1,253 research outputs found
PCN90 Cost-Effectiveness of a Biopsy-Based 8-Protein Prognostic Assay to Optimize Treatment Decisions In Gleason 3+3 And 3+4 Prostate Cancer
A modeling exercise to show why population models should incorporate distinct life histories of dispersers
A modeling exercise to show why population models should incorporate distinct life histories of dispersers
The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.
Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG <sub>4</sub> ) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG <sub>4</sub> -HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners
Tumor-Microenvironment Characterization of the MB49 Non-Muscle-Invasive Bladder-Cancer Orthotopic Model towards New Therapeutic Strategies.
Bacillus Calmette-Guérin (BCG) instillations for the treatment of non-muscle-invasive bladder cancer patients can result in significant side effects and treatment failure. Immune checkpoint blockade and/or decreasing tumor-infiltrating myeloid suppressor cells may be alternative or complementary treatments. Here, we have characterized immune cell infiltration and chemoattractant molecules in mouse orthotopic MB49 bladder tumors. Our data show a 100-fold increase in CD45 <sup>+</sup> immune cells from day 5 to day 9 tumors including T cells and mainly myeloid cells. Both monocytic myeloid-derived suppressor-cells (M-MDSC) and polymorphonuclear (PMN)-MDSC were strongly increased in day 9 tumors, with PMN-MDSC representing ca. 70% of the myeloid cells in day 12 tumors, while tumor associated macrophages (TAM) were only modestly increased. The kinetic of PD-L1 tumor expression correlated with published data from patients with PD-L1 expressing bladder tumors and with efficacy of anti-PD-1 treatment, further validating the orthotopic MB49 bladder-tumor model as suitable for designing novel therapeutic strategies. Comparison of chemoattractants expression during MB49 bladder tumors grow highlighted CCL8 and CCL12 (CCR2-ligands), CCL9 and CCL6 (CCR-1-ligands), CXCL2 and CXCL5 (CXCR2-ligands), CXCL12 (CXCR4-ligand) and antagonist of C5/C5a as potential targets to decrease myeloid suppressive cells. Data obtained with a single CCR2 inhibitor however showed that the complex chemokine crosstalk would require targeting multiple chemokines for anti-tumor efficacy
CROO: A universal infrastructure and protocol to detect identity fraud
Identity fraud (IDF) may be defined as unauthorized exploitation of credential information through the use of false identity. We propose CROO, a universal (i.e. generic) infrastructure and protocol to either prevent IDF (by detecting attempts thereof), or limit its consequences (by identifying cases of previously undetected IDF). CROO is a capture resilient one-time password scheme, whereby each user must carry a personal trusted device used to generate one-time passwords (OTPs) verified by online trusted parties. Multiple trusted parties may be used for increased scalability. OTPs can be used regardless of a transaction’s purpose (e.g. user authentication or financial payment), associated credentials, and online or on-site nature; this makes CROO a universal scheme. OTPs are not sent in cleartext; they are used as keys to compute MACs of hashed transaction information, in a manner allowing OTP-verifying parties to confirm that given user credentials (i.e. OTP-keyed MACs) correspond to claimed hashed transaction details. Hashing transaction details increases user privacy. Each OTP is generated from a PIN-encrypted non-verifiable key; this makes users’ devices resilient to off-line PIN-guessing attacks. CROO’s credentials can be formatted as existing user credentials (e.g. credit cards or driver’s licenses)
Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions.
Glucose is vital for life, serving as both a source of energy and carbon building block for growth. When glucose is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized genome-wide genetic screens and a PRISM growth assay across 482 cancer cell lines. We report that catabolism of uridine from the medium enables the growth of cells in the complete absence of glucose. While previous studies have shown that uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial oxidative phosphorylation deficiency <sup>1</sup> , our work demonstrates that the ribose moiety of uridine or RNA can be salvaged to fulfil energy requirements via a pathway based on: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/UPP2 into uracil and ribose-1-phosphate (R1P), (2) the conversion of uridine-derived R1P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Capacity for glycolysis from uridine-derived ribose appears widespread, and we confirm its activity in cancer lineages, primary macrophages and mice in vivo. An interesting property of this pathway is that R1P enters downstream of the initial, highly regulated steps of glucose transport and upper glycolysis. We anticipate that 'uridine bypass' of upper glycolysis could be important in the context of disease and even exploited for therapeutic purposes
Nanoscale Processing by Adaptive Laser Pulses
We theoretically demonstrate that atomically-precise ``nanoscale processing"
can be reproducibly performed by adaptive laser pulses. We present the new
approach on the controlled welding of crossed carbon nanotubes, giving various
metastable junctions of interest. Adaptive laser pulses could be also used in
preparation of other hybrid nanostructures.Comment: 4 pages, 4 Postscript figure
Effect of the Surface on the Electron Quantum Size Levels and Electron g-Factor in Spherical Semiconductor Nanocrystals
The structure of the electron quantum size levels in spherical nanocrystals
is studied in the framework of an eight--band effective mass model at zero and
weak magnetic fields. The effect of the nanocrystal surface is modeled through
the boundary condition imposed on the envelope wave function at the surface. We
show that the spin--orbit splitting of the valence band leads to the
surface--induced spin--orbit splitting of the excited conduction band states
and to the additional surface--induced magnetic moment for electrons in bare
nanocrystals. This additional magnetic moment manifests itself in a nonzero
surface contribution to the linear Zeeman splitting of all quantum size energy
levels including the ground 1S electron state. The fitting of the size
dependence of the ground state electron g factor in CdSe nanocrystals has
allowed us to determine the appropriate surface parameter of the boundary
conditions. The structure of the excited electron states is considered in the
limits of weak and strong magnetic fields.Comment: 11 pages, 4 figures, submitted to Phys. Rev.
Mixtures of Bosonic and Fermionic Atoms in Optical Lattices
We discuss the theory of mixtures of Bosonic and Fermionic atoms in periodic
potentials at zero temperature. We derive a general Bose--Fermi Hubbard
Hamiltonian in a one--dimensional optical lattice with a superimposed harmonic
trapping potential. We study the conditions for linear stability of the mixture
and derive a mean field criterion for the onset of a Bosonic superfluid
transition. We investigate the ground state properties of the mixture in the
Gutzwiller formulation of mean field theory, and present numerical studies of
finite systems. The Bosonic and Fermionic density distributions and the onset
of quantum phase transitions to demixing and to a Bosonic Mott--insulator are
studied as a function of the lattice potential strength. The existence is
predicted of a disordered phase for mixtures loaded in very deep lattices. Such
a disordered phase possessing many degenerate or quasi--degenerate ground
states is related to a breaking of the mirror symmetry in the lattice.Comment: 11 pages, 8 figures; added discussions; conclusions and references
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