RESUMO
Zinc is an essential element in living organisms, yet little is known about how cells ensure that zinc is allocated to the correct metalloproteins. Papers in Cell and Cell Reports demonstrate that the ZNG1 family of GTPases have metallochaperone functions: they directly transfer zinc to, and thereby activate, methionine aminopeptidases that are crucial for protein modification during or after translation.
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Metaloproteínas , Zinco , Metaloproteínas/metabolismo , Chaperonas Moleculares/metabolismo , Zinco/metabolismoRESUMO
Recently, Co-based honeycomb magnets have been proposed as promising candidate materials to host the Kitaev spin liquid (KSL) state. One of the front-runners is BaCo2(AsO4)2 (BCAO), where it was suggested that the exchange processes between Co2+ ions via the surrounding edge-sharing oxygen octahedra could give rise to bond-dependent Kitaev interactions. In this work, we present and analyze a comprehensive inelastic neutron scattering (INS) study of BCAO with fields in the honeycomb plane. Combining the constraints from the magnon excitations in the high-field polarized state and the inelastic spin structure factor measured in zero magnetic field, we examine two leading theoretical models: the Kitaev-type [Formula: see text] model and the XXZ[Formula: see text]model. We show that the existing experimental data can be consistently accounted for by the XXZ[Formula: see text]model but not by the [Formula: see text] model, and we discuss the implications of these results for the realization of a spin liquid phase in BCAO and more generally for the realization of the Kitaev model in cobaltates.
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The essential microelement zinc is absorbed in the small intestine mainly by the zinc transporter ZIP4, a representative member of the Zrt/Irt-like protein (ZIP) family. ZIP4 is reportedly upregulated in many cancers, making it a promising oncology drug target. To date, there have been no reports on the turnover number of ZIP4, which is a crucial missing piece of information needed to better understand the transport mechanism. In this work, we used a non-radioactive zinc isotope, 70Zn, and inductively coupled plasma mass spectrometry (ICP-MS) to study human ZIP4 (hZIP4) expressed in HEK293 cells. Our data showed that 70Zn can replace the radioactive 65Zn as a tracer in kinetic evaluation of hZIP4 activity. This approach, combined with the quantification of the cell surface expression of hZIP4 using biotinylation or surface-bound antibody, allowed us to estimate the apparent turnover number of hZIP4 to be in the range of 0.08-0.2 s-1. The turnover numbers of the truncated hZIP4 variants are significantly smaller than that of the full-length hZIP4, confirming a crucial role for the extracellular domain in zinc transport. Using 64Zn and 70Zn, we measured zinc efflux during the cell-based transport assay and found that it has little effect on the zinc import analysis under these conditions. Finally, we demonstrated that use of laser ablation (LA) ICP-TOF-MS on samples applied to a solid substrate significantly increased the throughput of the transport assay. We envision that the approach reported here can be applied to the studies of metal transporters beyond the ZIP family.
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Zinc fluctuations regulate key steps in late oocyte and preimplantation embryo development; however, roles for zinc in preceding stages in early ovarian follicle development, when cooperative interactions exist between the oocyte and somatic cells, are unknown. To understand the roles of zinc during early follicle development, we applied single cell X-ray fluorescence microscopy, a radioactive zinc tracer, and a labile zinc probe to measure zinc in individual mouse oocytes and associated somatic cells within early follicles. Here, we report a significant stage-specific increase and compartmental redistribution in oocyte zinc content upon the initiation of early follicle growth. The increase in zinc correlates with the increased expression of specific zinc transporters, including two that are essential in oocyte maturation. While oocytes in follicles exhibit high tolerance to pronounced changes in zinc availability, somatic survival and proliferation are significantly more sensitive to zinc chelation or supplementation. Finally, transcriptomic, proteomic, and zinc loading analyses reveal enrichment of zinc targets in the ubiquitination pathway. Overall, these results demonstrate that distinct cell type-specific zinc regulations are required for follicle growth and indicate that physiological fluctuation in the localization and availability of this inorganic cofactor has fundamental functions in early gamete development.
Assuntos
Folículo Ovariano , Zinco , Animais , Feminino , Camundongos , Oócitos/metabolismo , Oogênese/fisiologia , Folículo Ovariano/fisiologia , Proteômica , Zinco/metabolismoRESUMO
Bacteria can adapt in response to numerous stress conditions. One such stress condition is zinc depletion. The zinc-sensing transcription factor Zur regulates the way numerous bacterial species respond to severe changes in zinc availability. Under zinc sufficient conditions, Zn-loaded Zur (Zn2-Zur) is well-known to repress transcription of genes encoding zinc uptake transporters and paralogues of a few ribosomal proteins. Here, we report the discovery and mechanistic basis for the ability of Zur to up-regulate expression of the ribosomal protein L31 in response to zinc in E. coli. Through genetic mutations and reporter gene assays, we find that Zur achieves the up-regulation of L31 through a double repression cascade by which Zur first represses the transcription of L31p, a zinc-lacking paralogue of L31, which in turn represses the translation of L31. Mutational analyses show that translational repression by L31p requires an RNA hairpin structure within the l31 mRNA and involves the N-terminus of the L31p protein. This work uncovers a new genetic network that allows bacteria to respond to host-induced nutrient limiting conditions through a sophisticated ribosomal protein switching mechanism.
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Proteínas de Escherichia coli , Escherichia coli , Regulação Bacteriana da Expressão Gênica , Proteínas de Bactérias/metabolismo , Proteínas de Ligação a DNA/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , RNA/metabolismo , Zinco/farmacologia , Zinco/metabolismo , Interações entre Hospedeiro e MicrorganismosRESUMO
The MerR-family transcription factors (TFs) are a large group of bacterial proteins responding to cellular metal ions and multiple antibiotics by binding within central RNA polymerase-binding regions of a promoter. While most TFs alter transcription through protein-protein interactions, MerR TFs are capable of reshaping promoter DNA. To address the question of which mechanism prevails, we determined two cryo-EM structures of transcription activation complexes (TAC) comprising Escherichia coli CueR (a prototype MerR TF), RNAP holoenzyme and promoter DNA. The structures reveal that this TF promotes productive promoter-polymerase association without canonical protein-protein contacts seen between other activator proteins and RNAP. Instead, CueR realigns the key promoter elements in the transcription activation complex by clamp-like protein-DNA interactions: these induce four distinct kinks that ultimately position the -10 element for formation of the transcription bubble. These structural and biochemical results provide strong support for the DNA distortion paradigm of allosteric transcriptional control by MerR TFs.
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Proteínas de Bactérias/química , DNA Bacteriano/química , Proteínas de Ligação a DNA/química , RNA Polimerases Dirigidas por DNA/química , Proteínas de Escherichia coli/química , Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Transativadores/química , Regulação Alostérica , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Pareamento de Bases , Sequência de Bases , Sítios de Ligação , Microscopia Crioeletrônica , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Conformação de Ácido Nucleico , Regiões Promotoras Genéticas , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transativadores/genética , Transativadores/metabolismo , Ativação TranscricionalRESUMO
Zinc influx and efflux events are essential for meiotic progression in oocytes of several mammalian and amphibian species, but it is less clear whether this evolutionary conservation of zinc signals is also important in late-stage germline development in invertebrates. Using quantitative, single cell elemental mapping methods, we find that Caenorhabditis elegans oocytes undergo significant stage-dependent fluctuations in total zinc content, rising by over sevenfold from Prophase I through the beginning of mitotic divisions in the embryo. Live imaging of the rapid cell cycle progression in C. elegans enables us to follow changes in labile zinc pools across meiosis and mitosis in single embryo. We find a dynamic increase in labile zinc prior to fertilization that then decreases from Anaphase II through pronuclear fusion and relocalizes to the eggshell. Disruption of these zinc fluxes blocks extrusion of the second polar body, leading to a range of mitotic defects. We conclude that spatial temporal zinc fluxes are necessary for meiotic progression in C. elegans and are a conserved feature of germ cell development in a broad cross section of metazoa.
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Caenorhabditis elegans , Zinco , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Fertilização , Mamíferos/metabolismo , Meiose , Oócitos/metabolismo , Zinco/metabolismoRESUMO
While 199Hg NMR is a well-established tool for elucidating details of coordination chemistry in biochemical and inorganic complexes, historically the technique has been associated with the use of an extremely toxic chemical, dimethylmercury [Me2Hg or (CH3)2Hg], as a reference standard. In the 25 years since an accidental exposure to Me2Hg led to the tragic death of Dr. Karen Wetterhahn, the community has learned a great deal about the insidious neurotoxicity of this compound as well as more appropriate ways to avoid exposure. Here, we track the general shift toward the use of alternative mercury reference standards and away from Me2Hg.
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Mercúrio , Espectroscopia de Ressonância Magnética , Mercúrio/químicaRESUMO
PURPOSE: The requirement of zinc for the development and maturation of germ lines and reproductive systems is deeply conserved across evolution. The nematode Caenorhabditis elegans offers a tractable platform to study the complex system of distributing zinc to the germ line. We investigated several zinc importers to investigate how zinc transporters play a role in the reproductive system in nematodes, as well as establish a platform to study zinc transporter biology in germline and reproductive development. METHODS: Previous high throughput transcriptional datasets as well as phylogenetic analysis identified several putative zinc transporters that have a function in reproduction in worms. Phenotypic analysis of CRISPR-generated knockouts and tags included characterization of offspring output, gonad development, and protein localization. Light and immunofluorescence microscopy allowed for visualization of physiological and molecular effects of zinc transporter mutations. RESULTS: Disruption of two zinc transporters, ZIPT-2.4 and ZIPT-15, was shown to lead to defects in reproductive output. A mutation in zipt-2.4 has subtle effects on reproduction, while a mutation in zipt-15 has a clear impact on gonad and germline development that translates into a more pronounced defect in fecundity. Both transporters have germline expression, as well as additional expression in other cell types. CONCLUSIONS: Two ZIP-family zinc transporter orthologs of human ZIP6/10 and ZIP1/2/3 proteins are important for full reproductive fecundity and participate in development of the gonad. Notably, these zinc transporters are present in gut and reproductive tissues in addition to the germ line, consistent with a complex zinc trafficking network important for reproductive success.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Transporte , Proteínas de Transporte de Cátions , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Fertilidade , Células Germinativas/metabolismo , Humanos , Filogenia , Zinco/metabolismoRESUMO
Patients with triple negative breast cancers (TNBCs)-highly aggressive tumors that do not express estrogen, progesterone, and human epidermal growth factor 2 receptors-have limited treatment options. Fewer than 30% of women with metastatic TNBC survive five years after their diagnosis, with a mortality rate within three months after a recurrence of 75%. Although TNBCs show a higher response to platinum therapy compared to other breast cancers, drug resistance remains a major obstacle; thus, platinum drugs with novel mechanisms are urgently needed. Arsenoplatins (APs) represent a novel class of anticancer agents designed to contain the pharmacophores of the two FDA approved drugs cisplatin and arsenic trioxide (As2O3) as one molecular entity. Here, we present the syntheses, crystal structures, DFT calculations, and antiproliferative activity of iodide analogs of AP-1 and AP-2, i.e., AP-5 and AP-4, respectively. Antiproliferative studies in TNBC cell lines reveal that all AP family members are more potent than cisplatin and As2O3 alone. DFT calculations demonstrate there is a low energy barrier for hydrolysis of the platinum-halide bonds in arsenoplatins, possibly contributing to their higher cytotoxicities compared to cisplatin.
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Antineoplásicos/química , Trióxido de Arsênio/química , Cisplatino/química , Iodetos/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Trióxido de Arsênio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , Iodetos/farmacologia , Conformação Molecular , Preparações Farmacêuticas , Análise Espacial , Relação Estrutura-AtividadeRESUMO
Zinc dynamics are essential for oocyte meiotic maturation, egg activation, and preimplantation embryo development. During fertilisation and egg activation, the egg releases billions of zinc atoms (Zn2+) in an exocytotic event termed the 'zinc spark'. We hypothesised that this zinc transport and exocytosis is dependent upon the intracellular trafficking of cortical granules (CG) which requires myosin-actin-dependent motors. Treatment of mature mouse and human eggs with ML-7, a myosin light chain kinase inhibitor (MLCK), resulted in an 80% reduction in zinc spark intensity compared to untreated controls when activated with ionomycin. Moreover, CG migration towards the plasma membrane was significantly decreased in ML-7-treated eggs compared with controls when activated parthenogenetically with ionomycin. In sperm-induced fertilisation via intracytoplasmic sperm injection (ICSI), ML-7-treated mouse eggs exhibited decreased labile zinc intensity and cortical CG staining. Collectively, these data demonstrate that ML-7 treatment impairs zinc release from both murine and human eggs after activation, demonstrating that zinc exocytosis requires myosin light chain kinase activity. Further, these results provide additional support that zinc is likely stored and released from CGs. These data underscore the importance of intracellular zinc trafficking as a crucial component of egg maturation necessary for egg activation and early embryo development.
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Exocitose , Quinase de Cadeia Leve de Miosina/metabolismo , Óvulo/metabolismo , Adulto , Animais , Azepinas , Feminino , Humanos , Técnicas In Vitro , Masculino , Camundongos , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Naftalenos , Oogênese , Óvulo/citologia , Injeções de Esperma IntracitoplásmicasRESUMO
Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(µ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules-proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nε of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
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Antineoplásicos/farmacologia , Trióxido de Arsênio/análogos & derivados , Cisplatino/análogos & derivados , Compostos Organoplatínicos/farmacologia , Antineoplásicos/química , Trióxido de Arsênio/química , Trióxido de Arsênio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organoplatínicos/química , Relação Estrutura-AtividadeRESUMO
Previous work has shown that fluctuations in zinc content and subcellular localization play key roles in regulating cell cycle progression; however, a deep mechanistic understanding requires the determination of when, where, and how labile zinc pools are concentrated into or released from stores. Labile zinc ions can be difficult to detect with probes that require hydrolysis of toxic protecting groups or application at high concentrations that negatively impact cell function. We previously reported a BODIPY-based zinc probe, ZincBY-1, that can be used at working concentrations that are 20-200-fold lower than concentrations employed with other probes. To better understand how zinc pools can be visualized at such low probe concentrations, we modulated the photophysical properties via changes at the 5-position of the BODIPY core. One of these, ZincBY-4, exhibits an order of magnitude higher affinity for zinc, an 8-fold increase in brightness in response to zinc, and a 100 nm Stokes shift within cells. The larger Stokes shift of ZincBY-4 presents a unique opportunity for simultaneous imaging with GFP or fluorescein sensors upon single excitation. Finally, by creating a proxy for the cellular environment in spectrometer experiments, we show that the ZincBY series are highly effective at 50 nM because they can pass membranes and accumulate in regions of high zinc concentration within a cell. These features of the ZincBY probe class have widespread applications in imaging and for understanding the regulatory roles of zinc fluxes in live cells.
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Compostos de Boro/química , Espaço Intracelular/metabolismo , Sondas Moleculares/química , Zinco/química , Zinco/metabolismo , Linhagem Celular , Modelos Moleculares , Conformação Molecular , Imagem MolecularRESUMO
Platinum drugs (cisplatin, oxaliplatin, and carboplatin) and arsenic trioxide are the only commercial inorganic non-radioactive anticancer drugs approved by the US Food and Drug Administration. Numerous efforts are underway to take advantage of the synergy between the anticancer activity of cisplatin and arsenic trioxide - two drugs with strikingly different mechanisms of action. These include co-encapsulation of the two drugs in novel nanoscale delivery systems as well as the development of small molecule agents that combine the activity of these two inorganic materials. Several of these new molecular entities containing Pt-As bonds have broad anticancer activity, are robust in physiological buffer solutions, and form stable complexes with biopolymers. This review summarizes results from a number of preclinical studies involving the combination of cisplatin and As2O3, co-encapsulation and nanoformulation efforts, and the chemistry and cytotoxicity of the first member of platinum anticancer agents with an arsenous acid moiety bound to the platinum(II) center: arsenoplatins.
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Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.
Assuntos
Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Indóis/farmacologia , Maleimidas/farmacologia , Neuroblastoma/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Indóis/administração & dosagem , Irinotecano/administração & dosagem , Irinotecano/farmacologia , Maleimidas/administração & dosagem , Camundongos , Camundongos Nus , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Commensal microbes, whether they are beneficial or pathogenic, are sensitive to host processes that starve or swamp the prokaryote with large fluctuations in local zinc concentration. To understand how microorganisms coordinate a dynamic response to changes in zinc availability at the molecular level, we evaluated the molecular mechanism of the zinc-sensing zinc uptake regulator (Zur) protein at each of the known Zur-regulated genes in Escherichia coli. We solved the structure of zinc-loaded Zur bound to the P(znuABC) promoter and show that this metalloregulatory protein represses gene expression by a highly cooperative binding of two adjacent dimers to essentially encircle the core element of each of the Zur-regulated promoters. Cooperativity in these protein-DNA interactions requires a pair of asymmetric salt bridges between Arg52 and Asp49' that connect otherwise independent dimers. Analysis of the protein-DNA interface led to the discovery of a new member of the Zur-regulon: pliG. We demonstrate this gene is directly regulated by Zur in a zinc responsive manner. The pliG promoter forms stable complexes with either one or two Zur dimers with significantly less protein-DNA cooperativity than observed at other Zur regulon promoters. Comparison of the in vitro Zur-DNA binding affinity at each of four Zur-regulon promoters reveals ca. 10,000-fold variation Zur-DNA binding constants. The degree of Zur repression observed in vivo by comparison of transcript copy number in wild-type and Δzur strains parallels this trend spanning a 100-fold difference. We conclude that the number of ferric uptake regulator (Fur)-family dimers that bind within any given promoter varies significantly and that the thermodynamic profile of the Zur-DNA interactions directly correlates with the physiological response at different promoters.
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DNA Bacteriano/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Zinco/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Escherichia coli/genética , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Dados de Sequência Molecular , Purinas/metabolismo , RegulonRESUMO
BACKGROUND: Zinc is the most abundant transition metal in the mammalian oocyte, and dynamic fluxes in intracellular concentration are essential for regulating both meiotic progression and fertilization. Whether the defined pathways of zinc utilization in female meiosis directly translate to mitotic cells, including the mammalian preimplantation embryo, has not been studied previously. RESULTS: We determined that zinc is the most abundant transition metal in the preimplantation embryo, with levels an order of magnitude higher than those of iron or copper. Using a zinc-specific fluorescent probe, we demonstrated that labile zinc is distributed in vesicle-like structures in the cortex of cells at all stages of preimplantation embryo development. To test the importance of zinc during this period, we induced zinc insufficiency using the heavy metal chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN). Incubation of embryos in media containing TPEN resulted in a developmental arrest that was specific to zinc chelation and associated with compromised mitotic parameters. The developmental arrest due to zinc insufficiency was associated with altered chromatin structure in the blastomere nuclei and decreased global transcription. CONCLUSIONS: These results demonstrate for the first time that the preimplantation embryo requires tight zinc regulation and homeostasis for the initial mitotic divisions of life.
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Blastocisto/metabolismo , Embrião de Mamíferos/metabolismo , Zinco/metabolismo , Animais , Blastocisto/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Etilenodiaminas/farmacologia , Feminino , Camundongos , Microscopia de Fluorescência , Mitose/efeitos dos fármacos , GravidezRESUMO
Cardiomyopathy is an adverse outcome of antineoplastic drug therapy that has become increasingly relevant in the management of cancer survivors. As the efficacy of anticancer treatments has improved, long-term outcomes are altered by the development of cardiotoxicity, which may be associated with an even worse prognosis than that of the underlying malignancy. From the research into mechanisms, prevention, and treatment, the specialized field of cardio-oncology has evolved, but the recognition and appropriate management of these patients is important for the general internist and general cardiologist as well. Although antineoplastic chemotherapy can cause multiple forms of cardiotoxicity, including arrhythmia, pericardial disease, valvular dysfunction, and myocardial ischemia, in this review we will focus on chemotherapeutic agents associated with cardiomyopathies, from the anthracyclines to newer, the so-called targeted agents such as tyrosine kinase inhibitors. We also review the diagnostic modalities for chemotherapy-induced cardiomyopathy as well as the prevention and treatment strategies which may prolong the lives of those suffering from cancer.
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Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Cardiotoxicidade/prevenção & controle , Neoplasias/complicações , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores/análise , Insuficiência Cardíaca/etiologia , Humanos , Imageamento por Ressonância Magnética , Neoplasias/tratamento farmacológicoRESUMO
INTRODUCTION: Continuation of antiplatelet medications through major urologic surgery may increase the risk of intraoperative and postoperative bleeding complications. However, withdrawal of antiplatelet therapy may place some patients at high risk of serious cardiovascular or cerebrovascular complications. We assess the feasibility of performing robotic partial nephrectomy (RPN) in patients maintained on aspirin or dual antiplatelet therapy with aspirin and clopidogrel. MATERIAL AND METHODS: Perioperative data was collected prospectively on 230 subjects undergoing RPN enrolled in an IRB approved quality of life study. We analyzed subjects who were maintained on either aspirin alone or both aspirin and clopidogrel throughout the operative and perioperative period. RESULTS: Of the 230 patients, six were identified who continued antiplatelet medication throughout the perioperative period. Four patients were maintained on 81 mg of aspirin and two patients continued aspirin and clopidogrel. Average RENAL score was 7 with mean tumor size of 4.1 cm. There were no intraoperative complications and no conversions to open surgery. Average estimated blood loss was 242 mL. Ninety day complication rate was 33%. One patient had postoperative bleeding on day 14 after restarting coumadin in addition to their aspirin. CONCLUSIONS: We present a case series demonstrating that in carefully selected patients, RPN on aspirin and clopidogrel is feasible and safe. This is the first report of patients who underwent RPN while on both aspirin and clopidogrel.
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Aspirina/efeitos adversos , Perda Sanguínea Cirúrgica/prevenção & controle , Neoplasias Renais/cirurgia , Nefrectomia , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia Pós-Operatória/induzido quimicamente , Procedimentos Cirúrgicos Robóticos , Ticlopidina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspirina/administração & dosagem , Clopidogrel , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Período Perioperatório , Inibidores da Agregação Plaquetária/administração & dosagem , Hemorragia Pós-Operatória/prevenção & controle , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Suspensão de TratamentoRESUMO
An appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies. FROM THE CLINICAL EDITOR: Existing in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities.