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1.
J Orthop Surg (Hong Kong) ; 31(3): 10225536231214055, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37971330

RESUMO

BACKGROUND: The occurrence of prosthesis-related complications after total shoulder arthroplasty is devastating and costly. The purpose was to determine the incidence and risk of in-hospital prosthesis-related complications after total shoulder arthroplasty utilizing a large-scale sample database. METHODS: A retrospective database analysis was performed based on Nationwide Inpatient Sample from 2010 to 2014. Patients who underwent total shoulder arthroplasty were included. Patient demographics, hospital characteristics, length of stay, economic indicators, in-hospital mortality, comorbidities, and peri-operative complications were evaluated. RESULTS: A total of 34,198 cases were capture from the Nationwide Inpatient Sample database. There were 343 cases of in-hospital prosthesis-related complications after total shoulder arthroplasty and the overall incidence was 1%, with a more than 2.5-fold decrease from 2010 to 2014. Dislocation was the most common category among prosthesis-related complications (0.1%). The occurrence of in-hospital prosthesis-related complications was associated with significantly more total charges and slightly longer length of stay while less usage of Medicare. Risk factors of prosthesis-related complications were identified including younger age (<64 years), female, the native American, hospital in the South, alcohol abuse, depression, uncomplicated diabetes, diabetes with chronic complications, fluid and electrolyte disorders, metastatic cancer, neurological disorders, and renal failure. Interestingly, advanced age (≥65 years) and proprietary hospital were found as protective factors. Furthermore, prosthesis-related complications were associated with aseptic necrosis, rheumatoid arthritis, rotator cuff tear arthropathy, Parkinson's disease, prior shoulder arthroscopy, and blood transfusion. CONCLUSIONS: It is of benefit to study risk factors of prosthesis-related complications following total shoulder arthroplasty to ensure the appropriate management and optimize consequences although a relatively low incidence was identified.


Assuntos
Artroplastia do Ombro , Diabetes Mellitus , Articulação do Ombro , Humanos , Feminino , Idoso , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Artroplastia do Ombro/efeitos adversos , Articulação do Ombro/cirurgia , Incidência , Estudos Retrospectivos , Medicare , Fatores de Risco , Próteses e Implantes/efeitos adversos , Diabetes Mellitus/etiologia , Diabetes Mellitus/cirurgia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento
2.
Innovation (Camb) ; 4(5): 100459, 2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37560333

RESUMO

The search of quantum spin liquid (QSL), an exotic magnetic state with strongly fluctuating and highly entangled spins down to zero temperature, is a main theme in current condensed matter physics. However, there is no smoking gun evidence for deconfined spinons in any QSL candidate so far. The disorders and competing exchange interactions may prevent the formation of an ideal QSL state on frustrated spin lattices. Here we report comprehensive and systematic measurements of the magnetic susceptibility, ultralow-temperature specific heat, muon spin relaxation (µSR), nuclear magnetic resonance (NMR), and thermal conductivity for NaYbSe2 single crystals, in which Yb3+ ions with effective spin-1/2 form a perfect triangular lattice. All these complementary techniques find no evidence of long-range magnetic order down to their respective base temperatures. Instead, specific heat, µSR, and NMR measurements suggest the coexistence of quasi-static and dynamic spins in NaYbSe2. The scattering from these quasi-static spins may cause the absence of magnetic thermal conductivity. Thus, we propose a scenario of fluctuating ferrimagnetic droplets immersed in a sea of QSL. This may be quite common on the way pursuing an ideal QSL, and provides a brand new platform to study how a QSL state survives impurities and coexists with other magnetically ordered states.

3.
Artigo em Inglês | MEDLINE | ID: mdl-37216250

RESUMO

Sleep apnea (SA) is a common sleep-related breathing disorder that tends to induce a series of complications, such as pediatric intracranial hypertension, psoriasis, and even sudden death. Therefore, early diagnosis and treatment can effectively prevent malignant complications SA incurs. Portable monitoring (PM) is a widely used tool for people to monitor their sleep conditions outside of hospitals. In this study, we focus on SA detection based on single-lead electrocardiogram (ECG) signals which are easily collected by PM. We propose a bottleneck attention based fusion network named BAFNet, which mainly includes five parts of RRI (R-R intervals) stream network, RPA (R-peak amplitudes) stream network, global query generation, feature fusion, and classifier. To learn the feature representation of RRI/RPA segments, fully convolutional networks (FCN) with cross-learning are proposed. Meanwhile, to control the information flow between RRI and RPA networks, a global query generation with bottleneck attention is proposed. To further improve the SA detection performance, a hard sample scheme with k-means clustering is employed. Experiment results show that BAFNet can achieve competitive results, which are superior to the state-of-the-art SA detection methods. It means that BAFNet has great potential to be applied in the home sleep apnea test (HSAT) for sleep condition monitoring. The source code is released at https://github.com/Bettycxh/Bottleneck-Attention-Based-Fusion-Network-for-Sleep-Apnea-Detection.

4.
Hum Gene Ther ; 34(21-22): 1145-1161, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36851890

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies but has yet to achieve similar success in solid tumors due to a lack of persistence and function in the tumor microenvironment. We previously reported the augmentation of CAR T cell therapy in an engineered solid tumor model through the secretion of anti-PD-1 single-chain fragment variable region (scFv), as shown by enhanced CAR T cell antitumor efficacy, expansion, and vitality. We have since improved the platform to create a superior cellular product-CAR T cells secreting single-chain trimeric 4-1BB ligand fused to anti-PD-1 scFv (αPD1-41BBL). 4-1BB signaling promotes cytotoxic T lymphocyte proliferation and survival but targeting 4-1BB with agonist antibodies in the clinic has been hindered by low antitumor activity and high toxicity. CAR T cells using 4-1BB endodomain for costimulatory signals have demonstrated milder antitumor response and longer persistence compared to CAR T cells costimulated by CD28 endodomain. We have, for the first time, engineered CD28-costimulated CAR T cells to secrete a fusion protein containing the soluble trimeric 4-1BB ligand. In vitro and in vivo, CAR19.αPD1-41BBL T cells exhibited reduced inhibitory receptor upregulation, enhanced persistence and proliferation, and a less differentiated memory status compared to CAR T cells without additional 4-1BB:4-1BBL costimulation. Accordingly, CAR19.αPD1-41BBL T cell-treated mice displayed significantly improved tumor growth control and overall survival. Spurred on by our preclinical success targeting CD19 as a model antigen, we produced mesothelin-targeting CAR T cells and confirmed the enhanced solid tumor efficacy of αPD1-41BBL-secreting CAR T cells.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Animais , Camundongos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T , Antígenos CD28 , Ligante 4-1BB/metabolismo , Neoplasias/terapia , Imunoterapia Adotiva , Microambiente Tumoral
5.
Hum Gene Ther ; 33(5-6): 223-236, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34225478

RESUMO

Chimeric antigen receptor (CAR) T cell therapy mediates unprecedented benefit in certain leukemias and lymphomas, but has yet to achieve similar success in combating solid tumors. A substantial body of work indicates that the accumulation of adenosine in the solid tumor microenvironment (TME) plays a crucial role in abrogating immunotherapies. Adenosine deaminase 1 (ADA) catabolizes adenosine into inosine and is indispensable for a functional immune system. We have, for the first time, engineered CAR T cells to overexpress ADA. To potentially improve the pharmacokinetic profile of ADA, we have modified the overexpressed ADA in two ways, through the incorporation of a (1) albumin-binding domain or (2) collagen-binding domain. ADA and modified ADA were successfully expressed by CAR T cells and augmented CAR T cell exhaustion resistance. In a preclinical engineered ovarian carcinoma xenograft model, ADA and collagen-binding ADA overexpression significantly enhanced CAR T cell expansion, tumor tissue infiltration, tumor growth control, and overall survival, whereas albumin-binding ADA overexpression did not. Furthermore, in a syngeneic colon cancer solid tumor model, the overexpression of mouse ADA by cancer cells significantly reduced tumor burden and remodeled the TME to favor antitumor immunity. The overexpression of ADA for enhanced cell therapy is a safe, straightforward, reproducible genetic modification that can be utilized in current CAR T cell constructs to result in an armored CAR T product with superior therapeutic potential.


Assuntos
Receptores de Antígenos Quiméricos , Adenosina/metabolismo , Adenosina Desaminase/genética , Albuminas/metabolismo , Animais , Linhagem Celular Tumoral , Colágeno/metabolismo , Humanos , Imunoterapia Adotiva , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cell Rep Med ; 2(11): 100449, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34841295

RESUMO

Cell-based immunotherapy has become the new-generation cancer medicine, and "off-the-shelf" cell products that can be manufactured at large scale and distributed readily to treat patients are necessary. Invariant natural killer T (iNKT) cells are ideal cell carriers for developing allogeneic cell therapy because they are powerful immune cells targeting cancers without graft-versus-host disease (GvHD) risk. However, healthy donor blood contains extremely low numbers of endogenous iNKT cells. Here, by combining hematopoietic stem cell (HSC) gene engineering and in vitro differentiation, we generate human allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells at high yield and purity; these cells closely resemble endogenous iNKT cells, effectively target tumor cells using multiple mechanisms, and exhibit high safety and low immunogenicity. These cells can be further engineered with chimeric antigen receptor (CAR) to enhance tumor targeting or/and gene edited to ablate surface human leukocyte antigen (HLA) molecules and further reduce immunogenicity. Collectively, these preclinical studies demonstrate the feasibility and cancer therapy potential of AlloHSC-iNKT cell products and lay a foundation for their translational and clinical development.


Assuntos
Células Alógenas/imunologia , Engenharia Celular , Células-Tronco Hematopoéticas/imunologia , Imunoterapia , Células T Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Células Alógenas/metabolismo , Animais , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Antígenos HLA/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Células T Matadoras Naturais/metabolismo , Fenótipo , Receptores de Antígenos Quiméricos/metabolismo , Transcriptoma/genética
7.
Mol Ther Oncolytics ; 21: 144-157, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-33981830

RESUMO

Despite the remarkable success of chimeric antigen receptor-modified T (CAR-T) cell therapy for blood malignancies, the clinical efficacy of this novel therapy in solid tumor treatment is largely limited by the immunosuppressive tumor microenvironment (TME). For instance, immune checkpoints (e.g., programmed cell death protein 1 [PD-1]/programmed death ligand 1 [PD-L1]) in TME play an important role in inhibiting T cell proliferation and functions. Transforming growth factor ß (TGF)-ß secreted by cancer cells in TME induces regulatory T cells (Tregs) and inhibits cytotoxic T cells. To overcome the inhibitory effect of immune checkpoints, we have previously engineered CAR-T cells to secrete anti-PD-1 to block the PD-1/PD-L1 pathway activity, a step demonstrating superior antitumor efficacy compared with conventional CAR-T cells. In this study, we engineered CAR-T cells that secrete bispecific trap protein co-targeting PD-1 and TGF-ß, with the aim of further improving antitumor immunity. Compared with conventional CAR-T cells and anti-PD-1-secreting CAR-T cells, data from in vitro and in vivo experiments showed that CAR-T cells with trap protein secretion further attenuated inhibitory T cell signaling, enhanced T cell persistence and expansion, and improved effector function and resistance to exhaustion. In the xenograft mouse model, CAR-T cells with trap protein secretion exhibited significantly enhanced antitumor immunity and efficacy. With these observations, we demonstrate the potential of trap protein self-secreting CAR-T cells as a potent therapy for solid tumors.

8.
Inorg Chem ; 58(15): 9897-9903, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31291102

RESUMO

Two kinds of ternary thorium nitride compounds, ThNF and ThNCl, are synthesized. Via the refinement of X-ray diffraction patterns, the accurate crystal structure of the two compounds is solved. Although ThNF and ThNCl share a similar structure with MNX (M = Ti, Zr, Hf; X = Cl, Br) compounds, the interaction between adjacent ThNF and ThNCl layers is not a van der Waals gap. For ThNF, the strong electronegativity of F ions leads to the bonding of Th to the F both in the nearest neighbor layer and the next nearest neighbor layer, which results in the absence of a van der Waals gap between ThNF layers. However, for ThNCl, the reason for the absence of a van der Waals gap could be attributed to the large Th-Cl bond length due to the partially covalent Th-Cl bond as well as the flat ThN layer. It is the absence of van der Waals gap that results in the failure of intercalating cations into ThNF and ThNCl. Our result reveals the reason for unsuccessful intercalation in ThNF and ThNCl, thereby providing a deeper understanding for the interlayer interaction in ternary layer structures in metal nitride halides.

9.
Eur J Pharm Biopharm ; 133: 188-199, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30359716

RESUMO

As a unique macromolecular permeation enhancer, thiolated polymers (thiomers), especially the preactivated thiomers, have demonstrated great merits in oral delivery of protein/peptide drugs by triggering epithelial tight junctions (TJs) opening. However, the underlying molecular mechanism remains unclear. To clarify this issue, preactivated thiomers were synthesized and their TJs opening function as well as signaling pathways on MDCK and Caco-2 cell monolayers was investigated. The results showed that preactivated thiomers could reduce TEER and increase the permeation of Na-Flu and FITC-Insulin over 2-fold and 4-fold on MDCK monolayers, respectively, indicating their huge potential as macromolecular permeation enhancers. The signaling pathway study showed that intracellular PTK Src but not FAK, involved in the TJs opening by claudin-4 disruption. Src activation was based on interaction between thiol group of thiomers and cysteine-riched Src upstream membrane receptors, EGFR and IGFR. The deep comprehension of the thiomers-mediated TJs opening mechanisms provides goodness in application of protein/peptide drugs for the oral delivery.


Assuntos
Epitélio/efeitos dos fármacos , Polímeros/farmacologia , Compostos de Sulfidrila/farmacologia , Junções Íntimas/efeitos dos fármacos , Animais , Células CACO-2 , Linhagem Celular , Linhagem Celular Tumoral , Claudina-4/metabolismo , Cisteína/metabolismo , Cães , Sistemas de Liberação de Medicamentos/métodos , Epitélio/metabolismo , Receptores ErbB/metabolismo , Humanos , Substâncias Macromoleculares/farmacologia , Células Madin Darby de Rim Canino , Peptídeos/farmacologia , Preparações Farmacêuticas/administração & dosagem , Proteínas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismo
10.
Cancer Immunol Res ; 6(7): 812-824, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29720380

RESUMO

One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. Cancer Immunol Res; 6(7); 812-24. ©2018 AACR.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Nanopartículas , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Biomarcadores , Linhagem Celular , Modelos Animais de Doenças , Feminino , Imunofenotipagem , Imunoterapia Adotiva , Camundongos , Camundongos Transgênicos , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Ther ; 25(12): 2607-2619, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-28919377

RESUMO

The therapeutic limitations of conventional chemotherapeutic drugs include chemo-resistance, tumor recurrence, and metastasis. Numerous nanoparticle-based active targeting approaches have emerged to enhance the intracellular concentration of drugs in tumor cells; however, efficient delivery of these systems to the tumor site while sparing healthy tissue remains elusive. Recently, much attention has been given to human immune-cell-directed nanoparticle drug delivery, because immune cells can traffic to the tumor and inflammatory sites. Natural killer cells are a subset of cytotoxic lymphocytes that play critical roles in cancer immunosurveillance. Engineering of the human natural killer cell line, NK92, to express chimeric antigen receptors to redirect their antitumor specificity has shown significant promise. We demonstrate that the efficacy of chemotherapy can be enhanced in vitro and in vivo while reducing off-target toxicity by using chimeric antigen receptor-engineered NK92 cells as carriers to direct drug-loaded nanoparticles to the target site.


Assuntos
Antígenos de Neoplasias/imunologia , Portadores de Fármacos , Imunoterapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias/imunologia , Receptores de Antígenos/genética , Receptores de Antígenos/metabolismo , Proteínas Recombinantes de Fusão , Animais , Antígenos CD19/genética , Antígenos CD19/imunologia , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Expressão Gênica , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Lipossomos , Camundongos , Camundongos Knockout , Nanomedicina , Nanopartículas , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Paclitaxel/administração & dosagem , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nanomedicine ; 12(2): 387-97, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26711969

RESUMO

Though combination chemotherapy or antitumor nanomedicine is extensively investigated, their combining remains in infancy. Additionally, enhanced delivery of estrogen or its analogs to tumor with highly-expressed estrogen-receptor (ER) is seldom considered, despite its necessity for ER-positive breast cancer treatment. Here, nanomedicine based combination therapy using QLPVM conjugated liposomal tamoxifen (TAM) and doxorubicin (DOX) was designed and testified, where the penta-peptide was derived from Ku70 Bax-binding domain. Quantitative, semi-quantitative and qualitative approaches demonstrated the enhanced endocytosis and cytotoxicity of QLPVM conjugated sterically stabilized liposomes (QLPVM-SSLs) in vitro and in vivo. Mechanism studies of QLPVM excluded the possible electrostatic, hydrophobic or receptor-ligand interactions. However, as a weak cell-penetrating peptide, QLPVM significantly induced drug release from QLPVM-SSLs during their interaction with cells, which was favorable for drug internalization. These findings suggested that the nanomedicine based combination therapy using QLPVM-SSL-TAM and QLPVM-SSL-DOX might provide a rational strategy for Luminal A breast cancer. FROM THE CLINICAL EDITOR: Breast cancer remains a leading cause of mortality in women worldwide. Although combined therapy using hormonal antagonist and chemotherapy is the norm nowadays, the use of these agents together in a single delivery system has not been tested. Here, the authors investigated this approach using QLPVM conjugated liposomes in in-vitro and in-vivo models. The positive findings may provide a novel direction for breast cancer treatment in the near future.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Peptídeos Penetradores de Células/metabolismo , Doxorrubicina/análogos & derivados , Lipossomos/metabolismo , Oligopeptídeos/metabolismo , Tamoxifeno/administração & dosagem , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Autoantígeno Ku/química , Autoantígeno Ku/metabolismo , Lipossomos/química , Camundongos Nus , Nanomedicina , Oligopeptídeos/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Tamoxifeno/uso terapêutico , Proteína X Associada a bcl-2/metabolismo
13.
Nanoscale ; 7(36): 14838-47, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26224484

RESUMO

In situ thermo-sensitive hydrogels have attracted increasing attention for alternative cancer therapies due to their long-term and effective drug levels at local sites. Besides synthesizing new thermo-sensitive polymers, we can also fabricate this delivery system by combining a hydrogel with a thermo-response and drug in a different dispersion state, such as drug nanocrystals. However, the impact of the drug dispersion state or dimension on the quality of such a local injectable system is still unknown. So, here we developed and compared three types of F127 hydrogel systems with either paclitaxel or the near infra-red probe DiR in molecules (MOs), nanocrystals (NCs) and microcrystals (MCs), respectively. With 120 nm rod-shape nanocrystals, the NCs-Gel achieved a high drug loading, moderate drug release rate and gel erosion in vitro and in vivo, medium intratumoral drug residue but the best anti-tumor efficacy in 4T1 tumor bearing BALB/c mice. With the free drug solubilized in 20 nm micelles of the gel, the MOs-Gel system demonstrated the least drug loading and the fastest drug release and gel erosion, leading to the least intratumoral residue as well as the lowest anti-tumor effect. Finally, when dispersed in micron-grade rod-shape drug crystals, the MCs-Gel exhibited a high drug loading but poor stability, precipitating in vitro and in vivo, the highest intratumoral residue but the least drug release, resulting in moderate tumor inhibition. In conclusion, this study clarifies the effect of the drug dispersion state and scale on the behavior of a thermo-sensitive hydrogel, indicating the advantage of the NCs-Gel system, and it provides a basis for the future design of the local delivery of hydrophobic anti-cancer agents.


Assuntos
Hidrogéis , Neoplasias Mamárias Animais/tratamento farmacológico , Nanopartículas/química , Paclitaxel , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Temperatura Alta , Hidrogéis/química , Hidrogéis/farmacocinética , Hidrogéis/farmacologia , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Solubilidade
14.
Yao Xue Xue Bao ; 49(6): 942-8, 2014 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-25212045

RESUMO

The aimed of this study was to prepare stabilized thiomers to overcome the poor stability character of traditional thiomers. Poly(acrylic acid)-cysteine (PAA-Cys) was synthesized by conjugating cysteine with poly(acrylic acid) and poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, stabilized thiomers) was synthesized by grafting a protecting group 6-mercaptonicotinic acid (6MNA) with PAA-Cys. The free thiol of PAA-Cys was determined by Ellmann's reagent method and the ratio of 6MNA coupled was determined by glutathione reduction method. The study of permeation enhancement and stabilized function was conducted by using Franz diffusion cell method, with fluorescein isothiocyanate dextran (FD4) used as model drug. The influence of polymers on tight junctions of Caco-2 cell monolayer was detected with laser scanning confocal fluorescence microscope. The results indicated that both PAA-Cys and PAA-Cys-6MNA could promote the permeation of FD4 across excised rat intestine, and the permeation function of PAA-Cys-6MNA was not influence by the pH of the storage environment and the oxidation of air after the protecting group 6MNA was grafted. The distribution of tight junction protein of Caco-2 cell monolayer F-actin was influenced after incubation with PAA-Cys and PAA-Cys-6MNA. In conclusion, stabilized thiomers (PAA-Cys-6MNA) maintained the permeation function compared with the traditional thiomers (PAA-Cys) and its stability was improved. The mechanism of the permeation enhancement function of the polymers might be related to their influence on tight junction relating proteins of cells.


Assuntos
Resinas Acrílicas/química , Cisteína/química , Ácidos Nicotínicos/química , Compostos de Sulfidrila/química , Actinas/metabolismo , Animais , Células CACO-2 , Dextranos , Fluoresceína-5-Isotiocianato/análogos & derivados , Glutationa , Humanos , Absorção Intestinal , Mucosa Intestinal/efeitos dos fármacos , Ratos
15.
Mol Pharm ; 11(10): 3656-70, 2014 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-25208098

RESUMO

To address the obstacles facing cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer-drug conjugates/prodrugs, self-assembled NPs, high drug content, redox responsiveness, and programmed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC, and (1)H NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, as indicated by their triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. Additionally, by taking advantage of the difference in the drug-release rates between physically loaded and chemically conjugated drugs, a programmed drug-release phenomenon was observed, which was attributed to a higher concentration and longer action time of the drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, cell cycle progression, and cellular apoptosis was determined in the MCF-7 cell line, and the NPs demonstrated a superior anti-proliferative activity associated with PTX-induced cell cycle arrest in G2/M phase and apoptosis compared to their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in a breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored for use in effective intracellular drug delivery.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/química , Paclitaxel/uso terapêutico , Polietilenoglicóis/química , Polímeros/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos
16.
Phys Rev Lett ; 112(12): 127001, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24724672

RESUMO

We use scanning tunneling microscopy to investigate the doping dependence of quasiparticle interference (QPI) in NaFe1-xCoxAs iron-based superconductors. The goal is to study the relation between nematic fluctuations and Cooper pairing. In the parent and underdoped compounds, where fourfold rotational symmetry is broken macroscopically, the QPI patterns reveal strong rotational anisotropy. At optimal doping, however, the QPI patterns are always fourfold symmetric. We argue this implies small nematic susceptibility and, hence, insignificant nematic fluctuation in optimally doped iron pnictides. Since TC is the highest this suggests nematic fluctuation is not a prerequistite for strong Cooper pairing.

17.
Int J Med Mushrooms ; 13(2): 121-30, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22135888

RESUMO

Inonotus obliquus (Pers.:Fr.) Pilát has been traditionally used as a folk remedy for treatment of cancers, cardiovascular disease and diabetes in Russia, Poland, and most of the Baltic countries, but natural reserves of this fungus have nearly been exhausted. This study was designed to investigate the artificial cultivation of I. obliquus and the antitumor activity of its tissues. The ethanol extract of cultivated sclerotium had the highest cell growth inhibitory rate (74.6%) as determined by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 78% of the bags produced sclerotia and only 6.17 g/bag of sclerotium was obtained. Extracts of the cultivated fruiting body showed 44.2% inhibitory activity against tumor cells. However, the yield was as high as 18.24 g/bag, and 98% of the bags produced fruiting body. The results of gas chromatography-mass spectroscopy (GC-MS) showed that similar compounds were extracted from the wild and cultivated samples. The principal compounds observed were lanosterol, inotodiol, and ergosterol. Their percentages of the mass fraction were 86.1, 59.9, and 71.8% of the total, for the wild sclerotium, cultivated sclerotium, and cultivated fruiting body, respectively. Ergosterol was found to be much higher (27.32%) in cultivated fruiting body. We conclude that cultivated fruiting body of I. obliquus obtained by inoculation of the substrate with spawn mycelium of the fifth generation could serve as an ideal substitute for the wild I. obliquus.


Assuntos
Agaricales/química , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Agaricales/crescimento & desenvolvimento , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares , Medicina Tradicional
18.
Phytochem Anal ; 22(5): 419-23, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21433158

RESUMO

INTRODUCTION: In Eastern Europe, especially Russia, the fruiting body of Inonotus obliquus has been used as a folk medicine for cancer since the sixteenth or seventeenth century. Inotodiol and trametenolic acid are considered to be the main bioactive compounds of the fruiting body of the mushroom. These compounds show various biological activities, including anti-tumour, anti-viral, hypoglycaemic, anti-oxidant and cyto-protective. However, effective methods for isolating and purifying inotodiol and trametenolic acid from the fruiting body of Inonotus obliquus are not currently available. OBJECTIVE: To develop a suitable preparative method in order to isolate inotodiol and trametenolic acid from a complex Inonotus obliquus extract by preparative high-speed counter-current chromatography (HSCCC). METHODOLOGY: Inotodiol and trametenolic acid were rapidly isolated and purified from the chloroform extract of Inonotus obliquus (Fr.) by HSCCC with evaporative light scatting detection (ELSD). The purity of the obtained target compounds was analysed by high-performance liquid chromatography (HPLC) with ELSD. The structures of the two compounds were identified by ¹H NMR and ¹³C NMR. RESULT: The target compounds were finally isolated and purified with a solvent system of hexane:ethyl acetate:methanol:water (1:0.4:1:0.4, v/v/v/v). In a single operation, 100 mg of the I. obliquus extracts yielded 13.0 mg of inotodiol and 7.0 mg of trametenolic acid. The entire separation and purification process took less than 5 h. The purities of obtained inotodiol and trametenolic acid were 97.51 and 94.04%, respectively. CONCLUSION: HSCCC-ELSD was an efficient and rapid method for the separation and purification of inotodiol and trametenolic acid from I. obliquus.


Assuntos
Agaricales/química , Cromatografia Líquida de Alta Pressão/métodos , Lanosterol/análogos & derivados , Triterpenos/isolamento & purificação , Lanosterol/química , Lanosterol/isolamento & purificação , Ressonância Magnética Nuclear Biomolecular , Triterpenos/química
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