Pharmacology & therapeutics
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Migraine is a highly disabling neurovascular disorder characterized by a severe headache (associated with nausea, photophobia and/or phonophobia), and trigeminovascular system activation involving the release of calcitonin-gene related peptide (CGRP). Novel anti-migraine drugs target CGRP signaling through either stimulation of 5-HT1F receptors on trigeminovascular nerves (resulting in inhibition of CGRP release) or direct blockade of CGRP or its receptor. Lasmiditan is a highly selective 5-HT1F receptor agonist and, unlike the triptans, is devoid of vasoconstrictive properties, allowing its use in patients with cardiovascular risk. ⋯ Of these drugs targeting CGRP signaling directly, eptinezumab, erenumab, fremanezumab, galcanezumab, rimegepant and ubrogepant have been approved for clinical use, while atogepant is in the last stage before approval. Although all of these drugs seem highly promising for migraine treatment, their safety should be investigated in the long-term. Moreover, the exact mechanism(s) of action of these drugs need to be elucidated further, to increase both safety and efficacy and to increase the number of responders to the different treatments, so that all migraine patients can satisfactorily be treated.
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Chronic pulmonary conditions now account for 1 in 15 deaths in the US and mortality is increasing. Chronic obstructive pulmonary disease (COPD) is due to become the 3rd largest cause of mortality by 2030 and mortality from other respiratory conditions such as asthma, idiopathic pulmonary fibrosis and cystic fibrosis are not reducing. There is an urgent need for novel therapies to address this problem as many of the current strategies targeting inflammation are not sufficient. ⋯ These compounds include natural products such as quercetin which have anti-inflammatory properties but can also suppress viral replication. As viruses have been shown to suppress phagocytosis of macrophages, it is possible that these compounds could have benefit during viral exacerbations to protect this innate response. These compounds demonstrate that it is possible to address defective innate responses in the lung but a better understanding of the mechanisms driving defective innate immunity in pulmonary disease may lead to improved therapeutics.
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The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). ⋯ In peripheral organs, endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of endozepines and discuss the physiopathological implications of these regulatory gliopeptides.
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Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. ⋯ We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted therapy, including mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), the receptor tyrosine kinase ROS proto-oncogene 1 (ROS1), and the serine/threonine-protein kinase BRAF (v-Raf murine sarcoma viral oncogene homolog B). We also discuss the mechanism of action of less common oncoproteins, as in-depth understanding of these molecular mechanisms is important for optimizing treatment strategies.
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Review
Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions.
Chimeric antigen receptor (CAR) T cells are a form of autologous immunotherapy that has changed the therapeutic landscape of hematologic malignancies. CAR T cell therapy involves collection of a patient's T cells by apheresis, ex vivo genetic modification of the T cells to encode a synthetic receptor that binds a specific tumor antigen, and infusion of the T cells back into the patient. ⋯ Some of the most significant challenges for CAR T cell immunotherapy in solid cancers include a paucity of unique tumor target antigens, limited CAR T cell trafficking to tumor sites, tumor heterogeneity and antigen loss, and the severely immunosuppressive tumor microenvironment. This review article provides an update on completed and ongoing clinical trials of CAR T cells for solid tumors, as well as an overview of strategies to improve CAR T cell efficacy in non-hematologic malignancies.