tbuckley/cabot-search huggingface dataset:
The immediate and late allergic response to segmental bronchopulmonary provocation in asthma.
Authors: N N Jarjour, W J Calhoun, E A Kelly, G J Gleich, L B Schwartz, W W Busse
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The response to antigen is an important factor in the development of airway inflammation. Segmental bronchoprovocation (SBP) with antigen and subsequent bronchoalveolar lavage (BAL) have provided valuable insight into the mechanisms of allergic inflammation. To determine the features of allergic airway response in asthma, 19 subjects with mild asthma underwent antigen SBP in a dose-dependent manner. The amount of antigen used in SBP was 0 (saline), and 1, 5, or 20% of the antigen dose required to drop the FEV1 by 20% (APD20). BAL was done at 5 min and 48 h after SBP. BAL histamine levels increased modestly 5 min after antigen SBP. At 48 h, there was a marked increase in eosinophils and IL-5 concentration even in airway segments where the release of histamine was small. Moreover, eosinophils correlated with IL-5 levels at 48 h (r = 0.63; p < 0.001), but not with BAL histamine concentrations at 5 min. GM-CSF levels did not increase after antigen SBP and did not correlate with eosinophils. These observations indicate that asthmatic subjects can develop a dose-dependent response to antigen SBP that is characterized by a modest increase in histamine immediately after antigen exposure, and marked eosinophilia, which appears proportionately greater than the histamine response and relatively greater than what is seen in allergic nonasthmatic subjects. This feature might be important to the eventual development of airway inflammation in asthma.
A novel role for leucocytes in determining the severity of acute pancreatitis
Authors: J. Mayerle
Journal: Gut (2009)

For more than a century autodigestion has been regarded as the principal mechanism underlying pancreatitis.1 The modern version of this concept implies that a premature and intrapancreatic activation of pancreatic proteases occurs very early in the disease, and then overwhelms a multitude of protective mechanisms that physiologically prevent or inhibit digestive enzymes activity outside the small intestine.2 Novel treatments that target protease activity have, unfortunately, not been shown to be consistently beneficial in clinical pancreatitis. This is probably because they either target the wrong proteases or because they are administered too late in the disease process.3

Another line of experimental evidence suggests that, while initial protease activation may be a triggering event, the ultimate disease severity depends on the balance between pro- and anti-inflammatory responses of the affected patient and cellular and humoral factors have been shown to be involved in the process.4 While activities of pancreatic enzymes in the blood, ie, parameters of local damage such as amylase and lipase, can be used to determine the presence or absence of pancreatitis, they do not reflect disease severity in humans and the extent of their elevation is of no prognostic value. Parameters reflecting the inflammatory response, such as C-reactive protein, procalcitonin or polymorphonuclear (PMN)-elastase, on the other hand, have been found to correlate rather well with disease severity and are commonly used to triage patients to intensive care surveillance and treatment.5 6 Based on this “inflammation concept” of pancreatitis a number of experimental studies have been conducted in order to modulate the inflammatory response and to attain a beneficial therapeutic effect. Inhibiting pro-inflammatory mediators (eg, platelet activating factor (PAF), interleukin 6 (IL6), intracellular adhesion molecule (ICAM), S100A9, toll-like receptor 4 (TLR4)) or enhancing anti-inflammatory mechanisms (eg, IL10) or modulating cellular immune responses, have all been …
Renin Inhibition Improves Pressure Natriuresis in Essential Hypertension
Authors: PIETER VAN PAASSEN, DICK DE ZEEUW, PAUL E. DE JONG, GERJAN NAVIS
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Pressure natriuresis (PN), i.e. , a rise in renal sodium excretion in response to a higher BP, is involved in long-term BP regulation. PN is blunted in essential hypertension, but the mechanism is unknown. This study assessed the role of the renin-angiotensin-aldosterone system (RAAS) in PN in eight essential hypertensive men from the individual correlations between spontaneous fluctuations in BP and time corresponding changes in sodium excretion (collected at 2- and 4-h intervals for 48 h), during strict sodium balance, without treatment, and during renin inhibition (remikiren, 600 mg oral compound). Without treatment, daily values for mean arterial pressure were 109.5 ± 1.9 and 107 ± 1.9 mmHg, for urinary sodium excretion were 37.2 ± 2.8 and 42.0 ± 2.8 mmol/24 h, and for plasma renin activity were 2.34 ± 0.48 and 2.23 ± 0.44 nmol/L per h, respectively, for two consecutive days. During remikiren treatment, mean arterial pressure was 101.9 ± 1.7 and 100.8 ± 1.7 mmHg ( P &lt; 0.05, versus baseline). Urinary sodium excretion was 39.3 ± 3.7 and 45.2 ± 5.3 mmol/24 h (not significant versus baseline), and plasma renin activity was 0.79 ± 0.11 and 0.82 ± 0.13 nmol/L per h ( P &lt; 0.05 versus baseline). During remikiren treatment, BP correlated positively with sodium excretion in all patients but in only three of eight patients without treatment. The slope of the regression equation was steeper during remikiren treatment in seven of eight patients. Thus, the relationship between BP and natriuresis was more readily apparent during RAAS blockade, suggesting that RAAS activity blunts PN in hypertensive patients. Improved PN may contribute to the hypotensive effect of RAAS blockade and to maintenance of sodium balance at a lower BP level without volume expansion.
Epigenetic Profiling of Cutaneous T-Cell Lymphoma: Promoter Hypermethylation of Multiple Tumor Suppressor Genes Including <i>BCL7a</i>, <i>PTPRG</i>, and <i>p73</i>
Authors: Remco van Doorn, Willem H. Zoutman, Remco Dijkman, Renee X. de Menezes, Suzan Commandeur, Aat A. Mulder, Pieter A. van der Velden, Maarten H. Vermeer, Rein Willemze, Pearlly S. Yan, Tim H. Huang, Cornelis P. Tensen
Journal: Journal of Clinical Oncology (2005)

To analyze the occurrence of promoter hypermethylation in primary cutaneous T-cell lymphoma (CTCL) on a genome-wide scale, focusing on epigenetic alterations with pathogenetic significance.DNA isolated from biopsy specimens of 28 patients with CTCL, including aggressive CTCL entities (transformed mycosis fungoides and CD30-negative large T-cell lymphoma) and an indolent entity (CD30-positive large T-cell lymphoma), were investigated. For genome-wide DNA methylation screening, differential methylation hybridization using CpG island microarrays was applied, which allows simultaneous detection of the methylation status of 8640 CpG islands. Bisulfite sequence analysis was applied for confirmation and detection of hypermethylation of eight selected tumor suppressor genes.The DNA methylation patterns of CTCLs emerging from differential methylation hybridization analysis included 35 CpG islands hypermethylated in at least four of the 28 studied CTCL samples when compared with benign T-cell samples. Hypermethylation of the putative tumor suppressor genes BCL7a (in 48% of CTCL samples), PTPRG (27%), and thrombospondin 4 (52%) was confirmed and demonstrated to be associated with transcriptional downregulation. BCL7a was hypermethylated at a higher frequency in aggressive (64%) than in indolent (14%) CTCL entities. In addition, the promoters of the selected tumor suppressor genes p73 (48%), p16 (33%), CHFR (19%), p15 (10%), and TMS1 (10%) were hypermethylated in CTCL.Malignant T cells of patients with CTCL display widespread promoter hypermethylation associated with inactivation of several tumor suppressor genes involved in DNA repair, cell cycle, and apoptosis signaling pathways. In view of this, CTCL may be amenable to treatment with demethylating agents.
Characterization of the allergens of the house dust mite Euroglyphus maynei
Authors: Marjorie S. Morgan, Larry G. Arlian, Kathleen C. Barnes, Enrique Fernandez-Caldas
Journal: Journal of Allergy and Clinical Immunology (1997)

Background: The house dust mite Euroglyphus maynei inhabits homes in many parts of the world and is the source of many allergens. Objective: The purpose of this study was to biochemically and immunologically characterize the major allergens of E. maynei. Methods: Proteins in an extract of E. maynei were separated into 20 fractions by using preparative isoelectric focusing. Most proteins and allergens were contained in fractions 7 to 17 with pH of 4.8 to 8.0. The fractions were further characterized by nonreducing sodium dodecylsulfate–polyacrylamide gel electrophoresis and immunoblotting with the serum of 16 individuals sensitive to E. maynei. Results: Molecular weights and isoelectric points were assigned to 47 IgE-binding proteins in an E. maynei extract, and the frequency of IgE binding to each allergen was determined. Twenty-two of the allergens were recognized by more than 50% of the 16 sera, and all but one of the subjects had IgE that bound to more than 10 allergens (range, 0 to 32). One of the proteins was identified as the allergen Eur m 2. Conclusion: E. maynei is the source of at least 47 individual allergens that have been characterized by molecular weight, isoelectric point, and IgE-binding properties. (J Allergy Clin Immunol 1997;100:222-8.)
MHC Class III products: an electron microscopic study of the C3 convertases of human complement.
Authors: C A Smith, C W Vogel, H J Müller-Eberhard
Journal: The Journal of Experimental Medicine (1984)

We have reported a transmission electron microscopic study of the two C3 convertases of human complement and their precursors. The corresponding proteins and complexes of the classical and alternative pathway appear very similar. Cofactors C3b and C4b are nearly indistinguishable and display a characteristic but highly irregular substructure. C2 and Factor B are globular with diameters of 85 +/- 8 A and 80 +/- 8 A and both consist of three discrete globular domains each approximately 40 A in diameter. Bb and C2a each contain two domains connected by a short linker segment. Both domains of Bb and one domain of C2a are 42 A in diameter (28 kd), while the second domain of C2 is 47 A in diameter (39 kd). Attachment of the enzymatic subunits to cofactors occurs through one domain only.
Renal Cortical Vasoconstriction Contributes to Development of Salt-Sensitive Hypertension after Angiotensin II Exposure
Authors: MARTHA FRANCO, EDILIA TAPIA, JOSÉ SANTAMARÍA, IGNACIO ZAFRA, ROMEO GARCÍA-TORRES, KATHERINE L. GORDON, HÉCTOR PONS, BERNARDO RODRÍGUEZ-ITURBE, RICHARD J. JOHNSON, JAIME HERRERA-ACOSTA
Journal: Journal of the American Society of Nephrology (2001)

Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 ± 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngII+MMF showed similar responses to AngII; however, they developed lower proteinuria (P < 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 ± 8.2 mmHg at week 1 and 163 ± 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and single-nephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngII+MMF group, SBP remained unchanged throughout the HSD period (146 ± 2.3 mmHg at week 1 and 148 ± 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.
EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase Cγ, Ca++, and Erk, leading to granule polarization
Authors: Luis-Alberto Pérez-Quintero, Romain Roncagalli, Huaijian Guo, Sylvain Latour, Dominique Davidson, André Veillette
Journal: The Journal of Experimental Medicine (2014)

Ewing’s sarcoma-associated transcript 2 (EAT-2) is an Src homology 2 domain-containing intracellular adaptor related to signaling lymphocytic activation molecule (SLAM)–associated protein (SAP), the X-linked lymphoproliferative gene product. Both EAT-2 and SAP are expressed in natural killer (NK) cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells. SAP mediates this function by coupling SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target cells. We used a variety of genetic, biochemical, and imaging approaches to define the molecular and cellular mechanisms by which EAT-2 controls NK cell activation. We found that EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by one or two tyrosines located in the carboxyl-terminal tail of EAT-2 but not found in SAP. Unlike SAP, EAT-2 does not enhance conjugate formation. Rather, it accelerates polarization and exocytosis of cytotoxic granules toward hematopoietic target cells. Hence, EAT-2 promotes NK cell activation by molecular and cellular mechanisms distinct from those of SAP. These findings explain the cooperative and essential function of these two adaptors in NK cell activation.
Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex
Authors: Morane Le Hiress, Ly Tu, Nicolas Ricard, Carole Phan, Raphaël Thuillet, Elie Fadel, Peter Dorfmüller, David Montani, Frances de Man, Marc Humbert, Alice Huertas, Christophe Guignabert
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Inflammation and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). CD74 is a receptor for the proinflammatory cytokine macrophage migration inhibitory factor (MIF). This ligand/receptor complex initiates survival pathways and cell proliferation, and it triggers the synthesis and secretion of major proinflammatory factors and cell adhesion molecules.We hypothesized that the MIF/CD74 signaling pathway is overexpressed in idiopathic PAH (iPAH) and contributes to a proinflammatory endothelial cell (EC) phenotype.Primary early passage cultures of human ECs isolated from lung tissues obtained from patients with iPAH and controls were examined for their ability to secrete proinflammatory mediators and bind inflammatory cells with or without modulation of the functional activities of the MIF/CD74 complex. In addition, we tested the efficacies of curative treatments with either the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies on the aberrant proinflammatory EC phenotype in vitro and in vivo and on the progression of monocrotaline-induced pulmonary hypertension.In human lung tissues, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expressions are markedly up-regulated in the endothelium of distal iPAH pulmonary arteries. Circulating MIF levels are increased in the serum of patients with PAH compared with control subjects, and T-cell lymphocytes represent a source of this overabundance. In addition, CD74 is highly expressed in the endothelium of muscularized pulmonary arterioles and in cultured pulmonary ECs from iPAH, contributing to an exaggerated recruitment of peripheral blood mononuclear cells to pulmonary iPAH ECs. Finally, we found that curative treatments with the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies partially reversed development of pulmonary hypertension in rats and substantially reduced inflammatory cell infiltration.We report here that CD74 and MIF are markedly increased and activated in patients with iPAH, contributing to the abnormal proinflammatory phenotype of pulmonary ECs in iPAH.
Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells
Authors: Rei Watanabe, Ahmed Gehad, Chao Yang, Laura L. Scott, Jessica E. Teague, Christoph Schlapbach, Christopher P. Elco, Victor Huang, Tiago R. Matos, Thomas S. Kupper, Rachael A. Clark
Journal: Science Translational Medicine (2015)

Four different T cell populations with different functions and migration patterns protect human skin.
18F-Fluorodeoxy-glucose Positron Emission Tomography Marks MYC-Overexpressing Human Basal-Like Breast Cancers
Authors: Nicolaos Palaskas, Steven M. Larson, Nikolaus Schultz, Evangelia Komisopoulou, Justin Wong, Dan Rohle, Carl Campos, Nicolas Yannuzzi, Joseph R. Osborne, Irina Linkov, Edward R. Kastenhuber, Richard Taschereau, Seema B. Plaisier, Chris Tran, Adriana Heguy, Hong Wu, Chris Sander, Michael E. Phelps, Cameron Brennan, Elisa Port, Jason T. Huse, Thomas G. Graeber, Ingo K. Mellinghoff
Journal: Cancer Research (2011)

Abstract In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by positron emission tomography (PET) following i.v. injection of the glucose analogue 18F-fluorodeoxy-glucose (18FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To identify molecular determinants of 18FDG retention, we interrogated the transcriptomes of human-cancer cell lines and primary tumors for metabolic pathways associated with 18FDG radiotracer uptake. From ninety-five metabolic pathways that were interrogated, the glycolysis, and several glycolysis-related pathways (pentose phosphate, carbon fixation, aminoacyl-tRNA biosynthesis, one-carbon-pool by folate) showed the greatest transcriptional enrichment. This “FDG signature” predicted FDG uptake in breast cancer cell lines and overlapped with established gene expression signatures for the “basal-like” breast cancer subtype and MYC-induced tumorigenesis in mice. Human breast cancers with nuclear MYC staining and high RNA expression of MYC target genes showed high 18FDG-PET uptake (P &amp;lt; 0.005). Presence of the FDG signature was similarly associated with MYC gene copy gain, increased MYC transcript levels, and elevated expression of metabolic MYC target genes in a human breast cancer genomic dataset. Together, our findings link clinical observations of glucose uptake with a pathologic and molecular subtype of human breast cancer. Furthermore, they suggest related approaches to derive molecular determinants of radiotracer retention for other PET-imaging probes. Cancer Res; 71(15); 5164–74. ©2011 AACR.
Letter: Beta-blockade and myocardial infarction.
Authors: K M Fox, M P Chopra, R W Portal, C P Aber
Journal: BMJ (1975)

3±0-2% 18:0 Stearic 7-5% 8-4% 7.0% 9 5±0 3% 18:1 Oleic 44 0%/0 38-7% 256%o 29-3±0 5% 18:2 Linoleic .. ..
Structural Brain Development and Depression Onset During Adolescence: A Prospective Longitudinal Study
Authors: Sarah Whittle, Renee Lichter, Meg Dennison, Nandita Vijayakumar, Orli Schwartz, Michelle L. Byrne, Julian G. Simmons, Murat Yücel, Christos Pantelis, Patrick McGorry, Nicholas B. Allen
Journal: American Journal of Psychiatry (2014)

The authors sought to investigate whether the structural development of limbic, striatal, and prefrontal regions that are critically implicated in the pathophysiology of depression is associated with adolescent-onset depression.In a longitudinal design, a risk enriched community sample of 86 adolescents (41 of them female) who had no history of depressive disorders participated in neuroimaging assessments conducted during early (age 12) and midadolescence (age 16). Onset of depressive disorders was assessed for the period spanning early to late adolescence (ages 12 to 18). Thirty participants experienced a first episode of a depressive disorder during the follow-up period. The authors assessed whether onset of depressive disorder was associated with structural change in limbic, striatal, and prefrontal cortical regions from early to mid-adolescence.Volumetric change in the hippocampus, amygdala, and putamen from early to mid-adolescence was associated with the onset of depression during adolescence. Attenuated growth of the hippocampus and attenuated reduction in putamen volume over time were associated with the onset of depression. Sex moderated the association between amygdala growth and depression such that exaggerated growth and attenuated growth of the amygdala were associated with depression in females and males, respectively. Across time, smaller nucleus accumbens volume was associated with depression in females only.These findings suggest that alterations in the developmental trajectories of limbic and striatal regions during adolescence may represent a neurobiological manifestation of a risk factor for the development of depression during this critical period and thus may provide clues as to etiological mechanisms of this disorder.
The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor
Authors: D Karpova, K Dauber, G Spohn, D Chudziak, E Wiercinska, M Schulz, A R Pettit, J P Levesque, B Romagnoli, K Patel, E Chevalier, K Dembowsky, H Bonig
Journal: Leukemia (2013)

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be corroborated in humans.