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Blood Mar 2017The combination of all--retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk... (Clinical Trial)
Clinical Trial
The combination of all--retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m on day 1) added to high-risk patients (white blood cell count, >10 × 10/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Female; Follow-Up Studies; Gemtuzumab; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Polymerase Chain Reaction; Treatment Outcome; Tretinoin; Young Adult
PubMed: 28003274
DOI: 10.1182/blood-2016-09-736686 -
Journal of Clinical Oncology : Official... Feb 2017Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to... (Randomized Controlled Trial)
Randomized Controlled Trial
Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial.
Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Prospective Studies; Risk Factors; Treatment Outcome; Tretinoin; Young Adult
PubMed: 27400939
DOI: 10.1200/JCO.2016.67.1982 -
Nature Methods Mar 2020Despite the widespread adoption of organoids as biomimetic tissue models, methods to comprehensively analyze cell-type-specific post-translational modification (PTM)...
Despite the widespread adoption of organoids as biomimetic tissue models, methods to comprehensively analyze cell-type-specific post-translational modification (PTM) signaling networks in organoids are absent. Here, we report multivariate single-cell analysis of such networks in organoids and organoid cocultures. Simultaneous analysis by mass cytometry of 28 PTMs in >1 million single cells derived from small intestinal organoids reveals cell-type- and cell-state-specific signaling networks in stem, Paneth, enteroendocrine, tuft and goblet cells, as well as enterocytes. Integrating single-cell PTM analysis with thiol-reactive organoid barcoding in situ (TOBis) enables high-throughput comparison of signaling networks between organoid cultures. Cell-type-specific PTM analysis of colorectal cancer organoid cocultures reveals that shApc, Kras and Trp53 cell-autonomously mimic signaling states normally induced by stromal fibroblasts and macrophages. These results demonstrate how standard mass cytometry workflows can be modified to perform high-throughput multivariate cell-type-specific signaling analysis of healthy and cancerous organoids.
Topics: Animals; Biomimetics; Cell Differentiation; Coculture Techniques; Colorectal Neoplasms; Cytophotometry; Enterocytes; Enteroendocrine Cells; Female; Fibroblasts; Gene Expression Regulation; Goblet Cells; Humans; Intestine, Small; Macrophages; Mice; Mice, Inbred C57BL; Organ Culture Techniques; Organoids; Paneth Cells; Signal Transduction; Single-Cell Analysis; Sulfhydryl Compounds; Tumor Suppressor Protein p53
PubMed: 32066960
DOI: 10.1038/s41592-020-0737-8 -
Cellular & Molecular Immunology Jan 2023Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been...
Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8 T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.
Topics: Humans; Arsenic Trioxide; Cancer Vaccines; Ferroptosis; CD8-Positive T-Lymphocytes; Necroptosis; Arsenicals; Oxides; Antineoplastic Agents; Apoptosis; Neoplasms; Immunity; Cell Line, Tumor
PubMed: 36447031
DOI: 10.1038/s41423-022-00956-0 -
Journal of Proteome Research Dec 2014Mass spectrometry plays a key role in relative quantitative comparisons of proteins in order to understand their functional role in biological systems upon perturbation.... (Review)
Review
Mass spectrometry plays a key role in relative quantitative comparisons of proteins in order to understand their functional role in biological systems upon perturbation. In this review, we review studies that examine different aspects of isobaric labeling-based relative quantification for shotgun proteomic analysis. In particular, we focus on different types of isobaric reagents and their reaction chemistry (e.g., amine-, carbonyl-, and sulfhydryl-reactive). Various factors, such as ratio compression, reporter ion dynamic range, and others, cause an underestimation of changes in relative abundance of proteins across samples, undermining the ability of the isobaric labeling approach to be truly quantitative. These factors that affect quantification and the suggested combinations of experimental design and optimal data acquisition methods to increase the precision and accuracy of the measurements will be discussed. Finally, the extended application of isobaric labeling-based approach in hyperplexing strategy, targeted quantification, and phosphopeptide analysis are also examined.
Topics: Amines; Isotope Labeling; Mass Spectrometry; Phosphopeptides; Protein Carbonylation; Proteome; Proteomics; Reproducibility of Results; Sulfhydryl Compounds
PubMed: 25337643
DOI: 10.1021/pr500880b -
Environment International May 2019Arsenic is a non-essential, environmentally ubiquitous toxic metalloid. In response to this pervasive environmental challenge, organisms evolved mechanisms to confer... (Review)
Review
Arsenic is a non-essential, environmentally ubiquitous toxic metalloid. In response to this pervasive environmental challenge, organisms evolved mechanisms to confer resistance to arsenicals. Inorganic pentavalent arsenate is taken into most cells adventitiously by phosphate uptake systems. Similarly, inorganic trivalent arsenite is taken into most cells adventitiously, primarily via aquaglyceroporins or sugar permeases. The most common strategy for tolerance to both inorganic and organic arsenicals is by efflux that extrude them from the cytosol. These efflux transporters span across kingdoms and belong to various families such as aquaglyceroporins, major facilitator superfamily (MFS) transporters, ATP-binding cassette (ABC) transporters and potentially novel, yet to be discovered families. This review will outline the properties and substrates of known arsenic transport systems, the current knowledge gaps in the field, and aims to provide insight into the importance of arsenic transport in the context of the global arsenic biogeocycle and human health.
Topics: Animals; Arsenic; Arsenicals; Biological Transport; Humans; Membrane Transport Proteins
PubMed: 30852446
DOI: 10.1016/j.envint.2019.02.058 -
Archives of Toxicology Jun 2020Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As... (Review)
Review
Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator-metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.
Topics: Animals; Antidotes; Arsenic Poisoning; Arsenicals; Chelating Agents; Environmental Exposure; Environmental Pollutants; Humans; Plant Preparations; Risk Assessment; Treatment Outcome
PubMed: 32388818
DOI: 10.1007/s00204-020-02739-w -
Cell Feb 2017
Topics: Arsenic Trioxide; Arsenicals; China; France; History, 20th Century; History, 21st Century; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin
PubMed: 28187275
DOI: 10.1016/j.cell.2017.01.029 -
Journal of Chromatography. B,... May 2019Characterization of free thiol variants in antibody therapeutics is important for biopharmaceutical development, as the presence of free thiols may have an impact on...
Characterization of free thiol variants in antibody therapeutics is important for biopharmaceutical development, as the presence of free thiols may have an impact on aggregate formation, structural and thermal stability, as well as antigen-binding potency of monoclonal antibodies. Most current methods for free thiol quantification involve labeling of free thiol groups by different tagging molecules followed by UV, fluorescence or mass spectrometry (MS) detection. Here, we optimized a label-free liquid chromatography (LC)-UV/MS method for free thiol quantification at a subunit level and compared this method with two orthogonal and conventional approaches, Ellman's assay and peptide mapping with differential alkylation. This subunit unit approach was demonstrated to be able to provide domain-specific free thiol quantification and comparable results with labeling approaches, using a relatively simple and efficient workflow.
Topics: Animals; Antibodies, Monoclonal; Chromatography, Liquid; Dithionitrobenzoic Acid; Immunoglobulin G; Mass Spectrometry; Peptide Mapping; Reproducibility of Results; Sulfhydryl Compounds
PubMed: 30939413
DOI: 10.1016/j.jchromb.2019.03.032 -
Medicinal Research Reviews Mar 2019Given the ubiquity of the ⍺-helix in the proteome, there has been much research in developing mimics of ⍺-helices, and most of this study has been toward developing... (Review)
Review
Given the ubiquity of the ⍺-helix in the proteome, there has been much research in developing mimics of ⍺-helices, and most of this study has been toward developing protein-protein interaction inhibitors. A common strategy for mimicking ⍺-helices has been through the use of constrained, helical peptides. The addition of a constraint typically provides for conformational and proteolytic stability and, in some cases, cell permeability. Some of the most well-known strategies included are lactam formation and hydrocarbon "stapling." Beyond those strategies, there have been many recent advances in developing constrained peptides. The purpose of this review is to highlight recent advances in the development of new helix-stabilizing technologies, constraint diversification strategies, tether diversification strategies, and combination strategies that create new bicyclic helical peptides.
Topics: Animals; Chemistry, Pharmaceutical; Cross-Linking Reagents; Cysteine; Glucuronates; Humans; Hydrocarbons; Isocyanates; Lactams; Methionine; Nitrogen; Peptides; Permeability; Protein Conformation; Proteome; Pyrazoles; Selenocysteine; Sulfhydryl Compounds
PubMed: 30307621
DOI: 10.1002/med.21540