tbuckley/cabot-search huggingface dataset:
Connexin 30 is expressed in the mouse sino-atrial node and modulates heart rate
Authors: Daniel Gros, Magali Théveniau-Ruissy, Monique Bernard, Thierry Calmels, Frank Kober, Goran Söhl, Klaus Willecke, Joël Nargeot, Habo J. Jongsma, Matteo E. Mangoni
Journal: Cardiovascular Research (2009)

This study aimed at characterizing expression and the functional role of the Gjb6 gene, encoding for connexin 30 (Cx30) protein, in the adult mouse heart. The expression of the Gjb6 gene in the mouse heart was investigated by RT–PCR and sequencing of amplified cDNA fragments. The sites of Gjb6 expression were identified in the adult heart using transgenic mice with reporter genes (Cx30LacZ/LacZ and Cx30LacZ/LacZ/Cx40EGFP/EGFP mice), as well as anti-HCN4 (hyperpolarization activated cyclic nucleotide-gated potassium channel 4) or anti-connexin antibodies. Cine-magnetic resonance imaging and telemetric ECG recordings were used to evaluate the impact of Cx30 deficiency on cardiac physiology. Gjb6 was shown to be expressed in the sinoatrial (SA) node of the adult mouse heart. Eighty from 100 nuclei on average were LacZ-positive in the SA node of Cx30LacZ/LacZ mice. No significant LacZ expression was seen in other cardiac tissues. Cx30 protein was identified in low abundance in the SA node of wild-type mice, as indicated by immunofluorescence experiments. Telemetric ECG recordings indicated that Cx30-deficient mice displayed a mean daily heart rate (HR) that was 9% faster than that measured in control mice (572 ± 38 b.p.m. vs. 524 ± 23, P < 0.05). This moderate tachycardia was still observed after inhibition of the autonomic nervous system, demonstrating that Cx30 deficiency resulted in changes in the intrinsic electrical properties of the SA node. Consistent with this hypothesis, Cx30LacZ/LacZ displayed a significant reduction of SDNN (standard deviation of the interbeat interval) compared with control mice. Increase of both the cardiac index (20%) and the end-diastolic volume to body weight ratio (16%) with no deficiency in ejection fraction or stroke volume were observed in mutant mice. An increase in cardiac index was interpreted as being a direct consequence of high HR, whereas large end-diastolic volume may be an indirect consequence of prolonged high HR. Cx30 is functionally expressed, in low abundance, in the SA node of the adult mouse heart where it participates in HR regulation.
Phase II Intergroup Trial of Alisertib in Relapsed and Refractory Peripheral T-Cell Lymphoma and Transformed Mycosis Fungoides: SWOG 1108
Authors: Paul M. Barr, Hongli Li, Catherine Spier, Daruka Mahadevan, Michael LeBlanc, Mansoor Ul Haq, Bryan D. Huber, Christopher R. Flowers, Nina D. Wagner-Johnston, Steven M. Horwitz, Richard I. Fisher, Bruce D. Cheson, Sonali M. Smith, Brad S. Kahl, Nancy L. Bartlett, Jonathan W. Friedberg
Journal: Journal of Clinical Oncology (2015)

Aurora A kinase (AAK) is upregulated in highly proliferative lymphomas, suggesting its potential as a therapeutic target. Alisertib is a novel oral AAK inhibitor without adverse safety signals in early-phase studies that demonstrated preliminary activity in T-cell lymphoma. This phase II study was conducted to further investigate the efficacy of alisertib in relapsed or refractory peripheral T-cell non-Hodgkin lymphoma (PTCL).Eligible patients with histologically confirmed relapsed/refractory PTCL or transformed Mycosis fungoides (tMF) received alisertib 50 mg twice a day for 7 days on 21-day cycles.Of 37 eligible patients, the histologic subtypes enrolled included PTCL not otherwise specified (n = 13), angioimmunoblastic T-cell lymphoma (n = 9), tMF (n = 7), adult T-cell lymphoma/leukemia (n = 4), anaplastic large-cell lymphoma (n = 2), and extranodal natural killer/T-cell lymphoma (n = 2). Grade 3 and 4 adverse events in ≥ 5% of patients included neutropenia (32%), anemia (30%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%), and rash (5%). Treatment was discontinued most commonly for disease progression. Among the PTCL subtypes, the overall response rate was 30%, whereas no responses were observed in tMF. Aurora B kinase was more commonly overexpressed than AAK in tumor specimens. Analysis of AAK, Aurora B kinase, MYC, BCL-2, phosphatidylinositol 3-kinase γ, and Notch1 expression revealed no association with response.Alisertib has antitumor activity in PTCL, including heavily pretreated patients. These promising results are being further investigated in an ongoing international, randomized phase III trial comparing alisertib with investigator's choice in PTCL.
Monoclonal Antibody Therapy for Cancer
Authors: Margaret von Mehren, Gregory P. Adams, Louis M. Weiner
Journal: Annual Review of Medicine (2003)

Monoclonal antibody therapy has emerged as an important therapeutic modality for cancer. Unconjugated antibodies show significant efficacy in the treatment of breast cancer, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Promising new targets for unconjugated antibody therapy include cellular growth factor receptors, receptors or mediators of tumor-driven angiogenesis, and B cell surface antigens other than CD20. Immunoconjugates composed of antibodies conjugated to radionuclides or toxins show efficacy in non-Hodgkin's lymphoma. One immunoconjugate containing an antibody and a chemotherapy agent exhibits clinically meaningful antitumor activity in acute myeloid leukemia. Numerous efforts to exploit the ability of antibodies to focus the activities of toxic payloads at tumor sites are under way and show early promise. The ability to create essentially human antibody structures has reduced the likelihood of host-protective immune responses that otherwise limit the duration of therapy. Antibody structures now can be readily manipulated to facilitate selective interaction with host immune effectors. Other structural manipulations that improve the selective targeting properties and rapid systemic clearance of immunoconjugates should lead to the design of effective new treatments, particularly for solid tumors.
Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III–IVB head and neck squamous cell carcinoma (HNSCC)
Authors: M.G. Fury, E.J. Sherman, S.S. Rao, S. Wolden, S. Smith-Marrone, B. Mueller, K.K. Ng, P.R. Dutta, D.Y. Gelblum, J.L. Lee, R. Shen, S. Kurz, N. Katabi, S. Haque, N.Y. Lee, D.G. Pfister
Journal: Annals of Oncology (2014)
Tuberculosis and HIV co-infection: do we have a surveillance system in Europe?: Table 1–
Authors: E. Pontali, M.B. Pasticci, A. Matteelli, F. Baldelli, G.B. Migliori
Journal: European Respiratory Journal (2011)

s there any reason why a clinician should be interested in knowing about the state of the art in tuberculosis (TB) and HIV co-infection surveillance in Europe?A question like, ''Is TB-HIV co-infection a relevant issue?'' is probably easier to answer, at least at a global level: TB-HIV coinfection is responsible for almost 400,000 deaths every year and TB is by far the major killer of HIV-infected persons, being responsible for over a quarter of the global burden of HIVassociated deaths; people living with HIV/AIDS infected with Mycobacterium tuberculosis are at 20-30 times greater risk of developing TB compared with HIV-uninfected persons [1].And in Europe?To control TB and HIV co-infection, which, together with multidrug-resistant TB, is today the hardest obstacle to overcome in curbing the TB epidemic, the World Health Organization (WHO) promotes a specific package, included in the second element of the Stop TB Strategy [2].Developed in 2004 by WHO and UNAIDS (Joint United Nations programme on HIV/ AIDS), this package is based on the collaboration between TB and HIV/AIDS national programmes, and advocates 12 collaborative activities that are summarised in table 1 [3].
LINE-1 Hypomethylation, DNA Copy Number Alterations, and <i>CDK6</i> Amplification in Esophageal Squamous Cell Carcinoma
Authors: Yoshifumi Baba, Masayuki Watanabe, Asuka Murata, Hironobu Shigaki, Keisuke Miyake, Takatsugu Ishimoto, Masaaki Iwatsuki, Shiro Iwagami, Naoya Yoshida, Eiji Oki, Kentaro Sakamaki, Mitsuyoshi Nakao, Hideo Baba
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Global DNA hypomethylation plays a crucial role in genomic instability and carcinogenesis. DNA methylation of the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level, and is attracting interest as a useful marker for predicting cancer prognosis. Our previous study using more than 200 esophageal squamous cell carcinoma (ESCC) specimens demonstrated the significant relationship between LINE-1 hypomethylation and poor prognosis. However, the mechanism by which LINE-1 hypomethylation affects aggressive tumor behavior has yet to be revealed. Experimental Design: To examine the relationship between LINE-1 hypomethylation and DNA copy number variations, we investigated LINE-1–hypomethylated and LINE-1–hypermethylated ESCC tumors by comparative genomic hybridization array. Results: LINE-1–hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6. LINE-1 methylation levels were significantly associated with CDK6 mRNA and CDK6 protein expression levels in ESCC specimens. In our cohort of 129 patients with ESCC, cases with CDK6-positive expression experienced worse clinical outcome compared with those with CDK6-negative expression, supporting the oncogenic role of CDK6 in ESCC. In addition, we found that the prognostic impact of LINE-1 hypomethylation might be attenuated by CDK6 expression. Conclusion: LINE-1 hypomethylation (i.e., global DNA hypomethylation) in ESCC might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as CDK6. Clin Cancer Res; 20(5); 1114–24. ©2014 AACR.
TwHF versus methotrexate in the treatment of rheumatoid arthritis: response to Landewe's comment on the TRIFRA study
Authors: Qian-wen Lv, Tao Chen, Wen Zhang, Qun Shi, Wen-jie Zheng, Peter E Lipsky, Xuan Zhang
Journal: Annals of the Rheumatic Diseases (2014)

We read with interest, the comments of Drs Landewe and van der Heijde1 concerning our article on the treatment of patients with rheumatoid arthritis with an extract of Tripterygium wilfordii Hook F (TwHF).2 We are aware that non-inferiority trial design can be complex, and agree there are limitations of the study (TRIFRA; Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis). We hope that we can further clarify the trial design and its implications.

First, and most important, the TRIFRA study was designed as a non-inferiority trial from the very beginning. If this point was confusing in the final manuscript, we apologise, but the intent was always to design and carry out a non-inferiority trial comparing the extract of TwHF to methotrexate. As detailed in the Statistical Analysis Plan (developed in February 2012 and published as additional material), the a priori hypothesis underlying this trial was that the extract of TwHF was non-inferior to methotrexate (MTX) in treating subjects …
Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura
Authors: Giovanni Emilia, Monica Morselli, Mario Luppi, Giuseppe Longo, Roberto Marasca, Giovanna Gandini, Leonardo Ferrara, Nicola D'Apollo, Leonardo Potenza, Marcello Bertesi, Giuseppe Torelli
Journal: Blood (2002)
High-Sensitivity Cardiac Troponin in the Distinction of Acute Myocardial Infarction From Acute Cardiac Noncoronary Artery Disease
Authors: Philip Haaf, Beatrice Drexler, Tobias Reichlin, Raphael Twerenbold, Miriam Reiter, Julia Meissner, Nora Schaub, Claudia Stelzig, Michael Freese, Amely Heinzelmann, Christophe Meune, Cathrin Balmelli, Heike Freidank, Katrin Winkler, Kris Denhaerynck, Willibald Hochholzer, Stefan Osswald, Christian Mueller
Journal: Circulation (2012)

We hypothesized that high-sensitivity cardiac troponin (hs-cTn) and its early change are useful in distinguishing acute myocardial infarction (AMI) from acute cardiac noncoronary artery disease.In a prospective, international multicenter study, hs-cTn was measured with 3 assays (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI Siemens) in a blinded fashion at presentation and serially thereafter in 887 unselected patients with acute chest pain. Accuracy of the combination of presentation values with serial changes was compared against a final diagnosis adjudicated by 2 independent cardiologists. AMI was the adjudicated final diagnosis in 127 patients (15%); cardiac noncoronary artery disease, in 124 (14%). Patients with AMI had higher median presentation values of hs-cTnT (0.113 μg/L [interquartile range, 0.049-0.246 μg/L] versus 0.012 μg/L [interquartile range, 0.006-0.034 μg/L]; P<0.001) and higher absolute changes in hs-cTnT in the first hour (0.019 μg/L [interquartile range, 0.007-0.067 μg/L] versus 0.001 μg/L [interquartile range, 0-0.003 μg/L]; P<0.001) than patients with cardiac noncoronary artery disease. Similar findings were obtained with the hs-cTnI assays. Adding changes of hs-cTn in the first hour to its presentation value yielded a diagnostic accuracy for AMI as quantified by the area under the receiver-operating characteristics curve of 0.94 for hs-cTnT (0.92 for both hs-cTnI assays). Algorithms using ST-elevation, presentation values, and changes in hs-cTn in the first hour accurately separated patients with AMI and those with cardiac noncoronary artery disease. These findings were confirmed when the final diagnosis was readjudicated with the use of hs-cTnT values and validated in an independent validation cohort.The combined use of hs-cTn at presentation and its early absolute change excellently discriminates between patients with AMI and those with cardiac noncoronary artery disease.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.
ATP Released by Astrocytes Mediates Glutamatergic Activity-Dependent Heterosynaptic Suppression
Authors: Jing-ming Zhang, Hui-kun Wang, Chang-quan Ye, Wooping Ge, Yiren Chen, Zheng-lin Jiang, Chien-ping Wu, Mu-ming Poo, Shumin Duan
Journal: Neuron (2003)
Use of Central Venous Oxygen Saturation to Guide Therapy
Authors: Keith R. Walley
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

The use of pulmonary artery catheters has diminished, so that other technologies are emerging. Central venous oxygen saturation measurement (ScvO₂) as a surrogate for mixed venous oxygen saturation measurement (SvO₂) is simple and clinically accessible. To maximize the clinical utility of ScvO₂ (or SvO₂) measurement, it is useful to review what the measurement means in a physiologic context,how the measurement is made, important limitations, and how this measurement may be helpful in common clinical scenarios. Compared with cardiac output measurement, SvO₂ is more directly related to tissue oxygenation. Furthermore,when tissue oxygenation is a clinical concern, SvO₂ is less prone to error compared with cardiac output, where small measurement errors may lead to larger errors in interpreting adequacy of oxygen delivery. ScvO₂ should be measured from the tip of a central venous catheter placed close to, or within, the right atrium to reduce measurement error. Correct clinical interpretation of SvO₂, or its properly measured ScvO₂ surrogate, can be used to (1) estimate cardiac output using the Fick equation, (2) better understand whether a patient's oxygen delivery is adequate to meet their oxygen demands, (3) help guide clinical practice, particularly when resuscitating patients using validated early goal directed therapy treatment protocols, (4) understand and treat arterial hypoxemia, and (5) rapidly estimate shunt fraction (venous admixture).
Polyvalent Mesoporous Silica Nanoparticle‐Aptamer Bioconjugates Target Breast Cancer Cells
Authors: Le‐Le Li, Qian Yin, Jianjun Cheng, Yi Lu
Journal: Advanced Healthcare Materials (2012)

Abstract Spatiotemporal control over the delivery of therapeutic agents is an outstanding challenge to cancer treatment. By taking advantage of recent advances in DNA aptamer biology and mesoporous silica nanotechnology, we report a general approach to design and fabricate controlled release drug delivery systems that are able to effectively target cancer cells. Specifically, polyvalent mesoporous silica nanocarriers‐aptamer bioconjugates were constructed; the high‐surface‐area nanoporous core allowed high drug loading and the surface‐conjugated aptamer facilitated the nanoparticle targeting of nucleolin overexpressed MCF‐7 cells. The efficient cancer‐cell‐specific fluorescent imaging and drug delivery of the bioconjugates outline the great potential for therapeutic applications.
A Randomized, Controlled, Phase 2 Study of AMG 317, an IL-4Rα Antagonist, in Patients with Asthma
Authors: Jonathan Corren, William Busse, Eli O Meltzer, Lyndon Mansfield, George Bensch, John Fahrenholz, Sally E Wenzel, Yun Chon, Meleana Dunn, Haoling H Weng, Shao-Lee Lin
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

IL-4 and IL-13 share many biological functions important in the development of allergic airway inflammation and are implicated in the pathogenesis of asthma. AMG 317 is a fully human monoclonal antibody to IL-4Ralpha that blocks both IL-4 and IL-13 pathways.To evaluate efficacy and safety of AMG 317 in patients with moderate to severe asthma.In this phase 2, randomized, double-blind, placebo-controlled study, patients received weekly subcutaneous injections of placebo or AMG 317 (75-300 mg) for 12 weeks, followed by a 4-week follow-up period. The primary endpoint was change from baseline at Week 12 in Asthma Control Questionnaire (ACQ) symptom score.Mean ACQ change (SE) was -0.49 (0.09) in placebo (n = 74), and -0.43 (0.11), -0.58 (0.12), and -0.70 (0.09) in the AMG 317 75 mg (n = 73), 150 mg (n = 73), and 300 mg (n = 74) groups, respectively (treatment effect P = 0.25). No statistically significant differences were observed in the secondary endpoints. Numerical decreases in number of and time to exacerbations were noted in patients receiving AMG 317 150 mg and 300 mg. Preplanned analyses by tertile of baseline ACQ revealed that patients with higher baseline ACQ scores (>or=2.86) were more likely to respond to AMG 317. Serious adverse events were reported in three patients, each noted as not related to study drug.AMG 317 did not demonstrate clinical efficacy across the overall group of patients. Clinically significant improvements were observed in several outcome measures in patients with higher baseline ACQ scores. AMG 317 was safe and well tolerated in this study population. Clinical trial registered with www.clinicaltrials.gov (NCT 00436670).
An endogenous antigenic peptide bypasses the class I antigen presentation defect in RMA-S.
Authors: N A Hosken, M J Bevan
Journal: The Journal of Experimental Medicine (1992)

The RMA-S cell line was derived from the Raucher virus-induced murine cell line RBL-5 by ethylmethane sulfonate mutagenesis and anti-H-2 antibody plus complement selection (Ljunggren, H.-G., and K. Karre. 1985. J. Exp. Med. 162:1745). RMA-S is defective in the ability to present endogenously synthesized antigens to class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) (Townsend, A., C. Ohlen, J. Bastin, H.-G. Ljunggren, L. Foster, and K. Karre. 1989. Nature [Lond.]. 340:443; Ohlen, C., J. Bastin, H.-G. Ljunggren, L. Foster, E. Wolpert, G. Klein, A. R. M. Townsend, and K. Karre. 1990. J. Immunol. 145:52). This defect has been attributed to the inability of RMA-S to deliver antigenic peptides derived from antigens in the cytosol into the endoplasmic reticulum (ER), where they can associate with class I MHC molecules (Townsend, A., C. Ohlen, J. Bastin, H.-G. Ljunggren, L. Foster, and K. Karre. 1989. Nature [Lond.]. 340:443). We show that RMA-S can present at least one endogenous antigen, vesicular stomatitis virus nucleoprotein (VSV-N), to class I MHC-restricted CTL. RMA-S presents VSV-N to CTL both when infected with VSV or transfected with the VSV nucleoprotein gene. The natural antigenic VSV nucleoprotein peptides purified from either RMA or RMA-S are indistinguishable when analyzed by high performance liquid chromatography. We also show that the genetic defect responsible for the RMA-S phenotype maps to the murine chromosome 17. This chromosome encodes the murine class I MHC genes as well as two genes, HAM-1 and -2, with homology to the adenosine triphosphate-dependent transporter superfamily (Monaco, J. J., S. Cho, and M. Attaya. 1990. Science [Wash. DC]. 250:1723). These results suggest that the system that delivers antigenic peptides from the cytosol to the ER in RMA-S may still be present and retain partial function.
Epigenetic control of tissue-type plasminogen activator synthesis in human endothelial cells
Authors: S. Dunoyer-Geindre, E. K. O. Kruithof
Journal: Cardiovascular Research (2011)

Tissue-type plasminogen activator (t-PA) is produced by endothelial cells (EC) and is responsible for the removal of intravascular fibrin deposits. We investigated whether expression of t-PA by EC is under epigenetic control.Methylation analysis of the proximal t-PA promoter revealed a stretch of unmethylated CpG dinucleotides from position -121 to +59, while upstream CpG dinucleotides were all methylated. In contrast, in human primary hepatocytes, which express t-PA at much lower levels than EC, the proximal promoter was partially methylated. Treatment of EC with the non-specific histone deacetylase (HDAC) inhibitors butyrate and trichostatin and with MS275, a specific inhibitor of class I HDAC, resulted in a time- and dose-dependent increase in t-PA expression. Garcinol and anacardic acid, inhibitors of the histone acetyl transferases CBP/p300 and PCAF, reduced basal and HDAC inhibitor-induced t-PA expression, whereas curcumin, an inhibitor of CBP/p300 only, had no effect. We performed chromosome immunoprecipitation analysis of the t-PA promoter using antibodies specific for acetylated histone H3 or H4 and observed an increase in H3 acetylation of 10 ± 3 and 44 ± 14-fold in EC treated with trichostatin or MS275, respectively, and in H4 acetylation of 7.7 ± 1.4 and 16 ± 3-fold, respectively.The proximal t-PA promoter is unmethylated in human EC and partially methylated in human primary hepatocytes. Expression of t-PA by EC is repressed by HDACs in a mechanism that involves de-acetylation of histone H3 and H4.