tbuckley/cabot-search huggingface dataset:
Enhancement of the Therapeutic Efficacy of Taxol by the Mitogen-Activated Protein Kinase Kinase Inhibitor CI-1040 in Nude Mice Bearing Human Heterotransplants
Authors: Hayley M. McDaid, Lluis Lopez-Barcons, Aaron Grossman, Marie Lia, Steven Keller, Román Pérez-Soler, Susan Band Horwitz
Journal: Cancer Research (2005)

Abstract Taxol may contribute to intrinsic chemoresistance by activating the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) cytoprotective pathway in human cancer cell lines and tumors. We have previously shown additivity between Taxol and the MEK inhibitor, U0126 in human cancer cell lines. Here, the combination of Taxol with an orally bioavailable MEK inhibitor, CI-1040, was evaluated in human lung tumors heterotransplanted into nude mice. Unlike xenograft models that are derived from cells with multiple genetic alterations due to prolonged passage, heterotransplanted tumor models are more clinically relevant. Combined treatment with both drugs resulted in inhibition of tumor growth in all models and tumor regressions in three of four models tested, supporting our previous observation that Taxol's efficacy is potentiated by MEK inhibition. Concurrent administration was superior to intermittent dosing. Pharmacodynamic assessments of tumors indicated that suppression of MEK was associated with induction of S473 phosphorylated Akt and reduced proliferation in the combination groups relative to single agents, in addition to suppression of fibroblast growth factor–mediated angiogenesis and reduced expression of vascular endothelial growth factor. These findings are significant and indicate that this combination may have broad therapeutic applications in a diverse range of lung tumors with different intrinsic chemosensitivities.
Quantitative Importance of Changes in Postglomerular Colloid Osmotic Pressure in Mediating Glomerulotubular Balance in the Rat
Authors: Barry M. Brenner, Julia L. Troy, Terrance M. Daugharty, Robert M. MacInnes
Journal: Journal of Clinical Investigation (1973)

In recent studies in this laboratory employing normal hydropenic rats we have demonstrated that the reduction in absolute proximal reabsorption that attends the experimental reduction of single nephron glomerular filtration rate (SNGFR) (glomerulotubular balance) is mediated, at least in part, by the accompanying decline in postglomerular vascular protein concentration, and therefore, postglomerular colloid osmotic pressure (piEA). The present study was undertaken to define the quantitative contribution of these changes in piEA to the changes in absolute proximal reabsorption measured under these conditions. A protocol was employed which enabled us to examine the effects on absolute proximal reabsorption of reductions in filtered load brought about under conditions in which piEA remained essentially unchanged. Thus, after partial aortic constriction in 16 plasma-loaded rats, near constancy of piEA was observed in 10 (a change in efferent arteriolar protein concentration of 0.4 g/100 ml or less) and in these, uniform reductions in SNGFR averaging 16.7 nl/min were attended by reductions in absolute proximal reabsorption averaging only 1.7 nl/min, or 7% of preconstriction values. These findings, taken together with previous observations from this laboratory, suggest that the proximal reabsorptive adjustment that characterizes glomerulotubular balance in the rat is markedly blunted when changes in piEA are prevented. In the remaining six rats, a mean reduction in filtered load comparable to that observed in the above group was attended by slightly to moderately greater reductions in efferent arteriolar protein concentration, thereby fulfilling less well the stated aim of this study. Nevertheless, in accord with the above conclusion, these relatively greater reductions in piEA were accompanied by correspondingly greater reductions in absolute proximal reabsorption.
Beyond the dogma: novel 2-adrenoceptor signalling in the airways
Authors: M. A. Giembycz, R. Newton
Journal: European Respiratory Journal (2006)

β 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade. This classical model of β 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of β 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by β 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMP-dependent and -independent mechanisms that, in many cases, may act in concert. In this article, the current status of β 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.
Role of CD4<sup>+</sup>CD25<sup>+</sup>Regulatory T Cells in T Helper 2 Cell-mediated Allergic Inflammation in the Airways
Authors: AKIRA SUTO, HIROSHI NAKAJIMA, SHIN-ICHIRO KAGAMI, KOTARO SUZUKI, YASUSHI SAITO, ITSUO IWAMOTO
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

It has recently been shown that CD4+ CD25+ T cells are immunoregulatory T cells that prevent CD4+ T cell-mediated organ-specific autoimmune diseases. To determine whether CD4+ CD25+ T cells downregulate Th2 cell-mediated allergic inflammation in the airways, we studied antigen-induced eosinophil recruitment in the airways in BALB/c Rag-2− / − mice transferred with CD4+ CD25+ T cell-depleted or unfractionated T cells from ovalbumin-specific TCR transgenic mice. Antigen-induced eosinophil recruitment into the airways was significantly decreased in the mice transferred with CD4+ CD25+ T cell-depleted splenocytes as compared with those transferred with unfractionated splenocytes. On the other hand, the depletion of CD4+ CD25+ T cells increased antigen-induced neutrophil and T cell recruitment in the airways of the mice. The depletion of CD4+ CD25+ T cells also decreased antigen-induced IL-4 and IL-5 production in the airways of the mice. Finally, the depletion of CD4+ CD25+ T cells prevented antigen-induced Th2 cell differentiation in vitro but increased the differentiation of Th1 cells. These results indicate that CD4+ CD25+ T cells modulate the Th1 and Th2 cell balance toward Th2 cells and thus upregulate Th2 cell-mediated allergic inflammation in the airways.Keywords: allergic inflammation; eosinophils; CD4+ CD25+ T cells; Th1/Th2 cells
Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy
Authors: Lisa Marie Serrano, Timothy Pfeiffer, Simon Olivares, Tontanai Numbenjapon, Jennifer Bennitt, Daniel Kim, David Smith, George McNamara, Zaid Al-Kadhimi, Joseph Rosenthal, Stephen J. Forman, Michael C. Jensen, Laurence J. N. Cooper
Journal: Blood (2005)
Exercise in COPD: damned if you do and damned if you don't
Authors: P T Macklem
Journal: Thorax (2005)

A double-blind test to compare IV aminophylline with salbutamol in the treatment of acute, uncontrolled asthma showed that both drugs were equally effective during the first 24 hours. Salbutamol caused a relative tachycardia. Hydrocortisone was given after 2 hours, but did not appear to affect the rate of recovery.
Severity scoring of atopic dermatitis: a comparison of three scoring systems
Authors: A. B. Sprikkelman, R. A. Tupker, H. Burgerhof, J. P. Schouten, P. L. P. Brand, H. S. A. Heymans, W. M. C. van Aalderen, A. B. Sprikkelman
Journal: Allergy (1997)

In studies on atopic dermatitis (AD), different scoring systems are used to evaluate the severity of the disease. The objective of this study was to investigate agreement between observers in the assessment of the overall severity of AD, and interobserver variation in the assessment of severity of AD for each scoring item separately, using the Simple Scoring System (SSS), the Scoring Atopic Dermatitis (SCORAD) index, and the Basic Clinical Scoring System (BCSS), and, furthermore, to investigate agreement between these three scoring systems in the assessment of the overall severity of AD. Eighty‐two patients (42 male) with AD, mean age 13.4 years (range 0.2−67.0), were included. Agreement between observers in assessing the overall AD severity scores, and interobserver variation in assessing AD severity of each scoring item separately were determined in 34 of these 82 patients by two physicians scoring the severity of AD by the three scoring systems. To determine agreement between the scoring systems, one physician scored the severity of AD in all patients with the three scoring systems. Agreement between observers and agreement between the three scoring systems was calculated by Cohen's kappa (κ) and by the measure of agreement according to Bland &amp; Altaian. κ&gt;0.4 represents fair agreement; κ&gt;0.75 excellent agreement. In addition, interobserver variation for each scoring item separately was calculated by the Wilcoxon signed rank test. The mean differences (d) and the limits of agreement (d±2 SD of the differences) between observers by the SSS and the SCORAD were −0.82±5.58 and −0.28±7.49, respectively. κ between observers for the BCSS was 0.90 (95% CI 0.79−1.03). By the SSS, significant interobserver variation was found in assessing the severity of excoriations (P=0.02) and scales (P=0.02). By the SCORAD, significant interobserver variation was found in assessing the severity of edema/papulation (P=0.04), erythema (P=0.04), and excoriations (P=0.01). No significant interobserver variation was found in assessing the extent of AD. The mean difference and the limits of agreement between the SSS and the SCORAD were −4.17±9.52. k between the SSS and the BCSS was 0.21 (95% CI 0.09−0.33), and k between the SCORAD and the BCSS was 0.38 (95% CI 0.26−0.51). We found good agreement between observers assessing the overall severity of AD in the lower and higher scoring rates by the SSS and the SCORAD, and excellent agreement by the BCSS. Significant interobserver variation was found on the isolated intensity items scales, excoriations, edema/papulation, and erythema. We found poor agreement between the three scoring systems in assessing the overall severity of AD, indicating that the SSS, the SCORAD, and the BCSS cannot be used interchangeably to assess the overall severity of AD.
Prognostic Significance of CD55 Expression in Breast Cancer
Authors: Jun-ichiro Ikeda, Eiichi Morii, Yalan Liu, Ying Qiu, Naoto Nakamichi, Ryu Jokoji, Yasuo Miyoshi, Shinzaburo Noguchi, Katsuyuki Aozasa
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Our recent study revealed that CD55-high population in breast cancer cell line was resistant to apoptosis and formed colonies in vitro more efficiently than CD55-low population. The present study was conducted to examine whether CD55-high population in breast cancer cell line possesses higher tumorigenic potential in vivo and presence of CD55-high cells in breast cancer affects clinicopathologic behavior of patients. Experimental Design: CD55-high and CD55-low population was sorted from breast cancer cell line, injected into immunodeficient mice, and the resultant tumor volume was measured. CD55 expression was immunohistochemically examined in clinical samples from 74 cases with breast cancers, and cases with &amp;gt;1% of tumor cells showing high level of CD55 expression were categorized as CD55 high. Results: The xenotransplanted tumor volume derived from CD55-high population was significantly larger than that from CD55-low population. Fifty (67.6%) of 74 cases of breast cancer were CD55-high. A significant correlation was observed between CD55-high character and relapse rate (P &amp;lt; 0.001). Univariate analysis showed that tumor size (P = 0.005) and CD55 expression (P = 0.005) were unfavorable prognostic factors. Multivariate analysis revealed that the tumor size (P = 0.013) and CD55 expression (P = 0.011) were independent prognostic factors. Conclusions: CD55 play an important role in tumorigenesis of breast cancer, and presence of small population of cells with strong CD55 expression would be sufficient to predict poor prognosis of patients.
Functional Consequences of Elimination of <i>I</i> <sub>to, f</sub> and <i>I</i> <sub>to, s</sub>
Authors: Weinong Guo, Huilin Li, Barry London, Jeanne M. Nerbonne
Journal: Circulation Research (2000)

Abstract —It was recently reported that the slow transient outward K + current, I to, s , that is evident in mouse left ventricular septal cells is eliminated in mice with a targeted deletion of the Kv1.4 gene (Kv1.4 −/− ). The rapidly inactivating transient outward K + current, I to, f , in contrast, is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing a dominant-negative Kv4 α subunit, Kv4.2W362F. Expression of Kv4.2W362F results in marked prolongation of action potentials and QT intervals. In addition, a slow transient outward K + current, that is similar to I to, s in wild-type mouse left ventricular septal cells, is evident in all Kv4.2W362F-expressing (left and right) ventricular cells. To test directly the hypothesis that upregulation of Kv1.4 α subunit underlies the appearance of this slow transient outward K + current in Kv4.2W362F-expressing ventricular cells and to explore the functional consequences of elimination of I to, f and I to, s , mice expressing Kv4.2W362F in the Kv1.4 −/− background (Kv4.2W362F×Kv1.4 −/− ) were generated. Histological and echocardiographic studies revealed no evidence of structural abnormalities or contractile dysfunction in Kv4.2W362F×Kv1.4 −/− mouse hearts. Electrophysiological recordings from the majority (≈80%) of cells isolated from the right ventricle and left ventricular apex of Kv4.2W362F×Kv1.4 −/− animals demonstrated that both I to, f and I to, s are eliminated; action potentials are prolonged significantly; and, in some cells, early afterdepolarizations were observed. In addition, in vivo telemetric ECG recordings from Kv4.2W362F×Kv1.4 −/− animals revealed marked QT prolongation, atrioventricular block, and ventricular tachycardia. These observations demonstrate that upregulation of Kv1.4 contributes to the electrical remodeling evident in the ventricles of Kv4.2W362F-expressing mice and that elimination of both I to, f and I to, s has dramatic functional consequences. ( Circ Res. 2000;87:73-79.)
Macrophages Control the Retention and Trafficking of B Lymphocytes in the Splenic Marginal Zone
Authors: Mikael C.I. Karlsson, Rodolphe Guinamard, Silvia Bolland, Marko Sankala, Ralph M. Steinman, Jeffrey V. Ravetch
Journal: The Journal of Experimental Medicine (2003)

The marginal zone of the spleen is a precisely ordered region that contains specialized subsets of B lymphocytes and macrophages. Disruption of the negative signaling inositol phosphatase, SH2-containing inositol-5-phosphatase 1 (SHIP), results in the loss of marginal zone B cells (MZBs) with reorganization of marginal zone macrophages (MZMOs) to the red pulp of the spleen. This primary macrophage defect, as revealed by selectively depleting SHIP in myeloid cells shows that MZMOs are specifically required for the retention of MZBs. The MZMO phenotype was reverted in SHIP/Bruton's tyrosine kinase (Btk) double knockout mice, thus identifying the Btk activating pathway as an essential component being regulated by SHIP. Furthermore, we identified a direct interaction between the MARCO scavenger receptor on MZMOs and MZBs. Activation or disruption of this interaction results in MZB migration to the follicle. The migration of the MZMOs was further studied after the response to Staphylococcus aureus, which induced MZMOs to move into the red pulp while MZBs migrated into the follicular zone. The marginal zone is therefore a dynamic structure in which retention and trafficking of B cells requires specific macrophage–B cell interactions.
Is Peripheral Neuropathy Associated With Retinopathy and Albuminuria in Individuals With Impaired Glucose Metabolism?: The 1999-2000 AusDiab
Authors: E. L.M. Barr
Journal: Diabetes Care (2006)

Individuals with impaired glucoses tolerance (IGT) or impaired fasting glucose (IFG) are at substantially increased risk of developing diabetes and cardiovascular disease (1). The extent to which individuals with IGT/IFG are also at risk of microvascular complications, such as neuropathy, retinopathy, and nephropathy, has not been as well defined. Some (2,3), but not all (4–7), studies have shown that microvascular complications are more common in individuals with IGT/IFG than those with normal glucose metabolism.

Peripheral neuropathy, a common microvascular complication of diabetes (8), is often associated with concomitant retinopathy (9) and albuminuria (9,10). Whether peripheral neuropathy is also associated with retinopathy and albuminuria in people with IGT/IFG is unclear and is examined in the current study.

The Australian, Diabetes, Obesity, and Lifestyle Study (AusDiab) is a population-based survey of Australian adults aged ≥25 years (11). Glucose tolerance status was determined by a 75-g oral glucose tolerance test (12). The prevalence of diabetes in the AusDiab was 7.4%, while 16.4% had IGT or IFG (13). All participants with diabetes, IGT, IFG, and a random sample of normal control subjects were invited for complications testing (6). This analysis is based on the 1,154 individuals with IGT or IFG who attended the complications screening.

Neuropathy was classified by 1 ) the modified neuropathy symptom score (NSS), 2 ) the modified neuropathy disability score (NDS), 3 ) the pressure perception score (PPS), and 4 ) a postural systolic blood pressure drop score of ≥20 mmHg. The NSS measured …
Role of arginase in killing of schistosomula of schistosoma mansoni
Authors: GR Olds, JJ Ellner, LA Kearse, JW Kazura, AAF Mahmoud
Journal: The Journal of Experimental Medicine (1980)

Nonspecific resistance to the multicellular organism Schistosoma mansoni can be induced in mice by several infectious agents. We utilized the observed genetic restriction of such acquired resistance to study the mediators of killing of the larval stage of S. mansoni in vitro. Adherent peritoneal cell monolayers from Corynebacterium parvum-treated C57BL/6J but not from C. parvum-treated BALB/cJ mice killed an increased proportion of schistosomula in 24 h. Activated macrophages (Mφ) from both strains exhibited enhanced H(2)0(2) production after incubation with the parasites or phorbol myristate acetate. Thus H(2)0(2) production was not associated with schistosomula killing. Moreover, schistosomula killing was unaffected by catalase or superoxide dismutase. In contrast, activated C57BL/6J (but not BALB/cJ) Mφ released fourfold more arginase into supernates than control Mφ. Schistosomula killing by these Mφ correlated with arginase content of the supernates, was exaggerated in arginine-poor medium, and could be blocked by the addition of arginine. Exogenous bovine arginase added to Fischer's medium without macrophages produced comparable parasite mortality. Our data suggest that arginase is a critical mediator of in vitro killing of this multicellular organism by activated macrophages.
Masitinib, a c‐kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid‐dependent asthmatics
Authors: M. Humbert, F. De Blay, G. Garcia, A. Prud’homme, C. Leroyer, A. Magnan, J.‐M. Tunon‐de‐Lara, C. Pison, M. Aubier, D. Charpin, I. Vachier, A. Purohit, P. Gineste, T. Bader, A. Moussy, O. Hermine, P. Chanez
Journal: Allergy (2009)

Background: Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c‐kit) and platelet‐derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c‐kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma. Objectives: The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints. Methods: A 16‐week randomized, dose‐ranging (3, 4.5, and 6 mg/kg/day), placebo‐controlled study was undertaken in 44 patients with severe corticosteroid‐dependent asthma who remained poorly controlled despite optimal asthma management. Results: At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of ­78% and ­57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 ( P &lt; 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema. Conclusions: Masitinib, a c‐kit and PDGF‐receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid‐dependent asthma. These preliminary results warrant further long‐term clinical studies in severe asthma (ClinicalTrials.gov Identifier: NCT00842270).
Adipose Tissue-Derived Factors: Impact on Health and Disease
Authors: Maria E. Trujillo, Philipp E. Scherer
Journal: Endocrine Reviews (2006)

The endocrine functions of the adipose organ are widely studied at this stage. The adipose organ, and in particular adipocytes, communicate with almost all other organs. Although some adipose tissue pads assume the functions as distinct “miniorgans,” adipocytes can also be present in smaller numbers interspersed with other cell types. Although fat pads have the potential to have a significant systemic impact, adipocytes may also affect neighboring tissues through paracrine interactions. These local or systemic effects are mediated through lipid and protein factors. The protein factors are commonly referred to as adipokines. Their expression and posttranslational modifications can undergo dramatic changes under different metabolic conditions. Due to the fact that none of the mutations that affect adipose tissue trigger embryonic lethality, the study of adipose tissue physiology lends itself to genetic analysis in mice. In fact, life in the complete absence of adipose tissue is possible in a laboratory setting, making even the most extreme adipose tissue phenotypes genetically amenable to be analyzed by disruption of specific genes or overexpression of others. Here, we briefly discuss some basic aspects of adipocyte physiology and the systemic impact of adipocyte-derived factors on energy homeostasis.
Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men
Authors: Giovanni De Pergola, Vito De Mitrio, Marcello Sciaraffia, Nicola Pannaccuilli, Antonio Minenna, Francesco Giorgino, Mariella Petronelli, Ester Laudadio, Riccardo Giorgino
Journal: Metabolism (1997)