Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 464
Filtrar
1.
ACS Nano ; 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33844517

RESUMO

The therapeutic effect of chemodynamic therapy (CDT) is significantly restricted by the stern reaction conditions and slow reaction rate of the Fenton reaction (pH 3-4). Herein, we report an ultrasmall trimetallic (Pd, Cu, and Fe) alloy nanozyme (PCF-a NEs) possessing dynamic active-site synergism, thus exhibiting a cascade glutathione peroxidase and peroxidase (POD) mimicking activities in circumneutral pH. PCF-a NEs exhibit photothermally augmented POD property and high photothermal conversion efficiency (62%) for synergistic tumor cell apoptosis. In addition, ultrasound can also enhance the mass transfer at active catalytic sites of PCF-a NEs, in turn accelerating Fenton-like reaction for tumor-specific CDT. This work provides a strategy for engineering alloy nanozymes in a bioinspired way for the amplification of intratumor reactive oxygen species in response to external stimuli, demonstrating enhanced efficiency for the inhibition of tumor growth in vitro and in vivo.

2.
Biomaterials ; 272: 120809, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33839624

RESUMO

Live attenuated bacteria have been used as target vehicles for genetic therapy of malignant carcinoma because they can be reprogrammed by following simple genetic rules and have the ability to target tumor hypoxic region. In this research, noninvasive Escherichia coli (E. Coli) is genetically modified through the plasmid transfection to afford E. Coli(p) with overexpressed human catalase for catalyzing H2O2 into O2 in the tumor site. The produced O2 is consequently converted to cytotoxic 1O2 under near-infrared (NIR) light irradiation for photodynamic therapy. Chlorin e6 (Ce6) is chosen as the photosensitizer for its excellent photodynamic ability, and polydopamine (pDA) is employed to encapsulate Ce6 for its good biosafety, photothermal ability, and adhesion capacity with bacteria. Dopamine polymerizes in the presence of Ce6 to form pDA/Ce6, and then E. Coli(p) is coated with pDA/Ce6 to afford the final E. Coli(p)/pDA/Ce6. The obtained system is intravenously administrated for selective accumulation and replication in the hypoxic tumor. NIR light irradiation is introduced to enable photothermal and O2-enhanced photodynamic therapy. On account of complementary combination, the system exhibits efficient antitumor effect in vitro and in vivo. Thus, the integration of genetically modified bacteria with pDA/Ce6 presents a promising application potential for precise tumor inhibition.

3.
Sci Rep ; 11(1): 7577, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828168

RESUMO

Schizophrenia results in poor functional outcomes owing to numerous factors. This study provides the first test of a bottom-up causal model of functional outcome in schizophrenia, using neurocognition, vocal emotional cognition, alexithymia, and negative symptoms as predictors of functional outcome. We investigated a cross-sectional sample of 135 individuals with schizophrenia and 78 controls. Using a series of structural equation modelling analyses, a single pathway was generated among scores from the MATRICS Consensus Cognitive Battery (MCCB), vocal emotion recognition test, Toronto Alexithymia Scale (TAS), Brief Negative Symptom Scale, and the Personal and Social Performance Scale. The scores for each dimension of the MCCB in the schizophrenia group were significantly lower than that in the control group. The recognition accuracy for different emotions (anger, disgust, fear, sadness, surprise, and satire, but not calm was significantly lower in the schizophrenia group than in the control group. Moreover, the scores on the three dimensions of TAS were significantly higher in the schizophrenia group than in the control group. On path analysis modelling, the proposed bottom-up causal model showed a strong fit with the data and formed a single pathway, from neurocognition to vocal emotional cognition, to alexithymia, to negative symptoms, and to poor functional outcomes. The study results strongly support the proposed bottom-up causal model of functional outcome in schizophrenia. The model could be used to better understand the causal factors related to the functional outcome, as well as for the development of intervention strategies to improve functional outcomes in schizophrenia.

4.
Animals (Basel) ; 11(3)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809169

RESUMO

The present study investigated the effect of flaxseed grain or flaxseed oil on ileal microbiota and lipid deposition of cashmere goats. Sixty kid goats (average body weight 18.6 ± 0.1 kg) were allocated to three treatments, fed for 90 days, with control treatment: basal diet (CON, total-mixed ration), experimental treatment: basal diet with added flaxseed oil (LNO), experimental treatment: basal diet with added heated flaxseed grain (HLS). The final body weight, body weight gain, the weight of kidney fat, omental fat, tail fat, and fat tissue, the activity of fatty acid synthetase, acetyl-coa carboxylase, and malic dehydrogenase, and the relative abundance (RA) of unclassified_f_Peptostreptococcaceae and Intestinibacter were remarkably higher in the LNO treatment than in the HLS treatment, but the [Eubacterium]_coprostanoligenes_group RA showed the opposite result. The content of triglyceride, cholesterol, and low-density lipoprotein cholesterol were significantly higher in the CON and LNO treatments than in the HLS treatment, while the hormone-sensitive lipase activity and the non-esterified fatty acid content showed the opposite result. In conclusion, the flaxseed grain is more efficient than flaxseed oil in ameliorating the blood lipid profiles and it is a potential product for decreasing the lipid deposition of cashmere goats.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33768682

RESUMO

The presence of bacteria in the tumor can cause cancer resistance to chemotherapeutics. To fight against bacterium-induced drug resistance, herein we design self-traceable nanoreservoirs that are simultaneously loaded with gemcitabine and antibiotics ciprofloxacin and are decorated with hyaluronic acid for active tumor targeting. The nanoreservoirs have a pH-sensitive gate and an enzyme-responsive gate that can be opened in the acidic and hyaluronidase-abundant tumor microenvironment to control drug release rates. Moreover, the nanoreservoirs can specifically target the tumor regions without eliciting evident toxicity to normal tissues, kill the intratumoral bacteria, and inhibit the tumor growth even in the presence of the bacteria. Unexpectedly, the nanoreservoirs can activate T cell-mediated immune responses through promoting antigen-presenting dendritic cell maturation and depleting immunosuppressive myeloid-derived suppressor cells in bacterium-infected tumors.

6.
ACS Nano ; 15(3): 5322-5332, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33683099

RESUMO

Precise control of the emergence of macroscopic helicity with specific handedness is promising in rationally designing chiral nanomaterials, but it is rather challenging. Herein, we present a protocol to address the transmission of helicity at a molecularly resolved level to a macroscopically resolved level, in which process supramolecular chirality undergoes an inversion. A series of N-terminal aromatic amino acids could self-assemble in water, enabling the occurrence of helicity at the molecularly resolved scale, evidenced by the single crystal structure and chiroptical responses. While it failed to transmit the helicity to the macroscopic scale for individual self-assembly, the coassembly with small organic binder through hydrogen bonding interactions allows for the emergence of helical structures at the nano/micrometer scale. Experimental and theoretical results demonstrate that the introduction of extra hydrogen bonds enables a moderate crystallinity of coassemblies with remaining one-dimensional orientation to enhance the helical growth. The transmission of helicity to higher levels by coassembly is accompanied by the helicity inversion, resulting from the exchange of hydrogen bonds. This study presents a rational protocol to precisely control the emergence of macroscopic helicity from molecularly resolved helicity with finely tailored handedness, providing a deeper understanding of the chirality origin in the assembled systems in order to facilitate the design and construction of functional chiral nanomaterials.

7.
Adv Mater ; : e2004406, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33734506

RESUMO

The ability of photoanodes to simultaneously tailor light absorption, charge separation, and water oxidation processes represents an important endeavor toward highly efficient photoelectrochemical (PEC) water splitting. Here, a robust strategy is reported to render markedly improved PEC water splitting via sandwiching a photothermal Co3 O4 layer between a BiVO4 photoanode film and an FeOOH/NiOOH electrocatalyst sheet. The deposited Co3 O4 layer manifests compelling photothermal effect upon near-infrared irradiation and raises the temperature of the photoanodes in situ, leading to extended light absorption, enhanced charge transfer, and accelerated water oxidation kinetics simultaneously. The judiciously designed NiOOH/FeOOH/Co3 O4 /BiVO4 photoanode renders a superior photocurrent density of 6.34 mA cm-2 at 1.23 V versus a reversible reference electrode (VRHE ) with outstanding applied bias photon-to-current efficiency of 2.72% at 0.6 VRHE . In addition to the metal oxide, a wide variety of metal sulfides, nitrides, and phosphides (e.g., CoS, CoN, and CoP) can be exploited as the heaters to yield high-performance BiVO4 -based photoanodes. Apart from BiVO4 , other metal oxides (e.g., Fe2 O3 and TiO2 ) can also be covered by photothermal materials to impart significantly promoted water splitting. This simple yet general strategy provides a unique platform to capitalize on their photothermal characteristics to engineer high-performing energy conversion and storage materials and devices.

8.
Biosens Bioelectron ; 181: 113164, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33744670

RESUMO

The ingenious design and synthesis of novel macrocycles bring out renewed vigor of supramolecular chemistry in the past decade. As an intriguing class of macrocycles, pillararene and pillararene-based functional materials that are constructed through the noncovalent bond self-assembly approach have been undergoing a rapid growth, benefiting from their unique structures and physiochemical properties. This review elaborates recent significant advances of electrochemical studies based on pillararene systems. Fundamental electrochemical behavior of pillar[n]arene[m]quinone and pillararene-based self-assemblies as well as their applications in electrochemical biosensors are highlighted. In addition, the advantages and functions of pillararene self-assembly systems resulted from the unique molecular architectures are analyzed. Finally, current challenges and future development tendency in this burgeoning field are discussed from the viewpoint of both fundamental research and applications. Overall, this review not only manifests the main development vein of pillararene-based electrochemical systems, but also conquers a solid foundation for their further bioelectrochemical applications.

9.
Eur J Med Chem ; 215: 113276, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33611186

RESUMO

A series of novel amphiphilic paclitaxel (PTX) small molecule prodrugs, PTX-succinic anhydride-cystamine (PTX-Cys), PTX-dithiodipropionic anhydride (PTX-SS-COOH) and PTX-succinic anhydride-cystamine-valine (PTX-SS-Val) were designed, synthesized and evaluated against cancer cell lines. Compared with paclitaxel, these prodrugs contained water-soluble groups such as amino, carboxyl and amino acid, which improved the aqueous solubility of the prodrugs. More importantly, the valine was introduced in PTX-SS-Val molecule and made the molecule conform to the structural characteristics of intestinal oligopeptide transporter PEPT1 substrate. Thus the oral bioavailability of prodrug could be improved because of the mediation of PEPT1 transporter. These small molecule paclitaxel prodrugs could self-assemble into nanoparticles in aqueous solution, which effectively improved the solubility of paclitaxel, and had certain stability in pH 6.5, pH 7.4 buffer solutions and simulated gastrointestinal fluids. Some of these prodrugs, especially for PTX-Cys and PTX-SS-Val, exhibited nearly equal or slightly better anticancer activity when compared to paclitaxel. Further studies on PTX-Cys and PTX-SS-Val showed that both had good intestinal absorption in the rat single-pass intestinal perfusion (SPIP) experiments. Oral pharmacokinetic experiments showed that PTX-SS-Val could effectively improve the oral bioavailability of PTX.

10.
Angew Chem Int Ed Engl ; 60(16): 8938-8947, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33543529

RESUMO

Ferroptosis is a new form of regulated cell death that shows promise for tumor treatment. Most current ferroptosis tumor therapies are based on the intrinsic pathological features of the malignancies, and it would be of clinical significance to develop ferroptosis-inducing strategies with improved tumor specificity and modulability. Here we report a polydopamine-based nanoplatform (FeII PDA@LAP-PEG-cRGD) for the efficient loading of Fe2+ and ß-lapachone (LAP), which could readily initiate ferroptosis in tumor cells upon treatment with near-infrared light. PDA nanostructures could generate mild hyperthermia under NIR irritation and trigger the release of the ferroptosis-inducing Fe2+ ions. The NIR-actuated photothermal effect would also activate cellular heat shock response and upregulate the downstream NQO1 via HSP70/NQO1 axis to facilitate bioreduction of the concurrently released ß-lapachone and enhance intracellular H2 O2 formation to promote the Fe2+ -mediated lipid peroxidation.

11.
Nat Commun ; 12(1): 218, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431882

RESUMO

Development of organic theranostic agents that are active in the second near-infrared (NIR-II, 1000-1700 nm) biowindow is of vital significance for treating deep-seated tumors. However, studies on organic NIR-II absorbing agents for photo-to-heat energy-converting theranostics are still rare simply because of tedious synthetic routes to construct extended π systems in the NIR-II region. Herein, we design a convenient strategy to engineer highly stable organic NIR-II absorbing theranostic nanoparticles (Nano-BFF) for effective phototheranostic applications via co-assembling first NIR (NIR-I, 650-1000 nm) absorbing boron difluoride formazanate (BFF) dye with a biocompatible polymer, endowing the Nano-BFF with remarkable theranostic performance in the NIR-II region. In vitro and in vivo investigations validate that Nano-BFF can serve as an efficient theranostic agent to achieve photoacoustic imaging guided deep-tissue photonic hyperthermia in the NIR-II biowindow, achieving dramatic inhibition toward orthotopic hepatocellular carcinoma. This work thus provides an insight into the exploration of versatile organic NIR-II absorbing nanoparticles toward future practical applications.


Assuntos
Temperatura Alta , Raios Infravermelhos , Luz , Compostos Orgânicos/química , Nanomedicina Teranóstica , Animais , Linhagem Celular Tumoral , Formazans/administração & dosagem , Formazans/farmacocinética , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Neoplasias/terapia , Técnicas Fotoacústicas
12.
Hematology ; 26(1): 134-143, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33491597

RESUMO

Objective: The outcomes of alternative donor hematopoietic stem cell transplantation (HSCT) with unmanipulated grafts for Inherited bone marrow failure syndromes (IBMFS) are discouraging. Our study is to demonstrate that IBMFS with disease-specific characteristics requires a tailored conditioning regimens to enhance engraftment and reduce regimen related toxicities. Methods: We retrospectively analyzed 42 patients diagnosed with IBMFS and transplanted with an alternative donor graft at our center from November 2012 to August 2018. Twenty-seven patients had Fanconi anemia (FA), 7 had dyskeratosis congenita (DC), and 8 had severe congenital neutropenia (SCN). Patients received ex-vivo unmanipulated alternative donor grafts from a matched unrelated donor (MUD) (n = 22), haploidentical donor (HID) (n = 17) and unrelated cord blood donor (UCBD) (n = 3). FA and DC patient subgroups received reduce intensified conditioning (RIC), while SCN patients received a myeloablative conditioning (MAC) regimen. Results: The median follow-up time for the surviving patients was 38 months (range: 9-63 months). The failure-free survival (FFS) for entire cohort was 76.1%, and was 72.4%, 100% and 56.2% for patients with FA, DC and SCN, respectively. There were no primary graft failures. The cumulative incidence of aGVHD at day 100 was 48.1%. The cumulative incidence of cGVHD at 1 and 3 years was 35.0% and 69.3%, respectively. Conclusion: HSCT using alternative donors with unmanipulated grafts and disease-specific conditioning regimens for IBMFS patients shows promising survival.

13.
Cardiovasc Pathol ; 50: 107286, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32947039

RESUMO

BACKGROUND: Primary cardiac synovial sarcoma was an exceedingly rare tumor that less reported. The study investigated the clinicopathologic, immunohistochemical, and molecular features of primary cardiac synovial sarcoma. METHODS: A total of five cardiac synovial sarcoma cases were assessed and reviewed using H&E, immunohistochemical and fluorescence in situ hybridization staining methods. Clinicopathological data were retrospectively analyzed and followed up. RESULTS: The cases occurred in four males and one female ranging in age from 23 to 48 years (mean, 32 years). The tumors were grossly large and solid (7.4-13.7 cm; mean 8.6 cm). Microscopically, clinical cases were biphasic (n = 2) and monophasic (n = 3) types and were diffusely immunoreactive for EMA, vimentin, and BCL-2. All cases demonstrated SS18 rearrangement by fluorescence in situ hybridization staining. Clinically, three patients died within 1 year after surgery, while one patient had bone metastasis and still carried the disease. One last patient underwent a heart transplant and survived without evidence of the disease. CONCLUSION: Cardiac synovial sarcoma was an aggressive tumor whose differentiation may be a continuous and complex morphologic spectrum. SS18 rearrangement demonstration by fluorescence in situ hybridization was decisive in our study for differential diagnosis of cardiac synovial sarcoma and other tumors. Cardiac synovial sarcoma usually endured poor survival rates. Patients in advanced stages may undergo heart transplantation as a means of improving their survival rates.


Assuntos
Neoplasias Cardíacas , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Sarcoma Sinovial , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Feminino , Rearranjo Gênico , Predisposição Genética para Doença , Neoplasias Cardíacas/química , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/cirurgia , Transplante de Coração , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Estudos Retrospectivos , Sarcoma Sinovial/química , Sarcoma Sinovial/genética , Sarcoma Sinovial/secundário , Sarcoma Sinovial/cirurgia , Resultado do Tratamento , Adulto Jovem
14.
Cell Rep ; 33(10): 108487, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33296645

RESUMO

Ferroptosis is a recently discovered form of programed cell death caused by the metabolically regulated lipid peroxidation and holds promise for cancer treatment, but its regulatory mechanisms remain elusive. In this study, we observe that lactate-rich liver cancer cells exhibit enhanced resistance to the ferroptotic damage induced by common ferroptosis inducers such as Ras-selective lethal small molecule 3 (RSL3) and Erastin and that the monocarboxylate transporter 1 (MCT1)-mediated lactate uptake could promote ATP production in hepatocellular carcinoma (HCC) cells and deactivate the energy sensor AMP-activated protein kinase (AMPK), leading to the upregulation of sterol regulatory element-binding protein 1 (SREBP1) and the downstream stearoyl-coenzyme A (CoA) desaturase-1 (SCD1) to enhance the production of anti-ferroptosis monounsaturated fatty acids. Additionally, blocking the lactate uptake via hydroxycarboxylic acid receptor 1 (HCAR1)/MCT1 inhibition promotes ferroptosis by activating the AMPK to downregulate SCD1, which may synergize with its acyl-coenzyme A synthetase 4 (ACSL4)-promoting effect to amplify the ferroptotic susceptibility. In vitro and in vivo evidence confirms that lactate regulates the ferroptosis of HCC cells and highlights its translational potential as a therapeutic target for ferroptosis-based tumor treatment.

15.
Sensors (Basel) ; 20(23)2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33276491

RESUMO

Two types of configurations are theoretically proposed to achieve high responsivity polarization-insensitive waveguide Schottky photodetectors, i.e., a dual-layer structure for 1.55 µm and a single-layer structure for 2 µm wavelength band. Mode hybridization effects between quasi-TM modes and sab1 modes in plasmonic waveguides are first presented and further investigated under diverse metal types with different thicknesses in this work. By utilizing the mode hybridization effects between quasi-TE mode and aab0 mode, and also quasi-TM and sab1 mode in our proposed hybrid plasmonic waveguide, light absorption enhancement can be achieved under both TE and TM incidence within ultrathin and short metal stripes, thus resulting in a considerable responsivity for Si-based sub-bandgap photodetection. For 1.55 µm wavelength, the Au-6 nm-thick device can achieve absorptance of 99.6%/87.6% and responsivity of 138 mA·W-1/121.2 mA·W-1 under TE/TM incidence. Meanwhile, the Au-5 nm-thick device can achieve absorptance of 98.4%/90.2% and responsivity of 89 mA·W-1/81.7 mA·W-1 under TE/TM incidence in 2 µm wavelength band. The ultra-compact polarization-insensitive waveguide Schottky photodetectors may have promising applications in large scale all-Si photonic integrated circuits for high-speed optical communication.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33373196

RESUMO

It is a challenge to acquire, realize, and comprehend highly emissive phosphorescent molecules. Herein, we report that, using persulfurated benzene compounds as models, phosphorescence can be strongly enhanced through the modification of molecular conformation and crystal growth conditions. By varying the peripheral groups in these compounds, we were able to control their molecular conformation and crystal growth mode, leading to one- (1D), two- (2D), and three-dimensional (3D) crystal morphologies. Two kinds of typical molecular conformations were separately obtained in these crystals through substituent group control or the solvent effect. Importantly, a symmetrical 3,3-conformer exhibits that a planar central benzene ring prefers a 3D-type crystal growth mode, demonstrating high phosphorescence efficiency. Such outcome is attributed to the strong crystal protection effect of the 3D crystal and the bright global minimum (GM) boat-like T1 state of the symmetrical 3,3-conformer. The conformation studies further reveal small deformation of the inner benzene ring in both singlet and triplet states. The GM boat-like T1 state is indicated by theoretical calculations, which is far away from the conical intersection (CI) point between the S0 and T1 potential energy surfaces. Meanwhile, the small energy gap between S1 and T1 states and the considerable spin-orbit coupling matrix elements allow an efficient population of the T1 state. Combined with the crystal protection and conformation effect, the 3,3-conformer crystal shows high phosphorescence efficiency. The unsymmetrical 2,4-conformer conformation with the twisted central benzene ring leads to 1D or 2D crystal growth mode, which has a weak crystal protection effect. In addition, the unsymmetrical conformation has a dark GM T1 state that is very close to the T1-S0 CI point, implying an efficient nonradiative T1-S0 quenching. Thus, weak phosphorescence was observed from the unsymmetrical conformation. This study provides an insight for the development of highly emissive phosphorescent materials.

17.
J Dairy Sci ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33189285

RESUMO

Acetate is a short-chain fatty acid (SFA) that is the major substrate for de novo fatty acid synthesis. The mammalian target of rapamycin/eukaryotic initiation factor 4E (mTOR/eIF4E) signaling pathway is involved in fat synthesis. However, the effect and mechanism of acetate on fatty acid synthesis by the mTOR/eIF4E signaling pathway is unclear in bovine mammary epithelial cells (BMECs). The objectives of this study were to investigate the effect of acetate on cell viability, triacylglycerol (TG), and mRNA expression of the genes related to lipid synthesis. The mechanism of acetate regulation milk fat synthesis through the mTOR/eIF4E signaling pathway was assessed by blocking the mTOR signaling pathway and silencing eIF4E in BMECs. Third-passage BMECs were allocated to 6 treatments including 0, 4, 6, 8, 10, and 12 mM acetate to evaluate the effect of acetate on lipid synthesis; the optimum concentration in the first study was selected for the subsequent study. Subsequently, cells were randomly allocated to 4 treatments, 1 control group and 3 treated groups, consisting of acetate (6 mM), rapamycin (100 nM), and acetate + rapamycin to test the role of mTOR signaling pathway response to acetate in milk lipid synthesis. Finally, eIF4E was silenced by small interfering RNA (siRNA) to detect the role of eIF4E in milk lipid synthesis. Treatments included control, eIF4E siRNA, acetate (6 mM), and acetate+ eIF4E siRNA. Results showed that acetate increased TG accumulation and the relative expression of fatty acid synthase (FASN), acetyl-coenzyme A carboxylase α (ACACA), fatty acid-binding protein 3 (FABP3), sterol regulatory element binding protein 1 (SREBP1), peroxisome proliferator-activated receptor gamma (PPARG), mTOR, eIF4E, P70 ribosomal protein S6 kinase-1 (S6K1), and 4E-binding protein-1 (4EBP1) in a dose-dependent manner. Rapamycin effectively inhibited the positive effect of acetate on the relative expression of mTOR, eIF4E, S6K1, 4EBP1, FASN, ACACA, FABP3, stearoyl-CoA desaturase (SCD1), SREBP1, and PPARG. The upregulation of acetate on the relative expressions of FASN, ACACA, SCD1, and SREBP1 was suppressed when eIF4E was knocked down. It suggested that acetate regulated milk fat synthesis through mTOR/eIF4E signaling pathway in BMECs.

18.
Ann Hematol ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33236196

RESUMO

There are a limited number of studies comparing outcomes of busulfan (BU)-based myeloablative hematopoietic stem cell transplantation using unmanipulated haploidentical donors (HIDs), HLA-matched unrelated donors (MUDs), and HLA-matched sibling related donors (MSDs) in acute myeloid leukemia (AML) patients with complete remission (CR) status. With this background, we compared outcomes among 377 cases of CR following consecutive HID-HSCT for AML (CR) to 86 MUD and 92 MSD-HSCT cases. All patients received BU-based myeloablative conditioning and an unmanipulated graft within the same period. The median patient age was 23 years (range 1.1 to 65 years), and 230 patients (41.4%) were under age18. Among the 555 patients, 432 (77.8%) were of intermediate cytogenetic risk and 123 (22.2%) were of adverse risk. A total of 113 patients (20.5%) had FLT3-ITD+ AML, 425 patients (76.6%) were in first complete remission (CR1) post-transplant, and 130 (23.4%) patients were in second CR (CR2). GVHD prophylaxis included mycophenolate mofetil (MMF), cyclosporine-A (CSA) with short-term methotrexate (MTX) for HID, and MUD-HSCT. MMF is not used for MSD-HSCT. The median survival follow-up time was 42 months (range 18-91 months). The 3-year leukemia-free survival (LFS) among the HID, MUD, and MSD cohorts was 73.8% ± 4.8%, 66.4% ± 8.5%, 74.5% ± 2.4%, respectively (P = 0.637). Three-year overall survival (OS) was 74.9% ± 2.4%, 81.8% ± 4.3%, and 77.5% ± 4.5% among the HID, MUD, and MSD cohorts, respectively (P = 0.322). There were no difference among the relapse rate among the HID, MUD, and MSD donor cohorts (14.3% ± 4.0% vs 20.3% ± 6.4% vs 14.5% ± 2.2, respectively; P = 0.851) or the non-relapse mortality (NRM) (12.3% ± 3.5% vs 9.5% ± 3.2% vs 14.0% ± 1.8%, respectively; P = 0.441). Multivariate analyses showed that MRD-positive pre-HSCT was the only risk factor associated with a lower OS and LFS and higher risk of relapse among all 555 patients. Compared with the use of a MUD or MSD, an HID for HSCT had similar outcomes among AML patients with CR states who underwent an allo-HSCT with BU-based myeloablative conditioning. MFC-MRD-positive pre-HSCT was an independent negative factor impact on outcomes for AML patients in CR. We conclude that for AML patients who do not have a MSD or if an urgent transplant is required, HSCT from an HID is a valid option.

19.
Sci Adv ; 6(46)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33177081

RESUMO

Rationally regulating the reactivity of molecules or functional groups is common in organic chemistry, both in laboratory and industry synthesis. This concept can be applied to inorganic nanomaterials, particularly two-dimensional black phosphorus (BP) nanosheets. The high reactivity of few-layer (even monolayer) BP is expected to be "shut down" when not required and to be resumed upon application. Here, we demonstrate a protective chemistry-based methodology for regulating BP reactivity. The protective step initiates from binding Al3+ with lone pair electrons from P to decrease the electron density on the BP surface, and ends with an oxygen/water-resistant layer through the self-assembly of hydrophobic 1,2-benzenedithiol (BDT) on BP/Al3+ This protective step yields a stabilized BP with low reactivity. Deprotection of the obtained BP/Al3+/BDT is achieved by chelator treatment, which removes Al3+ and BDT from the BP surface. The deprotective process recovers the electron density of BP and thus restores the reactivity of BP.

20.
Ann Hematol ; 99(12): 2911-2925, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33000361

RESUMO

Prior studies have suggested that for leukemia patients with high-risk features, haplo-identical-hematopoietic stem cell transplantation (HID-HSCT) has a stronger anti-leukemia effect compared with HSCT using an identical sibling donor (ISD-HSCT). However, it is unclear whether an HID-HSC transplant also augments the graft-versus-leukemia (GVL) effect among refractory/relapsed (R/R) acute myeloid leukemia (AML) patients who are not in remission (NR). We conducted a retrospective analysis of 124 R/R AML patients with NR status who underwent HID-HSCT between April 2012 and December 2016 and compared these to 27 R/R AML patients who underwent an ISD-HSCT within the same timeframe. Among all of the patients, 68 (45.0%) had primary induction failure (PIF) and 83 (54.9%) were relapsed and had failed to respond to at least one cycle of salvage combination chemotherapy. Myeloablative conditioning regimens were administered to all patients. Here, we present a retrospective multivariate analysis of pre-transplantation risk factors and characteristics of all 151 patients and developed a predictive scoring system to predict patient survival. The median period of follow-up was 46 months for all patients. The HID cohort had a higher 5-year overall survival (OS) compared with the ISD cohort (48.6% ± 4.6% vs 25.9% ± 8.4, respectively; P = 0.017) and higher LFS (leukemia-free survival) (41.6% ± 7.5% vs 25.9% ± 8.4%, respectively; P = 0.019). There was no difference in the 5-year cumulative incidence of non-relapse mortality (NRM) (18.0% ± 3.8% and 34.9% ± 12.6%, respectively; P = 0.212) between the two group. However, the 5-year cumulative incidence of relapse (CIRs) was lower in the HID group compared with the ISD group (55.4% ± 8.9% vs 67.3% ± 9.9%, respectively; P = 0.021). Multivariate analysis showed three risk factors associated with OS and LFS: (1) ISD-HSCT, (2) use of a standardized conditioning regimen, and (3) less than 50% proportional reduction of blast cells in the bone marrow (BM). Based on these three risk factors, we developed a predictive scoring system for R/R AML patients undergoing HSCT. Patients who had a predictive score of 0 and 1 had a 66.6% ± 4.5% and 44.1% ± 3.6% OS rate at 5 years, respectively. Patients with a score ≥ 2 had only a 4.4 ± 0.2% OS rate at 5 years. An HID-HSCT had a better anti-leukemia effect among R/R AML patients with an NR status compared with an ISD-HSCT. We also identified pre-transplantation risk factors to delineate subgroups that could derive maximal benefit from HSCT.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...