Role of Antigen Spread and Distinctive Characteristics of Immunotherapy in Cancer Treatment

Contains fulltext : 174163.pdf (publisher's version ) (Open Access)Immunotherapy is an important breakthrough in cancer. US Food and Drug Administration-approved immunotherapies for cancer treatment (including, but not limited to, sipuleucel-T, ipilimumab, nivolumab, pembrolizumab, and atezolizumab) substantially improve overall survival across multiple malignancies. One mechanism of action of these treatments is to induce an immune response against antigen-bearing tumor cells; the resultant cell death releases secondary (nontargeted) tumor antigens. Secondary antigens prime subsequent immune responses (antigen spread). Immunotherapy-induced antigen spread has been shown in clinical studies. For example, in metastatic castration-resistant prostate cancer patients, sipuleucel-T induced early immune responses to the immunizing antigen (PA2024) and/or the target antigen (prostatic acid phosphatase). Thereafter, most patients developed increased antibody responses to numerous secondary proteins, several of which are expressed in prostate cancer with functional relevance in cancer. The ipilimumab-induced antibody profile in melanoma patients shows that antigen spread also occurs with immune checkpoint blockade. In contrast to chemotherapy, immunotherapy often does not result in short-term changes in conventional disease progression end points (eg, progression-free survival, tumor size), which may be explained, in part, by the time taken for antigen spread to occur. Thus, immune-related response criteria need to be identified to better monitor the effectiveness of immunotherapy. As immunotherapy antitumor effects take time to evolve, immunotherapy in patients with less advanced cancer may have greater clinical benefit vs those with more advanced disease. This concept is supported by prostate cancer clinical studies with sipuleucel-T, PSA-TRICOM, and ipilimumab. We discuss antigen spread with cancer immunotherapy and its implications for clinical outcomes

Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels\ud

Objectives: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of VWF and FVIII. Methods and Results: We genotyped the control populations of two population-based studies for four AVPR2 variations: a-245c, G12E, L309L, and S331S. Rare alleles of a-245c, G12E, and S331S, which were in linkage disequilibrium, were associated with higher VWF propeptide, VWF and FVIII levels. The functionality of the G12E variant was studied in stably transfected MDCKII cells, expressing constructs of either 12G-V2R or 12E-V2R. Both V2R variants were fully glycosylated and expressed on the basolateral membrane. The binding affinity of V2R for AVP was increased three-fold in 12E-V2R–green fluorescent protein (GFP) cells, which is in accordance with increased levels of VWF propeptide associated with the 12E variant. The dissociation constant (KD) was 4.5 nm [95% confidence interval (CI) 3.6–5.4] for 12E-V2R–GFP and 16.5 nm (95% CI 10.1–22.9) for 12G-V2R–GFP. AVP-induced cAMP generation was enhanced in 12E-V2R–GFP cells. Conclusions: The 12E-V2R variant has increased binding affinity for AVP, resulting in increased signal transduction, and is associated with increased levels of VWF propeptide, VWF, and FVII

t→bWt \to b W in NonCommutative Standard Model

We study the top quark decay to b quark and W boson in the NonCommutative Standard Model (NCSM). The lowest contribution to the decay comes from the terms quadratic in the matrix describing the noncommutative (NC) effects while the linear term is seen to identically vanish because of symmetry. The NC effects are found to be significant only for low values of the NC characteristic scale.Comment: 11 page Latex file containing 2 eps figures (redrawn). More discussion included. To appear in PR

Breaking CPT by mixed non-commutativity

The mixed component of the non-commutative parameter \theta_{\mu M}, where \mu = 0,1,2,3 and M is an extra dimensional index may violate four-dimensional CPT invariance. We calculate one and two-loop induced couplings of \theta_{\mu 5} with the four-dimensional axial vector current and with the CPT odd dim=6 operators starting from five-dimensional Yukawa and U(1) theories. The resulting bounds from clock comparison experiments place a stringent constraint on \theta_{\mu 5}, |\theta_{\mu 5}|^{-1/2} > 5\times 10^{11} GeV. The orbifold projection and/or localization of fermions on a 3-brane lead to CPT-conserving physics, in which case the constraints on \theta{\mu 5} are softened.Comment: 4 pages, latex, 1 figur

Experimental tests of slender reinforced concrete columns under combined axial load and lateral force

The use of high strength concrete (HSC) in columns has become more frequent since a substantial reduction of the cross-section is obtained, meaning that slenderness increases for the same axial load and length, producing higher second order effects. However, the experimental tests in the literature of reinforced concrete columns subjected to axial load and lateral force focus on shear span ratios, according to Eurocode 2 (2004), clause 5.6.3., (M/(V·h)) lower than 6.5. This gap in the literature limits technological development for the construction of these structural elements. This paper presents 44 experimental tests on reinforced concrete columns subjected to constant axial load and monotonic lateral force. The aim of this is to gain greater knowledge of the types of elements which will also be of use in calibrating the numerical models and validating the simplified methods. The test parameters are strength of concrete (normal- and high-strength concrete), shear span ratio, axial load level and longitudinal and transversal reinforcement ratios. The strength and deformation of the columns were studied, and an analysis of the simplified methods from Eurocode 2 (2004) and ACI-318 (2008) concluded that both are very conservative. © 2011 Elsevier Ltd.The authors wish to express their sincere gratitude to the Spanish Ministry of Science and Innovation for the help provided through project BIA2009-10207 and to the European Union for the financial support from Feder funds.Barrera Puerto, A.; Bonet Senach, JL.; Romero, ML.; Miguel Sosa, P. (2011). Experimental tests of slender reinforced concrete columns under combined axial load and lateral force. Engineering Structures. 33(12):3676-3689. https://doi.org/10.1016/j.engstruct.2011.08.003S36763689331

Fermions from Half-BPS Supergravity

We discuss collective coordinate quantization of the half-BPS geometries of Lin, Lunin and Maldacena (hep-th/0409174). The LLM geometries are parameterized by a single function $u$ on a plane. We treat this function as a collective coordinate. We arrive at the collective coordinate action as well as path integral measure by considering D3 branes in an arbitrary LLM geometry. The resulting functional integral is shown, using known methods (hep-th/9309028), to be the classical limit of a functional integral for free fermions in a harmonic oscillator. The function $u$ gets identified with the classical limit of the Wigner phase space distribution of the fermion theory which satisfies u * u = u. The calculation shows how configuration space of supergravity becomes a phase space (hence noncommutative) in the half-BPS sector. Our method sheds new light on counting supersymmetric configurations in supergravity.Comment: 28 pages, 2 figures, epsf;(v3) eq. (3.3) clarified and notationally simplified; version to appear in JHE

Probing Noncommutative Space-Time in the Laboratory Frame

The phenomenological investigation of noncommutative space-time in the laboratory frame are presented. We formulate the apparent time variation of noncommutativity parameter $\theta_{\mu\nu}$ in the laboratory frame due to the earth's rotation. Furthermore, in the noncommutative QED, we discuss how to probe the electric-like component $\overrightarrow{\theta_{E}}=(\theta_{01},\theta_{02},\theta_{03})$ by the process $e^-e^+\to\gamma\gamma$ at future $e^-e^+$ linear collider. We may determine the magnitude and the direction of $\overrightarrow{\theta_{E}}$ by detailed study of the apparent time variation of total cross section. In case of us observing no signal, the upper limit on the magnitude of $\overrightarrow{\theta_E^{}}$ can be determined independently of its direction.Comment: 12 pages, 7 figures, typos are corrected, one graph have been added in figure

Amplitudes With Different Helicity Configurations Of Noncommutative QED

The amplitudes of purely photonic and photon{2-fermion processes of non- commutative QED (NCQED) are derived for different helicity configurations of photons. The basic ingredient is the NCQED counterpart of Yang-Mills recursion relations by means of Berends and Giele. The explicit solutions of recursion relations for NCQED photonic processes with special helicity configurations are presented.Comment: 23 pages, 2 figure

Phenomenology of Particle Production and Propagation in String-Motivated Canonical Noncommutative Spacetime

We outline a phenomenological programme for the search of effects induced by (string-motivated) canonical noncommutative spacetime. The tests we propose are based, in analogy with a corresponding programme developed over the last few years for the study of Lie-algebra noncommutative spacetimes, on the role of the noncommutativity parameters in the $E(p)$ dispersion relation. We focus on the role of deformed dispersion relations in particle-production collision processes, where the noncommutativity parameters would affect the threshold equation, and in the dispersion of gamma rays observed from distant astrophysical sources. We emphasize that the studies here proposed have the advantage of involving particles of relatively high energies, and may therefore be less sensitive to "contamination" (through IR/UV mixing) from the UV sector of the theory. We also explore the possibility that the relevant deformation of the dispersion relations could be responsible for the experimentally-observed violations of the GZK cutoff for cosmic rays and could have a role in the observation of hard photons from distant astrophysical sources.Comment: With respect to the experimental information available at the time of writing version 1 of this manuscript (hep-th/0109191v1) the situation has evolved significantly. Our remarks on the benefits of high-energy observations found additional encouragement from the results reported in hep-th/020925