tbuckley/cabot-search huggingface dataset:
Plasma semicarbazide-sensitive amine oxidase is elevated in patients with congestive heart failure
Authors: F Boomsma
Journal: Cardiovascular Research (1997)

Objective: Semicarbazide-sensitive amine oxidase (SSAO) is present in various mammalian tissues, especially in vascular smooth muscle cells, but also in plasma. The enzyme has been suggested to play a role in vascular endothelial damage through conversion of amines into cytotoxic aldehydes, ammonia and hydrogen peroxide. Endothelial dysfunction is present in diabetes mellitus (DM) and congestive heart failure (CHF). Elevated plasma SSAO activities have been reported in patients with DM, but no data on patients with CHF are as yet available. Methods and Results: Plasma SSAO was measured in 271 patients with CHF and compared to values in 77 controls. SSAO was found to be elevated in patients with CHF compared to controls (589±252 vs. 455±114 mU/l; P<0.0001). Plasma SSAO was higher in NYHA class III/IV than in class III (662±288 vs. 555±226 mU/l; P=0.004) and also higher in patients with concomitant DM than in those without (706±248 vs. 557±245 mU/l; P<0.0001). Plasma SSAO correlated with plasma atrial natriuretic peptide (r=0.42; P<0.0001), with plasma norepinephrine (r=0.27; P<0.0001) and with left ventricular ejection fraction (r=−0.13; P=0.0162). Multiple regression analysis showed atrial natriuretic peptide, norepinephrine, DM and cardiothoracic ratio to be the main determinants of plasma SSAO. Conclusion: The finding of elevated plasma SSAO in CHF, increasing with severity of the disease and with the concomitant presence of DM, supports the suggestion that SSAO may be involved in the pathogenesis of vascular endothelial damage. Plasma SSAO may be a useful parameter in assessing severity of CHF and in prognostic evaluation. Pharmacologic manipulation of SSAO activity might be an interesting new concept for prevention of vascular endothelial damage in various vascular disease entities.
RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension
Authors: Christopher J. Rhodes, Hogune Im, Aiqin Cao, Jan K. Hennigs, Lingli Wang, Silin Sa, Pin-I Chen, Nils P. Nickel, Kazuya Miyagawa, Rachel K. Hopper, Nancy F. Tojais, Caiyun G. Li, Mingxia Gu, Edda Spiekerkoetter, Zhaoying Xian, Rui Chen, Mingming Zhao, Mark Kaschwich, Patricia A. del Rosario, Daniel Bernstein, Roham T. Zamanian, Joseph C. Wu, Michael P. Snyder, Marlene Rabinovitch
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function.RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts.The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse.Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries.The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.
Disseminated Tumor Cells of Breast Cancer Patients: A Strong Prognostic Factor for Distant and Local Relapse
Authors: Francois-Clément Bidard, Anne Vincent-Salomon, Stéphanie Gomme, Claude Nos, Yann de Rycke, Jean Paul Thiery, Brigitte Sigal-Zafrani, Laurent Mignot, Xavier Sastre-Garau, Jean-Yves Pierga
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Clinical significance of disseminated tumor cells (DTC) in bone marrow of early breast cancer patients has been reported, but improvements in detection methods are needed. Experimental Design: Bone marrow aspirates from 621 patients with stage I to III breast cancer were screened for cytokeratin-positive (CK+) cells. CK+ cells were categorized into DTC only if they had specific morphologic features of tumor cells. Bone marrow status and clinical and pathologic variables of the patients were correlated with clinical outcome after a median follow-up of 56 months. Results: DTC and non-DTC CK+ cells were detected in 15% and 34% of patients, respectively, with no correlation with clinical and pathologic variables. On univariate analysis, DTC detection was associated with a poorer distant metastasis-free survival (DMFS; P = 0.0013) and overall survival (OS; P = 0.005). Moreover, DTC detection was also associated with local relapse-free survival (P = 0.0009). On multivariate analysis, DTC detection was an independent prognostic factor for DMFS, local relapse-free survival, and OS. There was no significant interaction between DTC detection and hormonal receptors status (P = 0.34). Non-DTC CK+ cells had no clinical significance. Conclusion: DTC detection is a powerful prognostic marker for DMFS and OS in early breast cancer patients and can be individualized from irrelevant non-DTC CK+ cells by morphologic criteria. Biologically, despite high rates of systemic adjuvant therapy and locoregional irradiation in this series, DTC detection remains a prognostic factor of distant and, more strikingly, of local relapse, in favor of resistance to treatment of locally or distant disseminated cancer cells in DTC-positive patients.
Possible association between anti-Ro antibodies and myocarditis or cardiac conduction defects in adults with systemic lupus erythematosus.
Authors: D Logar, T Kveder, B Rozman, J Dobovisek
Journal: Annals of the Rheumatic Diseases (1990)

In view of the association of congenital heart block with maternal antibody to cellular antigen Ro (SSA), and one report linking anti-Ro with myocarditis in a patient with myositis an association between anti-Ro antibodies and cardiac disease was sought in adults with systemic lupus erythematosus (SLE). Among 67 patients with SLE, of whom 36 were anti-Ro positive, a significantly higher prevalence of myocarditis and conduction defects was found in the anti-Ro positive group (eight of 36) than in those who were anti-Ro negative (one of 31) and healthy controls (one of 50). Of the 36 anti-Ro positive patients with SLE, three had symptoms diagnostic of myocarditis, and an electrocardiogram showed first degree atrioventricular block and unifascicular block in three cases (including one with myocarditis), right bundle branch block alone (two cases), and first degree atrioventricular block alone (one case). Complete atrioventricular block was not seen. In the anti-Ro negative group there was no myocarditis and only one case of conduction defect (right bundle branch block). Among healthy controls only one of 50 had first degree atrioventricular block. It is concluded that myocarditis and conduction defects are reasonably common in adults with SLE and are associated with anti-Ro antibodies.
The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.
Authors: R Nishinakamura, R Wiler, U Dirksen, Y Morikawa, K Arai, A Miyajima, S Burdach, R Murray
Journal: The Journal of Experimental Medicine (1996)

Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation.
Impaired Angiotensin Conversion and Bradykinin Clearance in Experimental Canine Pulmonary Emphysema
Authors: S. A. Stalcup, P. J. Leuenberger, J. S. Lipset, M. M. Osman, J. M. Cerreta, R. B. Mellins, G. M. Turino
Journal: Journal of Clinical Investigation (1981)

Chronic hypoxic lung diseases are associated with abnormal blood pressure regulation. Because the lung is the principal site of angiotensin conversion and because hypoxia decreases converting enzyme activity, we examined whether angiotensin converting enzyme activity was impaired in lung disease. 12 dogs received a 6 wk course of aerosolized and intratracheal papain that produced moderate panlobular emphysema. These dogs and 24 control dogs were anesthetized and sampling catheters were placed under fluoroscopic control. Angiotensin conversion was measured by a blood pressure response bioassay. Pulmonary converting enzyme activity was also assessed by infusing bradykinin (BK) and using radioimmunoassay to measure the instantaneous clearance of BK and the concentration of BK in the pulmonary artery which first produced spillover of BK into left atrial blood. Angiotensin conversion was reduced in the emphysematous dogs to 81.1% (13.2 SD) from 92% (6 SD) in the control dogs (P < 0.01). Instantaneous clearance of BK in the emphysematous dogs was only slightly reduced (93%), despite reduction in their Pao2 to 75 mm Hg, indicating that the greatest proportion of the perfused vascular bed was exposed to alveolar Po2 of >90 mm Hg. However, the barrier to BK passage provided by the lung, and measured by the spillover level, was reduced ¼ to ½ that observed in control animals. That the defect was promptly corrected by supplemental oxygen indicates that regional pulmonary vascular converting enzyme activity had been impaired by regional alveolar hypoxia, which permitted some peptide to pass through the lungs unmetabolized. Determination of peptide metabolism in the lungs may provide a useful measure of regional alveolar hypoxia and may lead to new ways of assessing lung injury.
Global Transcriptome Analysis of Formalin-Fixed Prostate Cancer Specimens Identifies Biomarkers of Disease Recurrence
Authors: Qi Long, Jianpeng Xu, Adeboye O. Osunkoya, Soma Sannigrahi, Brent A. Johnson, Wei Zhou, Theresa Gillespie, Jong Y. Park, Robert K. Nam, Linda Sugar, Aleksandra Stanimirovic, Arun K. Seth, John A. Petros, Carlos S. Moreno
Journal: Cancer Research (2014)

Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we performed global RNA sequencing on 106 formalin-fixed, paraffin-embedded prostatectomy samples from 100 patients at three independent sites, defining a 24-gene signature panel. The 24 genes in this panel function in cell-cycle progression, angiogenesis, hypoxia, apoptosis, PI3K signaling, steroid metabolism, translation, chromatin modification, and transcription. Sixteen genes have been associated with cancer, with five specifically associated with prostate cancer (BTG2, IGFBP3, SIRT1, MXI1, and FDPS). Validation was performed on an independent publicly available dataset of 140 patients, where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence. Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors, including several genes involved in the epithelial-to-mesenchymal transition and developmental pathways. Overall, this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer.
Telephone Modem Access Improves Diabetes Control in Those with Insulin-Requiring Diabetes
Authors: Kirsten Kiar Ahring, Jørgen Philip Kiaer Ahring, Carol Joyce, Nadir R Farid
Journal: Diabetes Care (1992)

To assess whether modem access improves diabetes control in IDDM patients.Forty-two patients participated in the study and were followed for 12 wk. The patients were randomly divided into two groups at baseline, a modem group and a control group. There were no significant differences between HbA1c, random blood glucose, and weight between the groups at the beginning of the study. Patients were asked to perform five blood glucose determinations/day (before breakfast, before lunch, afternoon [1500], before dinner, and at bedtime) twice/week. The modem group transferred their data over the phone once/week. The control group would bring in their results on their regular visits every 6 wk. Patients in the modem group were counseled every week over the telephone after transferring results to adjust insulin and food intake if necessary.In the modem group, HbA1c improved from 0.106 to 0.092 (13.20%). The control group improved from 0.112 to 0.102 (8.9%). There was no significant change in weight, random blood glucose, or insulin.The use of telephone modem-based patient-monitoring systems in diabetes clinical research seems to stimulate the patient to keep closer control of blood glucose levels. It might be especially useful in rural settings, for which this study was designed.
Regression of Indolent B-Cell Lymphoma After Lamivudine Prophylaxis of Hepatitis B Virus Infection
Authors: Luca Arcaini, Michele Merli, Sara Rattotti, Raffaele Bruno, Alessandro Vercelli, Marco Lucioni, Roberta Riboni, Marco Paulli
Journal: Journal of Clinical Oncology (2011)

Case ReportA 63-year-old woman was known to be a carrier of the hepatitis B virus (HBV) for 9 years, and for this reason, she had periodic hepatologic controls in another hospital without any treatment.In October 2008, she underwent an ultrasound scan for hematuria that incidentally revealed the presence of multiple spleen lesions.Magnetic resonance imaging of the abdomen documented three distinct focal lesions, the largest with a diameter of 2.8 cm (Fig 1A).An ultrasoundguided biopsy of the major lesion was performed; histologic examination showed vaguely nodular aggregates consisting of small cells with rounded to slightly irregular nuclei (Fig 2A, hematoxylin and eosin stain ϫ200) exhibiting a B-cell phenotype of CD20ϩ, CD79aϩ, B-cell lymphoma 2 (BCL2) positive (Fig 2B, streptavidin-biotin-peroxidase complex stain ϫ40), CD10ϩ (Fig 2C, streptavidin-biotin-peroxidase complex ϫ40), CD5Ϫ, cyclin-D1Ϫ, consistent with a follicular center cell origin.A clonal rearrangement of immunoglobulin heavy chain genes was documented by means of polymerase chain reaction.Polymerase chain reaction (major breakpoint region) assay and fluorescent in situ hybridization analysis with Vysis LSI IGH/BCL2 Dual Color Dual Fusion Translocation Probe (Abbott Laboratories, Abbott Park, IL) confirmed the presence of t(14;18)(q32;q21) involving IGH and BCL2 genes (Fig 2D, arrows).On the basis of these data, a diagnosis of low-grade B-cell lymphoma, consistent with follicular derivation, was established.The patient was referred to our hematology department.Blood counts and laboratory liver tests were normal; lactate dehydrogenase level was 504 mU/mL (upper normal limit, 475 mU/mL); computed tomography scan of the thorax and bone marrow (BM) biopsy were normal; BCL2 rearrangement (major breakpoint region) was found in BM and peripheral blood (PB).HBV
Influence of the NH2-terminal Amino Acid of the T Cell Receptor α Chain on Major Histocompatibility Complex (MHC) Class II + Peptide Recognition
Authors: Jeffrey L. Seibel, Nancy Wilson, Haruo Kozono, Philippa Marrack, John W. Kappler
Journal: The Journal of Experimental Medicine (1997)

The α/β T cell receptor (TCR) recognizes peptide fragments bound in the groove of major histocompatibility complex (MHC) molecules. We modified the TCR α chain from a mouse T cell hybridoma and tested its ability to reconstitute TCR expression and function in an α chain–deficient variant of the hybridoma. The modified α chain differed from wild type only in its leader peptide and mature NH2-terminal amino acid. Reconstituted cell surface TCR complexes reacted normally with anti-TCR and anti-CD3 antibodies. Although cross-linking of this TCR with an antibody to the TCR idiotype elicited vigorous T cell hybridoma activation, stimulation with its natural MHC + peptide ligand did not. We demonstrated that this phenotype could be reproduced simply by substituting the glutamic acid (E) at the mature NH2 terminus of the wild type TCR α chain with aspartic acid (D). The substitution also dramatically reduced the affinity of soluble α/β-TCR heterodimers for soluble MHC + peptide molecules in a cell-free system, suggesting that it did not exert its effect simply by disrupting TCR interactions with accessory molecules on the hybridoma. These results demonstrate for the first time that amino acids which are not in the canonical TCR complementarity determining regions can be critical in determining how the TCR engages MHC + peptide.
Consciousness without a cortex, but what kind of consciousness is this?
Authors: Anton M. L. Coenen
Journal: Behavioral and Brain Sciences (2007)

Merker suggests that the thalamocortical system is not an essential system for consciousness, but, instead, that the midbrain reticular system is responsible for consciousness. Indeed, the latter is a crucial system for consciousness, when consciousness is regarded as the waking state. However, when consciousness is regarded as phenomenal consciousness, for which experience and perception are essential elements, the thalamocortical system seems to be indispensable.
Anti-tumor innate immunity activated by intermittent metronomic cyclophosphamide treatment of 9L brain tumor xenografts is preserved by anti-angiogenic drugs that spare VEGF receptor 2
Authors: Joshua C Doloff, Chong-Sheng Chen, David J Waxman
Journal: Molecular Cancer (2014)

Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis. Mice bearing implanted 9L gliomas were used to investigate the effects of this 6-day repeating, immunogenic cyclophosphamide schedule on myeloid-derived suppressor cells, which are pro-angiogenic and can inhibit anti-tumor immunity, and to elucidate the mechanism whereby the innate immune cell-dependent tumor regression response to metronomic cyclophosphamide treatment is blocked by several anti-angiogenic receptor tyrosine kinase inhibitors. Intermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b+ immune cells but not CD11b+Gr1+ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased. The inhibition of immune cell recruitment and tumor regression by anti-angiogenic receptor tyrosine kinase inhibitors, previously observed in several brain tumor models, was recapitulated in the 9L tumor model with the VEGFR2-specific inhibitory monoclonal antibody DC101 (p < 0.01), implicating VEGFR2 signaling as an essential step in metronomic cyclophosphamide-stimulated immune cell recruitment. In contrast, sorafenib, a multi-receptor tyrosine kinase inhibitor with comparatively weak VEGF receptor phosphorylation inhibitory activity, was strongly anti-angiogenic but did not block metronomic cyclophosphamide-induced innate immunity or tumor regression (p > 0.05). The interference by receptor tyrosine kinase inhibitors in the immunogenic actions of intermittent metronomic chemotherapy is not a consequence of anti-angiogenesis per se, as demonstrated in an implanted 9L tumor model. Furthermore, this undesirable interaction with tyrosine kinase inhibitors can be avoided by using anti-angiogenic drugs that spare the VEGFR2 pathway.
Combination Strategy Targeting the Hypoxia Inducible Factor-1α with Mammalian Target of Rapamycin and Histone Deacetylase Inhibitors
Authors: Henk M.W. Verheul, Brenda Salumbides, Karen Van Erp, Hans Hammers, David Z. Qian, Tolib Sanni, Peter Atadja, Roberto Pili
Journal: Clinical Cancer Research (2008)

The hypoxia-inducible factor-1 alpha (HIF-alpha) is a key regulator of tumor angiogenesis. Mammalian target of rapamycin (mTOR) and histone deacetylase (HDAC) inhibitors suppress tumor-induced angiogenesis by reducing tumor HIF-1 alpha protein expression. Thus, we hypothesized that combination treatment of rapamycin and the HDAC inhibitor LBH589 has greater antiangiogenic and antitumor activity compared with single agents.To evaluate the effect of LBH589 and rapamycin on HIF-1 alpha in human prostate PC3, renal C2 carcinoma cell lines, and endothelial cells (human umbilical vein endothelial cells), we did Western blot analysis. To determine the antitumor activity of LBH589 and rapamycin, cell proliferation assays and xenograft experiments were conducted.Western blotting showed that combination treatment of human umbilical vein endothelial cells, C2 and PC3, significantly reduced HIF-1 alpha protein expression compared with single agents. Treatment with rapamycin resulted in inhibition of the downstream signals of the mTOR pathway and increased phosphorylation of Akt in C2 cells, whereas the constitutively activated Akt in PC3 cells was not modulated. LBH589 decreased both constitutively expressed and rapamycin-induced phosphorylated Akt levels in PC3 and C2 cell lines. In clonogenic assays, the combination treatment had a greater inhibitory effect in PC3 cells (93 +/- 1.4%) compared with single agents (66 +/- 9% rapamycin and 43 +/- 4% LBH589). Combination of rapamycin and LBH589 significantly inhibited PC3 and C2 in vivo tumor growth and angiogenesis as measured by tumor weight and microvessel density.Combination treatment of mTOR and HDAC inhibitors represents a rational therapeutic strategy targeting HIF-1 alpha that warrants clinical testing.
Paris staging system for primary gastrointestinal lymphomas
Authors: A Ruskone-Fourmestraux
Journal: Gut (2003)

Currently, much effort is put into the development of specific therapeutical approaches that are tailored to specific lymphoma entities. As a consequence, more specific information needs to be collected to support the choice of therapy. In gastric marginal zone B cell lymphoma of MALT-type, the need for specialised documentation of tumour extent in the organ wall has been stressed by the high predictive value for failure of response after Helicobacter pylori eradication of infiltration beyond the mucosa, a predictive parameter irrespective of the presence of the t(11;18) translocation.1–5 With new techniques such as endosonography, this infiltration depth can be assessed with improving accuracy. However, the information cannot be translated into the current staging systems. …