A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector

A General-Purpose CRN-to-DSD Compiler with Formal Verification, Optimization, and Simulation Capabilities

The mathematical formalism of mass-action chemical reaction networks (CRNs) has been proposed as a mid-level programming language for dynamic molecular systems. Several systematic methods for translating CRNs into domain-level strand displacement (DSD) systems have been developed theoretically, and in some cases demonstrated experimentally. Software that facilitates the simulation of CRNs and DSDs, and that helps automate the construction of DSDs from CRNs, has been instrumental in advancing the field, but as yet has not incorporated the fundamental enabling concept for programming languages and compilers: a rigorous abstraction hierarchy with well-defined semantics at each level, and rigorous correctness proofs establishing the correctness of compilation from a higher level to a lower level. Here, we present a CRN-to-DSD compiler, Nuskell, that makes a first step in this direction. To support the wide range of translation schemes that have already been proposed in the literature, as well as potential new ones that are yet to be proposed, Nuskell provides a domain-specific programming language for translation schemes. A notion of correctness is established on a case-by-case basis using the rate-independent stochastic-level theories of pathway decomposition equivalence and/or CRN bisimulation. The “best” DSD implementation for a given CRN can be found by comparing the molecule size, network size, or simulation behavior for a variety of translation schemes. These features are illustrated with a 3-reaction oscillator CRN and a 32-reaction feedforward boolean circuit CRN

Differences in cytokine synthesis by the sub-populations of dendritic cells from afferent lymph

Two phenotypically distinct subpopulations of dendritic cells (SIRPα(+) CC81Ag(−) DC and SIRPα(−) CC81Ag(+) DC) have previously been identified in bovine afferent lymph which show functional differences when assayed in vitro. The purpose of this study was to investigate whether differences in cytokine production between the two subpopulations might occur which could influence the bias of the immune response they stimulate. Qualitative and quantitative polymerase chain reactions were used to detect specific mRNA transcripts and flow cytometry and enzyme-linked immunosorbent assays were used to detect protein production. The SIRPα(−) CC81Ag(+) DC produced considerably more interleukin-12 (IL-12) mRNA transcripts and protein than the SIRPα(+) CC81Ag(−) DC. Conversely, SIRPα(+) CC81Ag(−) DC contained more of both transcripts and protein for IL-1 and of transcripts for IL-6. A small percentage of both subpopulations produced interferon-γ (IFN-γ) as evidenced by cytoplasmic staining. Stimulation of DC by culture with CD40L(+) cells increased the production of IL-1, IL-6 and IL-12 but quantitative differences between the subpopulations remained. Production of IL-10 was also evident following culture with CD40L(+) cells or lipopolysaccharide primarily by the SIRPα(+) CC81Ag(−) DC. No evidence was found for type 1 IFN production, and hence plasmacytoid DC, by DC in afferent lymph; both subpopulations appear to be myeloid in origin. These different cytokine repertoires of the two subpopulations of ex vivo DC isolated from afferent lymph imply functional differences that could influence the presentation of antigen to T cells and bias of the immune response following vaccination or infection

Fatal pericardial tamponade after superior vena cava stenting.

Contains fulltext : 80672.pdf (publisher's version ) (Closed access)We discuss a fatal complication of percutaneous superior vena cava (SVC) self-expandable stent placement in a patient with superior vena cava syndrome (SVCS). The SVCS was caused by a malignant mediastinal mass with total occlusion of the SVC. Twenty-four hours after the procedure, the patient died of a hemopericardial tamponade. In the literature, only seven cases have been described with this life-threatening complication. Patients with a necrotic tumor mass are more likely to develop this complication. Knowledge of this complication may increase patient survival

Antigen Presenting Properties of a Myeloid Dendritic-Like Cell in Murine Spleen

<div><p>This paper distinguishes a rare subset of myeloid dendritic-like cells found in mouse spleen from conventional (c) dendritic cells (DC) in terms of phenotype, function and gene expression. These cells are tentatively named “L-DC” since they resemble dendritic-like cells produced in longterm cultures of spleen. L-DC can be distinguished on the basis of their unique phenotype as CD11b^hiCD11c^loMHCII^-CD43⁺Ly6C^-Ly6G^-Siglec-F^- cells. They demonstrate similar ability as cDC to uptake and retain complex antigens like mannan via mannose receptors, but much lower ability to endocytose and retain soluble antigen. While L-DC differ from cDC by their inability to activate CD4⁺ T cells, they are capable of antigen cross-presentation for activation of CD8⁺ T cells, although less effectively so than the cDC subsets. In terms of gene expression, CD8^- cDC and CD8⁺ cDC are quite distinct from L-DC. CD8⁺ cDC are distinguishable from the other two subsets by expression of <i>CD24a</i>, <i>Clec9a</i>, <i>Xcr1</i> and <i>Tlr11</i>, while CD8^- cDC are distinguished by expression of <i>Ccnd1</i> and <i>H-2Eb2</i>. L-DC are distinct from the two cDC subsets through upregulated expression of <i>Clec4a3</i>, <i>Emr4</i>, <i>Itgam</i>, <i>Csf1r</i> and <i>CD300ld</i>. The L-DC gene profile is quite distinct from that of cDC, confirming a myeloid cell type with distinct antigen presenting properties.</p></div