tbuckley/cabot-search huggingface dataset:
Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance
Authors: Amany F. Elbehairy, Casey E. Ciavaglia, Katherine A. Webb, Jordan A. Guenette, Dennis Jensen, Sahar M. Mourad, J. Alberto Neder, Denis E. O’Donnell
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Several studies in mild chronic obstructive pulmonary disease (COPD) have shown a higher than normal ventilatory equivalent for carbon dioxide ([Formula: see text]e/[Formula: see text]co2) during exercise. Our objective was to examine pulmonary gas exchange abnormalities and the mechanisms of high [Formula: see text]e/[Formula: see text]co2 in mild COPD and its impact on dyspnea and exercise intolerance.Twenty-two subjects (11 patients with GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade 1B COPD, 11 age-matched healthy control subjects) undertook physiological testing and a symptom-limited incremental cycle exercise test with arterial blood gas collection.Patients (post-bronchodilator FEV1: 94 ± 10% predicted; mean ± SD) had evidence of peripheral airway dysfunction and reduced peak oxygen uptake compared with control subjects (80 ± 18 vs. 113 ± 24% predicted; P<0.05). Arterial blood gases were within the normal range and effective alveolar ventilation was not significantly different from control subjects throughout exercise. The alveolar-arterial O2 tension gradient was elevated at rest and throughout exercise in COPD (P<0.05). [Formula: see text]e/[Formula: see text]co2, dead space to tidal volume ratio (Vd/Vt), and arterial to end-tidal CO2 difference were all higher (P<0.05) in patients with COPD than in control subjects during exercise. In patients with COPD versus control subjects, there was significant dynamic hyperinflation and greater tidal volume constraints (P<0.05). Standardized dyspnea intensity ratings were also higher (P<0.05) in patients with COPD versus control subjects in association with higher ventilatory requirements. Within all subjects, Vd/Vt correlated with the [Formula: see text]e/[Formula: see text]co2 ratio during submaximal exercise (r=0.780, P<0.001).High Vd/Vt was the most consistent gas exchange abnormality in smokers with only mild spirometric abnormalities. Compensatory increases in minute ventilation during exercise maintained alveolar ventilation and arterial blood gas homeostasis but at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD.
Nerve growth factor is released by IL-1 and induces hyperresponsiveness of the human isolated bronchus
Authors: N. Frossard, E. Naline, C. Olgart Höglund, O. Georges, C. Advenier
Journal: European Respiratory Journal (2005)

Nerve growth factor (NGF) is a neurotrophic factor essential for the development and survival of neurons, and is also an important mediator of inflammation. It is released by airway cells stimulated by interleukin (IL)-1β. As IL-1β induces airway hyperresponsiveness (AHR) to the tachykinin NK-1 receptor agonist [Sar 9 ,Met(O 2 ) 11 ]-substance P in human isolated bronchi, the aim of this study was to determine whether IL-1β was able to induce NGF release from isolated bronchi, and whether NGF might participate into IL-1β-induced AHR. IL-1β (10 ng·mL −1 ; 21°C; 15 h) increased the release of NGF from human isolated bronchi in vitro , and, in organ bath studies, the response of human bronchi to [Sar 9 ,Met(O 2 ) 11 ]-substance P (0.1 µm). A significant correlation was found between these responses. AHR induced by IL-1β was abolished by a blocking anti-human NGF antibody. Finally, NGF (1 ng·mL −1 ; 37°C; 0.5 h) by itself induced a significant increase in [Sar 9 ,Met(O 2 ) 11 ]-substance P responsiveness. By contrast, it did not change the maximal contraction to acetylcholine. In conclusion, the present study clearly demonstrated that nerve growth factor may participate in the airway hyperresponsiveness induced by interleukin-1β, which supports the neuro-immune cross-talk that may be active in the development of hyperresponsiveness in the human airways, and suggests nerve growth factor is active in the airways in asthma.
Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC)
Authors: S. J. Faivre, E. Raymond, J. Douillard, E. Boucher, H. Y. Lim, J. S. Kim, S. Lanzalone, M. J. Lechuga, L. Sherman, A. Cheng
Journal: Journal of Clinical Oncology (2007)

3546 Background: VEGFRs and PDGFRs play key roles in the proliferation of HCC and tumor angiogenesis. Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3. This study reports the results of the first European/Asian, open-label, single-agent SU phase II study in pts with unresectable HCC. Methods: Key eligibility criteria include histologically confirmed measurable HCC; ECOG PS =1; Child-Pugh (CP)-A/-B; adequate organ function; and no brain metastases, ascites, or prior liver transplant. Pts receive SU at 50 mg/d for 4 wks every 6 wks (4/2 schedule). The primary endpoint is ORR by RECIST. Other assessments include safety (NCI CTCAE v3.0), PK and antitumor activity (tumor density, volumetric measurement of percent tumor necrosis [VMTN] and intratumor blood perfusion on monthly CT scan). Results: 37 pts (median 61 yrs [range 34–82]; male 92%; PS 0:1, 50%:44%; CP-A/-B, 84%/14%; 40.5% with prior local treatments) received a median of 2 cycles (range 1–7+) of SU. Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and hemorrhage (14%). Grade 1–2 skin toxicity was frequently reported. Dose reductions were required in 27% of pts. Four pts developed grade 5 events including ascites, edema, bleeding, drowsiness and hepatic encephalopathy. Decreased tumor density was observed in 68% of pts and activity assessed by VMTN showed minor (&lt;50%) and major (=50%) post-treatment tumor necrosis in 25% and 46% of pts, respectively. One confirmed PR and 39% SD (best confirmed response) have been achieved. Post-treatment tumor blood perfusion parameters (blood volume and blood flow), decreased by an average of 39% (range: 13–72%). Preliminary PK data do not suggest any differences in drug exposure between risk groups (CP-A or CP-B). Conclusions: Evidence of =50% tumor necrosis in 46% of pts receiving SU suggests outstanding antitumor activity. However, change in tumor size (RECIST) may be inappropriate as a primary endpoint to evaluate SU in patients with HCC. Initial safety findings indicate that further evaluation of SU in this pt population with improved pt selection and dose schedule modification is warranted. [Table: see text]
Down-Regulation of TLR9 Expression Affects the Maturation and Function of Murine Bone Marrow-Derived Dendritic Cells Induced by CpG
Authors: Ling Ma, Guangfeng Zhao, Chunyan Hua, Xiaoxi Li, Xiaoyin Zhao, Lingyun Sun, Yayi Hou
Journal: Cellular and Molecular Immunology (2009)
Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models
Authors: Ling Cen, Brett L. Carlson, Jenny L. Pokorny, Ann C. Mladek, Patrick T. Grogan, Mark A. Schroeder, Paul A. Decker, S. Keith Anderson, Caterina Giannini, Wenting Wu, Karla V. Ballman, Gaspar J. Kitange, Jann N. Sarkaria
Journal: Neuro-Oncology (2013)

Temozolomide (TMZ) is important chemotherapy for glioblastoma multiforme (GBM), but the optimal dosing schedule is unclear. The efficacies of different clinically relevant dosing regimens were compared in a panel of 7 primary GBM xenografts in an intracranial therapy evaluation model. Protracted TMZ therapy (TMZ daily M–F, 3 wk every 4) provided superior survival to a placebo-treated group in 1 of 4 O6-DNA methylguanine-methyltransferase (MGMT) promoter hypermethylated lines (GBM12) and none of the 3 MGMT unmethylated lines, while standard therapy (TMZ daily M–F, 1 wk every 4) provided superior survival to the placebo-treated group in 2 of 3 MGMT unmethylated lines (GBM14 and GBM43) and none of the methylated lines. In comparing GBM12, GBM14, and GBM43 intracranial specimens, both GBM14 and GBM43 mice treated with protracted TMZ had a significant elevation in MGMT levels compared with placebo. Similarly, high MGMT was found in a second model of acquired TMZ resistance in GBM14 flank xenografts, and resistance was reversed in vitro by treatment with the MGMT inhibitor O6-benzylguanine, demonstrating a mechanistic link between MGMT overexpression and TMZ resistance in this line. Additionally, in an analysis of gene expression data, comparison of parental and TMZ-resistant GBM14 demonstrated enrichment of functional ontologies for cell cycle control within the S, G2, and M phases of the cell cycle and DNA damage checkpoints. Across the 7 tumor models studied, there was no consistent difference between protracted and standard TMZ regimens. The efficacy of protracted TMZ regimens may be limited in a subset of MGMT unmethylated tumors by induction of MGMT expression.
Repression of B7.2 on Self-reactive B Cells Is Essential to Prevent Proliferation and Allow Fas-mediated Deletion by CD4+ T Cells
Authors: Jeffrey C. Rathmell, Sylvie Fournier, Bennett C. Weintraub, James P. Allison, Christopher C. Goodnow
Journal: The Journal of Experimental Medicine (1998)

Peripheral tolerance mechanisms normally prevent delivery of T cell help to anergic self-reactive B cells that accumulate in the T zones of spleen and lymph nodes. Chronic exposure to self-antigens desensitizes B cell antigen receptor (BCR) signaling on anergic B cells so that they are not stimulated into clonal expansion by CD4+ T cells but instead are eliminated by Fas (CD95)-induced apoptosis. Because a range of BCR-induced signals and responses are repressed in anergic B cells, it is not known which of these are critical to regulate for Fas-mediated peripheral tolerance. Display of the costimulatory molecule, B7.2 (CD86), represents a potentially important early response to acute BCR engagement that is poorly induced by antigen on anergic B cells. We show here that restoring B7.2 expression on tolerant B cells using a constitutively expressed B7.2 transgene is sufficient to prevent Fas-mediated deletion and to trigger extensive T cell–dependent clonal expansion and autoantibody secretion in the presence of specific T cells. Dysregulated expression of B7.2 on tolerant B cells caused a more extreme reversal of peripheral tolerance than that caused by defects in Fas or Fas ligand, and resulted in T cell–dependent clonal expansion and antibody secretion comparable in magnitude to that made by foreign antigen-specific B cells. These findings demonstrate that repression of B7.2 is critical to eliminate autoreactive B cells by Fas in B cell–T cell interactions. The possible role of B7.2 dysregulation in systemic autoimmune diseases is discussed.
Androgen Receptors Mediate Hypertrophy in Cardiac Myocytes
Authors: James D. Marsh, Michael H. Lehmann, Rebecca H. Ritchie, Judith K. Gwathmey, Glenn E. Green, Rick J. Schiebinger
Journal: Circulation (1998)

Background —The role of androgens in producing cardiac hypertrophy by direct action on cardiac myocytes is uncertain. Accordingly, we tested the hypothesis that cardiac myocytes in adult men and women express an androgen receptor gene and that myocytes respond to androgens by a hypertrophic response. Methods and Results —We used reverse transcription–polymerase chain reaction methods to demonstrate androgen receptor transcripts in multiple tissues and [ 3 H]phenylalanine incorporation and atrial natriuretic peptide secretion as markers of hypertrophy in cultured rat myocytes. Messenger RNA encoding androgen receptors was detected in myocytes of male and female adult rats, neonatal rat myocytes, rat heart, dog heart, and infant and adult human heart. Both testosterone and dihydrotestosterone produced a robust receptor-specific hypertrophic response in myocytes, determined by indices of protein synthesis and atrial natriuretic peptide secretion. Conclusions —Androgen receptors are present in cardiac myocytes from multiple species, including normal men and women, in a context that permits androgens to modulate the cardiac phenotype and produce hypertrophy by direct, receptor-specific mechanisms. There are clinical implications for therapeutic or illicit use of androgens in humans.
A Genome-wide screen identifies frequently methylated genes in haematological and epithelial cancers
Authors: Thomas Dunwell, Luke Hesson, Tibor A Rauch, Lihui Wang, Richard E Clark, Ashraf Dallol, Dean Gentle, Daniel Catchpoole, Eamonn R Maher, Gerd P Pfeifer, Farida Latif
Journal: Molecular Cancer (2010)

Genetic as well as epigenetic alterations are a hallmark of both epithelial and haematological malignancies. High throughput screens are required to identify epigenetic markers that can be useful for diagnostic and prognostic purposes across malignancies.Here we report for the first time the use of the MIRA assay (methylated CpG island recovery assay) in combination with genome-wide CpG island arrays to identify epigenetic molecular markers in childhood acute lymphoblastic leukemia (ALL) on a genome-wide scale. We identified 30 genes demonstrating methylation frequencies of > or =25% in childhood ALL, nine genes showed significantly different methylation frequencies in B vs T-ALL. For majority of the genes expression could be restored in methylated leukemia lines after treatment with 5-azaDC. Forty-four percent of the genes represent targets of the polycomb complex. In chronic myeloid leukemia (CML) two of the genes, (TFAP2A and EBF2), demonstrated increased methylation in blast crisis compared to chronic phase (P < 0.05). Furthermore hypermethylation of an autophagy related gene ATG16L2 was associated with poorer prognosis in terms of molecular response to Imatinib treatment. Lastly we demonstrated that ten of these genes were also frequently methylated in common epithelial cancers.In summary we have identified a large number of genes showing frequent methylation in childhood ALL, methylation status of two of these genes is associated with advanced disease in CML and methylation status of another gene is associated with prognosis. In addition a subset of these genes may act as epigenetic markers across hematological malignancies as well as common epithelial cancers.
Ascending aorta-right pulmonary artery anastomosis: Waterston's operation
Authors: F. Alvarez-Diaz, J. M. Brito, G. Cordovilla, J. P. De Leon, P. A. Sanchez, C. M. Bordiu
Journal: Thorax (1973)

The results of 180 cases of congenital heart disease with diminished pulmonary flow operated upon with Waterston9s technique are presented. It is considered that Waterston9s operation is to be preferred in children under 2 years of age and in older children who have had a previous thrombotic or insufficient Blalock operation and in whom total correction is not indicated. The problem of pseudotruncus with hypoplastic pulmonary arteries is discussed. The convenience of the Waterston operation in these cases, and the importance of creating an anastomosis at the pulmonary bifurcation and as far back as possible in the aorta, is emphasized. The need to perform this technique in the correct way is stressed. This will avoid the kinking and pulling of the right pulmonary artery, which are causes of preferential blood flow to the right lung, as we have demonstrated experimentally. The possible complications caused by such a technical failure are discussed. The necessity for previous angiocardiographic study, in order properly to repair the defect during total correction, is also considered.
Early pulmonary disease in systemic sclerosis: a comparison between carbon monoxide transfer factor and static lung compliance.
Authors: A Scheja, A Akesson, P Wollmer, F A Wollheim
Journal: Annals of the Rheumatic Diseases (1993)

OBJECTIVES--Pulmonary disease is responsible for considerable morbidity and mortality in systemic sclerosis (SSc). Static lung compliance (Cst) has been observed to be decreased more often in SSc than the vital capacity, indicating that it is a sensitive measure of lung restriction. In this study Cst was compared with the carbon monoxide transfer factor (TLCO), a widely used measure of the function of the alveolar capillary unit, and with lung volumes in 59 patients with confirmed or suspected SSc. METHODS--Cst was calculated from the oesophageal pressure at different lung volumes and the TLCO was measured with the single breath method. RESULTS--The TLCO was found to be the earliest sign of pulmonary disease and was already decreased at a disease duration of one year or less. Surprisingly, no relation was found between the TLCO and smoking habits, nor the degree of peripheral vascular disease. The TLCO correlated with the Cst and vital capacity. CONCLUSIONS--An early pulmonary lesion can be identified in patients with SSc with decreased TLCO at a time when no fibrotic changes are manifested.
Obesity-Induced Hypertension
Authors: John E. Hall, Jussara M. do Carmo, Alexandre A. da Silva, Zhen Wang, Michael E. Hall
Journal: Circulation Research (2015)

Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin–angiotensin–aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin–angiotensin–aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase.
B-TYPE NATRIURETIC PEPTIDE MAY PROMOTE ARRHYTHMIA IN HEART FAILURE THROUGH INHIBITING TRANSIENT OUTWARD POTASSIUM CURRENT
Authors: Junping Sun, Yutao Xi, Geru Wu, Nancy Cheng, Shahrzad Abbasi, MacArthur A. Elayda, Suwei Wang, Reynolds M. Delgado, Jie Cheng
Journal: Journal of the American College of Cardiology (2013)
Non-invasive In-Vivo Imaging of Stem Cells after Transplantation in Cardiovascular Tissue
Authors: Anders Bruun Mathiasen, Jens Kastrup
Journal: Theranostics (2013)

Stem cell therapy for degenerative diseases, including ischemic heart disease is now a clinical reality. In the search for the optimal cell type for each patient category, many different stem cell subpopulations have been used. In addition, different cell processing procedures and delivery methods have been utilized. Moreover, choices of endpoints have varied between studies. Diverging results have been reported from clinical experiences, with some studies demonstrating promising results with improved cardiac function and reduced mortality and clinical symptoms, and others have seen no improvements. To better understand the underlying mechanisms of these results, a reverse translation from bedside to bench has been opened. Non-invasive cell tracking after implantation has a pivotal role in this translation. Imaging based methods can help elucidate important issues such as retention, migration and efficacy of the transplanted cells. Great effort is being made in finding new and better imaging techniques for different imaging modalities, and much have already been learned. But there are still many unanswered questions. In this review, we give an overview of the imaging modalities used for cell tracking and summarize the latest advances within the field.
One-Year Treatment with Different Dosing Schedules of Fluticasone Propionate in Childhood Asthma
Authors: MARTIN J. VISSER, DIRKJE S. POSTMA, LIDIA R. ARENDS, TJALLING W. DE VRIES, ERIC J. DUIVERMAN, PAUL L. P. BRAND
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Dose-dependent effects of inhaled corticosteroids have been described. Although it has been advised to start treatment with inhaled corticosteroids with a high dose tapering off subsequently (stepdown approach), no clinical studies have assessed this strategy. We compared two different dosage schedules of inhaled fluticasone propionate (FP) in chronic persistent childhood asthma with respect to efficacy (airways hyperresponsiveness [PD20], lung function, exhaled nitric oxide [eNO]) and safety (height). During this double-blind study, children with asthma (aged 6–10 yr) were randomized to receive either FP 200 μ g/d (constant dose approach) or to start with 1000 μ g/d with two monthly reductions to 500, 200, and 100 μ g/d (stepdown approach). PD20 improved in both approaches during treatment with FP, with a significantly better PD20 after 2 mo of 1000 μ g/d followed by 500 μ g/d in the stepdown approach versus 200 μ g/d in the constant dose approach. No significant differences in PD20 or other efficacy parameters were found after 1 yr. Changes in standing height were similar in both treatment approaches. This study showed no superior clinical effect of a stepdown approach compared with a constant dose strategy of FP for 1 yr in children with chronic persistent asthma.
Incidence, treatment and survival of patients with craniopharyngioma in the surveillance, epidemiology and end results program
Authors: B. E. Zacharia, S. S. Bruce, H. Goldstein, H. R. Malone, A. I. Neugut, J. N. Bruce
Journal: Neuro-Oncology (2012)

Craniopharyngioma is a rare primary central nervous system neoplasm. Our objective was to determine factors associated with incidence, treatment, and survival of craniopharyngiomas in the United States. We used the surveillance, epidemiology and end results program (SEER) database to identify patients who received a diagnosis of craniopharyngioma during 2004–2008. We analyzed clinical and demographic information, including age, race, sex, tumor histology, and treatment. Age-adjusted incidence rates and age, sex, and race-adjusted expected survival rates were calculated. We used Cox proportional hazards models to determine the association between covariates and overall survival. We identified 644 patients with a diagnosis of craniopharyngioma. Black race was associated with an age-adjusted relative risk for craniopharyngioma of 1.26 (95% confidence interval [CI], 0.98–1.59), compared with white race. One- and 3-year survival rates of 91.5% (95% CI, 88.9%–93.5%), and 86.2% (95% CI, 82.7%–89.0%) were observed for the cohort; relative survival rates were 92.1% (95% CI, 89.5%–94.0%) and 87.6% (95% CI, 84.1%–90.4%) for 1- and 3-years, respectively. In the multivariable model, factors associated with prolonged survival included younger age, smaller tumor size, subtotal resection, and radiation therapy. Black race, on the other hand, was associated with worse overall survival in the final model. We demonstrated that >85% of patients survived 3 years after diagnosis and that subtotal resection and radiation therapy were associated with prolonged survival. We also noted a higher incidence rate and worse 1- and 3-year survival rates in the black population. Future investigations should examine these racial disparities and focus on evaluating the efficacy of emerging treatment paradigms.