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Expert Opinion on Therapeutic Targets

Carlo Riccardi, Simona Ronchetti, Giuseppe Nocentini
Introduction Triggering of the glucocorticoid-induced TNFR-related gene (GITR) increases the activation of T lymphocytes and other immune system cells; furthermore, its ligand, GITRL, delivers signals in the cells where it is expressed. Areas covered This review describes the effects of GITR/GITRL triggering/inhibition in conventional T cells, regulatory T cells (Tregs), monocytes/macrophages, endothelial cells and other cells of the immune system. GITR triggering appears to be an approach for promoting tumor rejection, treating infection and boosting vaccinations in several murine models...
August 14, 2018: Expert Opinion on Therapeutic Targets
Valentina Pucino, Danilo Cucchi, Claudio Mauro
Inflammation is associated with the accumulation of lactate at sites of tumour growth and inflammation. Lactate initiates tissue responses contributing to disease. We discuss the potential of targeting lactate transporters in the treatment of cancer and inflammatory conditions. Areas covered: Lactate is the product of glycolysis, which is considered to be a waste metabolite and a fuel for oxidative cells. It is also an active signalling molecule with immunomodulatory and angiogenic properties. They are the consequence of lactate binding to membrane receptor(s) or being transported through specific carrier-mediated transporters across the cellular membrane...
August 14, 2018: Expert Opinion on Therapeutic Targets
Sabina Ranjit, Benjamin J Patters, Kelli A Gerth, Sanjana Haque, Sanjeev Choudhary, Santosh Kumar
HIV-1-infected smokers are at risk of oxidative damage to neuronal cells in the central nervous system by both HIV-1 and cigarette smoke. Since neurons have a weak antioxidant defense system, they mostly depend on glial cells, particularly astrocytes, for protection against oxidative damage and neurotoxicity. Astrocytes augment the neuronal antioxidant system by supplying cysteine-containing products for glutathione synthesis, antioxidant enzymes such as SOD and catalase, glucose for antioxidant regeneration via the pentose-phosphate pathway, and by recycling of ascorbic acid...
August 3, 2018: Expert Opinion on Therapeutic Targets
Abhijit Aithal, Sanchita Rauth, Prakash Kshirsagar, Ashu Shah, Imayavaramban Lakshmanan, Wade M Junker, Maneesh Jain, Moorthy P Ponnusamy, Surinder K Batra
MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research...
July 26, 2018: Expert Opinion on Therapeutic Targets
Tatiana Akimova, Wayne W Hancock
No abstract text is available yet for this article.
July 19, 2018: Expert Opinion on Therapeutic Targets
Ramon Bartrons, Ana Rodríguez-García, Helga Simon-Molas, Esther Castaño, Anna Manzano, Àurea Navarro-Sabaté
It has been known for over half a century that tumors exhibit an increased demand for nutrients to fuel their rapid proliferation. Interest in targeting cancer metabolism to treat the disease has been renewed in recent years with the discovery that many cancer-related pathways have a profound effect on metabolism. Considering the recent increase in our understanding of cancer metabolism and the enzymes and pathways involved, the question arises as to whether metabolism is cancer's Achilles heel. Areas covered: This review summarizes the role of 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in glycolysis, cell proliferation, and tumor growth, discussing PFKFB3 gene and isoenzyme regulation and the changes that occur in cancer and inflammatory diseases...
July 16, 2018: Expert Opinion on Therapeutic Targets
Patrick J Moore, Robert Tarran
Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for the CFTR anion channel. In the absence of functional CFTR, the epithelial Na+ channel is also dysregulated. Airway surface liquid (ASL) hydration is maintained by a balance between epithelial sodium channel (ENaC)-led Na+ absorption and CFTR-dependent anion secretion. This finely tuned homeostatic mechanism is required to maintain sufficient airway hydration to permit the efficient mucus clearance necessary for a sterile lung environment...
August 2018: Expert Opinion on Therapeutic Targets
Pieter H Anborgh, Danny J Lee, Pieter F Stam, Alan B Tuck, Ann F Chambers
OBJECTIVE: Effective targeted therapies for patients with triple-negative breast cancer (TNBC) present an unmet clinical need. There is evidence that TNBCs often have increased expression of the epidermal growth factor receptor (EGFR) and of osteopontin (OPN). OPN-mediated signaling can activate EGFR-dependent signaling pathways. Here, we assessed OPN as a potential predictive biomarker for response to anti-EGFR therapy in TNBC. RESEARCH DESIGN AND METHODS: Using two different TNBC cell lines, MDA-MB-468 and MDA-MB-231, we investigated the impact of stable expression of OPN on efficacy of the EGFR inhibitor erlotinib in vitro...
August 2018: Expert Opinion on Therapeutic Targets
Longfa Kou, Rui Sun, Vadivel Ganapathy, Qing Yao, Ruijie Chen
Transporters in the plasma membrane have been exploited successfully for the delivery of drugs in the form of prodrugs and nanoparticles. Organic cation/carnitine transporter 2 (OCTN2, SLC22A5) has emerged as a viable target for drug delivery. OCTN2 is a Na+ -dependent high-affinity transporter for L-carnitine and a Na+ -independent transporter for organic cations. OCTN2 is expressed in the blood-brain barrier, heart, liver, kidney, intestinal tract and placenta and plays an essential role in L-carnitine homeostasis in the body...
August 2018: Expert Opinion on Therapeutic Targets
Mahip K Verma, Rajan Goel, Nandakumar Krishnadas, Kumar V S Nemmani
Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e...
July 2018: Expert Opinion on Therapeutic Targets
Ina Nepstad, Kimberley J Hatfield, Elise Aasebø, Maria Hernandez-Valladares, Annette K Brenner, Sushma Bartaula-Brevik, Frode Berven, Frode Selheim, Jørn Skavland, Bjørn Tore Gjertsen, Håkon Reikvam, Øystein Bruserud
OBJECTIVES: Constitutive signaling through the phosphatidylinositol-3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is present in acute myeloid leukemia (AML) cells. The aim of the study was to compare constitutive PI3K-Akt-mTOR activation of primary AML cells for a large group of unselected patients. METHODS: We investigated expression and phosphorylation of 18 mediators in the PI3K-Akt-mTOR main track by flow cytometry for AML cells derived from 77 patients, and compared this with global gene expression profiles, proteomic, and transcriptomic profiles, and susceptibility to antileukemic agents...
July 2018: Expert Opinion on Therapeutic Targets
Santiago Haase, María Belén Garcia-Fabiani, Stephen Carney, David Altshuler, Felipe J Núñez, Flor M Méndez, Fernando Núñez, Pedro R Lowenstein, Maria G Castro
ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered: We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma...
July 2018: Expert Opinion on Therapeutic Targets
Daniela Galimberti, Chiara Fenoglio, Elio Scarpini
Progranulin (PGRN) is an acrosomal glycoprotein that is synthesized during spermatogenesis. It is overexpressed in tumors and has anti-inflammatory properties. The protein may be cleaved into granulins which display pro-inflammatory properties. In 2006, mutations in progranulin gene (GRN) that cause haploinsufficiency were found in familial cases of frontotemporal dementia (FTD). Patients with null mutations in GRN display very low-plasma PGRN levels; this analysis is useful for identifying mutation carriers, independent of the clinical presentation, and in those before the appearance of symptoms...
July 2018: Expert Opinion on Therapeutic Targets
Yuetiva Deming, Zeran Li, Bruno A Benitez, Carlos Cruchaga
There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD...
July 2018: Expert Opinion on Therapeutic Targets
Diana Passaro, Dominique Bonnet
No abstract text is available yet for this article.
July 2018: Expert Opinion on Therapeutic Targets
Puneet Agarwal, Renu Agarwal
Disturbances of extracellular matrix (ECM) homeostasis in trabecular meshwork (TM) cause increased aqueous outflow resistance leading to elevated intraocular pressure (IOP) in glaucomatous eyes. Therefore, restoration of ECM homeostasis is a rational approach to prevent disease progression. Since renin-angiotensin system (RAS) inhibition positively alters ECM homeostasis in cardiovascular pathologies involving pressure and volume overload, it is likely that RAS inhibitors reduce IOP primarily by restoring ECM homeostasis...
July 2018: Expert Opinion on Therapeutic Targets
Donghui Shen, Yue Lang, Fengna Chu, Xiujuan Wu, Ying Wang, Xiangyu Zheng, Hong-Liang Zhang, Jie Zhu, Kangding Liu
Macrophage migration inhibitory factor (MIF) plays an important role in the pathogenesis of Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN), which may offer an opportunity for the development of the novel therapeutic strategies for GBS. Areas covered: 'macrophage migration inhibitory factor' and 'Guillain-Barré syndrome' were used as keywords to search for related publications on Pub-Med, National Center for Biotechnology Information (NCBI), USA. MIF is involved in the etiology of various inflammatory and autoimmune disorders...
July 2018: Expert Opinion on Therapeutic Targets
Ariel Fernández
No abstract text is available yet for this article.
July 2018: Expert Opinion on Therapeutic Targets
James S Novak, Jyoti K Jaiswal, Terence A Partridge
No abstract text is available yet for this article.
June 2018: Expert Opinion on Therapeutic Targets
Annika Borde, Annika Åstrand
This review aims to raise the potential of the modern society's impact on gut integrity often leading to increased intestinal permeability, as a cause or driver of Alopecia Areata (AA) in genetically susceptible people. With the increasing rate of T cell-driven autoimmunity, we hypothesize that there is a common root cause of these diseases that originates from chronic inflammation, and that the gut is the most commonly exposed area with our modern lifestyle. Areas covered: We will discuss the complexity in the induction of AA and its potential link to increased intestinal permeability...
June 2018: Expert Opinion on Therapeutic Targets
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