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Combining NK cells and mAb9.2.27 to combat NG2-dependent and anti-inflammatory signals in glioblastoma

Glioblastoma is a deadly brain cancer with limited treatment options. Targeting chondroitin sulfate proteoglycan 4 (CSPG4, best known as NG2) with the monoclonal antibody mAb9.2.27 and activated natural killer (NK) cells abrogated the tumor growth and prolonged the survival of glioblastoma-bearing animals by favoring the establishment of a pro-inflammatory microenvironment. The combination of NK cells and mAb9.2.27 recruited ED1+CCR2low macrophages that stimulated ED1+ED2lowMHCIIhigh microglial cells to exert robust cytotoxicity. Our findings demonstrate the therapeutic potential of targeting salient tumor associated-antigens.publishedVersio

Can indicators for sustainable tourism improve tourism planning in the coastal destinations? Empirical evidence from Catalonia, Istrian Region and Tuscany Region

Due to the continuous increase of the tourism industry, tourism destinations need to be managed under a sustainable framework, with the main aim of minimizing the adverse effects caused by tourism flows. In recent years, several attempts have been made to measure those effects and value the level of sustainability of every destination. A clear example of this is the European Tourism Indicator System (ETIS). In the paper, the results are presented of a project which aimed to test indicators of sustainable tourism in coastal destinations of Catalonia, Istrian Region, and Tuscany Region. The results of 33 collected indicators are available on the online platform of the project INTERREG MED MITOMED+. During the first year, in every category of indicators (economic, social-cultural and environmental) only some indicators were collected, which was expected because different regions apply different methodologies. The collected data is the starting point that shows destinations how the indicator can be obtained and what its purpose is. Furthermore, collected data can help local and regional tourism stakeholders to prevent factors of risk, to take decisions and to improve the implementation of policies for sustainable maritime and coastal tourism development in the Mediterranean area

Pregnancy outcomes in anti-NMDA receptor encephalitis: Case series

To report the effects of anti-NMDA receptor (NMDAR) encephalitis in pregnant patients and their babies.We studied a retrospective cohort of patients who developed anti-NMDAR encephalitis during pregnancy or became pregnant while recovering from the encephalitis. In addition, we reviewed the English literature between 2010 and 2019 related to this topic.We studied 11 patients; 6 developed anti-NMDAR encephalitis during pregnancy, and 5 became pregnant while recovering. There were no obstetrical complications, but 6 (55%) babies were premature. Ten newborns were healthy, and 1 (9%) developed transient respiratory distress. Nine infants had assessable follow-up (median 18 months; range, 7-96 months), and all showed normal development. We identified 21 cases in the English literature. Obstetrical complications occurred in 7 (33%) pregnancies. Two patients died of septic shock (1 baby successfully delivered), another 2 had miscarriages, and in 2, the pregnancy was terminated. Sixteen babies (76%) were delivered, 9 (56%) premature. At birth, 13/16 (81%) newborns were healthy, 2/16 (13%) had transient neurologic or respiratory symptoms, and 1 (6%) died of brain edema. Follow-up (median 12 months; range, 6-36 months) was reported for 8 children: 7 (88%) showed normal development and behavior, and 1 (13%) cortical dysplasia. Immunotherapy was used during pregnancy in 7 (64%) of our patients and 18 (86%) of the reported cases, including rituximab in 4 cases, without adverse effects.Patients who develop anti-NMDAR encephalitis during pregnancy or become pregnant during recovery often have obstetrical complications, but most of the newborns are healthy and appear to have normal development.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells

Lymphangioleiomyomatosis (LAM) is a progressive neoplastic disorder that leads to lung destruction and respiratory failure primarily in women. LAM is typically caused by tuberous sclerosis complex 2 (TSC2) mutations resulting in mTORC1 activation in proliferative smooth muscle–like cells in the lung. The female predominance of LAM suggests that estradiol contributes to disease development. Metabolomic profiling identified an estradiol-enhanced prostaglandin biosynthesis signature in Tsc2-deficient (TSC−) cells, both in vitro and in vivo. Estradiol increased the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, which was also increased at baseline in TSC-deficient cells and was not affected by rapamycin treatment. However, both Torin 1 treatment and Rictor knockdown led to reduced COX-2 expression and phospho-Akt-S473. Prostaglandin production was also increased in TSC-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had significantly higher serum prostaglandin levels than healthy women. 15-epi-lipoxin-A4 was identified in exhaled breath condensate from LAM subjects and was increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of LAM patient–derived cells in a dose-dependent manner. Targeting COX-2 and prostaglandin pathways may have therapeutic value in LAM and TSC-related diseases, and possibly in other conditions associated with mTOR hyperactivation

Progress in autoimmune epileptic encephalitis

Purpose of review Autoimmune epileptic encephalopathy is a potentially treatable neurological syndrome characterized by the coexistence of a neuronal antibody in serum and, often, cerebrospinal fluid. Patients present with combinations of seizures, neuropsychiatric features, movement disorder, and cognitive decline, but some patients have isolated seizures either at first presentation or during their illness. This review summarizes our current understanding of the roles of specific neuronal antibodies in epilepsy-related syndromes and aims to aid the clinician in diagnosis and treatment. Recent findings Antigen discovery methods in three neuroimmunology centres independently identified antibodies to different subunits of the γ amino butyric acid-A receptor; high levels of these antibodies were found mainly in patients with severe refractory seizures. These and other antibodies were also found in a proportion (<10%) of children and adults with epilepsy. A clinical study comparing immunotherapy in patients with autoantibodies or without an identified target antigen found neuroinflammatory features were predictive of a therapeutic response. New in-vitro and in-vivo studies, and spontaneous animal models, have confirmed the pathogenicity and epileptogenicity of neuronal antibodies and their relevance to other mammals. Summary Neuronal antibodies are an important cause of autoimmune epileptic encephalopathy, early recognition is important as there may be an underlying tumour, and early treatment is associated with a better outcome. In the absence of an antibody, the clinician should adopt a pragmatic approach and consider a trial of immunotherapy when other causes have been excluded

Corticosteroid suppression of lipoxin A4 and leukotriene B4from alveolar macrophages in severe asthma

<p>Abstract</p> <p>Background</p> <p>An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B₄(LTB₄), and lipoxin A₄(LXA₄) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.</p> <p>Methods</p> <p>AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 μg/ml) with or without dexamethasone (10^-6M). LTB₄and LXA₄were measured by enzyme immunoassay.</p> <p>Results</p> <p>LXA₄biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA₄induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB₄were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB₄was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB₄and LXA₄, with lesser suppression of LTB₄in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA₄and FEV₁(% predicted) (r_s= 0.60; p < 0.01).</p> <p>Conclusions</p> <p>Decreased LXA₄and increased LTB₄generation plus impaired corticosteroid sensitivity of LPS-induced LTB₄but not of LXA₄support a role for AMs in establishing a pro-inflammatory balance in severe asthma.</p

Novel n-3 Docosapentaneoic Acid-Derived Pro-resolving Mediators Are Vasculoprotective and Mediate the Actions of Statins in Controlling Inflammation

“This is a post-peer-review, pre-copyedit version of a chapter published in Advances in Experimental Medicine and Biology book series (AEMB, volume 1161). The final publication is available athttps://doi.org/10.1007/978-3-030-21735-8_7