1,146 research outputs found
CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success
Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient's own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted United States Food and Drug Administration (FDA) approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma. Human trials of CAR T cells targeting CD19 or B cell maturation antigen in multiple myeloma have also reported early successes. However, a clear and consistently reproducible demonstration of the clinical efficacy of CAR T cells in the setting of solid tumors has not been reported to date. Here, we review the history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies. In addition, we summarize recent strategies and innovations that aim to augment the potency of CAR T cells in the face of multiple immunosuppressive barriers operative within the solid tumor microenvironment. Advances in the field of CAR T cell biology over the coming years in the areas of safety, reliability and efficacy against non-hematopoietic cancers will ultimately determine how transformative adoptive T cell therapy will be in the broader battle against cancer
Increased Programmed Death-1 Molecule Expression in Cytomegalovirus Disease and Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation
To study the role of the programmed death-1 molecule (PD-1) in cytomegalovirus (CMV) infection and disease after allogeneic hematopoietic cell transplantation (HCT), 206 subjects were followed prospectively for immune response to CMV and assigned to 3 groups based on CMV outcome. The subjects were analyzed retrospectively for PD-1 expression in cryopreserved CD4+ and CD8+T cells collected at days 40, 90, 120, 150, 180, and 360 posttransplantation. HCT recipients with CMV disease (n=14) were compared with recipients with prolonged CMV infection, but no CMV disease (median duration of infection, 3 months; n=14) and with controls with no CMV infection who received similar transplants (n=22). The CMV disease group had a significantly higher mean fluorescein intensity of PD-1 in CD4+ (P < .05) and CD8+ (PÂ < .05) lymphocytes at all time points studied. PD-1 expression also was significantly elevated in those with severe acute graft-versus-host disease (aGVHD), including the no-viremia group. The data suggest that PD-1 is induced by aGVHD even in the absence of CMV infection. This enhanced PD-1 expression during severe aGVHD and with CMV reactivation could explain the known role of aGVHD as a risk factor for CMV disease
The phase-space structure of a dark-matter halo: Implications for dark-matter direct detection experiments
We study the phase-space structure of a dark-matter halo formed in a high
resolution simulation of a Lambda CDM cosmology. Our goal is to quantify how
much substructure is left over from the inhomogeneous growth of the halo, and
how it may affect the signal in experiments aimed at detecting the dark matter
particles directly. If we focus on the equivalent of ``Solar vicinity'', we
find that the dark-matter is smoothly distributed in space. The probability of
detecting particles bound within dense lumps of individual mass less than 10^7
M_\sun h^{-1} is small, less than 10^{-2}. The velocity ellipsoid in the Solar
neighbourhood deviates only slightly from a multivariate Gaussian, and can be
thought of as a superposition of thousands of kinematically cold streams. The
motions of the most energetic particles are, however, strongly clumped and
highly anisotropic. We conclude that experiments may safely assume a smooth
multivariate Gaussian distribution to represent the kinematics of dark-matter
particles in the Solar neighbourhood. Experiments sensitive to the direction of
motion of the incident particles could exploit the expected anisotropy to learn
about the recent merging history of our Galaxy.Comment: 13 pages, 13 figures, Phys. Rev. D in press. Postscript version with
high resolution figures available from
http://www.mpa-garching.mpg.de/~ahelmi/research/lcdm_dm.html; some changes in
the text; constraints on the effect of bound dark-matter lumps revised;
remaining conclusions unchange
Facile synthesis and proposed mechanism of α,Ïâoxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane) by an SN2(i) nitrato displacement method in basic media
The synthesis of a novel heterocyclicâtelechelic polymer, α,Ï-oxetanyl-telechelic poly(3-nitratomethyl-3-methyl oxetane), is described. Infrared spectroscopy (IR), gel permeation chromatography (GPC), and nuclear magnetic resonance (NMR) spectroscopy have been used to confirm the successful synthesis, demonstrating the presence of the telechelic-oxetanyl moieties. Synthesis of the terminal functionalities has been achieved via displacement of nitrato groups, in a manner similar to that employed with other leaving groups such as azido, bromo, and nitro, initiated by nucleophiles. In the present case, displacement occurs on the ends of a nitrato-functionalized polymer driven by the formation of sodium nitrate, which is supported by the polar aprotic solvent N,N-dimethyl formamide. The formation of an alkoxide at the polymer chain ends is favored and allows internal back-biting to the nearest carbon bearing the nitrato group, intrinsically in an SN2(i) reaction, leading to α,Ï-oxetanyl functionalization. The telechelic-oxetanyl moieties have the potential to be cross-linked by chemical (e.g., acidic) or radiative (e.g., ultraviolet) curing methods without the use of high temperatures, usually below 100°C. This type of material was designed for future use as a contraband simulant, whereby it would form the predominant constituent of elastomeric composites comprising rubbery polymer with small quantities of solids, typically crystals of contraband substances, such as explosives or narcotics. This method also provides an alternative approach to ring closure and synthesis of heterocycles
An ancient founder mutation in PROKR2 impairs human reproduction
Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same âŒ123 kb haplotype whose population frequency is â€10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproductio
Understanding Galaxy Formation and Evolution
The old dream of integrating into one the study of micro and macrocosmos is
now a reality. Cosmology, astrophysics, and particle physics intersect in a
scenario (but still not a theory) of cosmic structure formation and evolution
called Lambda Cold Dark Matter (LCDM) model. This scenario emerged mainly to
explain the origin of galaxies. In these lecture notes, I first present a
review of the main galaxy properties, highlighting the questions that any
theory of galaxy formation should explain. Then, the cosmological framework and
the main aspects of primordial perturbation generation and evolution are
pedagogically detached. Next, I focus on the ``dark side'' of galaxy formation,
presenting a review on LCDM halo assembling and properties, and on the main
candidates for non-baryonic dark matter. It is shown how the nature of
elemental particles can influence on the features of galaxies and their
systems. Finally, the complex processes of baryon dissipation inside the
non-linearly evolving CDM halos, formation of disks and spheroids, and
transformation of gas into stars are briefly described, remarking on the
possibility of a few driving factors and parameters able to explain the main
body of galaxy properties. A summary and a discussion of some of the issues and
open problems of the LCDM paradigm are given in the final part of these notes.Comment: 50 pages, 10 low-resolution figures (for normal-resolution, DOWNLOAD
THE PAPER (PDF, 1.9 Mb) FROM http://www.astroscu.unam.mx/~avila/avila.pdf).
Lectures given at the IV Mexican School of Astrophysics, July 18-25, 2005
(submitted to the Editors on March 15, 2006
Flow Measurements via Two-particle Azimuthal Correlations in Au + Au Collisions at sqrt(s_NN) = 130 GeV
Two particle azimuthal correlation functions are presented for charged
hadrons produced in Au + Au collisions at RHIC sqrt(s_NN) = 130 GeV. The
measurements permit determination of elliptic flow without event-by-event
estimation of the reaction plane. The extracted elliptic flow values v_2 show
significant sensitivity to both the collision centrality and the transverse
momenta of emitted hadrons, suggesting rapid thermalization and relatively
strong velocity fields. When scaled by the eccentricity of the collision zone,
epsilon, the scaled elliptic flow shows little or no dependence on centrality
for charged hadrons with relatively low p_T. A breakdown of this epsilon
scaling is observed for charged hadrons with p_T > 1.0 GeV/c for the most
central collisions.Comment: 6 pages, RevTeX 3, 4 figures, 307 authors, submitted to Phys. Rev.
Lett. on 11 April 2002. Plain text data tables for the points plotted in
figures for this and previous PHENIX publications are (will be made) publicly
available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm
Vascular endothelial growth factor-A165b is protective and restores endothelial glycocalyx in diabetic nephropathy
Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy
Net Charge Fluctuations in Au + Au Interactions at sqrt(s_NN) = 130 GeV
Data from Au + Au interactions at sqrt(s_NN) = 130 GeV, obtained with the
PHENIX detector at RHIC, are used to investigate local net charge fluctuations
among particles produced near mid-rapidity. According to recent suggestions,
such fluctuations may carry information from the Quark Gluon Plasma. This
analysis shows that the fluctuations are dominated by a stochastic distribution
of particles, but are also sensitive to other effects, like global charge
conservation and resonance decays.Comment: 6 pages, RevTeX 3, 3 figures, 307 authors, submitted to Phys. Rev.
Lett. on 21 March, 2002. Plain text data tables for the points plotted in
figures for this and previous PHENIX publications are (will be made) publicly
available at http://www.phenix.bnl.gov/phenix/WWW/run/phenix/papers.htm
B-cell Zone Reticular Cell Microenvironments Shape CXCL13 Gradient Formation
Through the formation of concentration gradients, morphogens drive graded responses to extracellular signals, thereby fine-tuning cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular reticular cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B-cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extracellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B cell homing to but not within lymph nodes. Our data thus suggest that reticular cells of the B cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradient
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