Neuroimmune interactions in chronic itch of atopic dermatitis Yosipovitch, G.; Berger, T.; Fassett, M.S.
JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology,
February 2020, Letnik:
34, Številka:
2
Journal Article
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Itch is a defining symptom of atopic dermatitis. Crosstalk between keratinocytes, the immune system and non‐histaminergic sensory nerves is responsible for the pathophysiology of chronic itch in ...atopic dermatitis. An expanding understanding of the contribution of the nervous system and its interaction with immune pathways in atopic itch are helping to identify new therapeutic strategies.
In this review, the immune‐to‐brain communication pathways are briefly summarized, with emphasis on the impact of immune cells and their mediators on learning, memory and other cognitive domains. ...Further, the acute response of the central nervous system to peripherally generated inflammatory stimuli – termed as sickness behaviour – is described, and the central role of microglia in this immune‐to‐brain crosstalk in physiological and pathological conditions is highlighted. Finally, the role and consequences of immunological processes related to cognitive impairment in multiple sclerosis are discussed.
Caspase functions in cell death and disease McIlwain, David R; Berger, Thorsten; Mak, Tak W
Cold Spring Harbor perspectives in biology,
2013-Apr-01, 2013-04-01, 20130401, Letnik:
5, Številka:
4
Journal Article
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Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their ...production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.
The binding affinity and kinetics of target engagement are fundamental to establishing structure-activity relationships (SARs) for prospective therapeutic agents. Enhancing these binding parameters ...for operative targets, while minimizing binding to off-target sites, can translate to improved drug efficacy and a widened therapeutic window. Compound activity is typically assessed through modulation of an observed phenotype in cultured cells. Quantifying the corresponding binding properties under common cellular conditions can provide more meaningful interpretation of the cellular SAR analysis. Consequently, methods for assessing drug binding in living cells have advanced and are now integral to medicinal chemistry workflows. In this review, we survey key technological advancements that support quantitative assessments of target occupancy in cultured cells, emphasizing generalizable methodologies able to deliver analytical precision that heretofore required reductionist biochemical approaches.
The increasing number of disease‐modifying treatments available for multiple sclerosis has broadened treatment options for patients, but also challenges clinicians to select the best therapy for each ...individual at the appropriate stage of the disease. Early prediction of treatment response still remains one of the main difficulties in the management of multiple sclerosis patients. The concept of ‘no evidence of disease activity’ (NEDA) has been proposed as a surrogate for treatment response based on the absence of relapses, disability progression and radiological activity. Although there are several apparently logical arguments for the NEDA approach, there are also some major concerns that have to be considered and that are not sufficiently addressed yet. Amongst others, each parameter's limitations are not eliminated solely by its use within a composite score, and the contribution of each parameter to NEDA is not well balanced, as the detection of, for example, a single new magnetic resonance imaging lesion is considered as significant as the occurrence of a severely disabling relapse. NEDA in its current form also neglects underlying pathophysiology of the disease, has not been shown to fulfil formal criteria of a surrogate marker and its prognostic value has not been sufficiently evidenced yet. From a clinical point of view, ‘evidence of disease activity’ seems the more relevant surrogate; however, its implications are even less clear than those of NEDA. Here, existing literature on NEDA is critically reviewed and improvements are discussed that value its potential use in clinical trials and, even more importantly, treatment decision making in daily routine.
Exoplanet catalogs produced by surveys suffer from a lack of completeness (not every planet is detected) and less than perfect reliability (not every planet in the catalog is a true planet), ...particularly near the survey's detection limit. Exoplanet occurrence rate studies based on such a catalog must be corrected for completeness and reliability. The final Kepler data release, DR25, features a uniformly vetted planet candidate catalog and data products that facilitate corrections. We present a new probabilistic approach to the characterization of Kepler completeness and reliability, making full use of the Kepler DR25 products. We illustrate the impact of completeness and reliability corrections with a Poisson-likelihood occurrence rate method, using a recent stellar properties catalog that incorporates Gaia stellar radii and essentially uniform treatment of the stellar population. Correcting for reliability has a significant impact: the exoplanet occurrence rate for orbital period and radius within 20% of Earth's around GK dwarf stars, corrected for reliability, is , whereas not correcting results in -correcting for reliability reduces this occurrence rate by more than a factor of two. We further show that using Gaia-based versus DR25 stellar properties impacts the same occurrence rate by a factor of two. We critically examine the the DR25 catalog and the assumptions behind our occurrence rate method. We propose several ways in which confidence in both the Kepler catalog and occurrence rate calculations can be improved. This work provides an example of how the community can use the DR25 completeness and reliability products.
Treatment of head and neck cancer (HNC) often leads to visible and severe functional impairments. In addition, patients often suffer from a variety of psychosocial problems, significantly associated ...with a decreased quality of life. We aimed to compare depression, anxiety, fatigue and quality of life (QoL) between HNC patients and a large sample of the general population in Germany and to examine the impact of sociodemographic, behavioral and clinical factors on these symptoms.
We assessed data of HNC patients during the aftercare consultation at the Leipzig University Medical Center with a patient reported outcome (PRO) tool named "OncoFunction". Depression, anxiety, fatigue and QoL were assessed using validated outcome measures including the PHQ-9, the GAD-2, and the EORTC QLQ-C30 questionnaire.
A total of 817 HNC patients were included in our study and compared to a sample of 5018 individuals of the general German population. HNC patients showed significantly higher levels of impairment in all dimensions assessed. Examination of association between depression, anxiety, fatigue and QoL and clinical as well as sociodemographic variables showed significant relationships between occupational status, ECOG-state, body mass index and time since diagnosis.
HNC patients suffer significantly from psychological distress. The used questionnaires are suitable for the use in daily routine practice and can be helpful to increase the detection of depression, anxiety and fatigue and therefore can improve HNC aftercare.
It is well known that web-based interventions can be effective treatments for depression. However, dropout rates in web-based interventions are typically high, especially in self-guided web-based ...interventions. Rigorous empirical evidence regarding factors influencing dropout in self-guided web-based interventions is lacking due to small study sample sizes. In this paper we examined predictors of dropout in an individual patient data meta-analysis to gain a better understanding of who may benefit from these interventions.
A comprehensive literature search for all randomized controlled trials (RCTs) of psychotherapy for adults with depression from 2006 to January 2013 was conducted. Next, we approached authors to collect the primary data of the selected studies. Predictors of dropout, such as socio-demographic, clinical, and intervention characteristics were examined.
Data from 2705 participants across ten RCTs of self-guided web-based interventions for depression were analysed. The multivariate analysis indicated that male gender relative risk (RR) 1.08, lower educational level (primary education, RR 1.26) and co-morbid anxiety symptoms (RR 1.18) significantly increased the risk of dropping out, while for every additional 4 years of age, the risk of dropping out significantly decreased (RR 0.94).
Dropout can be predicted by several variables and is not randomly distributed. This knowledge may inform tailoring of online self-help interventions to prevent dropout in identified groups at risk.
Over several decades, studies sought potential markers to diagnose and to predict the clinical course of central nervous system (CNS) demyelinating disorders, especially in multiple sclerosis, acute ...disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. Reliable biomarkers would ensure correct diagnoses, determine future disease evolvements, stratify patients for appropriate treatments and monitor disease activity and treatment effects – in summary, meet the longing for personalized medicine in these diseases. Out of a plethora of potential biomarker candidates antibodies have turned (again) into the scientific focus, due to pivotal immunological and neuropathological findings in the past 20 years. A major breakthrough and stimulus for further research was the identification of anti‐aquaporin‐4 antibodies in neuromyelitis optica. Various other myelin and non‐myelin antigens were investigated in detail for diagnostic and prognostic purposes, such as antibodies to myelin oligodendrocyte glycoprotein or to the potassium channel KIR4.1. Further, the use of biopharmaceutical treatments in multiple sclerosis led to intense research activities to identify anti‐treatment neutralizing antibodies and their clinical consequences. This review briefly summarizes the current knowledge on antibodies in the diagnosis, prognosis, disease and treatment monitoring of CNS demyelinating disorders.
The adaptive immune system recognizes antigens
an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance ...for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.
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