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1.
Nano Lett ; 24(11): 3525-3531, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38466128

RESUMO

Variegation and complexity of polarization relaxation loss in many heterostructured materials provide available mechanisms to seek a strong electromagnetic wave (EMW) absorption performance. Here we construct a unique heterostructured compound that bonds α-Fe2O3 nanosheets of the (110) plane on carbon microtubes (CMTs). Through effective alignment between the Fermi energy level of CMTs and the conduction band position of α-Fe2O3 nanosheets at the interface, we attain substantial polarization relaxation loss via novel atomic valence reversal between Fe(III) ↔ Fe(III-) induced with periodic electron injection from conductive CMTs under EMW irradiation to give α-Fe2O3 nanosheets. Such heterostructured materials possess currently reported minimum reflection loss of -84.01 dB centered at 10.99 GHz at a thickness of 3.19 mm and an effective absorption bandwidth (reflection loss ≤ -10 dB) of 7.17 GHz (10.83-18 GHz) at 2.65 mm. This work provides an effective strategy for designing strong EMW absorbers by combining highly efficient electron injection and atomic valence reversal.

3.
Front Endocrinol (Lausanne) ; 14: 1302965, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38075064

RESUMO

Introduction: Multiple factors can contribute to sub-fecundity, including genetics, lifestyle, and environmental contaminants. PFASs are characterized as "forever chemicals" due to their ubiquitous contamination and their persistence in the environment, wildlife, and humans. Numerous studies have demonstrated that PFAS exposure adversely affects multiple bodily functions, including liver metabolism and gonadal function. It is unclear, however, how the disruption of hepatic fatty acid metabolism affects testicular function. Methods: In this study, male mice were administered 0.3 and 3 µg/g body weight of PFOS for 21 days. Results: Our data showed that PFOS exposure caused hepatic steatosis, as evidenced by significant increases in triglyceride levels, expression of ATP-citrate lyase, and fatty acid synthase, as well as fasting insulin levels. PFOS perturbed the expression levels of hepatokines, of which fibroblast growth factor-21 (Fgf-21), leukocyte cell-derived chemotaxin-2 (Lect-2), and retinol-binding protein-4 (Rbp-4) were significantly reduced, whereas angiopoietin-like 4 (Angptl4) was noticeably increased. While Rbp-4 and Fgf-21 are known to contribute to spermatogenesis and testosterone synthesis. In PFOS-exposed groups, testicular ATP, and testosterone decreased significantly with a significant increase in the expression of peroxisome proliferator-activated receptor-coactivator 1α. Mass spectrophotometry imaging revealed the localization of PFOS in testes, along with significant increases in fatty acid metabolites. These included arachidonic acid, dihomo-α-linolenic acid, dihomo-γ-linolenic acid, oxidized ceramide, diacylglycerol, phosphatidylcholine, and phosphatidylethanolamine, which are associated with inflammation and post-testicular causes of infertility. Discussion: This study revealed potential links between PFOS-elicited changes in hepatic metabolism and their impacts on testicular biology. This study provides insights into alternative targets elicited by PFOS that can be used to develop diagnostic and therapeutic strategies for improving testicular dysfunction.


Assuntos
Ácidos Graxos , Testículo , Humanos , Camundongos , Masculino , Animais , Testículo/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Testosterona/metabolismo , Trifosfato de Adenosina/metabolismo
4.
Environ Sci Technol ; 57(40): 14892-14903, 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37759171

RESUMO

Prenatal exposure to perfluorooctanesulfonate (PFOS) increases fetus' metabolic risk; however, the investigation of the underlying mechanism is limited. In this study, pregnant mice in the gestational days (GD, 4.5-17.5) were exposed to PFOS (0.3 and 3 µg/g of body weight). At GD 17.5, PFOS perturbed maternal lipid metabolism and upregulated metabolism-regulating hepatokines (Angptl4, Angptl8, and Selenop). Mass-spectrometry imaging and whole-genome bisulfite sequencing revealed, respectively, selective PFOS localization and deregulation of gene methylation in fetal livers, involved in inflammation, glucose, and fatty acid metabolism. PCR and Western blot analysis of lipid-laden fetal livers showed activation of AMPK signaling, accompanied by significant increases in the expression of glucose transporters (Glut2/4), hexose-phosphate sensors (Retsat and ChREBP), and the key glycolytic enzyme, pyruvate kinase (Pk) for glucose catabolism. Additionally, PFOS modulated the expression levels of PPARα and PPARγ downstream target genes, which simultaneously stimulated fatty acid oxidation (Cyp4a14, Acot, and Acox) and lipogenesis (Srebp1c, Acaca, and Fasn). Using human normal hepatocyte (MIHA) cells, the underlying mechanism of PFOS-elicited nuclear translocation of ChREBP, associated with a fatty acid synthesizing pathway, was revealed. Our finding implies that in utero PFOS exposure altered the epigenetic landscape associated with dysregulation of fetal liver metabolism, predisposing postnatal susceptibility to metabolic challenges.

5.
Nano Lett ; 23(9): 3694-3700, 2023 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-37074399

RESUMO

Peroxide dianion (O22-) has strong oxidizing activity and ease of proton abstraction and is extremely unstable. Direct and controllable adsorption and release of O22- has large application implication and is a large challenge so far. Here, we use a unique metal (Ni)-organic (diphenylalanine, DPA) framework (MOF), Ni(DPA)2, as adsorbents for absorption and release of O22-. This MOF structure has room-temperature magnetoelectricity via distortion of the Ni-centered octahedron {NiN2O4} and thus possesses a tunable ferroelectric polarization under applied electric/magnetic fields. Controllable adsorption and release of O22- are realized in such a MOF system via electrochemical redox measurements. Structural/spectroscopic characterization and calculations reveal that a number of NH active sites in the nanopores of MOF can effectively adsorb O22- by hydrogen bonds and then tunable ferroelectric polarization induces controllable release of O22- under applied magnetic fields. This work presents a constructive way for controllable adsorption and release of reactive oxygen species.

7.
Life Sci Alliance ; 5(11)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35798563

RESUMO

Stanniocalcin-1 (STC1) is a hypocalcemic hormone originally identified in bony fishes. The mammalian homolog is found to be involved in inflammation and carcinogenesis, among other physiological functions. In this study, we used the TriCEPS-based ligand-receptor methodology to identify the putative binding proteins of human STC1 (hSTC1) in the human leukemia monocytic cell line, ThP-1. LC-MS/MS analysis of peptides from shortlisted hSTC1-binding proteins detected 32 peptides that belong to IGF2/MPRI. Surface plasmon resonance assay demonstrated that hSTC1 binds to immobilized IGF2R/MPRI with high affinity (10-20 nM) and capacity (Rmax 70-100%). The receptor binding data are comparable with those of (CREG) cellular repressor of E1A-stimulated gene a known ligand of IGF2R/MPRI, with Rmax of 75-80% and affinity values of 1-2 nM. The surface plasmon resonance competitive assays showed CREG competed with hSTC1 in binding to IGF2R/MPRI. The biological effects of hSTC1 on ThP-1 cells were demonstrated via IGF2R/MPRI to significantly reduce secreted levels of IL-1ß. This is the first study to reveal the high-affinity binding of hSTC1 to the membrane receptor IGF2R/MPRI.


Assuntos
Glicoproteínas , Proteínas de Membrana , Espectrometria de Massas em Tandem , Cromatografia Líquida , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Ligantes , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células THP-1
8.
Kaohsiung J Med Sci ; 37(11): 940-950, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34414664

RESUMO

To investigate the role of the lncRNA growth arrest special 5 (GAS5) in ovarian clear cell carcinoma (OCCC), we measured the expression of GAS5 and miR-31-5p in OCCC tissue samples and OCCC cell lines using RT-qPCR. MTT and colony formation assays were used to measure cell viability and colony formation ability. Cell invasion was determined by Transwell assays. The binding between GAS5 and miR-31-5p as well as miR-31-5p and ARID1A was determined by dual-luciferase reporter assays. The ARID1A protein levels were detected using western blotting. Kaplan-Meier curves were used for the analysis of the 5-year survival rate of patients with OCCC. GAS5 and ARID1A levels were significantly decreased, while miR-31-5p levels were strongly elevated in the OCCC tissues and cell lines. Patients with lower GAS5/ARID1A levels had shorter overall survival times. Overexpression of GAS5 or inhibition of miR-31-5p suppressed cell viability and invasion of OCCC cells and upregulated the protein levels of ARID1A. Moreover, overexpression of miR-31-5p reversed the effects of overexpression of GAS5. Cotransfection with pcDNA3.1-GAS5 and miR-31-5p inhibitor led to the lowest cell viability and cell invasion rates. A dual-luciferase reporter assay was performed to confirm the target relationship between GAS5 and miR-31-5p, as well as between miR-31-5p and ARID1A. LncRNA GAS5 inhibited cell viability and invasion of OCCC through activation of ARID1A by sponging miR-31-5p.


Assuntos
Adenocarcinoma de Células Claras/genética , Proteínas de Ligação a DNA/genética , MicroRNAs/genética , Neoplasias Ovarianas/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Pareamento de Bases , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Estimativa de Kaplan-Meier , Luciferases/genética , Luciferases/metabolismo , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo
9.
Nanomaterials (Basel) ; 11(5)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066828

RESUMO

There are abundant water resources in nature, and hydrogen production from electrolyzed water can be one of the main ways to obtain green and sustainable energy. Traditional water electrolysis uses precious metals as catalysts, but it is difficult to apply in massive volumes due to low reserves and high prices. It is still a challenge to develop hydrogen electrocatalysts with excellent performance but low cost to further improve the efficiency of hydrogen production. This article reported a potential candidate, the Co-NiS2/CoS2 (material is based on NiS2, and after Co doping, The NiS2/CoS2 heterostructure is formed) heterostructures, prepared by hydrothermal method with carbon paper as the substrate. In a 0.5 M sulfuric acid solution, the hydrogen evolution reaction with Co-NiS2/CoS2 as the electrode showed excellent catalytic performance. When the Co (Cobalt) doping concentration is increased to 27%, the overpotential is -133.3 mV, which is a drop of 81 mV compared with -214.3 mV when it is not doped. The heterostructure formed after doping also has good stability. After 800 CV cycles, the difference in overpotential is only 3 mV. The significant improvement of the catalytic performance can be attributed to the significant changes in the crystal structure and properties of the doped heterostructures, which provide an effective method for efficient electrocatalytic hydrogen production.

10.
J Nanosci Nanotechnol ; 21(4): 2117-2122, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33500026

RESUMO

Heavy metal Cadmium (Cd) will continuously pollute the atmosphere, soil and various water environments through material circulation, and even pose a threat to human safety. It has been designated as a first-class pollutant in sewage by China, therefore there is an urgent need to find new, more effective, and low-cost method to accurately detect Cadmium ion (Cd2+) concentration. We experimentally prepared a new Cd2+ sensor based on NiS2 nanomaterials capable of measuring Cd2+ concentration. The corresponding relationship between over potential of NiS2 nanomaterials in H2SO4 electrolyte solutions with different Cd2+ concentration and reduction peak with change of Cd2+ concentration was obtained by electrochemical method.

11.
World J Clin Cases ; 9(35): 11036-11042, 2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-35047615

RESUMO

BACKGROUND: Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene (AR). However, the underlying molecular mechanisms for the majority of AR variants remain unclear. In this study, we identified a point variant in three patients with complete androgen insensitivity syndrome (CAIS), summarized the correlation analysis, and performed a literature review. CASE SUMMARY: The proband was raised as a girl. In infancy, she was first referred to hospital with a right inguinal hernia. Ultrasonography revealed the absence of a uterus and ovaries, and a testis-like structure located at the inguinal canal. Further diagnostic workup detected a 46, XY karyotype, and fluorescence in situ hybridization analysis showed the presence of the SRY gene. Histological analysis revealed the excised tissue to be testicular. Twelve years later, she was admitted to our hospital with a lack of breast development. Her pubic hair and breasts were Tanner stage I. She had normal female external genitalia. Blood hormone tests showed normal testosterone levels, low estradiol levels, and high gonadotropin levels. Her two siblings underwent similar examinations, and all three had a rare hemizygous missense mutation in AR: c.2678C>T. In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells. CONCLUSION: This case of CAIS was caused by an AR variant (c.2678C>T). Functional studies showed impaired nuclear translocation ability of the mutant protein.

12.
Sensors (Basel) ; 20(19)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003284

RESUMO

Biosensors are widely used in production and life, and can be used in medicine, industrial production, and scientific research. Among them, the detection of pH has always received extensive attention. In this study, we demonstrate the use of a one-step hydrothermal method to prepare Co-FeS2/CoS2 nanomaterials as pH sensor (pH vs. overpotential) for the first time. The proposed pH sensor exhibits outstanding performance in KOH solutions via electrochemical methods with good stability. Overall, the results of this study not only add to the non-noble transition metal electrocatalysis research, but also identify important sensing characteristics for electrocatalysts.

13.
Nanomaterials (Basel) ; 10(11)2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33114399

RESUMO

Transition metal sulfides are cheap and efficient catalysts for water splitting to produce hydrogen; these compounds have attracted wide attention. Nickel sulfide (NiS2) has been studied in depth because of its simple preparation process, excellent performance and good stability. Here, we propose a modification to the hydrothermal synthesis method for the fabrication of a highly efficient and stable NiS2 electrocatalyst prepared by two different sulfur sources, i.e., sulfur powder and C3H7NaO3S2 (MPS), for application in hydrogen evolution reactions. The obtained NiS2 demonstrated excellent HER performance with an overpotential of 131 mV to drive -10 mA cm-1 in 0.5 M H2SO4 solution with 5mV performance change after 1000 cycles of stability testing. We believe that this discovery will promote the industrial development of nonprecious metal catalysts.

14.
J Am Soc Mass Spectrom ; 31(12): 2488-2494, 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-32813518

RESUMO

Rotaxane dendrimers with hyperbranched macromolecular interlocked structures and size modulation capacity demonstrate drug binding and release ability upon external stimuli. Mass spectrometry imaging (MSI) can offer the high-throughput screening of endogenous/exogenous compounds. Herein, we reported a novel method to display the in situ spatial distribution of label-free monodispersed type III rotaxane dendrimers (RDs) G1 (first generation, size ∼1.5 nm) and G2 (second generation, size ∼5 nm) that were explored as potential drug vehicles in spleen tissue by using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-MSI). Experimental results indicated that the trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB) matrix exhibited the best performance for monodispersed type III RDs G1 and G2. The optimized method was successfully applied to map the in vivo spatial distribution of type III RDs G1 and G2 in the spleen from intraperitoneally injected mice. The MALDI-MSI images revealed that RDs G1 and G2 were relatively stable in the spleen within 24 h after administration. It was found that the identified type III RDs G1 and G2 penetrated through the tunica serosa and were predominantly localized in red pulp regions of spleens. They were also mapped in a marginal zone of spleens simultaneously. There was almost no toxicity of type III RDs G1 and G2 to mice spleens from the H&E results. Furthermore, the type III RDs did not induce the expression of inflammatory cytokines from peripheral blood mononuclear cells (PBMCs) or THP-1 monocytes. The MSI analysis not only demonstrated its ability to image select rotaxane dendrimers in a rapid and efficient manner but also provided tremendous assistance on the applications of the further treatment of cancerous tissue as safe drug carriers. Furthermore, the new strategy demonstrated in this study could be applied on other label-free mechanically interlocked molecules, molecular machines, and macromolecules, which opened a new path to evaluate the toxicological and pharmacokinetic characteristics of these novel materials at the suborgan level.


Assuntos
Dendrímeros/análise , Portadores de Fármacos/análise , Rotaxanos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Dendrímeros/farmacocinética , Portadores de Fármacos/farmacocinética , Camundongos , Rotaxanos/farmacocinética , Baço/metabolismo , Distribuição Tecidual
15.
J Nanosci Nanotechnol ; 20(4): 2628-2632, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492287

RESUMO

As a new topological insulator material, the ß-phase silver telluride (Ag2Te) nanowire is a narrow bandgap semiconductor, which is attractive for its excellent properties. In this study, Ag2Te nanowires were synthesized by one-step hydrothermalmethod. The nanowires showed good electrical properties with maximum drain-source voltage of 1.5 V, and the output current was up to 20 µA. The gate voltage has a significant effect on output current for the device. The Ag2Te nanowires will have more extensive and in-depth applications in the fields of optoelectronics and thermoelectricity.

16.
Nanomaterials (Basel) ; 9(9)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480597

RESUMO

Tin disulfide (SnS2) has gained a lot of interest in the field of converting solar energy into chemical fuels in light-assisted electrochemical water splitting due to its visible-light band gap and high electronic mobility. However, further decreasing the recombination rate of electron-hole pairs and increasing the density of active states at the valence band edge of the photoelectrodes were a critical problem. Here, we were successful in fabricating the super-thin SnS2 nanostructure by a hydrothermal and solution etching method. The super-thin SnS2 nanostructure as a photo-electrocatalytic material exhibited low overpotential of 0.25 V at the current density of -10 mA·cm-2 and the potential remained basically unchanged after 1000 cycles in an H2SO4 electrolyte solution, which was better than that of the SnS2 nanosheet and SnS/SnS2 heterojunction nanosheet. These results show the potential application of super-thin SnS2 nanostructure in electrochemical/photo-electrocatalytic field.

17.
Exp Ther Med ; 18(1): 237-241, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31281437

RESUMO

The present study investigated the influence of sevoflurane on the cytotoxicity of neural stem cells of rats and deoxyribonucleic acid (DNA) methylation, and analyzed the correlation between degree of methylation and neurotoxicity of sevoflurane. Ten healthy Sprague-Dawley rats aged 6-8 weeks were randomly selected. The neural stem cells in the hippocampus of rats were isolated, followed by multiplication culture and induced differentiation. The nerve-related factors were observed and detected under a microscope. Moreover, the neural stem cells were treated with sevoflurane in different concentrations. Three wells were only added with the normal medium as the control group (C0), 3 wells were added with the low-concentration sevoflurane (0.2 g/ml) prepared by the medium as the low-concentration group (C1), 3 wells were added with the moderate-concentration of sevoflurane (0.5 g/ml) as the moderate-concentration group (C2), and 3 wells were added with the high-concentration sevoflurane (1 g/ml) as the high-concentration group (C3). The apoptosis rate was detected and calculated via Cell Counting Kit-8 (CCK-8) assay, the content of genomic DNA methylation in neural stem cells in each group was detected via high-performance liquid chromatography (HPLC), and the distribution of methylation in the chromosome in each group was compared. During the culture, neurospheres were produced, and the expression levels of four neural markers were increased. With the increase of sevoflurane concentration and the prolongation of time, the apoptosis rate of stem cells was increased. The content of methylation in cells treated with sevoflurane in a higher concentration was higher than that in other groups (P<0.05). According to the Pearsons correlation analysis, the content of methylation in neural stem cells was directly proportional to the concentration of sevoflurane. Methylation mostly occurred in the autosome, and the content of methylation in the high-concentration group was higher than those in the moderate-concentration, low-concentration and control groups (P<0.05). In conclusion, the concentration of sevoflurane can affect the degree of methylation in neural stem cells of rats and produce certain cytotoxicity.

18.
J Nanosci Nanotechnol ; 19(2): 950-955, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30360178

RESUMO

Semiconducting metal sulfides have raised strong research interest among researchers as a promising candidate for light-assisted electrochemical water splitting, because they have wide band gap. In order to harvest more light wavelengths for improvement of light-assisted electrochemical water splitting capacity, we fabricated SnS2/SnS heterojunction nanosheets via facile and environmental route. The SnS2/SnS heterojunction nanosheets were used as photo-electrocatalytic material which exhibited low over potential of -0.64 V at the current density of 10 mA·cm-2 in 0.5 M NaSO4 solution. Moreover, the SnS and SnS2 nanosheets displayed high over potential values of -0.80 and -0.88 V at the current density of 10 mA·cm-2, respectively. This research finding may therefore show the potential for use of SnS2/SnS heterojunction nanosheets as low cost and environmentally friendly photo-electrocatalysis.

19.
RSC Adv ; 8(50): 28684-28691, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35542473

RESUMO

The traditional method of preparing hydrogen and oxygen as efficient clean energy sources mainly relies on the use of platinum, palladium, and other precious metals. However, the high cost and low abundance limit wide application of such metals. As such, one challenging issue is the development of low-cost and high-efficiency electrocatalysts for such purposes. In this study, we synthesized Co-FeS2/CoS2 heterostructures via a hydrothermal method for efficient hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Benefitting from their unique three-dimensional hierarchical nanostructures, Co-doped FeS2, and CoS2 formed heterostructures on Co-FeS2 petals, which bestowed remarkable electrocatalytic properties upon Co-FeS2/CoS2 nanostructures. Co-FeS2/CoS2 effectively catalyzed the OER with an overpotential of 278 mV at a current density of 10 mA cm-2 in 1 M KOH solution, and also is capable of driving a current density -10 mA cm-2 at an overpotential of -103 mV in 0.5 M H2SO4 solution. The overpotential of the OER and HER only decreased by 5 mV and 3 mV after 1000 cycles. Our Co-FeS2/CoS2 materials may offer a promising alternative to noble metal-based electrocatalysts for water splitting.

20.
Cancer Chemother Pharmacol ; 79(4): 661-671, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28314990

RESUMO

PURPOSE: RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug-drug interaction observed when RO5323441 was administered in combination with bevacizumab. METHODS: The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4). A two-compartment linear population PK model was developed from these four studies to characterize the PK of RO5323441 in patients with cancer. RESULTS: The PK properties of RO5323441 were similar in the first three studies. However, substantially higher RO5323441 exposures were observed in Study 4 when RO5323441 was administered in combination with bevacizumab. A linear two-compartmental population PK model indicated that the co-administration of bevacizumab would decrease the clearance of RO5323441 by 53%. Clinical data suggested that the decrease in RO5323441 clearance was inversely associated with bevacizumab exposure. CONCLUSIONS: The exact reason for the increase in RO5323441 exposure following bevacizumab co-administration is not currently known. One possibility is a drug-drug interaction via a target-trapping mechanism that is mediated by the vascular endothelial growth factor receptor-1 (VEGFR-1).


Assuntos
Inibidores da Angiogênese/farmacocinética , Anticorpos Monoclonais/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/farmacocinética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/imunologia , Anticorpos Monoclonais Humanizados , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Masculino , Modelos Estatísticos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Caracteres Sexuais
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