tbuckley/cabot-search huggingface dataset:
Cytomegalovirus Misleads Its Host by Priming of CD8 T Cells Specific for an Epitope Not Presented in Infected Tissues
Authors: Rafaela Holtappels, Jürgen Podlech, Marcus-Folker Pahl-Seibert, Markus Jülch, Doris Thomas, Christian O. Simon, Markus Wagner, Matthias J. Reddehase
Journal: The Journal of Experimental Medicine (2003)

Cytomegaloviruses (CMVs) code for several proteins that inhibit the presentation of antigenic peptides to CD8 T cells. Although the molecular mechanisms of CMV interference with the major histocompatibility complex class I pathway are long understood, surprisingly little evidence exists to support a role in vivo. Here we document the first example of the presentation of an antigenic peptide being blocked by a CMV immune evasion protein in organs relevant to CMV disease. Although this Db-restricted peptide, which is derived from the antiapoptotic protein M45 of murine CMV (mCMV), is classified as an immunodominant peptide based on response magnitude and long-term memory, adoptive transfer of M45 epitope-specific CD8 T cells did not protect against infection with wild-type mCMV. Notably, the same cells protected C57BL/6 mice infected with an mCMV mutant in which immune evasion protein m152/gp40 is deleted. These data indicate that direct presentation or cross-presentation of an antigenic peptide by professional antigen-presenting cells can efficiently prime CD8 T cells that fail in protection against CMV organ disease because m152/gp40 prevents presentation of this peptide in pathogenetically relevant tissue cells.
Combined-Modality Oncotherapy With Cyclophosphamide (NSC-26271) and Radiotherapy: Control of Murine Mastocytoma2
Authors: Larry L. Schenken, Ronald F. Hagemann, Dennis R. Burholt, S. Lesher
Journal: JNCI Journal of the National Cancer Institute (1976)

We investigated the effects of cyclophosphamide, alone and in combination with a 1,000-R/week radiotherapy schedule, on the growth of solid P815X2 tumors in 12-week-old male DBA/2 mice. Single-dose treatments of 150 mg cyclophosphamide/kg were given to animals bearing tumors of different ages. Such treatment of young tumors resulted in proportionately greater degrees of regression and steeper regrowth curves than did treatment of older tumors. Although slopes of regrowth curves differed greatly, time to regrowth (to pretreatment size) was the same for all age classes of tumors. Graded weekly exposures of 50-250 mg/kg for 4 weeks resulted in dose-dependent increases in incidence of complete remission, duration of remission (time to regrowth), and mean animal life-spans. The combination of radiotherapy to the tumor and 75, 150, or 225 mg cyclophosphamide/kg/week resulted in better local tumor control than occurred with radiotherapy or the drug alone. However, a dose-dependent increase in radiosensitivity of the gastrointestinal mucosa included in radiotherapy fields was observed. A 3-week course of radiotherapy plus 75 mg cyclophosphamide/kg/week (which is tolerated by the mucosa) increased animal lifespans to 165% of those of controls.
The polygenic profiles in participants with achilles tendinopathy and controls
Authors: M Posthumus, C Saunders, A V September, M Collins
Journal: British Journal of Sports Medicine (2011)

<h3>Introduction</h3> Achilles tendinopathy (AT) is a multifactorial condition for which various genetic risk factors have been identified. More specifically, five single nucleotide polymorphisms (SNPs) have been associated with and/or suggested to be implicated in AT. These SNPs are (1) the COL5A1 rs12722, (2) the MMP3 rs679620, (3) the GDF5 rs143383, (4) the IL1B −511, and (5) the IL6 −172 polymorphisms. <h3>Objective</h3> This study determines the validity of a polygenic profile, as proposed by Williams and Folland, as a discriminating ‘tool’ for identifying individuals at risk of developing AT. <h3>Methods</h3> All five polymorphisms was previously genotyped in 69 South African (SA) Caucasian participants with AT and 93 SA Caucasian control participants (CON) with no previous history of AT. Using the model developed by Williams and Folland (<i>Journal of Physiology</i>, 586.1, 113–21:2008), the ‘total genotype score’ (TGS) was calculated from the combination of each of the five SNPs. Individual genotypes were each given a ‘score’ of 2, 1 or 0. The homozygote genotype most closely associated with an increased risk of AT was given the score ‘2’, heterozygote9s were scored 1 and the homozygote most closely associated with reduced risk of AT were scored 0. Receiver operating characteristic (ROC) curves were used to evaluate the ability of the TGS to correctly distinguish participants at high and low risk of AT. Significance was accepted when p&lt;0.05. <h3>Results</h3> The TGS of the AT participants (TGS=63.6±15.3) was significantly greater (p&lt;0.001) than the CON participants (TGS=54.3±16.3). ROC analysis showed a significant discriminating accuracy of TGS to identify risk of AT in the SA population (AUC=0.64; 95% CI 0.56 to 0.73; p=0.002). <h3>Conclusion</h3> The method of using TGSs to discriminate between individuals at risk of AT and not, seems valid. This method may be used in future multifactorial models developed to identify ‘at-risk’ individuals.
Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study
Authors: Jorge E. Cortes, Michele Baccarani, François Guilhot, Brian J. Druker, Susan Branford, Dong-Wook Kim, Fabrizio Pane, Ricardo Pasquini, Stuart L. Goldberg, Matt Kalaycio, Beatriz Moiraghi, Jacob M. Rowe, Elena Tothova, Carmino De Souza, Marc Rudoltz, Richard Yu, Tillmann Krahnke, Hagop M. Kantarjian, Jerald P. Radich, Timothy P. Hughes
Journal: Journal of Clinical Oncology (2009)

Purpose To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Patients and Methods A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. Results At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. Conclusion MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.
OC-149 Secretin-enhanced magnetic resonance cholangio-pancreatography (secretin-MRCP): a case series and review of clinical utility
Authors: K Arndtz, K Maleki, A Hall, N Fisher
Journal: Gut (2012)

<h3>Introduction</h3> MRCP is a standard investigation in pancreato-biliary disease. Secretin-MRCP has been shown to have value in the investigation of suspected Sphincter of Oddi dysfunction (SOD). We have used this modality since 2005 and review here the clinical utility of secretin-MRCP in our institution, with reference to indications, findings, and clinical outcomes. <h3>Methods</h3> Patients undergoing secretin MRCP had a conventional MRCP, with determination of the best imaging plane for pancreatic and biliary ductal assessment. Secretin was then injected (1 U/Kg) and imaging was repeated every minute for 15 min, with documentation of ductal and exocrine responses. For this review, persistent ductal dilatation at 15 min was considered probable SOD and onset of pain after secretin possible SOD. All patients undergoing secretin-MRCP were identified from a radiology database. A casenote review was done, with documentation of indications and outcome measures as outlined above. <h3>Results</h3> Seventy patients underwent secretin-MRCP between 2005 and 2011 (mean age 44, range 17-84, M:F ratio 3:1). Indications were; biliary pain with abnormal LFTs or ultrasound (suspected type 2 SOD, N=9), pain with normal investigations (suspected type 3 SOD, N=42), unexplained pancreatitis (N=13) or assessment of complicated pancreatitis (N=6). Forty-four scans were normal, 12 showed anatomical abnormalities and 14 probable/possible SOD (persistent ductal dilatation six, secretin-induced pain six, both two). Most (13/14) MRCP diagnoses of SOD were in patients where the clinical indication was biliary pain. In patients with SOD, 4/13 underwent ERCP with sphincterotomy and 9/13 were treated conservatively. In patients undergoing sphincterotomy, there were no procedural complications and all had relief of pain (two patients later solicited further ERCP and sphincterotomy). <h3>Conclusion</h3> In this series, secretin-MRCP was valuable in a group of patients with suspected SOD. Most scan findings for this indication are normal, but in some patients an abnormal scan is valuable in giving a positive diagnosis. A subgroup of these may benefit from ERCP with sphincterotomy, while others respond adequately to conservative therapy. <h3>Competing interests</h3> None declared.
Coronary pressure-function and steady-state pressure-flow relations during autoregulation in the unanesthetized dog.
Authors: J M Canty
Journal: Circulation Research (1988)

The present study was intended to define the interrelation among endocardial flow, endocardial function, and coronary arterial pressure during spontaneous autoregulation in the left ventricle of chronically instrumented unanesthetized dogs. Steady-state sonomicrometric measurements of regional function and epicardial coronary artery pressure were used to determine the lower pressure limit of endocardial autoregulation while global indexes of myocardial demand remained constant. Transmural wall thickening in the circumflex bed remained unchanged (+/- 5% of control values) until coronary pressure fell below 39 +/- 5.6 (SD) mm Hg. Endocardial segment shortening was similarly constant until coronary pressure fell below 42 +/- 7.4 mm Hg. There was no significant change in endocardial flow as coronary pressure was reduced over the autoregulatory plateau from 84 to 49 mm Hg (1.05-0.99 ml/min/g, p = NS). Below the critical pressure limits, small additional reductions in pressure were associated with marked reductions in both endocardial flow and function. The coronary pressure-function relation was linear as well as steep in this range for both wall thickening (r = 0.94 +/- 0.05) and segment shortening (r = 0.96 +/- 0.03). Although the relation between endocardial flow and function showed more variability than pressure-function relations at low pressures, wall thickening reductions and endocardial flow reductions related on a nearly one-to-one basis. The present study establishes that the coronary pressure-function relation can be used to define the lower limit of endocardial autoregulation. It also indicates that the lower pressure limit of endocardial autoregulation is considerably less than in anesthetized animals (40 vs. 70 mm Hg) and that steady-state flow above this limit is controlled more tightly. Although these differences may relate to systemic hemodynamics, it seems likely that general anesthesia and/or acute surgical instrumentation alter coronary autoregulation under at least some experimental circumstances.
Cellular Mechanisms in Acid Secretion
Authors: A H Soll, M I Grossman
Journal: Annual Review of Medicine (1978)

The secretion of acid by the upper gastrointestinal tract first appeared among the lowest vertebrates on the phylogenetic tree and has since been retained by most species (1). The obvious physiological role for this acid is in the digestion of food by pepsin; however the importance of acid-peptic digestion in man appears quite limited in light of the normal nutritional status of persons with achlorhydria. The stomach may have retained the ability to secrete acid not primarily for digestion, but rather to sterilize the upper gastrointestinal tract. Although secretion of acid appears to be a dispensable function in man, acid does play a major role in the pathophysiology of peptic ulcer disease and of most of the bleeding disorders of the upper gastrointestinal tract. This review concerns our current, admittedly limited, knowledge of the cellular mechanisms of gastric acid secretion. It attempts to lay a groundwork for understanding certain aspects of acid-peptic disorders, particularly the pathophysiology and the mechanisms underlying the effectiveness of some of the therapeutic modalities used.
Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary disease
Authors: I Vogiatzis
Journal: Thorax (2005)

<b>Background:</b> Not all patients with severe chronic obstructive pulmonary disease (COPD) progressively hyperinflate during symptom limited exercise. The pattern of change in chest wall volumes (Vcw) was investigated in patients with severe COPD who progressively hyperinflate during exercise and those who do not. <b>Methods:</b> Twenty patients with forced expiratory volume in 1 second (FEV<sub>1</sub>) 35 (2)% predicted were studied during a ramp incremental cycling test to the limit of tolerance (Wpeak). Changes in Vcw at the end of expiration (EEVcw), end of inspiration (EIVcw), and at total lung capacity (TLCVcw) were computed by optoelectronic plethysmography (OEP) during exercise and recovery. <b>Results:</b> Two significantly different patterns of change in EEVcw were observed during exercise. Twelve patients had a progressive significant increase in EEVcw during exercise (early hyperinflators, EH) amounting to 750 (90) ml at Wpeak. In contrast, in all eight remaining patients EEVcw remained unchanged up to 66% Wpeak but increased significantly by 210 (80) ml at Wpeak (late hyperinflators, LH). Although at the limit of tolerance the increase in EEVcw was significantly greater in EH, both groups reached similar Wpeak and breathed with a tidal EIVcw that closely approached TLCVcw (EIVcw/TLCVcw 93 (1)% and 93 (3)%, respectively). EEVcw was increased by 254 (130) ml above baseline 3 minutes after exercise only in EH. <b>Conclusions:</b> Patients with severe COPD exhibit two patterns during exercise: early and late hyperinflation. In those who hyperinflate early, it may take several minutes before the hyperinflation is fully reversed after termination of exercise.
Secretory leucoprotease inhibitor binds to NF-κB binding sites in monocytes and inhibits p65 binding
Authors: Clifford C. Taggart, Sally-Ann Cryan, Sinead Weldon, Aileen Gibbons, Catherine M. Greene, Emer Kelly, Teck Boon Low, Shane J. O'Neill, Noel G. McElvaney
Journal: The Journal of Experimental Medicine (2005)

Secretory leucoprotease inhibitor (SLPI) is a nonglycosylated protein produced by epithelial cells. In addition to its antiprotease activity, SLPI has been shown to exhibit antiinflammatory properties, including down-regulation of tumor necrosis factor α expression by lipopolysaccharide (LPS) in macrophages and inhibition of nuclear factor (NF)-κB activation in a rat model of acute lung injury. We have previously shown that SLPI can inhibit LPS-induced NF-κB activation in monocytic cells by inhibiting degradation of IκBα without affecting the LPS-induced phosphorylation and ubiquitination of IκBα. Here, we present evidence to show that upon incubation with peripheral blood monocytes (PBMs) and the U937 monocytic cell line, SLPI enters the cells, becoming rapidly localized to the cytoplasm and nucleus, and affects NF-κB activation by binding directly to NF-κB binding sites in a site-specific manner. SLPI can also prevent p65 interaction with the NF-κB consensus region at concentrations commensurate with the physiological nuclear levels of SLPI and p65. We also demonstrate the presence of SLPI in nuclear fractions of PBMs and alveolar macrophages from individuals with cystic fibrosis and community-acquired pneumonia. Therefore, SLPI inhibition of NF-κB activation is mediated, in part, by competitive binding to the NF-κB consensus-binding site.
Repeated questionnaire about smoking at the annual meetings of the Japanese Respiratory Society held in 1996, 1999, 2001, 2003, 2005, 2007, 2010, and 2012
Authors: Jun Kobayashi, Tetsuhiro Shigenaga, Satoshi Kitamura
Journal: European Respiratory Journal (2012)

Questionnaire was distributed at the Annual Meetings of the Japanese Respiratory Society held in 1996, 1999, 2001, 2003, 2005, 2007, 2010, and 2012 repeatedly, in order to know how attendants think and behave about smoking as respiratory care specialists. Questionnaire paper was handed to the attendants around the table for meeting registration, and was recovered voluntarily in the boxes. Smoking prevalence of all attendants in 1996, 1999, 2001, 2003, 2005, 2007, and 2010 was 22.7%, 19.7%, 15.1%, 13.9%, 7.9%, 5.8%, and 3.7% respectively. Recovery rate of questionnaire in 1996, 1999, 2001, 2003, 2005, 2007, and 2010 was 64.7%, 70.4%, 48.6%, 52.2%, 85.9%, 93.2% and 87.8%, respectively. Smoking prevalence of physician in 2001,2003,2005,2007, and 2010 was 12.9%, 12.7%, 5.1%, 3.9%, and 2.4% respectively. Attendants from smoke-free hospital in 1996, 1999, 2001, 2003, 2005, 2007, and 2010 was 7.5%, 15.8%, 21.7%, 28.4%, 61.1%, 61.1%, and 72.5% respectively. Tobacco sales in the hospital retail shop were 55.2%, 49.1%, 44.8%, 39.0%, 19.4%, and 10.0%, respectively. Tobacco sales in the hospital vending machine was 50.3%, 41.5%, 37.2%, 31.1%, 12.3%, 7.1%, and 3.1% respectively. New 2012 data will be merged with those data, which will shows that smoking behaviors of the attendants have improved for 16 years. Japanese government recently accerelated to promote smoke-free lifestyle, planning to reduce smoking prevelence from 20% to 12% in the next ten years. Japanese Respiratory Association is responsible to encourage its members to intervene in smoking behavior or policy of hospitals which has been generous for tobacco sales.
Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo
Authors: Marie-Luise von Brühl, Konstantin Stark, Alexander Steinhart, Sue Chandraratne, Ildiko Konrad, Michael Lorenz, Alexander Khandoga, Anca Tirniceriu, Raffaele Coletti, Maria Köllnberger, Robert A. Byrne, Iina Laitinen, Axel Walch, Alexander Brill, Susanne Pfeiler, Davit Manukyan, Siegmund Braun, Philipp Lange, Julia Riegger, Jerry Ware, Annekathrin Eckart, Selgai Haidari, Martina Rudelius, Christian Schulz, Katrin Echtler, Volker Brinkmann, Markus Schwaiger, Klaus T. Preissner, Denisa D. Wagner, Nigel Mackman, Bernd Engelmann, Steffen Massberg
Journal: The Journal of Experimental Medicine (2012)

Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
Use of Three-Dimensional Tissue Cultures to Model Extravascular Transport and Predict In Vivo Activity of Hypoxia-Targeted Anticancer Drugs
Authors: Kevin O. Hicks, Frederik B. Pruijn, Timothy W. Secomb, Michael P. Hay, Richard Hsu, J. Martin Brown, William A. Denny, Mark W. Dewhirst, William R. Wilson
Journal: JNCI Journal of the National Cancer Institute (2006)

Because of the inefficient vasculature of solid tumors, anticancer drugs must penetrate relatively long distances through the extravascular compartment. The requirement for such diffusion may limit their activity, especially that of hypoxia-targeted drugs. We tested whether a three-dimensional pharmacokinetic/pharmacodynamic (PK/PD) model based on a representative mapped tumor microvascular network could predict the therapeutic activity of anticancer drugs in mouse xenograft tumors.Diffusion coefficients of the hypoxia-activated anticancer drug tirapazamine (TPZ) and of 15 TPZ analogs were estimated by measuring their transport through HT29 colon cancer multicellular layers (MCLs). Anoxic cytotoxic potency (by clonogenic assay) and metabolism of the TPZ analogs were measured in HT29 cell suspensions, and their plasma pharmacokinetics was measured in CD-1 nude mice. This information was used to create a spatially resolved PK/PD model for the tumor microvascular network. Model predictions were compared with actual hypoxic cell kill as measured by clonogenic assays on HT29 xenograft tumors 18 hours after treatment with each TPZ analog.Modeling TPZ transport in the tumor microvascular network showed substantial drug depletion in the most hypoxic regions, with predicted maximum cell kill of only 3 logs, compared with more than 10 logs if there were no transport impediment. A large range of tissue diffusion coefficients (0.027 x 10(-6)-1.87 x 10(-6) cm2/s) was observed for the TPZ analogs. There was a strong correlation between model-predicted and measured hypoxic cell kill (R2 = 0.89) but a poor correlation when the model did not include extravascular transport (R2 = 0.32).Extravascular transport in tumors, and its consequences for tumor cell killing, can be predicted by measuring drug penetration through MCLs in vitro and modeling pharmacokinetics at each position in three-dimensional microvascular networks.