Induction treatment strategy in multiple sclerosis: a review of past experiences and future perspectives

Abstract The scenario of multiple sclerosis (MS) treatment has changed profoundly in recent decades. In this setting, one of two strategies is usually used: escalation or induction. The first involves a pyramid of possible treatments of increasing efficacy (but also increasing safety risks) that are introduced progressively as needed. The induction strategy, on the other hand, immediately pursues higher efficacy, since drugs with a higher risk profile are used from the outset. Understanding which of these treatment strategies is the more suitable for a given patient is the first step in the therapeutic decision-making process. Prognostic factors evaluated on the basis of the clinical presentation and any disease activity on magnetic resonance imaging (MRI) should guide and help clinicians in making their choices. Even though the pathogenesis of MS is not yet completely understood, specific pathological changes are known to occur in the adaptive and innate immune system over the course of the disease. To date, treatment has been based mainly on two drugs, mitoxantrone and cyclophosphamide, autologous haematopoietic stem cell therapy (within clinical trial setting), but new compounds are now emerging. Among the new treatments, alemtuzumab and cladribine appear to be valid candidates as induction drugs. In this review we provide an overview of induction strategies based on literature evidence and our own past experiences, providing descriptions of clinical cases. We also outline the future perspectives in this field

Engineered exosomes boost the HCV NS3-specific CD8+ T lymphocyte immunity in humans

AbstractAt the present, no anti-Hepatitis C virus (HCV) HCV vaccine is available, and many patients failed the treatment with new class of HCV inhibitors. In HCV infection, both experimental and clinic evidences indicate that a strong CTL-immune response could have significant therapeutic effects. We developed an innovative anti-HCV CD8+ T immunogen based on the uploading in engineered exosomes of full-length HCV-NS3 protein. HCV NS3 exosomes appeared immunogenic when injected in mice, as proven by the detection of a memory CD8+ T lymphocyte pool two weeks after the last of three immunizations. On the other hand, dendritic cells isolated from PBMCs of HCV infected patients activate autologous HCV NS3-specific CD8+ T lymphocytes upon challenge with HCV NS3 exosomes. These results provide the proof-of-principle that engineered exosomes can boost the CD8+ T cell immunity in HCV-infected patients, thus representing a suitable option for patients resisting the therapies with recently discovered HCV inhibitors

Counteraction of HCV-induced oxidative stress concurs to establish chronic infection in liver cell cultures

Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection

Educational ecosystems for Information Science: the case of the University of Pisa

Interdisciplinarity is becoming increasingly important in education. With the rapidly evolving job market, an interdisciplinary education can prepare students for the flexibility and broad knowledge base required to adapt. At the University of Pisa, we recognized the value of an interdisciplinary educational environment during our participation in the European project EINFOSE, where we harmonized the entry requirements for master programs in Information Science. Prior to this project, we had been building study programs in Digital Humanities and Data Science, whose intersection organically nurtured a diverse learning space. Through this lens, we will reflect on the obstacles constituted by disciplinary barriers and stress the importance of a flexible and open ‘ecosystem’ for education. These conclusions will be supported by data analysis on the careers of our students over the last eight years

The role of upper-ocean heat content in the regional variability of Arctic sea ice at sub-seasonal timescales

In recent decades, the Arctic Ocean has undergone changes associated with enhanced poleward inflow of Atlantic and Pacific waters and increased heat flux exchange with the atmosphere in seasonally ice-free regions. The associated changes in upper-ocean heat content can alter the exchange of energy at the ocean–ice interface. Yet, the role of ocean heat content in modulating Arctic sea ice variability at sub-seasonal timescales is still poorly documented. We analyze ocean heat transports and surface heat fluxes between 1980–2021 using two eddy-permitting global ocean reanalyses, C-GLORSv5 and ORAS5, to assess the surface energy budget of the Arctic Ocean and its regional seas. We then assess the role of upper-ocean heat content, computed in the surface mixed layer (Qml) and in the 0–300 m layer (Q300), as a sub-seasonal precursor of sea ice variability by means of lag correlations. Our results reveal that in the Pacific Arctic regions, sea ice variability in autumn is linked with Qml anomalies leading by 1 to 3 months, and this relationship has strengthened in the Laptev and East Siberian seas during 2001–2021 relative to 1980–2000, primarily due to reduced surface heat loss since the mid-2000s. Q300 anomalies act as a precursor for wintertime sea ice variability in the Barents and Kara seas, with considerable strengthening and expansion of this link from 1980–2000 and 2001–2021 in both reanalyses. Our results highlight the role played by upper-ocean heat content in modulating the interannual variability of Arctic sea ice at sub-seasonal timescales. Heat stored in the ocean has important implications for the predictability of sea ice, calling for improvements in forecast initialization and a focus upon regional predictions in the Arctic region.</p

Limitations of Anti-Angiogenic Treatment of Tumors

Clinical trials using anti-vascular endothelial growth factor /(VEGF) molecules induce a modest improvement in overall survival, measurable in weeks to just a few months, and tumors respond differently to these agents. In this review article, we have exposed some tumor characteristics and processes that may impair the effectiveness of anti-angiogenic approaches, including genotypic changes on endothelial cells, the vascular normalization phenomenon, and the vasculogenic mimicry. The usage of anti-angiogenic molecules leads to hypoxic tumor microenvironment which enhances tumor invasiveness. The role of tumor-infiltrating cells, including tumor associated macrophages and fibroblasts (TAMs and TAFs) in the therapeutic response to anti-angiogenic settings was also highlighted. Finally, among the new therapeutic approaches to target tumor vasculature, anti-PD-1 or anti-PD-L1 therapy sensitizing and prolonging the efficacy of anti-angiogenic therapy, have been discussed

Fibroblast growth factor modulates mast cell recruitment in a murine model of prostate cancer

Mast cells are important modifiers of prostate tumor microenvironment. The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system plays a non-redundant autocrine/paracrine role in the growth, vascularization and progression of prostate tumors. Accordingly, the FGF antagonist long pentraxin-3 (PTX3) and the PTX3-derived small molecule FGF-trap NSC12 have been shown to inhibit the growth and vascularization of different FGF-dependent tumor types, including prostate cancer. In this study, we show that recombinant FGF2 is able to cause mast cell recruitment in vivo in the Matrigel plug assay. Conversely, PTX3 overexpression in transgenic mice or treatment with the FGF inhibitor NSC12 result in a significant inhibition of the growth and vascularization of TRAMP-C2 tumor grafts, a murine model of prostate cancer, that were paralleled by a decrease of mast cell infiltrate into the lesion. These data confirm and extend previous observations about the capacity of mast cells to respond chemotactically to FGF2 stimulation and provide evidence about a relationship among mast cell recruitment, angiogenesis, and tumor growth in human prostate adenocarcinom

Sex differences in antiviral immunity in SARS-CoV-2 infection. Mitochondria and mitomiR come into view

Mitochondria are multifaceted organelles representing the ‘powerhouse of cells’ for their function as bioenergetics and biosynthetic hubs. In addition, they play an essential role in the regulation of innate and adaptive immune responses, including host defences against viruses, as well as in in- flammatory responses. This peculiar role of mitochondria is principally because of the activation of adaptor mitochon- drial proteins, known as mitochondrial antiviral signalling (MAVS) proteins. MAVS senses viral RNA and triggers the activation of the transcription factor NF-kB or IFN pathways and autophagy, in order to clear the infection and avoid exces- sive inflammation respectively

Sex-Dependent Outcome of Hepatitis B and C Viruses Infections: Synergy of Sex Hormones and Immune Responses?

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic viruses that differ in their genomic content, life cycle and molecular prognosis. HBV and HCV establish chronic lifespan infections that can evolve to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). This malignant liver cancer affects more commonly male patients than females, with a male-to-female incidence ratio of &lt;Capword&gt;2&lt;/Capword&gt;:1 up to 7:1. Sex significantly contributes to shape the immune responses, contributing to differences in the pathogenesis of infectious diseases, in males and females patients. Females usually develop more intense innate, humoral and cellular immune responses to viral infections and to vaccination compared to male subjects. Sex hormones, in turn, differentially affect the immune responses to viruses, by specific binding to the hormone receptors expressed on the immune cells. In general, estrogens have immune-stimulating effect, while androgens are immune-suppressing. However, sex hormones, such as androgen, can also directly interact with HBV genome integrated into the cell nucleus and activate transcription of HBV oncoproteins. On the other side, estradiol and estrogen receptors protect liver cells from inflammatory damage, apoptosis and oxidative stress, which contribute to fibrosis and malignant transformation preceding HCC. In HCV-associated cirrhosis and HCC the decreased expression of estrogen receptor alfa (ERα) in male patients may explain the worse outcome of HCV infection in men than in women. The synergistic action of male and female sex hormones and of immune responses, together with viral factors contribute to the mechanism of sex/gender disparity in the outcome and progression of hepatitis viruses infection

Erythropoietin is involved in the angiogenic potential of bone marrow macrophages in multiple myeloma

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