tbuckley/cabot-search huggingface dataset:
Global Phylogeny Determined by the Combination of Protein Domains in Proteomes
Authors: Minglei Wang, Gustavo Caetano-Anollés
Journal: Molecular Biology and Evolution (2006)

The majority of proteins consist of multiple domains that are either repeated or combined in defined order. In this study, we survey the combination of protein domains defined at fold and fold superfamily levels in 185 genomes belonging to organisms that have been fully sequenced and introduce a method that reconstructs rooted phylogenomic trees from the content and arrangement of domains in proteins at a genomic level. We find that the majority of domain combinations were unique to Archaea, Bacteria, or Eukarya, suggesting most combinations originated after life had diversified. Domain repeat and domain repeat within multidomain proteins increased notably in eukaryotes, mainly at the expense of single-domain and domain-pair proteins. This increase was mostly confined to Metazoa. We also find an unbalanced sharing of domain combinations which suggests that Eukarya is more closely related to Bacteria than to Archaea, an observation that challenges the widely assumed eukaryote–archaebacterial sisterhood relationship. The occurrence and abundance of the molecular repertoire (interactome) of domain combinations was used to generate phylogenomic trees. These global interactome-based phylogenies described organismal histories satisfactorily, revealing the tripartite nature of life, and supporting controversial evolutionary patterns, such as the Coelomata hypothesis, the grouping of plants and animals, and the Gram-positive origin of bacteria. Results suggest strongly that the process of domain combination is not random but curved by evolution, rejecting the null hypothesis of domain modules combining in the absence of natural selection or an optimality criterion.
Exit of leucocytes across the alveolar epithelium worsens lung injury
Authors: J. C. Porter
Journal: Thorax (2011)

without a huge expansion of critical care beds that could not be justified without evidence of benefit to patients.It should be noted that most of the studies reported by Dr Challen failed to exclude patients with do not attempt resuscitation orders or with directives not to be admitted to the ICU.Therefore, these percentages and the pooled performance characteristics do not necessarily reflect their 'real life' clinical utility.Expanding on Dr Challen's statement that application of these tools 'should be with caution', we would suggest that severity scores should only be used to predict outcomes for which they have been validated and, as suggested by McGinn, 4 scoring systems should have their impact assessed in clinical studies before being applied to guide clinical decisions.
Aortic valve replacement in rheumatoid aortic incompetence.
Authors: A B Devlin, P Goldstraw, P K Caves
Journal: Thorax (1978)

Rheumatoid aortic valve disease is uncommon. and there are few reports of valve replacement in this condition. Aortic valve replacement and partial pericardiectomy was performed in a patient with acute rheumatoid aortitis and aortic incompetence. Previous reports suggest that any patient with rheumatoid arthritis who develops cardiac symptoms should be carefully assessed for surgically treatable involvement of the pericardium or heart valves.
A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors
Authors: Elena Gabriela Chiorean, Patricia LoRusso, Robert Matthew Strother, Jennifer R. Diamond, Anne Younger, Wells A. Messersmith, Lieve Adriaens, Liming Liu, Richard J. Kao, Albert Thomas DiCioccio, Ana Kostic, Russell Leek, Adrian Harris, Antonio Jimeno
Journal: Clinical Cancer Research (2015)

Enoticumab (REGN421) is a fully human IgG1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab. Enoticumab was administered intravenously, with dose escalations from 0.25 to 4 mg/kg every 3 weeks (Q3W) and 0.75 to 3 mg/kg every 2 weeks (Q2W). Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5 mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). An MTD was not reached on either schedule. The most frequent adverse events (AE) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: brain natriuretic peptide (BNP) increase (0.25 mg/kg Q3W, Gr1), troponin I increase (4 mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5 mg/kg Q2W, both Gr3), and left ventricular dysfunction and pulmonary hypertension (3 mg/kg Q2W, both Gr3). Enoticumab was characterized by nonlinear, target-mediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included two partial responses (non-small cell lung cancer bronchoalveolar-type with a β-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3> 6 months). Enoticumab was tolerated, with RP2D of 4 mg/kg Q3W and 3 mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors. Clin Cancer Res; 21(12); 2695-703. ©2015 AACR.
Role of NAD(P)H:quinone oxidoreductase 1 on tumor necrosis factor-α-induced migration of human vascular smooth muscle cells
Authors: S LEE, Y CHANG, K WHANG, C KIM, I LEE
Journal: Cardiovascular Research (2007)

Objectives In a preliminary study, NAD(P)H:quinone oxidoreductase 1 (NQO1) was found to be highly expressed in cultured human aortic smooth muscle cells (HASMC) and dicumarol, a NQO1 inhibitor and a coumarin-derived natural anticoagulant, suppressed tumor necrosis factor (TNF)-α-induced HASMC migration. Therefore, it was hypothesized that NQO1 plays an important role in the regulation of vascular smooth muscle cells (VSMC) migration activated by TNF-α. Methods and results Gelatin zymography, reporter gene, electrophoretic mobility shift and Western blotting assays showed that dicumarol, but not other coumarin-derived anticoagulants, inhibited TNF-α-induced HASMC migration and suppressed TNF-α-induced matrix metalloproteinase (MMP)-9 expression and secretion in a dose-dependent manner. In addition, down-regulation of NQO1 by transfection of its small interfering RNA similarly inhibited TNF-α-induced MMP-9 secretion, indicating that dicumarol-mediated inhibition of MMP-9 expression is due in large part to inhibition of NQO1. Down-regulation of NQO1 inhibits MMP-9 gene expression by suppressing activation of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), well-known key elements mediating MMP-9 gene expression in its promoter, via the p38 MAPK and JNK pathways. Conclusion The results of the present study demonstrate that down-regulation of NQO1 effectively suppresses TNF-α-induced HASMC migration through inhibition of MMP-9 expression, suggesting that NQO1 may be a potential target for the prevention of vascular disorders related to migration of VSMC.
Forecasting Unanticipated Consequences of “The Sunshine Act”: Mostly Cloudy
Authors: Mark J. Ratain
Journal: Journal of Clinical Oncology (2014)

On September 6, 2007, Senator Chuck Grassley (R-Iowa) and five bipartisan cosponsors introduced the Physician Payment Sunshine Act (S. 2029)1 in the wake of public concerns regarding conflict of interest of practicing physicians. Although the Grassley bill was never passed, its fundamental concept was incorporated into Section 6002 of the Patient Protection and Affordable Care Act (ACA), which was signed into law by President Barack Obama on March 22, 2010.2 This section of the ACA is commonly referred to as “The Sunshine Act,” which was subsequently implemented by the Centers for Medicare & Medicaid Services (CMS) through its Final Rule, as published on February 8, 2013, in the Federal Register.3
Evidence for Recent Population Expansion in the Evolutionary History of the Malaria Vectors Anopheles arabiensis and Anopheles gambiae
Authors: Martin J. Donnelly, Monica C. Licht, Tovi Lehmann
Journal: Molecular Biology and Evolution (2001)

Gene flow in malaria vectors is usually estimated based on differentiation indices (e.g., FST) in order to predict the contemporary spread of genes such as those conferring resistance to insecticides. This approach is reliant on a number of assumptions, the most crucial, and the one most likely to be violated in these species, being mutation-migration-drift equilibrium. Tests of this assumption for the African malaria vectors Anopheles gambiae and Anopheles arabiensis are the focus of this study. We analyzed variation at 18 microsatellite loci and the ND5 region of the mitochondrial genome in two populations of each species. Equilibrium was rejected by six of eight tests for the A. gambiae population from western Kenya and by three tests in eastern Kenya. In western Kenya, all departures from equilibrium were consistent with a recent population expansion, but in eastern Kenya, there were traces of a recent expansion and a bottleneck. Equilibrium was also rejected by two of the eight tests for both A. arabiensis populations; the departure from equilibrium was consistent with an expansion. These multiple-locus tests detected a genomewide effect and therefore a demographic event rather than a locus-specific effect, as would be caused by selection. Disequilibrium due to a recent expansion in these species implies that rates of gene flow, as inferred from differentiation indices, are overestimates as they include a historical component. We argue that the same effect applies to the majority of pest species due to the correlation of their demography with that of humans.
Novel therapeutic agents for cutaneous T-Cell lymphoma
Authors: Salvia Jain, Jasmine Zain, Owen O’Connor
Journal: Journal of Hematology & Oncology (2012)

Abstract Mycosis fungoides (MF) and Sezary Syndrome (SS) represent the most common subtypes of primary Cutaneous T-cell lymphoma (CTCL). Patients with advanced MF and SS have a poor prognosis leading to an interest in the development of new therapies with targeted mechanisms of action and acceptable safety profiles. In this review we focus on such novel strategies that have changed the treatment paradigm of this rare malignancy.
FORMATION OF C3a AND C5a ANAPHYLATOXINS IN WHOLE HUMAN SERUM AFTER INHIBITION OF THE ANAPHYLATOXIN INACTIVATOR
Authors: Enrique H. Vallota, Hans J. Müller-Eberhard
Journal: The Journal of Experimental Medicine (1973)

Two biologically and chemically distinct anaphylatoxins (ATs) could be generated in whole human serum after removal of the AT inactivator (AI) by immune-absorption or after inhibition of AI with 1 M epsilon-aminocaproic acid (EACA). Both human ATs could be generated by treatment of serum with antigen-antibody complexes, which activate the classical complement pathway, and with inulin or yeast, both of which trigger the alternate pathway. The ATs were isolated from serum in active form and characterized as C3a and C5a. Although human C3a had been characterized previously, C5a had not. The molecular weight of human C5a AT was 17,500; its electrophoretic mobility at pH 8.5 was –1.7 x 10–5 cm2 V–1 s–1. The minimal effective concentration in vitro was 7.5 x 10–10 M. The minimal effective doses of human C5a in producing a wheal and erythema in the human skin was 1 x 10–15 mol. The results strongly suggest a biological function for both ATs and indicate that the expression of their activity is controlled by the AI of normal blood plasma.
Non-invasive assessment of pulmonary blood flow using an inert gas rebreathing device in fibrotic lung disease
Authors: T. J Corte, A. U Wells, M. A Gatzoulis, D. Cramer, S. Ward, P. S Macdonald, K. Dimopoulos, S. J Wort
Journal: Thorax (2010)

<h3>Background and aims</h3> Pulmonary hypertension (PH) is increasingly recognised in patients with diffuse lung disease, and is associated with increased mortality. Cardiac output (CO) is a prognostic marker in PH. Non-invasive assessment of pulmonary blood flow (PBF<sub>INNOCOR</sub>) with the inert gas rebreathing Innocor device has been validated against CO in PH, but not in PH associated with parenchymal lung disease. PBF<sub>INNOCOR</sub> may be less accurate in patients with lung disease because of intrapulmonary shunting and/or incomplete gas mixing. Our aim was to determine the variability of PBF<sub>INNOCOR</sub> in normal subjects, before evaluating PBF<sub>INNOCOR</sub> in diffuse lung disease against CO measured by the indirect Fick method (CO<sub>FICK</sub>) at right heart catheterisation (RHC). <h3>Methods and results</h3> 23 normal subjects had lung volume measurements by a constant-volume body plethysmograph and three consecutive PBF<sub>INNOCOR</sub> measurements on the same day. 20 subjects returned for repeat assessment. PBF<sub>INNOCOR</sub> had good intrasession repeatability (coefficient of variation (CV)=6.57%) and intersession reproducibility (mean CO difference=0.13; single determinant SD=0.49; CV=9.7%). 28 consecutive patients with lung fibrosis referred for RHC had PBF<sub>INNOCOR</sub> measured within 24 h of RHC. There was good agreement between CO<sub>FICK</sub> and PBF<sub>INNOCOR</sub>, with no evidence of systematic bias (mean CO<sub>FICK</sub> 4.3±1.0; PBF<sub>INNOCOR</sub> 4.0±1.2l/ min; p=0.07). Bland–Altman analysis revealed a mean difference of −0.32 and limits of agreement of −2.10 to +1.45. <h3>Conclusion</h3> Non-invasive PBF measured by the inert gas rebreathing Innocor device has good intrasession repeatability and intersession reproducibility. In diffuse lung disease, CO can be accurately and non-invasively measured by the Innocor device.
Characteristic bimodal profiles of RNA polymerase II at thousands of active mammalian promoters
Authors: Mathieu Quinodoz, Cédric Gobet, Felix Naef, Kyle B Gustafson
Journal: Genome biology (2014)

In mammals, ChIP-seq studies of RNA polymerase II (PolII) occupancy have been performed to reveal how recruitment, initiation and pausing of PolII may control transcription rates, but the focus is rarely on obtaining finely resolved profiles that can portray the progression of PolII through sequential promoter states.Here, we analyze PolII binding profiles from high-coverage ChIP-seq on promoters of actively transcribed genes in mouse and humans. We show that the enrichment of PolII near transcription start sites exhibits a stereotypical bimodal structure, with one peak near active transcription start sites and a second peak 110 base pairs downstream from the first. Using an empirical model that reliably quantifies the spatial PolII signal, gene by gene, we show that the first PolII peak allows for refined positioning of transcription start sites, which is corroborated by mRNA sequencing. This bimodal signature is found both in mouse and humans. Analysis of the pausing-related factors NELF and DSIF suggests that the downstream peak reflects widespread pausing at the +1 nucleosome barrier. Several features of the bimodal pattern are correlated with sequence features such as CpG content and TATA boxes, as well as the histone mark H3K4me3.We thus show how high coverage DNA sequencing experiments can reveal as-yet unnoticed bimodal spatial features of PolII accumulation that are frequent at individual mammalian genes and reminiscent of transcription initiation and pausing. The initiation-pausing hypothesis is corroborated by evidence from run-on sequencing and immunoprecipitation in other cell types and species.
Dihydropyridine Ca <sup>2+</sup> Channel Blockers Increase Cytosolic [Ca <sup>2+</sup> ] by Activating Ca <sup>2+</sup> -sensing Receptors in Pulmonary Arterial Smooth Muscle Cells
Authors: Aya Yamamura, Hisao Yamamura, Qiang Guo, Adriana M. Zimnicka, Jun Wan, Eun A. Ko, Kimberly A. Smith, Nicole M. Pohl, Shanshan Song, Amy Zeifman, Ayako Makino, Jason X.-J. Yuan
Journal: Circulation Research (2013)

Rationale: An increase in cytosolic free Ca 2+ concentration ([Ca 2+ ] cyt ) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation and pulmonary vascular remodeling. The dihydropyridine Ca 2+ channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca 2+ -sensing receptor (CaSR) was upregulated and the extracellular Ca 2+ -induced increase in [Ca 2+ ] cyt was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca 2+ ] cyt by activating CaSR in PASMC from IPAH patients (in which CaSR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca 2+ ] cyt in IPAH-PASMC was concentration dependent with a half maximal effective concentration of 0.20 µmol/L. Knockdown of CaSR with siRNA in IPAH-PASMC significantly inhibited the nifedipine-induced increase in [Ca 2+ ] cyt , whereas overexpression of CaSR in normal PASMC conferred the nifedipine-induced rise in [Ca 2+ ] cyt . Other dihydropyridines, nicardipine and Bay K8644, had similar augmenting effects on the CaSR-mediated increase in [Ca 2+ ] cyt in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca 2+ ] cyt . Conclusions: The dihydropyridine derivatives increase [Ca 2+ ] cyt by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca 2+ channels; therefore, it is possible that the use of dihydropyridine Ca 2+ channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.
Evolution in surgical approach and techniques for lung cancer
Authors: Calvin S H Ng, Kelvin K W Lau, Diego Gonzalez-Rivas, Gaetano Rocco
Journal: Thorax (2013)

To improve is to change; to be perfect is to change often. Sir Winston Churchill (1874–1965)

We thoroughly enjoyed reading the succinct review article by Vallieres et al 1 on therapeutic advances in non-small cell lung cancer. The authors pointed out that improvements in chest imaging and use of CT for diagnostic workup and screening have led to many more small tumours, and suspicious nodules being identified. In our practice, this has increasingly changed our management and surgical approach. For example, …
Growth Hormone Increases Inducible Nitric Oxide Synthase Expression in Mesangial Cells
Authors: SONIA Q. DOI, TERRY A. JACOT, DONALD F. SELLITTI, PRZEMYSLAW HIRSZEL, MARIO H. HIRATA, GARY E. STRIKER, LILIANE J. STRIKER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Mice transgenic for bovine growth hormone (GH) develop progressive glomerulosclerosis. However, the proximal signaling events that lead to increased matrix deposition in this pathologic condition are still unclear. Components of the L-arginine metabolic pathway, especially inducible nitric oxide (NO) synthase (iNOS), ornithine aminotransferase (OAT), and ornithine decarboxylase (ODC), have been associated with glomerular scarring. In this study, mesangial cells were treated with GH, and the expression of iNOS, ODC, and OAT was determined using reverse transcription-PCR. In addition, nitrite accumulation in the conditioned media of mesangial cell cultures was measured in the presence or absence of GH. The findings revealed that GH increased iNOS transcript levels in a dose-dependent manner, with the highest levels being attained at GH concentrations of 20 to 50 ng/ml. The GH-induced increase in iNOS transcript levels was accompanied by a significant increase in nitrite concentrations in conditioned media, which was blocked by the addition of L- N G -monomethylarginine. The effect of GH (50 ng/ml) in eliciting nitrite production was as potent as that of bacterial lipopolysaccharide (10 μg/ml). The expression of OAT and ODC, in contrast, was not altered at any of the GH concentrations tested. GH receptor mRNA was also expressed by mesangial cells, independently of the GH concentration present in the cell culture medium. These data indicate that GH may interact with its receptor to regulate the L-arginine/NO pathway in mesangial cells, by directly modulating iNOS expression and NO production, without altering the arginase/OAT/ODC pathway.
Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome
Authors: Dan Hu, Hector Barajas-Martínez, Ryan Pfeiffer, Fabio Dezi, Jenna Pfeiffer, Tapan Buch, Matthew J. Betzenhauser, Luiz Belardinelli, Kristopher M. Kahlig, Sridharan Rajamani, Harry J. DeAntonio, Robert J. Myerburg, Hiroyuki Ito, Pramod Deshmukh, Mark Marieb, Gi-Byoung Nam, Atul Bhatia, Can Hasdemir, Michel Haïssaguerre, Christian Veltmann, Rainer Schimpf, Martin Borggrefe, Sami Viskin, Charles Antzelevitch
Journal: Journal of the American College of Cardiology (2014)
The ultrastructural changes in the skin in dermatitis herpetiformis after withdrawal of dapsone
Authors: D.J. RICHES, B.G.H. MARTIN, P.P. SEAH, LIONEL FRY
Journal: British Journal of Dermatology (1976)

The development of skin lesions in patients with dermatitis herpetiformis after the withdrawal of their dapsone therapy was studied with the electron microscope. In control biopsies from patients prior to cessation of treatment, membrane-bound vacuoles were found beneath the basal lamina of the epidermis as previously described. After dapsone withdrawal, there was an apparent increase in the number of vacuoles and occasionally several vacuoles appeared to have coalesced forming an early blister. At this stage, the basal lamina and associated hemidesmosomes were normal although in places there were small discontinuities in the basal lamina. Where the reaction was more intense, vacuoles and cells, mainly eosinophils, were embedded in fibrin de posits. Above this, the basal lamina was usually disrupted with involvement of the basal epidermal cells. These results suggest that the vacuoles do play a part in the formation of the pathological lesion in dermatitis herpetiformis. In addition, the basal lamina is shown to be only secondarily involved. The nature of the vacuoles has still to be elucidated.