Metabolic responses to PD1 immune-checkpoint blockade and association with therapeutic benefits - Part II
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Blood
DISEASE(S): Cancer
PROVIDER: ST001236 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:Neuromyelitis optica spectrum disorder (NMO/SD) and its clinical variants have at their core the loss of immune tolerance to aquaporin-4 and perhaps other autoantigens. The characteristic phenotype is disruption of astrocyte function and demyelination of spinal cord, optic nerves, and particular brain regions. In this second of a 2-part article, we present further perspectives regarding the pathogenesis of NMO/SD and how this disease might be amenable to emerging technologies aimed at restoring immune tolerance to disease-implicated self-antigens. NMO/SD appears to be particularly well-suited for these strategies since aquaporin-4 has already been identified as the dominant autoantigen. The recent technical advances in reintroducing immune tolerance in experimental models of disease as well as in humans should encourage quantum leaps in this area that may prove productive for novel therapy. In this part of the article series, the potential for regulatory T and B cells is brought into focus, as are new approaches to oral tolerization. Finally, a roadmap is provided to help identify potential issues in clinical development and guide applications in tolerization therapy to solving NMO/SD through the use of emerging technologies. Each of these perspectives is intended to shine new light on potential cures for NMO/SD and other autoimmune diseases, while sparing normal host defense mechanisms.
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Project description:During music listening, humans routinely acquire the regularities of the acoustic sequences and use them to anticipate and interpret the ongoing melody. Specifically, in line with this predictive framework, it is thought that brain responses during such listening reflect a comparison between the bottom-up sensory responses and top-down prediction signals generated by an internal model that embodies the music exposure and expectations of the listener. To attain a clear view of these predictive responses, previous work has eliminated the sensory inputs by inserting artificial silences (or sound omissions) that leave behind only the corresponding predictions of the thwarted expectations. Here, we demonstrate a new alternate approach in which we decode the predictive electroencephalography (EEG) responses to the silent intervals that are naturally interspersed within the music. We did this as participants (experiment 1, 20 participants, 10 female; experiment 2, 21 participants, 6 female) listened or imagined Bach piano melodies. Prediction signals were quantified and assessed via a computational model of the melodic structure of the music and were shown to exhibit the same response characteristics when measured during listening or imagining. These include an inverted polarity for both silence and imagined responses relative to listening, as well as response magnitude modulations that precisely reflect the expectations of notes and silences in both listening and imagery conditions. These findings therefore provide a unifying view that links results from many previous paradigms, including omission reactions and the expectation modulation of sensory responses, all in the context of naturalistic music listening.SIGNIFICANCE STATEMENT Music perception depends on our ability to learn and detect melodic structures. It has been suggested that our brain does so by actively predicting upcoming music notes, a process inducing instantaneous neural responses as the music confronts these expectations. Here, we studied this prediction process using EEGs recorded while participants listen to and imagine Bach melodies. Specifically, we examined neural signals during the ubiquitous musical pauses (or silent intervals) in a music stream and analyzed them in contrast to the imagery responses. We find that imagined predictive responses are routinely co-opted during ongoing music listening. These conclusions are revealed by a new paradigm using listening and imagery of naturalistic melodies.
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Project description:Biomaterials employed to raise therapeutic immune responses have become a complex and active field. Historically, vaccines have been developed primarily to fight infectious diseases, but recent years have seen the development of immunologically active biomaterials towards an expanding list of non-infectious diseases and conditions including inflammation, autoimmunity, wounds, cancer, and others. This review structures its discussion of these approaches around a progression from single-target strategies to those that engage increasingly complex and multifactorial immune responses. First, the targeting of specific individual cytokines is discussed, both in terms of delivering the cytokines or blocking agents, and in terms of active immunotherapies that raise neutralizing immune responses against such single cytokine targets. Next, non-biological complex drugs such as randomized polyamino acid copolymers are discussed in terms of their ability to raise multiple different therapeutic immune responses, particularly in the context of autoimmunity. Last, biologically derived matrices and materials are discussed in terms of their ability to raise complex immune responses in the context of tissue repair. Collectively, these examples reflect the tremendous diversity of existing approaches and the breadth of opportunities that remain for generating therapeutic immune responses using biomaterials.
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