216 research outputs found
2OACTIVATION OF T CELLS UPON TREATMENT WITH BISPECIFIC ANTIBODIES CORRELATES WITH THE EXPRESSION OF CO-INHIBITORY RECEPTORS ON TUMOR-INFILTRATING LYMPHOCYTES IN HUMAN LUNG CANCER
Introduction: T cell bispecific antibodies (TCB) are designed to recruit and simultaneously activate T cells against target cells such as tumor cells expressing a particular surface antigen. However, it is currently unknown how immuno-modulatory mechanisms active in the tumor microenvironment such as the expression of T cell co-inhibitory receptors may influence the therapeutic effect of TCBs. Methods: We performed a comprehensive phenotypic analysis of tumor infiltrating immune cells from lung carcinoma digests by multicolour flow cytometry. In particular, expression of T cell co-inhibitory and -stimulatory receptors was analyzed. Tumor digests were treated with catumaxomab, a TCB directed against CD3 and EpCAM. T cell activation and effector functions were assessed upon exposure to catumaxomab. Results: CD8+ T cells in lung carcinoma showed a broad heterogeneity in expression of the T cell co-inhibitory receptors PD-1, Tim-3, CTLA-4, Lag-3 and BTLA. Tumor stage and nodal status correlated with number and intensity of expressed receptors. Upon exposure to catumaxomab, a considerable heterogeneity in T cell activation among different tumors was observed. Of note, T cells expressing high levels and multiple co-inhibitory receptors were more impaired in their activation and effector functions after treatment with catumaxomab indicating a higher level of exhaustion. In a further analysis of CD8+ TIL subsets we found that BTLA+ T cells expressed more additional inhibitory receptors than all other subsets, namely PD-1, Tim-3, CTLA-4 and Lag-3, whereas only a small part of PD-1+ T cells expressed another receptor. Tim-3+ T cells usually co-expressed PD-1, but multiple receptors were found only on a low number of cells. Conclusion: In summary, our data suggest that the activity of TCBs is largely affected by the expression of T cell co-inhibitory receptors on tumor-infiltrating immune cells. Furthermore, these data provide a clinical rationale for combining bispecific antibodies with compounds which antagonize T cell exhaustion. Disclosure: D. Thommen, J. Schreiner, P. Herzig, P. Mueller and A. Zippelius: received research funding from Roche Glycart; V. Karanikas: is employed by Roche Glycart. All other authors have declared no conflicts of interes
Classical chaos with Bose-Einstein condensates in tilted optical lattices
A widely accepted definition of ``quantum chaos'' is ``the behavior of a
quantum system whose \emph{classical} \emph{limit is chaotic}''. The dynamics
of quantum-chaotic systems is nevertheless very different from that of their
classical counterparts. A fundamental reason for that is the linearity of
Schr{\"o}dinger equation. In this paper, we study the quantum dynamics of an
ultra-cold quantum degenerate gas in a tilted optical lattice and show that it
displays features very close to \emph{classical} chaos. We show that its phase
space is organized according to the Kolmogorov-Arnold-Moser theorem.Comment: 4 pages, 3 figure
Wavepacket reconstruction via local dynamics in a parabolic lattice
We study the dynamics of a wavepacket in a potential formed by the sum of a
periodic lattice and of a parabolic potential. The dynamics of the wavepacket
is essentially a superposition of ``local Bloch oscillations'', whose frequency
is proportional to the local slope of the parabolic potential. We show that the
amplitude and the phase of the Fourier transform of a signal characterizing
this dynamics contains information about the amplitude and the phase of the
wavepacket at a given lattice site. Hence, {\em complete} reconstruction of the
the wavepacket in the real space can be performed from the study of the
dynamics of the system.Comment: 4 pages, 3 figures, RevTex
Head-to-head comparison of length of stay, patients' outcome and satisfaction in Switzerland before and after SwissDRG-Implementation in 2012 in 2012: an observational study in two tertiary university centers.
On 1 January 2012 Swiss Diagnosis Related Groups (DRG), a new uniform payment system for in-patients was introduced in Switzerland with the intention to replace a "cost-based" with a "case-based" reimbursement system to increase efficiency. With the introduction of the new payment system we aim to answer questions raised regarding length of stay as well as patients' outcome and satisfaction.
This is a prospective, two-centre observational cohort study with data from University Hospital Basel and the Cantonal Hospital Aarau, Switzerland, from January to June 2011 and 2012, respectively. Consecutive in-patients with the main diagnosis of either community-acquired pneumonia, exacerbation of COPD, acute heart failure or hip fracture were included. A questionnaire survey was sent out after discharge investigating changes before and after SwissDRG implementation. Our primary endpoint was LOS.
Of 1,983 eligible patients 841 returned the questionnaire and were included into the analysis (429 in 2011, 412 in 2012). The median age was 76.7 years (50.8% male). Patients in the two years were well balanced in regard to main diagnoses and co-morbidities. Mean LOS in the overall patient population was 10.0 days and comparable between the 2011 cohort and the 2012 cohort (9.7 vs 10.3; p = 0.43). Overall satisfaction with care changed only slightly after introduction of SwissDRG and remained high (89.0% vs 87.8%; p = 0.429).
Investigating the influence of the implementation of SwissDRG in 2012 regarding LOS patients' outcome and satisfaction, we found no significant changes. However, we observed some noteworthy trends, which should be monitored closely
Harmonic generation and energy transport in dielectric and semiconductors at visible and UV wavelengths: the case of GaP
We study inhibition of absorption, transparency, energy and momentum
transport of the inhomogeneous component of harmonic pulses in dielectrics and
semiconductors, at visible and UV wavelengths, focusing on materials like GaP.
In these spectral regions GaP is characterized by large absorption, metallic
behavior or a combination of both. We show that phase locking causes the
generated inhomogeneous signals to propagate through a bulk metallic medium
without being absorbed, that is occurs even in centrosymmetric materials via
the magnetic Lorentz force, and that the transport of energy and momentum is
quite peculiar and seemingly anomalous. These results make it clear that there
are new opportunities in ultrafast nonlinear optics and nano-plasmonics in new
wavelength ranges.Comment: 16 pages, 5 figures, 1 vide
Optical lattice quantum simulator for QED in strong external fields: spontaneous pair creation and the Sauter-Schwinger effect
Spontaneous creation of electron-positron pairs out of the vacuum due to a
strong electric field is a spectacular manifestation of the relativistic
energy-momentum relation for the Dirac fermions. This fundamental prediction of
Quantum Electrodynamics (QED) has not yet been confirmed experimentally as the
generation of a sufficiently strong electric field extending over a large
enough space-time volume still presents a challenge. Surprisingly, distant
areas of physics may help us to circumvent this difficulty. In condensed matter
and solid state physics (areas commonly considered as low energy physics), one
usually deals with quasi-particles instead of real electrons and positrons.
Since their mass gap can often be freely tuned, it is much easier to create
these light quasi-particles by an analogue of the Sauter-Schwinger effect. This
motivates our proposal of a quantum simulator in which excitations of
ultra-cold atoms moving in a bichromatic optical lattice represent particles
and antiparticles (holes) satisfying a discretized version of the Dirac
equation together with fermionic anti-commutation relations. Using the language
of second quantization, we are able to construct an analogue of the spontaneous
pair creation which can be realized in an (almost) table-top experiment.Comment: 21 pages, 10 figure
The nonlinear Schroedinger equation for the delta-comb potential: quasi-classical chaos and bifurcations of periodic stationary solutions
The nonlinear Schroedinger equation is studied for a periodic sequence of
delta-potentials (a delta-comb) or narrow Gaussian potentials. For the
delta-comb the time-independent nonlinear Schroedinger equation can be solved
analytically in terms of Jacobi elliptic functions and thus provides useful
insight into the features of nonlinear stationary states of periodic
potentials. Phenomena well-known from classical chaos are found, such as a
bifurcation of periodic stationary states and a transition to spatial chaos.
The relation of new features of nonlinear Bloch bands, such as looped and
period doubled bands, are analyzed in detail. An analytic expression for the
critical nonlinearity for the emergence of looped bands is derived. The results
for the delta-comb are generalized to a more realistic potential consisting of
a periodic sequence of narrow Gaussian peaks and the dynamical stability of
periodic solutions in a Gaussian comb is discussed.Comment: Enhanced and revised version, to appear in J. Nonlin. Math. Phy
Robustness of circadian clocks to daylight fluctuations: hints from the picoeucaryote Ostreococcus tauri
The development of systemic approaches in biology has put emphasis on
identifying genetic modules whose behavior can be modeled accurately so as to
gain insight into their structure and function. However most gene circuits in a
cell are under control of external signals and thus quantitative agreement
between experimental data and a mathematical model is difficult. Circadian
biology has been one notable exception: quantitative models of the internal
clock that orchestrates biological processes over the 24-hour diurnal cycle
have been constructed for a few organisms, from cyanobacteria to plants and
mammals. In most cases, a complex architecture with interlocked feedback loops
has been evidenced. Here we present first modeling results for the circadian
clock of the green unicellular alga Ostreococcus tauri. Two plant-like clock
genes have been shown to play a central role in Ostreococcus clock. We find
that their expression time profiles can be accurately reproduced by a minimal
model of a two-gene transcriptional feedback loop. Remarkably, best adjustment
of data recorded under light/dark alternation is obtained when assuming that
the oscillator is not coupled to the diurnal cycle. This suggests that coupling
to light is confined to specific time intervals and has no dynamical effect
when the oscillator is entrained by the diurnal cycle. This intringuing
property may reflect a strategy to minimize the impact of fluctuations in
daylight intensity on the core circadian oscillator, a type of perturbation
that has been rarely considered when assessing the robustness of circadian
clocks
A transcriptionally and functionally distinct PD-1<sup>+</sup> CD8<sup>+</sup> T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade.
Evidence from mouse chronic viral infection models suggests that CD8 <sup>+</sup> T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8 <sup>+</sup> T lymphocyte populations with high (PD-1 <sup>T</sup> ), intermediate (PD-1 <sup>N</sup> ) and no PD-1 expression (PD-1 <sup>-</sup> ) from non-small-cell lung cancer patients. PD-1 <sup>T</sup> T cells showed a markedly different transcriptional and metabolic profile from PD-1 <sup>N</sup> and PD-1 <sup>-</sup> lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1 <sup>T</sup> lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1 <sup>T</sup> cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention
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