276 research outputs found
Viral Hepatitides, Inflammation and Tumour Microenvironment
No full textIn this chapter, we discuss the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in the establishment of hepatocellular carcinoma (HCC), highlighting the key role of the multiple, non-mutually exclusive, pathways involved in the modulation of immune responses and in the orchestration of a chronic low-level inflammation state favouring HCC development. In particular, we discuss (i) HCC as a classical paradigm of inflammation-linked cancer; (ii) the role of the most relevant inflammatory cytokines involved (i.e. IL-6, TNF-α, IL-18, IL-1β, TGF-β IL-10); (iii) the role of T cell exhaustion by immune checkpoints; (iv) the role of the Wnt3a/β-catenin signalling pathway and (v) the role of different subsets of suppressor cells
Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia patients after clearance of HCV viremia with direct-acting antivirals
Get PDFIntroduction
Type II Mixed cryoglobulinemia (MC) is an autoimmune and benign lymphoproliferative disorder caused by
Hepatitis C virus (HCV) and characterized by the expansion of monoclonal CD27+ IgM+ B cells producing a
rheumatoid factor often encoded by the VH1-69 and VK3-20 genes. These cells display peculiar phenotypic and
functional features: in particular, they commonly express low levels of CD21 (CD21low B cells), an array of
inhibitory and apoptosis-related genes and a distinctive pattern of homing receptors, fail to proliferate in
response to the stimulation of BCR or of TLR9 and, similarly to murine B cells made anergic by continual
antigenic stimulation, overexpress pERK and are prone to apoptosis.
Usually MC regresses after eradication of HCV with interferon (IFN), whose immunomodulatory activity might
contribute to this effect; the newly available direct-acting antivirals (DAAs) rapidly suppress HCV viremia in
HCV+MC patients and lack the immunomodulatory properties of IFN.
Aim
To investigate phenotypic and functional changes in clonal B cells of MC patients with sustained virologic
response to DAAs, untangling the effects of BCR disengagement in a human model of virus-driven anergy and
exhaustion.
Results
In patients treated with DAA, B cell phenotype, constitutive and BCR-induced ERK signaling, spontaneous
apoptosis and cell proliferation were analyzed before and after HCV eradication, using healthy donors as
control. Immunophenotyping studies were performed with combinations of fluorochrome-labeled monoclonal
antibodies, using the VH1-69-specific G6 mAb (which recognize an epitope of the VH1-69-encoded protein) to
identify VH1-69+ B cells; spontaneous apoptosis was assessed by staining cells with annexin V and 7-
aminoactinomycin D; the intracellular pERK content was measured by the BD PhosFlow system and
represented as pERK-specific Mean Fluorescence Intensity (MFI); finally, cell proliferation was evaluated at day
5 of in vitro culture by the carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution assay. All these
experiments have been done by flow cytometry. Phenotypic and functional analyses in untreated patients
were in agreement with previous data showing an anergic status and an exhausted behavior of VH1-69+ CD21low
B cells. After treatment with DAA, when all patients were negative for HCV RNA, it was observed a slow
reduction of VH1-69+ CD21low B cells in peripheral blood; moreover, these cells showed a significantly reduced
constitutive ERK phosphorylation and a significative decrease in spontaneous apoptosis after eradication of the
virus. To investigate whether reduced lifespan was related to ERK signaling, MC B cells were treated with the
MEK/ERK inhibitor U0126; no effect on spontaneous in vitro apoptosis was observed, suggesting that ERK
signaling is not directly involved in the pro-apoptotic pathway of these cells. Despite phenotypic changes,
clonal B cells failed to restore their capacity to proliferate in response to TLR9 stimulation.
Conclusions
Clonal B cells of HCV+MC display signatures of anergy induced by continual BCR occupancy and of exhaustion
driven by chronic viral infection. Anergy features (pERK overexpression and accelerated apoptosis) rapidly
revert after disengagement from HCV; phenotypic and functional features of exhaustion persist for several
months. The rapid clearance of HCV viremia with DAAs offers a unique model for untangling the interplay of
virus-driven anergy and exhaustion in human B cells
Barnaba: software for analysis of nucleic acid structures and trajectories
Get PDFRNA molecules are highly dynamic systems characterized by a complex interplay between sequence, structure, dynamics, and function. Molecular simulations can potentially provide powerful insights into the nature of these relationships. The analysis of structures and molecular trajectories of nucleic acids can be nontrivial because it requires processing very high-dimensional data that are not easy to visualize and interpret. Here we introduce Barnaba, a Python library aimed at facilitating the analysis of nucleic acid structures and molecular simulations. The software consists of a variety of analysis tools that allow the user to (i) calculate distances between three-dimensional structures using different metrics, (ii) back-calculate experimental data from three-dimensional structures, (iii) perform cluster analysis and dimensionality reductions, (iv) search three-dimensional motifs in PDB structures and trajectories, and (v) construct elastic network models for nucleic acids and nucleic acids-protein complexes. In addition, Barnaba makes it possible to calculate torsion angles, pucker conformations, and to detect base-pairing/base-stacking interactions. Barnaba produces graphics that conveniently visualize both extended secondary structure and dynamics for a set of molecular conformations. The software is available as a command-line tool as well as a library, and supports a variety of file formats such as PDB, dcd, and xtc files. Source code, documentation, and examples are freely available at https://github.com/srnas/barnaba under GNU GPLv3 license
Therapeutic Implications of Immunogenic Cell Death in Human Cancer
Get PDFDendritic cells (DCs) are central to the adoptive immune response, and their function is regulated by diverse signals in a context-specific manner. Different DCs have been described in physiologic conditions, inflammation, and cancer, prompting a series of questions on how adoptive immune responses, or tolerance, develop against tumors. Increasing evidence suggests that tumor treatments induce a dramatic change on tumor-infiltrating lymphocytes and, in particular, on some DC subtypes. In this review, we summarize the latest evidence on the role of DCs in cancer and preliminary evidence on chemotherapy-associated antigens identified in human cancers
Adults’ representation of children’s emotions and coping strategies related to earthquakes
No full textBackground and aims. For children, the traumatic psychological impact of natural disasters such as earthquakes has been documented. Also the study of children’s earthquake-related emotions and coping strategies has gathered increasing attention. However, little is known on the corresponding adults’ representation. Examining the influence of earthquake experience: (a) we hypothesized adults to consider fear more salient than sadness, during and after earthquakes, and (b) we explored how adults represent the efficacy of coping strategies related to children’s fear and sadness. Methods. The participants were 569 Italian university students with different earthquake experience (no experience/damage: 70%; experience with damage: 30%). Referring to what happens during and after earthquakes, they were asked to list children’s (a) expected emotions, and (b) coping strategies for diminishing fear and sadness. We coded (a) the number of fear and sadness terms; (b) the presence of 13 coping strategies (Zimmer-Gembeck & Skinner, 2011), i.e. problem solving, information-seeking, helplessness, escape, self-reliance, support-seeking, delegation, social isolation, accomodation, negotiation, submission, opposition, and support-giving (agreement for reliability: 95%). Results. We used Generalized Linear Mixed Model. Fear was reported more frequently than sadness, and more frequently during vs. after earthquakes (and vice versa for sadness). Some coping strategies were reported rarely (≤ 5%: helplessness, escape, delegation, social isolation, negotiation, submission, opposition, and support-giving). Among the others, problem solving, information-seeking, self-reliance, and support-seeking were more salient for fear vs. sadness, and vice versa for accommodation. Problem solving was more salient during vs. after earthquakes, and vice versa for accommodation. These effects partially depended from earthquake experience. Conclusions. Our findings enable to deepen the knowledge on adults’ emotional representation of earthquakes, filling a gap in the literature. At an applied level, they can help professionals to develop prevention trainings to prepare children to disasters, promoting their knowledge on earthquake-related emotions and efficacious coping strategies
La tomba e il testamento di Barnaba da Morano, un giurista nella Verona fra Tre e Quattrocento
No full textIl saggio considera le ultime volontà di Barnaba da Morano, stese nel 1411, in rapporto al suo monumento funebre che, pur disgregato, si conserva ancora nella chiesa di San Fermo Maggiore a Verona e che si caratterizzava per una stretta integrazione tra pittura e scultura
The immune system view of the coronavirus SARS-CoV-2
Get PDFKnowing the “point of view” of the immune system is essential to understand the characteristic of a pandemic, such as that generated by the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2, responsible for the Coronavirus Disease (COVID)-19. In this review, we will discuss the general host/pathogen interactions dictating protective immune response or immunopathology, addressing the role of immunity or immunopathology in influencing the clinical infection outcome, and debate the potential immunoprophylactic and immunotherapy strategies required to fight the virus infectio
Barnaba: Software for Analysis of Nucleic Acids Structures and Trajectories
No full textAbstractRNA molecules are highly dynamic systems characterized by a complex interplay between sequence, structure, dynamics, and function. Molecular simulations can potentially provide powerful insights into the nature of these relationships. The analysis of structures and molecular trajectories of nucleic acids can be non-trivial because it requires processing very high-dimensional data that are not easy to visualize and interpret.Here we introduce Barnaba, a Python library aimed at facilitating the analysis of nucleic acids structures and molecular simulations. The software consists of a variety of analysis tools that allow the user to i) calculate distances between three-dimensional structures using different metrics, ii) back-calculate experimental data from three-dimensional structures, iii) perform cluster analysis and dimensionality reductions, iv) search three-dimensional motifs in PDB structures and trajectories and v) construct elastic network models (ENM) for nucleic acids and nucleic acids-protein complexes.In addition, Barnaba makes it possible to calculate torsion angles, pucker conformations and to detect base-pairing/base-stacking interactions. Barnaba produces graphics that conveniently visualize both extended secondary structure and dynamics for a set of molecular conformations. The software is available as a command-line tool as well as a library, and supports a variety of 1le formats such as PDB, dcd and xtc 1les. Source code, documentation and examples are freely available athttps://github.com/srnas/barnabaunder GNU GPLv3 license.</jats:p
Selective killing of hepatitis B envelope antigen-specific B cells by class I-restricted, exogenous antigen-specific T lymphocytes.
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