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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...
June 11, 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...
June 11, 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...
June 11, 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...
June 11, 2018: Expert Opinion on Therapeutic Targets
Diana Passaro, Dominique Bonnet
No abstract text is available yet for this article.
June 11, 2018: Expert Opinion on Therapeutic Targets
Puneet Agarwal, Renu Agarwal
Disturbances of extracellular matrix (ECM) homeostasis 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. Areas covered: Current evidence showing the presence of RAS components in ocular tissue and its role in regulating aqueous humor dynamics is briefly summarized...
June 8, 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 7, 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...
June 1, 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...
May 29, 2018: Expert Opinion on Therapeutic Targets
Michael D Schwartz, Juan J Canales, Riccardo Zucchi, Stefano Espinoza, Ilya Sukhanov, Raul R Gainetdinov
The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a trace amine-sensitive G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of trace amine signaling. Areas covered. Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed...
May 25, 2018: Expert Opinion on Therapeutic Targets
Emily Smith, Wei Zhou, Polina Shindiapina, Said Sif, Chenglong Li, Robert A Baiocchi
Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis...
May 21, 2018: Expert Opinion on Therapeutic Targets
Davood Rostamzadeh, Tohid Kazemi, Zahra Amirghofran, Mahdi Shabani
Fc receptor-like (FCRL) molecules, as recently identified members of the immunoglobulin superfamily (IgSF), are preferentially expressed by B-cells. They have variable number of extracellular immunoglobulin-like domains and cytoplasmic activating ITAMs and/or inhibitory ITIMs. FCRL1-5 are dominantly expressed in different stages of B-cells development. But, FCRL6 is preferentially expressed in different subsets of T-cells and NK cells. FCRL1-5 could regulate different features of B-cell evolution such as development, differentiation, activation, antibody secretion and isotype switching...
May 10, 2018: Expert Opinion on Therapeutic Targets
Shyam Sundar, Bhawana Singh
Parasitic diseases that pose a threat to human life include leishmaniasis - caused by protozoan parasite Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity, high cost and drug resistance. This calls for the need to have an insight into therapeutic aspects of disease. Areas covered: We have identified different drug targets via. molecular, imuunological, metabolic as well as by system biology approaches. We bring these promising drug targets into light so that they can be explored to their maximum...
May 9, 2018: Expert Opinion on Therapeutic Targets
Varun Sasidharan Nair, Salman M Toor, Bassam R Ali, Eyad Elkord
OBJECTIVES: Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals...
April 27, 2018: Expert Opinion on Therapeutic Targets
Jules C Hancox, Dominic G Whittaker, Chunyun Du, A Graham Stuart, Henggui Zhang
INTRODUCTION: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. AREAS COVERED: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed...
April 26, 2018: Expert Opinion on Therapeutic Targets
Ana Saavedra, Gerardo García-Díaz Barriga, Esther Pérez-Navarro, Jordi Alberch
Huntington's disease (HD), an autosomal dominant neurodegenerative disorder caused by an expansion of CAG repeats in the huntingtin gene, has long been characterized by the presence of motor symptoms due to the loss of striatal projection neurons. Cognitive dysfunction and neuropsychiatric symptoms are also present and they occur in the absence of cell death in most mouse models, pointing to neuronal dysfunction and abnormal synaptic plasticity as causative mechanisms. Areas covered: Here, we focus on those common mechanisms altered by the presence of mutant huntingtin affecting corticostriatal and hippocampal function as therapeutic targets that could prove beneficial to ameliorate both cognitive and motor function in HD...
May 2018: Expert Opinion on Therapeutic Targets
James A Walker, Meena Upadhyaya
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of one in 3000-4000 individuals with no currently effective therapies. The NF1 gene encodes neurofibromin, which functions as a negative regulator of RAS. NF1 is a chronic multisystem disorder affecting many different tissues. Due to cell-specific complexities of RAS signaling, therapeutic approaches for NF1 will likely have to focus on a particular tissue and manifestation of the disease. Areas covered: We discuss the multisystem nature of NF1 and the signaling pathways affected due to neurofibromin deficiency...
May 2018: Expert Opinion on Therapeutic Targets
Franco Di Padova, Valerie F J Quesniaux, Bernhard Ryffel
Myeloid differentiation primary response protein 88 (MyD88) is a critical adaptor protein involved in Toll-like and IL-1 receptor family signaling controlling innate immune responses and inflammation. Genetic deletion of MyD88 function results in profound suppression of inflammation and reduced resistance of the host to pathogens indicating non-redundant roles of MyD88. The TIR domain is critical for MyD88 dimerization and signaling for TLR and IL-1R family receptor. Areas covered: Emerging evidence suggests that chemical disruption of the TIR domain attenuates cell activation and inhibits in vivo MyD88-dependent inflammation...
May 2018: Expert Opinion on Therapeutic Targets
Montreh Tavakkoli, Stephen S Chung, Christopher Y Park
Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) are clonal hematopoietic neoplasms that arise from leukemia stem cells (LSCs) and hematopoietic stem cells (HSCs), respectively. Standard chemotherapy can efficiently eliminate the bulk of neoplastic cells, however, LSCs and MDS HSCs are relatively resistant to these therapies and can reinitiate and maintain disease. CD99 is a 32-kDa transmembrane polypeptide that is highly expressed on disease stem cells in the vast majority of AML and MDS...
May 2018: Expert Opinion on Therapeutic Targets
Nils Ludwig, Theresa L Whiteside
Tumor-derived exosomes (TEX) and their role in tumor progression by accelerating angiogenesis are of great current interest. A better understanding of the mechanisms underlying TEX-blood vessels cross-talk may lead to improvements in current diagnosis, prognosis and treatment of cancer. Areas covered: For solid tumors, an adequate blood supply is of critical importance for their development, growth and metastasis. TEX, virus-size vesicles which circulate freely throughout body fluids and accumulate in the tumor microenvironment (TME), have been recognized as a new contributor to angiogenesis...
May 2018: Expert Opinion on Therapeutic Targets
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