Skeletal Muscle Is an Early Site of Zika Virus Replication and Injury, Which Impairs Myogenesis.

Zika virus (ZIKV) infection became a worldwide concern due to its correlation with the development of microcephaly and other neurological disorders. ZIKV neurotropism is well characterized, but the role of peripheral viral amplification to brain infection remains unknown. Here, we found that ZIKV replicates in human primary skeletal muscle myoblasts, impairing its differentiation into myotubes but not interfering with the integrity of the already-formed muscle fibers. Using mouse models, we showed ZIKV tropism to muscle tissue either during embryogenesis after maternal transmission or when infection occurred after birth. Interestingly, ZIKV replication in the mouse skeletal muscle started immediately after ZIKV inoculation, preceding viral RNA detection in the brain and causing no disruption to the integrity of the blood brain barrier, and remained active for more than 2 weeks, whereas replication in the spleen and liver were not sustained over time. In addition, ZIKV infection of the skeletal muscle induces necrotic lesions, inflammation, and fiber atrophy. We also found a reduction in the expression of regulatory myogenic factors that are essential for muscle repair after injury. Taken together, our results indicate that the skeletal muscle is an early site of viral amplification and lesion that may result in late consequences in muscle development after ZIKV infection. IMPORTANCE Zika Virus (ZIKV) neurotropism and its deleterious effects on central nervous system have been well characterized. However, investigations of the initial replication sites for the establishment of infection and viral spread to neural tissues remain underexplored. A complete description of the range of ZIKV-induced lesions and others factors that can influence the severity of the disease is necessary to prevent ZIKV's deleterious effects. ZIKV has been shown to access the central nervous system without significantly affecting blood-brain barrier permeability. Here, we demonstrated that skeletal muscle is an earlier site of ZIKV replication, contributing to the increase of peripheral ZIKV load. ZIKV replication in muscle promotes necrotic lesions and inflammation and also impairs myogenesis. Overall, our findings showed that skeletal muscle is involved in pathogenesis and opens new fields in the investigation of the long-term consequences of early infection.

JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis.

Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.

Potential Pathogenic Role of Anti-Signal Recognition Protein and Anti-3-hydroxy-3-methylglutaryl-CoA Reductase Antibodies in Immune-Mediated Necrotizing Myopathies.

PURPOSE OF REVIEW: This review provides an overview of the potential pathogenic roles of anti-SRP and anti-HMGCR in IMNM over the past 5 years. RECENT FINDINGS: Idiopathic inflammatory myopathies (IIM) are a group of acquired autoimmune disorders that mainly affect the skeletal muscle tissue. Classification criteria of IIM are comprised of polymyositis, dermatomyositis, inclusion body myositis and immune-mediated necrotizing myopathies. One important hallmark of autoimmune diseases is the detection of autoantibodies in patient sera. The anti-SRP (signal recognition particle) and anti-HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) antibodies are specifically associated with IMNM patients, and their detection has been described as related to disease severity. The muscles of IMNM patients are characterized by necrosis, atrophy and regenerating fibres with sparse inflammatory infiltrates. Although an important correlation between autoantibody titres, creatine kinase levels and disease progression/severity has been described in the last few years, the potential pathogenic roles of these autoantibodies have only recently been described.

Biosimilar Use in Breast Cancer Treatment: A National Survey of Brazilian Oncologists' Opinions, Practices, and Concerns.

PURPOSE: Breast cancer is the most common malignancy in Brazilian women, with 66,280 new cases in 2020 (with 20% overexpressing human epidermal growth factor receptor 2 [HER2]). The trastuzumab biosimilar was the first oncology biosimilar approved in Brazil for HER2-positive breast cancer treatment. This study aimed to assess the current level of knowledge of biosimilars, comfort of use, extrapolation indications, and switching of practices among oncologists in Brazil. METHODS: A 24-question survey was developed using an online platform that sought information regarding responders' characteristics and use of biosimilars. The survey analyzed the basic knowledge of biosimilars, trastuzumab biosimilars, level of comfort with extrapolation, switching treatment regimens, and opinions concerning the cost of HER2-positive breast cancer therapy. Data were collected between July and September 2019 and included 144 oncologists from five Brazilian regions. RESULTS: In total, 95% of respondents could identify the most appropriate definition of biosimilars and 96% felt comfortable prescribing trastuzumab biosimilars. Although 63% of respondents would use the biosimilar in all settings wherein the reference biologic was approved, 35% would use the biosimilar for cases involving metastatic disease. Although 82% of oncologists were in favor of switching from a reference biologic to a biosimilar, 18% would avoid switching regimens. The lack of studies detailing switching to other regimens and the correct timing to switch was the major concern. The cost of HER2 therapy was a significant concern for most oncologists. CONCLUSION: Oncologists demonstrated a high level of knowledge of biosimilars and encouraging levels of prescriber use; however, extrapolation and switching treatment regimens are barriers to the effective use of biosimilars in cancer treatment. Efforts should be concentrated on strategies involving medical education programs on biosimilars.

Activated dendritic cells modulate proliferation and differentiation of human myoblasts.

Idiopathic Inflammatory Myopathies (IIMs) are a heterogeneous group of autoimmune diseases affecting skeletal muscle tissue homeostasis. They are characterized by muscle weakness and inflammatory infiltration with tissue damage. Amongst the cells in the muscle inflammatory infiltration, dendritic cells (DCs) are potent antigen-presenting and key components in autoimmunity exhibiting an increased activation in inflamed tissues. Since, the IIMs are characterized by the focal necrosis/regeneration and muscle atrophy, we hypothesized that DCs may play a role in these processes. Due to the absence of a reliable in vivo model for IIMs, we first performed co-culture experiments with immature DCs (iDC) or LPS-activated DCs (actDC) and proliferating myoblasts or differentiating myotubes. We demonstrated that both iDC or actDCs tightly interact with myoblasts and myotubes, increased myoblast proliferation and migration, but inhibited myotube differentiation. We also observed that actDCs increased HLA-ABC, HLA-DR, VLA-5, and VLA-6 expression and induced cytokine secretion on myoblasts. In an in vivo regeneration model, the co-injection of human myoblasts and DCs enhanced human myoblast migration, whereas the absolute number of human myofibres was unchanged. In conclusion, we suggest that in the early stages of myositis, DCs may play a crucial role in inducing muscle-damage through cell-cell contact and inflammatory cytokine secretion, leading to muscle regeneration impairment.

Emerging Role of HMGB1 in the Pathogenesis of Schistosomiasis Liver Fibrosis.

In chronic schistosomiasis, liver fibrosis is linked to portal hypertension, which is a condition associated with high mortality and morbidity. High mobility group box 1 (HMGB1) was originally described as a nuclear protein that functions as a structural co-factor in transcriptional regulation. However, HMGB1 can also be secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 acts as a multifunctional cytokine that contributes to infection, injury, inflammation, and immune responses by binding to specific cell-surface receptors. HMGB1 is involved in fibrotic diseases. From a clinical perspective, HMGB1 inhibition may represent a promising therapeutic approach for treating tissue fibrosis. In this study, we demonstrate elevated levels of HMGB1 in the sera in experimental mice or in patients with schistosomiasis. Using immunohistochemistry, we demonstrated that HMGB1 trafficking in the hepatocytes of mice suffering from acute schistosomiasis was inhibited by Glycyrrhizin, a well-known HMGB1 direct inhibitor, as well as by DIC, a novel and potential anti-HMGB1 compound. HMGB1 inhibition led to significant downregulation of IL-6, IL4, IL-5, IL-13, IL-17A, which are involved in the exacerbation of the immune response and liver fibrogenesis. Importantly, infected mice that were treated with DIC or GZR to inhibit HMGB1 pro-inflammatory activity showed a significant increase in survival and a reduction of over 50% in the area of liver fibrosis. Taken together, our findings indicate that HMGB1 is a key mediator of schistosomotic granuloma formation and liver fibrosis and may represent an outstanding target for the treatment of schistosomiasis.