617 research outputs found
Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K-mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid- and gas-chromatography mass spectrometry-based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism
Polarization control of metal-enhanced fluorescence in hybrid assemblies of photosynthetic complexes and gold nanorods
Fluorescence imaging of hybrid nanostructures composed of a bacterial light-harvesting complex LH2 and Au nanorods with controlled coupling strength is employed to study the spectral dependence of the plasmon-induced fluorescence enhancement. Perfect matching of the plasmon resonances in the nanorods with the absorption bands of the LH2 complexes facilitates a direct comparison of the enhancement factors for longitudinal and transverse plasmon frequencies of the nanorods. We find that the fluorescence enhancement due to excitation of longitudinal resonance can be up to five-fold stronger than for the transverse one. We attribute this result, which is important for designing plasmonic functional systems, to a very different distribution of the enhancement of the electric field due to the excitation of the two characteristic plasmon modes in nanorods
CENOZOIC DINOFLAGELLATE CYSTS FROM THE NAVARIN BASIN, NORTON SOUND AND ST. GEORGE BASIN, BERING SEA
Biostratigraphic studies in the Navarin Basin COST No.1 well, Norton Sound COST No.1 well and St. George Basin COST No.2 well in the Bering Sea were carried out based on dinoflagellate cyst and acritarch assemblages. Several local dinoflagellate cyst zones are independently proposed for each well, and then the composite dinoflagellate cyst zones are established for the central to eastern Bering Sea based on the composite ranges of dinoflagellate cysts obtained from the three wells. These zones are follows in descending order ; Filisphaera filifera Zone (late Pliocene to early Pleistocene), Filisphaera pilosa Zone (early to late Pliocene), Hystrichosphaeropsis variabile Zone (late Miocene), Heteraulacacysta campanula Zone (latest late Oligocene to early Miocene) , Impagidinium velorum Zone (early Oligocene) and Areosphaeridium diktyoplokus Zone (late Eocene). Correlation of these zones with other Cenozoic dinoflagellate zonations are also discussed. Totally thirty-four genera and seventy species of dinoflagellates including one new genus (Algidasphaeridium) and twenty new species, and three genera and three species of acritarchs containing one new genus and species (Joviela magnifica) are recorded from the three wells
GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus
Background:
The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.<p></p>
Methods:
Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).<p></p>
Results:
Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.<p></p>
Conclusions:
Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients
Comparing large lecture mechanics curricula using the Force Concept Inventory: A five thousand student study
The performance of over 5000 students in introductory calculus-based
mechanics courses at the Georgia Institute of Technology was assessed using the
Force Concept Inventory (FCI). Results from two different curricula were
compared: a traditional mechanics curriculum and the Matter & Interactions
(M&I) curriculum. Post-instruction FCI averages were significantly higher for
the traditional curriculum than for the M&I curriculum; the differences between
curricula persist after accounting for factors such as pre-instruction FCI
scores, grade point averages, and SAT scores. FCI performance on categories of
items organized by concepts was also compared; traditional averages were
significantly higher in each concept. We examined differences in student
preparation between the curricula and found that the relative fraction of
homework and lecture topics devoted to FCI force and motion concepts correlated
with the observed performance differences. Limitations of concept inventories
as instruments for evaluating curricular reforms are discussed.Comment: 21 pages, 4 figures, submitted to Am. J. Phys. arXiv admin note:
substantial text overlap with arXiv:1112.559
Forward Neutron Production at the Fermilab Main Injector
We have measured cross sections for forward neutron production from a variety
of targets using proton beams from the Fermilab Main Injector. Measurements
were performed for proton beam momenta of 58 GeV/c, 84 GeV/c, and 120 GeV/c.
The cross section dependence on the atomic weight (A) of the targets was found
to vary as where is for a beam momentum of
58 GeV/c and 0.540.05 for 120 GeV/c. The cross sections show reasonable
agreement with FLUKA and DPMJET Monte Carlos. Comparisons have also been made
with the LAQGSM Monte Carlo.Comment: Accepted for publication in Physical Review D. This version
incorporates small changes suggested by referee and small corrections in the
neutron production cross sections predicted by FLUK
Structural chemistry of metal coordination complexes at high pressure
The application of pressures of up to about 10 GPa may induce significant geometric, configurational, conformational and packing changes in molecular solids. This review highlights and describes recent advances in high pressure studies of coordination complexes, many of which have been conducted at synchrotrons or other central facilities. The main focus is on the wide range of geometric changes which occur with pressure. In some cases these changes have associated physical effects, and the review describes materials exhibiting negative linear compressibility, spin cross-over phenomena, magnetism and molecular conduction, as well as detailing the exciting possibilities for future developments in this area of research
A synthetic biological quantum optical system
In strong plasmonâexciton coupling, a surface plasmon mode is coupled to an array of localized emitters to yield new hybrid lightâmatter states (plexcitons), whose properties may in principle be controlled via modification of the arrangement of emitters. We show that plasmon modes are strongly coupled to synthetic light-harvesting maquette proteins, and that the coupling can be controlled via alteration of the protein structure. For maquettes with a single chlorin binding site, the exciton energy (2.06 Âą 0.07 eV) is close to the expected energy of the Qy transition. However, for maquettes containing two chlorin binding sites that are collinear in the field direction, an exciton energy of 2.20 Âą 0.01 eV is obtained, intermediate between the energies of the Qx and Qy transitions of the chlorin. This observation is attributed to strong coupling of the LSPR to an H-dimer state not observed under weak coupling
Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction
The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cellâmatrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor β (TGF)âmediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-β rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI
Plasma Levels of Transforming Growth Factor-β1 Reflect Left Ventricular Remodeling in Aortic Stenosis
Background: TGF-b1 is involved in cardiac remodeling through an auto/paracrine mechanism. The contribution of TGF-b1
from plasmatic source to pressure overload myocardial remodeling has not been analyzed. We investigated, in patients with
valvular aortic stenosis (AS), and in mice subjected to transverse aortic arch constriction (TAC), whether plasma TGF-b1
relates with myocardial remodeling, reflected by LV transcriptional adaptations of genes linked to myocardial hypertrophy
and fibrosis, and by heart morphology and function.
Methodology/Principal Findings: The subjects of the study were: 39 patients operated of AS; 27 healthy volunteers; 12
mice subjected to TAC; and 6 mice sham-operated. Myocardial samples were subjected to quantitative PCR. Plasma TGF-b1
was determined by ELISA. Under pressure overload, TGF-b1 plasma levels were significantly increased both in AS patients
and TAC mice. In AS patients, plasma TGF-b1 correlated directly with aortic transvalvular gradients and LV mass surrogate
variables, both preoperatively and 1 year after surgery. Plasma TGF-b1 correlated positively with the myocardial expression
of genes encoding extracellular matrix (collagens I and III, fibronectin) and sarcomeric (myosin light chain-2, b-myosin heavy
chain) remodelling targets of TGF-b1, in TAC mice and in AS patients.
Conclusions/Significance: A circulating TGF-b1-mediated mechanism is involved, in both mice and humans, in the
excessive deposition of ECM elements and hypertrophic growth of cardiomyocytes under pressure overload. The possible
value of plasma TGF-b1 as a marker reflecting preoperative myocardial remodeling status in AS patients deserves further
analysis in larger patient cohorts
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