HDAC inhibition potentiates immunotherapy in triple negative breast cancer.

Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy. Tumor cells were co-cultured with human peripheral blood mononuclear cells (PBMCs) and flow cytometric immunophenotyping was performed to define the role of epigenetic priming in promoting tumor antigen presentation and immune cell activation. We found that HDACi up-regulate PD-L1 mRNA and protein expression in a time-dependent manner in TNBC cells, but not in hormone responsive cells. Focusing on TNBC, HDACi up-regulated PD-L1 and HLA-DR on tumor cells when co-cultured with PBMCs and down-regulated CD4+ Foxp3+ Treg in vitro. HDACi significantly enhanced the in vivo response to PD-1/CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model, the only currently available experimental system with functional resemblance to human TNBC. This resulted in a significant decrease in tumor growth and increased survival, associated with increased T cell tumor infiltration and a reduction in CD4+ Foxp3+ T cells in the tumor microenvironment. Overall, our results suggest a novel role for HDAC inhibition in combination with immune checkpoint inhibitors and identify a promising therapeutic strategy, supporting its further clinical evaluation for TNBC treatment

Absolute Present, Zen and Schrödinger’s One Mind

Erwin Schrödinger holds a prominent place in the history of science primarily due to his crucial role in the development of quantum physics. What is perhaps lesser known are his insights into subject-object duality, consciousness and mind. He documented himself that these were influenced by the Upanishads, a collection of ancient Hindu spiritual texts. Central to his thoughts in this area is that Mind is only One and there is no separation between subject and object. This chapter aims to bridge Schrödinger’s view on One Mind with the teachings of Dōgen, a twelfth century Zen master. This bridge is formed by addressing the question of how time relates to One Mind, and subject-object duality. Schrödinger describes the experience of One Mind to be like a timeless now, whereas subject-object duality involves a linear continuum of time. We show how these differing positions are unified in the notion of ‘absolute present’, which was put forward in the philosophy of Nishida Kitarō (1871–1945). In addition, we argue that it is in this notion of absolute present that the views of Schrödinger, Dōgen and Nishida meet

Asymptotically stable phase synchronization revealed by autoregressive circle maps

A new type of nonlinear time series analysis is introduced, based on phases, which are defined as polar angles in spaces spanned by a finite number of delayed coordinates. A canonical choice of the polar axis and a related implicit estimation scheme for the potentially underlying auto-regressive circle map (next phase map) guarantee the invertibility of reconstructed phase space trajectories to the original coordinates. The resulting Fourier approximated, Invertibility enforcing Phase Space map (FIPS map) is well suited to detect conditional asymptotic stability of coupled phases. This rather general synchronization criterion unites two existing generalisations of the old concept and can successfully be applied e.g. to phases obtained from ECG and airflow recordings characterizing cardio-respiratory interaction.Comment: PDF file, 232 KB, 24 pages, 3 figures; cheduled for Phys. Rev. E (Nov) 200

Measuring Information Transfer

An information theoretic measure is derived that quantifies the statistical coherence between systems evolving in time. The standard time delayed mutual information fails to distinguish information that is actually exchanged from shared information due to common history and input signals. In our new approach, these influences are excluded by appropriate conditioning of transition probabilities. The resulting transfer entropy is able to distinguish driving and responding elements and to detect asymmetry in the coupling of subsystems.Comment: 4 pages, 4 Figures, Revte

A Unified Model of Internet Scale Alerting Services

In the last years, alerting systems have gained strengthened attention. Several systems have been implemented. For the evaluation and cooperation of these systems, the following problems arise: The systems and their models are not compatible, and existing models are only appropriate for a subset of conceivable application domains. Due to modeling differences, a simple integration of different alerting systems is impossible. What is needed, is a unified model that covers the whole variety of alerting service applications. This paper provides a unified model for alerting services that captures the special constraints of most application areas. The model can serve as a basis for an evaluation of alerting service implementations. In addition to the unified model, we define a general profile structure by which clients can specify their interest. This structure is independent of underlying profile definition languages. To eliminate drawbacks of the existing non-cooperating solitary services we introduce a new technique, the Mediating Alerting Service (MediAS). It establishes the cooperation of alerting services in an hierarchical and parallel way

Self-adjoint Lyapunov variables, temporal ordering and irreversible representations of Schroedinger evolution

In non relativistic quantum mechanics time enters as a parameter in the Schroedinger equation. However, there are various situations where the need arises to view time as a dynamical variable. In this paper we consider the dynamical role of time through the construction of a Lyapunov variable - i.e., a self-adjoint quantum observable whose expectation value varies monotonically as time increases. It is shown, in a constructive way, that a certain class of models admit a Lyapunov variable and that the existence of a Lyapunov variable implies the existence of a transformation mapping the original quantum mechanical problem to an equivalent irreversible representation. In addition, it is proved that in the irreversible representation there exists a natural time ordering observable splitting the Hilbert space at each t>0 into past and future subspaces.Comment: Accepted for publication in JMP. Supercedes arXiv:0710.3604. Discussion expanded to include the case of Hamiltonians with an infinitely degenerate spectru

de Branges-Rovnyak spaces: basics and theory

For $S$ a contractive analytic operator-valued function on the unit disk ${\mathbb D}$, de Branges and Rovnyak associate a Hilbert space of analytic functions ${\mathcal H}(S)$ and related extension space ${\mathcal D(S)}$ consisting of pairs of analytic functions on the unit disk ${\mathbb D}$. This survey describes three equivalent formulations (the original geometric de Branges-Rovnyak definition, the Toeplitz operator characterization, and the characterization as a reproducing kernel Hilbert space) of the de Branges-Rovnyak space ${\mathcal H}(S)$, as well as its role as the underlying Hilbert space for the modeling of completely non-isometric Hilbert-space contraction operators. Also examined is the extension of these ideas to handle the modeling of the more general class of completely nonunitary contraction operators, where the more general two-component de Branges-Rovnyak model space ${\mathcal D}(S)$ and associated overlapping spaces play key roles. Connections with other function theory problems and applications are also discussed. More recent applications to a variety of subsequent applications are given in a companion survey article

Generalized Chaotic Synchronizationin Coupled Ginzburg-Landau Equations

Generalized synchronization is analyzed in unidirectionally coupled oscillatory systems exhibiting spatiotemporal chaotic behavior described by Ginzburg-Landau equations. Several types of coupling betweenthe systems are analyzed. The largest spatial Lyapunov exponent is proposed as a new characteristic of the state of a distributed system, and its calculation is described for a distributed oscillatory system. Partial generalized synchronization is introduced as a new type of chaotic synchronization in spatially nonuniform distributed systems. The physical mechanisms responsible for the onset of generalized chaotic synchronization in spatially distributed oscillatory systems are elucidated. It is shown that the onset of generalized chaotic synchronization is described by a modified Ginzburg-Landau equation with additional dissipation irrespective of the type of coupling. The effect of noise on the onset of a generalized synchronization regime in coupled distributed systems is analyzed.Comment: 12 page

Olive phenology as a sensitive indicator of future climatic warming in the Mediterranean

Experimental and modelling work suggests a strong dependence of olive flowering date on spring temperatures. Since airborne pollen concentrations reflect the flowering phenology of olive populations within a radius of 50 km, they may be a sensitive regional indicator of climatic warming. We assessed this potential sensitivity with phenology models fitted to flowering dates inferred from maximum airborne pollen data. Of four models tested, a thermal time model gave the best fit for Montpellier, France, and was the most effective at the regional scale, providing reasonable predictions for 10 sites in the western Mediterranean. This model was forced with replicated future temperature simulations for the western Mediterranean from a coupled ocean-atmosphere general circulation model (GCM). The GCM temperatures rose by 4·5 °C between 1990 and 2099 with a 1% per year increase in greenhouse gases, and modelled flowering date advanced at a rate of 6·2 d per °C. The results indicated that this long-term regional trend in phenology might be statistically significant as early as 2030, but with marked spatial variation in magnitude, with the calculated flowering date between the 1990s and 2030s advancing by 3–23 d. Future monitoring of airborne olive pollen may therefore provide an early biological indicator of climatic warming in the Mediterranean