tbuckley/cabot-search huggingface dataset:
P73 The complexities of defining atopy in severe childhood asthma
Authors: J. Frith, L. Fleming, C. Bossley, N. Ullmann, A. Bush
Journal: Thorax (2010)

<h3>Background</h3> Defining atopy in children with severe therapy resistant asthma is complex. There is currently no gold standard test; skin prick testing (SPT) and allergen specific immunoglobulin E (sIgE) are both used. Atopy is increasingly considered to be a spectrum, not an all-or-none phenomenon (Allergy 2007;<b>62</b>:1379–86). <h3>Hypothesis</h3> SPTs and sIgE cannot be used interchangeably, and that if both tests are not performed opportunities for intervention will be missed. Furthermore, severity of atopy will be defined differently by the two tests. Total IgE and fractional exhaled nitric oxide (FeNO<sub>50</sub>) may also help quantify atopy. <h3>Methods</h3> Cross-sectional study of 47 children with severe therapy resistant asthma, mean age 11.8 years (range 5.3–16.6 years) who underwent measurement of a standard panel (house dust mite (HDM), dog, cat, weed pollens and grass pollens) of SPTs and sIgEs, total IgE and FeNO<sub>50</sub> as part of their clinical work up. <h3>Results</h3> Overall 42/47 (89%) were atopic (defined as either a single positive SPT or sIgE). There was 98% concordance between the two tests in classifying atopy. When each allergen was considered individually, in 40/201 (19.8%) the SPT and sIgE results were discordant (Abstract P73 Figure 1), most commonly, 25/201 (12.4%) the SPT was negative and the sIgE was positive. HDM and cat sensitisation were more likely detected by sIgE, but dog by SPT. When atopy was quantified the sum of sIgEs compared with the sum of SPT wheal diameter showed only moderate correlation (r=0.66, p=&lt;0.001). Total IgE increased with an increasing number of positive sIgEs (p=0.028), but not significantly with number of positive SPTs. There was a significant correlation between FeNO<sub>50</sub> and total IgE (r=0.34, p=0.02), but no difference in FeNO<sub>50</sub> when patients were defined as atopic on either SPT or sIgE, and no relationship with increasing numbers of positive SPTs or sIgEs. <h3>Conclusions</h3> SPT and sIgE identify the group prevalence of atopy equally well; however for some allergens, concordance is poor, and when used to quantify atopy SPT and sIgE show only moderate correlation. If allergen avoidance is contemplated in children with severe therapy resistant asthma, then both tests should be performed in order to detect sensitisation.
Functional B7.2 and B7-H2 Molecules on Myeloma Cells Are Associated with a Growth Advantage
Authors: Taishi Yamashita, Hideto Tamura, Chikako Satoh, Eiji Shinya, Hidemi Takahashi, Lieping Chen, Asaka Kondo, Takashi Tsuji, Kazuo Dan, Kiyoyuki Ogata
Journal: Clinical Cancer Research (2009)

Abstract Purpose: B7 family molecules expressed on antigen-presenting cells stimulate or inhibit normal immune responses. The aim of this study was to investigate whether functional B7.2 and B7-H2 molecules are expressed on myeloma cells and, if so, whether they are associated with pathophysiology in myeloma. Experimental Design: The expression of B7.2 and B7-H2 molecules on normal plasma and neoplastic (myeloma) plasma cells was analyzed. The cell proliferation and immunomodulatory function of myeloma cells related to B7.2 and B7-H2 expression were examined. Results: Human myeloma cell lines commonly expressed B7.2 and B7-H2 molecules. B7.2 expression on plasma cells was more common in myeloma patients (n = 35) compared with that in patients with monoclonal gammopathy of unknown significance (n = 12) or hematologically normal individuals (n = 10). Plasma cells expressing B7-H2 were observed in myeloma patients alone, although rarely. Patients whose myeloma cells showed high B7.2 expression were more anemic and thrombocytopenic than other myeloma patients. The expression of these molecules was induced or augmented by cultivating myeloma cells with autologous stroma cells or tumor necrosis factor-α, a key cytokine in myeloma biology. Cell proliferation was more rapid in the B7.2+ and B7-H2+ populations compared with the B7.2− and B7-H2− populations, respectively, in the human myeloma cell lines examined. B7.2 and B7-H2 molecules on myeloma cells induced normal CD4+ T cells to proliferate and produce soluble factors, including interleukin-10 that stimulate myeloma cell proliferation. Conclusions: Functional B7.2 and B7-H2 molecules detected on myeloma cells may be involved in the pathophysiology of myeloma.
Combined Metabolomic and Proteomic Analysis of Human Atrial Fibrillation
Authors: Manuel Mayr, Shamil Yusuf, Graeme Weir, Yuen-Li Chung, Ursula Mayr, Xiaoke Yin, Christophe Ladroue, Basetti Madhu, Neil Roberts, Ayesha De Souza, Salim Fredericks, Marion Stubbs, John R. Griffiths, Marjan Jahangiri, Qingbo Xu, A. John Camm
Journal: Journal of the American College of Cardiology (2008)
Biochemical Studies in Advancing and Regressing Rat Mammary Carcinomas Induced by 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene (Huggins Tumors)
Authors: Eberhard Heise, Max Görlich, Giovanni Bacigalupo
Journal: JNCI Journal of the National Cancer Institute (1970)

The activities of aspartate transcarbamylase (ATC) and phosphoglucomutase (PGM) and the contents of RNA, DNA, and protein were estimated in rat mammary carcinomas (Huggins) induced by 7,12-dimethylbenz[a]anthracene. The growth of these tumors could be influenced by testosterone administration or ovariectomy. Advancing carcinomas showed high ATC levels and high RNA-DNA ratios. Regressing carcinomas had low ATC levels and low RNA-DNA ratios. The activity of PGM did not correlate with tumor growth rate; it was decreased by testosterone administration. By repeated biochemical analyses of tissue specimens taken serially from the same carcinoma, it was possible to follow directly some of the metabolic changes linked with the hormonally induced growth rate alterations in experimental mammary tumors.
The α2β1 integrin is a metastasis suppressor in mouse models and human cancer
Authors: Norma E. Ramirez, Zhonghua Zhang, Aasakiran Madamanchi, Kelli L. Boyd, Lynda D. O’Rear, Abudi Nashabi, Zhengzi Li, William D. Dupont, Andries Zijlstra, Mary M. Zutter
Journal: Journal of Clinical Investigation (2010)

Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that β1 integrins may stimulate metastasis of a number of cancers, expression of the β1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the α2β1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data are consistent with previous studies indicating high expression of α2β1 integrin in normal breast epithelium and loss of α2β1 in poorly differentiated breast cancer. They are also consistent with our systematic analysis of microarray databases of human breast and prostate cancer, which revealed that decreased expression of the gene encoding α2 integrin, but not genes encoding α1, α3, or β1 integrin, was predictive of metastatic dissemination and decreased survival. The predictive value of α2 expression persisted within both good-risk and poor-risk cohorts defined by estrogen receptor and lymph node status. Thus, the α2β1 integrin functionally inhibits breast tumor metastasis, and α2 expression may serve as an important biomarker of metastatic potential and patient survival.
Autoimmune sequence of streptococcal M protein shared with the intermediate filament protein, vimentin.
Authors: W Kraus, K Ohyama, D S Snyder, E H Beachey
Journal: The Journal of Experimental Medicine (1989)

The crossreactivity of antibodies against a renal autoimmune epitope of Streptococcus pyogenes M protein with glomerular mesangial cells was investigated. The antibodies directed against the amino acid sequence Ile-Arg-Leu-Arg of the nephritogenic type 1 M protein reacted in a fibrillar pattern with mesangial cells cultured from isolated glomeruli. In Western blots of urea-extracted mesangial proteins, the antibodies reacted with a 56-kD protein. Monoclonal and polyclonal antibodies identified the 56-kD mesangial protein as vimentin. Two synthetic peptides of human vimentin containing the sequence Arg-Leu-Arg reacted with the autoimmune antibodies raised against a streptococcal M protein peptide. These results provide evidence that the intermediate filament protein vimentin shares autoimmune epitopes with streptococcal M protein.
Tumor Antigen Acrosin Binding Protein Normalizes Mitotic Spindle Function to Promote Cancer Cell Proliferation
Authors: Angelique W. Whitehurst, Yang Xie, Scott C. Purinton, Kathryn M. Cappell, Jackie T. Swanik, Brittany Larson, Luc Girard, John O. Schorge, Michael A. White
Journal: Cancer Research (2010)

Abstract Cancer cells manage to divide in the context of gross chromosomal abnormalities. These abnormalities can promote bypass of normal restraints on cell proliferation but at a cost of mitotic vulnerabilities that can be attacked by chemotherapy. Determining how cancer cells balance these issues may permit chemotherapeutic sensitivity to be leveraged more efficiently. From a pan-genomic small interfering RNA screen for modifiers of chemoresponsiveness, we identified the tumor antigen acrosin binding protein (ACRBP)/OY-TES-1 as a specifier of paclitaxel resistance. ACRBP expression is normally restricted to the testes but is detected in a wide variety of cancers, including most ovarian cancers. We found that ACRBP is both necessary and sufficient for paclitaxel resistance in ovarian cancer cell lines and ovarian tumor explants. Moreover, high ACRBP expression correlated with reduced survival time and faster relapse among ovarian cancer patients. We identified the mitotic spindle protein NuMA as an ACRBP-interacting protein that could account for the effects of ACRBP on paclitaxel sensitivity. In cancer cells, ACRBP restricted a NuMA-dependent abrogation of a mitotic spindle assembly that is otherwise pathologic. As a consequence, ACRBP depletion resulted in mitotic errors and reduced proliferative fitness that could be rescued by NuMA codepletion. We propose that the codependent relationship of ACRBP and NuMA in cancer cells reflects their passage through a selection bottleneck during tumor evolution, one which requires the acquisition of traits that normalize mitotic perturbations that originally drove the plasticity of a preneoplastic genome. The molecular definition of such traits as defined by the ACRBP-NuMA complex may represent conceptually ideal intervention targets based on the wide therapeutic windows they may offer. Cancer Res; 70(19); 7652–61. ©2010 AACR.
Fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy are deficient in uridine 5'-diphosphate-N-acetylglucosamine: glycoprotein N-acetylglucosaminylphosphotransferase activity.
Authors: M L Reitman, A Varki, S Kornfeld
Journal: Journal of Clinical Investigation (1981)

Newly synthesized acid hydrolases, destined for transport to lysosomes, acquire a phosphomannosyl targeting signal by the transfer of N-acetylglucosamine 1-phosphate from uridine 5'-diphosphate (UDP)-N-acetylglucosamine to a mannose residue of the acid hydrolase followed by removal of the outer, phosphodiester-linked N-acetylglucosamine to expose 6-phosphomannose. This study demonstrates that fibroblasts from patients with the lysosomal enzyme storage diseases, I-cell disease (mucolipidosis II) and pseudo-Hurler polydystrophy (mucolipidosis III), are severely deficient in UDP-N-acetylglucosamine:glycoprotein N-acetylglucosaminylphosphotransferase, the first enzyme of the sequence. The N-acetylglucosaminylphosphotransferase activity (assayed using endogenous acceptors) in cultures from six normal subjects ranged from 0.67 to 1.46 pmol N-acetylglucosamine-1-phosphate transferred/mg protein per h, whereas five pseudo-Hurler polydystrophy and five I-cell disease cultures transferred less than 0.02 pmol/mg protein per h. The activity in five other pseudo-Hurler cultures ranged from 0.02 to 0.27 pmol transferred/mg protein per h. The activity of alpha-N-acetylglucosaminyl phosphodiesterase, the enzyme responsible for phosphomonoester exposure, is normal or elevated in cultured fibroblasts from both I-cell disease and pseudo-Hurler polydystrophy patients. The deficiency of UDP-N-acetylglucosamine:glycoprotein N-acetylglucosaminylphosphotransferase explains the biochemical abnormalities previously observed in I-cell disease and pseudo-Hurler polydystrophy.
The left ventricular dP/dtmax-end-diastolic volume relation in closed-chest dogs.
Authors: W C Little
Journal: Circulation Research (1985)

I investigated the relation of the maximum rate of left ventricular pressure rise to the end-diastolic volume and the comparison of the maximum rate of left ventricular pressure rise-end-diastolic volume relation to the end-systolic pressure-volume relation, using the time-varying elastance model. These studies were performed in 11 dogs chronically instrumented to measure left ventricular pressure and determine left ventricular volume from three orthogonal dimensions. During vena caval occlusions, the relations between the maximum rate of left ventricular pressure rise and end-diastolic volume were described by straight lines (r = 0.97 +/- 0.01, mean +/- SD). Dobutamine increased the slope of the maximum rate of left ventricular pressure rise-end-diastolic volume relation to 358 +/- 94% of control. This increase was greater than the 244 +/- 61% increase in the slope of the end-systolic pressure-volume relation (P less than 0.005). The volume intercepts of the maximum rate of left ventricular pressure rise-end-diastolic volume relation and end-systolic pressure-volume relation were similar and were not significantly altered by dobutamine. The ratio of the slope of the maximum rate of left ventricular pressure rise-end-diastolic volume relation to the slope of the end-systolic pressure-volume relation divided by the time from end-diastole to end-systole was similar before (2.2 +/- 0.7) and after dobutamine (2.3 +/- 0.7, P = NS). Angiotensin II did not significantly alter the maximum rate of left ventricular pressure rise-end-diastolic volume relation generated by caval occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
The Long and Short of MicroRNAs in the Kidney
Authors: Jacqueline Ho, Jordan A. Kreidberg
Journal: Journal of the American Society of Nephrology (2012)

MicroRNAs (miRNAs) are a group of small, noncoding RNAs that act as novel regulators of gene expression through the post-transcriptional repression of their target mRNAs. miRNAs have been implicated in diverse biologic processes, and it is estimated that up to half of all transcripts are regulated by miRNAs. Recent studies also demonstrate a critical role for miRNAs in renal development, physiology, and pathophysiology. Understanding the function of miRNAs in the kidney may lead to innovative approaches to renal disease.
Smallpox as a Biological Weapon
Authors: Donald A. Henderson, Thomas V. Inglesby, John G. Bartlett, Michael S. Ascher, Edward Eitzen, Peter B. Jahrling, Jerome Hauer, Marcelle Layton, Joseph McDade, Michael T. Osterholm, Tara O'Toole, Gerald Parker, Trish Perl, Philip K. Russell, Kevin Tonat, None for the Working Group on Civilian Biodefense
Journal: JAMA (1999)

ObjectiveTo develop consensus-based recommendations for measures to be taken by medical and public health professionals following the use of smallpox as a biological weapon against a civilian population.ParticipantsThe working group included 21 representatives from staff of major medical centers and research, government, military, public health, and emergency management institutions and agencies.EvidenceThe first author (D.A.H.) conducted a literature search in conjunction with the preparation of another publication on smallpox as well as this article. The literature identified was reviewed and opinions were sought from experts in the diagnosis and management of smallpox, including members of the working group.Consensus ProcessThe first draft of the consensus statement was a synthesis of information obtained in the evidence-gathering process. Members of the working group provided formal written comments that were incorporated into the second draft of the statement. The working group reviewed the second draft on October 30, 1998. No significant disagreements existed and comments were incorporated into a third draft. The fourth and final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members.ConclusionsSpecific recommendations are made regarding smallpox vaccination, therapy, postexposure isolation and infection control, hospital epidemiology and infection control, home care, decontamination of the environment, and additional research needs. In the event of an actual release of smallpox and subsequent epidemic, early detection, isolation of infected individuals, surveillance of contacts, and a focused selective vaccination program will be the essential items of an effective control program.
Role of the Grb2-Associated Binder 1/SHP-2 Interaction in Cell Growth and Transformation
Authors: Marina Holgado-Madruga, Albert J. Wong
Journal: Cancer Research (2004)

Grb2-associated binder 1 (Gab1) is a docking protein that is tyrosine phosphorylated following the activation of multiple cytokine receptors and receptor tyrosine kinases. Its function then is to recruit and activate multiple signaling molecules. In our previous work, we showed that Gab1 enhances cell growth and induces the transformed phenotype in NIH3T3 cells downstream of the epidermal growth factor (EGF) receptor. In this report, we analyze how it produces these effects. Because SHP-2 is the major binding partner of Gab1, we mutated its binding site in the Gab1 cDNA (Gab1/DeltaSHP-2). This construct was stably overexpressed in NIH3T3 cells (3T3-Gab1/DeltaSHP-2) and in the wild-type Gab1 cDNA (3T3-Gab1) or an empty expression vector (3T3-CTR). Our findings show that after EGF stimulation, Gab1/DeltaSHP-2 has a higher level of tyrosine phosphorylation at early time points than Gab1. Gab1/DeltaSHP-2 recruits more phosphatidylinositol 3'-kinase than Gab1 after EGF triggering, which accounts for a higher and more sustained AKT activation in 3T3-Gab1/DeltaSHP-2 cells relative to 3T3-Gab1 fibroblasts. Moreover, 3T3-Gab1/DeltaSHP-2 cells demonstrate a higher level of extracellular-regulated kinase 1 activation at early time points of EGF stimulation. However, there was an unexpected decrease in c-fos promoter induction in 3T3-Gab1/DeltaSHP-2 cells when compared with 3T3-Gab1 cells. Additionally, the 3T3-Gab1/DeltaSHP-2 cells show a reversion of the transformed phenotype, including fewer morphologic changes, an increase in stress fiber cytoskeletal organization, and a decrease in cell proliferation and anchorage independent growth. These results reveal that the Gab1/SHP-2 interaction is essential for cell growth and transformation but that this must occur through a novel pathway that is independent of extracellular-regulated kinase or AKT. On the basis of its role in growth and transformation, the Gab1/SHP-2 interaction may become an attractive target for the pharmacologic intervention of malignant cell growth.
Association Between Prophylactic Implantable Cardioverter-Defibrillators and Survival in Patients With Left Ventricular Ejection Fraction Between 30% and 35%
Authors: Sana M. Al-Khatib, Anne S. Hellkamp, Gregg C. Fonarow, Daniel B. Mark, Lesley H. Curtis, Adrian F. Hernandez, Kevin J. Anstrom, Eric D. Peterson, Gillian D. Sanders, Hussein R. Al-Khalidi, Bradley G. Hammill, Paul A. Heidenreich, Stephen C. Hammill
Journal: JAMA (2014)

Clinical trials of prophylactic implantable cardioverter-defibrillators (ICDs) have included a minority of patients with a left ventricular ejection fraction (LVEF) between 30% and 35%. Because a large number of ICDs in the United States are implanted in such patients, it is important to study survival associated with this therapy.To characterize patients with LVEF between 30% and 35% and compare the survival of those with and without ICDs.Retrospective cohort study of Medicare beneficiaries in the National Cardiovascular Data Registry ICD registry (January 1, 2006, through December 31, 2007) with an LVEF between 30% and 35% who received an ICD during a heart failure hospitalization and similar patients in the Get With The Guidelines-Heart Failure (GWTG-HF) database (January 1, 2005, through December 31, 2009) with no ICD. The analysis was repeated in patients with an LVEF less than 30%. There were 3120 patients with an LVEF between 30% and 35% (816 in matched cohorts) and 4578 with an LVEF less than 30% (2176 in matched cohorts). Propensity score matching and Cox models were applied.The primary outcome was all-cause mortality; data were obtained from Medicare claims through December 31, 2011.There were no significant differences in the baseline characteristics of the matched groups (n = 408 for both groups). Among patients with an LVEF between 30% and 35%, there were 248 deaths in the ICD Registry group, within a median follow-up of 4.4 years (interquartile range, 2.7-4.9) and 249 deaths in the GWTG HF group, within a median follow-up of 2.9 years (interquartile range, 2.1-4.4). The risk of all-cause mortality in patients with an LVEF between 30% and 35% and an ICD was significantly lower than that in matched patients without an ICD (3-year mortality rates: 51.4% vs 55.0%; hazard ratio, 0.83 [95% CI, 0.69-0.99]; P = .04). Presence of an ICD also was associated with better survival in patients with an LVEF less than 30% (3-year mortality rates: 45.0% vs 57.6%; 634 and 660 total deaths; hazard ratio, 0.72 [95% CI, 0.65-0.81]; P < .001) (P = .20 for interaction).Among Medicare beneficiaries hospitalized for heart failure and with an LVEF between 30% and 35% and less than 30%, survival at 3 years was better in patients who received a prophylactic ICD than in comparable patients with no ICD. These findings support guideline recommendations to implant prophylactic ICDs in eligible patients with an LVEF of 35% or less.
Narrative Review: The Role of Th2 Immune Pathway Modulation in the Treatment of Severe Asthma and Its Phenotypes
Authors: Stewart J. Levine
Journal: Annals of Internal Medicine (2010)

New therapeutic approaches are needed for patients with severe asthma who are refractory to standard therapy comprising high doses of inhaled corticosteroids plus long-acting β2-agonists. Current treatment guidelines for patients with severe asthma from the National Asthma Education and Prevention Program recommend the addition of oral corticosteroids, which are associated with substantial morbidity, and, for those with allergic asthma, anti-IgE. Genetic and translational studies, as well as clinical trials, suggest that in a subgroup of patients, the pathobiology of severe asthma is mediated by immune pathways driven by T-helper 2 (Th2)–type CD4+ T cells, which produce a characteristic repertoire of interleukins (ILs), including IL-4, IL-5, and IL-13. Therefore, biological modifiers of Th2-type ILs, such as monoclonal antibodies, soluble receptors, and receptor antagonists, are a rational strategy for developing new treatment approaches but will need to be targeted to selected patients in whom the appropriate Th2 immune pathway is "active." The benefits of immune-modifier therapies targeting Th2-type cytokines, however, need to be weighed against the toxicities associated with inhibition of key biological pathways, as well as the expense of future medications. Therefore, future clinical trials need to clearly establish the efficacy and safety of biological modifiers of Th2 immune pathways before these approaches can enter routine clinical practice for the treatment of severe asthma.