tbuckley/cabot-search huggingface dataset:
Vascular Remodeling in Response to Altered Blood Flow Is Mediated by Fibroblast Growth Factor-2
Authors: Shane R. Bryant, Robert J. Bjercke, David A. Erichsen, Ajay Rege, Volkhard Lindner
Journal: Circulation Research (1999)

Vascular structures adapt to changes in blood flow by adjusting their diameter accordingly. The factors mediating this process are only beginning to be identified. We have recently established a mouse model of arterial remodeling in which flow in the common carotid artery is interrupted by ligation of the vessel near the carotid bifurcation, resulting in a dramatic reduction in vessel diameter as a consequence of inward remodeling and intimal lesion formation. In the present study, we used this model to determine the role of fibroblast growth factor-2 (FGF-2) in the remodeling response by maintaining neutralizing serum levels of a mouse monoclonal antibody against FGF-2 for 4 weeks. Morphometric analysis revealed that intimal lesion formation was not affected by the antibody. However, lumen narrowing was significantly inhibited, resulting in a greater than 3-fold increase in lumen area in anti-FGF-2-treated animals compared with controls. Treatment with anti-FGF-2 antibody significantly inhibited the reduction in vessel diameter (inward remodeling) and shortening of the internal elastic lamina in the ligated vessel. In addition, anti-FGF-2 treatment also caused outward remodeling of the contralateral carotid artery. These findings identify FGF-2 as an important factor in vascular remodeling, and its effects are likely to be mediated by increasing vascular tone. The results are consistent with the recent observation of reduced vascular tone in the FGF-2-deficient mouse.
Surface and fluid phase activities of two forms of activated Hageman factor produced during contact activation of plasma.
Authors: S D Revak, C G Cochrane, B N Bouma, J H Griffin
Journal: The Journal of Experimental Medicine (1978)

The ability of the two forms of activated Hageman factor (HFa) produced during contact activation of plasma to activate prekallikrein and factor XI was studied. alpha-HFa, defined as an 80,000 mol wt two-chain enzyme which remains bound to the surface was capable of cleaving surface-bound prekallikrein and factor XI. beta-HFa, a 28,000 mol wt single chain molecule, released from the surface during contact activation was able to cleave prekallikrein but showed no activity on factor XI. Cleavage of prekallikrein by beta-HFa occurred irrespective of whether the substrate was surface-bound or in solution. Cleavage of factor XI occurred only when it was surface bound and only the alpha-form of HFa was capable of this proteolytic action. Factor XI was found to remain bound to the surface while prekallikrein and kallikrein rapidly dissociated from the surface into the supernate. These findings suggest that the initiation of intrinsic coagulation through the activation factor XI is a localized event occurring at the site of contact activation and is the result of the action of alpha-HFa. By contrast, kinin generation and fibrinolysis resulting from the formation of kallikrein can be initiated either at the site of contact activation, by alpha-HFa action, or throughout the plasma, by beta-HFa; further dissemination of these activities is assured by the rapid dissociation of kallikrein itself from the surface.
Translating Scientific Advancement into Clinical Benefit for Castration-Resistant Prostate Cancer Patients
Authors: Gerhardt Attard, Johann S. de Bono
Journal: Clinical Cancer Research (2011)

Abstract In the past 12 months, three novel therapeutics—sipuleucel-T, cabazitaxel, and abiraterone acetate—were granted Food and Drug Administration regulatory approval for the treatment of metastatic castration-resistant prostate cancer (CRPC) patients based on phase III studies that showed a survival advantage. Other agents, including the novel antiandrogen MDV3100, are at an advanced stage of clinical phase III evaluation. The treatment paradigm for CRPC has now changed significantly, and this has introduced new challenges for physicians, including selecting patients for specific therapies, developing the best sequencing and combination regimens for the several new effective agents that have recently been approved or are in development, and dissecting mechanisms of resistance that will inform the development of a new generation of therapeutics. This Focus issue reviews the results obtained with immunotherapies, taxane cytotoxics, and androgen receptor targeting therapeutics for CRPC, as well as the postulated mechanisms of resistance to these protocols and proposed strategies for improvement. The use of biomarkers for patient selection, monitoring of treatment activity, and acceleration of drug approval will be critical for achieving further improvements in the treatment for CRPC, and is also discussed in detail. Clin Cancer Res; 17(12); 3867–75. ©2011 AACR.
Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer
Authors: Carmen Z. Michaylira, Gabrielle S. Wong, Charles G. Miller, Christie M. Gutierrez, Hiroshi Nakagawa, Rachel Hammond, Andres J. Klein-Szanto, Ju-Seog Lee, Sang Bae Kim, Meenhard Herlyn, J. Alan Diehl, Phyllis Gimotty, Anil K. Rustgi
Journal: Cancer Research (2010)

Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. Here, we report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor-invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor-invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain-of-loss and loss-of-function experiments. Inhibition of epidermal growth factor receptor signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting the interdependence of two common genetic alterations with periostin function. Collectively, our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (three-dimensional) culture can offer an important tool to discover novel biological effectors in cancer.
Patient Education Level As a Predictor of Survival In Lung Cancer Clinical Trials
Authors: James E. Herndon, Alice B. Kornblith, Jimmie C. Holland, Electra D. Paskett
Journal: Journal of Clinical Oncology (2008)

Purpose To investigate the effect of socioeconomic status, as measured by education, on the survival of 1,577 lung cancer patients treated on 11 studies conducted by the Cancer and Leukemia Group B. Patients and Methods Sociodemographic data, including education, was reported by the patient at the time of clinical trial accrual. Cox proportional hazards model stratified by treatment arm/study was used to examine the effect of education on survival after adjustment for known prognostic factors. Results The patient population included 1,177 patients diagnosed with non–small-cell lung cancer (NSCLC; stage III or IV) and 400 patients diagnosed with small-cell lung cancer (SCLC; extensive or limited). Patients with less than an eighth grade education (13% of patients) were significantly more likely to be male, nonwhite, and older; have a performance status (PS) of 1 or 2; and have chest pain. Significant predictors of poor survival in the final model included male sex, PS of 1 or 2, dyspnea, weight loss, liver or bone metastases, unmarried, presence of adrenal metastases and high alkaline phosphatase levels among patients with NSCLC, and high WBC levels among patients with advanced disease. Education was not predictive of survival. Conclusion The physical condition of patients with low education who enroll onto clinical trials is worse than patients with higher education. Once enrolled onto a clinical trial, education does not affect the survival of patients with SCLC or stage III or IV NSCLC. The standardization of treatment and follow-up within a clinical trial, regardless of education, is one possible explanation for this lack of effect.
Suppression of in vivo tumor formation induced by simian virus 40-transformed cells in mice receiving antiidiotypic antibodies.
Authors: R C Kennedy, G R Dreesman, J S Butel, R E Lanford
Journal: The Journal of Experimental Medicine (1985)

This study characterizes four private idiotypes (Id) associated with monoclonal antibodies (mAb) to simian virus 40 (SV40) tumor antigen (T-Ag), and to a cellular protein, p53. Anti-Id recognized Id determinants associated with the antibody-combining site. BALB/c mice receiving a pool of anti-Id directed against mAb recognizing distinct amino and carboxyl terminal epitopes of T-Ag before receiving a tumorigenic dose of SV40-transformed cells showed suppression of tumor formation. Serum obtained from these mice before tumor challenge contained anti-anti-Id that failed to bind T-Ag. These data support the potential role of regulatory idiotopes in tumor immunity.
Delivering quality and value in heart failure
Authors: F D R. Hobbs
Journal: BMJ (2009)

New guidance fails to communicate exactly what is needed and how much it will cost

The NHS Institute for Innovation and Improvement recently published the first in a series of guidance documents Focus on heart failure .1 The series is aimed principally at healthcare managers, commissioners, and general practitioners.

Heart failure and left ventricular systolic dysfunction are associated with a poor prognosis, worse quality of life than most other chronic disorders,2 and high admission and readmission rates (nearly a quarter of patients are readmitted within 12 weeks of discharge).3 Heart failure accounts for at least 2% of total healthcare expenditure4—€26m (£23m; $34m) per million population in the United Kingdom and €70m per million population in the United States. Annual mortality in severe heart failure is around 60%,5 with a five year mortality in the general population of around 42%.6

So heart failure is important, but what is the aim of the publication and does it succeed? The stated purpose is to “help local health communities and organisations improve the quality and value of the care they deliver.” It attempted this by …
Three forms of xanthine: acceptor oxidoreductase in rat heart.
Authors: Z W Kaminski, R Pohorecki, C L Ballast, E F Domino
Journal: Circulation Research (1986)

The enzyme xanthine: acceptor oxidoreductase found in rat heart equilibrates between three forms differing in electron acceptor specificity. Form D transfers electrons exclusively to NAD+ and accounts for 85% of total oxidoreductase activity. Form O transfers electrons to molecular oxygen and accounts for 8%. The D/O form prefers NAD+, but without NAD+ transfers electrons to oxygen. Interconversion from D to O and O to D forms is catalyzed by sulfhydryl group-modifying reagents: Cd2+, Cu2+, disulfiram, and heating with dithiothreitol. This suggests that sulfhydryl groups participate in the first stage of enzyme conversion. The NADH/NAD+ concentration ratio may regulate the dehydrogenase activity of xanthine:acceptor oxidoreductase (NAD+-dependent activity of D and D/O forms). Accumulating NADH inhibits hypoxanthine hydroxylation. The amount of form O increases during cardiac ischemia, facilitating superoxide radical-ion generation. Also, NADH/NAD+ does not regulate form O, promoting adenylate nucleotide pool depletion, especially in the heart which has low de novo purine nucleotide synthesis.
Angiosarcoma arising in an angiomatous naevus following irradiation in childhood
Authors: S.E. HANDFIELD-JONES, C.T.C. KENNEDY, J.B. BRADFIELD
Journal: British Journal of Dermatology (1988)

We describe a patient who developed an angiosarcoma on her face at the age of 24. The tumour arose from an angiomatous naevus that had been treated with radiotherapy when the patient was 7 months old.
Heterogeneity of intracellular potassium activity and membrane potential in hypoxic guinea pig ventricle.
Authors: C M Baumgarten, C J Cohen, T F McDonald
Journal: Circulation Research (1981)

The relationship between membrane potential (Em) and the potassium equilibrium potential (EK) was investigated in hypoxic guinea pig papillary muscle. After more than 8 hours of hypoxia, cells with near normal Em (-86.2 +/- 0.9 mV) and action potentials were observed. However, the intracellular potassium concentration ([K+]i) based on chemical analysis and the assumption that potassium was homogeneously distributed was 41.8 +/- 4.3 mM; the apparent EK was -55.7 +/- 2.9 mV, significantly positive to Em. Measurements with potassium ion-selective microelectrodes revealed that prolonged hypoxia results in at least two populations of cells with different characteristics. The first population had an intracellular potassium activity (aiK) of 101.5 +/- 1.9 mM, and EK was 4.7 mV negative to Em. In contrast, EK was 33.4 +/- 1.3 mV negative to Em in the second population. These cells also exhibited a reduced sensitivity to changes in bath potassium, and calculations suggest aiK was about 18 mM. The existence of cell populations with a near normal and very low aiK can explain the intermediate value of [K+]i calculated assuming a homogenous potassium distribution. Cells with near normal Em and action potentials represent the population with near normal aiK. Hypoxia may also cause non-uniform changes in other cellular characteristics.
Plasma metabolomic signature in COPD patients: Associations to proteomic profile and clinical outcomes
Authors: Victor Pinto-Plata, Miguel Divo, Yohannes Tesfaigzi, Hans Peterson, Vince Calhoum, Dustin Holloway, Yaoyu Wang, Caroline Owen, Bartolome Celli
Journal: European Respiratory Journal (2013)

RATIONALE: The association of plasma metabolomic to clinical outcomes in COPD patients is limited. METHODS: We studied 60 COPD patients, 30 survivors (S) and 30 non-survivors (NS)(mean survival 24 (19) months)and 30 aged-gender matched control group (C). Participants completed lung function tests and components of the BODE index.Plasma samples were studied using Liquid and Gas Chromatography/Mass Spectrometry and 8 biomarkers (ELISA tests). Spearman9s rank correlation coefficient was used to measure associations. Each variable is represented by a node, the number of associations between variables as edges and the size of COPD nodes represent the Z-score related to controls. The thickness of the edge represents the strength (rho value) of the association.RESULTS: Survivors had better lung function and lower BODE index than Non survivors. Using a system biology approach, a distinctive pattern of association of metabolites, biomarkers and clinical outcomes in the control group differed from survivors and non-survivors (Figure 1 A-C), characterized by a progressive increment of association(edges) in the COPD groups.  CONCLUSION: Global associations between plasma metabolites, biomarkers and clinical outcomes is altered in COPD patients compared to age matched controls. The alterations are more profound in non-survivors COPD patients suggesting that plasma metabolites would predict clinical outcome in COPD.
Myocardin Enhances Smad3-Mediated Transforming Growth Factor-β <sub>1</sub> Signaling in a CArG Box-Independent Manner
Authors: Ping Qiu, Raquel P. Ritchie, Zhiyao Fu, Dongsun Cao, Jerry Cumming, Joseph M. Miano, Da-Zhi Wang, Hui J. Li, Li Li
Journal: Circulation Research (2005)

Transforming growth factor (TGF)-beta1 is an important cytokine involved in various diseases. However, the molecular mechanism whereby TGF-beta1 signaling modulates the regulatory network for smooth muscle gene transcription remains largely unknown. To address this question, we previously identified a Smad-binding element (SBE) in the SM22alpha promoter as one of the TGF-beta1 response elements. Here, we show that mutation of the SBE reduces the activation potential of a SM22alpha promoter in transgenic mice during embryogenesis. Chromatin immunoprecipitation assays reveal that TGF-beta1 induces Smad3 binding to the SM22alpha promoter in vivo. A multimerized SBE promoter responsive to TGF-beta1 signaling is highly activated by Smad3 but not by the closely related Smad2. Intriguingly, myocardin (Myocd), a known CArG box-dependent serum response factor coactivator, participates in Smad3-mediated TGF-beta1 signaling and synergistically stimulates Smad3-induced SBE promoter activity independent of the CArG box; no such synergy is seen with Smad2. Importantly, Myocd cooperates with Smad3 to activate the wild-type SM22alpha, SM myosin heavy chain, and SMalpha-actin promoters; they also activate the CArG box-mutated SM22alpha promoter as well as the CArG box-independent aortic carboxypeptidase-like protein promoter. Immunopreciptiation assays reveal that Myocd and Smad3 directly interact both in vitro and in vivo. Mutagenesis studies indicate that the C-terminal transactivation domains of Myocd and Smad3 are required for their functional synergy. These results reveal a novel regulatory mechanism whereby Myocd participates in TGF-beta1 signal pathway through direct interaction with Smad3, which binds to the SBEs. This is the first demonstration that Myocd can act as a transcriptional coactivator of the smooth muscle regulatory network in a CArG box-independent manner.
Baff Binds to the Tumor Necrosis Factor Receptor–Like Molecule B Cell Maturation Antigen and Is Important for Maintaining the Peripheral B Cell Population
Authors: Jeffrey S. Thompson, Pascal Schneider, Susan L. Kalled, LiChun Wang, Eric A. Lefevre, Teresa G. Cachero, Fabienne MacKay, Sarah A. Bixler, Mohammad Zafari, Zhong-Ying Liu, Stephen A. Woodcock, Fang Qian, Marcel Batten, Christine Madry, Yolande Richard, Christopher D. Benjamin, Jeffrey L. Browning, Andreas Tsapis, Jurg Tschopp, Christine Ambrose
Journal: The Journal of Experimental Medicine (2000)

The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor-triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.
Directed migration of human neural progenitor cells to interleukin-1β is promoted by chemokines stromal cell-derived factor-1 and monocyte chemotactic factor-1 in mouse brains
Authors: Yumei Wu, Qiang Chen, Hui Peng, Huanyu Dou, You Zhou, Yunlong Huang, Jialin C Zheng
Journal: Translational Neurodegeneration (2012)

Neurogenesis, including the proliferation, migration and differentiation of neural progenitor cells (NPCs), is impaired in HIV-1 associated dementia (HAD). We previously demonstrated HIV-1-infected macrophages (HIV-MDM) regulate stromal cell-derived factor 1 (SDF-1) production in astrocytes through Interleukin-1β (IL-1β). Chemokines are known to induce NPC migration; however, it remains unclear how chemokines produced in inflammation regulate NPC migration.The secretion of SDF-1 and Monocyte chemotactic preotein-1 (MCP-1) in astrocytes upon IL-1β stimulation was measured by ELISA assay. Human NPCs were injected parallel along with IL-1β, SDF-1 or MCP-1 intracranially into basal ganglion 1 mm apart in SCID mice, and immunofluorescent staining was used to study the survival and migration of injected human NPCs.SDF-1 and MCP-1 are secreted by astrocytes upon IL-1β stimulation in a time-dependent manner. Injected human NPCs survived in SCID mice and migrated towards sites of IL-1β, SDF-1 and MCP-1 injection.In conclusion, chemokines SDF-1 or MCP-1 secreted by astrocytes in the presence of IL-1β injection are attractive to NPCs injected into SCID mouse brains, suggesting that SDF-1 and MCP-1 play important roles in NPC migration during neuroinflammation.
Prognostic Significance of p16<sup>INK4A</sup> and Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial
Authors: Danny Rischin, Richard J. Young, Richard Fisher, Stephen B. Fox, Quynh-Thu Le, Lester J. Peters, Ben Solomon, Jimin Choi, Brian O'Sullivan, Lizbeth M. Kenny, Grant A. McArthur
Journal: Journal of Clinical Oncology (2010)

To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial.Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction.Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74%; hazard ratio [HR], 0.36; 95% CI, 0.17 to 0.74; P = .004) and failure-free survival (87% v 72%; HR, 0.39; 95% CI, 0.20 to 0.74; P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95% CI, 0.21 to 0.96; P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95% CI, 0.09 to 1.24; P = .13).HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial
Authors: Johann Sebastian de Bono, Stephane Oudard, Mustafa Ozguroglu, Steinbjørn Hansen, Jean-Pascal Machiels, Ivo Kocak, Gwenaëlle Gravis, Istvan Bodrogi, Mary J Mackenzie, Liji Shen, Martin Roessner, Sunil Gupta, A Oliver Sartor
Journal: The Lancet (2010)
Response to Comment on Palmas et al. Results of the Northern Manhattan Diabetes Community Outreach Project: A Randomized Trial Studying a Community Health Worker Intervention to Improve Diabetes Care in Hispanic Adults. Diabetes Care 2014;37:963–969
Authors: Walter Palmas, Sally E. Findley, Jeanne Teresi, Jose A. Luchsinger, Olveen Carrasquillo
Journal: Diabetes Care (2015)

The comments by Ramesh and Haldar (1) point out several limitations of the Northern Manhattan Diabetes Community Outreach Project (NOCHOP), several of which we discussed at length in our original article (2). We do agree with their concern regarding the lack of statistical power, which we believe was mostly due to lower-than-expected intervention fidelity. Our participants experienced great difficulty attending …