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  • Mccubrey, James A
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  • 1
    Language: English
    In: Recent Patents on Anti-Infective Drug Discovery, 2010, Vol.5(3), p.181-194
    Description: Despite the improvements in HCV-therapy achieved in the last 20 years, the occurrence of high frequency of non-responders and of therapy-related side effects has lead to an ongoing interest in optimizing duration and dosage of current antiviral regimens as well as to the research and development of new antiviral treatment. Recently, the discovery of a system for in vitro HCV replication provided a useful tool for a better understanding of the viral life cycle followed by the discovery of new compounds that unlike classical drugs specifically target fundamental steps of this process. The aim of this review is to provide an update on the preclinical and clinical development of novel anti-HCV treatments targeting the first steps of the viral life cycle. The recent patents in this review article discuss the new perspectives in HCV therapy.
    Keywords: Hcv ; Entry Inhibitors ; Preclinical Development ; Clinical Development ; Hcv-Therapy ; Antiviral Treatment ; Replication ; Anti-Hcv Treatments ; Flavivirus ; Chronic ; Acute ; Cirrhosis ; Hepatocellular ; Glomerulonephritis ; Cryoglobulinemia ; Porphyria Cutanea Tarda ; Lymphoproliferative ; Liver Transplantation ; Hcc ; Prognosis ; Fibrosis ; Ifn-Alpha ; Ribavirin ; Peginterferon ; Peg-Ifn ; Viral Rna ; Anaemia ; Thrombocytopenia ; Hepacivirus ; Flaviviridae ; Heterodimer ; Glycosaminoglycans ; Glycoprotein ; Drug Design ; Albumin ; Boceprevir ; Telaprevir ; Albinterferon Alpha-2b ; Luciferase Assay ; Liver-Upa-Scid ; Viral Envelope ; Epitopes ; Monoclonal Antibodies ; Plasma Donor Antibodies ; Polyclonal Antibodies ; Hcv-Genotypes ; Glycosylation ; Glycans ; Cyanovirin-N ; High-Mannose Oligosaccharides ; Iminosugars ; Bvdv ; Adenovirus ; Vaccinia Virus ; Canary Pox Virus ; Alphavirus ; Cd81 ; Tetraspanin ; Endocytosis ; Claudin-1 ; Occludin ; Cldn1 ; Chlorpromazine ; Chloroquine ; Concanamycin A ; Bafilomycin ; Heparin ; Heparinase ; Lamiridosins ; Phosphorothioate ; Oligonucleotides (Ps-Ons) ; Arbidol ; C5a ; Amphipathic-Helical Peptide ; Paramyxoviruses ; Sp-30 ; Pro 206 ; Civacir ; Itx5061 ; Rep 9ac ; Jtk-652 ; Immune Serum Globulin ; Placebo ; Monotherapy ; Clinical Trials ; Lamiaceae
    ISSN: 1574-891X
    E-ISSN: 2212-4071
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(3), p.e0152104
    Description: BACKGROUND:Malignant melanoma is an aggressive tumor of the skin and seems to be resistant to current therapeutic approaches. Melanocytic transformation is thought to occur by sequential accumulation of genetic and molecular alterations able to activate the Ras/Raf/MEK/ERK (MAPK) and/or the PI3K/AKT (AKT) signalling pathways. Specifically, mutations of B-RAF activate MAPK pathway resulting in cell cycle progression and apoptosis prevention. According to these findings, MAPK and AKT pathways may represent promising therapeutic targets for an otherwise devastating disease. RESULT:Here we show a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. Overall, this computational approach may accelerate the drug discovery process and encourages the identification of novel pathway activators with consequent development of novel antioncogenic compounds to overcome tumor cell resistance to conventional therapeutic agents. The source code of the various versions of the model are available as S1 Archive.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    In: British Journal of Clinical Pharmacology, December 2010, Vol.70(6), pp.784-793
    Description: The strong need for the development of alternative anti‐HIV agents is primarily due to the emergence of strain‐resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti‐HIV properties both and that qualifies it as a potential new anti‐HIV drug. It represents a literature review of published studies that evaluated the and activity of RAPA in HIV. RAPA represses HIV‐1 replication through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti‐HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide . RAPA also inhibits HIV‐1 infection in human peripheral blood leucocytes‐SCID reconstituted mice. In addition, a prospective nonrandomized trial of HIV patient series receiving RAPA monotherapy after liver transplantation indicated significantly better control of HIV and hepatitis C virus (HCV) replication among patients taking RAPA monotherapy. Taken together, the evidence presented in this review suggests that RAPA may be a useful drug that should be evaluated for the prevention and treatment of HIV‐1 infection.
    Keywords: Ccr5 ; Hiv ; Mtor ; Rapamycin
    ISSN: 0306-5251
    E-ISSN: 1365-2125
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  • 4
    Language: English
    In: Oncotarget, March 2011, Vol.2(3), pp.109-12
    Keywords: Neoplasms -- Drug Therapy ; Tumor Suppressor Protein P53 -- Genetics
    E-ISSN: 1949-2553
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  • 5
    Language: English
    In: BBA - Molecular Cell Research, December 2016, Vol.1863(12), pp.2942-2976
    Description: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.
    Keywords: Gsk-3 ; Wnt/Beta-Catenin ; Pi3k ; Akt ; Mtor ; Hedgehog ; Notch ; Targeted Therapy ; Therapy Resistance ; Biology ; Chemistry
    ISSN: 0167-4889
    E-ISSN: 1879-2596
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  • 6
    In: Basic & Clinical Pharmacology & Toxicology, January 2013, Vol.112(1), pp.63-69
    Description: Rapamycin is a macrocyclic lactone currently used for the treatment of cancer and for the prevention of transplant rejection. The primary pharmacological mode of action of rapamycin occurs through the inhibition (blocking) of the mammalian target of rapamycin (). By doing so, rapamycin interferes with the phosphoinositide 3‐kinase (3)‐kt‐ axis that controls several cellular functions involving cell growth, proliferation and angiogenesis. The frequent activation of the phosphoinositide 3‐kinase (3)/ pathway in advanced prostate cancer has provided a rationale for the use of inhibitors in this setting. We carried out a comparative study on the effects of rapamycin and temsirolimus on the and growth of the prostate cancer cell lines, nap and 3. Our results demonstrate that rapamycin and temsirolimus exert similar and anti‐proliferative effects against prostate cancer cells.
    Keywords: Cancer Cells -- Comparative Analysis ; Cancer Research -- Comparative Analysis ; Prostate Cancer -- Comparative Analysis ; Caprolactone -- Comparative Analysis ; Antineoplastic Agents -- Comparative Analysis ; Rapamycin -- Comparative Analysis;
    ISSN: 1742-7835
    E-ISSN: 1742-7843
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  • 7
    Language: English
    In: Cell Cycle, 01 February 2010, Vol.9(3), pp.557-563
    Description: Yin Yang 1 (YY1), a multifunctional transcription factor, has been shown to be involved in the pathogenesis of several cancer types. However, its role in hematological malignancies has not yet been fully investigated. In the present study, using computational methods, we showed that YY1 transcript...
    Keywords: Biology
    ISSN: 1538-4101
    E-ISSN: 1551-4005
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  • 8
    Language: English
    In: Forum on Immunopathological Diseases and Therapeutics, 2010, Vol.1(1-2), pp.65-79
    Description: Cytokine-dependent, drug-sensitive, p53 wild-type (WT) FL5.12 cells and the doxorubicin-resistant derivative line (FL/Doxo) were used to determine the roles of the mechanisms by which p53 could alter Ying Yang 1 (YY1) transcription factor expression in early hematopoietic precursor cells. Drug resistance was associated with decreased p53 induction after doxorubicin treatment, which was caused by a higher level of proteosomal degradation of p53 and also resulted in a lower level of YY1 expression. Insertion of a dominant negative p53 gene further increased the resistance of the cells to chemotherapeutic drugs and also resulted in low levels of YY1 expression. Thus, in our system we could examine the effects of p53 and chemotherapeutic drugs on YY1 expression in a series of cells that were all derived from the common parental cell line. Doxorubicin increased the expression of the YY1 protein more in the parental cells, which have higher levels of WT p53, than in the doxorubicin-resistant cells. Thus, in our system of early hematopoietic cells YY1 expression was associated with functional p53 activity. In summary, our studies indicate that regulating YY1 activity may be a potential approach to regulate drug resistance.
    Keywords: Leukemia ; Stem Cells ; Transcription Factors ; Drug Resistance ; Hemopoiesis ; Yy1 Protein ; Doxorubicin ; P53 Protein ; Cancer Immunology;
    ISSN: 2151-8017
    E-ISSN: 21518025
    Source: Begell House, Inc. (via CrossRef)
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  • 9
    Language: English
    In: Advances in Biological Regulation, September 2014, Vol.56, pp.81-107
    Description: Over the past 10 years there have been significant advances in our understanding of breast cancer and the important roles that breast cancer initiating cells (CICs) play in the development and resistance of breast cancer. Breast CICs endowed with self-renewing and tumor-initiating capacities are believed to be responsible for the relapses which often occur after various breast cancer therapies. In this review, we will summarize some of the key developments in breast CICs which will include discussion of some of the key genes implicated: estrogen receptor ( ), , , , , , and various miRs as well some drugs which are showing promise in targeting CICs. In addition, the concept of combined therapies will be discussed. Basic and clinical research is resulting in novel approaches to improve breast cancer therapy by targeting the breast CICs.
    Keywords: Cancer Stem Cells ; Her2 ; Mirs ; Targeted Therapy ; Hormonal Therapy ; Therapy Resistance ; Anatomy & Physiology
    ISSN: 2212-4926
    E-ISSN: 2212-4934
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  • 10
    Language: English
    In: Cell Cycle, 15 March 2012, Vol.11(6), pp.1174-1182
    Description: We previously reported that the NO-modified form of HIV protease inhibitor Saquinavir (Saq) is a potent antitumoral agent efficient against numerous tumor cell lines in vitro and in vivo. In acute toxicity studies, doses of Saq-NO equivalent to DL100 of the parental drug were completely nontoxic....
    Keywords: Xiap ; Trail ; S6 Protein ; Saquinavir ; Saquinavir-No ; Biology
    ISSN: 1538-4101
    E-ISSN: 1551-4005
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