tbuckley/cabot-search huggingface dataset:
Inducible Expression of Active Protein Phosphatase-1 Inhibitor-1 Enhances Basal Cardiac Function and Protects Against Ischemia/Reperfusion Injury
Authors: Persoulla Nicolaou, Patricia Rodriguez, Xiaoping Ren, Xiaoyang Zhou, Jiang Qian, Sakthivel Sadayappan, Bryan Mitton, Anand Pathak, Jeffrey Robbins, Roger J. Hajjar, Keith Jones, Evangelia G. Kranias
Journal: Circulation Research (2009)

Ischemic heart disease, which remains the leading cause of morbidity and mortality in the Western world, is invariably characterized by impaired cardiac function and disturbed Ca(2+) homeostasis. Because enhanced inhibitor-1 (I-1) activity has been suggested to preserve Ca(2+) cycling, we sought to define whether increases in I-1 activity in the adult heart may ameliorate contractile dysfunction and cellular injury in the face of an ischemic insult. To this end, we generated an inducible transgenic mouse model that enabled temporally controlled expression of active I-1 (T35D). Active I-1 expression in the adult heart elicited significant enhancement of contractile function, associated with preferential phospholamban phosphorylation and enhanced sarcoplasmic reticulum Ca(2+)-transport. Further phosphoproteomic analysis revealed alterations in proteins associated with energy production and protein synthesis, possibly to support the increased metabolic demands of the hyperdynamic hearts. Importantly, on ischemia/reperfusion-induced injury, active I-1 expression augmented contractile function and recovery. Further examination revealed that the infarct region and apoptotic as well as necrotic injuries were significantly attenuated by enhanced I-1 activity. These cardioprotective effects were associated with suppression of the endoplasmic reticulum stress response. The present findings indicate that increased I-1 activity in the adult heart enhances Ca(2+) cycling and improves mechanical recovery, as well as cell survival after an ischemic insult, suggesting that active I-1 may represent a potential therapeutic strategy in myocardial infarction.
MRI findings in the lumbar spines of asymptomatic, adolescent, elite tennis players
Authors: F Alyas, M Turner, D Connell
Journal: British Journal of Sports Medicine (2007)

Objective: To describe magnetic resonance imaging (MRI) findings in the lumbar spine in asymptomatic elite adolescent tennis players, to serve as the baseline for a future prospective longitudinal cohort study. Design: Observational study. Setting: Institutional, national tennis centre. Participants: 33 asymptomatic elite adolescent tennis players, mean (SD) age, 17.3 (1.7) years (18 male, 15 female). Methods: Sagittal T1, T2, STIR, and axial T2 weighted MRI images were reviewed for the presence of abnormalities by two radiologists in consensus. Abnormalities included disc degeneration, disc herniation, pars lesions (fracture or stress reaction), and facet joint arthropathy. Results: Five players (15.2%) had a normal MRI examination and 28 (84.8%) had an abnormal examination. Nine players showed pars lesions (10 lesions; one at two levels) predominately at the L5 level (9/10, L5; 1/10, L4). Three of the 10 lesions were complete fractures; two showed grade 1 and one grade 2 spondylolisthesis, both of which resulted in moderate narrowing of the L5 exit foramen. There were two acute and five chronic stress reactions of the pars. Twenty three patients showed signs of early facet arthropathy occurring at L5/S1 (15/29 joints) and L4/5 (12/29 joints). These were classified as mild degeneration (20/29) and moderate degeneration (9/29), with 20/29 showing sclerosis and 24/29 showing hypertrophy of the facet joint. Synovial cysts were identified in 14 of the 29 joints. Thirteen players showed disc desiccation and disc bulging (mild in 13; moderate in two) most often at L4/5 and L5/S1 levels (12 of 15 discs). Conclusions: Abnormalities were frequent, predominately in the lower lumbar spine, almost exclusively at L4/5 and L5/S1 levels. Pars injuries and facet joint arthroses were relatively common.
A randomised controlled trial of spinal manipulative therapy in acute low back pain
Authors: P Jüni, M Battaglia, E Nüesch, G Hämmerle, P Eser, R van Beers, D Vils, J Bernhard, H-R Ziswiler, M Dähler, S Reichenbach, P M Villiger
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To determine whether treatment with spinal manipulative therapy (SMT) administered in addition to standard care is associated with clinically relevant early reductions in pain and analgesic consumption. Methods: 104 patients with acute low back pain were randomly assigned to SMT in addition to standard care (n = 52) or standard care alone (n = 52). Standard care consisted of general advice and paracetamol, diclofenac or dihydrocodeine as required. Other analgesic drugs or non-pharmacological treatments were not allowed. Primary outcomes were pain intensity assessed on the 11-point box scale (BS-11) and analgesic use based on diclofenac equivalence doses during days 1–14. An extended follow-up was performed at 6 months. Results: Pain reductions were similar in experimental and control groups, with the lower limit of the 95% CI excluding a relevant benefit of SMT (difference 0.5 on the BS-11, 95% CI −0.2 to 1.2, p = 0.13). Analgesic consumptions were also similar (difference −18 mg diclofenac equivalents, 95% CI −43 mg to 7 mg, p = 0.17), with small initial differences diminishing over time. There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups. The extended follow-up showed similar patterns. Conclusions: SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain.
Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3+ dendritic cells at cross presentation
Authors: Lillian Cohn, Bithi Chatterjee, Filipp Esselborn, Anna Smed-Sörensen, Norihiro Nakamura, Cécile Chalouni, Byoung-Chul Lee, Richard Vandlen, Tibor Keler, Peter Lauer, Dirk Brockstedt, Ira Mellman, Lélia Delamarre
Journal: The Journal of Experimental Medicine (2013)

Human BDCA3(+) dendritic cells (DCs), the proposed equivalent to mouse CD8α(+) DCs, are widely thought to cross present antigens on MHC class I (MHCI) molecules more efficiently than other DC populations. If true, it is unclear whether this reflects specialization for cross presentation or a generally enhanced ability to present antigens on MHCI. We compared presentation by BDCA3(+) DCs with BDCA1(+) DCs using a quantitative approach whereby antigens were targeted to distinct intracellular compartments by receptor-mediated internalization. As expected, BDCA3(+) DCs were superior at cross presentation of antigens delivered to late endosomes and lysosomes by uptake of anti-DEC205 antibody conjugated to antigen. This difference may reflect a greater efficiency of antigen escape from BDCA3(+) DC lysosomes. In contrast, if antigens were delivered to early endosomes through CD40 or CD11c, BDCA1(+) DCs were as efficient at cross presentation as BDCA3(+) DCs. Because BDCA3(+) DCs and BDCA1(+) DCs were also equivalent at presenting peptides and endogenously synthesized antigens, BDCA3(+) DCs are not likely to possess mechanisms for cross presentation that are specific to this subset. Thus, multiple DC populations may be comparably effective at presenting exogenous antigens to CD8(+) T cells as long as the antigen is delivered to early endocytic compartments.
MYRbase: analysis of genome-wide glycine myristoylation enlarges the functional spectrum of eukaryotic myristoylated proteins
Authors: Sebastian Maurer-Stroh, Masaki Gouda, Maria Novatchkova, Alexander Schleiffer, Georg Schneider, Fernanda L Sirota, Michael Wildpaner, Nobuhiro Hayashi, Frank Eisenhaber
Journal: Genome biology (2004)
<i>Nf1</i> Regulates Hematopoietic Progenitor Cell Growth and Ras Signaling in Response to Multiple Cytokines
Authors: You-Yan Zhang, Terry A. Vik, John W. Ryder, Edward F. Srour, Tyler Jacks, Kevin Shannon, D. Wade Clapp
Journal: The Journal of Experimental Medicine (1998)

Neurofibromin, the protein encoded by the NF1 tumor-suppressor gene, negatively regulates the output of p21ras (Ras) proteins by accelerating the hydrolysis of active Ras-guanosine triphosphate to inactive Ras-guanosine diphosphate. Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile chronic myelogenous leukemia (JCML) and other malignant myeloid disorders, and heterozygous Nf1 knockout mice spontaneously develop a myeloid disorder that resembles JCML. Both human and murine leukemias show loss of the normal allele. JCML cells and Nf1−/− hematopoietic cells isolated from fetal livers selectively form abnormally high numbers of colonies derived from granulocyte-macrophage progenitors in cultures supplemented with low concentrations of granulocyte-macrophage colony stimulating factor (GM-CSF). Taken together, these data suggest that neurofibromin is required to downregulate Ras activation in myeloid cells exposed to GM-CSF. We have investigated the growth and proliferation of purified populations of hematopoietic progenitor cells isolated from Nf1 knockout mice in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF), as well as to GM-CSF. We found abnormal proliferation of both immature and lineage-restricted progenitor populations, and we observed increased synergy between SCF and either IL-3 or GM-CSF in Nf1−/− progenitors. Nf1−/− fetal livers also showed an absolute increase in the numbers of immature progenitors. We further demonstrate constitutive activation of the Ras-Raf-MAP (mitogen-activated protein) kinase signaling pathway in primary c-kit+ Nf1−/− progenitors and hyperactivation of MAP kinase after growth factor stimulation. The results of these experiments in primary hematopoietic cells implicate Nf1 as playing a central role in regulating the proliferation and survival of primitive and lineage-restricted myeloid progenitors in response to multiple cytokines by modulating Ras output.
Elevated Levels of <i>S</i> -Nitrosoalbumin in Preeclampsia Plasma
Authors: Vladimir A. Tyurin, Shang-Xi Liu, Yulia Y. Tyurina, Nancy B. Sussman, Carl A. Hubel, James M. Roberts, Robert N. Taylor, Valerian E. Kagan
Journal: Circulation Research (2001)

Abstract —The availability of nitric oxide (NO), which is required for the normal regulation of vascular tone, may be decreased in preeclampsia, thus contributing to the vascular pathogenesis of this pregnancy disorder. Because ascorbate is essential for the decomposition of S -nitrothiols and the release of NO, we speculated that the ascorbate deficiency typical of preeclampsia plasma might result in decreased rates of decomposition of S -nitrosothiols. We tested the hypothesis that total S -nitrosothiol and S -nitrosoalbumin concentrations are increased in preeclampsia plasma, reflecting a decreased release of NO from these major reservoirs of NO. Gestationally matched plasma samples were obtained (before labor or intravenous MgSO 4 ) from 21 women with preeclampsia and 21 women with normal pregnancy, and plasma samples were also obtained from 12 nonpregnant women of similar age and body mass index during the follicular phase of the menstrual cycle. All were nonsmokers. The assay included ultraviolet-induced decomposition of S -nitrosothiols to liberate NO captured by a florigenic reagent, 4,5-diaminofluoresceine, to produce diaminofluoresceine-Triazole. Preeclampsia plasma contained significantly higher concentrations of total S -nitrosothiols (11.1±2.9 nmol/mL) than normal pregnancy samples (9.4±1.5 nmol/mL). Even greater differences were found between preeclampsia plasma and plasma samples from normal pregnancies and nonpregnant women (294±110, 186±25, and 151±25 pmol/mg protein, respectively) when S -nitrosothiol content was expressed per milligram protein. The albumin fraction contained 49.4% of total plasma S -nitrosothiols in the control samples and 53.7% and 56.8% of plasma S -nitrosothiols in normal pregnancy and preeclampsia, respectively. The level of S -nitrosoalbumin was significantly higher in preeclampsia than in normal pregnancy or nonpregnancy plasma (6.3±1.4, 5.1±0.7, and 4.2±1.0 nmol/mL, respectively). The increased concentration of S -nitrosoalbumin in preeclampsia almost completely accounted for the increased levels of S -nitrosothiols in total plasma. Due to combined increases in nitrosothiols and decreases in protein, the preeclampsia plasma concentration of S -nitrosoalbumin was greatly increased on a per milligram of protein basis (271% and 186% compared with normal nonpregnancy and normal pregnancy plasma, respectively). We conclude that S -nitrosoalbumin and total S -nitrosothiol concentrations are significantly increased in preeclampsia plasma and may reflect insufficient release of NO groups in this condition.
2-Methoxyestradiol Suppresses Osteolytic Breast Cancer Tumor Progression <i>In vivo</i>
Authors: Muzaffer Cicek, Urszula T. Iwaniec, Michael J. Goblirsch, Anne Vrabel, Ming Ruan, Denis R. Clohisy, Russell R. Turner, Merry Jo Oursler
Journal: Cancer Research (2007)

Abstract 2-Methoxyestradiol (2ME2), a physiologic metabolite of 17β-estradiol (estrogen), has emerged as a promising cancer therapy because of its potent growth-inhibitory and proapoptotic effects on both endothelial and tumor cells. 2ME2 also suppresses osteoclast differentiation and induces apoptosis of mature osteoclasts, and has been shown to effectively repress bone loss in an animal model of postmenopausal osteoporosis. Given these observations, we have examined whether 2ME2 could effectively target metastasis to bone, osteolytic tumors, and soft tissue tumors. A 4T1 murine metastatic breast cancer cell line was generated that stably expressed Far Red fluorescence protein (4T1/Red) to visualize tumor development and metastasis to bone. In an intervention study, 4T1/Red cells were injected into bone marrow of the left femur and the mammary pad. In the latter study, 2ME2 (10, 25, and 50 mg/kg/d) treatment began on the same day as surgery and was continued for the 16-day duration of study. Tumor cell growth and metastasis to bone were monitored and bone volume was determined by micro-computed tomography. 2ME2 inhibited tumor growth in soft tissue, metastasis to bone, osteolysis, and tumor growth in bone, with maximum effects at 50 mg/kg/d. Furthermore, tumor-induced osteolysis was significantly reduced in mice receiving 2ME2. In vitro, 2ME2 repressed osteoclast number by inducing apoptosis of osteoclast precursors as well as mature osteoclasts. Our data support the conclusion that 2ME2 could be an important new therapy in the arsenal to fight metastatic breast cancer. [Cancer Res 2007;67(21):10106–11]
The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy
Authors: Julio Rosenstock, Salomon Banarer, Vivian A. Fonseca, Silvio E. Inzucchi, William Sun, Wenqing Yao, Gregory Hollis, Robert Flores, Richard Levy, William V. Williams, Jonathan R. Seckl, Reid Huber
Journal: Diabetes Care (2010)

OBJECTIVE 11-β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11βHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7–11%). RESEARCH DESIGN AND METHODS This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety. RESULTS After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (−0.6%), fasting plasma glucose (−24 mg/dl), and homeostasis model assessment–insulin resistance (HOMA-IR) (−24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups. CONCLUSIONS INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11βHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes.
Abnormal platelet response to thromboxane A2.
Authors: K K Wu, G C Le Breton, H H Tai, Y C Chen
Journal: Journal of Clinical Investigation (1981)

To determine the pathogenetic mechanism of a hereditary primary platelet release disorder, arachidonic acid metabolism via the cyclooxygenase pathway was investigated. The propositus' platelets exhibited defective release reaction and second-wave aggregation when stimulated by sodium arachidonate or U46619, a thromboxane A2 (TXA2) agonist. The lack of platelet response to U46619 suggested that the defect was beyond the thromboxane synthetase level. Furthermore, thromboxane B2 (TXB2) formation in the propositus' platelets (558.52 ng/10(8) platelets) was within the normal range (574.29 +/- SD 27.39 ng/10(8) platelets) and TXA2 formation appeared to be adequate for aggregating normal platelets. The results were indicative of an abnormal platelet response to TXA2. Failure of the propositus' platelets to aggregate in response to TXA2 formed in normal platelet-rich plasma induced by arachidonate confirmed this notion. To gain further insight, platelet cyclic (c) AMP content was determined. Prostacyclin induced a significant elevation of the propositus' platelet cAMP level comparable to normal values. U46619 suppressed prostaglandin I2-induced cAMP elevation in normal subjects but had no such effect in the patient. We conclude that the primary release disorder observed in this kindred is due to an abnormal platelet respnse to TXA2 possibly because of TXA2/PGH2 receptor abnormalities.
Contributions of the T Cell Receptor–associated CD3γ–ITAM to Thymocyte Selection
Authors: Mariëlle C. Haks, Elsa Pépin, Jeroen H.N. van den Brakel, Sigrid A.A. Smeele, Stanley M. Belkowski, Helmut W.H.G. Kessels, Paul Krimpenfort, Ada M. Kruisbeek
Journal: The Journal of Experimental Medicine (2002)

The immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 chains associated with the T cell receptor (TCR) are crucial for TCR signaling. To probe the role of the CD3γ–ITAM in T cell development, we created knock-in mice in which the CD3γ chain of the TCR complex is replaced by a mutant signaling-deficient CD3γ chain, lacking the CD3γ–ITAM. This mutation results in considerable impairment in positive selection in the polyclonal TCR repertoire. When CD3γ–ΔITAM mice are crossed to mice expressing transgenic F5 TCRs, their thymocytes are completely unable to perform positive selection in vivo in response to intrathymic ligands. Also, the in vitro positive selection response of double-positive (DP) thymocytes with F5–CD3γ–ΔITAM mutant receptors to their agonist ligand and many of its variants is severely impaired or abrogated. Yet, the binding and dissociation constants of agonist ligands for the F5 receptor are not affected by the CD3γ–ΔITAM mutation. Furthermore, DP thymocytes with mutant receptors can respond to agonist ligand with normal antigen sensitivity and to normal levels, as shown by their ability to induce CD69 up-regulation, TCR down-regulation, negative selection, and ZAP70 and c-Jun NH2-terminal kinase activation. In sharp contrast, induction of extracellular signal-regulated kinase (ERK) activation and linker for activation of T cells (LAT) phosphorylation are severely impaired in these cells. Together, these findings underscore that intrinsic properties of the TCR–CD3 complex regulate selection at the DP checkpoint. More importantly, this analysis provides the first direct genetic evidence for a role of the CD3γ–ITAM in TCR-driven thymocyte selection.
Temporal Trends in Mortality From Diseases of the Circulatory System After Treatment for Hodgkin Lymphoma: A Population-Based Cohort Study in Sweden (1973 to 2006)
Authors: Sandra Eloranta, Paul C. Lambert, Jan Sjöberg, Therese M.L. Andersson, Magnus Björkholm, Paul W. Dickman
Journal: Journal of Clinical Oncology (2013)

Purpose Hodgkin lymphoma (HL) survival in Sweden has improved dramatically over the last 40 years, but little is known about the extent to which efforts aimed at reducing long-term treatment-related mortality have contributed to the improved prognosis. Methods We used population-based data from Sweden to estimate the contribution of treatment-related mortality caused by diseases of the circulatory system (DCS) to temporal trends in excess HL mortality among 5,462 patients diagnosed at ages 19 to 80 between 1973 and 2006. Flexible parametric survival models were used to estimate excess mortality. In addition, we used recent advances in statistical methodology to estimate excess mortality in the presence of competing causes of death. Results Excess DCS mortality within 20 years after diagnosis has decreased continually since the mid-1980s and is expected to further decrease among patients diagnosed in the modern era. Age at diagnosis and sex were important predictors for excess DCS mortality, with advanced age and male sex being associated with higher excess DCS mortality. However, when accounting for competing causes of death, we found that excess DCS mortality constitutes a relatively small proportion of the overall mortality among patients with HL in Sweden. Conclusion Excess DCS mortality is no longer a common source of mortality among Swedish patients with HL. The main causes of death among long-term survivors today are causes other than HL, although other (non-DCS) excess mortality also persists for as long as 20 years after diagnosis, particularly among older patients.
A major house dust mite allergen disrupts the immunoglobulin E network by selectively cleaving CD23: innate protection by antiproteases.
Authors: C R Hewitt, A P Brown, B J Hart, D I Pritchard
Journal: The Journal of Experimental Medicine (1995)

Asthma is a chronic life-threatening disease of worldwide importance. Although allergic asthma and related atopic conditions correlate strongly with immune sensitization to house dust mites, it is unclear why antigens from mites provoke such powerful allergic immune responses. We have characterized the protease activity of Der p I, the group I protease allergen of the house dust mite Dermatophagoides pteronyssinus, and here report that it cleaves the low-affinity immunoglobulin (Ig) E Fc receptor (CD23) from the surface of human B lymphocytes. Der p I selectively cleaves CD23 and has no effect on the expression of any other B cell surface molecules tested. We speculate that this loss of cell surface CD23 from IgE-secreting B cells may promote and enhance IgE immune responses by ablating an important feedback inhibitory mechanism that normally limits IgE synthesis. Furthermore, since soluble CD23 is reported to promote IgE production, fragments of CD23 released by Der p I may directly enhance the synthesis of IgE. alpha 1-Antiprotease, a pulmonary antiprotease, is also shown to inhibit the cleavage of CD23 by Der p I. This may be significant in the etiopathogenesis of asthma, because other indoor pollutants associated with asthma are known to potently inhibit this antiprotease. These data suggest that the proteolytic activity of Der p I, the group I allergen of the house dust mite D. pteronyssinus, is mechanistically linked to the potent allergenicity of house dust mites. Furthermore, inhibition of Der p I by alpha 1-antiprotease suggests a mechanism by which confounding factors, such as tobacco smoke, may act as a risk factor for allergic asthma.