tbuckley/cabot-search huggingface dataset:
Predictive and Pharmacodynamic Biomarker Studies in Tumor and Skin Tissue Samples of Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Treated With Erlotinib
Authors: Mark Agulnik, Gilda da Cunha Santos, David Hedley, Trudey Nicklee, Patricia Pintor dos Reis, James Ho, Gregory R. Pond, Heidi Chen, Shuo Chen, Yu Shyr, Eric Winquist, Denis Soulieres, Eric X. Chen, Jeremy A. Squire, Paula Marrano, Suzanne Kamel-Reid, Janet Dancey, Lillian L. Siu, Ming S. Tsao
Journal: Journal of Clinical Oncology (2007)

PURPOSE Pharmacodynamic tissue studies were conducted on a phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream signaling components, and markers of angiogenesis and apoptosis were evaluated to determine the relationship between correlative end points and clinical outcomes. PATIENTS AND METHODS Pretreatment and during-treatment tumor and skin biopsies, and archival tumor specimens were evaluated for EGFR, phosphorylated (p) -EGFR, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-Akt, Ki67, p27, p-nuclear factor kappa B (NFkappaB), p-signal transducer and activator of transcription 3 (STAT3), and EGFR gene copy number. Results On 37 archival samples, response to therapy was evident in two of four (50%) patients with high EGFR gene copy number tumors and in four of 27 (15%) patients with low gene copy number tumors. On nine paired tumor biopsies, elevated pretreatment levels of p27 and p-STAT3 predicted for prolonged time to progression (TTP) and overall survival (OS; P < or = .03). With treatment, a decrease in p-EGFR, p-NFkappaB, and p27 correlated with increased TTP, OS, or both TTP and OS, respectively (P < or = .04). Multidimensional scaling (MDS) models revealed clustering profiles of tumor markers by immunofluorescence could predict response. On 32 paired skin biopsies, suppression of p-EGFR with therapy correlated with increased OS (P = .045). CONCLUSION High EGFR gene copy in tumor specimens may predict which patients have an increased likelihood of response to erlotinib, and decreased p-EGFR level in skin biopsies during therapy may represent a potential surrogate marker for improved clinical outcome. MDS represents a novel way to evaluate the relationships between molecular markers and clinical outcome. Additional biomarker studies with larger sample sizes are required to elucidate HNSCC patients who may benefit from this targeted therapy.
Effect of QVA149 on lung function in the subgroup of patients with a history of exacerbations in the previous year and baseline ICS use from the SHINE study
Authors: Kenneth R. Chapman, Eric D. Bateman, Petter Olsson, Hungta Chen, Donald Banerji, Robert Fogel
Journal: European Respiratory Journal (2014)

Introduction   QVA149 is an approved, once-daily dual bronchodilator combination of LABA, indacaterol (IND), and LAMA, glycopyrronium bromide (GLY), for the maintenance treatment of symptomatic COPD. The SHINE study compared QVA149 with its mono-components, open-label tiotropium (OL TIO) and placebo (PBO). Here, we report the subgroup analysis of patients (pts) with history of ≥1 exacerbation and who used inhaled corticosteroids (ICS) at baseline in SHINE.   Methods   SHINE was a 26-wk, multicentre, parallel-group study that randomised pts with moderate-to-severe COPD (2:2:2:2:1) to receive QVA149 110/50μg, IND 150μg, GLY 50μg, OL TIO 18μg or PBO. This post-hoc analysis studied the effect of QVA149 on trough (t) FEV 1  and tFVC vs comparators using a linear mixed model in pts with ≥1 exacerbation (in the previous year) and baseline ICS use.   Results   In total, 542 pts (out of 2135 in full-analysis set; 25.4%) had a history of exacerbations. Of them, 465 (85.8%) pts were included in this subgroup analysis who used ICS at baseline and were continued on fixed ICS doses (Table). At Wk 26, QVA149 significantly improved tFEV 1  and tFVC vs comparators with the exception of non-significant improvement vs GLY for tFVC (Table).   Conclusion   In pts with a history of ≥1 exacerbation and baseline ICS use, QVA149 provided greater improvement in lung function vs IND, GLY, OL TIO or PBO.
Improvements in 1-Year Cardiovascular Clinical Outcomes Associated with a Hospital-Based Discharge Medication Program
Authors: Jason M. Lappé, Joseph B. Muhlestein, Donald L. Lappé, Rodney S. Badger, Tami L. Bair, Ruth Brockman, Thomas K. French, Linda C. Hofmann, Benjamin D. Horne, Susan Kralick-Goldberg, Nan Nicponski, Janette A. Orton, Robert R. Pearson, Dale G. Renlund, Holly Rimmasch, Colleen Roberts, Jeffrey L. Anderson
Journal: Annals of Internal Medicine (2004)

Background: Despite recent advances in the treatment and prevention of cardiovascular disease, a treatment gap for secondary prevention medications still exists. Objective: To develop and implement a program ensuring appropriate prescription of aspirin, statins, β-blockers, angiotensin-converting enzyme inhibitors, and warfarin at hospital discharge. Design: A nonrandomized before–after study comparing patients hospitalized before (1996–1998) and after (1999–2002) implementation of a discharge medication program (DMP). Patients were followed for up to 1 year. Setting: The 10 largest hospitals in the Utah-based Intermountain Health Care system. Patients: In the pre-DMP and DMP time periods, 26 000 and 31 465 patients, respectively, were admitted to cardiovascular services (n = 57 465). Measurements: Prescription of indicated medications at hospital discharge; postdischarge death or readmission. Results: By 1 year, the rate of prescription of each medication increased significantly to more than 90% (P < 0.001); this rate was sustained. At 1 year, unadjusted absolute event rates for readmission and death, respectively, were 210 per 1000 person-years and 96 per 1000 person-years before DMP implementation and 191 per 1000 person-years and 70 per 1000 person-years afterward. Relative risk for death and readmission at 30 days decreased after DMP implementation; hazard ratios (HRs) for death and readmission were 0.81 (95% CI, 0.73 to 0.89) and 0.92 (CI, 0.87 to 0.99) (P < 0.001 and P = 0.017, respectively). At 1 year, risk for death continued to decrease (hazard ratio, 0.79 [CI, 0.75 to 0.84]; P < 0.001) while risk for readmission stabilized (hazard ratio, 0.94 [CI, 0.90 to 0.98]; P = 0.002), probably because survivors had more opportunities to be readmitted. Limitations: The study design was observational and nonrandomized, and the authors could not control for potential confounders or determine the extent to which secular trends accounted for the observed improvements. Conclusions: A relatively simple quality improvement program aimed at enhancing the prescription of appropriate discharge medications among cardiovascular patients is feasible and can be sustained within an integrated multihospital system. Such a program may be associated with improvements in cardiovascular readmission rates and mortality.
Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma
Authors: C Ward
Journal: Thorax (2002)

Background: There are few data in asthma relating airway physiology, inflammation and remodelling and the relative effects of inhaled corticosteroid (ICS) treatment on these parameters. A study of the relationships between spirometric indices, airway inflammation, airway remodelling, and bronchial hyperreactivity (BHR) before and after treatment with high dose inhaled fluticasone propionate (FP 750 μg bd) was performed in a group of patients with relatively mild but symptomatic asthma. Methods: A double blind, randomised, placebo controlled, parallel group study of inhaled FP was performed in 35 asthmatic patients. Bronchoalveolar lavage (BAL) and airway biopsy studies were carried out at baseline and after 3 and 12 months of treatment. Twenty two normal healthy non-asthmatic subjects acted as controls. Results: BAL fluid eosinophils, mast cells, and epithelial cells were significantly higher in asthmatic patients than in controls at baseline (p&lt;0.01). Subepithelial reticular basement membrane (rbm) thickness was variable, but overall was increased in asthmatic patients compared with controls (p&lt;0.01). Multiple regression analysis explained 40% of the variability in BHR, 21% related to rbm thickness, 11% to BAL epithelial cells, and 8% to BAL eosinophils. The longitudinal data corroborated the cross sectional model. Forced expiratory volume in 1 second improved after 3 months of treatment with FP with no further improvement at 12 months. PD<sub>20</sub> improved throughout the study. BAL inflammatory cells decreased following 3 months of treatment with no further improvement at 12 months (p&lt;0.05 <i>v</i> placebo). Rbm thickness decreased in the FP group, but only after 12 months of treatment (mean change –1.9, 95% CI –3 to –0.7 μm; p&lt;0.01 <i>v</i> baseline, p&lt;0.05 <i>v</i> placebo). A third of the improvement in BHR with FP was associated with early changes in inflammation, but the more progressive and larger improvement was associated with the later improvement in airway remodelling. Conclusion: Physiology, airway inflammation and remodelling in asthma are interrelated and improve with ICS. Changes are not temporally concordant, with prolonged treatment necessary for maximal benefit in remodelling and PD<sub>20</sub>. Determining the appropriate dose of inhaled steroids only by reference to symptoms and lung function, as specified in current international guidelines, and even against indices of inflammation may be over simplistic. The results of this study support the need for early and long term intervention with ICS, even in patients with relatively mild asthma.
Pulmonary Arterial Hypertension
Authors: John H. Newman, Barry L. Fanburg, Stephen L. Archer, David B. Badesch, Robyn J. Barst, Joe G.N. Garcia, Peter N. Kao, James A. Knowles, James E. Loyd, Michael D. McGoon, Jane H. Morse, William C. Nichols, Marlene Rabinovitch, David M. Rodman, Troy Stevens, Rubin M. Tuder, Norbert F. Voelkel, Dorothy B. Gail
Journal: Circulation (2004)
Tissue Factor–Activated Coagulation Cascade in the Tumor Microenvironment Is Critical for Tumor Progression and an Effective Target for Therapy
Authors: Yuan Liu, Pengfei Jiang, Katerina Capkova, Dong Xue, Longwu Ye, Subhash C. Sinha, Nigel Mackman, Kim D. Janda, Cheng Liu
Journal: Cancer Research (2011)

Tissue factor (TF), a rate-limiting enzyme cofactor in activating coagulation, is highly expressed in a wide spectrum of human tumor and tumor stromal cells. Using TF-deficient cancer cells and a conditional TF-knockout mouse model, we show that TF expressed by cancer cells, but not by the host stromal cells, plays a critical role in tumor growth. In the tumor microenvironment, serum coagulation factors are readily extravasated and therefore lead to continuous TF-mediated activation of coagulation proteases. To target this highly specific cascade of serine proteases, we used both a TF:VIIa inhibitor and doxorubicin-based prodrugs that are selectively activated by TF:FVIIa, FXa, and thrombin. Treatment with the TF:FVIIa inhibitor led to growth retardation in breast tumor models. In contrast, treatment with the prodrug eliminated primary tumor cells and lung metastases without apparent toxicity. Our findings offer preclinical proof of principle that targeting the coagulation cascade that is activated in the tumor microenvironment can be a highly effective approach for cancer therapy.
Regulation of the Receptor Specificity and Function of the Chemokine RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) by Dipeptidyl Peptidase IV (CD26)-mediated Cleavage
Authors: Tamas Oravecz, Marina Pall, Gregory Roderiquez, Mark D. Gorrell, Mary Ditto, Nga Y. Nguyen, Robert Boykins, Edward Unsworth, Michael A. Norcross
Journal: The Journal of Experimental Medicine (1997)

CD26 is a leukocyte activation marker that possesses dipeptidyl peptidase IV activity but whose natural substrates and immunological functions have not been clearly defined. Several chemo-kines, including RANTES (regulated on activation, normal T cell expressed and secreted), have now been shown to be substrates for recombinant soluble human CD26. The truncated RANTES(3–68) lacked the ability of native RANTES(1–68) to increase the cytosolic calcium concentration in human monocytes, but still induced this response in macrophages activated with macrophage colony-stimulating factor. Analysis of chemokine receptor messenger RNAs and patterns of desensitization of chemokine responses showed that the differential activity of the truncated molecule results from an altered receptor specificity. RANTES(3–68) showed a reduced activity, relative to that of RANTES(1–68), with cells expressing the recombinant CCR1 chemokine receptor, but retained the ability to stimulate CCR5 receptors and to inhibit the cytopathic effects of HIV-1. Our results indicate that CD26-mediated processing together with cell activation–induced changes in receptor expression provides an integrated mechanism for differential cell recruitment and for the regulation of target cell specificity of RANTES, and possibly other chemokines.
A VIRUS-INDUCED EPIZOOTIC HEMORRHAGIC DISEASE OF THE VIRGINIA WHITE-TAILED DEER (ODOCOILEUS VIRGINIANUS)
Authors: Richard E. Shope, Lester G. MacNamara, Robert Mangold
Journal: The Journal of Experimental Medicine (1960)

A circumscribed natural outbreak of a highly fatal disease of deer, which we have designated epizootic hemorrhagic disease (EHD), has been studied. The disease has proven readily transmissible in deer but not in other experimental or domestic animals tested, nor in embryonating eggs or deer kidney cell cultures. The causative agent is a virus which is readily filterable and is capable of storage, either frozen or in glycerol, for relatively long periods of time. It produces a solid immunity in the few animals that survive and the blood sera of such convalescent animals contain virus-neutralizing antibodies. The disease is one in which large and small hemorrhages occur in both the viscera and skeletal structures of the body, as well as in the subcutaneous tissues. It is probably the same as one known popularly in the southeastern United States as "black tongue" of deer. It is unrelated to epidemic hemorrhagic fever of man or to the disease caused in horses by the equine arteritis virus. At least two serologically different types of EHD virus exist. The New Jersey strain is of greater lethality for experimental deer than the serologically different one obtained from an outbreak that occurred in South Dakota a year after the New Jersey epizootic.
“Abnormal” Fasting Plasma Glucose During Pregnancy
Authors: Veerasamy Seshiah, Vijayam Balaji, Arunachalam Panneerselvam, Madhuri S. Balaji
Journal: Diabetes Care (2008)

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy (1) and is a major medical complication of pregnancy. Untreated, the would-be mother and yet-to-be-born child are likely to suffer morbidity and mortality.

The World Health Organization criterion for diagnosis of GDM is 2-h plasma glucose (PG) ≥140 mg/dl on a 75-g oral glucose tolerance test (2). However, birth weight of the child and cumulative risk of type 2 diabetes both increase with any rise in 2-h PG ≥120 mg/dl (3). Further, data regarding the correlation between maternal fasting PG (FPG) levels and macrosomia are scant. Hence, we analyzed the relationship between the birth weight of neonates …
Co-Sensitization Patterns to Tree Nuts in a Pediatric Population
Authors: Brooke I. Polk, Chitra Dinakar, Charles S. Barnes, Jodi A. Shroba, Katherine A. Preston, Jeanne L.D. Osnas, Alison L. Humphrey, David A. Jara, Jill R. Hanson, Neha N. Patel, Christina E. Ciaccio
Journal: Journal of Allergy and Clinical Immunology (2015)

Tree nut allergy is a common, generally lifelong, and potentially severe food allergy that can be psychosocially and nutritionally limiting. Once deemed allergic to a particular tree nut, patients are often instructed to avoid all tree nuts. A less restrictive approach could be proposed if cross-reactivity patterns among select subsets of nuts were determined. A retrospective analysis of serum specific IgE levels (ImmunoCAP, Phadia, Uppsala, Sweden) to almond, Brazil nut, cashew, chestnut, coconut, hazelnut, macadamia, pecan, pistachio, and walnut was performed. Pearson correlation coefficients (rho, ρ) were calculated. Correlation strength was stratified as weak (ρ<0.5), moderate (0.5<ρ<0.8) or strong (ρ>0.8). Correlations with milk and peanut specific IgEs were used as controls. Results from 5849 panels of food specific IgEs collected between 2000 and 2012 were retrieved from the clinical records of one institution. Of all relationships assayed between tree nuts, a strong correlation was noted only between cashew and pistachio (ρ=0.955, n=1227, p<0.0001), and between pecan and walnut (ρ=0.940, n=1327, p<0.0001). Other tree nut pairs exhibited weak to moderate correlations similar to that between individual tree nuts and milk, and between individual tree nuts and peanuts. A strong relationship exists between cashew and pistachio (Anacardiaceae) and between pecan and walnut (Juglandaceae). Our results imply that it is likely unnecessary to avoid ingestion of phylogenetically unrelated nuts over concern of cross-reactivity. Further studies could potentially elucidate clinical cross-reactivity and possibly eliminate the need for pan-avoidance of all nuts in certain patients.
Some bases of differences in vascular response to sympathetic activity.
Authors: J A Bevan
Journal: Circulation Research (1979)

Basic patterns of neuroeffector organization vary widely in the vasculature, in general, with vessel diameter and type, and confer distinctive properties. The smaller the vessel, the more intimate the neuroeffector relationship, the more localized the action of the released transmitter, and the more important myogenic conduction compared to transmitter diffusion for the coordination of vascular effector response. Seemingly superimposed upon these basic general patterns are other variable features, conferring upon vessels of similar size and type diversity of function. These variables include sensitivity and magnitude and possible location of alpha- and beta-receptors and their subtypes, presence and nature of intrinsic vascular tone, and the density and pattern of adrenergic innervation to mention the more important. Functional diversity in neuroeffector characteristics can, to some extent, be understood in relation to embryological development, neurotrophic influences, effector regulation of innervation, and the mural response to an increase in intravascular pressure.
[630] CAN DEPLETION OF B-CELLS BY ANTI-CD20 MONOCLONAL ANTIBODY IN HCV+ MIXED CRYOGLOBULINEMIA (MC) IMPROVE LIVER CIRRHOSIS?
Authors: A. Petrarca, L. Rigacci, C. Giannini, R. Caporale, P. Montalto, A. Bosi, G. Laffi, A.L. Zignego
Journal: Journal of Hepatology (2007)
Syndrome of symptomatic adult acetabular dysplasia (SAAD syndrome)
Authors: F Birrell
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objectives:</b> To determine the prevalence of acetabular dysplasia in subjects presenting with hip pain to primary care and its relationship with radiographic osteoarthritis (OA) of the hip. <b>Design:</b> Cross sectional analysis of a prospective cohort. <b>Setting:</b> 35 general practices across the UK. <b>Subjects:</b> 195 patients (63 male, 132 female) aged 40 years and over presenting with a new episode of hip pain <b>Results:</b> The prevalence of acetabular dysplasia in this study of new presenters with hip pain was high (32%). There was no significant relationship between acetabular dysplasia and radiographic OA overall. <b>Conclusions:</b> The high prevalence of acetabular dysplasia across all grades of OA severity suggests that dysplasia itself may be an important cause of hip pain ("symptomatic adult acetabular dysplasia").
Evaluation of the ϵfficacy of medical thoracoscopy in the τreatment of pleural ιnfection
Authors: Andreas Koulelidis, Stavros Anevlavis, Kostas Archontogiorgis, Dimitrios Mikroulis, Kostas Kltsas, George Kouliatsis, Panos Boglou, Savvas Eleftheriadis, Demosthenes Bouros, Marios Froudarakis
Journal: European Respiratory Journal (2014)

Background : The role of rigid thoracoscopy under local anesthesia in pleural infection is unknown as few studies reported results, none of them prospective and randomized. The aim of our study was to evaluate the efficacy of medical thoracoscopy in comparison to the treatment with pleural drainage in pleural infection.  Methods : Between 01/2008 and 08/2013, 63 patients (median age 54, 52 males) with primary non-tuberculous pleural infection were treated in our department. We compared characteristics and outcome of patients with pleural infection, who underwent rigid thoracoscopy under local anesthesia only, versus classic chest tube drainage.  Results  All 63 patients initially received antibiotic treatment for their infection. 21 patients (18 early and 3 late) underwent thoracoscopy under local anesthesia and 42 chest tube drainage for the treatment of their pleural infection. No significant difference was observed in age, gender, presence of comorbidities, pleural pH, LDH, proteins, serum CRP, or amount of drained fluid between the two groups. Significant difference in favor of thoracoscopy was observed in total days of hospitalization (p=0.01), days of pleural drainage (p=0.02), referral to surgery (p=0.02). A trend towards a worst outcome of patients referred from another hospital was noted overall (p=0.09), but especially in relation to the classic treatment (p=0.06).  Conclusion : In this retrospective cohort study medical thoracoscopy provides better results than chest tube drainage in an experienced center of the management of patients with pleural infections. These results should be further confirmed by a prospective randomized study.
Myocardial Contractile Reserve by Dobutamine Stress Echocardiography Predicts Improvement in Ejection Fraction With β-Blockade in Patients With Heart Failure
Authors: Eric J. Eichhorn, Paul A. Grayburn, Susan A. Mayer, Martin St John Sutton, Christopher Appleton, Jonathan Plehn, Jae Oh, Barry Greenberg, Anthony DeMaria, Robert Frantz, Heidi Krause-Steinrauf
Journal: Circulation (2003)

beta-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF.Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r=-0.72, P<0.0001) and was the most significant multivariate predictor of change in LVEF (P=0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687+/-333 versus 420+/-246 pg/mL, P<0.05) and greater decrease in plasma norepinephrine in response to bucindolol (-249+/-171 versus -35+/-277 pg/mL, P<0.05).This study suggests a direct relationship between contractile reserve and improvement in LVEF with beta-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.