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Introduction: CAR T-cell therapy has emerged as a promising new immuno-oncology treatment that engages the patient's immune system to fight certain hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). In the European Union (EU), CAR T-cell therapies have been approved for relapsed/refractory (R/R) DLBCL patients since 2018, but patient access is often still limited or delayed. This paper is aimed at discussing challenges to access and possible solutions in the largest four EU countries. Methods: The analysis relied on literature review, market data collection, since homogeneous data coming from registries were not available, and discussion with experts coming from all four countries. Results: We calculated that in 2020, between 58% and 83% of R/R DLBCL patients (EMA approved label population) or between 29% and 71% of the estimated medically eligible R/R DLBCL patients, were not treated with a licensed CAR T-cell therapy. Common challenges along the patient journey that may result in limited access or delays to CAR T-cell therapy were identified. These include timely identification and referral of eligible patients, pre-treatment funding approval by authorities and payers, and resource needs at CAR T-cell centers. Discussion: These challenges, existing best practices and recommended focus areas for health systems are discussed here, with the aim to inform necessary actions for overcoming patient access challenges for current CAR T-cell therapies as well as for future cell and gene therapies.
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Currently, little is known about the impact of aging on astrocytes in substantia nigra pars compacta (SNpc), where dopaminergic neurons degenerate both in physiological aging and in Parkinson's disease, an age-related neurodegenerative disorder. We performed a morphometric analysis of GFAP+ astrocytes in SNpc and, for comparison, in the pars reticulata (SNpr) of young (4-6 months), middle-aged (14-17 months) and old (20-24 months) C57BL/6J male mice. We demonstrated an age-dependent increase of structural complexity only in astrocytes localized in SNpc, and not in SNpr. Astrocytic structural remodelling was not accompanied by changes in GFAP expression, while GFAP increased in SNpr of old compared to young mice. In parallel, transcript levels of selected astrocyte-enriched genes were evaluated. With aging, decreased GLT1 expression occurred only in SNpc, while xCT transcript increased both in SNpc and SNpr, suggesting a potential loss of homeostatic control of extracellular glutamate only in the subregion where age-dependent neurodegeneration occurs. Altogether, our results support an heterogenous morphological and biomolecular response to aging of GFAP+ astrocytes in SNpc and SNpr.
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Parte Compacta da Substância Negra , Parte Reticular da Substância Negra , Camundongos , Masculino , Animais , Substância Negra/metabolismo , Astrócitos/metabolismo , Camundongos Endogâmicos C57BL , Envelhecimento/genéticaRESUMO
Microglia, together with astrocytes and pericytes, cooperate to ensure blood-brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation of S1P receptors may result in a reduced inflammatory response and increased BBB stability. An in vitro BBB model was reproduced using human-derived endothelial cells, astrocytes and microglia. Co-cultures were exposed to inflammatory cytokines (TNFα, 10 UI and IFNγ, 5 UI) in the presence of BAF-312 (100 nM), and the BBB properties and microglia role were evaluated. The drug facilitated microglial migration towards endothelial/astrocyte co-cultures, involving the activity of the metalloprotease 2 (MMP2). Microglia actively cooperated with astrocytes in the maintenance of endothelial barrier stability: in the triple co-culture, selective treatment of microglial cells with BAF-312 significantly prevented cytokines' effects on the endothelial barrier. In conclusion, BAF-312, modulating S1P receptors in microglia, may contribute to the reinforcement of the endothelial barrier at the BBB, suggesting an additional effect of the drug in the treatment of multiple sclerosis.
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Barreira Hematoencefálica , Esclerose Múltipla , Azetidinas , Compostos de Benzil , Citocinas , Células Endoteliais , Humanos , Metaloproteinase 2 da Matriz , Microglia , Esclerose Múltipla/tratamento farmacológico , Fosfatos , Esfingosina/farmacologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Adolescence represents a crucial period for maturation of brain structures involved in cognition. Early in life unhealthy dietary patterns are associated with inferior cognitive outcomes at later ages; conversely, healthy diet is associated with better cognitive results. In this study we analyzed the effects of a short period of hypercaloric diet on newborn hippocampal doublecortin+ (DCX) immature neurons in adolescent mice. Male mice received high fat diet (HFD) or control low fat diet (LFD) from the 5th week of age for 1 or 2 weeks, or 1 week HFD followed by 1 week LFD. After diet supply, mice were either perfused for immunohistochemical (IHC) analysis or their hippocampi were dissected for biochemical assays. Detailed morphometric analysis was performed in DCX+ cells that displayed features of immature neurons. We report that 1 week-HFD was sufficient to dramatically reduce dendritic tree complexity of DCX+ cells. This effect occurred specifically in dorsal and not ventral hippocampus and correlated with reduced BDNF expression levels in dorsal hippocampus. Both structural and biochemical changes were reversed by a return to LFD. Altogether these studies increase our current knowledge on potential consequences of hypercaloric diet on brain and in particular on dorsal hippocampal neuroplasticity.
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Dieta Hiperlipídica/efeitos adversos , Proteína Duplacortina/metabolismo , Hipocampo/patologia , Células-Tronco Neurais/patologia , Neurogênese , Plasticidade Neuronal , Neurônios/patologia , Animais , Peso Corporal , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Neurônios/metabolismoRESUMO
BACKGROUND: Advanced therapy medicinal products (ATMPs) represent an important cornerstone for innovation in healthcare. However, uncertainty on the value, the high average cost per patient and their one-shot nature has raised a debate on their assessment and appraisal process for pricing and reimbursement (P&R) purposes. This debate led experts providing for recommendations on this topic. Our primary objective is to investigate the ATMPs P&R process in the main five European countries and to understand if this process is consistent with published P&R expert recommendations. We also investigated the current ATMP pipelines to understand if future ATMPs will create challenges for their P&R process. METHODS: P&R framework for ATMPs in the European Major five (EU5) countries was investigated through a literature search on PubMed, institutional websites of National Health Authorities and grey literature. The ATMPs pipeline database was populated from a clinical trial database (clinicaltrials.gov), relying on inclusion and exclusion criteria retrieved from the literature. RESULTS: Reimbursement status of ATMPs is different across the EU5 countries, with the exception of CAR-Ts which are reimbursed in all countries. Standard P&R process in place for other medicinal products is extended to ATMPs, with the exception of some cases in Germany. List prices, where available, are high and, tend to be aligned across countries. Outcome-based Managed Entry Agreements (MEAs) have been extensively used for ATMPs. Extra-funds for hospitals managing ATMPs were provided only in Germany and, as additional fund per episode, in France. The accreditation process of hospitals for ATMPs management was in most countries managed by the national authorities. As far as ATMPs pipeline is concerned, ATMPs in development are mostly targeting non-rare diseases. CONCLUSIONS: Expert recommendations for ATMPs P&R were partially applied: the role of outcome-based MEAs has increased and the selection process of the centres authorized to use these treatments has been enhanced; additional funding for ATMPs management to accredited centres has not been completely considered and annuity payment and broader perspective in cost considerations are far from being put in place. These recommendations should be considered for future P&R negotiations to pursue rational resource allocation and deal with budget constraints.
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Positive modulation of adult hippocampal neurogenesis may contribute to the therapeutic effects of clinically relevant antidepressant drugs, including atypical antipsychotics. Quetiapine, an antipsychotic which represents a therapeutic option in patients who are resistant to classical antidepressants, promotes adult hippocampal neurogenesis in preclinical studies. Norquetiapine, the key active metabolite of quetiapine in humans, has a distinctive receptor profile than the parent compound. The drug is indeed a high affinity norepinephrine transporter inhibitor and such activity has been proposed to contribute to its antidepressant effect. At present, no information is available on the effects of norquetiapine on adult neurogenesis. We extensively investigated the activity of quetiapine and norquetiapine on adult murine neural stem/progenitor cells and their progeny. Additionally, selective antagonists for ß2/α2 adrenergic receptors allowed us to evaluate if these receptors could mediate quetiapine and norquetiapine effects. We demonstrated that both drugs elicit in vitro proneurogenic effects but also that norquetiapine had distinctive properties which may depend on its ability to inhibit norepinephrine transporter and involve ß2/α2 adrenergic receptors. Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committees (IACUC) at University of Piemonte Orientale, Italy (approval No. 1033/2015PR) on September 29, 2015.
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During aging, alterations in astrocyte phenotype occur in areas associated with age-related cognitive decline, including hippocampus. Previous work reported subregion-specific changes in surface, volume, and soma size of hippocampal astrocytes during physiological aging. Herein we extensively analyzed, by morphometric analysis, fine morphological features of GFAP+ astrocytes in young (6-month-old) and middle-aged (14-month-old) male mice. We observed remarkable heterogeneity in the astrocytic response to aging in distinct subfields and along the dorsoventral axis of hippocampus and in entorhinal cortex. In middle-aged mice dorsal granule cell and molecular layers, but not hilus, astrocytes underwent remarkable increase in their morphological complexity. These changes were absent in ventral Dentate Gyrus (DG). In addition, in entorhinal cortex, the major input to dorsal DG, astrocytes underwent remarkable atrophic changes in middle-aged mice. Since dorsal DG, and not ventral DG, is involved in cognitive functions, these findings appear worth of further evaluation. Our findings also suggest an additional level of complexity in the structural changes associated with brain aging.
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Envelhecimento/metabolismo , Envelhecimento/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Animais , Giro Denteado , Córtex Entorrinal/citologia , Córtex Entorrinal/metabolismo , Córtex Entorrinal/patologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Astrocytes are essential for proper regulation of the central nervous system (CNS). Importantly, these cells are highly secretory in nature. Indeed they can release hundreds of molecules which play pivotal physiological roles in nervous tissues and whose abnormal regulation has been associated with several CNS disorders. In agreement with these findings, recent studies have provided exciting insights into the key contribution of astrocyte-derived signals in the pleiotropic functions of these cells in brain health and diseases. In the future, deeper analysis of the astrocyte secretome is likely to further increase our current knowledge on the full potential of these cells and their secreted molecules not only as active participants in pathophysiological events, but as pharmacological targets or even as therapeutics for neurological and psychiatric diseases. Herein we will highlight recent findings in our and other laboratories on selected molecules that are actively secreted by astrocytes and contribute in two distinct functions with pathophysiological relevance for the astroglial population: i) regulation of neural stem cells (NSCs) and their progeny within adult neurogenic niches; ii) modulation of the blood-brain barrier (BBB) integrity and function.
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The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA) was then conducted to assess reliability of the accumulated evidence in breast cancer patients. In our cohort study, no association was found between ATM rs1801516 and grade ≥ 2 telangiectasia (GA+AA vs GG, HRadjusted: 0.699; 95%CI: 0.273-1.792, P = 0.459) or grade ≥ 2 fibrosis (GA+AA vs GG, HRadjusted: 1.175; 95%CI: 0.641-2.154, P = 0.604). Twelve independent cohorts of breast cancer patients were identified through the systematic review, of which 11 and 9 cohorts focused respectively on the association with radiation-induced fibrosis and radiation-induced telangiectasia. Pooled analyses of 10 (n = 2928 patients) and 12 (n = 2783) cohorts revealed, respectively, no association of ATM rs1801516 with radiation-induced telangiectasia (OR: 1.14; 95%CI: 0.88-1.48, P = 0.316) and a significant correlation with radiation-induced fibrosis (OR: 1.23; 95%CI: 1.00-1.51, P = 0.049), which however did not remain significant after TSA adjustment (TSA-adjusted 95%CI: 0.85-1.78). These results do not support an impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer, nevertheless further large studies are still required for conclusive evidences.
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Proteínas Mutadas de Ataxia Telangiectasia/genética , Raios gama/efeitos adversos , Dermatopatias/etiologia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Feminino , Raios gama/uso terapêutico , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Dermatopatias/diagnóstico , Telangiectasia/diagnóstico , Telangiectasia/etiologiaRESUMO
Neurogenesis persists in the subgranular zone of the hippocampal formation in the adult mammalian brain. In this area, neural progenitor cells (NPCs) receive both permissive and instructive signals, including neurotransmitters, that allow them to generate adult-born neurons which can be functionally integrated in the preexisting circuit. Deregulation of adult hippocampal neurogenesis (ahNG) occurs in several neuropsychiatric and neurodegenerative diseases, including major depression, and represents a potential therapeutic target. Of interest, several studies suggested that, both in rodents and in humans, ahNG is increased by chronic administration of classical monoaminergic antidepressant drugs, suggesting that modulation of this process may participate to their therapeutic effects. Since the established observation that noradrenergic innervations from locus coeruleus make contact with NPC in the dentate gyrus, we investigated the role of beta adrenergic receptor (ß-AR) on ahNG both in vitro and in vivo. Here we report that, in vitro, activation of ß2-AR by norepinephrine and ß2-AR agonists promotes the formation of NPC-derived mature neurons, without affecting NPC survival or differentiation toward glial lineages. Additionally, we show that a selective ß2-AR agonist able to cross the blood-brain barrier, salmeterol, positively modulates hippocampal neuroplasticity when chronically administered in adult naïve mice. Indeed, salmeterol significantly increased number, maturation, and dendritic complexity of DCX+ neuroblasts. The increased number of DCX+ cells was not accompanied by a parallel increase in the percentage of BrdU+/DCX+ cells suggesting a potential prosurvival effect of the drug on neuroblasts. More importantly, compared to vehicle, salmeterol promoted ahNG, as demonstrated by an increase in the actual number of BrdU+/NeuN+ cells and in the percentage of BrdU+/NeuN+ cells over the total number of newly generated cells. Interestingly, salmeterol proneurogenic effects were restricted to the ventral hippocampus, an area related to emotional behavior and mood regulation. Since salmeterol is commonly used for asthma therapy in the clinical setting, its novel pharmacological property deserves to be further exploited with a particular focus on drug potential to counteract stress-induced deregulation of ahNG and depressive-like behavior.
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The 'Science of Relief' event, held in Milan on 10-11 May 2019, was aimed at promoting dialog between different stakeholders among scientific associations, pharma industry, healthcare services and related institutions. The goal was to renew interest and attention on the management of pain, sharing new solutions in order to bring the patients and their quality of life to the center of attention. An international group of scientists and clinicians presented and discussed new and known evidence in the field of chronic pain, from physiopathology and diagnosis to the choice of appropriate and timely pharmacological treatments. This paper reports the highlights of those presentations.
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Analgésicos/administração & dosagem , Dor Crônica/tratamento farmacológico , Manejo da Dor , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Dor Crônica/fisiopatologia , Congressos como Assunto , Humanos , Qualidade de Vida , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Resultado do TratamentoRESUMO
Chronic pain could be considered as a neurological disorder. Therefore, appropriate selection of the therapy, which should consider the pathophysiological mechanisms of pain, can result in a successful analgesic outcome. Tapentadol is an analgesic drug which acts both as a µ-opioid receptor (MOR) agonist and as a noradrenaline reuptake inhibitor (NRI), thereby generating a synergistic action in terms of analgesic efficacy, but not for the burden of adverse effects. Therefore, tapentadol can be defined as the first "MOR-NRI" drug. This molecule holds the potential to address at least some of the current limitations of analgesic therapy due to its unique mechanism of action and has shown to be safe and effective in the treatment of chronic pain of cancer and noncancer etiologies including nociceptive, neuropathic and mixed pain. In particular, the MOR component of tapentadol activity predominantly allows for analgesia in nociceptive pain; on the other hand, the NRI component contributes, now in a predominant manner, for analgesic efficacy in cases of neuropathic pain states. This paper will discuss recent pieces of evidence on the pathophysiology of pain, the background on tapentadol and then present some new studies on how the unique mechanism of action of tapentadol provides a key role in its analgesic efficacy in a number of pain states and with a favorable safety profile.
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Long-term opioid therapy may be associated with analgesic efficacy and also predictable adverse events, including cardiovascular and pulmonary events, gastrointestinal disorders, endocrinological harms, psychological problems, impairment of driving ability, and risk of abuse. These effects of opioids are mostly due to the wide expression of the mu receptor. Tapentadol, a centrally acting analgesic, is the first agent of a new class of drugs (MOR-NRI), since it combines two mechanisms of action, namely µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. Noteworthy, MOR activation with tapentadol is markedly lower compared with that exerted by classical opioids, thus likely resulting in fewer opioid-related adverse effects. In this review, we discuss current safety data on tapentadol, with a focus on some specific events, risk of abuse, and driving ability, a well-accepted proxy of the ability of taking critical decisions.
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Evidence is rapidly growing regarding a role of astroglial cells in the pathogenesis of Alzheimer's disease (AD), and the hippocampus is one of the important brain regions affected in AD. While primary astroglial cultures, both from wild-type mice and from rodent models of AD, have been useful for studying astrocyte-specific alterations, the limited cell number and short primary culture lifetime have limited the use of primary hippocampal astrocytes. To overcome these limitations, we have now established immortalized astroglial cell lines from the hippocampus of 3xTg-AD and wild-type control mice (3Tg-iAstro and WT-iAstro, respectively). Both 3Tg-iAstro and WT-iAstro maintain an astroglial phenotype and markers (glutamine synthetase, aldehyde dehydrogenase 1 family member L1 and aquaporin-4) but display proliferative potential until at least passage 25. Furthermore, these cell lines maintain the potassium inward rectifying (Kir) current and present transcriptional and proteomic profiles compatible with primary astrocytes. Importantly, differences between the 3Tg-iAstro and WT-iAstro cell lines in terms of calcium signaling and in terms of transcriptional changes can be re-conducted to the changes previously reported in primary astroglial cells. To illustrate the versatility of this model we performed shotgun mass spectrometry proteomic analysis and found that proteins related to RNA binding and ribosome are differentially expressed in 3Tg-iAstro vs WT-iAstro. In summary, we present here immortalized hippocampal astrocytes from WT and 3xTg-AD mice that might be a useful model to speed up research on the role of astrocytes in AD.
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Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Sinalização do Cálcio , Expressão Gênica , Hipocampo/patologia , Proteoma , Animais , Células Cultivadas , Modelos Animais de Doenças , Transportador 2 de Aminoácido Excitatório/metabolismo , Ácido Glutâmico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mapas de Interação de Proteínas , Transmissão Sináptica , TransfecçãoRESUMO
In recent years, channels that mediate store-operated calcium entry (SOCE, i.e., the ability of cells to sense a decrease in endoplasmic reticulum luminal calcium and induce calcium entry across the plasma membrane) have been associated with a number of disorders, spanning from immune disorders to acute pancreatitis and have been suggested to be druggable targets. In the present contribution, we exploited the click chemistry approach to synthesize a class of SOCE modulators where the arylamide substructure that characterizes most inhibitors so far described is substituted by a 1,4-disubstituted 1,2,3-triazole ring. Within this series, inhibitors of SOCE were identified and the best compound proved effective in an animal model of acute pancreatitis, a disease characterized by a hyperactivation of SOCE. Strikingly, two enhancers of the process were discovered, affording invaluable research tools to further explore the (patho)physiological role of capacitative calcium entry.