3,746 research outputs found
Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.
The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8(+) T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted
UK Immunotherapy Study: reanalysis by a combined symptom and medication score
Reanalysis of UK22 subcutaneous immunotherapy trial according to WAO/EAACI recommendations revealed clinically relevant improvements at both doses. Starting at the lower dose should enable efficacy with lower risk of adverse events
Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells
Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, Kd for binding to RARs = 2–5 nM) inhibited colony formation (by 50%) by all three lines at 16–34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12–22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RARβ, and an antagonist with predominant activity at RARβ and RARγ (AGN194431) inhibited colony formation at concentrations (∼100 nM) commensurate with a Kd value of 70 nM at RARγ. An RARα antagonist (AGN194301) was less potent (IC50 ∼200 nM), but was more active than specific agonists of RARα and of βγ. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARγ-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma. © 2001 Cancer Research Campaign http://www.bjcancer.co
Tests of cosmic ray radiography for power industry applications
In this report, we assess muon multiple scattering tomography as a
non-destructive inspection technique in several typical areas of interest to
the nuclear power industry, including monitoring concrete degradation, gate
valve conditions, and pipe wall thickness. This work is motivated by the need
for radiographic methods that do not require the licensing, training, and
safety controls of x-rays, and by the need to be able to penetrate considerable
overburden to examine internal details of components that are otherwise
inaccessible, with minimum impact on industrial operations. In some scenarios,
we find that muon tomography may be an attractive alternative to more typical
measurements.Comment: LA-UR-15-2212
Electrostatics and the Assembly of an RNA Virus
Electrostatic interactions play a central role in the assembly of
single-stranded RNA viruses. Under physiological conditions of salinity and
acidity, virus capsid assembly requires the presence of genomic material that
is oppositely charged to the core proteins. In this paper we apply basic
polymer physics and statistical mechanics methods to the self-assembly of a
synthetic virus encapsidating generic polyelectrolyte molecules. We find that
(i) the mean concentration of the encapsidated polyelectrolyte material depends
on the surface charge density, the radius of the capsid, and the linear charge
density of the polymer but neither on the salt concentration or the Kuhn
length, (ii) the total charge of the capsid interior is equal but opposite to
that of the empty capsid, a form of charge reversal. Unlike natural viruses,
synthetic viruses are predicted not to be under an osmotic swelling pressure.
The design condition that self-assembly only produces filled capsids is shown
to coincide with the condition that the capsid surface charge exceeds the
desorption threshold of polymer surface adsorption. We compare our results with
studies on the self-assembly of both synthetic and natural viruses.Comment: 41 pages, 4 figure
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Electronic structure and x-ray magnetic dichroism in random substitutional alloys of f-electron elements
The Koringa-Kohn-Rostoker —coherent-potential-approximation method combines multiple-scattering theory and the coherent-potential approximation to calculate the electronic structure of random substitutional alloys of transition metals. In this paper we describe the generalization of this theory to describe f-electron alloys. The theory is illustrated with a calculation of the electronic structure and magnetic dichroism curves for a random substitutional alloy containing rare-earth or actinide elements from first principles
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