tbuckley/cabot-search huggingface dataset:
Cerebral Structural Changes in Severe Obstructive Sleep Apnea
Authors: Fergal J. O'Donoghue, Regula S. Briellmann, Peter D. Rochford, David F. Abbott, Gaby S. Pell, Chow Huat Patrick Chan, Natalie Tarquinio, Graeme D. Jackson, Robert J. Pierce
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Obstructive sleep apnea is associated with abnormalities in neuropsychologic function, and defects in respiratory control may contribute to pathogenesis. Abnormalities may be reflected in structural brain changes. Twenty-seven male untreated patients with severe sleep apnea without comorbidities, and 24 age-matched control subjects, had T1-weighted brain imaging in a high-resolution magnetic resonance scanner. Twenty-three patients with sleep apnea had repeat imaging after 6 months of continuous positive airways pressure treatment. No areas of gray matter volume change were found in patients using an optimized voxel-based morphometry technique, at p < 0.05 adjusted for multiple comparisons (despite the method being sensitive to changes in gray matter fraction of 0.17 or less in all voxels). Furthermore, no differences were seen in bilateral hippocampal, temporal lobe, or whole brain volumes, assessed by manual tracing of anatomical borders. No longitudinal changes were seen in gray matter density or regional volumes after treatment, but whole brain volume decreased slightly. We have found no gray matter volume deficits nor focal structural changes in severe obstructive sleep apnea. Whole brain volume decreases without focal changes after 6 months of continuous positive airways pressure treatment.
Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis
Authors: Judit López‐Luque, Daniel Caballero‐Díaz, Adoración Martinez‐Palacián, César Roncero, Joaquim Moreno‐Càceres, María García‐Bravo, Esther Grueso, Almudena Fernández, Eva Crosas‐Molist, María García‐Álvaro, Annalisa Addante, Esther Bertran, Angela M. Valverde, Águeda González‐Rodríguez, Blanca Herrera, Lluis Montoliu, Teresa Serrano, Jose‐Carlos Segovia, Margarita Fernández, Emilio Ramos, Aránzazu Sánchez, Isabel Fabregat
Journal: Hepatology (2015)

Different data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte‐specific truncated form of human EGFR, which acts as negative dominant mutant (ΔEGFR) and allows definition of its tyrosine kinase–dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two‐thirds partial hepatectomy, ΔEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor‐β pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor‐β through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in ΔEGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, ΔEGFR livers were able to recover liver mass by overactivating compensatory signals, such as c‐Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because ΔEGFR mice showed a delay in the appearance of diethyl‐nitrosamine‐induced tumors, which correlated with decreased proliferation and delay in the diethyl‐nitrosamine‐induced inflammatory process. Conclusion : These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology. (H epatology 2016;63:604–619)
Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation.
Authors: H Schunkert, V J Dzau, S S Tang, A T Hirsch, C S Apstein, B H Lorell
Journal: Journal of Clinical Investigation (1990)

We compared the activity and physiologic effects of cardiac angiotensin converting enzyme (ACE) using isovolumic hearts from male Wistar rats with left ventricular hypertrophy due to chronic experimental aortic stenosis and from control rats. In response to the infusion of 3.5 X 10(-8) M angiotensin I in the isolated buffer perfused beating hearts, the intracardiac fractional conversion to angiotensin II was higher in the hypertrophied hearts compared with the controls (17.3 +/- 4.1% vs 6.8 +/- 1.3%, P less than 0.01). ACE activity was also significantly increased in the free wall, septum, and apex of the hypertrophied left ventricle, whereas ACE activity from the nonhypertrophied right ventricle of the aortic stenosis rats was not different from that of the control rats. Northern blot analyses of poly(A)+ purified RNA demonstrated the expression of ACE mRNA, which was increased fourfold in left ventricular tissue obtained from the hearts with left ventricular hypertrophy compared with the controls. In both groups, the intracardiac conversion of angiotensin I to angiotensin II caused a comparable dose-dependent increase in coronary resistance. In the control hearts, angiotensin II activation had no significant effect on systolic or diastolic function; however, it was associated with a dose-dependent depression of left ventricular diastolic relaxation in the hypertrophied hearts. These novel observations suggest that cardiac ACE is induced in hearts with left ventricular hypertrophy, and that the resultant intracardiac activation of angiotensin II may have differential effects on myocardial relaxation in hypertrophied hearts relative to controls.
PWE-090 Outcomes of Patients with Ulcerative Colitis who are Azathioprine Tolerant and Azathioprine Intolerant: Abstract ﻿PWE-090 Table
Authors: L Lee, A Syed, G Macfaul, S Lanzon-Miller
Journal: Gut (2013)

<h3>Introduction</h3> Azathioprine therapy is an immunosuppressive drug that is widely used in the management of ulcerative colitis. 20% of patients with normal TPMT are not able to tolerate the drug and 30% do not respond [1]. For patients who are intolerant to azathioprine, other medicines have been proposed and these include methotrexate, mercaptopurine and infliximab. <h3>Methods</h3> A cross sectional study was performed using the Milton Keynes Hospital IBD database to compare patients were azathioprine intolerant and those that were azathioprine tolerant. A descriptive analysis of clinical features and outcomes of these two groups was performed. Disease activity scores were based on the montreal classification ranging from S0 (clinical remission) to S3 (severe disease). <h3>Results</h3> 98 patients were recruited of which 32.7% were intolerant to azathioprine. The median age of azathioprine intolerant patients was 47.5 years and 30.3% were male. In the azathioprine tolerant cohort, the median age was 46 years and 53.0% were male. Azathioprine was not tolerated due to deranged liver function tests in 43.3%, gastrointestinal symptoms of nausea/vomiting in 23.3%, cutaneous side effects in 10.0%, migraines in 6.7% and infections in 3.3%. <h3>Conclusion</h3> Azathioprine is a drug that is not tolerated in nearly a third of Ulcerative Colitis patients and this effect demonstrated a sex bias towards females. The most likely reason for azathioprine intolerance was deranged liver function tests, however, intolerable gastrointestinal symptoms are noted. The intolerance of azathioprine is not a prognostic marker that patients will be more likely to undergo colectomy or that their ulcerative colitis will become extensive. However, there is evidence that compared to azathioprine tolerant patients, for every 100 who are intolerant, 8 less will be in remission and 6 will have more severe disease. Finally, we note that prolonged use of low-dose steroids in modern practise is utilised rarely and it is feasible that this trend may lead to increased symptoms at a population level. <h3>Disclosure of Interest</h3> None Declared. <h3>References</h3> M. Wahed, J. R. Louis-Auguste, L. M. Baxter, J. K. Limdi, S. A. Mccartney, J. O. Lindsay, and S. L. Bloom, “Efficacy of methotrexate in Crohn’s disease and ulcerative colitis patients unresponsive or intolerant to azathioprine/mercaptopurine,”<i> Alimentary Pharmacology &amp; Therapeutic</i>s, vol. 30, no. 6, pp. 614–620, 2009.
Inositol-1,4,5-trisphosphate increases contractions but not L-type calcium current in guinea pig ventricular myocytes
Authors: T Saeki
Journal: Cardiovascular Research (1999)

Objective: We studied the effects of intracellularly applied inositol-1,4,5-trisphosphate (InsP3) to test the hypothesis that InsP3 is a messenger for stimulation of L-type calcium current (ICa(L)) and contractions by muscarinic agonists. Methods: Voltage clamp pulses elicited ICa(L) that evoked contractions recorded with an edge detector in single guinea pig ventricular myocytes superfused with Tyrode’s solution (36°C). InsP3 or cyclic AMP (cAMP) was dialyzed into the cell at selected times via the patch electrode. Results: InsP3 (1–10 μM) transiently increased isotonic contractions when applied for 4–5 min; higher concentrations (50–300 μM) caused a sustained decrease in contractions. InsP3 had no effect on ICa(L) at any concentration tested. Caffeine (10 mM)-induced contractures were increased and decreased, respectively, at 3 and 100 μM InsP3. Pentosan polysulfate (50 μg/ml), an InsP3 receptor antagonist, opposed the increased contractions by InsP3. Intrapipette cyclic AMP (10–300 μM) caused sustained increases of ICa(L) and contractions. Cyclic AMP, but not InsP3, also increased ICa(L) when intrapipette Cs+ suppressed K+ currents. Conclusions: Increased myocyte shortening at low InsP3 concentrations accords with receptor-initiated sarcoplasmic reticulum Ca2+ release. The transient stimulation of contractions at low concentrations and the sustained reduction of contractions at high concentrations are not consistent with a role for InsP3 in the persistent increase of contractions by muscarinic agonist in ventricular muscle and myocytes. The failure of InsP3 to change ICa(L) when contractions were increased or decreased militates against the L-type calcium channel being an effector of InsP3.
Predominance of HLA-DRB1*0405 in Korean patients with rheumatoid arthritis.
Authors: H Y Kim, T G Kim, S H Park, S H Lee, C S Cho, H Han
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To identify the association of HLA-DR4 subtypes with rheumatoid arthritis (RA) in Koreans. METHODS--Ninety five patients with RA and 118 normal control subjects were examined for HLA-DR antigens by serology. Subtypes of HLA-DR4 were determined by allele specific oligonucleotide typing. RESULTS--The phenotype frequency of HLA-DR4 in RA patients was significantly greater than that in controls (60.0% versus 31.4%, odds ratio (OR) 3.28, 95% confidence interval (CI) 1.79 to 6.02 (p &lt; 0.001)), but HLA-DR6 was decreased in RA patients (15.8% versus 32.2%, OR 0.39, 95% CI 0.19 to 0.81 (p &lt; 0.001)). When DR4 was excluded from analysis of patients and controls, the allele frequency of DR1 was significantly increased in the patients compared with controls (11.3% versus 4.5%, OR 2.73, 95% CI 0.87 to 5.95 (p &lt; 0.001)). Forty two of 57 DR4 positive patients (73.7%) possessed DRB1*0405, which was strongly associated with RA (44.2% of patients, versus 11.9% of controls: OR 5.88, 95% CI 2.81 to 12.47 (p &lt; 0.001)). DRB1*0403 was not found in the patients, but was present in 8.5% of controls. Examining the third hyper-variable region at position 70-74 in the DRB1*04 chain by oligotyping, we found that 52 of 57 DR4 positive patients (91.2%) carried one of the conserved amino acid sequences QRRAA or QKRAA, known to be the epitope conferring predisposition to RA. CONCLUSION--This study confirms that RA is strongly associated with DR4, especially with DRB1*0405, and that the presence of the inferred QRRAA sequence may be important in susceptibility to RA in Koreans.
Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment
Authors: John T. Isaacs, Lizamma Antony, Susan L. Dalrymple, W. Nathaniel Brennen, Stephanie Gerber, Hans Hammers, Michel Wissing, Sushant Kachhap, Jun Luo, Li Xing, Per Björk, Anders Olsson, Anders Björk, Tomas Leanderson
Journal: Cancer Research (2012)

Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn(2+) binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1α, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. ©2012 AACR.
The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions
Authors: Akito Tanoue, Shuji Ito, Kenji Honda, Sayuri Oshikawa, Yoko Kitagawa, Taka-aki Koshimizu, Toyoki Mori, Gozoh Tsujimoto
Journal: Journal of Clinical Investigation (2004)

The neurohypophyseal peptide [Arg(8)]-vasopressin (AVP) exerts major physiological actions through three distinct receptor isoforms designated V1a, V1b, and V2. Among these three subtypes, the vasopressin V1b receptor is specifically expressed in pituitary corticotrophs and mediates the stimulatory effect of vasopressin on ACTH release. To investigate the functional roles of V1b receptor subtypes in vivo, gene targeting was used to create a mouse model lacking the V1b receptor gene (V1bR-/-). Under resting conditions, circulating concentrations of ACTH and corticosterone were lower in V1bR-/- mice compared with WT mice (V1bR+/+). The normal increase in circulating ACTH levels in response to exogenous administration of AVP was impaired in V1bR-/- mice, while corticotropin-releasing hormone-stimulated ACTH release in the V1bR-/- mice was not significantly different from that in the V1bR+/+ mice. AVP-induced ACTH release from primary cultured pituitary cells in V1bR-/- mice was also blunted. Furthermore, the increase in ACTH after a forced swim stress was significantly suppressed in V1bR-/- mice. Our results clearly demonstrate that the V1b receptor plays a crucial role in regulating hypothalamic-pituitary-adrenal axis activity. It does this by maintaining ACTH and corticosterone levels, not only under stress but also under basal conditions.
Janus Kinase 2: A Critical Target in Chronic Myelogenous Leukemia
Authors: Ajoy K. Samanta, Hui Lin, Tong Sun, Hagop Kantarjian, Ralph B. Arlinghaus
Journal: Cancer Research (2006)

Abstract The Bcr-Abl tyrosine kinase is the causative factor in most chronic myelogenous leukemia (CML) patients. We have shown that Bcr-Abl is associated with a cluster of signaling proteins, including Janus kinase (Jak) 2, growth factor receptor binding protein 2–associated binder (Gab) 2, Akt, and glycogen synthase kinase (GSK)-3β. Treatment of CML cell lines and mouse Bcr-Abl+ 32D cells with either Jak2 short interfering RNA or Jak2 kinase inhibitor AG490 inhibited pTyr Gab2 and pSer Akt formation, inhibited the activation of nuclear factor-κB, and caused the activation of GSK-3β, leading to the reduction of c-Myc. Importantly, BaF3 cells expressing T315I and E255K imatinib-resistant mutants of Bcr-Abl underwent apoptosis on exposure to AG490 yet were resistant to imatinib. Similar to wild-type Bcr-Abl+ cells, inhibition of Jak2 by Ag490 treatment resulted in decrease of pSer Akt and c-Myc in imatinib-resistant cells. These results identify Jak2 as a potentially important therapeutic target for CML. (Cancer Res 2006; 66(13): 6468-72)
Safe Delivery of Radiotherapy to Patients With Pacemakers or Cardioverter-Defibrillator Devices
Authors: Charles R. Thomas
Journal: JAMA Oncology (2015)

Jonathan D. Grant, MD; Garrett L. Jensen, BS; Chad Tang, MD; Julianne M. Pollard, PhD; Stephen F. Kry, PhD; Sunil Krishnan, MD; Anne H. Dougherty, MD; Daniel R. Gomez, MD; Marc A. Rozner, PhD, MD
EGF61 Polymorphism Predicts Complete Pathologic Response to Cetuximab-Based Chemoradiation Independent of KRAS Status in Locally Advanced Rectal Cancer Patients
Authors: Siwen Hu-Lieskovan, Daniel Vallbohmer, Wu Zhang, Dongyun Yang, Alexander Pohl, Melissa J. Labonte, Peter P. Grimminger, Arnulf H. Hölscher, Robert Semrau, Dirk Arnold, Kathrin Dellas, Annelies Debucquoy, Karin Haustermans, Jean-Pascal H. Machiels, Christine Sempoux, Claus Rödel, Matej Bracko, Vaneja Velenik, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2011)

Abstract Background: Cetuximab has shown significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in epidermal growth factor receptor pathway, angiogenesis, antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation. Methods: 130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was done by using PCR-RFLP assays. Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade III vs. grade IV: complete response). Results: Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P &amp;lt; 0.001). In addition, this association between EGF 61 G allele and pCR remained significant (P = 0.019) in the 59 patients with wild-type KRAS. Conclusion: This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer. Clin Cancer Res; 17(15); 5161–9. ©2011 AACR.
Circadian rhythm of peak expiratory flow in children passively exposed and not exposed to cigarette smoke.
Authors: R Casale, G Natali, D Colantonio, P Pasqualetti
Journal: Thorax (1992)

BACKGROUND: Because airway calibre shows a circadian rhythm and since exposure to passive smoking reduced lung function this study was undertaken to investigate whether passive smoking affects the circadian rhythm of peak expiratory flow (PEF) in schoolchildren. METHODS: Twenty schoolchildren (12 boys and 8 girls, aged 10-11 years) exposed to passive smoking were matched for sex, age, and height with 20 children who had not been exposed to cigarette smoke. Exposure to passive smoking was assessed by questionnaire and by urinary cotinine concentrations. A portable spirometer was used to measure PEF at 16:00, 20:00, 22:00, 06:00, 08:00, and 12:00 hours on a consecutive Saturday and Sunday. The circadian changes in PEF were measured by the cosinor method. RESULTS: Both groups showed diurnal fluctuation in PEF values with a noticeable circadian rhythm. PEF peaks were the same in the two groups and occurred around 15:00 hours. The cosinor mean was approximately 10% lower in children exposed to passive smoking and the amplitude was approximately 60% higher than in the unexposed children. CONCLUSION: Passive smoking in children is associated with a reduction in the cosinor mean and an increase in the amplitude of the normal circadian rhythm of airway calibre. This increased PEF rhythm amplitude may be considered as an early indication of airway obstruction.
IFNγ: Issuing macrophages a license to kill
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2007)

T cells tell macrophages when to start making the toxic soup of lysosomal enzymes, reactive oxygen species, and nitric oxide that destroys intracellular pathogens. In 1983, Carl Nathan proved that this start signal comes in the form of the secreted cytokine IFNγ.
Patterns of home mechanical ventilation use in Europe: results from the Eurovent survey
Authors: S. J. Lloyd-Owen, G. C. Donaldson, N. Ambrosino, J. Escarabill, R. Farre, B. Fauroux, D. Robert, B. Schoenhofer, A. K. Simonds, J. A. Wedzicha
Journal: European Respiratory Journal (2005)

The study was designed to assess the patterns of use of home mechanical ventilation (HMV) for patients with chronic respiratory failure across Europe. A detailed questionnaire of centre details, HMV user characteristics and equipment choices was sent to carefully identified HMV centres in 16 European countries. A total of 483 centres treating 27,118 HMV users were identified. Of these, 329 centres completed surveys between July 2001 and June 2002, representing up to 21,526 HMV users and a response rate of between 62% and 79%. The estimated prevalence of HMV in Europe was 6.6 per 100,000 people. The variation in prevalence between countries was only partially related to the median year of starting HMV services. In addition, there were marked differences between countries in the relative proportions of lung and neuromuscular patients using HMV, and the use of tracheostomies in lung and neuromuscular HMV users. Lung users were linked to a HMV duration of <1 yr, thoracic cage users with 6-10 yrs of ventilation and neuromuscular users with a duration of > or =6 yrs. In conclusion, wide variations exist in the patterns of home mechanical ventilation provision throughout Europe. Further work is needed to monitor its use and ensure equality of provision and access.