tbuckley/cabot-search huggingface dataset:
Phase I Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors
Authors: Roy S. Herbst, Kenneth R. Hess, Hai T. Tran, Jennifer E. Tseng, Nizar A. Mullani, Chusilp Charnsangavej, Timothy Madden, Darren W. Davis, David J. McConkey, Michael S. O’Reilly, Lee M. Ellis, James Pluda, Waun K. Hong, James L. Abbruzzese
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors. PATIENTS AND METHODS: Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m 2 /d, and seven patients were treated at 300 mg/m 2 /d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers. RESULTS: Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 ± 4.1 hours. A dose of 300 mg/m 2 achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endo’s activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed. CONCLUSION: rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated.
Livedo reticularis caused by cholesterol embolization may improve with simvastatin
Authors: T.M. Finch, K.S. Ryatt
Journal: British Journal of Dermatology (2000)

Journal Article Livedo reticularis caused by cholesterol embolization may improve with simvastatin Get access T.M. Finch, T.M. Finch Birmingham Skin Centre, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH, U.K. Correspondence: Dr Tracey Finch, Heartlands and Solihull NHS Trust, Lode Lane, Solihull B91 2JL, U.K. Search for other works by this author on: Oxford Academic Google Scholar K.S. Ryatt K.S. Ryatt Birmingham Skin Centre, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH, U.K. Correspondence: Dr Tracey Finch, Heartlands and Solihull NHS Trust, Lode Lane, Solihull B91 2JL, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 143, Issue 6, 1 December 2000, Pages 1319–1320, https://doi.org/10.1046/j.1365-2133.2000.03910.x Published: 01 December 2000
Inhibition of Repair of Radiation-Induced DNA Damage Enhances Gene Expression from Replication-Defective Adenoviral Vectors
Authors: Mohan Hingorani, Christine L. White, Andrew Merron, Inge Peerlinck, Martin E. Gore, Andrew Slade, Simon D. Scott, Christopher M. Nutting, Hardev S. Pandha, Alan A. Melcher, Richard G. Vile, Georges Vassaux, Kevin J. Harrington
Journal: Cancer Research (2008)

Radiation has been shown to up-regulate gene expression from adenoviral vectors in previous studies. In the current study, we show that radiation-induced dsDNA breaks and subsequent signaling through the mitogen-activated protein kinase (MAPK) pathway are responsible, at least in part, for this enhancement of transgene expression both in vitro and in vivo. Inhibitors of ataxia-telangiectasia-mutated, poly(ADP-ribose) polymerase-mutated, and DNA-dependent protein kinase (DNA-PK)-mediated DNA repair were shown to maintain dsDNA breaks (gammaH2AX foci) by fluorescence-activated cell sorting and microscopy. Inhibition of DNA repair was associated with increased green fluorescent protein (GFP) expression from a replication-defective adenoviral vector (Ad-CMV-GFP). Radiation-induced up-regulation of gene expression was abrogated by inhibitors of MAPK (PD980059 and U0126) and phosphatidylinositol 3-kinase (LY294002) but not by p38 MAPK inhibition. A reporter plasmid assay in which GFP was under the transcriptional control of artificial Egr-1 or cytomegalovirus promoters showed that the DNA repair inhibitors increased GFP expression only in the context of the Egr-1 promoter. In vivo administration of a water-soluble DNA-PK inhibitor (KU0060648) was shown to maintain luciferase expression in HCT116 xenografts after intratumoral delivery of Ad-RSV-Luc. These data have important implications for therapeutic strategies involving multimodality use of radiation, targeted drugs, and adenoviral gene delivery and provide a framework for evaluating potential advantageous combinatorial effects.
Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits
Authors: Daniel Wong, Ana Teixeira, Spyros Oikonomopoulos, Peter Humburg, Imtiaz Nisar Lone, David Saliba, Trevor Siggers, Martha Bulyk, Dimitar Angelov, Stefan Dimitrov, Irina A Udalova, Jiannis Ragoussis
Journal: Genome biology (2011)

Genetic studies have provided ample evidence of the influence of non-coding DNA polymorphisms on trait variance, particularly those occurring within transcription factor binding sites. Protein binding microarrays and other platforms that can map these sites with great precision have enhanced our understanding of how a single nucleotide polymorphism can alter binding potential within an in vitro setting, allowing for greater predictive capability of its effect on a transcription factor binding site.We have used protein binding microarrays and electrophoretic mobility shift assay-sequencing (EMSA-Seq), a deep sequencing based method we developed to analyze nine distinct human NF-κB dimers. This family of transcription factors is one of the most extensively studied, but our understanding of its DNA binding preferences has been limited to the originally described consensus motif, GGRRNNYYCC. We highlight differences between NF-κB family members and also put under the spotlight non-canonical motifs that have so far received little attention. We utilize our data to interpret the binding of transcription factors between individuals across 1,405 genomic regions laden with single nucleotide polymorphisms. We also associated binding correlations made using our data with risk alleles of disease and demonstrate its utility as a tool for functional studies of single nucleotide polymorphisms in regulatory regions.NF-κB dimers bind specifically to non-canonical motifs and these can be found within genomic regions in which a canonical motif is not evident. Binding affinity data generated with these different motifs can be used in conjunction with data from chromatin immunoprecipitation-sequencing (ChIP-Seq) to enable allele-specific analyses of expression and transcription factor-DNA interactions on a genome-wide scale.
Cardiovascular Risk, Myocardial Injury, and Exacerbations of Chronic Obstructive Pulmonary Disease
Authors: Anant R. C. Patel, Beverly S. Kowlessar, Gavin C. Donaldson, Alex J. Mackay, Richa Singh, Siobhan N. George, Davinder S. Garcha, Jadwiga A. Wedzicha, John R. Hurst
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Rationale: Patients with chronic obstructive pulmonary disease (COPD) have elevated cardiovascular risk, and myocardial injury is common during severe exacerbations. Little is known about the prevalence, magnitude, and underlying mechanisms of cardiovascular risk in community-treated exacerbations.Objectives: To investigate how COPD exacerbations and exacerbation frequency impact cardiovascular risk and myocardial injury, and whether this is related to airway infection and inflammation.Methods: We prospectively measured arterial stiffness (aortic pulse wave velocity [aPWV]) and cardiac biomarkers in 98 patients with stable COPD. Fifty-five patients had paired stable and exacerbation assessments, repeated at Days 3, 7, 14, and 35 during recovery. Airway infection was identified using polymerase chain reaction.Measurements and Main Results: COPD exacerbation frequency was related to stable-state arterial stiffness (rho = 0.209; P = 0.040). Frequent exacerbators had greater aPWV than infrequent exacerbators (mean ± SD aPWV, 11.4 ± 2.1 vs. 10.3 ± 2.0 ms−1; P = 0.025). Arterial stiffness rose by an average of 1.2 ms−1 (11.1%) from stable state to exacerbation (n = 55) and fell slowly during recovery. In those with airway infection at exacerbation (n = 24) this rise was greater (1.4 ± 1.6 vs. 0.7 ± 1.3 ms−1; P = 0.048); prolonged; and related to sputum IL-6 (rho = 0.753; P < 0.001). Increases in cardiac biomarkers at exacerbation were higher in those with ischemic heart disease (n = 12) than those without (n = 43) (mean ± SD increase in troponin T, 0.011 ± 0.009 vs. 0.003 ± 0.006 μg/L, P = 0.003; N-terminal pro–brain natriuretic peptide, 38.1 ± 37.7 vs. 5.9 ± 12.3 pg/ml, P < 0.001).Conclusions: Frequent COPD exacerbators have greater arterial stiffness than infrequent exacerbators. Arterial stiffness rises acutely during COPD exacerbations, particularly with airway infection. Increases in arterial stiffness are related to inflammation, and are slow to recover. Myocardial injury is common and clinically significant during COPD exacerbations, particularly in those with underlying ischemic heart disease.
VEGF-C and aortic cardiomyocytes guide coronary artery stem development
Authors: Heidi I. Chen, Aruna Poduri, Harri Numi, Riikka Kivela, Pipsa Saharinen, Andrew S. McKay, Brian Raftrey, Jared Churko, Xueying Tian, Bin Zhou, Joseph C. Wu, Kari Alitalo, Kristy Red-Horse
Journal: Journal of Clinical Investigation (2014)

Coronary arteries (CAs) stem from the aorta at 2 highly stereotyped locations, deviations from which can cause myocardial ischemia and death. CA stems form during embryogenesis when peritruncal blood vessels encircle the cardiac outflow tract and invade the aorta, but the underlying patterning mechanisms are poorly understood. Here, using murine models, we demonstrated that VEGF-C-deficient hearts have severely hypoplastic peritruncal vessels, resulting in delayed and abnormally positioned CA stems. We observed that VEGF-C is widely expressed in the outflow tract, while cardiomyocytes develop specifically within the aorta at stem sites where they surround maturing CAs in both mouse and human hearts. Mice heterozygous for islet 1 (Isl1) exhibited decreased aortic cardiomyocytes and abnormally low CA stems. In hearts with outflow tract rotation defects, misplaced stems were associated with shifted aortic cardiomyocytes, and myocardium induced ectopic connections with the pulmonary artery in culture. These data support a model in which CA stem development first requires VEGF-C to stimulate vessel growth around the outflow tract. Then, aortic cardiomyocytes facilitate interactions between peritruncal vessels and the aorta. Derangement of either step can lead to mispatterned CA stems. Studying this niche for cardiomyocyte development, and its relationship with CAs, has the potential to identify methods for stimulating vascular regrowth as a treatment for cardiovascular disease.
Mapping the future for pulmonary fibrosis: report from the 17th International Colloquium on Lung and Airway Fibrosis
Authors: Luca Richeldi, Harold R. Collard, Roland M. du Bois, Gisli Jenkins, Martin Kolb, Toby M. Maher, Ganesh Raghu, Carlo Vancheri, Geoffrey J. Laurent
Journal: European Respiratory Journal (2013)

Pulmonary fibrosis is the ultimate outcome of various interstitial lung diseases, many of which have a dismal prognosis. Pulmonary fibrosis, therefore, represents a critical unmet medical need. Progress in research over the past 30 years has been encouraging. This work, which has been funded by governments, charitable trusts, industries and patient groups, has resulted in clinical trials testing novel drugs, giving hope to patients. In late September 2012, representatives from academia, industry and funding agencies met at the 17th International Colloquium on Airway and Lung Fibrosis to discuss state-of-the-art knowledge of pulmonary fibrosis. This manuscript summarises the outcomes of the meeting, highlighting the most relevant results and discoveries. It also attempts to provide a roadmap for future studies. It is hoped that such a roadmap may help interested parties to generate new research, which will be vital to continued progress. We are encouraged by the commitment expressed by all participants at this meeting and the shared vision of promoting future progress through international collaboration, the pooling of valuable resources, and the involvement of a new generation of physicians and scientists.
Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis.
Authors: B S Nepom, J Palmer, S J Kim, J A Hansen, S L Holbeck, G T Nepom
Journal: The Journal of Experimental Medicine (1986)

HLA-DR4, Dw4-associated haplotypes associated with IDDM and JRA were compared using genomic DNA restriction fragment analysis to distinguish among DQ beta and alpha alleles linked to DR4. DQ beta polymorphisms that subdivide the HLA-DQw3 specificity into DQ3.1 and 3.2 alleles were identified. More than 90% of DR4+ IDDM patients express one of these alleles, DQ3.2; restriction enzyme mapping indicates that the presence of this allele also accounts for the genomic fragment patterns previously reported in IDDM. Furthermore, haplo-identical siblings of DQ3.2 IDDM patients also carry the DQ3.2 allele, regardless of clinical presentation. In contrast, DR4+ JRA patients show no allelic preference at DQ beta, implicating different HLA genetic contributions in these two DR4-associated diseases.
Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation
Authors: K. Venuprasad
Journal: Journal of Clinical Investigation (2006)

The immune system is capable of mounting robust responses against invading pathogens but refrains from attacking self. Many studies have focused on tolerance induction of Th1 cells, whose failure results in development of autoimmune diseases. However, the molecular mechanisms governing tolerance induction in Th2 cells and its relation to allergic responses remain unclear. Here we used both in vivo and in vitro protocols to demonstrate that Th2 cells either containing a mitogen and extracellular kinase kinase 1 (MEKK1) mutant or lacking JNK1 or the E3 ubiquitin ligase Itch cannot be tolerized. In a mouse allergic model, injection of high-dose tolerizing antigen failed to block the development of airway inflammation in Itch-/- mice. This study suggests that MEKK1-JNK signaling regulates Itch E3 ligase-mediated tolerogenic process in Th2 cells. These findings have therapeutic implications for allergic diseases.
Targeting Vascular Endothelial Growth Factor in Advanced Carcinoid Tumor: A Random Assignment Phase II Study of Depot Octreotide With Bevacizumab and Pegylated Interferon Alfa-2b
Authors: James C. Yao, Alexandria Phan, Paulo M. Hoff, Helen X. Chen, Chusilp Charnsangavej, Sai-Ching J. Yeung, Kenneth Hess, Chaan Ng, James L. Abbruzzese, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2008)

Purpose Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alfa-2b was evaluated among patients with metastatic or unresectable carcinoid tumors. Patients and Methods Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alfa-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow. Results In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P &lt; .01) and 28% (P &lt; .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alfa-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P &lt; .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed. Conclusion Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment.
Clinical judgement of airway inflammation versus sputum cell counts in patients with asthma
Authors: K. Parameswaran, E. Pizzichini, M.M. Pizzichini, P. Hussack, A. Efthimiadis, F.E. Hargreave
Journal: European Respiratory Journal (2000)

The inflammatory component of asthma is usually assessed indirectly by symptoms and spirometry, these may be inaccurate. It can now be assessed directly and reliably by the examination of sputum cell counts. There is no information on how clinical assessment of the presence and type of airway inflammation compares with actual measurements. In this single-centre observational study, sputum was collected from 76 consecutive adults with asthma attending a tertiary chest clinic after their physicians had recorded the expected cell counts in sputum. The authors examined the extent of agreement between clinical judgement of sputum cell counts and actual counts in asthmatic patients (Cohen9s Kappa) and the possible predictors of agreement (multiple logistic regression). Sixty-seven of the 76 sputum samples were suitable for analysis. Agreement between expected and actual cell counts occurred in 30/67 patients. The overall agreement for the different cell types was poor (estimated K=0.14, 95% confidence interval (CI)=0.02, 0.26). The experience of the physician in using sputum cell counts in clinical practice, steroid requirement at the time of assessment, and control of asthma as assessed by the physician or by the patient could not predict the chances of agreement or disagreement. Unaware of the sputum results, the physicians often changed treatment in a way that seemed inappropriate for the cell counts present. There is poor agreement between clinical judgement of the presence and type of airway inflammation in asthmatic patients and sputum cell counts. The impact of sputum examination on the outcomes of anti-inflammatory treatment now needs investigation.
American Society of Clinical Oncology Clinical Practice Guideline for the Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer
Authors: David G. Pfister, Scott A. Laurie, Gregory S. Weinstein, William M. Mendenhall, David J. Adelstein, K. Kian Ang, Gary L. Clayman, Susan G. Fisher, Arlene A. Forastiere, Louis B. Harrison, Jean-Louis Lefebvre, Nancy Leupold, Marcy A. List, Bernard O. O'Malley, Snehal Patel, Marshall R. Posner, Michael A. Schwartz, Gregory T. Wolf
Journal: Journal of Clinical Oncology (2006)

To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials.A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors.Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated.All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.
Modifications of the Aortic and Vagal Depressor Reflexes by Hypercapnia in the Rabbit
Authors: NORBERT T. OTT, JOHN T. SHEPHERD
Journal: Circulation Research (1973)

Changes in muscle and renal vascular resistances when the traffic in aortic or vagal nerves was interrupted were compared during normocapnia and hypercapnia in rabbits. The rabbits were anesthetized with sodium pentobarbital, paralyzed, and artificially ventilated; the sinus nerves were cut. A hind limb and a kidney were perfused at constant flow with autologous blood. With the vagi cut or cooled, blocking the aortic nerves by cooling caused a 49% and a 28% increase in limb and kidney perfusion pressures, respectively, during normocapnia (end-tidal CO 2 3-4%) and a 56% and a 69% increase during hypercapnia (end-tidal CO 2 8-10%). With the aortic nerves cut or cooled, vagal cold block increased the limb and kidney perfusion pressures 10% and 15%, respectively, during normocapnia and 17% and 61%, respectively, during hypercapnia. These responses were attenuated, especially in the kidney, when one of these pairs of nerves was intact (aortic nerve or vagus) and the other pair was blocked. Thus, hypercapnia augmented the vasodepressor reflexes from the aortic arch and the cardiopulmonary area. The effects of this phenomenon were greater on the renal vascular bed than they were on the muscle vascular bed.