406 research outputs found
Inflammation and endothelial function: Direct vascular effects of human C-reactive protein on nitric oxide bioavailability
No full textBackground - Circulating concentrations of the sensitive inflammatory marker C-reactive protein (CRP) predict future cardiovascular events, and CRP is elevated during sepsis and inflammation, when vascular reactivity may be modulated. We therefore investigated the direct effect of CRP on vascular reactivity. Methods and Results - The effects of isolated, pure human CRP on vasoreactivity and protein expression were studied in vascular rings and cells in vitro, and effects on blood pressure were studied in rats in vivo. The temporal relationship between changes in CRP concentration and brachial flow-mediated dilation was also studied in humans after vaccination with Salmonella typhi capsular polysaccharide, a model of inflammatory endothelial dysfunction. In contrast to some previous reports, highly purified and well-characterized human CRP specifically induced hyporeactivity to phenylephrine in rings of human internal mammary artery and rat aorta that was mediated through physiological antagonism by nitric oxide (NO). CRP did not alter endothelial NO synthase protein expression but increased protein expression of GTP cyclohydrolase-1, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the NO synthase cofactor. In the vaccine model of inflammatory endothelial dysfunction in humans, increased CRP concentration coincided with the resolution rather than the development of endothelial dysfunction, consistent with the vitro findings; however, administration of human CRP to rats had no effect on blood pressure. Conclusions - Pure human CRP has specific, direct effects on vascular function in vitro via increased NO production; however, further clarification of the effect, if any, of CRP on vascular reactivity in humans in vivo will require clinical studies using specific inhibitors of CRP. © 2005 American Heart Association, Inc
Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma : Three-year Follow-up of CASTOR
No full textBackground: In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed.
Patients and methods: Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m2) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression.
Results: Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)-negativity rates (10-5) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed.
Conclusion: After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates
Satellite-based delivery of educational content to geographically isolated communities: A service based approach
No full textEnabling learning for members of geographically
isolated communities presents benefits in terms of
promoting regional development and cost savings for governments and companies. However, notwithstanding recent advances in e-Learning, from both technological and pedagogical perspectives, there are very few, if any,
recognised methodologies for user-led design of satellite-based e-learning infrastructures. In this paper, we present a methodology for designing a satellite and wireless based network infrastructure and learning services to support distance learning for such isolated communities. This methodology entails (a) the involvement of community members in the development of targeted learning services from an early stage, and (b) a service-oriented approach to learning solution deployment. Results show, that, while the technological premises of distance learning can be
accommodated by hybrid satellite/wireless infrastructures,this has to be complemented with (a) high-quality audio–visual educational material, and (b) the opportunity for community members to interact with other community
members either as groups (common-room oriented scenarios) or individuals (home-based scenarios), thus providing an impetus for learner engagement in both formal and informal activities
Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide
No full textBackground: Ischemia/reperfusion (I/R) injury complicates myocardial infarction and stroke by exacerbating tissue damage and increasing risk of mortality. We have recently identified C-type natriuretic peptide (CNP) as an endothelium-derived hyperpolarizing factor in the mesenteric resistance vasculature and described a novel signaling pathway involving activation of natriuretic peptide receptor C (NPR-C), which plays a pivotal role in the regulation of local blood flow. We tested the hypothesis that CNP/NPR-C signaling is a novel regulatory pathway governing coronary blood flow and protecting against I/R injury.
Methods and Results: CNP and (Cys18)-atrial natriuretic factor (4-23) amide (cANF4–23) elicited dose-dependent decreases in coronary perfusion pressure (CPP) that were blocked by Ba2+ and ouabain in the isolated Langendorff rat heart. The endothelium-dependent vasodilator acetylcholine elicited the release of CNP from the coronary endothelium. CNP and cANF4–23 reduced infarct size after 25 minutes of global ischemia and 120 minutes of reperfusion, maintaining CPP and left ventricular pressure at preischemic values. The vasorelaxant and protective activity of CNP and cANF4–23 were enhanced in the absence of endothelium-derived nitric oxide.
Conclusion: Endothelium-derived CNP is involved in the regulation of the coronary circulation, and NPR-C activation underlies the vasorelaxant activity of this peptide. Moreover, this newly defined pathway represents a protective mechanism against I/R injury and a novel target for therapeutic intervention in ischemic cardiovascular disorders
Childhood asthma and environmental exposures at swimming pools: state of the science and research recommendations.
No full textOBJECTIVES: Recent studies have explored the potential for swimming pool disinfection by-products (DBPs), which are respiratory irritants, to cause asthma in young children. Here we describe the state of the science on methods for understanding children's exposure to DBPs and biologics at swimming pools and associations with new-onset childhood asthma and recommend a research agenda to improve our understanding of this issue. DATA SOURCES: A workshop was held in Leuven, Belgium, 21-23 August 2007, to evaluate the literature and to develop a research agenda to better understand children's exposures in the swimming pool environment and their potential associations with new-onset asthma. Participants, including clinicians, epidemiologists, exposure scientists, pool operations experts, and chemists, reviewed the literature, prepared background summaries, and held extensive discussions on the relevant published studies, knowledge of asthma characterization and exposures at swimming pools, and epidemiologic study designs. SYNTHESIS: Childhood swimming and new-onset childhood asthma have clear implications for public health. If attendance at indoor pools increases risk of childhood asthma, then concerns are warranted and action is necessary. If there is no such relationship, these concerns could unnecessarily deter children from indoor swimming and/or compromise water disinfection. CONCLUSIONS: Current evidence of an association between childhood swimming and new-onset asthma is suggestive but not conclusive. Important data gaps need to be filled, particularly in exposure assessment and characterization of asthma in the very young. Participants recommended that additional evaluations using a multidisciplinary approach are needed to determine whether a clear association exists
Analysis of shape, properties and "druggability" of protein binding pockets
No full textKenntnisse über die dreidimensionale Struktur therapeutisch relevanter Zielproteine bieten wertvolle Informationen für den rationalen Wirkstoffentwurf. Die stetig wachsende Zahl aufgeklärter Kristallstrukturen von Proteinen ermöglicht eine qualitative und quantitative rechnergestützte Untersuchung von spezifischen Protein-Liganden Wechselwirkungen. Im Rahmen dieser Arbeit wurden neue Algorithmen für die Identifikation und den Ähnlichkeitsvergleich von Proteinbindetaschen und ihren Eigenschaften entwickelt und in dem Programm PocketomePicker zusammengefasst. Die Software gliedert sich in die Routinen PocketPicker, PocketShapelets und PocketGraph. Ferner wurde in dieser Arbeit die Methode ReverseLIQUID reimplementiert und im Rahmen einer Kooperation für das strukturbasierte Virtuelle Screening angewendet. Die genannten Methoden und ihre wissenschaftliche Anwendungen sollte hier zusammengefasst werden: Die Methode PocketPicker ermöglicht die Vorhersage potentieller Bindetaschen auf Proteinoberflächen. Diese Technik implementiert einen geometrischen Ansatz auf Basis „künstlicher Gitter“ zur Identifikation zusammenhängender vergrabener Bereiche der Proteinoberfläche als Orte möglicher Ligandenbindestellen. Die Methode erreicht eine korrekte Vorhersage der tatsächlichen Bindetasche für 73 % der Einträge eines repräsentativen Datensatzes von Proteinstrukturen. Für 90 % der Proteinstrukturen wird die tatsächlich Ligandenbindestelle unter den drei wahrscheinlichsten vorhergesagten Taschen gefunden. PocketPicker übertrifft die Vorhersagequalität anderer etablierter Algorithmen und ermöglicht Taschenidentifikationen auf apo-Strukturen ohne signifikante Einbußen des Vorhersageerfolges. Andere Verfahren weisen deutlich eingeschränkte Ergebnisse bei der Anwendung auf apo-Strukturen auf. PocketPicker erlaubt den alignmentfreien Ähnlichkeitsvergleich von Bindetaschenfor-men durch die Kodierung berechneter Bindevolumen als Korrelationsdeskriptoren. Dieser Ansatz wurde erfolgreich für Funktionsvorhersage von Bindetaschen aus Homologiemodellen von APOBEC3C und Glutamat Dehydrogenase des Malariaerregers Plasmodium falciparum angewendet. Diese beiden Projekte wurden in Zusammenarbeit mit Kollaborationspartnern durchgeführt. Zudem wurden PocketPicker Korrelationsdeskriptoren erfolgreich für die automatisierte Konformationsanalyse der enzymatischen Tasche von Aldose Reduktase angewendet. Für detaillierte Analysen der Form und der physikochemischen Eigenschaften von Proteinbindetaschen wurde in dieser Arbeit die Methode PocketShapelets entwickelt. Diese Technik ermöglicht strukturelle Alignments von extrahierten Bindevolumen durch Zerlegungen der Oberfläche von Proteinbindetaschen. Die Überlagerung gelingt durch die Identifikation strukturell ähnlicher Oberflächenkurvaturen zweier Taschen. PocketShapelets wurde erfolgreich zur Analyse funktioneller Ähnlichkeit von Bindetaschen verwendet, die auf Betrachtungen physikochemischer Eigenschaften basiert. Zur Analyse der topologischen Vielfalt von Bindetaschengeometrien wurde in dieser Arbeit die Methode PocketGraph entwickelt. Dieser Ansatz nutzt das Konzept des sog. „Wachsenden Neuronalen Gases“ aus dem Bereich des maschinellen Lernens für eine automatische Extraktion des strukturellen Aufbaus von Bindetaschen. Ferner ermöglicht diese Methode die Zerlegung einer Bindestelle in ihre Subtaschen. Die von PocketPicker charakterisierten Taschenvolumen bilden die Grundlage für die Methode ReverseLIQUID. Dieses Programm wurde in dieser Arbeit weiterentwickelt und im Rahmen einer Kooperation zur Identifikation eines Inhibitors der Serinprotease HtrA des Erregers Helicobacter pylori verwendet. Mit ReverseLIQUID konnte ein strukturbasiertes Pharmakophormodell für das Virtuelle Screening erstellt werden. Dieser Ansatz ermöglichte die Identifikation einer Substanz mit niedrig mikromolarer Affinität gegenüber der Zielstruktur.Knowledge of the three-dimensional structure therapeutically relevant target proteins provides valuable information for rational drug design. The constantly increasing numbers of available crystal structures enable qualitative and quantitative analysis of specific protein-ligand interactions in silico. In this work novel algorithms for the identification and the comparison of protein binding sites and their properties were developed and combined in the program PocketomePicker. The software combines the routines PocketPicker, PocketShapelets and PocketGraph. Furthermore, the method ReverseLIQUID was re-implemented in this work and used for the structure-based virtual screening with a cooperation partner. The programs and their scientific applications are summarized here: The method PocketPicker is designed for the prediction of potential binding sites on protein surfaces. The technique implements a geometric approach based on the concept of “artificial grids” for the identification of continuous buried regions of the protein surface that might act as potential ligand binding sites. The method yields correct predications of the actual binding site for 73 % of the entries in a representative data set of protein structures. For 90 % of the proteins the actual binding site is found among the top three predicted binding pockets. PocketPicker exceeds the predictive quality of other established algorithms and enables correct binding site identifications on apo structures without significant drops of the prediction success. This is not achieved by other programs. PocketPicker enables alignment-free comparisons of binding site shapes by encoding extracted binding volumes as correlation vectors. This approach was used for successful predictions of binding site functionality for homology models of APOBEC3C and glutamate dehydrogenase of the malaria pathogen Plasmodium falciparum. These projects were carried out with collaboration partners. Furthermore, PocketPicker correlation descriptors were used for automated analysis of binding site conformations of aldose reductase active sites. The method PocketShapelets was implemented in this work for detailed analysis of shapes and physicochemical properties of protein binding sites. This approach enables structural alignments of extracted binding volumes by surface decomposition of protein binding sites. The structural superposition is achieved by identification of structurally similar surface curvatures of different binding pockets. PocketShapelets was successfully used for the analysis of functional similarity of binding sites based on observations of physicochemical properties. PocketGraph was developed for the analysis of the structural diversity of binding site geometries. This approach uses the “Growing Neural Gas” concept used in machine learning for an automated extraction of the structural organization of binding sites. Furthermore, the method enables the decomposition of binding sites into subpockets. The pocket volumes characterized by PocketPicker are the foundation of another program called ReverseLIQUID. This method was refined in this work and used for the identification of a Helicobacter pylori serine protease HtrA inhibitor. This project was performed with a collaboration partner. A receptor-based pharmacophore model was derived using ReverseLIQUID and used for virtual screening. This approach led to the identification of a substance with low micromolar affinity towards the target protein
Deepening responses associated with improved progression-free survival with ixazomib versus placebo as posttransplant maintenance in multiple myeloma
No full textIn the TOURMALINE-MM3 study, post-autologous stem cell transplantation maintenance therapy with the oral proteasome inhibitor ixazomib versus placebo significantly improved progression-free survival (PFS), with a favorable safety profile. With ixazomib versus placebo maintenance, deepening responses occurred in 139/302 (46%) versus 60/187 (32%) patients with very good partial response or partial response (VGPR/PR) at study entry (relative risk 1.41, P = 0.004), and median time to best confirmed deepened response was 19.9 versus 30.8 months (24-month rate: 54.2 versus 41.4%; hazard ratio (HR): 1.384; P = 0.0342). Median PFS in patients with VGPR/PR at study entry was 26.2 versus 18.5 months (HR: 0.636, P < 0.001) with ixazomib versus placebo; in a pooled analysis across arms, in patients with versus without deepening responses, the median PFS was not reached versus 15.9 months (HR: 0.245, P < 0.001). In patients with deepening responses, 24-month PFS rate was 77.4 versus 68.3% with ixazomib versus placebo (HR: 0.831; P = 0.466); in patients without deepening responses, median PFS was 17.9 versus 14.1 months (HR: 0.741; P = 0.028). These analyses demonstrate the significantly higher rate of deepening responses with ixazomib versus placebo maintenance and the association between deepening response and prolonged PFS
Characterization of the Dust/Smoke Aerosol that Settled East of the World Trade Center (WTC) in Lower Manhattan after the Collapse of the WTC 11 September 2001
No full textThe explosion and collapse of the World Trade Center (WTC) was a catastrophic event that produced an aerosol plume impacting many workers, residents, and commuters during the first few days after 11 September 2001. Three bulk samples of the total settled dust and smoke were collected at weather-protected locations east of the WTC on 16 and 17 September 2001; these samples are representative of the generated material that settled immediately after the explosion and fire and the concurrent collapse of the two structures. We analyzed each sample, not differentiated by particle size, for inorganic and organic composition. In the inorganic analyses, we identified metals, radionuclides, ionic species, asbestos, and inorganic species. In the organic analyses, we identified polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, pesticides, phthalate esters, brominated diphenyl ethers, and other hydrocarbons. Each sample had a basic pH. Asbestos levels ranged from 0.8% to 3.0% of the mass, the PAHs were > 0.1% of the mass, and lead ranged from 101 to 625 µg/g. The content and distribution of material was indicative of a complex mixture of building debris and combustion products in the resulting plume. These three samples were composed primarily of construction materials, soot, paint (leaded and unleaded), and glass fibers (mineral wool and fiberglass). Levels of hydrocarbons indicated unburned or partially burned jet fuel, plastic, cellulose, and other materials that were ignited by the fire. In morphologic analyses we found that a majority of the mass was fibrous and composed of many types of fibers (e.g., mineral wool, fiberglass, asbestos, wood, paper, and cotton). The particles were separated into size classifications by gravimetric and aerodynamic methods. Material 53 µm in diameter. The results obtained from these samples can be used to understand the contact and types of exposures to this unprecedented complex mixture experienced by the surviving residents, commuters, and rescue workers directly affected by the plume from 11 to 12 September and the evaluations of any acute or long-term health effects from resuspendable dust and smoke to the residents, commuters, and local workers, as well as from the materials released after 11 September until the fires were extinguished. Further, these results support the need to have the interior of residences, buildings, and their respective HVAC systems professionally cleaned to reduce long-term residential risks before rehabitation.Reproduced with permission from Environmental Health PerspectivesFunded in part by supplemental funds from the National Institute of Environmental Health Sciences (NIEHS) to the NIEHS Centers at EOHSI (ES05022-12) and the NYU Institute of Medicine (ES00260). NYU is also funded in part by a U.S. Environmental Protection Agency (EPA) PM Center Grant (R827351). P.J. Lioy was also supported in part by a U.S. EPA University Partnership (CR827033)
NUP98 dysregulation in myeloid leukemogenesis
No full textNucleoporin 98 (NUP98) is a component of the nuclear pore complex that facilitates mRNA export from the nucleus. It is mapped to 11p15.5 and is fused to a number of distinct partners, including nine members of the homeobox family as a consequence of leukemia-associated chromosomal translocations. NUP98-HOXA9 is associated with the t(7;11)(p15;p15) translocation, in acute myeloid leukemia (AML), myelodysplastic syndrome, and blastic crisis of chronic myeloid leukemia. Expression of NUP98-HOXA9 in murine bone marrow resulted in a myeloproliferative disease progressing to AML by 7-8 months. Transduction of NUP98 fusion genes into human CD34(+) cells confers a proliferative advantage in long-term cytokine-stimulated and stromal cocultures and in NOD-SCID engrafted mice, associated with a five- to eight-fold increase in hematopoietic stem cells. NUP98-HOXA9 expression inhibited erythroid and myeloid differentiation but enhanced serial progenitor replating. NUP98-HOXA9 upregulated a number of homeobox genes of the A and B cluster as well as MEIS1 and Pim-1, and downmodulated globin genes and C/EBP alpha. The HOXA9 component of the NUP98-HOXA9 fusion protein was protected from cullin-4A-mediated ubiquitination and subsequent proteasome-dependent degradation. In NUP98-HOX-transduced CD34+ cells and cells from AML patients with t(7; 11)(p15;p15) NUP98 was no longer associated with the Ann. N.Y. Acad.</p
A single subcutaneous or intranasal immunization with adenovirus‐based SARS‐CoV‐2 vaccine induces robust humoral and cellular immune responses in mice
No full textOptimal vaccines are needed for sustained suppression of SARS-CoV-2 and other novel coronaviruses. Here, we developed a recombinant type 5 adenovirus vector encoding the gene for the SARS-CoV-2 S1 subunit antigen (Ad5.SARS-CoV-2-S1) for COVID-19 immunization and evaluated its immunogenicity in mice. A single immunization with Ad5.SARS-CoV-2-S1 via S.C. injection or I.N delivery induced robust antibody and cellular immune responses. Vaccination elicited significant S1-specific IgG, IgG1, and IgG2a endpoint titers as early as 2 weeks, and the induced antibodies were long lasting. I.N. and S.C. administration of Ad5.SARS-CoV-2-S1 produced S1-specific GC B cells in cervical and axillary LNs, respectively. Moreover, I.N. and S.C. immunization evoked significantly greater antigen-specific T-cell responses compared to unimmunized control groups with indications that S.C. injection was more effective than I.N. delivery in eliciting cellular immune responses. Mice vaccinated by either route demonstrated significantly increased virus-specific neutralization antibodies on weeks 8 and 12 compared to control groups, as well as BM antibody forming cells (AFC), indicative of long-term immunity. Thus, this Ad5-vectored SARS-CoV-2 vaccine candidate showed promising immunogenicity following delivery to mice by S.C. and I.N. routes of administration, supporting the further development of Ad-based vaccines against COVID-19 and other infectious diseases for sustainable global immunization programs.</p
- …
