and molecular nature of two distinct waves of clonal deletion in the normal thymus.
Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants
Authors: Nga Bien-Ly, Y. Joy Yu, Daniela Bumbaca, Justin Elstrott, C. Andrew Boswell, Yin Zhang, Wilman Luk, Yanmei Lu, Mark S. Dennis, Robby M. Weimer, Inhee Chung, Ryan J. Watts
Journal: The Journal of Experimental Medicine (2014)

Antibodies to transferrin receptor (TfR) have potential use for therapeutic entry into the brain. We have shown that bispecific antibodies against TfR and β-secretase (BACE1 [β-amyloid cleaving enzyme-1]) traverse the blood-brain barrier (BBB) and effectively reduce brain amyloid β levels. We found that optimizing anti-TfR affinity improves brain exposure and BACE1 inhibition. Here we probe the cellular basis of this improvement and explore whether TfR antibody affinity alters the intracellular trafficking of TfR. Comparing high- and low-affinity TfR bispecific antibodies in vivo, we found that high-affinity binding to TfR caused a dose-dependent reduction of brain TfR levels. In vitro live imaging and colocalization experiments revealed that high-affinity TfR bispecific antibodies facilitated the trafficking of TfR to lysosomes and thus induced the degradation of TfR, an observation which was further confirmed in vivo. Importantly, high-affinity anti-TfR dosing induced reductions in brain TfR levels, which significantly decreased brain exposure to a second dose of low-affinity anti-TfR bispecific. Thus, high-affinity anti-TfR alters TfR trafficking, which dramatically impacts the capacity for TfR to mediate BBB transcytosis.
Testosterone-mediated sexual dimorphism of the rodent heart. Ventricular lysosomes, mitochondria, and cell growth are modulated by androgens.
Authors: H Koenig, A Goldstone, C Y Lu
Journal: Circulation Research (1982)

The ventricular myocardium was studied in A/J mice and in Sprague-Dawley rats. In male mice, the ventricles were slightly larger and the specific activities of the lysosomal hydrolases, beta-glucuronidase, hexosaminidase, beta-galactosidase, and arylsulphatase, and the inner mitochondrial enzyme cytochrome c oxidase were substantially higher than in female mice. Orchiectomy abolished this sex difference. Testosterone administration induced myocardial hypertrophy and accretion of RNA and protein without altering the DNA, and substantial increases in the activities of the lysosomal hydrolases and cytochrome c oxidase. However, the mitochondrial membrane enzyme monoamine oxidase was unaffected by sex, orchiectomy, and testosterone administration. Heart lysosomes from male mice showed a smaller structure-linked latency of the lysosomal enzymes and a greater fragility of the lysosomal membrane to osmotic and mechanical stress than those from female mice. This sex difference was also abolished by orchiectomy and restored by testosterone replacement. Similar sex differences were observed in the rat with respect to heart size, acid hydrolase activities, and lysosomal enzyme latency and membrane stability. These findings indicate that endogenous androgens regulate myocardial cell growth, the activity of enzymes associated with lysosomes and the inner mitochondrial membrane, and some physiochemical properties of lysosomes.
Associations Between Aldosterone Antagonist Therapy and Risks of Mortality and Readmission Among Patients With Heart Failure and Reduced Ejection Fraction
Authors: Adrian F. Hernandez, Xiaojuan Mi, Bradley G. Hammill, Stephen C. Hammill, Paul A. Heidenreich, Frederick A. Masoudi, Laura G. Qualls, Eric D. Peterson, Gregg C. Fonarow, Lesley H. Curtis
Journal: JAMA (2012)

URING THE PAST 30 YEARS, large randomized trials have established the efficacy of multiple therapies for reducing mortality among patients with heart failure and reduced ejection fraction. 1Among the most efficacious therapies for heart failure are the aldosterone antagonists spironolactone and eplerenone.In 2 landmark trials, these agents reduced mortality by 24% to 30% and readmission for heart failure by nearly 40%. 2,3Despite these findings and subsequent class I guideline recommendations, the use of aldosterone antagonist therapy remains lower than expected. 1,4,5low and varied adoption of aldosterone antagonists in clinical practice may be due, in part, to uncertainty about their effectiveness and safety outside clinical trials. 6This uncertainty is especially relevant for patients at high risk See also pp
Sensitivity and sensitisation in relation to pain severity in knee osteoarthritis: trait or state?
Authors: Tuhina Neogi, Laura Frey-Law, Joachim Scholz, Jingbo Niu, Lars Arendt-Nielsen, Clifford Woolf, Michael Nevitt, Laurence Bradley, David T Felson
Journal: Annals of the Rheumatic Diseases (2013)

It is not clear whether heightened pain sensitivity in knee osteoarthritis (OA) is related to sensitisation induced by nociceptive input from OA pathology ('state') versus other confounding factors. Conversely, some individuals may be predisposed to sensitisation irrespective of OA ('trait').The Multicenter Osteoarthritis Study is a longitudinal cohort of persons with or at risk of knee OA. We obtained knee X-rays, pain questionnaires and comprehensive assessment of factors that can influence pain sensitivity. We examined the relation of sensitisation and sensitivity assessed by mechanical temporal summation (TS) and pressure pain thresholds (PPTs) to knee OA and knee pain severity. To test whether sensitisation and sensitivity is a 'state' induced by OA pathology, we examined the relation of PPT and TS to knee OA duration and severity.In 2126 subjects (mean age 68, mean body mass index (BMI) 31, 61% female), PPT and TS were not associated with radiographic OA (ORs 0.9-1.0 for PPT and TS; p>0.05). However, PPT and TS were associated with pain severity (ORs: 1.7-2.0 for PPT; 1.3-1.6 for TS; p<0.05). Knee OA duration and radiographic severity were not associated with PPT or TS.PPT and TS were associated with OA-related pain, but not radiographic OA after accounting for pertinent confounders in this large cohort. Lack of association with disease duration suggests at least some sensitisation and pain sensitivity may be a trait rather than state. Understanding the relationship between pathological pain and pain sensitivity/sensitisation offers insight into OA pain risk factors and pain management opportunities.
Methacholine and macrolides
Authors: G.P. Currie, D.K.C. Lee
Journal: European Respiratory Journal (2004)

two types of mask ventilation.Although the questions of this study are relevant, I believe that the design of the study was not adequate to answer these questions.First, all patients were on NM for w3 months and one patient even for 70 months, whereas they trained only for 1 day on FFM.In our centre (Dept of Pulmonary Diseases/ Home mechanical ventilation, University Hospital Groningen, Groningen, The Netherlands), patients routinely need more time (y7 days) to adjust to their specific mask.As a result of this short time of training on FFM compared with a long-term adjustment on NM, it is not surprising that total sleep time and sleep efficiency were worse in the FFM group compared with the NM group.As a consequence of their longer experience with the NM mask, the patients also rated less leak and more comfort in the NM night compared with the FFM night.Secondly, no differences were found between pressure settings if NM was compared with FFM.However, this study will not detect any differences if pressure settings, optimalised during their review night, remained unchanged during the subsequent mask trials.Due to the previously mentioned issues, I believe that the study by WILLSON et al. [1], with its present design, makes it difficult to draw strong conclusions.It would have been preferable to compare both mask ventilations in a parallel study of naı ¨ve patients in whom noninvasive ventilation was started.In this way, it would have been possible to compare the time it takes to adjust to either nasal mask or full face mask.If the patients were adjusted to the mask, it would be possible to determine differences in terms of sleep quality, tolerability and pressure needed to maintain an effective noninvasive ventilation.
Ozone Air Pollution Is Associated With Acute Myocardial Infarction
Authors: Jean-Bernard Ruidavets, Maxime Cournot, Sylvie Cassadou, Michel Giroux, Mariam Meybeck, Jean Ferrières
Journal: Circulation (2005)

Background— Despite the diversity of the studied health outcomes, types and levels of pollution, and various environmental settings, there is substantial evidence for a positive link between urban air pollution and cardiovascular diseases. The objective of this study was to test the associations between air pollutants and the occurrence of acute myocardial infarction (AMI). Methods and Results— Pollutant concentrations (SO 2 , NO 2 , and O 3 ) were measured hourly as part of the automated air quality network. Since 1985, an AMI registry (the Toulouse MONICA Project) has been collecting data in the southwest of France. All cases of AMI and sudden and probable cardiac deaths are recorded for subjects 35 to 64 years of age. We studied the short-term exposure effect of pollution on the risk of AMI (from January 1, 1997, to June 30, 1999) using a case-crossover design method. We performed a conditional logistic regression analysis to calculate relative risks (RRs) and their 95% CIs. After adjustment for temperature, relative humidity, and influenza epidemics, the RRs (for an increase of 5 μg/m 3 of O 3 concentration) for AMI occurrence were significant for the current-day and 1-day-lag measurements (RR, 1.05; 95% CI, 1.01 to 1.08; P =0.009; and RR, 1.05; 95% CI, 1.01 to 1.09; P =0.007, respectively). Subjects 55 to 64 years of age with no personal history of ischemic heart disease were the most susceptible to develop an AMI (RR, 1.14; 95% CI, 1.06 to 1.23). NO 2 and SO 2 exposures were not significantly associated with the occurrence of AMI. Conclusions— Observational data confirm that short-term O 3 exposure within a period of 1 to 2 days is related to acute coronary events in middle-aged adults without heart disease, whereas NO 2 and SO 2 are not.
A new promising treatment in systemic sclerosis: 5-fluorouracil.
Authors: J A Casas, C P Subauste, G S Alarcon
Journal: Annals of the Rheumatic Diseases (1987)

Twelve patients with systemic sclerosis according to American Rheumatism Association criteria were treated with intravenous 5-fluorouracil. Significant subjective and objective improvement occurred initially in the skin and subsequently in the involved viscera and vasculature. These preliminary results suggest that 5-fluorouracil may be an effective treatment for systemic sclerosis.
Systemic inflammation and comorbidity in COPD: a result of 'overspill' of inflammatory mediators from the lungs? Review of the evidence
Authors: N. J. Sinden, R. A. Stockley
Journal: Thorax (2010)

Chronic obstructive pulmonary disease (COPD) is characterised by an inflammatory response by the lungs to inhaled substances such as cigarette smoking and air pollutants. In addition to the pulmonary features of COPD, several systemic effects have been recognised even after controlling for common aetiological factors such as smoking or steroid use. These include skeletal muscle dysfunction, cardiovascular disease, osteoporosis and diabetes. Individuals with COPD have significantly raised levels of several circulating inflammatory markers indicating the presence of systemic inflammation. This raises the issue of cause and effect. The role of tumour necrosis factor α in COPD is thought to be central to both lung and systemic inflammation and has been implicated in skeletal muscle dysfunction, osteoporosis and type 2 diabetes. It has been hypothesised that inflammation in the lung results in 'overspill' into the circulation causing systemic inflammation. There is supportive evidence that protein movement can occur from the lung surface to the systemic circulation. Evidence from inhaled substances such as air pollutants and cigarette smoke has demonstrated a temporal link between the inflammatory process in the lung and systemic inflammation. Also, studies have shown alterations in circulating inflammatory cells in patients with COPD compared with controls which may reflect the effects of inflammatory mediators (derived from the lung) on circulating cells or the bone marrow. This paper considers the concept of 'overspill' in depth, reviews the current evidence and highlights problems in generating direct evidence to support or refute this concept.
Cooling strategies improve intermittent sprint performance in the heat of athletes with tetraplegia
Authors: N Webborn, M J Price, P Castle, V L Goosey-Tolfrey
Journal: British Journal of Sports Medicine (2008)

Precooling has been shown to enhance performance in repeated sprint exercise in able-bodied subjects in a hot environment. Spinal cord injury causes thermoregulatory impairment with a detrimental effect on performance. This study assessed whether cooling strategies before and during exercise in the heat enhances sprint performance in athletes with tetraplegia.Eight male athletes with tetraplegia performed intermittent arm crank exercise in the heat (32.0 degrees C (0.1 degrees C); humidity, 50% (0.1%)) for a maximum of 60 min or until exhaustion. Trials involved a no-cooling control (CON), precooling (PRE) or cooling during exercise (DUR). Each intermittent sprint protocol consisted of varied periods of passive rest, maximal sprinting and active recovery.Both PRE and DUR cooling strategies improved the ability of the athletes to repeatedly perform high-intensity sprints, with times to exhaustion (TTE), whereas during the CON trial, athletes demonstrated a reduction in the total number of sprints and TTE (47.2 (10.8), 52.8 (5.8) and 36.2 (9.6) min for CON, PRE and DUR, respectively). Core temperature was significantly higher for CON (37.3 degrees C (0.3 degrees C)) when compared with both PRE and DUR (36.5 degrees C (0.6 degrees C) and 37.0 degrees C (0.5 degrees C), respectively, p<0.01). Ratings of perceived exertion and thermal sensation upon exhaustion or completion were not different.Athletes with tetraplegia should use a precooling or during-exercise cooling strategy specific to the characteristics of their sport when exercising in hot conditions.
Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan
Authors: Christine Krämer, Julia Sunkomat, Jana Witte, Maren Luchtefeld, Michael Walden, Boris Schmidt, Rainer H. Böger, Wolf-Georg Forssmann, Helmut Drexler, Bernhard Schieffer
Journal: Circulation Research (2002)

Angiotensin II (Ang II) type 1 receptor (AT 1 ) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography–mass spectrometry (LC-MS) from serum samples revealed a maximum of 10 −7 mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (−35±4%, P &lt;0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450–dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10 −7 mol/L). LPS- and Ang II–induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II– and LPS-induced formation of prostaglandin F2α as determined by LC-MS. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2α generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.
Identification of a Thymic Epithelial Cell Subset Sharing Expression of the Class Ib HLA-G Molecule with Fetal Trophoblasts
Authors: Laura Crisa, Michael T. McMaster, Jennifer K. Ishii, Susan J. Fisher, Daniel R. Salomon
Journal: The Journal of Experimental Medicine (1997)

HLA-G is the only class I determinant of the major histocompatibility complex (MHC) expressed by the trophoblasts, the fetal cells invading the maternal decidua during pregnancy. A unique feature of this nonclassical HLA molecule is its low polymorphism, a property that has been postulated to play an important role in preventing local activation of maternal alloreactive T and natural killer cells against the fetus. Yet, the mechanisms by which fetal HLA-G can be recognized as a self-MHC molecule by the maternal immune system remain unclear. Here we report the novel observation that HLA-G is expressed in the human thymus. Expression is targeted to the cell surface of thymic medullary and subcapsular epithelium. Thymic epithelial cell lines were generated and shown to express three alternatively spliced HLA-G transcripts, previously identified in human trophoblasts. Sequencing of HLA-G1 transcripts revealed a few nucleotide changes resulting in amino acid substitutions, all clustered within exon 3 of HLA-G, encoding for the α2 domain of the molecule. Our findings raise the possibility that maternal unresponsiveness to HLA-G–expressing fetal tissues may be shaped in the thymus by a previously unrecognized central presentation of this MHC molecule on the medullary epithelium.
Inhibition of exercise-induced asthma by different pharmacological pathways.
Authors: S Godfrey, P Konig
Journal: Thorax (1976)

Exercise-induced asthma (EIA) was provoked by standardized treadmill running for 6 minutes in 15 asthmatic children. The tests were carried out after the administration of a placebo, salbutamol, sodium cromoglycate, choline theophyllinate, and atrophine methonitrate aerosol in randomized fashion on different days. The mean post-exercise percent fall in peak expiratory flow rate was 45-2, 4-1, 19-6, 18-3, and 24-9 respectively. The proportion of children having significant amelioration of their EIA compared with those taking the placebo was 100% for salbutamol, 80% for cromoglycate and theophyllinate, and 60% for atropine. Salbutamol, choline theophyllinate, and atropine were bronchodilators at rest whereas cromoglycate was not, and the ability to suppress EIA was unrelated to bronchodilator effect. Even after bronchodilatation at rest, further broncho-dilatation occurred during the exercise period.
Circulating Retinol-Binding Protein-4, Insulin Sensitivity, Insulin Secretion, and Insulin Disposition Index in Obese and Nonobese Subjects
Authors: José-Manuel Fernández-Real, Joan Vendrell, Wifredo Ricart, Cristóbal Richart, Montserrat Broch
Journal: Diabetes Care (2007)

We acknowledge the interest of Stefan et al. (1) in our findings in which they tried to replicate in their study of 75 men and women (mean BMI 29 kg/m2). Circulating retinol-binding protein (RBP)-4 did not correlate with insulin secretion even after adjustment for age, sex, and insulin sensitivity. We studied only men ( n = 107). Marked sex differences in glucose-stimulated insulin secretion have been described in humans (2) and experimental models (3). Sex has been described to impact insulin secretion, insulin action, and hepatic insulin extraction, which results in substantial differences in the regulation of postprandial glucose metabolism in men and women …