tbuckley/cabot-search huggingface dataset:
Effects of Intercellular Adhesion Molecule 1 (ICAM-1) Null Mutation on Radiation-Induced Pulmonary Fibrosis and Respiratory Insufficiency in Mice
Authors: Dennis E. Hallahan, Ling Geng, Yu Shyr
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Therapy-induced inflammation and progressive fibrosis limit the efficacy of thoracic radiotherapy for lung neoplasms. However, mice bearing a null mutation of intercellular adhesion molecule 1 (ICAM-1) have previously been found to display no inflammatory cell infiltration into the lung following thoracic irradiation. We investigated the role of ICAM-1-mediated inflammation in the pathogenesis of radiation-induced pulmonary fibrosis in mice with a homozygous null mutation in the ICAM-1 gene (ICAM-1−/−) and in wild-type mice (ICAM-1+/+). Methods: Groups of 10 mice were each irradiated with total doses of 12.5, 14, 16, 17, or 18 Gy to the thorax or were mock irradiated. Inflammatory cell infiltration was measured by immunohistochemical staining of lung sections for leukocyte-common antigen (LCA). Dynamic pulmonary compliance was determined by plethysmography. Pulmonary fibrosis was evaluated by measuring alveolar septal wall thickness and the hydroxyproline content of lungs by immunohistochemical staining of lung sections for collagen III and by Masson's trichrome staining of lung sections. All statistical tests were two-sided. Results: Lungs of irradiated ICAM-1−/− mice had statistically significantly fewer LCA-positive cells than the lungs of irradiated ICAM-1+/+ mice at all radiation doses (P<.001). ICAM-1−/− mice had a higher mean dynamic pulmonary compliance than ICAM-1+/+ mice following irradiation. The incidence of respiratory insufficiency 18 months after thoracic irradiation was statistically significantly lower in ICAM-1−/− mice than in ICAM-1+/+ mice (odds ratio = 0.19 [95% confidence interval = 0.06 to 0.58], overall P = .0036). ICAM-1−/− mice had less pulmonary fibrosis and reduced thickening of the alveolar septum following thoracic irradiation than did ICAM-1+/+ mice. The lungs of irradiated ICAM-1−/− mice had less hydroxyproline than did the lungs of irradiated ICAM-1+/+ mice (P = .04). Conclusions: ICAM-1 and inflammation contribute to pulmonary fibrosis and impaired pulmonary compliance following thoracic irradiation. Agents that block ICAM-1 function or expression should be studied for their effects on the prevention of radiation-induced pulmonary fibrosis.
T Cell Regulation as a Side Effect of Homeostasis and Competition
Authors: Thomas Barthlott, George Kassiotis, Brigitta Stockinger
Journal: The Journal of Experimental Medicine (2003)

We have previously hypothesized that maintaining a balanced peripheral immune system may not be the sole responsibility of a specialized subset of T cells dedicated to immune regulation, but also a side effect of normal competition for shared resources within an intact immune system. Here we show that regulatory activity is correlated with high homeostatic expansion potential, reflecting the avidity for self-peptide:MHC complexes. Monoclonal transgenic T cells with high homeostatic expansion potential and lacking characteristics previously associated with regulatory function were able to regulate wasting disease induced by transfer of a small number of naive CD45RBhi CD4 T cells into lymphopenic hosts. Self-regulatory function is also found in the naive polyclonal T cell repertoire depleted of CD25+ T cells. T cells capable of preventing immune pathology, like the transgenic T cells, express higher than average levels of CD5, an indicator of avidity for self:MHC peptide complexes. We therefore propose that dysregulated expansion of potentially pathogenic T cells in a lymphopenic environment can be prevented by members of the naive T cell repertoire, irrespective of their specificity, as a side effect of their response to homeostatic and antigenic stimulation.
Can the increase in body mass index explain the rising trend in asthma in children?
Authors: S Chinn
Journal: Thorax (2001)

<h3>BACKGROUND</h3> The reported association between asthma and obesity and the documented rise in each over time have led to suggestions that rising obesity might explain the increase in the prevalence of asthma. Trends in both in British children participating in the National Study of Health and Growth were marked from 1982 to 1994. <h3>METHODS</h3> Odd ratios for trends in asthma and symptoms in 8 and 9 year old children were calculated with and without adjustment for body mass index (BMI). <h3>RESULTS</h3> In a representative sample of white children the odds ratio per year for asthma was 1.09 (95% CI 1.07 to 1.11) before and after adjustment for BMI for boys and 1.09 (95% CI 1.07 to 1.12) and 1.09 (95% CI 1.05 to 1.12), respectively, for girls. Unadjusted and adjusted odds ratios were also virtually identical for wheeze and "asthma or bronchitis". The lack of effect of adjustment was due to a change in the association between BMI and symptoms with time. <h3>CONCLUSIONS</h3> Trends in overweight and obesity do not explain the increase in asthma. The evidence points towards the association between asthma and obesity being of recent origin. This may be explained by obesity being a marker of recent lifestyle differences now associated with both asthma and overweight.
Carcinoembryonic antigen mRNA analysis detects micrometastatic cells in blood from lung cancer patients: Table 1
Authors: G. Castaldo, R. Tomaiuolo, A. Sanduzzi, A. Ponticiello, I. Marchetiello, F. Salvatore
Journal: European Respiratory Journal (2003)

The current authors previously identified circulating cells expressing carcinoembryonic antigen (CEA) messenger ribonucleic acid (mRNA) in 80% of lung cancer patients bearing distant metastases. The current study prospectively validated the data on a novel cohort and extended the study to other mRNAs expressed by neoplastic cells. CEA, cytokeratin 19 and 20, aldolase A and epithelial glycoprotein 2 (EPG2) mRNA was analysed by reverse transcriptase-polymerase chain reaction in circulating cells from 19 healthy controls, and in biopsies and blood at diagnosis from 32 lung cancer patients monitored for 24 months. Aldolase A and cytokeratin 19 mRNA occurred in circulating cells of all controls; cytokeratin 20 was not expressed by any lung cancer biopsy. EPG2 mRNA occurred in all biopsies but not in the patients9 circulating cells. CEA mRNA occurred in 29/32 (90.6%) biopsies and in 17/32 mRNA samples from circulating cells from lung cancer patients. Of these positive patients 12/17 developed metastases within 9 months of mRNA analysis. Three positive patients died, one was lost to follow-up, and one did not develop metastases within 24 months. Of the negative patients 12/15 did not develop metastases during the 24-month follow-up; one patient was lost to follow-up, one did not express CEA, and another developed metastases. Unlike in other neoplasias, cytokeratin 19 and 20, aldolase A and epithelial glycoprotein 2 messenger ribonucleic acid are not useful for the detection of circulating cancer cells in lung cancer. Carcinoembryonic antigen messenger ribonucleic acid analysis in circulating cells helps to identify lung cancer patients at a greater risk of metastases.
Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment
Authors: Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Kumi Takata, Hiroaki Nagashima, Naoko Satoh, Katsusuke Kyotani, Takashi Mizowaki, Taichiro Imahori, Yasuo Ejima, Kenta Masui, Beatrice Gini, Huijun Yang, Kohkichi Hosoda, Ryohei Sasaki, Paul S. Mischel, Eiji Kohmura
Journal: Journal of Clinical Investigation (2015)

The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor–dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate–dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.
A Human 3′ miR-499 Mutation Alters Cardiac mRNA Targeting and Function
Authors: Gerald W. Dorn, Scot J. Matkovich, William H. Eschenbacher, Yan Zhang
Journal: Circulation Research (2012)

MyomiRs miR-499, miR-208a and miR-208b direct cardiac myosin gene expression. Sequence complementarity between miRs and their mRNA targets determines miR effects, but the functional consequences of human myomiR sequence variants are unknown.To identify and investigate mutations in human myomiRs in order to better understand how and to what extent naturally-occurring sequence variation can impact miR-mRNA targeting and end-organ function.Screening of ≈2,600 individual DNAs for myomiR sequence variants identified a rare mutation of miR-499, u17c in the 3' end, well outside the seed region thought to determine target recognition. In vitro luciferase reporter analysis showed that the 3' miR-499 mutation altered suppression of a subset of artificial and natural mRNA targets. Cardiac-specific transgenic expression was used to compare consequences of wild-type and mutant miR-499. Both wild-type and mutant miR-499 induced heart failure in mice, but miR-499 c17 misdirected recruitment of a subset of miR-499 target mRNAs to cardiomyocyte RNA-induced silencing complexes, altering steady-state cardiac mRNA and protein make-up and favorably impacting cardiac function. In vitro analysis of miR-499 target site mutations and modeling of binding energies revealed abnormal miR-mRNA duplex configurations induced by the c17 mutation.A naturally occurring miR-499 mutation outside the critical seed sequence modifies mRNA targeting and end-organ function. This first description of in vivo effects from a natural human miR mutation outside the seed sequence supports comprehensive studies of individual phenotypes or disease-modification conferred by miR mutations.
Drug Transporters and Na<sup>+</sup>/H<sup>+</sup>Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins
Authors: Dustin R. Walsh, Thomas D. Nolin, Peter A. Friedman
Journal: Pharmacological Reviews (2015)

Drug transporters govern the absorption, distribution, and elimination of pharmacologically active compounds. Members of the solute carrier and ATP binding-cassette drug transporter family mediate cellular drug uptake and efflux processes, thereby coordinating the vectorial movement of drugs across epithelial barriers. To exert their physiologic and pharmacological function in polarized epithelia, drug transporters must be targeted and stabilized to appropriate regions of the cell membrane (i.e., apical versus basolateral). Despite the critical importance of drug transporter membrane targeting, the mechanisms that underlie these processes are largely unknown. Several clinically significant drug transporters possess a recognition sequence that binds to PSD-95/Drosophila discs large/ZO-1 (PDZ) proteins. PDZ proteins, such as the Na<sup>+</sup>/H<sup>+</sup> exchanger regulatory factor (NHERF) family, act to stabilize and organize membrane targeting of multiple transmembrane proteins, including many clinically relevant drug transporters. These PDZ proteins are normally abundant at apical membranes, where they tether membrane-delimited transporters. NHERF expression is particularly high at the apical membrane in polarized tissue such as intestinal, hepatic, and renal epithelia, tissues important to drug disposition. Several recent studies have highlighted NHERF proteins as determinants of drug transporter function secondary to their role in controlling membrane abundance and localization. Mounting evidence strongly suggests that NHERF proteins may have clinically significant roles in pharmacokinetics and pharmacodynamics of several pharmacologically active compounds and may affect drug action in cancer and chronic kidney disease. For these reasons, NHERF proteins represent a novel class of post-translational mediators of drug transport and novel targets for new drug development.
Effect of inhaled 15-(s)-hydroxyeicosatetraenoic acid on tracheobronchial clearance in normal human airways.
Authors: C K Lai, R Polosa, D Pavia, A Hasani, J E Agnew, S W Clarke, S T Holgate
Journal: Thorax (1991)

15-(s)-Hydroxyeicosatetraenoic acid (15-HETE) is the predominant metabolite of arachidonic acid in normal and asthmatic human airways and a potent mucus secretagogue in canine and human airways. A study was carried out on the effect of inhaled 15-HETE on tracheobronchial clearance, measured for six hours by a radioaerosol technique, in 10 normal subjects. Subjects inhaled 80 nmol 15-HETE or the diluent (sodium phosphate buffer) on two occasions at least two weeks apart in a double blind and randomised fashion (20 minutes after radioaerosol inhalation. Tracheobronchial clearance after inhaled 15-HETE was almost identical to that after placebo for all measurements up to six hours. It is concluded that 15-HETE has no effect on tracheobronchial clearance in normal human airways and is unlikely to account for the impaired mucociliary clearance seen in asthma.
Bugs and the gut: breaking barriers to understanding
Authors: P BORRIELLO
Journal: Gut (2001)

See article on page 503 

There has been a re-emergence of interest in the interplay between the faecal microbiota and its associated metabolisms and gastrointestinal function. This has recently been driven by the current interest in human and veterinary probiotics, and in the recent past by hypotheses which linked gut bacterial metabolism of ingested foodstuffs and colorectal and other cancers. However, what is less widely known is the extent of involvement of gastrointestinal bacteria in gut function, gut disease, and particularly diseases of other organs.

Some of the less generally well known aspects of this interplay relate to gut bacterial metabolites: for example, the production of volatile fatty acids exacerbating acidaemias such as methylmalonic acidaemia, and the associated role of antibiotics in patient management.1 An area where there has been a resurgence of interest is the production of phytooestrogens …
The response of bone to nanocrystalline hydroxyapatite-coated Ti13Nb11Zr alloy in an animal model
Authors: Adriana Bigi, Milena Fini, Barbara Bracci, Elisa Boanini, Paola Torricelli, Gianluca Giavaresi, Nicolò N. Aldini, Alessandro Facchini, Fausto Sbaiz, Roberto Giardino
Journal: Biomaterials (2008)
Right atrial enlargement and prognosis in the hemodinamically stable pulmonary embolism
Authors: J.L. Lobo, J.A. García Fuertes, A. Rivas, E.M. Rodriguez-Beltrán, D. Jiménez, M. Barrón, J. De Miguel, M.R. Toda
Journal: European Respiratory Journal (2012)

INTRODUCTION:The Right-Atrium (RA) is easily accessible from the apical 4-chamber view (4Cv) and its enlargement is easily verifiable. AIM:To study if RA enlargement is associated with increased short-term mortality in patients with acute symptomatic hemodinamically stable PE. METHODS:The RIETE Registry is international registry of patients with symptomatic acute VTE. Patients diagnosed of hemodinamically stable PE were included in the current study. RA enlargement was considered if the RA End-Systolic (ES) area in the apical 4Cv, was greater than the Left Atrium ES area. Right Ventricle/Left Ventricle (RV/LV) ED ratio and RV dyskinesia were also determined. Student's t test and Mann-Whitney to analyze continuous variables. Fisher test to analyze categorical variables. Statistical analysis with SPSS (v.15,SPSSInc.,Chicago,Illinois). P<0.05 was considered as statistically significant. RESULTS: From 6308 patients included in the study, 45% were males and medium age 68. Global mortality during the 30 days after diagnosis was 4.6% and due to PE 2.2%.

![Figure][1] 



CONCLUSIONS: 1. The presence of RA enlargement is significantly associated with mortality from all causes during the first month after diagnosis. 2. This association is particularly strong with mortality caused by PE itself. 3. Compared to patients with normal RA, the risk of dying from PE during the first month is 4 times higher in patients with RA dilatation.

 [1]: pending:yes
Mast cells in Waldenstrom's macroglobulinemia support lymphoplasmacytic cell growth through CD154/CD40 signaling
Authors: O. Tournilhac, D.D. Santos, L. Xu, J. Kutok, Y.-T. Tai, S. Le Gouill, L. Catley, Z. Hunter, A.R. Branagan, J.A. Boyce, N. Munshi, K.C. Anderson, S.P. Treon
Journal: Annals of Oncology (2006)
Myocardial Contractile Response to Norepinephrine, Isoproterenol, and Calcium Chloride in Hyperthyroid Guinea Pigs
Authors: M. Jay Goodkind
Journal: Circulation Research (1969)

Myocardial contractility, measured as the maximum left ventricular systolic pressure response to aortic constriction, is greater than normal in the hyperthyroid guinea pig. The effect of inotropic agents on this response was determined in anesthetized, open-chest, euthyroid, and hyperthyroid guinea pigs. Norepinephrine and isoproterenol in single doses, 1 µg/kg, and isoproterenol infused intravenously, 1, 4 and 10 µg/kg/min, caused a smaller increase in myocardial contractile response to aortic constriction in hyperthyroid than in euthyroid animals. Hyperthyroid guinea pigs also responded to an infusion of calcium chloride, 11 mg/kg/min, with an increase in maximum systolic pressure which was less than normal. With each drug the maximum systolic pressure level attained during aortic constriction was greater in the euthyroid than in the hyperthyroid animals. Cardiac pacing of euthyroid guinea pigs at 430 beats/min, a rate similar to the spontaneous rate of the hyperthyroid guinea pig, did not alter the inotropic response to infused calcium, though single injections and intravenous infusions of isoproterenol had less of an effect than in the spontaneously beating normal heart. These results suggest that the increased myocardial contractility of the hyperthyroid guinea pig may have reached a near maximum level. As a result, the added inotropic effects of isoproterenol and calcium in these animals are less than in normal controls.
Compensation for Increase in Respiratory Workload during Mechanical Ventilation
Authors: SALVATORE GRASSO, FILOMENA PUNTILLO, LUCIANA MASCIA, GIOVANNI ANCONA, TOMMASO FIORE, FRANCESCO BRUNO, ARTHUR S. SLUTSKY, V. MARCO RANIERI
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Variation in respiratory impedance may occur in mechanically ventilated patients. During pressure-targeted ventilatory support, this may lead to patient–ventilator asynchrony. We assessed the hypothesis that during pressure-support ventilation (PSV), preservation of minute ventilation (V˙ e) consequent to added mechanical loads would result in an increase in respiratory rate (RR) due to the large reduction in tidal volume (Vt). With proportional-assist ventilation (PAV), preservation of V˙ e would occur through the preservation of Vt, with a smaller effect on RR. We anticipated that this compensatory strategy would result in greater patient comfort and a reduce work of breathing. An increase in respiratory impedance was obtained by chest and abdominal binding in 10 patients during weaning from mechanical ventilation. V˙ e remained constant in both ventilatory modes after chest and abdominal compression. During PSV, this maintenance of Ve was obtained through a 58 ± 3% increase in RR that compensated for a 29 ± 2% reduction in Vt. The magnitudes of the reduction in Vt (10 ± 3%) and of the increase in RR (14 ± 2%) were smaller (p < 0.001) during PAV. During both PSV and PAV, chest and abdominal compression caused increases in both the pressure–time product (PTP) of the diaphragm per minute (142.9 ± 26.9 cm H2O · s/min, PSV, and 117.6 ± 16.4 cm H2O · s/min, PAV) and per liter (13.4 ± 2.5 cm H2O · s/L, PSV, and 9.6 ± 0.7 cm H2O · s/L, PAV). These increments were greater (p < 0.001) during PSV than during PAV. The capability of keeping Vt and V˙ e constant through increases in inspiratory effort after increases in mechanical loads is relatively preserved only during PAV. The ventilatory response to an added respiratory load during PSV required greater muscle effort than during PAV. Grasso S, Puntillo F, Mascia L, Ancona G, Fiore T, Bruno F, Slutsky AS, Ranieri VM. Compensation for increase in respiratory workload during mechanical ventilation: pressure-support versus proportional-assist ventilation.
Management of lower gastrointestinal bleeding: endoscopist or radiologist?
Authors: Kirsten McArdle, Edmund Leung, Sherif Latif, Ashok Bohra, Sauid Ishaq
Journal: Gut (2010)

An 83-year-old male presented to the emergency department with a history of heavy rectal blood loss. He described copious amounts of fresh blood with multiple clots. There was no previous history of colonic bleeding or prior colonic investigation. Past medical history included atrial fibrillation for which he was on warfarin.

On examination he was haemodynamically unstable with a pulse rate of 100 bpm and blood pressure of 104/50 mm Hg. Haemoglobin was 8.6 g/dl and international normalised ratio (INR) was 3. He was immediately resuscitated with packed red cells and fresh frozen plasma.

Colonoscopy was not possible as the rate of bleeding and the fact …
Eptifibatide provides additional platelet inhibition in Non–ST-Elevation myocardial infarction patients already treated with aspirin and clopidogrel
Authors: Miles Dalby, Gilles Montalescot, Claire Bal dit Sollier, Eric Vicaut, Thierry Soulat, Jean-Philippe Collet, Rémi Choussat, Vanessa Gallois, Gérard Drobinski, Ludovic Drouet, Daniel Thomas
Journal: Journal of the American College of Cardiology (2004)
Early PSA decrease is an independent predictive factor of clinical failure and specific survival in patients with localized prostate cancer treated by radiotherapy with or without androgen deprivation therapy
Authors: R. de Crevoisier, K. Slimane, T. Messai, P. Wibault, F. Eschwege, A. Bossi, S. Koscielny, A. Bridier, C. Massard, K. Fizazi
Journal: Annals of Oncology (2009)