tbuckley/cabot-search huggingface dataset:
A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1
Authors: Melanie Blasius, Josep V Forment, Neha Thakkar, Sebastian A Wagner, Chunaram Choudhary, Stephen P Jackson
Journal: Genome biology (2011)

Abstract Background The cell-cycle checkpoint kinase Chk1 is essential in mammalian cells due to its roles in controlling processes such as DNA replication, mitosis and DNA-damage responses. Despite its paramount importance, how Chk1 controls these functions remains unclear, mainly because very few Chk1 substrates have hitherto been identified. Results Here, we combine a chemical genetics approach with high-resolution mass spectrometry to identify novel Chk1 substrates and their phosphorylation sites. The list of targets produced reveals the potential impact of Chk1 function not only on processes where Chk1 was already known to be involved, but also on other key cellular events such as transcription, RNA splicing and cell fate determination. In addition, we validate and explore the phosphorylation of transcriptional co-repressor KAP1 Ser473 as a novel DNA-damage-induced Chk1 site. Conclusions By providing a substantial set of potential Chk1 substrates, we present opportunities for studying unanticipated functions for Chk1 in controlling a wide range of cellular processes. We also refine the Chk1 consensus sequence, facilitating the future prediction of Chk1 target sites. In addition, our identification of KAP1 Ser473 phosphorylation as a robust readout for Chk1 activity could be used to explore the in vivo effects of Chk1 inhibitors that are being developed for clinical evaluation.
Over-expression of calpastatin aggravates cardiotoxicity induced by doxorubicin
Authors: Yanpeng Wang, Dong Zheng, Meng Wei, Jian Ma, Yong Yu, Ruizhen Chen, James C. Lacefield, Huaxi Xu, Tianqing Peng
Journal: Cardiovascular Research (2013)

Doxorubicin causes damage to the heart, which may present as cardiomyopathy. However, the mechanisms by which doxorubicin induces cardiotoxicity remain not fully understood and no effective prevention for doxorubicin cardiomyopathy is available. Calpains, a family of calcium-dependent thiol-proteases, have been implicated in cardiovascular diseases. Their activities are tightly controlled by calpastatin. This study employed transgenic mice over-expressing calpastatin to investigate the role of calpain in doxorubicin-induced cardiotoxicity.Doxorubicin treatment decreased calpain activities in cultured neonatal mouse cardiomyocytes and in vivo mouse hearts, which correlated with down-regulation of calpain-1 and calpain-2 proteins. Over-expression of calpastatin or incubation with pharmacological calpain inhibitors enhanced apoptosis in neonatal and adult cardiomyocytes induced by doxorubicin. In contrast, over-expression of calpain-2 but not calpain-1 attenuated doxorubicin-induced apoptosis in cardiomyocytes. The pro-apoptotic effects of calpain inhibition were associated with down-regulation of protein kinase B (AKT) protein and mRNA expression, and a concomitant reduction in glycogen synthase kinase-3beta (GSK-3β) phosphorylation (Ser9) in doxorubicin-treated cardiomyocytes. Blocking AKT further increased doxorubicin-induced cardiac injuries, suggesting the effects of calpain inhibition may be mediated by inactivating the AKT signalling. In an in vivo model of doxorubicin-induced cardiotoxicity, over-expression of calpastatin exacerbated myocardial dysfunction as assessed by echocardiography and haemodynamic measurement in transgenic mice 5 days after doxorubicin injection. The 5-day mortality was higher in transgenic mice (29.16%) compared with their wild-type littermates (8%) after doxorubicin treatment.Over-expression of calpastatin enhances doxorubicin-induced cardiac injuries through calpain inhibition and thus, calpains may protect cardiomyocytes against doxorubicin-induced cardiotoxicity.
Labile anticoagulant in a patient with lymphoma
Authors: G. H. Goldsmith, H. Saito, W. A. Muir
Journal: American Journal of Hematology (1981)

Abstract A patient with diffuse lymphocytic lymphoma and monoclonal IgM kappa immunoglobulin was found to have an unstable circulating anticoagulant. The anticoagulant inhibited phospholipid‐dependent plasma coagulation reactions. Unlike previously described anticoagulants of this type, this plasma inhibitor was neutralized in vitro by products of platelet lysis but not by exogenous addition of other phospholipids or by intact platelets. Inhibitory activity seemed dependent on the monoclonal immunoglobulin, but isolated immunoglobulin fractions lacked anticoagulant activity, suggesting that the inhibitory function was dependent on an easily disrupted macromolecular aggregate. Recognition and characterization of other similar anticoagulants may provide a means of studying the role of phospholipids in normal hemostasis.
Immunogenicity, Including Vitiligo, and Feasibility of Vaccination With Autologous<i>GM-CSF</i>–Transduced Tumor Cells in Metastatic Melanoma Patients
Authors: Rosalie M. Luiten, Esther W.M. Kueter, Wolter Mooi, Maarten P.W. Gallee, Elaine M. Rankin, Winald R. Gerritsen, Shirley M. Clift, Willem J. Nooijen, Pauline Weder, Willeke F. van de Kasteele, Johan Sein, Paul C.M. van den Berk, Omgo E. Nieweg, Anton M. Berns, Hergen Spits, Gijsbert C. de Gast
Journal: Journal of Clinical Oncology (2005)

To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients.Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays.The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation.We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.
Primary Cutaneous CD4<sup>+</sup>Small- to Medium-Sized Pleomorphic T-cell Lymphoma
Authors: Ferdinand Toberer, Wolfgang Hartschuh, Eva Hadaschik
Journal: JAMA Dermatology (2013)

In the recent World Health Organization-European Organisation for Research and Treatment of Cancer classification, primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma is listed as a provisional entity that is histopathologically characterized by pleomorphic CD3+/CD4+/CD8-/CD30- T lymphocytes. Clinically, it is characterized by solitary tumors mostly affecting the head and neck area and by an indolent clinical course with an estimated 5-year survival of about 60% to 80%. Currently, therapeutic options include topical or systemic treatment with glucocorticoids, local excision of solitary lesions, radiotherapy, and chemotherapy (e.g., cyclophosphamide) in cases of aggressive clinical behavior or systemic disease.We present the case of a 21-year-old female patient with a 5-year history of a solitary, slowly growing tumor of the right cheek. Histopathologic findings revealed a primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma with an admixture of numerous CD20+ B cells representing almost half of the infiltrate. In this patient we achieved a temporary (13 months) complete remission of the lymphoma by oral treatment with doxycycline monohydrate, 200 mg per day.Doxycycline is a relatively nontoxic and well-tolerated oral agent and should be considered as a therapeutic option in primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma, especially in cases with a high percentage of B lymphocytes and no signs of systemic disease.
Effect of in utero growth retardation on lung function at follow-up of prematurely born infants
Authors: A. Greenough, B. Yuksel, P. Cheeseman
Journal: European Respiratory Journal (2004)

The aim of the study was to determine if prematurely born children who had suffered intra-uterine growth retardation (IUGR) had more severe lung function abnormalities than those born an appropriate weight for gestational age (AGA). Analysis of the lung function results of 119 infants (median (range) gestational age of 30 (23-35) weeks) was undertaken. In total, 31 of the infants had suffered IUGR and were born small for gestational age (SGA). Functional residual capacity and airways resistance (Raw) were measured at a median post-natal age of 10 (6-24) months. Specific airway conductance (sGaw) was calculated from thoracic gas volume and Raw. The SGA children were born at a greater gestational age and had a lower body weight at testing than the AGA children. Raw and sGaw differed between the SGA and AGA children. Regression analysis demonstrated that lung volumes were significantly related to body weight at testing, Raw was related to IUGR, maternal smoking and bronchopulmonary dysplasia, and sGaw to maternal smoking. In conclusion, these results suggest that prematurely born infants who have suffered intra-uterine growth retardation may be at increased risk of impaired lung function at follow-up.
Haemoptysis and a cavity in a young man
Authors: M Pasto, V Curull, J Minguella, MA Jimenez, C Sanjuas, J Broquetas
Journal: European Respiratory Journal (1995)

Case HistoryA 23 year old Algerian male was admitted to hospital due to intermittent mucopurulent and blood-stained sputum of 2 yrs duration.Temperature, blood pressure, cardiorespiratory and abdominal examination were normal.Laboratory findings showed 480 eosinophils•ml -1 in peripheral blood.The lateral and posteroanterior (PA) chest roentgenograms are shown in figures 1 and 2.Empirical treatment with clindamycin was administered but no changes in chest roentgenogram were observed after one week.Computed tomography of the thorax is shown in figure 3.A fibreoptic bronchoscopy was performed and bronchial washing was taken for cytological and microbiological analysis, with negative results.
A 35-year-old male with chronic cough
Authors: C. Moschos, I. Kalomenidis, C. Roussos, G. T. Stathopoulos
Journal: European Respiratory Journal (2007)

A 35-yr-old male was examined in the outpatient clinic of the present authors' department.He complained of a dry paroxysmal cough of indeterminate origin that he had noticed 3 months earlier.The cough was associated with a tickling feeling in the throat.There was no association between coughing flares and meals, nasal discharge, season, time of day or body posture.The patient did not recall having symptoms compatible with an upper airway viral infection in the past 3 months and reported no gastro-intestinal symptoms like daily heartburn and regurgitation.He lived in the city, was a lifetime nonsmoker, his previous medical history was unremarkable and he was not taking any medication.He worked as an electronic engineer in a smoke-and dust-free environment and exhibited a type A personality.Upon appearance of the cough 3 months earlier, he had been examined by a physician and had
Predictors of abrupt closure and consequences of emergency endpoints in the IMPACT II trial
Authors: Bruce A. Bergelson, Charles J. Davidson, Gail Hafley, Russell Ivanhoe, James J. Ferguson, Barbara E. Tardiff, Kenneth W. Mahaffey, A.Michael Lincoff, James T. Tcheng, Robert M. Califf, Eric J. Topol
Journal: Journal of the American College of Cardiology (1996)
Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis
Authors: Britta Maurer, Nicole Reich, Astrid Juengel, Jörg Kriegsmann, Renate E Gay, Georg Schett, Beat A Michel, Steffen Gay, Jörg H W Distler, Oliver Distler
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Systemic sclerosis-associated pulmonary arterial hypertension differs from idiopathic pulmonary arterial hypertension with respect to histopathology, treatment responses and survival. Medical progress on PAH is hampered by the lack of human biosamples and suitable animal models. In this study, the authors evaluated fos-related antigen 2 (Fra-2) transgenic mice as a novel model for systemic sclerosis-associated pulmonary arterial hypertension. <h3>Methods</h3> Lung sections of Fra-2 transgenic (n=12) and wild-type mice (n=6) were analysed at 16 weeks by histology using Dana Point criteria. Cellular and molecular key players were assessed by immunohistochemistry. To test the model9s sensitivity to change over treatment, a subgroup of Fra-2 transgenic mice (n=6) was treated with the tyrosine kinase inhibitor nilotinib twice daily 37.5 mg orally from 8 weeks of age. <h3>Results</h3> Fra-2 transgenic mice developed severe vascular remodelling of pulmonary arteries and non-specific interstitial pneumonia-like interstitial lung disease resembling human systemic sclerosis-associated pulmonary hypertension. Histological features typical for systemic sclerosis-associated pulmonary arterial hypertension, such as intimal thickening with concentric laminar lesions, medial hypertrophy, perivascular inflammatory infiltrates, adventitial fibrosis, but not pulmonary occlusive venopathy were frequently detected. Platelet-derived growth factor signalling pathways were activated in pulmonary vessels of Fra-2 transgenic compared with wild-type mice. Since treatment with nilotinib strongly prevented the development of proliferative vasculopathy and lung fibrosis, the model proved to be sensitive to treatment. <h3>Conclusions</h3> This study suggests that Fra-2 transgenic mice as an animal model of systemic sclerosis-associated pulmonary arterial hypertension display main characteristic features of the human disease. It therefore allows studying pathophysiological aspects and might serve as a preclinical model for interventional proof-of-concept studies.
Tissue responses to ischemia: local and remote responses for preserving perfusion of ischemic muscle
Authors: Jeffrey M. Isner
Journal: Journal of Clinical Investigation (2000)

The sequence of biological events that permits an organism to maintain tissue viability in the face of acute or chronic ischemia constitutes a fundamental survival response. Among mammalian species, this response may be best exemplified by the Israeli mole-rat (1), a creature that lives only in Egypt, Israel, and Syria. What is fascinating about this animal is that its entire life is spent underground in subterranean burrows at decidedly low oxygen tensions; accordingly, its tissues have been shown to be highly vascularized, and the vascular density is associated with upregulated endogenous expression of VEGF.

Among supraterranean species confronted with tissue ischemia localized to cardiac or skeletal muscle, at least two options are available. The first is to reduce demand for tissue oxygenation. This may be accomplished by “biochemical splinting,” in which metabolic functions are converted from primarily aerobic to predominantly anaerobic. In the extreme, reduced blood flow may be associated with literal splinting, that is impaired wall motion characteristic of hibernating myocardium (2). Alternatively, “behavioral splinting” may be employed. For cardiac muscle, this may be achieved by reduced activity and, if necessary, pharmacologic therapies that reduce myocardial wall stress. For skeletal muscle, pharmacologic interventions are so limited that reduced levels of activity constitute the typical response to claudication. These adjustments, however, are necessary only if natural reparative mechanisms have failed to address the problem of ischemia successfully by restoring blood flow to the affected muscle group. Our current notions concerning the means by which this is achieved, as well as the factors that may selectively obviate this adaptive response, are the subject of this Perspective.
Self-Reported Anxiety, General Medical Conditions, and Disability Bed Days
Authors: Steven C. Marcus, Mark Olfson, Harold Alan Pincus, M. Katherine Shear, Deborah A. Zarin
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: This study examined the effect of self-reported anxiety on the number of days persons with various general medical conditions spend in bed owing to disability. METHOD: Self-reported medical illness and disability data from a nationally representative household survey sample (N=20,884) were analyzed. RESULTS: Among respondents with general medical conditions, those with self-reported anxiety had a nearly fourfold greater length of disability (mean=18.0 bed days) than the nonanxious respondents (mean=4.8 bed days). After adjustment for differences in demographic characteristics and burden of general medical illness, anxiety was associated with an additional 3.8 bed days. CONCLUSIONS: Self-reported anxiety in combination with general medical conditions may be associated with extensive functional impairment. (Am J Psychiatry 1997; 154:1766–1768)
Long-Term Outcomes of IgA Nephropathy Presenting with Minimal or No Proteinuria
Authors: Eduardo Gutiérrez, Isabel Zamora, José Antonio Ballarín, Yolanda Arce, Sara Jiménez, Carlos Quereda, Teresa Olea, Jorge Martínez-Ara, Alfons Segarra, Carmen Bernis, Asunción García, Marian Goicoechea, Soledad García de Vinuesa, Jorge Rojas-Rivera, Manuel Praga
Journal: Journal of the American Society of Nephrology (2012)

The long-term outcome of patients with IgA nephropathy who present with normal renal function, microscopic hematuria, and minimal or no proteinuria is not well described. Here, we studied 141 Caucasian patients with biopsy-proven IgA nephropathy who had minor abnormalities at presentation and a median follow-up of 108 months. None of the patients received corticosteroids or immunosuppressants. We reviewed renal biopsies using the Oxford classification criteria. In this sample, 46 (32%) patients had mesangial proliferation, whereas endocapillary proliferation, focal glomerulosclerosis, and tubulointerstitial abnormalities were uncommon. Serum creatinine increases >50% and >100% were observed in five (3.5%) patients and one (0.7%) patient, respectively; no patients developed ESRD. After 10, 15, and 20 years, 96.7%, 91.9%, and 91.9% of patients maintained serum creatinine values less than a 50% increase, respectively. Using Cox proportional hazards regression, the presence of segmental glomerulosclerosis was the only factor that significantly associated with a >50% increase in serum creatinine. Clinical remission occurred in 53 (37.5%) patients after a median of 48 months. Proteinuria>0.5 and >1.0 g/24 h developed in 21 (14.9%) and 6 (4.2%) patients, respectively. Median proteinuria at the end of follow-up was 0.1 g/24 h, with 41 (29.1%) patients having no proteinuria. At presentation, 23 (16.3%) patients were hypertensive compared with 30 (21.3%) patients at the end of follow-up; 59 (41.8%) patients were treated with renin-angiotensin blockers because of hypertension or increasing proteinuria. In summary, the long-term prognosis for Caucasian patients with IgA nephropathy who present with minor urinary abnormalities and normal renal function is excellent.
Widespread Occurrence of Spliceosomal Introns in the rDNA Genes of Ascomycetes
Authors: Debashish Bhattacharya, François Lutzoni, Valérie Reeb, Dawn Simon, John Nason, Fernando Fernandez
Journal: Molecular Biology and Evolution (2000)

Spliceosomal (pre-mRNA) introns have previously been found in eukaryotic protein-coding genes, in the small nuclear RNAs of some fungi, and in the small- and large-subunit ribosomal DNA genes of a limited number of ascomycetes. How the majority of these introns originate remains an open question because few proven cases of recent and pervasive intron origin have been documented. We report here the widespread occurrence of spliceosomal introns (69 introns at 27 different sites) in the small- and large-subunit nuclear-encoded rDNA of lichen-forming and free-living members of the Ascomycota. Our analyses suggest that these spliceosomal introns are of relatively recent origin, i.e., within the Euascomycetes, and have arisen through aberrant reverse-splicing (in trans) of free pre-mRNA introns into rRNAs. The spliceosome itself, and not an external agent (e.g., transposable elements, group II introns), may have given rise to these introns. A nonrandom sequence pattern was found at sites flanking the rRNA spliceosomal introns. This pattern (AG-intron-G) closely resembles the proto-splice site (MAG-intron-R) postulated for intron insertions in pre-mRNA genes. The clustered positions of spliceosomal introns on secondary structures suggest that particular rRNA regions are preferred sites for insertion through reverse-splicing.
Continuous Autonomic Assessment in Patients With Symptomatic Heart Failure
Authors: Philip B. Adamson, Andrew L. Smith, William T. Abraham, Karen J. Kleckner, Robert W. Stadler, Alex Shih, Melissa M. Rhodes
Journal: Circulation (2004)

Heart rate variability (HRV) as an indirect autonomic assessment provides prognostic information when measured over short time periods in patients with heart failure. Long-term continuous HRV can be measured from an implantable device, but the clinical value of these measurements is unknown.A total of 397 patients with New York Heart Association class III or IV heart failure were studied. Of these, 370 patients had information from their implanted cardiac resynchronization device for mortality risk stratification, and 288 patients had information for measured parameters (ie, HRV, night heart rate, and patient activity) and clinical event analyses. Continuous HRV was measured as the standard deviation of 5-minute median atrial-atrial intervals (SDAAM) sensed by the device. SDAAM <50 ms when averaged over 4 weeks was associated with increased mortality risk (hazard ratio 3.20, P=0.02) and SDAAM were persistently lower over the entire follow-up period in patients who required hospitalization or died. SDAAM decreased a median of 16 days before hospitalization and returned to baseline after treatment. Automated detection of decreases in SDAAM was 70% sensitive in detecting cardiovascular hospitalization, with 2.4 false-positives per patient-year of follow-up.This study demonstrates that SDAAM continuously measured from an implanted cardiac resynchronization device is lower in patients at high mortality and hospitalization risk. SDAAM declines as patient status decompensates. Continuous long-term SDAAM may be a useful tool in the clinical management of patients with chronic heart failure.