tbuckley/cabot-search huggingface dataset:
Ischemia-Reperfusion Induces Glomerular and Tubular Activation of Proinflammatory and Antiapoptotic Pathways
Authors: Antonia Loverre, Pasquale Ditonno, Antonio Crovace, Loreto Gesualdo, Elena Ranieri, Paola Pontrelli, Giovanni Stallone, Barbara Infante, Antonio Schena, Salvatore Di Paolo, Carmen Capobianco, Michele Ursi, Silvano Palazzo, Michele Battaglia, Francesco Paolo Selvaggi, Francesco Paolo Schena, Giuseppe Grandaliano
Journal: Journal of the American Society of Nephrology (2004)

Ischemia-reperfusion (I-R) injury in transplanted kidney, a key pathogenic event of delayed graft function (DGF), is characterized by tubular cell apoptosis and interstitial inflammation. Akt-mammalian target of rapamycin-S6k and NF-kappaB-inducing kinase (NIK)-NF-kappaB axis are the two main signaling pathways regulating cell survival and inflammation. Rapamycin, an immunosuppressive drug inhibiting the Akt axis, is associated with a prolonged DGF. The aim of this study was to evaluate Akt and NF-kappaB axis activation in patients who had DGF and received or not rapamycin and in a pig model of I-R and the role of coagulation priming in this setting. In graft biopsies from patients who were not receiving rapamycin, phosphorylated Akt increased in proximal tubular, interstitial, and mesangial cells with a clear nuclear translocation. The same pattern of activation was observed for S6k and NIK. However, in rapamycin-treated patients, a significant reduction of S6k but not Akt and NIK activation was observed. A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin. Extensive interstitial and glomerular fibrin deposition was observed both in pig kidneys upon reperfusion and in DGF human biopsies. It is interesting that the activation of both Akt and NIK-NF-kappaB pathways was induced by thrombin in cultured proximal tubular cells. In conclusion, the data suggest that (1) coagulation may play a pathogenic role in I-R injury; (2) the Akt axis is activated after I-R, and its inhibition may explain the prolonged DGF observed in rapamycin-treated patients; and (3) NIK activation in I-R and DGF represents a proinflammatory, rapamycin-insensitive signal, potentially leading to progressive graft injury.
Circulating Tumor Cells in Patients with Breast Cancer Dormancy
Authors: Songdong Meng, Debasish Tripathy, Eugene P. Frenkel, Sanjay Shete, Elizabeth Z. Naftalis, James F. Huth, Peter D. Beitsch, Marilyn Leitch, Susan Hoover, David Euhus, Barbara Haley, Larry Morrison, Timothy P. Fleming, Dorothee Herlyn, Leon W. M. M. Terstappen, Tanja Fehm, Thomas F. Tucker, Nancy Lane, Jianqiang Wang, Jonathan W. Uhr
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this study was to test the hypothesis that circulating tumor cells (CTCs) are present in patients many years after mastectomy without evidence of disease and that these CTCs are shed from persisting tumor in patients with breast cancer dormancy. Experimental Design: We searched for CTCs in 36 dormancy candidate patients and 26 age-matched controls using stringent criteria for cytomorphology, immunophenotype, and aneusomy. Results: Thirteen of 36 dormancy candidates, 7 to 22 years after mastectomy and without evidence of clinical disease, had CTCs, usually on more than one occasion. Only 1 of 26 controls had a possible CTC (no aneusomy). The statistical difference of these two distributions was significant (exact P = 0.0043). The CTCs in patients whose primary breast cancer was just removed had a half-life measured in 1 to 2.4 hours. Conclusions: The CTCs that are dying must be replenished every few hours by replicating tumor cells somewhere in the tissues. Hence, there appears to be a balance between tumor replication and cell death for as long as 22 years in dormancy candidates. We conclude that this is one mechanism underlying tumor dormancy.
Histopathology of the synovial membrane of peripheral joints in ankylosing spondylitis.
Authors: P A Revell, V Mayston
Journal: Annals of the Rheumatic Diseases (1982)

The histological features of the synovial membrane of peripheral joints in ankylosing spondylitis are similar to those seen in rheumatoid arthritis. There is intimal cell hyperplasia, a diffuse lymphocyte and plasma cell infiltrate, and formation of lymphoid follicles. Peroxidase-antiperoxidase staining shows the presence of IgG-, IgA-, and IgM-containing plasma cells in ankylosing spondylitis. The percentage of IgM-containing cells is significantly lower in ankylosing spondylitis than in rheumatoid arthritis.
Preliminary data suggestive of a novel translational approach to mesothelioma treatment: imatinib mesylate with gemcitabine or pemetrexed
Authors: P. Bertino, C. Porta, D. Barbone, S. Germano, S. Busacca, S. Pinato, G. Tassi, R. Favoni, G. Gaudino, L. Mutti
Journal: Thorax (2007)

<b>Background:</b> Malignant mesothelioma is a cancer which is refractory to current treatments. Imatinib mesylate is a selective inhibitor of tyrosine kinases such as bcr-abl, c-Kit, c-Fms and platelet derived growth factor receptor β (PDGFRβ). PDGFRβ is often overexpressed in mesothelioma cells and is a therapeutic target for imatinib in some solid tumours. A study was undertaken to assess whether imatinib alone or combined with chemotherapeutic agents may be effective for treating mesothelioma. <b>Methods:</b> Cultures from mesothelioma MMP, REN and ISTMES2 cell lines were treated with imatinib alone or in combination with a chemotherapeutic agent. <b>Results:</b> Imatinib induced cytotoxicity and apoptosis selectively on PDGFRβ positive mesothelioma cells via blockade of receptor phosphorylation and interference with the Akt pathway. Of the chemotherapeutic agents tested in combination with imatinib, a synergistic effect was obtained with gemcitabine and pemetrexed. <b>Conclusions:</b> This study provides a rationale for a novel translational approach to the treatment of mesothelioma which relies on enhancement of tumour chemosensitivity by inhibition of Akt.
Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus.
Authors: M Amagai, T Hashimoto, N Shimizu, T Nishikawa
Journal: Journal of Clinical Investigation (1994)

Pemphigus vulgaris (PV) is an autoimmune blistering disease, in which autoantibodies against PV antigen (PVA or Dsg3) play a pathogenic role in inducing blister formation. Bacterial fusion proteins of PVA failed to absorb pathogenic autoantibodies from PV patients' sera probably because they did not represent the proper conformation. Therefore, a chimeric protein, PVIg, consisting of the whole extracellular domain of PVA and the constant region of human IgG1, was produced in either in COS7 or in insect Sf9 eucaryotic cells. Both PVIg-COS7 and PVIg-Sf9 were recognized by all of the 35 PV sera tested, but not by any of 10 pemphigus foliaceus (PF), 16 Brazilian PF, 10 bullous pemphigoid, or five normal control sera. Incubation of PV patients' sera with PVIg-Sf9 removed heterogeneous autoantibodies and significantly reduced their immunofluorescence titers on normal human epidermis, although PVIg-Sf9 did not affect the titers of PF sera at all. Furthermore, PVIg-Sf9 absorbed pathogenic autoantibodies from patients' sera and prevented gross blister formation in a neonatal mouse model for pemphigus. These results indicate that this baculovirus product has the proper conformation of the authentic PVA and that its conformation is important in pathogenicity of pemphigus.
The Secondary Leukemias: Challenges and Research Directions
Authors: Malcolm A. Smith, Ronald P. McCaffrey, Judith E. Karp
Journal: JNCI Journal of the National Cancer Institute (1996)

Acute myelogenous leukemia (AML) arising following exposure to genotoxic agents has been recognized as a distinctive entity for more than 40 years. Secondary, or therapy-related, AML accounts for 10%–20% of all AML cases. This review addresses four overarching areas of investigation focused on secondary AMLs: 1) dissection of the molecular structure of the induced genetic lesions and identification of the functional consequences of these changes, thereby providing clues to the pathogenesis of secondary AML and potentially serving as a basis for innovative therapeutic interventions; 2) identification and characterization of mechanisms of DNA damage and the orderly repair of such damage; 3) identification and application of accurate biomarkers of leukemogenesis for the purpose of risk prediction and quantification, potentially allowing recognition of patients especially susceptible to the leukemogenic effects of chemotherapy (for genetic or acquired reasons) and allowing their treatment for cancer to be modified on the basis of this susceptibility; and 4) design and implementation of longitudinal clinical and genetic monitoring of high-risk populations (i.e., individuals undergoing cytotoxic therapies for primary cancers). This review of the literature relating to these areas builds upon these themes and attempts to synthesize these seemingly disparate areas of research so that they can be more effectively utilized together to address the problem of secondary AML. Ultimately, the evaluation of these areas will improve our understanding of de novo leukemia and will serve as a springboard for the development of new concepts of therapy and prevention. [J Natl Cancer Inst 1996;88:407–18]
Phase II Pilot Study of Intravenous High-Dose Interferon With or Without Maintenance Treatment in Melanoma at High Risk of Recurrence
Authors: Miranda J. Payne, Katerina Argyropoulou, Paul Lorigan, James J. McAleer, David Farrugia, Neville Davidson, Charles Kelly, David Chao, Ernest Marshall, Cheng Han, Sandie Wellman, Mark R. Middleton
Journal: Journal of Clinical Oncology (2013)

Purpose High-dose interferon alfa-2b (HDI) has emerged as a potentially effective adjuvant therapy in patients with resected melanoma at high risk of recurrence. Evidence suggests it may be the early, very-high-dose part of the regimen that is critical. This pilot study sought to provide an early indication of whether the same effects can be achieved with the intravenous component of HDI alone and inform the feasibility and design of a phase III trial. Patients and Methods Patients with stage 2B, 2C, 3B, and 3C melanoma were randomly assigned to receive interferon alfa-2b (IFN-α-2b) 20 MIU/m 2 intravenously (IV) daily 5 days per week for 4 weeks (arm A) versus the same regimen followed by IFN-α-2b 10 MIU/m 2 administered subcutaneously three times per week for 48 weeks (arm B) and observed for relapse-free survival (RFS) and overall survival. Results Between 2003 and 2009, 194 patients were enrolled (arm A, 96; arm B, 98). After median follow-up of 39.5 months, RFS was 22.7 months (95% CI, 14.1 to 38.1 months) in arm A versus 33.3 months (95% CI, 18.2 to not reached) in arm B (P = .28). The proportions of patients free of relapse at 2 years were 50% and 54.1% (P = .569; hazard ratio, 0.89), respectively. Overall survival favored arm B (median, 41.5 months v not reached; P = .05). Conclusion Clinical outcomes were better in patients who had the longer regimen. Our results do not support either the use of a month of IV HDI alone in place of the year-long regimen or the initiation of a larger trial on this question.
Exocrine function in primary Sjogren syndrome: natural course and prognostic factors
Authors: K Haldorsen, K Moen, H Jacobsen, R Jonsson, J G Brun
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> Few studies have addressed the natural course of, or prognostic factors for the salivary and lacrimal function in primary Sjögren syndrome (SS). Except for the early stages, glandular function has been seemingly stable, and SS A antigen (SSA) seropositivity and hypocomplementemia may predict a decline in the van Bijsterveld score. The aim of the present study was to assess the natural course of the exocrine function in a larger cohort based on the American–European consensus criteria for SS, and to address possible predictive factors for a declining exocrine function. <h3>Methods:</h3> We performed a retrospective cohort study. A total of 141 patients were investigated with the Schirmer I test and unstimulated whole saliva (UWS). Historical data regarding these tests and focus score were collected from the files of 111 patients. Median time from diagnosis to follow-up investigation was 5.0 years. <h3>Results:</h3> Median UWS was unchanged during follow-up. Median Schirmer I test improved from 5.0 to 7.0 mm/5 min (p&lt;0.05). Present Schirmer I test was associated with historical high IgG and IgA, positive SSA and SS B antigen (SSB) tests and high focus score, and present UWS with historical low C3/C4. Logistic regression identified high focus scores (odds ratio (OR) = 1.343), and low UWS (OR = 0.692) as factors predicting a 30% or more worsening of the Schirmer I test. High focus scores (OR = 1.488) predicted a 30% or more worsening of the UWS. <h3>Conclusion:</h3> We confirmed previous studies showing a stable or slightly improved exocrine function over time. High focus scores and low UWS were identified as independent predictors of a worsened exocrine function.
One-Year Trajectories of Care and Resource Utilization for Recipients of Prolonged Mechanical Ventilation
Authors: Mark Unroe
Journal: Annals of Internal Medicine (2010)

Background: Growing numbers of critically ill patients receive prolonged mechanical ventilation. Little is known about the patterns of care as patients transition from acute care hospitals to postacute care facilities or about the associated resource utilization. Objective: To describe 1-year trajectories of care and resource utilization for patients receiving prolonged mechanical ventilation. Design: 1-year prospective cohort study. Setting: 5 intensive care units at Duke University Medical Center, Durham, North Carolina. Participants: 126 patients receiving prolonged mechanical ventilation (defined as ventilation for ≥4 days with tracheostomy placement or ventilation for ≥21 days without tracheostomy), as well as their 126 surrogates and 54 intensive care unit physicians, enrolled consecutively over 1 year. Measurements: Patients and surrogates were interviewed in the hospital, as well as 3 and 12 months after discharge, to determine patient survival, functional status, and facility type and duration of postdischarge care. Physicians were interviewed in the hospital to elicit prognoses. Institutional billing records were used to assign costs for acute care, outpatient care, and interfacility transportation. Medicare claims data were used to assign costs for postacute care. Results: 103 (82%) hospital survivors had 457 separate transitions in postdischarge care location (median, 4 transitions [interquartile range, 3 to 5 transitions]), including 68 patients (67%) who were readmitted at least once. Patients spent an average of 74% (95% CI, 68% to 80%) of all days alive in a hospital or postacute care facility or receiving home health care. At 1 year, 11 patients (9%) had a good outcome (alive with no functional dependency), 33 (26%) had a fair outcome (alive with moderate dependency), and 82 (65%) had a poor outcome (either alive with complete functional dependency [4 patients; 21%] or dead [56 patients; 44%]). Patients with poor outcomes were older, had more comorbid conditions, and were more frequently discharged to a postacute care facility than patients with either fair or good outcomes (P < 0.05 for all). The mean cost per patient was $306 135 (SD, $285 467), and total cohort cost was $38.1 million, for an estimated $3.5 million per independently functioning survivor at 1 year. Limitation: The results of this single-center study may not be applicable to other centers. Conclusion: Patients receiving prolonged mechanical ventilation have multiple transitions of care, resulting in substantial health care costs and persistent, profound disability. The optimism of surrogate decision makers should be balanced by discussions of these outcomes when considering a course of prolonged life support. Primary Funding Source: None.
Structural evidence for distinct IgG subclass-specific Fc receptors on mouse peritoneal macrophages
Authors: BC Lane, J Kan-Mitchell, MS Mitchell, SM Cooper
Journal: The Journal of Experimental Medicine (1980)

Membrane proteins which selectively bind to the Fc portion of IgG were identified in the Nonidet P-40 extracts of radiolabeled thioglycollate- elicited mouse peritoneal macrophages. Affinity columns of various IgG preparations coupled to Sepharose 4B were used to absorb the Fc-binding proteins. Analysis of the acetic acid or sodium dodecyl sulfate (SDS) eluates from aggregated human IgG or antigen-complexed rabbit IgG columns revealed two Fc(gamma)/-specific proteins with apparent 67,000 and 52,000 mol wt. These proteins were not detected in acid or SDS eluates from F(ab')(2) columns or in eluates from IgG column, over which were passed lysates of Fc receptor-negative cells. With the use of affinity columns that contained aggregated mouse myeloma proteins of different IgG subclasses, we found that the 67,000-dahon protein selectively binds to IgG2a, whereas the 52,000-dalton protein binds to IgG1 and IgG2b. Neither protein was found in SDS eluates from IgG3 columns. Trypsin treatment of the macrophages before detergent lysis removed the 67,000-dalton protein, although it leaves intact the 52,000-dalton protein. These results provide structural confirmation for the existence of separate Fc receptors on mouse macrophages and indicate that the two Fc-binding proteins identified in this study represent all or part of the trypsin- sensitive Fc receptor which binds IgG2a and the trypsin-resistant Fc receptor which binds IgG2b and IgG1.
The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis
Authors: G. O Ceyhan, F. Bergmann, M. Kadihasanoglu, M. Erkan, W. Park, U. Hinz, T. Giese, M. W Muller, M. W Buchler, N. A Giese, H. Friess
Journal: Gut (2006)

Chronic pancreatitis is characterised by severe abdominal neuropathic pain, perineural inflammatory cell infiltrations and intrapancreatic neural growth. Artemin was recently shown to eliminate neuropathic pain and reverse neurochemical damage after nerve injury. The role of artemin and its receptor GFRalpha3 was investigated in patients with chronic pancreatitis.Expression of artemin and its receptor GFRalpha3 was studied in chronic pancreatitis (n = 66) and normal (n = 22) pancreatic tissues by quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and western blot analysis. Artemin expression was correlated with pain and pathomorphological changes (inflammation, perineural inflammatory cell infiltration, neural alterations and fibrosis). Immunohistochemistry was used to localise artemin and GFRalpha3 in the tissues. To detect sources of artemin, primary human pancreatic stellate cells (hPSCs) were isolated and analysed by QRT-PCR and immunocytology analysis.In chronic pancreatitis, artemin and GFRalpha3 were significantly overexpressed and located in smooth muscle cells of arteries, Schwann cells and neural ganglia. Increased levels of artemin mRNA correlated with pain severity, inflammation, perineural inflammatory cell infiltration, neural density and hypertrophy. Furthermore, the severity of fibrosis was positively related with artemin expression and neural alterations. Activated hPSCs expressed low basal levels of artemin mRNA which were upregulated by exposure to transforming growth factor (TGF)beta1.Overexpression of artemin in chronic pancreatitis might function as a compensatory upregulation in order to repair neural damage incurred by ongoing pancreatic inflammation. Upregulation of TGFbeta1 seems not only to increase pancreatic fibrosis but also to contribute to neural alteration by stimulating artemin expression in hPSCs. However, overexpression of endogenous artemin does not seem to be sufficient to prevent pain in chronic pancreatitis.
Mechanisms of Vascular Calcification in Chronic Kidney Disease
Authors: Sharon M. Moe, Neal X. Chen
Journal: Journal of the American Society of Nephrology (2007)

Vascular calcification is common in chronic kidney disease and associated with increased morbidity and mortality. Its mechanism is multifactorial and incompletely understood. Patients with chronic kidney disease are at risk for vascular calcification because of multiple risk factors that induce vascular smooth muscle cells to change into a chondrocyte or osteoblast-like cell; high total body burden of calcium and phosphorus due to abnormal bone metabolism; low levels of circulating and locally produced inhibitors; impaired renal excretion; and current therapies. Together these factors increase risk and complicate the management of vascular calcification.
Systems Biology through Mouse Imaging Centers: Experience and New Directions
Authors: R. Mark Henkelman
Journal: Annual Review of Biomedical Engineering (2010)

The completed sequencing of genomes has forced upon us the challenge of understanding how the detailed information in the genome gives rise to the specific characteristics—phenotype—of the individual. This is crucial for understanding not only normal development but also, from a medical perspective, the genetic basis of disease. Much of the mammalian genome-to-phenotype relationship will be worked out in the mouse, for which powerful genetic-manipulation tools are available. Mouse imaging combined with powerful statistical methods has a unique and growing role to play in phenotyping genetically modified mice. This review outlines the challenges for image-based phenotyping, summarizes the current state of three-dimensional imaging technologies for the mouse, and highlights new opportunities in systems biology that are opened by imaging mice.
Human nebulin-related anchoring protein a critical structural protein, sequence, genomic structure, tissue distribution, and association with cardiomyopathy
Authors: Saidi A. Mohiddin, John-Paul Cardoso, Shajia Lu, Judy Winkler, Sanjaya Jha, Robert Horowits, Lameh Fananapazir
Journal: Journal of the American College of Cardiology (2003)
Structural and functional studies on hemoglobin Bethesda (α2β2145 His), a variant associated with compensatory erythrocytosis
Authors: H. Franklin Bunn, Thomas B. Bradley, William E. Davis, James W. Drysdale, John F. Burke, William S. Beck, Myron B. Laver
Journal: Journal of Clinical Investigation (1972)

Studies have been performed on a 12-yr-old Chinese girl with compensatory erythrocytosis due to the presence of hemoglobin Bethesda comprising about 45% of the red cell hemoglobin. Her parents and three siblings were normal. The oxygen affinity of her blood was markedly increased: under physiological conditions (pH 7.40, 37 degrees C). P(50) was 12.8 mm Hg (normal = 26.5 mm Hg). The red cell 2,3-diphosphoglycerate (2.3-DPG) level was normal. The abnormal hemoglobin could not be separated from hemoglobin A by zone electrophoresis at pH 8.6 or isoelectric focusing on polyacrylamide gel. However, after the hemoglobin was split into free alpha and beta chains by treatment with p-hydroxymercuribenzoate (PMB) or 6 M urea, an abnormal beta chain was readily demonstrated having a higher isoelectric point (more positive net charge) than normal beta(A). Structural analysis of the variant beta chain demonstrated the substitution of histidine for tyrosine at position 145: hemoglobin Bethesda (alpha(2)beta(2) (145His)). From earlier chemical and crystallographic studies, it has been postulated that this residue is a critical determinant of hemoglobin function. Hemoglobin Bethesda was separated from hemoglobin A by column chromatography. Oxygen equilibria of purified hemoglobin Bethesda revealed an extremely high oxygen affinity (exceeding that of isolated alpha and beta chains), and markedly reduced cooperativity. The Bohr effect of hemoglobin Bethesda was 1/3 that of hemoglobin A. However, hemoglobin Bethesda showed a significant interaction with 2.3-DPG and inositol hexaphosphate.