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Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.
While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer
Zero mode in the time-dependent symmetry breaking of theory
We apply the quartic exponential variational approximation to the symmetry
breaking phenomena of scalar field in three and four dimensions. We calculate
effective potential and effective action for the time-dependent system by
separating the zero mode from other non-zero modes of the scalar field and
treating the zero mode quantum mechanically. It is shown that the quantum
mechanical properties of the zero mode play a non-trivial role in the symmetry
breaking of the scalar theory.Comment: 10 pages, 3 figure
Pulse-shape discrimination between electron and nuclear recoils in a NaI(Tl) crystal
We report on the response of a high light-output NaI(Tl) crystal to nuclear
recoils induced by neutrons from an Am-Be source and compare the results with
the response to electron recoils produced by Compton scattered 662 keV
-rays from a Cs source. The measured pulse-shape discrimination
(PSD) power of the NaI(Tl) crystal is found to be significantly improved
because of the high light output of the NaI(Tl) detector. We quantify the PSD
power with a quality factor and estimate the sensitivity to the interaction
rate for weakly interacting massive particles (WIMPs) with nucleons, and the
result is compared with the annual modulation amplitude observed by the
DAMA/LIBRA experiment. The sensitivity to spin-independent WIMP-nucleon
interactions based on 100 kgyear of data from NaI detectors is estimated
with simulated experiments, using the standard halo model.Comment: 11page
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