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1
Suzuki, Jun-ichi, Mitsuaki Isobe, Ryuichi Morishita, and Ryozo Nagai. "Nucleic Acid Drugs for Prevention of Cardiac Rejection." Journal of Biomedicine and Biotechnology 2009 (2009): 1–5. http://dx.doi.org/10.1155/2009/916514.
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Heart transplantation has been broadly performed in humans. However, occurrence of acute and chronic rejection has not yet been resolved. Several inflammatory factors, such as cytokines and adhesion molecules, enhance the rejection. The graft arterial disease (GAD), which is a type of chronic rejection, is characterized by intimal thickening comprised of proliferative smooth muscle cells. Specific treatments that target the attenuation of acute rejection and GAD formation have not been well studied in cardiac transplantation. Recent progress in the nucleic acid drugs, such as antisense oligodeoxynucleotides (ODNs) to regulate the transcription of disease-related genes, has important roles in therapeutic applications. Transfection of cis-element double-stranded DNA, named as “decoy,” has been also reported to be a useful nucleic acid drug. This decoy strategy has been not only a useful method for the experimental studies of gene regulation but also a novel clinical strategy. In this paper, we reviewed the experimental results ofNF-κB, E2F, AP-1, and STAT-1 decoy and other ODNs using the experimental heart transplant models.
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MORISHITA, RYUICHI, MOTOKUNI AOKI, and YASUFUMI KANEDA. "Decoy Oligodeoxynucleotides As Novel Cardiovascular Drugs for Cardiovascular Disease." Annals of the New York Academy of Sciences 947, no. 1 (January 25, 2006): 294–302. http://dx.doi.org/10.1111/j.1749-6632.2001.tb03950.x.
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Аrtykov, Аrtem А., Dmitry A. Belov, Victoria O. Shipunova, Daria B. Trushina, Sergey M. Deyev, Dmitry A. Dolgikh, Mikhail P. Kirpichnikov, and Marine E. Gasparian. "Chemotherapeutic Agents Sensitize Resistant Cancer Cells to the DR5-Specific Variant DR5-B more Efficiently than to TRAIL by Modulating the Surface Expression of Death and Decoy Receptors." Cancers 12, no. 5 (April 30, 2020): 1129. http://dx.doi.org/10.3390/cancers12051129.
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TRAIL is considered a promising antitumor agent because it causes apoptosis of transformed cells without affecting normal cells. However, many types of tumors are cytokine resistant, and combination therapy with various chemotherapeutic drugs is being developed to overcome the resistance. We have demonstrated that the combination of TRAIL with doxorubicin, bortezomib, and panobinostat dramatically reduced the viability of TRAIL-resistant A549 and HT-29 cells. Chemotherapy even more efficiently sensitized cells to the DR5-specific mutant variant of TRAIL DR5-B, which does not have an affinity for decoy receptors. Bortezomib and doxorubicin greatly enhanced the surface expression of the death receptors DR5 and DR4, while panobinostat increased expression of DR5 and suppressed expression of DR4 in both cell lines. All drugs increased surface expression of the decoy receptors DcR1 and DcR2. Unlike the combined treatment, if the cells were pretreated with chemotherapy for 24 h, the cytotoxic activity of TRAIL was less pronounced, while sequential treatment of cells enhanced the effectiveness of DR5-B. The same results were obtained with agonistic anti-DR5 antibodies. Thus, the effectiveness of TRAIL was rather limited due to changes in the ratio of death and decoy receptors and DR5-specific agonists may be preferred in combination antitumor therapy regimens.
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Federico, Isabella, Francesca Federico, Fernando Rojas, James Zapf, and Babak Esmaeli-Azad. "A Medical Countermeasure Against Drugs of Abuse with Detoxifying Biomimetic “Nanosponge” Decoy Receptors Directed Against Opioid Drugs and Methamphetamines." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.04493.
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Chandra, Naresh, Lars Frängsmyr, and Niklas Arnberg. "Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus." Viruses 11, no. 3 (March 12, 2019): 242. http://dx.doi.org/10.3390/v11030242.
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Epidemic keratoconjunctivitis (EKC) is a severe ocular disease and can lead to visual impairment. Human adenovirus type-37 (HAdV-D37) is one of the major causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. Currently, there are no approved antivirals available for the treatment of EKC. Recently, we have reported that sulfated glycosaminoglycans (GAGs) bind to HAdV-D37 via the fiber knob (FK) domain of the viral fiber protein and function as decoy receptors. Based on this finding, we speculated that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Repurposing of approved drugs to identify new antivirals has drawn great attention in recent years. Here, we report the antiviral effect of suramin, a WHO-approved drug and a widely known GAG-mimetic, against HAdV-D37. Commercially available suramin analogs also show antiviral effects against HAdV-D37. We demonstrate that suramin exerts its antiviral activity by inhibiting the attachment of HAdV-D37 to cells. We also reveal that the antiviral effect of suramin is HAdV species-specific. Collectively, in this proof of concept study, we demonstrate for the first time that virus binding to a decoy receptor constitutes a novel and an unexplored target for antiviral drug development.
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Rao, Lang, Shuai Xia, Wei Xu, Rui Tian, Guocan Yu, Chenjian Gu, Pan Pan, et al. "Decoy nanoparticles protect against COVID-19 by concurrently adsorbing viruses and inflammatory cytokines." Proceedings of the National Academy of Sciences 117, no. 44 (October 6, 2020): 27141–47. http://dx.doi.org/10.1073/pnas.2014352117.
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The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte−macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.
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Sumbria, Rachita K., Ruben J. Boado, and William M. Pardridge. "Brain Protection from Stroke with Intravenous TNFα Decoy Receptor-Trojan Horse Fusion Protein." Journal of Cerebral Blood Flow & Metabolism 32, no. 10 (June 20, 2012): 1933–38. http://dx.doi.org/10.1038/jcbfm.2012.97.
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Tumor necrosis factor (TNF)- α is produced in brain in response to acute cerebral ischemia, and promotes neuronal apoptosis. Biologic TNF inhibitors (TNFIs), such as the etanercept, cannot be developed as new stroke treatments because these large molecule drugs do not cross the blood–brain barrier (BBB). A BBB-penetrating biologic TNFI was engineered by fusion of the type II human TNF receptor (TNFR) to each heavy chain of a genetically engineered chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated as cTfRMAb-TNFR fusion protein. The cTfRMAb domain of the fusion protein acts as a molecular Trojan horse to deliver the fused TNFR across the BBB. Etanercept or the cTfRMAb-TNFR fusion protein (1 mg/kg) was administered intravenously in adult mice subjected to 1-hour reversible middle cerebral artery occlusion up to 90 minutes after the occlusion. Neuroprotection was assessed at 24 hours or 7 days after occlusion. The cTfRMAb-TNFR fusion protein treatment caused a significant 45%, 48%, 42%, and 54% reduction in hemispheric, cortical, and subcortical stroke volumes, and neural deficit, respectively. Intravenous etanercept had no therapeutic effect. Biologic TNFIs can be reengineered for BBB penetration, and the IgG-TNFR fusion protein is therapeutic after delayed intravenous administration in experimental stroke.
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Rastoin, Olivia, Gilles Pagès, and Maeva Dufies. "Experimental Models in Neovascular Age Related Macular Degeneration." International Journal of Molecular Sciences 21, no. 13 (June 29, 2020): 4627. http://dx.doi.org/10.3390/ijms21134627.
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Neovascular age-related macular degeneration (vAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease depends on angiogenesis mediated by the vascular endothelial growth factor A (VEGF) and to inflammation. The only available treatments consist of monthly intravitreal injections of antibodies directed against VEGF or VEGF/VEGFB/PlGF decoy receptors. Despite their relative efficacy, these drugs only delay progression to blindness and 30% of the patients are insensitive to these treatments. Hence, new therapeutic strategies are urgently needed. Experimental models of vAMD are essential to screen different innovative therapeutics. The currently used in vitro and in vivo models in ophthalmic translational research and their relevance are discussed in this review.
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Loiarro, Maria, Vito Ruggiero, and Claudio Sette. "Targeting TLR/IL-1R Signalling in Human Diseases." Mediators of Inflammation 2010 (2010): 1–12. http://dx.doi.org/10.1155/2010/674363.
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The members of Toll-like receptor/Interleukin (IL)-1 receptor (TLR/IL-1R) superfamily play a fundamental role in the immune response. These receptors detect microbial components and trigger complex signalling pathways that result in increased expression of multiple inflammatory genes. On the other hand, an aberrant activation of TLR/IL-1R signalling can promote the onset of inflammatory and autoimmune diseases, raising the interest in the development of therapeutic strategies for the control of their function. In this review, we illustrate the structural and functional features of TLR/IL-1R proteins and discuss some recent advances in the approaches undertaken to develop anti-inflammatory therapeutic drugs. In particular, we will focus on inhibitors, such as decoy peptides and synthetic mimetics, that interfere with protein-protein interactions between signalling molecules of the TLR/IL-1R superfamily. Given their central role in innate and adaptive immune responses, it is foreseen that pharmaceutical modulation of TLR/IL-1R signalling pathways by these drugs might yield clinical benefits in the treatment of inflammatory and autoimmune diseases.
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Wesselborg, Sebastian, Ingo H. Engels, Evi Rossmann, Marek Los, and Klaus Schulze-Osthoff. "Anticancer Drugs Induce Caspase-8/FLICE Activation and Apoptosis in the Absence of CD95 Receptor/Ligand Interaction." Blood 93, no. 9 (May 1, 1999): 3053–63. http://dx.doi.org/10.1182/blood.v93.9.3053.
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Abstract Proteases of the caspase family are the critical executioners of apoptosis. Their activation has been mainly studied upon triggering of death receptors, such as CD95 (Fas/APO-1) and tumor necrosis factor-R1, which recruit caspase-8/FLICE as the most proximal effector to the receptor complex. Because apoptosis induced by anticancer drugs has been proposed to involve CD95/CD95 ligand interaction, we investigated the mechanism of caspase activation by daunorubicin, doxorubicin, etoposide, and mitomycin C. In Jurkat leukemic T cells, all drugs induced apoptosis and the cleavage of procaspase-8 to its active p18 subunit. However, cells resistant to CD95 were equally susceptible to anticancer drugs and activated caspase-8 with a similar kinetic and dose response as CD95-sensitive cells. The broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis and caspase-8 activation in response to CD95 and drug treatment, whereas a neutralizing CD95 decoy as well as a dominant-negative FADD construct selectively abrogated CD95, but not drug-induced effects. A potent activation of caspase-8 was also induced by cycloheximide, indicating that it was independent of protein synthesis. Our data, therefore, show that (1) anticancer drug-induced apoptosis does not require de novo synthesis of death ligands or CD95 interaction, and (2) that caspase-8 can be activated in the absence of a death receptor signaling.
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Wesselborg, Sebastian, Ingo H. Engels, Evi Rossmann, Marek Los, and Klaus Schulze-Osthoff. "Anticancer Drugs Induce Caspase-8/FLICE Activation and Apoptosis in the Absence of CD95 Receptor/Ligand Interaction." Blood 93, no. 9 (May 1, 1999): 3053–63. http://dx.doi.org/10.1182/blood.v93.9.3053.409a33_3053_3063.
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Proteases of the caspase family are the critical executioners of apoptosis. Their activation has been mainly studied upon triggering of death receptors, such as CD95 (Fas/APO-1) and tumor necrosis factor-R1, which recruit caspase-8/FLICE as the most proximal effector to the receptor complex. Because apoptosis induced by anticancer drugs has been proposed to involve CD95/CD95 ligand interaction, we investigated the mechanism of caspase activation by daunorubicin, doxorubicin, etoposide, and mitomycin C. In Jurkat leukemic T cells, all drugs induced apoptosis and the cleavage of procaspase-8 to its active p18 subunit. However, cells resistant to CD95 were equally susceptible to anticancer drugs and activated caspase-8 with a similar kinetic and dose response as CD95-sensitive cells. The broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis and caspase-8 activation in response to CD95 and drug treatment, whereas a neutralizing CD95 decoy as well as a dominant-negative FADD construct selectively abrogated CD95, but not drug-induced effects. A potent activation of caspase-8 was also induced by cycloheximide, indicating that it was independent of protein synthesis. Our data, therefore, show that (1) anticancer drug-induced apoptosis does not require de novo synthesis of death ligands or CD95 interaction, and (2) that caspase-8 can be activated in the absence of a death receptor signaling.
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Rampogu, Shailima, Amir Zeb, Ayoung Baek, Chanin Park, Minky Son, and Keun Woo Lee. "Discovery of Potential Plant-Derived Peptide Deformylase (PDF) Inhibitors for Multidrug-Resistant Bacteria Using Computational Studies." Journal of Clinical Medicine 7, no. 12 (December 17, 2018): 563. http://dx.doi.org/10.3390/jcm7120563.
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Bacterial peptide deformylase (PDF) is an attractive target for developing novel inhibitors against several types of multidrug-resistant bacteria. The objective of the current study is to retrieve potential phytochemicals as prospective drugs against Staphylococcus aureus peptide deformylase (SaPDF). The current study focuses on applying ligand-based pharmacophore model (PharmL) and receptor-based pharmacophore (PharmR) approaches. Utilizing 20 known active compounds, pharmL was built and validated using Fischer’s randomization, test set method and the decoy set method. PharmR was generated from the knowledge imparted by the Interaction Generation protocol implemented on the Discovery Studio (DS) v4.5 and was validated using the decoy set that was employed for pharmL. The selection of pharmR was performed based upon the selectivity score and further utilizing the Pharmacophore Comparison module available on the DS. Subsequently, the validated pharmacophore models were escalated for Taiwan Indigenous Plants (TIP) database screening and furthermore, a drug-like evaluation was performed. Molecular docking was initiated for the resultant compounds, employing CDOCKER (available on the DS) and GOLD. Eventually, the stability of the final PDF–hit complexes was affirmed using molecular dynamics (MD) simulation conducted by GROMACS v5.0.6. The redeemed hits demonstrated a similar binding mode and stable intermolecular interactions with the key residues, as determined by no aberrant behaviour for 50 ns. Taken together, it can be stated that the hits can act as putative scaffolds against SaPDF, with a higher therapeutic value. Furthermore, they can act as fundamental structures for designing new drug candidates.
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Estaquier, Jérôme, Jean-Daniel Lelièvre, Frédéric Petit, Thomas Brunner, Laure Moutouh-de Parseval, Douglas D. Richman, Jean Claude Ameisen, and Jacques Corbeil. "Effects of Antiretroviral Drugs on Human Immunodeficiency Virus Type 1-Induced CD4+ T-Cell Death." Journal of Virology 76, no. 12 (June 15, 2002): 5966–73. http://dx.doi.org/10.1128/jvi.76.12.5966-5973.2002.
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ABSTRACT Apoptosis of peripheral blood T cells plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 (HIV-1) primes CD4+ T cells from healthy donors for apoptosis, which occurs after CD95 ligation or CD3-T-cell receptor (TCR) stimulation. CD95-mediated death did not depend on CD4 T-cell infection, since it occurred in the presence of the reverse transcriptase inhibitor didanosine (ddI). In contrast, apoptosis induced by productive infection (CD3-TCR stimulation) is prevented by both CD95 decoy receptor and ddI. Our data suggest that HIV-1 triggers at least two distinct death pathways: a CD95-dependent pathway that does not require viral replication and a viral replication-mediated cell death independent of the CD95 pathway. Further experiments indicated that saquinavir, a protease inhibitor, at a 0.2 μM concentration, decreased HIV-mediated CD95 expression and thus cell death, which is independent of its role in inhibiting viral replication. However, treatment of peripheral blood mononuclear cells from healthy donors with a higher concentration (10 μM) of an HIV protease inhibitor, saquinavir or indinavir, induced both a loss in mitochondrial membrane potential (ΔΨm) and cell death. Thus, protease inhibitors have the potential for both beneficial and detrimental effects on CD4+ T cells independent of their antiretroviral effects.
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Chaccour, Carlos. "Veterinary endectocides for malaria control and elimination: prospects and challenges." Philosophical Transactions of the Royal Society B: Biological Sciences 376, no. 1818 (December 28, 2020): 20190810. http://dx.doi.org/10.1098/rstb.2019.0810.
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Residual transmission is the persistence of malaria transmission after scale-up of appropriate vector control tools and is one of the key challenges for malaria elimination today. Although long associated with outdoor biting, other mosquito behaviours such as partly feeding upon animals contribute greatly to sustaining transmission. Peri-domestic livestock can be used as decoy to protect humans from blood-seeking vectors but this approach often leads to an increased malaria risk in a phenomenon known as zoopotentiation. Treating the said livestock with drugs capable of killing intestinal parasites as well as mosquitoes that feed upon them has the potential to tackle malaria through a previously unexplored mechanism. The advantages and challenges associated with this approach are briefly discussed here. Numerous references are purposely provided. This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases’.
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Lee, Michelle Ji-Eun, Nan Jin, Janice Cho, Patrick Kwok-shing, Gordon B. Mills, Daniel E. Johnson, and Jennifer R. Grandis. "4373 Defining the role of non-canonical PIK3CA mutations in head and neck squamous cell carcinoma." Journal of Clinical and Translational Science 4, s1 (June 2020): 5. http://dx.doi.org/10.1017/cts.2020.60.
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OBJECTIVES/GOALS: To characterize the oncogenic potential of HNSCC cell lines harboring 17 non-canonical PIK3CA mutations. METHODS/STUDY POPULATION: Non-canonical PIK3CA mutant constructs generated via site-directed mutagenesis are subcloned into doxycycline-inducible vector pLVX-Puro. Serum-dependent HNSCC cell line (PCI-52-SD1) is then stably transfected with vectors and undergo doxycycline-induction. Cell survival is determined by depriving cells of fetal bovine serum for 72 hours and quantifying remaining cells with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Cell proliferation and migration is evaluated with colony formation assays and transwell assays respectively. RESULTS/ANTICIPATED RESULTS: To date, the survival behavior of eight non-canonical mutants was assessed. Three mutants – Q75E, V71I, and E970K – exhibited 18.7-26.7% greater survival rate relative to cells transfected with wild-type. Five mutants – R519G, Y606C, W328S, C905S, and M1040I – demonstrated survival rates that differed only by −4.3% to +6.6% relative to wild-type. We hypothesize the three activating mutants that exhibited increased survival will also demonstrate increased cell proliferation and migratory behavior whereas the three neutral mutants will not differ from control. DISCUSSION/SIGNIFICANCE OF IMPACT: Ongoing HNSCC PI3K inhibitor trials could be more effective if all PIK3CA hyperactivation mutations are known. Identifying non-canonical mutation effects could result in greater efficacy if drugs are restricted only to those with activating mutations. CONFLICT OF INTEREST DESCRIPTION: JRG and DEJ are co-inventors of cyclic STAT3 decoy and have financial interests in STAT3 Therapeutics, Inc. STAT3 Therapeutics, Inc. holds an interest in a cyclic STAT3 decoy oligonucleotide. The remaining authors declare no conflicts.
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Cao, Jiong, Jenni I. Viholainen, Caroline Dart, Helen K. Warwick, Mark L. Leyland, and Michael J. Courtney. "The PSD95–nNOS interface." Journal of Cell Biology 168, no. 1 (January 3, 2005): 117–26. http://dx.doi.org/10.1083/jcb.200407024.
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The stress-activated protein kinase p38 and nitric oxide (NO) are proposed downstream effectors of excitotoxic cell death. Although the postsynaptic density protein PSD95 can recruit the calcium-dependent neuronal NO synthase (nNOS) to the mouth of the calcium-permeable NMDA receptor, and depletion of PSD95 inhibits excitotoxicity, the possibility that selective uncoupling of nNOS from PSD95 might be neuroprotective is unexplored. The relationship between excitotoxic stress–generated NO and activation of p38, and the significance of the PSD95–nNOS interaction to p38 activation also remain unclear. We find that NOS inhibitors reduce both glutamate-induced p38 activation and the resulting neuronal death, whereas NO donor has effects consistent with NO as an upstream regulator of p38 in glutamate-induced cell death. Experiments using a panel of decoy constructs targeting the PSD95–nNOS interaction suggest that this interaction and subsequent NO production are critical for glutamate-induced p38 activation and the ensuing cell death, and demonstrate that the PSD95–nNOS interface provides a genuine possibility for design of neuroprotective drugs with increased selectivity.
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Wen, Jinghai, Nimmanapalli Ramadevi, Diep Nguyen, Charles Perkins, Elizabeth Worthington, and Kapil Bhalla. "Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L–induced apoptosis of human acute leukemia cells." Blood 96, no. 12 (December 1, 2000): 3900–3906. http://dx.doi.org/10.1182/blood.v96.12.3900.
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Abstract In present studies, treatment with tumor necrosis factor (TNF)–related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 μg/mL of Apo-2L (95.0% ± 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53wt function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L–induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L–induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-xL. Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L–induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L–induced apoptosis.
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Wen, Jinghai, Nimmanapalli Ramadevi, Diep Nguyen, Charles Perkins, Elizabeth Worthington, and Kapil Bhalla. "Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L–induced apoptosis of human acute leukemia cells." Blood 96, no. 12 (December 1, 2000): 3900–3906. http://dx.doi.org/10.1182/blood.v96.12.3900.h8003900_3900_3906.
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In present studies, treatment with tumor necrosis factor (TNF)–related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 μg/mL of Apo-2L (95.0% ± 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53wt function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L–induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L–induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-xL. Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L–induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L–induced apoptosis.
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Zocchi, Maria Raffaella, Francesca Tosetti, Roberto Benelli, and Alessandro Poggi. "Cancer Nanomedicine Special Issue Review Anticancer Drug Delivery with Nanoparticles: Extracellular Vesicles or Synthetic Nanobeads as Therapeutic Tools for Conventional Treatment or Immunotherapy." Cancers 12, no. 7 (July 13, 2020): 1886. http://dx.doi.org/10.3390/cancers12071886.
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Both natural and synthetic nanoparticles have been proposed as drug carriers in cancer treatment, since they can increase drug accumulation in target tissues, optimizing the therapeutic effect. As an example, extracellular vesicles (EV), including exosomes (Exo), can become drug vehicles through endogenous or exogenous loading, amplifying the anticancer effects at the tumor site. In turn, synthetic nanoparticles (NP) can carry therapeutic molecules inside their core, improving solubility and stability, preventing degradation, and controlling their release. In this review, we summarize the recent advances in nanotechnology applied for theranostic use, distinguishing between passive and active targeting of these vehicles. In addition, examples of these models are reported: EV as transporters of conventional anticancer drugs; Exo or NP as carriers of small molecules that induce an anti-tumor immune response. Finally, we focus on two types of nanoparticles used to stimulate an anticancer immune response: Exo carried with A Disintegrin And Metalloprotease-10 inhibitors and NP loaded with aminobisphosphonates. The former would reduce the release of decoy ligands that impair tumor cell recognition, while the latter would activate the peculiar anti-tumor response exerted by γδ T cells, creating a bridge between innate and adaptive immunity.
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Estrada, Chelsea C., Alejandro Maldonado, and Sandeep K. Mallipattu. "Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities." Journal of the American Society of Nephrology 30, no. 2 (January 14, 2019): 187–200. http://dx.doi.org/10.1681/asn.2018080853.
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Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in oncology, with new drugs continuously in development. In this review, we consider the experimental and clinical evidence behind the diverse nephrotoxicities associated with the inhibition of this pathway. We also review the renal effects of VEGF inhibition’s mediation of key downstream signaling pathways, specifically MAPK/ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Reports also indicate that tyrosine kinase inhibition of the VEGF receptors is preferentially associated with glomerulopathies such as minimal change disease and FSGS. Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with albuminuria and podocyte injury, but has also been linked to renal-specific TMA. In all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 inhibitors contribute to nephrotoxicity, as well as the wide range of clinical manifestations that have been reported with their use. We also highlight potential avenues for future research to elucidate mechanisms for minimizing nephrotoxicity while maintaining therapeutic efficacy.
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Rider, Peleg, Yaron Carmi, and Idan Cohen. "Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations." International Journal of Cell Biology 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/9259646.
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Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra) and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically.
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Nigi, Laura, Giuseppina Grieco, Giuliana Ventriglia, Noemi Brusco, Francesca Mancarella, Caterina Formichi, Francesco Dotta, and Guido Sebastiani. "MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes." International Journal of Molecular Sciences 19, no. 12 (November 22, 2018): 3705. http://dx.doi.org/10.3390/ijms19123705.
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The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3′UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.
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Stevens, Megan, and Sebastian Oltean. "Modulation of Receptor Tyrosine Kinase Activity through Alternative Splicing of Ligands and Receptors in the VEGF-A/VEGFR Axis." Cells 8, no. 4 (March 28, 2019): 288. http://dx.doi.org/10.3390/cells8040288.
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Vascular endothelial growth factor A (VEGF-A) signaling is essential for physiological and pathological angiogenesis. Alternative splicing of the VEGF-A pre-mRNA gives rise to a pro-angiogenic family of isoforms with a differing number of amino acids (VEGF-Axxxa), as well as a family of isoforms with anti-angiogenic properties (VEGF-Axxxb). The biological functions of VEGF-A proteins are mediated by a family of cognate protein tyrosine kinase receptors, known as the VEGF receptors (VEGFRs). VEGF-A binds to both VEGFR-1, largely suggested to function as a decoy receptor, and VEGFR-2, the predominant signaling receptor. Both VEGFR-1 and VEGFR-2 can also be alternatively spliced to generate soluble isoforms (sVEGFR-1/sVEGFR-2). The disruption of the splicing of just one of these genes can result in changes to the entire VEGF-A/VEGFR signaling axis, such as the increase in VEGF-A165a relative to VEGF-A165b resulting in increased VEGFR-2 signaling and aberrant angiogenesis in cancer. Research into this signaling axis has recently focused on manipulating the splicing of these genes as a potential therapeutic avenue in disease. Therefore, further research into understanding the mechanisms by which the splicing of VEGF-A/VEGFR-1/VEGFR-2 is regulated will help in the development of drugs aimed at manipulating splicing or inhibiting specific splice isoforms in a therapeutic manner.
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BRANKA, Jean-Eric, Geneviève VALLETTE, Anne JARRY, and Christian L. LABOISSE. "Stimulation of mucin exocytosis from human epithelial cells by nitric oxide: evidence for a cGMP-dependent and a cGMP-independent pathway." Biochemical Journal 323, no. 2 (April 15, 1997): 521–24. http://dx.doi.org/10.1042/bj3230521.
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The aim of this work was to investigate the role of nitric oxide (NO) on the macromolecular exocytotic function of human epithelial cells. We tested the effects of two NO-generating drugs, i.e. 1-hexanamine 6-(2-hydroxy-1-methyl-2-nitrosohydrazine)-N-methyl (MAHMA NONOate) and sodium nitroprusside (SNP), on mucin exocytosis from the human colonic epithelial HT29-Cl.16E cell line. Our results show that MAHMA NONOate and SNP elicited a rapid mucin exocytotic response through a cGMP-dependent and a cGMP-independent pathway respectively. Indeed, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a newly available specific inhibitor of soluble guanylate cyclase, inhibited both cGMP accumulation and subsequent mucin exocytosis evoked by MAHMA NONOate. By contrast, SNP did not alter intracellular cGMP levels, and SNP-mediated mucin exocytosis was not inhibited by ODQ. As expected from two NO donors acting through distinct pathways, the combined action of MAHMA NONOate and SNP led to an additive effect on mucin exocytosis. SNP was likely to act through S-nitrosylation of a cellular target, because cysteine, a reductive thiol that provides decoy targets for SNP through the formation of nitrosocysteine, abolished the early stimulatory effect of SNP on mucin exocytosis. Finally, the fact that in the presence of cysteine SNP was able to trigger a late, ODQ-inhibitable, mucin exocytotic response demonstrates the ability of NO to shift its intracellular signalling pathway depending on the changes of the redox state of the milieu.
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Adriaens, Lieve, Kyriakos P. Papadopoulos, Donna M. Graham, Amita Patnaik, Albiruni R. A. Razak, Anthony W. Tolcher, Lillian L. Siu, et al. "A phase Ib study of combined angiogenesis blockade with REGN910 (SAR307746), a selective monoclonal antibody (MAb) against angiopoietin-2 (Ang2) and ziv-aflibercept in patients with advanced solid tumor malignancies." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): TPS2618. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps2618.
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TPS2618 Background: REGN910 is a selective, fully human Angiopoietin-2 (ANG-2) MAb, which potently blocks signaling through the Tie2 receptor. Ziv-aflibercept (ZAFL) is a recombinant human fusion protein that acts as a decoy receptor for vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF), thereby preventing the interaction of these ligands with their receptors. In several mouse xenograft models, combination of the 2 anti-angiogenic compounds, REGN910 and ZAFL, demonstrated significantly enhanced tumor growth inhibition relative to either agent alone, suggesting that dual angiogenic blockade is worth exploring in cancer patients. Methods: This phase 1b study employs a standard 3+3 dose escalation design exploring 5 different combination treatment dose levels of REGN910 and ZAFL. Once the recommended phase 2 dose (RD) of the combination treatment is determined, additional patients will be enrolled in a safety expansion cohort, for a planned total enrollment of up to 40 patients. The primary study objectives are to evaluate the safety and determine the RD of the 2 drugs in combination when both are administered IV every 2 weeks in patients with advanced solid tumors. Secondary endpoints include characterization of the PK and potential immunogenicity of REGN910 and ZAFL when given in combination, evaluation of correlative PD biomarkers related to REGN910 and ZAFL, and identification of antitumor activity. Enrollment to cohorts 1 and 2 has been completed without DLT. Enrollment to cohort 3 opened in December 2012. Updated enrollment status will be presented. Reference: ClinicalTrials.gov Identifier: NCT01688960. Clinical trial information: NCT01688960.
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Siddiqui, Fakiha, Alfonso Tafur, Emily Bontekoe, Omer Iqbal, Walter Jeske, Siddharth Mehrotra, Debra Hoppensteadt, Eduardo Ramacciotti, and Jawed Fareed. "Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa." Clinical and Applied Thrombosis/Hemostasis 26 (January 1, 2020): 107602961989512. http://dx.doi.org/10.1177/1076029619895120.
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Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anticoagulant profile of UFH, enoxaparin, and fondaparinux was studied using the activated partial thromboplastin time (aPTT), thrombin time (TT), and amidolytic anti-Xa, and anti-IIa methods. Thrombin generation inhibition was studied using the calibrated automated thrombogram system. Reversal of each of these agents was studied by supplementing andexanet alfa at 100 µg/mL. In the TEG, andexanet alfa produced almost a complete reversal of the anticoagulant effects of UFH and enoxaparin; however, it augmented the effects of fondaparinux. In the ACT, aPTT, and TT, UFH produced strong anticoagulant effects that were almost completely neutralized by andexanet alfa. Enoxaparin produced milder anticoagulant responses that were partially neutralized, whereas fondaparinux did not produce any sizeable effects. In the anti-Xa and anti-IIa assays, UFH exhibited partial neutralization whereas enoxaparin and fondaparinux did not show any neutralization. All agents produced varying degrees of the inhibition of thrombin generation, which were differentially neutralized by andexanet alfa. These results indicate that andexanet alfa is capable of differentially neutralizing anticoagulant and antiprotease effects of UFH and enoxaparin in an assay-dependent manner. However, andexanet alfa is incapable of neutralizing the anti-Xa effects of fondaparinux.
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Liscano, Yamil, Ana Amú, Astrid González, Jose Oñate-Garzón, and Constain H. Salamanca. "In Silico Characterization of the Interaction between the PBP2a “Decoy” Protein of Resistant Staphylococcus aureus and the Monomeric Units of Eudragit E-100 and Poly(Maleic Acid-alt-Octadecene) Polymers." Polymers 13, no. 14 (July 15, 2021): 2320. http://dx.doi.org/10.3390/polym13142320.
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Antimicrobial treatment alternatives for methicillin-resistant Staphylococcus aureus (MRSA) are increasingly limited. MRSA strains are resistant to methicillin due to the formation of β-lactamase enzymes, as well as the acquisition of the mecA gene, which encodes the penicillin-binding protein (PBP2a) that reduces the affinity for β-lactam drugs. Previous studies have shown that the use of ampicillin-loaded nanoparticles can improve antimicrobial activity on resistant S. aureus strains. However, the biological mechanism of this effect has not yet been properly elucidated. Therefore, this short communication focused on characterizing the in silico interactions of the PBP2a membrane receptor protein from S. aureus against the monomeric units of two polymeric materials previously used in the development of different nanoparticles loaded with ampicillin. Such polymers correspond to Eudragit E-100 chloride (EuCl) and the sodium salt of poly(maleic acid-alt-octadecene) (PAM-18Na). For this, molecular coupling studies were carried out in the active site of the PBP2a protein with the monomeric units of both polymers in neutral and ionized form, as well as with ampicillin antibiotic (model β-lactam drug). The results showed that ampicillin, as well as the monomeric units of EuCl and PAM18Na, described a slight binding free energy to the PBPa2 protein. In addition, it was found that the amino acids of the active site of the PBPa2 protein have interactions of different types and intensities, suggesting, in turn, different forms of protein–substrate coupling.
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Sargur Madabushi, Srideshikan, Darren Zuro, Yu-Lin SU, Paresh Vishwasrao, Jamison Brooks, Liliana E Parra, James F. Sanchez, Jeffrey Wong, Marcin Kortylewski, and Susanta Hui. "Targeted Marrow Radiation (TMI) Improves Therapeutic Efficacy of STAT3 Decoy Molecules By Augmenting Its Delivery and Immune Modulation in an AML Mouse Model." Blood 134, Supplement_1 (November 13, 2019): 3929. http://dx.doi.org/10.1182/blood-2019-127470.
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Introduction Acute myeloid leukemia (AML) is a highly aggressive form of leukemia with poor long-term survival. Our clinical development of a targeted radiation treatment for relapsed/refractory AML disease led to an impressive two-year overall survival (OS) rate of 41% (Stein et al., 2019) in contrast to <10% reported for similar patients (Duval et al., 2019). Unfortunately, a lack of a preclinical model for TMI has impaired further scientific advancement. Ionizing radiation therapy (RT) has been shown to have immune modulatory functions; however, previous studies demonstrated that its efficacy is limited by activation of the radiation-induced tolerogenic TLR9/IL-6/STAT3 signaling axis in myeloid immune cells (Gao et al., 2013; Won et al., 2017). TLR9+ myeloid cells (macrophages, AML, etc) can be efficiently targeted using TLR9 agonists (CpG) conjugated with oligonucleotide (ODN) drugs (e.g., siRNA) to eliminate STAT3 signaling. Such a strategy has been shown to synergize with local tumor RT to prevent tumor recurrence (Gao et al., 2013). A CPG-STAT3-dODN inhibitor (CSI) has been previously reported as an effective immunotherapy for AML (Zhang et al., 2016), but the efficacy of immunotherapeutic agents is drastically reduced at high disease burden (Pai et al., 2019). Therefore, we hypothesized that the immunomodulatory effects of low dose RT can be augmented by blocking the STAT3 signaling in AML cells, enhancing the efficacy of CSI in a high-disease burden model. Methods We first developed a TMI treatment methodology using a Precision X-RAD small animal irradiator. A whole body CT image was acquired, and three-dimensional (3D) dose calculations were performed using a Monte Carlo dose engine-based SmART-Plan treatment system (van Hoof et al, 2013; Downes et al., 2009; Faddegon et al., 2009). Before treatment, mice were further imaged to verify target anatomy prior to delivering precise radiation doses to the entire skeletal system and spleen while sparing vital organs (lungs, liver, gut). We used a Cbfb-MYH11/Mpl (CMM)-induced mice leukemia model. At 5-10% CMM-GFP cells in peripheral blood (~20-30% in bone marrow; high disease burden), the mice were treated with three doses of CSI (2.5mg/kg) on alternate days with or without 4 Gy radiation (TMI or total body irradiation [TBI]). Cy3 labeled CSI uptake studies were carried out 48h post RT by flow cytometry, and immune cell trafficking and activation studies were conducted by harvesting bone marrow and spleen cells on day 8 post RT. Results Dose volume histogram (DVH) and radiation dose painting show that the TMI treatment plan significantly reduced doses to critical organs (lungs, liver, gut) while maintianing the same dose to the skeleton and spleen, unlike TBI (same dose to entire body) (Figure 1A-D). In TMI-treated mice, the CSI-Cy3 uptake was significantly higher in CMM cells than in the CMM cells of mice treated with CSI alone, indicating improved delivery post RT (Figure 1E, F). The trafficking of T helper cells (CD4+) and cytotoxic T lymphocytes (CD8+; CTLs) as well as effector (CD62L-CD44+) and effector memory T cells (CD62L+CD44+) is significantly augmented in the bone marrow of TMI+CSI treated mice compared to levels in mice treated with TBI+CSI or CSI alone (Figure 1G, H). An increased total number of IFNγ secreting CTLs, and a higher CD8:Treg (CD4+CD25+FOXP3+) ratio indicate enhanced anti-tumerogenic activity in TMI+CSI treated mice over that of mice treated with TBI+CSI or CSI alone (Figure 1I, J). Similarly, myeloid cell trafficking and activation was augmented in TMI-treated bone marrow (data not shown). The benefit of augmented immune modulation in TMI+CSI combinatorial therapy is reflected in a significantly increased survival (~39 median survival days) over untreated mice and those treated with CSI or TMI alone ( ~8-9 days median survival) (Figure 1K). Conclusion This is the first report of a novel radio-immunotherapy using a systemic targeted precise RT (TMI) in combination with STAT3 down-regulation (CSI) in AML. As hypothesized, low-dose targeted RT in combination with blocking of STAT3 signaling improved immune cell trafficking and activation, thereby enhancing the efficacy of this combinatorial therapy in high-disease burden. Further, newly developed low-dose TMI shows enhanced immune modulation over conventional TBI, suggesting the benefits of localized targeted RT in hematological malignancies. Disclosures Hui: Janssen Research & Development, LLC: Consultancy, Honoraria.
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Rana, Rabia Mukhtar, Shailima Rampogu, Noman Bin Abid, Amir Zeb, Shraddha Parate, Gihwan Lee, Sanghwa Yoon, Yumi Kim, Donghwan Kim, and Keun Woo Lee. "In Silico Study Identified Methotrexate Analog as Potential Inhibitor of Drug Resistant Human Dihydrofolate Reductase for Cancer Therapeutics." Molecules 25, no. 15 (July 31, 2020): 3510. http://dx.doi.org/10.3390/molecules25153510.
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Drug resistance is a core issue in cancer chemotherapy. A known folate antagonist, methotrexate (MTX) inhibits human dihydrofolate reductase (hDHFR), the enzyme responsible for the catalysis of 7,8-dihydrofolate reduction to 5,6,7,8-tetrahydrofolate, in biosynthesis and cell proliferation. Structural change in the DHFR enzyme is a significant cause of resistance and the subsequent loss of MTX. In the current study, wild type hDHFR and double mutant (engineered variant) F31R/Q35E (PDB ID: 3EIG) were subject to computational study. Structure-based pharmacophore modeling was carried out for wild type (WT) and mutant (MT) (variant F31R/Q35E) hDHFR structures by generating ten models for each. Two pharmacophore models, WT-pharma and MT-pharma, were selected for further computations, and showed excellent ROC curve quality. Additionally, the selected pharmacophore models were validated by the Guner-Henry decoy test method, which yielded high goodness of fit for WT-hDHFR and MT-hDHFR. Using a SMILES string of MTX in ZINC15 with the selections of ‘clean’, in vitro and in vivo options, 32 MTX-analogs were obtained. Eight analogs were filtered out due to their drug-like properties by applying absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment tests and Lipinski’s Rule of five. WT-pharma and MT-pharma were further employed as a 3D query in virtual screening with drug-like MTX analogs. Subsequently, seven screening hits along with a reference compound (MTX) were subjected to molecular docking in the active site of WT- and MT-hDHFR. Through a clustering analysis and examination of protein-ligand interactions, one compound was found with a ChemPLP fitness score greater than that of MTX (reference compound). Finally, a simulation of molecular dynamics (MD) identified an MTX analog which exhibited strong affinity for WT- and MT-hDHFR, with stable RMSD, hydrogen bonds (H-bonds) in the binding site and the lowest MM/PBSA binding free energy. In conclusion, we report on an MTX analog which is capable of inhibiting hDHFR in wild type form, as well as in cases where the enzyme acquires resistance to drugs during chemotherapy treatment.
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Koseki, Shiori, Jun Ohkawa, Rika Yamamoto, Yutaka Takebe, and Kazunari Taira. "A simple assay system for examination of the inhibitory potential in vivo of decoy RNAs, ribozymes and other drugs by measuring the Tat-mediated transcription of a fusion gene composed of the long terminal repeat of HIV-1 and a gene for luciferase." Journal of Controlled Release 53, no. 1-3 (April 1998): 159–73. http://dx.doi.org/10.1016/s0168-3659(97)00250-2.
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Ojo, Oluwafemi Adeleke, Adebola Busola Ojo, Charles Okolie, Mary-Ann Chinyere Nwakama, Matthew Iyobhebhe, Ikponmwosa Owen Evbuomwan, Charles Obiora Nwonuma, et al. "Deciphering the Interactions of Bioactive Compounds in Selected Traditional Medicinal Plants against Alzheimer’s Diseases via Pharmacophore Modeling, Auto-QSAR, and Molecular Docking Approaches." Molecules 26, no. 7 (April 1, 2021): 1996. http://dx.doi.org/10.3390/molecules26071996.
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Neurodegenerative diseases, for example Alzheimer’s, are perceived as driven by hereditary, cellular, and multifaceted biochemical actions. Numerous plant products, for example flavonoids, are documented in studies for having the ability to pass the blood-brain barrier and moderate the development of such illnesses. Computer-aided drug design (CADD) has achieved importance in the drug discovery world; innovative developments in the aspects of structure identification and characterization, bio-computational science, and molecular biology have added to the preparation of new medications towards these ailments. In this study we evaluated nine flavonoid compounds identified from three medicinal plants, namely T. diversifolia, B. sapida, and I. gabonensis for their inhibitory role on acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) activity, using pharmacophore modeling, auto-QSAR prediction, and molecular studies, in comparison with standard drugs. The results indicated that the pharmacophore models produced from structures of AChE, BChE and MAO could identify the active compounds, with a recuperation rate of the actives found near 100% in the complete ranked decoy database. Moreso, the robustness of the virtual screening method was accessed by well-established methods including enrichment factor (EF), receiver operating characteristic curve (ROC), Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC), and area under accumulation curve (AUAC). Most notably, the compounds’ pIC50 values were predicted by a machine learning-based model generated by the AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best models achieved for AChE, BChE and MAO were models kpls_radial_17 (R2 = 0.86 and Q2 = 0.73), pls_38 (R2 = 0.77 and Q2 = 0.72), kpls_desc_44 (R2 = 0.81 and Q2 = 0.81) and these externally validated models were utilized to predict the bioactivities of the lead compounds. The binding affinity results of the ligands against the three selected targets revealed that luteolin displayed the highest affinity score of −9.60 kcal/mol, closely followed by apigenin and ellagic acid with docking scores of −9.60 and −9.53 kcal/mol, respectively. The least binding affinity was attained by gallic acid (−6.30 kcal/mol). The docking scores of our standards were −10.40 and −7.93 kcal/mol for donepezil and galanthamine, respectively. The toxicity prediction revealed that none of the flavonoids presented toxicity and they all had good absorption parameters for the analyzed targets. Hence, these compounds can be considered as likely leads for drug improvement against the same.
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Stewart, David J., Dominick Bossé, Andrew George Robinson, Michael Ong, Stephanie Yasmin Brule, Michael Fung-Kee-Fung, John Frederick Hilton, Mark J. Clemons, and Alberto Ocana. "Population kinetics of progression free survival (PFS)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e18251-e18251. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18251.
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e18251 Background: We assessed drug type impact on whether PFS curves could be fit by 2 phase decay models on nonlinear regression analysis (NLRA). Methods: We digitized 894 published PFS curves for incurable cancers. We used GraphPad Prism 7 for 1 phase and 2 phase decay NLRA, with constraints Y0 = 100 and plateau = 0. We defined curves as fitting 2 phase models if each subpopulation was ≥1% of the entire population and if subpopulation half-lives differed by a factor of ≥2, or if log-linear plots demonstrated unequivocal 2 phase decay. Results: PFS curves for single agents showed either high (≥75%) or low ( < 30%) probability of 2 phase decay, depending on drug type (p < 0.0001, Table). 11/11 PD1/ipilimumab combinations had 2 phase decay vs 36/209 curves (17%) for all other combinations. Conclusions: Drugs have either high or low probability of PFS curve 2 phase decay. Clinical trial methods or some mechanisms of acquired resistance might contribute to 2 phase decay, but 2 phase decay also could indicate a dichotomous factor (eg gene mutation/deletion or complete pathway silencing) producing 2 distinct subpopulations with differing progression rates. Drugs with high 2 phase decay could be prime candidates for RNA & whole genome sequencing, pathway expression studies etc to identify dichotomous predictive factors. Further assessment is needed to better understand why some drugs behave differently when given in combinations vs as single agents. [Table: see text]
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Osterweil, Emily K. "A no-nonsense treatment for autism spectrum disorder." Science Translational Medicine 11, no. 516 (October 30, 2019): eaaz3723. http://dx.doi.org/10.1126/scitranslmed.aaz3723.
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Crunkhorn, Sarah. "Decoy receptor targets lung cancer." Nature Reviews Drug Discovery 19, no. 1 (December 3, 2019): 22. http://dx.doi.org/10.1038/d41573-019-00206-5.
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Burnier, Laurent, Didier Le Roy, Thierry Roger, Thierry Fumeaux, François Saller, Marc Chanson, Delphine Borgel, et al. "Role of Growth Arrest-Specific Gene 6 Product (Gas6) in Severe Sepsis." Blood 108, no. 11 (November 16, 2006): 1640. http://dx.doi.org/10.1182/blood.v108.11.1640.1640.
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Abstract Gas6 binding to its cognate receptor tyrosine kinases (Tyro3, Axl and Mer) down-regulates the activation state of macrophages and thereby their production of proinflammatory cytokines induced by various stimuli. Mer activation inhibits TNF-α production by macrophages and alleviates endotoxic shock in mice. Gas6 receptors are cleaved in the extracellular domain to generate soluble receptors. Soluble receptors function as decoy receptors, thereby inhibiting the Gas6 interaction with cell-associated receptors. The aim of the study was to determine whether Gas6 pathway plays a role in sepsis in human and mice. In the first part of the study, we measured plasma levels of Gas6 and its soluble receptors sTyro3 and sAxl in 13 healthy subjects, 29 patients with severe sepsis, and 18 patients with acute non-infectious inflammatory diseases. Gas6 and sAxl concentrations were higher in septic patients than in healthy subjects or in patients with non-infectious inflammatory disease (P≤ 0.0001 for Gas6 and <0.004 for sAxl) and correlated with C-reactive protein levels (P=0.0019 for Gas6 and =0.0037 for sAxl). The sensitivity and specificity of Gas6 levels to predict fatal outcome was 83% and 88%. In the second part of the study, we investigated whether Gas6 affects cytokine production and outcome in experimental models of endotoxemia and peritonitis in Gas6+/+ and Gas6−/ − mice. Circulating levels of Gas6 after LPS 50mg/kg i.p. peaked at 1 h. (66±3ng/ml), were still elevated 4 h. later (47±1ng/ml) and returned approximately to baseline levels 8 h. after the LPS challenge (34±1ng/ml); P<0.001 for all time points versus baseline (23±1ng/ml). Cytokine (TNF-α and IL-6) production was higher in Gas6−/ − than Gas6+/+ mice after LPS 50mg/kg (TNF-α at 1 h.: 10±1ng/ml in Gas6−/ − versus 4.5±0.5ng/ml in Gas6+/+ mice, P<0.001; IL-6 at 4h.: 77±4ng/ml in Gas6+/+ versus 56±6ng/ml in Gas6−/ − mice, P=0.02). Similar data were obtained with Tyro3−/ − and Axl−/ − mice. Mortality induced by LPS 25mg/kg was 25% in Gas6+/+ versus 87% in Gas6−/ − mice (P=0.0023). In peritonitis models (cecal ligation and puncture, and i.p. injection of E. coli), plasma levels of Gas6 increased two-fold above baseline and remained elevated at least 24h. Increases of Gas6 levels were proportional to the importance of the size of the E. coli inoculum. In vitro experiments revealed that Gas6−/ − LPS-stimulated macrophages produced more TNF-α than Gas6+/+ macrophages. In conclusion, in septic patients, plasma levels of Gas6 and its cognate receptors were elevated and associated with fatal outcome. In mice, Gas6 plasma levels raised in experimental endotoxemia and sepsis models, and correlated also with sepsis severity. Thus, Gas6 and its receptors hold promise as early sepsis markers and outcome predictors, and could constitute therapeutic targets for new immunomodulating drugs.
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Mitsiades, Nicholas, Ciaran J. McMullan, Vassiliki Poulaki, Reshma Shringarpure, Towia A. Libermann, Teru Hideshima, Dharminder Chauhan, et al. "NVP-AEW541: A Selective Small Molecule IGF-1R Tyrosine Kinase Inhibitor Is Active Against Multiple Myeloma and Other Hematologic Neoplasias and Solid Tumors." Blood 104, no. 11 (November 16, 2004): 766. http://dx.doi.org/10.1182/blood.v104.11.766.766.
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Abstract We have shown that insulin-like growth factors (IGFs) and their receptor IGF-1R play critical roles in proliferation, survival and drug-resistance of a broad spectrum of hematologic malignancies and solid tumors and that selective inhibitors of IGF-1R kinase activity have in vivo anti-tumor activity in clinically relevant orthotopic tumor models (Cancer Cell2004;5:221–30). We now describe the in vitro and in vivo activity of NVP-AEW541, a novel pyrrolo[2,3-d] pyrimidine selective IGF-1R tyrosine kinase inhibitor with 27-fold selectivity for IGF-1R vs. its highly homologous insulin receptor. NVP-AEW541 is active (at sub-uM levels) against diverse tumor types, including >30 MM cell lines and >10 primary tumor cells from MM patients (including cells resistant to Dex, alkylating agents, anthracyclines, thalidomide, or its immunomodulatory derivatives, IMiDs, bortezomib, and/or Apo2L/TRAIL); and cell lines from diverse hematologic malignancies (including B- and T-ALL, AML, CML, and lymphoma subtypes) and solid tumors (e.g. breast, prostate, lung, thyroid, ovarian, renal Ca, retinoblastoma and sarcomas). All studied tumor cells expressed IGF-1R, without any correlation between mean fluorescence intensity of expression of IGF-1R (or its decoy non-signaling counterpart IGF-2R/CD222) and the degree of tumor cell sensitivity to NVP-AEW541. The in vitro anti-tumor effects of NVP-AEW541 were highly consistent with those of other selective anti-IGF-1R neutralizing agents, including another IGF-IR inhibitor of the pyrrolo[2,3-d] pyrimidine structural class (NVP-ADW742) or anti-human IGF-1R-specific neutralizing mAb’s (aIR3). NVP-AEW541 counteracts the proliferative/anti-apoptotic effect of serum on tumor cells from the entire spectrum of diseases that were studied, but more prominently against MM cells. Importantly, NVP-AEW541 had in vivo anti-tumor activity in a SCID/NOD mice model of diffuse MM. Mechanistically, IGF-1R inhibition by NVP-AEW541 blocks key growth/survival pathways (e.g. PI-3K/Akt, Ras/Raf/MAPK, IKK-a/NF-kB); blocks expression of inhibitors of apoptosis (e.g. FLIP, cIAP-2, survivin); and suppresses both constitutive and serum- or IGF-1-induced upregulation of proteasome activity. These molecular sequelae can explain why NVP-AEW541 sensitized tumor cells (e.g. MM, PrCa, BrCa or sarcomas) to other anti-cancer drugs (e.g. Dex, cytotoxic chemotherapeutics and PS-341); blunted tumor cell responses to other growth factors (e.g. MM or PrCa cell response to IL-6); overcame the drug-resistance phenotype conferred by bone marrow stromal cells; and abrogated VEGF production in co-cultures of MM cells with BMSCs. These studies further confirm that IGF-1R plays major role in growth/survival of neoplastic cells, indicate that IGF-1R pathway can be targeted with multiple clinically applicable approaches; and provide proof-of-principle for clinical trials of NVP-AEW541, e.g. in MM, a disease particularly dependent upon IGF-1R function.
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Sergievsky, M., and G. Zabusov. "On the question of the significance of tissue decay products. Experiments with the prostate gland." Kazan medical journal 32, no. 4 (September 20, 2021): 359–68. http://dx.doi.org/10.17816/kazmj80555.
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Siddiqui, Fakiha, Alfonso J. Tafur, Debra Hoppensteadt, Jeanine Walenga, Walter Jeske, Emily Bontekoe, Ahmed Kouta, and Jawed Fareed. "Andexanet Alpha Differentially Neutralizes the Anticoagulant, Antiprotease and Thrombin Generation Inhibitory Effects of Unfractionated Heparin, Enoxaparin and Fondaparinux." Blood 134, Supplement_1 (November 13, 2019): 1158. http://dx.doi.org/10.1182/blood-2019-127072.
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Introduction: Andexanet Alpha (Coagulation factor Xa recombinant, inactivated Zh-zo; AA, Portola Pharmaceuticals) is a recombinant factor Xa decoy protein which is designed to reverse the effects of apixaban and rivaroxaban and is approved for the control of bleeding complications associated with their use. The molecular modification in this recombinant protein involves the substitution of serine active site by alanine and the removal of the gamma-carboxyglutamic acid (GLA) domain to restrict its assemblage into prothrombinase complex. Beside the reversal of the effects of anti-Xa agents AA is also reported to neutralize the biologic effects of heparin and related drugs. Assay dependent variations in the neutralization profile of various factor Xa inhibitors by andexanet has been recently reported https://doi.org/10.1177/1076029619847524. Since heparin and related drugs also mediate their biologic actions by inhibiting factor Xa via AT complexation, it is hypothesized that AA may also inhibit their biologic effects as measured in various laboratory assays. It is the purpose of this study is to compare the relative neutralization profile of heparin (UFH), a low molecular weight heparin, enoxaparin (E) and a chemically synthetic pentasaccharide, Fondaparinux (F) by AA. Materials and Methods: API versions of UFH, E and F were commercially obtained in powdered forms and dissolved in saline at a working dilution of 1mg/ml. AA was dissolved in saline to obtain a 10mg/ml working solution. The anticoagulant profile of UFH, E and F was studied using the activated partial thromboplastin time (APTT) and thrombin time (TT) in a concentration range of 0 - 10 ug/ml in pooled human plasma. The anti-Xa and anti-IIa studies were carried out in amidolytic assays in the same concentration range. The thrombin generation inhibition was studied using calibrated automated thrombin generation systems (CAT, Diagnostica Stago). The effect of AA on the reversal of the anticoagulant and anti-protease and thrombin generation effects of each of these agents were studied by supplementing this agent at 100 ug/ml. The results are compared to determine the difference between pre and post AA neutralization settings. Results: All agents produce a concentration dependent effect in the anticoagulant and anti-protease assays with the exception of F which showed mild anticoagulant effects, and very weak anti-IIa actions and strong anti-Xa activity. In the anti-Xa assay the IC-50 for UFH was 2.1ug/ml (0.13 um), E 4.3 ug/ml (0.95 um) and F 0.7 ug/ml (0.41 um) upon supplementation of AA the IC50s for UFH was increased to 5 ug/ml (0.31 um) and for E 5 ug/ml (1.11 um). However, there was no neutralization of the anti-Xa effects of the F by AA and the IC50 remained the same for both pre and post andexxa studies. The anticoagulant effects of UFH as measured by aPTT and TT was strongly neutralized whereas E was only partially neutralized in the aPTT assay and almost completely neutralized in the thrombin time assay. At concentrations of up to 10 ug/ml F did not produced any significant anticoagulant effects, both in the presence and absence of AA. In the thrombin generation inhibition assays, UFH produced a complete inhibition of thrombin generation which was completely reversed by AA. Although both E and F produced strong inhibition of thrombin generation, AA did not completely neutralize these effects. The results are tabulated on table 1 for the studies carried out at 10 ug/ml of UFH, E and F. Conclusion: These results indicate that AA is capable of differentially neutralizing anticoagulant and anti-protease effects of UFH in an assay dependent manner. However, AA is incapable of neutralizing the anti-Xa effects of E and F. This may be due to the relatively differential affinities of enoxaparin and fondaparinux AT complex to factor Xa rendering it inhibited in the presence of AA. These studies also demonstrate that the primary surrogate marker anti-Xa activity for measuring the activities of anti-Xa agents is not proportional to the anticoagulant and thrombin generation inhibitory effects of these agents. A global clotting assay may be a better indication of the biologic effects of these agents and their reversal by AA. Disclosures Tafur: Recovery Force: Consultancy; Janssen: Other: Educational Grants, Research Funding; BMS: Research Funding; Idorsia: Research Funding; Daichi Sanyo: Research Funding; Stago: Research Funding; Doasense: Research Funding.
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Armstrong, Gerald M., and Calvin P. Midgley. "Applications: The Exponential-Decay Law Applied to Medical Dosages." Mathematics Teacher 80, no. 2 (February 1987): 110–13. http://dx.doi.org/10.5951/mt.80.2.0110.
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Many drugs are used up by the human body at rates described in terms of exponential decay. Two simple exponential formulas are given in this article. One describes how a therapeutic level of a drug is achieved in terms of its half-life and other parameters. The other describes how this level is maintained.
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Willyard, Cassandra. "Prisoners, hard hit by hepatitis C, decry lack of access to drugs." Nature Medicine 18, no. 11 (November 2012): 1594–95. http://dx.doi.org/10.1038/nm1112-1594.
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Jones, Georgia Wilson, Marco P. Monopoli, Luisa Campagnolo, Antonio Pietroiusti, Lang Tran, and Bengt Fadeel. "No small matter: a perspective on nanotechnology-enabled solutions to fight COVID-19." Nanomedicine 15, no. 24 (October 2020): 2411–27. http://dx.doi.org/10.2217/nnm-2020-0286.
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There is an urgent need for safe and effective approaches to combat COVID-19. Here, we asked whether lessons learned from nanotoxicology and nanomedicine could shed light on the current pandemic. SARS-CoV-2, the causative agent, may trigger a mild, self-limiting disease with respiratory symptoms, but patients may also succumb to a life-threatening systemic disease. The host response to the virus is equally complex and studies are now beginning to unravel the immunological correlates of COVID-19. Nanotechnology can be applied for the delivery of antiviral drugs or other repurposed drugs. Moreover, recent work has shown that synthetic nanoparticles wrapped with host-derived cellular membranes may prevent virus infection. We posit that nanoparticles decorated with ACE2, the receptor for SARS-CoV-2, could be exploited as decoys to intercept the virus before it infects cells in the respiratory tract. However, close attention should be paid to biocompatibility before such nano-decoys are deployed in the clinic.
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Toshchakov, Vladimir Y., and Stefanie N. Vogel. "Cell-penetrating TIR BB loop decoy peptides." Expert Opinion on Biological Therapy 7, no. 7 (July 2007): 1035–50. http://dx.doi.org/10.1517/14712598.7.7.1035.
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Graves, Alan P., Ruth Brenk, and Brian K. Shoichet. "Decoys for Docking." Journal of Medicinal Chemistry 48, no. 11 (June 2005): 3714–28. http://dx.doi.org/10.1021/jm0491187.
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Donahue, Daniel A., Richard D. Sloan, Björn D. Kuhl, Tamara Bar-Magen, Susan M. Schader, and Mark A. Wainberg. "Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture." Antimicrobial Agents and Chemotherapy 54, no. 3 (December 28, 2009): 1047–54. http://dx.doi.org/10.1128/aac.01537-09.
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ABSTRACT Recent clinical trials have shown that the use of the HIV-1 integrase (IN) inhibitor raltegravir (RAL) results in drops in the viral load that are more rapid than those achieved by use of the reverse transcriptase (RT) inhibitor efavirenz. Previously, mathematical modeling of viral load decay that takes into account the stage of viral replication targeted by a drug has yielded data that closely approximate the clinical trial results. This model predicts greater inhibition of viral replication by drugs that act later in the viral replication cycle. In the present study, we have added drugs that target entry, reverse transcription, integration, or proteolytic processing to acutely infected cells and have shown modest viral inhibition by entry inhibitors, intermediate levels of inhibition by RT and IN inhibitors, and high levels of inhibition by protease inhibitors relative to the levels of growth for the no-drug controls. When dual or triple combinations of these drugs were added to acutely infected cells, we found that the levels of inhibition achieved by any given combination were comparable to those achieved by the latest-acting drug in the combination. In single-round infections in which the kinetics of reverse transcription and integration had been determined by quantitative PCR, addition of IN inhibitors at various times postinfection resulted in levels of inhibition equal to or greater than those achieved by addition of RT inhibitors. Collectively, our data provide in vitro evidence of the stage-dependent inhibition of HIV-1 by clinically relevant drugs. We discuss how stage-dependent inhibition helps to explain the unique viral load decay dynamics observed clinically with RAL.
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Zaki Ahmad, Mohammad, Sohail Akhter, Neha Mallik, Mohammad Anwar, Wajda Tabassum, and Farhan Jalees Ahmad. "Application of Decoy Oligonucleotides as Novel Therapeutic Strategy: A Contemporary Overview." Current Drug Discovery Technologies 10, no. 1 (March 1, 2013): 71–84. http://dx.doi.org/10.2174/157016313804998898.
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Zaki Ahmad, Mohammad, Sohail Akhter, Neha Mallik, Mohammad Anwar, Wajda Tabassum, and Farhan Jalees Ahmad. "Application of Decoy Oligonucleotides as Novel Therapeutic Strategy: A Contemporary Overview." Current Drug Discovery Technologies 10, no. 1 (January 16, 2013): 71–84. http://dx.doi.org/10.2174/1570163811310010009.
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Tehran, Maryam Mahjoubin, Samaneh Rezaei, Amin Jalili, Seyed Hamid Aghaee-Bakhtiari, and Amirhossein Sahebkar. "Decoy oligodeoxynucleotide technology: an emerging paradigm for breast cancer treatment." Drug Discovery Today 25, no. 1 (January 2020): 195–200. http://dx.doi.org/10.1016/j.drudis.2019.10.008.
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Arora, Garima, Gerry Humphris, Satu Lahti, Derek Richards, and Ruth Freeman. "Depression, drugs and dental anxiety in prisons: A mediation model explaining dental decay experience." Community Dentistry and Oral Epidemiology 48, no. 3 (February 10, 2020): 248–55. http://dx.doi.org/10.1111/cdoe.12522.
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Manuel, ST, M. Kundabaka, N. Shetty, and A. Parolia. "Asthma and dental erosion." Kathmandu University Medical Journal 6, no. 3 (April 6, 2009): 370–74. http://dx.doi.org/10.3126/kumj.v6i3.1714.
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Asthma is a chronic inflammatory condition of the airway, characterised by the presence of airflow obstruction which is variable over short periods of time, or is reversible with treatment. Medication comprises of bronchodilators, corticosteroids and anticholinergic drugs. Most asthma drugs are inhaled using various forms of inhalers or nebulizers. Inhaled drugs must be used regularly. The effects of these drugs on the dentition such as tooth decay and erosion have been a subject of debate among dental practitioners. Asthmatic medications can place the patient at risk of dental erosion by reducing salivary protection against extrinsic or intrinsic acids. Asthmatic individuals are one of the higher risk groups suffering from dental erosion. Therefore patients with bronchial asthma should receive special prophylactic attention. This article presents a case of an asthmatic with dental manifestations and reviews the possible causes and management of the same. Key words: Asthma, dry powder inhalers, beta-2 agonist, gastro-esophageal reflux, dental erosion. doi: 10.3126/kumj.v6i3.1714 Kathmandu University Medical Journal (2008), Vol. 6, No. 3, Issue 23, 370-374
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Wardman, Peter, Madeleine F. Dennis, Steven A. Everett, Kantilal B. Patel, Michael R. L. Stratford, and Michael Tracy. "Radicals from one-electron reduction of nitro compounds, aromatic N-oxides and quinones: the kinetic basis for hypoxia-selective, bioreductive drugs." Biochemical Society Symposia 61 (November 1, 1995): 171–94. http://dx.doi.org/10.1042/bss0610171.
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Drugs based on nitroarene, aromatic N-oxide or quinone structures are frequently reduced by cellular reductases to toxic products. Reduction often involves free radicals as intermediates which react rapidly with oxygen to form superoxide radicals, inhibiting drug reduction. The elevation of cellular oxidative stress accompanying oxygen inhibition of reduction is generally less damaging than drug reduction to toxic products, so the drugs offer selective toxicity to hypoxic cells. Since such cells are resistant to radiotherapy, these bioreductive drugs offer potential in tumour therapy. The basis for the selectivity of action entails kinetic competition involving the contesting reaction pathways. The reduction potential of the drug, radical pKa and nature of radical/radical decay kinetics all influence drug activity and selectivity, including the range of oxygen tensions over which the drug offers selective toxicity. These properties may be quantified using generation of radicals by pulse radiolysis, presenting a physicochemical basis for rational drug design.