tbuckley/cabot-search huggingface dataset:
Citrullination of myofilament proteins in heart failure
Authors: Justyna Fert-Bober, John T. Giles, Ronald J. Holewinski, Jonathan A. Kirk, Helge Uhrigshardt, Erin L. Crowgey, Felipe Andrade, Clifton O. Bingham, Jin Kyun Park, Marc K. Halushka, David A. Kass, Joan M. Bathon, Jennifer E. Van Eyk
Journal: Cardiovascular Research (2015)

Citrullination, the post-translational conversion of arginine to citrulline by the enzyme family of peptidylarginine deiminases (PADs), is associated with several diseases, and specific citrullinated proteins have been shown to alter function while others act as auto-antigens. In this study, we identified citrullinated proteins in human myocardial samples, from healthy and heart failure patients, and determined several potential functional consequences. Further we investigated PAD isoform cell-specific expression in the heart. A citrullination-targeted proteomic strategy using data-independent (SWATH) acquisition method was used to identify the modified cardiac proteins. Citrullinated-induced sarcomeric proteins were validated using two-dimensional gel electrophoresis and investigated using biochemical and functional assays. Myocardial PAD isoforms were confirmed by RT-PCR with PAD2 being the major isoform in myocytes. In total, 304 citrullinated sites were identified that map to 145 proteins among the three study groups: normal, ischaemia, and dilated cardiomyopathy. Citrullination of myosin (using HMM fragment) decreased its intrinsic ATPase activity and inhibited the acto-HMM-ATPase activity. Citrullinated TM resulted in stronger F-actin binding and inhibited the acto-HMM-ATPase activity. Citrullinated TnI did not alter the binding to F-actin or acto-HMM-ATPase activity. Overall, citrullination of sarcomeric proteins caused a decrease in Ca2+ sensitivity in skinned cardiomyocytes, with no change in maximal calcium-activated force or hill coefficient. Citrullination unique to the cardiac proteome was identified. Our data indicate important structural and functional alterations to the cardiac sarcomere and the contribution of protein citrullination to this process.
Humor and Oncology
Authors: Anthony M. Joshua, Angela Cotroneo, Stephen Clarke
Journal: Journal of Clinical Oncology (2005)

Most clinical oncologists face the general perception that their specialty is constantly both humorless and depressing. The truth, as many medical oncologists are aware, is that the specialty offers a great deal of emotional variability. Anecdotally, the use of humor is widespread in the oncologist-patient relationship and in patient literature. Humor serves many roles for the patient, their family, and the treating physician. Limited evidence suggests that the use of humor is becoming more widespread within patientbased literature; the profession has largely ignored this aspect of cancer care.
Serum Adiponectin Is Increased in Type 1 Diabetic Patients With Nephropathy
Authors: Markku Saraheimo, Carol Forsblom, Johan Fagerudd, Anna-Maija Teppo, Kim Pettersson-Fernholm, Jan Frystyk, Allan Flyvbjerg, Per-Henrik Groop
Journal: Diabetes Care (2005)

OBJECTIVE—To elucidate whether serum adiponectin is associated with renal function, low-grade inflammatory markers, metabolic control, and insulin resistance in type 1 diabetic patients with and without nephropathy. RESEARCH DESIGN AND METHODS—A total of 189 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based on their urinary albumin excretion rate (AER): patients with normal AER (n = 66) had no antihypertensive medication, while patients with microalbuminuria (n = 63) or macroalbuminuria (n = 60) were all treated with an ACE inhibitor. Renal function was estimated with the Cockcroft-Gault formula. Adiponectin was measured by an in-house time-resolved immunofluorometric assay. RESULTS—Adiponectin concentrations were higher in women than in men, but since there was no significant difference in sex distribution between the groups, data were pooled. Adiponectin concentrations were higher in patients with macroalbuminuria (19.8 ± 12.0 mg/l) than in patients with microalbuminuria (13.1 ± 4.8 mg/l) or normoalbuminuria (11.8 ± 4.2 mg/l). In a univariate analysis, adiponectin was positively associated with creatinine (r = 0.41; P &amp;lt; 0.0001), AER (r = 0.33; P &amp;lt; 0.0001), interleukin-6 (r = 0.22; P = 0.002), systolic blood pressure (r = 0.22; P = 0.004), HbA1c (r = 0.17; P = 0.02), total cholesterol (r = 0.16; P = 0.03), and HDL cholesterol (r = 0.16; P = 0.03) and negatively with estimated glomerular filtration rate (GFR; r = −0.52; P &amp;lt; 0.0001) and waist-to-hip ratio (WHR; r = −0.16; P = 0.03). In a multiple linear regression analysis including the above variables, estimated GFR, AER, and WHR were independently associated with adiponectin levels (r2 = 0.32). CONCLUSIONS—Serum adiponectin concentrations are increased in type 1 diabetic patients with nephropathy, and levels are further associated with renal insufficiency.
Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation
Authors: Richard C Davis, Ian T Marsden, Michael T Maloney, Laurie S Minamide, Marcia Podlisny, Dennis J Selkoe, James R Bamburg
Journal: Molecular Neurodegeneration (2011)

Abstract Background Previously we reported 1 μM synthetic human amyloid beta 1-42 oligomers induced cofilin dephosphorylation (activation) and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus. Results Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Aβ dimers and trimers (Aβd/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aβ oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Aβ 1-42 , the latter lacking tyrosine, acquires a marked increase (620 fold for EC 50 ) in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 Aβd/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state), lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing Aβ monomers are not active, suggesting oxidized SDS-stable Aβ 1-42 dimers in a low-n state are the most active rod-inducing species. Aβd/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after Aβd/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Aβd/t, whereas overexpression of a cofilin kinase inhibits Aβd/t-induced rod formation. Conclusions Together these data support a mechanism by which Aβd/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.
Association of bronchial hyperresponsiveness and lung function with C-reactive protein (CRP): a population based study
Authors: S Kony
Journal: Thorax (2004)

<b>Background:</b> C-reactive protein (CRP), a marker of systemic inflammation, is a powerful predictor of adverse cardiovascular events. Respiratory impairment is also associated with cardiovascular risk. Although some studies have found an inverse relationship between lung function and markers of systemic inflammation, only one study has reported a relationship between lung function and CRP levels. In contrast, little is known about the relationship between bronchial hyperresponsiveness (BHR) and systemic inflammation. The association between lung function and CRP and between BHR and CRP has been investigated. <b>Methods:</b> As part of the European Community Respiratory Health Survey follow up study serum CRP levels, forced expiratory volume in 1 second (FEV<sub>1</sub>), and BHR to methacholine (⩾20% decrease in FEV<sub>1</sub> to &lt;4 mg methacholine) were measured in 259 adults aged 28–56 years free of cardiovascular disease or respiratory infection. <b>Results:</b> Mean (SD) FEV<sub>1</sub> (adjusted for age, sex, height, and smoking status) was lower in subjects with a high CRP level (high tertile) (3.29 (0.44) l/s <i>v</i> 3.50 (0.44) l/s; p&lt;0.001) and BHR was more frequent (41.9% <i>v</i> 24.9%; p = 0.005) than in subjects with lower CRP levels (low+middle tertiles). Similar results were obtained when the potential confounding factors were taken into account. Similar patterns of results were found in non-smokers and in non-asthmatic subjects. <b>Conclusions:</b> Increased CRP levels are strongly and independently associated with respiratory impairment and more frequent BHR. These results suggest that both respiratory impairment and BHR are associated with a systemic inflammatory process.
Cardiac Angiotensin II Receptors Are Upregulated by Long-Term Inhibition of Nitric Oxide Synthesis in Rats
Authors: Makoto Katoh, Kensuke Egashira, Makoto Usui, Toshihiro Ichiki, Hideharu Tomita, Hiroaki Shimokawa, Hiromi Rakugi, Akira Takeshita
Journal: Circulation Research (1998)

Abstract —It has been shown that nitric oxide (NO) may regulate angiotensin II (Ang II) receptors in vitro. To determine whether the chronic inhibition of NO synthesis upregulates cardiac Ang II receptors in a rat model, we evaluated the in vivo effect of N ω -nitro- l -arginine methyl ester (L-NAME) on several Ang II receptors and on the expression of AT1 receptor mRNA in heart tissue. The chronic administration of L-NAME to normal rats increased the arterial blood pressure. The number of AT1 and AT2 receptors was increased, with no change in affinity, during the first week of L-NAME administration but returned to control levels after 4 weeks of treatment. The AT1 receptor mRNA was changed parallel to AT1 receptor number. Inflammatory changes (monocyte infiltration and myofibroblast formation) in perivascular areas surrounding coronary vessels and myocardial interstitial spaces were observed during the first week. The immunohistochemistry revealed that myofibroblasts expressed AT1 receptor. AT1 receptor blockade or cotreatment with l -arginine, but not cotreatment with hydralazine, prevented the L-NAME–induced increase in Ang II receptors and inflammatory changes. In conclusion, rat cardiac Ang II receptors are upregulated at an early phase of chronic inhibition of NO synthesis. This may contribute to cardiovascular inflammatory changes in an early phase and to remodeling at the later phase, which occurs after inhibition of NO synthesis.
Let us try pirfenidone in paraquat poisoning: Effect of pirfenidone on pulmonary fibrosis due to paraquat poisoning in rats
Authors: Soroush Seifirad, Farzad Masoudkabir, Shervin Taslimi
Journal: European Respiratory Journal (2012)

Background: This study investigated the effectiveness of pirfenidone (PF) compared with antioxidants, in the prevention of pulmonary fibrosis and increasing the survival in acutely paraquat (PQ) poisoned rats.  Methods: Fifty rats equally randomized into 5 groups. Three groups poisoned with intraperitoneal injection of 15 mg/kg PQ. From these three groups one also received vitamin C (500 mg/kg, IP), E (200mg/kg, IP) and N-acetylcysteine (250 mg/kg, IV). Two others received either Normal Saline (NS) or PF (200 mg/kg- IV). Two groups were not poisoned and received NS or PF (200mg/kg, IV). All injections except PQ repeated for another 4 times in consecutive days. On the 15th day of study or the corresponding day of death a semi-quantitative determination of lung fibrous was done using Ashcroft staging criteria on the lung sections.  Results: PF decreased PQ induced lung fibrosis (P  Conclusion: This study showed that PF is able to decrease pulmonary fibrosis following PQ poisoning.
Expert on AIDS says epidemic can now be reversed
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

On the eve of the United Nations' summit in New York this week, Peter Piot, executive director of UNAIDS (the joint UN programme on HIV and AIDS), told journalists that the AIDS epidemic could be reversed because of greater awareness of the disease among political leaders and increased funding.

“Even two years ago the money wasn't there. It's not enough, but it's a big change. If we had had that kind of money and political will years ago, we would have saved millions of lives. Now more people have access to treatment,” he said.

Dr Piot was speaking at a meeting on Monday sponsored …
T cell receptor contact to restricting MHC molecules is a prerequisite for peripheral interclonal T cell competition
Authors: Fabien Agenès, Jean-Pierre Dangy, Jörg Kirberg
Journal: The Journal of Experimental Medicine (2008)

T cell survival and homeostatic proliferation in the periphery requires T cell receptor (TCR) binding to restricting major histocompatability complex (MHC)−encoded molecules, as well as the availability of certain lymphokines. However, the exact mechanisms by which these signals interrelate and contribute to homeostasis are not understood. By performing T cell transfers into TCR transgenic hosts we detected a hierarchical order of homeostatic proliferation for T cells differing in MHC restriction, such that OT1 cells (Kb restricted) proliferated in P14 (Db-restricted TCR) recipients, but not vice versa. Using Kb mutant mice, we demonstrated that proliferation of OT1 cells in P14 recipients, as well as the ability of host OT1 cells to hinder the proliferation of donor P14 cells, were dependent on OT1-TCR binding to Kb molecules. However, interclonal T cell competition was not mediated simply by competition for physical access to the MHC-bearing cell. This was shown in parabiotic pairs of OT1 and Kb mutant mice in which P14 cells failed to proliferate, even though the OT1 cells could not interact with half of the APCs in the system. Thus, we conclude that the interaction between the TCR and restricting MHC molecule influences the ability to compete for trophic resources not bound to the stimulating APC. This mechanism allows a local competitiveness that extends beyond a T cell's specificity.
Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activatable Fluorescence Sensor
Authors: Farouc A. Jaffer, Dong-Eog Kim, Luisa Quinti, Ching-Hsuan Tung, Elena Aikawa, Ashvin N. Pande, Rainer H. Kohler, Guo-Ping Shi, Peter Libby, Ralph Weissleder
Journal: Circulation (2007)

Cathepsin K (CatK), a potent elastinolytic and collagenolytic cysteine protease, likely participates in the evolution and destabilization of atherosclerotic plaques. To assess better the biology of CatK activity in vivo, we developed a novel near-infrared fluorescence (NIRF) probe for imaging of CatK and evaluated it in mouse and human atherosclerosis.The NIRF imaging agent consists of the CatK peptide substrate GHPGGPQGKC-NH2 linked to an activatable fluorogenic polymer. In vitro, CatK produced a 2- to 14-fold activation of the agent over other cysteine and matrix metalloproteinases (P<0.0001), as well as a >8-fold activation over a control imaging agent (P<0.001). Optical imaging of atheroma revealed >100% NIRF signal increases in apolipoprotein E-/- mice in vivo (n=13; P<0.05, CatK imaging agent versus control agent) and in human carotid endarterectomy specimens ex vivo (n=14; P<0.05). Fluorescence microscopy of plaque sections demonstrated that enzymatically active CatK (positive NIRF signal) localized primarily in the vicinity of CatK-positive macrophages. Augmented NIRF signal (reflecting CatK activity) colocalized with disrupted elastin fibers within the media underlying plaques.Use of this novel protease-activatable NIRF agent for optical imaging in vivo demonstrated preferential localization of enzymatically active CatK to macrophages, consistent with their known greater elastinolytic capabilities compared with smooth muscle cells. Augmented CatK proteolysis in atheromata further links CatK to vascular remodeling and plaque vulnerability.
The Inducible CXCR3 Ligands Control Plasmacytoid Dendritic Cell Responsiveness to the Constitutive Chemokine Stromal Cell–derived Factor 1 (SDF-1)/CXCL12
Authors: Béatrice Vanbervliet, Nathalie Bendriss-Vermare, Catherine Massacrier, Bernhard Homey, Odette de Bouteiller, Francine Brière, Giorgio Trinchieri, Christophe Caux
Journal: The Journal of Experimental Medicine (2003)

The recruitment of selected dendritic cell (DC) subtypes conditions the class of the immune response. Here we show that the migration of human plasmacytoid DCs (pDCs), the blood natural interferon α–producing cells, is induced upon the collective action of inducible and constitutive chemokines. Despite expression of very high levels of CXCR3, pDCs do not respond efficiently to CXCR3 ligands. However, they migrate in response to the constitutive chemokine stromal cell–derived factor 1 (SDF-1)/CXCL12 and CXCR3 ligands synergize with SDF-1/CXCL12 to induce pDC migration. This synergy reflects a sensitizing effect of CXCR3 ligands, which, independently of a gradient and chemoattraction, decrease by 20–50-fold the threshold of sensitivity to SDF-1/CXCL12. Thus, the ability of the constitutive chemokine SDF-1/CXCL12 to induce pDC recruitment might be controlled by CXCR3 ligands released during inflammation such as in virus infection. SDF-1/CXCL12 and the CXCR3 ligands Mig/CXCL9 and ITAC/CXCL1 display adjacent expression both in secondary lymphoid organs and in inflamed epithelium from virus-induced pathologic lesions. Because pDCs express both the lymph node homing molecule l-selectin and the cutaneous homing molecule cutaneous lymphocyte antigen, the cooperation between inducible CXCR3 ligands and constitutive SDF-1/CXCL12 may regulate recruitment of pDCs either in lymph nodes or at peripheral sites of inflammation.
MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers
Authors: Luigi Laghi, Paolo Bianchi, Gabriele Delconte, Giuseppe Celesti, Giuseppe Di Caro, Monica Pedroni, Anna Maria Chiaravalli, Barbara Jung, Carlo Capella, Maurizio Ponz de Leon, Alberto Malesci
Journal: Clinical Cancer Research (2012)

Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis.One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed.Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P < 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 ± 1.56 vs. 2.79 ± 1.75; P = 0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P < 0.001], and better disease-free survival (P = 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P = 0.02).MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome.
Spinal loading during circuit weight-training and running.
Authors: P Leatt, T Reilly, J G Troup
Journal: British Journal of Sports Medicine (1986)

Spinal shrinkage was used as an indicant of loading on the spine in circuit weight-training and running regimes. The loss of stature during two sets of a circuit of weight-training (n = 10), a 6 km run by novices (n = 9) and a 25 km run by trained runners (n = 7) was assessed in male subjects. Shrinkage was not significantly different between the weight-training regime and the 6 km run by novices, mean losses being 5.4 and 3.25 mm respectively. The rate of height loss in the experienced runners was 2.35 mm over 6 km run at 12.2 km.h-1, representing 0.4 mm.km-1 over the 6 km run, this shrinkage rate being continued over the last 19 km run at 14.7 km.h-1. The loss of height could not be predicted from a set of covariates. The magnitude of the circadian variation, mean 14.4 mm, exceeded the change in height during the 25 km run. The diurnal variation conformed to a cosine function, though a better fit was obtained with a power function equation. A marked diurnal pattern was also observed in lumbar extension. Though reversal of spinal shrinkage was observed during a night's sleep, no significant recovery occurred during a 20 min resting period immediately following the exercise regimes. These results have implications for the warm-up and timing of exercise regimes that impose significant loading on the spine.
TAHRE, a Novel Telomeric Retrotransposon from Drosophila melanogaster, Reveals the Origin of Drosophila Telomeres
Authors: José P. Abad, Beatriz de Pablos, Kazutoyo Osoegawa, Pieter J. de Jong, Antonia Martín-Gallardo, Alfredo Villasante
Journal: Molecular Biology and Evolution (2004)

Drosophila telomeres do not have typical telomerase repeats. Instead, two families of non-LTR retrotransposons, HeT-A and TART, maintain telomere length by occasional transposition to the chromosome ends. Despite the work on Drosophila telomeres, its evolutionary origin remains controversial. Herein we describe a novel telomere-specific retroelement that we name TAHRE (Telomere-Associated and HeT-A-Related Element). The structure of the three telomere-specific elements indicates a common ancestor. These results suggest that preexisting transposable elements were recruited to perform the cellular function of telomere maintenance. A recruitment similar to that of a retrotransposal reverse transcriptase has been suggested as the common origin of telomerases.
Clinical and Radiologic Diagnostic Features of Acute Leukemia
Authors: M. L. Murphy
Journal: CA A Cancer Journal for Clinicians (1964)

are fairly uniform for all cell types.Ex animation of stained smears of blood and bone marrow makes it possible to classify leukemic cells into four main types, de pendent Upon morphological characteristics:(1) stem cell: (2) lymphoblastic:(3) gran ulocytic (subtypes such as myelomonocytic, di Guglielmo.esoinophihic and basophilic); and (4) monocytic.3â€•Â°The stein cell type, classified with lympho.blastic by some morphogists, is more com mon in children than in adults.It is charac terized b@ mild to moderate lymphadenop atil)' and hepatosplenomegaly; bone pain is :1160 frequent.The peripheral leucocy'te