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1.
Neurotherapeutics ; 2021 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-33830476

RESUMEN

Many adult and most childhood neurological diseases have a genetic basis. CRISPR/Cas9 biotechnology holds great promise in neurological therapy, pending the clearance of major delivery, efficiency, and specificity hurdles. We applied CRISPR/Cas9 genome editing in its simplest modality, namely inducing gene sequence disruption, to one adult and one pediatric disease. Adult polyglucosan body disease is a neurodegenerative disease resembling amyotrophic lateral sclerosis. Lafora disease is a severe late childhood onset progressive myoclonus epilepsy. The pathogenic insult in both is formation in the brain of glycogen with overlong branches, which precipitates and accumulates into polyglucosan bodies that drive neuroinflammation and neurodegeneration. We packaged Staphylococcus aureus Cas9 and a guide RNA targeting the glycogen synthase gene, Gys1, responsible for brain glycogen branch elongation in AAV9 virus, which we delivered by neonatal intracerebroventricular injection to one mouse model of adult polyglucosan body disease and two mouse models of Lafora disease. This resulted, in all three models, in editing of approximately 17% of Gys1 alleles and a similar extent of reduction of Gys1 mRNA across the brain. The latter led to approximately 50% reductions of GYS1 protein, abnormal glycogen accumulation, and polyglucosan bodies, as well as ameliorations of neuroinflammatory markers in all three models. Our work represents proof of principle for virally delivered CRISPR/Cas9 neurotherapeutics in an adult-onset (adult polyglucosan body) and a childhood-onset (Lafora) neurological diseases.

2.
Neoplasma ; 2021 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-33847134

RESUMEN

Many studies have verified the safety of combined radiotherapy and immune checkpoint blockades (ICBs) without the specific radiation dose or sequencing of combination. We aimed to evaluate the expression and response of PD-1, TIM-3, LAG-3 after neoadjuvant radiotherapy (NRT) and explore the possibility and optimal schedule of combining immunotherapy with radiotherapy in treating rectal cancer. Immunohistochemistry was performed to detect the expression of PD-1, TIM-3, LAG-3, CD8, and CD3. These molecules' expression was detected on the specimens of 76 rectal cancer patients following NRT and 13 of these patients before NRT. The expression of ICBs was assessed by the percentage of positive cells. The levels of PD-1 and immune cells (ICs) LAG-3 in rectal cancer increased after NRT (0% vs. 3%, P = 0.043 and 5% vs. 45%, P = 0.039, respectively). However, TIM-3 in ICs and tumor cells (TCs) were both decreased (80% vs. 50%, P = 0.011, 90% vs. 0%, P = 0.000, respectively). The LAG-3 expression was higher in patients treated with short-course RT than long-course RT (22.5% vs. 8.0%, P = 0.0440 in ICs; 0% vs. 70%, P < 0.001 in TCs). On the contrary, CD8 was higher after long-course RT (15% vs. 8%, P = 0.0146). Interestingly, the level of ICs TIM-3 was low in > eight weeks after long-course RT (P = 0.045). The expressions of PD-1, ICs TIM-3, ICs LAG-3, CD3, and CD8 were associated with the disease-free survival (DFS) in univariate analysis (P = 0.036, 0.008, 0.018, 0.025, and 0.004, respectively). Adjusted by the relevant variables, PD-1 (HR 0.274; 95% CI 0.089-0.840; P = 0.024) and ICs TIM-3 (HR 0.425; 95% CI 0.203-0.890; P = 0.023) were independent prognostic factors of DFS in rectal cancer patients following NRT. In conclusion, we have identified that PD-1 and ICs LAG-3 presented a trend towards increased expression after NRT, supporting the ICBs and NRT combination as a potential treatment option for local advanced rectal cancer patients. The radiotherapeutic mode and timing of the treatment might significantly affect the expression of ICBs, which indicated that the sequencing and time window of ICBs immunotherapy utility might deserve a high value.

3.
Chemosphere ; 278: 130508, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33839383

RESUMEN

The large scale lignocellulosic biomass wastes could also be regarded as abundantly-available renewable resources, and how to convert them into value-added products via sustainable approaches is still a big challenge. In this work, we demonstrated a facile pyrolysis method to construct N, P-dually doped biochar materials from the lignocellulosic biomass wastes. The as-synthesized N, P-dually doped biochar samples could act as electrocatalysts for oxygen reduction and evolution reactions (ORR/OER), showing excellent catalytic performance and long-term durability, as well as robust tolerance to CO and methanol. The unique hierarchical porous structure, favorable electronic structure modified by the N and P doping, as well as a variety of defect sites induced by the N and P doping into the carbon framework were identified as the main contributions to the prominent catalytic activity of the as-synthesized N, P-dually doped biochar materials. We expect this work would spur more efforts into developing advanced materials from the large scale lignocellulosic biomass wastes.

4.
Environ Sci Technol ; 2021 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-33843193

RESUMEN

The application of nanosized zerovalent iron (nZVI) for reductive immobilization of selenite (Se(IV)) or selenate (Se(VI)) alone has been extensively investigated. However, as the predominant species, Se(IV) and Se(VI) usually coexist in the environment. Thus, it is essential to remove both species simultaneously in the solution by nZVI. Negligible Se(VI) removal (∼7%) by nZVI was observed in the absence of Se(IV). In contrast, the Se(VI) was completely removed in the presence of Se(IV), and the removal rate and electron selectivity of Se(VI) increased from 0.12 ± 0.01 to 0.29 ± 0.02 h-1 and from 1% to 4.5%, respectively, as the Se(IV) concentration increased from 0.05 to 0.20 mM. Se(IV) was rapidly removed by nZVI, and Se(VI) exerted minor influence on Se(IV) removal. Se(IV) promoted the generation of corrosion products that were mainly composed of magnetite (26%) and lepidocrocite (67%) based on the Fe K-edge XANES spectra and k3-weighted EXAFS analysis. Fe(II) released during the Se(IV) reduction was not the main reductant for Se(VI) but accelerated the transformation of F(0) to magnetite and lepidocrocite. The formation of lepidocrocite contributed to the enrichment of Se(VI) on the nZVI surface, and magnetite promoted electron transfer from Fe(0) to Se(VI). This study demonstrated that Se(IV) acted as an oxidant to activate nZVI, thus improving the reactivity of nZVI toward Se(VI), which displays a potential application of nZVI in the remediation of Se(IV)- and Se(VI)-containing water.

5.
IEEE Trans Image Process ; 30: 4212-4224, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33822724

RESUMEN

Person re-identification (re-id) suffers from the significant challenge of occlusion, where an image contains occlusions and less discriminative pedestrian information. However, certain work consistently attempts to design complex modules to capture implicit information (including human pose landmarks, mask maps, and spatial information). The network, consequently, focuses on discriminative features learning on human non-occluded body regions and realizes effective matching under spatial misalignment. Few studies have focused on data augmentation, given that existing single-based data augmentation methods bring limited performance improvement. To address the occlusion problem, we propose a novel Incremental Generative Occlusion Adversarial Suppression (IGOAS) network. It consists of 1) an incremental generative occlusion block, generating easy-to-hard occlusion data, that makes the network more robust to occlusion by gradually learning harder occlusion instead of hardest occlusion directly. And 2) a global-adversarial suppression (G&A) framework with a global branch and an adversarial suppression branch. The global branch extracts steady global features of the images. The adversarial suppression branch, embedded with two occlusion suppression module, minimizes the generated occlusion's response and strengthens attentive feature representation on human non-occluded body regions. Finally, we get a more discriminative pedestrian feature descriptor by concatenating two branches' features, which is robust to the occlusion problem. The experiments on the occluded dataset show the competitive performance of IGOAS. On Occluded-DukeMTMC, it achieves 60.1% Rank-1 accuracy and 49.4% mAP.

6.
Leukemia ; 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33824464

RESUMEN

Although chimeric antigen receptor T-cell (CAR-T) therapy produces a high complete remission rate among patients with relapsed/refractory B-cell acute lymphoblastic leukemia, relapse remains an urgent issue. It is uncertain whether consolidative haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) is suitable for achieving sustainable remission. Therefore, we aimed to assess the efficacy and safety of bridging CAR-T therapy to haplo-HSCT. Fifty-two patients with relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who underwent haplo-HSCT after CAR-T therapy were analyzed. The median time from CAR-T therapy to haplo-HSCT was 61 days. After a median follow-up of 24.6 months, the 1-year probabilities of event-free survival, overall survival, and cumulative incidence of relapse were 80.1% (95% confidence interval (CI), 69.0-90.9), 92.3% (95% CI, 85.0-99.5), and 14.1% (95% CI, 10.7-17.4), respectively, while the corresponding 2-year probabilities were 76.0% (95% CI, 64.2-87.7), 84.3% (95% CI, 74.3-94.3), and 19.7% (95% CI, 15.3-24.0), respectively. No increased risk of 2-year cumulative incidence of graft-versus-host disease, treatment-related mortality, or infection was observed. A pre-HSCT measurable residual disease-positive status was an independent factor associated with poor overall survival (hazard radio: 4.201, 95% CI: 1.034-17.063; P = 0.045). Haplo-HSCT may be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.

7.
Artículo en Inglés | MEDLINE | ID: mdl-33797717

RESUMEN

Microbiome plays an important role in evaluating soil quality for sustainable agriculture. However, the suitability of biological indicators in reclaimed farmland is less understood. Using high-throughput sequencing, we evaluated the soil microbial community of the newly created farmland (NF) after reclamation with two local high-yield farmlands (slope farmland (SF), check-dam farmland (CF)) on the Loess Plateau. Soil enzyme activities and the amount of culturable microorganism were also quantified to assess the soil quality. Results showed that the microbial diversity, cultural microorganism abundance, and soil enzyme activities indicated poor soil quality in NF. The dominant bacterial phyla were Proteobacteria, Bacteroidetes, Acidobacteria, and Cyanobacteria. The abundance of Acidobacteria was significantly lower in NF (13.31%) than in SF (27.25%) and CF (27.91%). Soil enzyme activities had a significant correlation with the abundance of culturable microorganism, Proteobacteria and Bacteroidetes, soil organic matter, total nitrogen, cation exchange capacity, and pH, suggesting that soil microbes have driven the formation of nutrition and further mediated crop growth. Therefore, the application of bacterial fertilizers could be a potential way to improve the soil quality of reclaimed farmland for crop growth.

8.
Chemosphere ; 278: 130410, 2021 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-33819880

RESUMEN

Two types of continuous stirred tank moving bed biofilm reactors (ST-MBBR) and plug flow MBBR (PF-MBBR) were compared for nitrification. PF-MBBR showed strong shock resistance to temperature, and ammonium oxidation ratio (AOR) was 9.63% higher than that in the ST-MBBR, although the average biomass and biofilm thickness of ST-MBBR were 7.32-18.59%, 9.44-14.06% higher than those in the PF-MBBR. Meanwhile, a lower nitrite accumulation ratio (NAR) was observed (54.88%) in the PF-MBBR than the ST-MBBR (78.92%) due to different operation modes, and the divergence was demonstrated by the microbial quantitative analysis. Nitrification kinetics revealed that the temperature coefficient (θ) in the ST-MBBR (1.068) was much higher than that in the PF-MBBR (1.006-1.015), proving the contrasting nitrification performances caused by temperature shock. According to the Monod equation, the half-saturation coefficient (KN) in the ST-MBBR was 0.19 mg/L while it varied around 0.12-0.24 mg/L in the PF-MBBR, revealing various NH4+ affinity owing to different biofilm thickness and microbial composition. Finally, MBBR optimization related to operation mode, temperature, and free ammonium (FA) inhibition for nitrite accumulation was discussed.

9.
Artículo en Inglés | MEDLINE | ID: mdl-33829657

RESUMEN

BACKGROUND AND AIMS: Endoscopic radiofrequency ablation (RFA) is an emerging technique for the palliation of inoperable malignant biliary strictures (MBSs). We aimed to systemically investigate the long-term outcome of RFA in a large cohort of patients. METHODS: We recruited 883 patients with various MBSs who underwent endoscopic interventions at two large-volume centers; 124 patients underwent RFA and stenting, whereas 759 underwent stenting alone. To overcome selection bias, we performed 1:4 propensity score matching (PSM). The main outcome was overall survival (OS). RESULTS: Following PSM, patients in the RFA group showed significantly longer OS (9.5 months; 95% CI: 7.7-11.3 months) than those in the stenting alone group (6.1 months; 95% CI: 5.6-6.6 months; P<0.001). In stratified analyses, the improved OS was only demonstrated in the subgroup of extrahepatic cholangiocarcinoma (11.3 months (95% CI: 10.2-12.4) vs. 6.9 months (95% CI: 6.0-7.8); P<0.001), but not in the subgroups of gallbladder cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, pancreatic cancer, and other metastatic cancers (all P>0.05). The survival benefits were noted only in the patients with non-metastatic cholangiocarcinoma (11.5 vs. 7.4 months, P<0.001). CONCLUSIONS: The survival benefits of endoscopic RFA appear to be limited to patients with extrahepatic cholangiocarcinoma without distant metastasis.

10.
Medicine (Baltimore) ; 100(14): e24775, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832066

RESUMEN

BACKGROUND: The new emerging application of decompression combined with fusion comes with a concern of cost performance, however, it is a lack of big data support. We aimed to evaluate the necessity or not of the addition of fusion for decompression in patients with lumbar degenerative spondylolisthesis. METHODS: Potential studies were selected from PubMed, Web of Science, and Cochrane Library, and gray relevant studies were manually searched. We set the searching time spanning from the creating date of electronic engines to August 2020. STATA version 11.0 was exerted to process the pooled data. RESULTS: Six RCTs were included in this study. A total of 650 patients were divided into 275 in the decompression group and 375 in the fusion group. No statistic differences were found in the visual analog scales (VAS) score for low back pain (weighted mean difference [WMD], -0.045; 95% confidence interval [CI], -1.259-1.169; P = .942) and leg pain (WMD, 0.075; 95% CI, -1.201-1.35; P = .908), Oswestry Disability Index (ODI) score (WMD, 1.489; 95% CI, -7.232-10.211; P = .738), European Quality of Life-5 Dimensions (EQ-5D) score (WMD, 0.03; 95% CI, -0.05-0.12; P = .43), Odom classification (OR, 0.353; 95% CI 0.113-1.099; P = .072), postoperative complications (OR, 0.437; 95% CI, 0.065-2.949; P = .395), secondary operation (OR, 2.541; 95% CI 0.897-7.198; P = .079), and postoperative degenerative spondylolisthesis (OR = 8.59, P = .27). Subgroup analysis of VAS score on low back pain (OR = 0.77, 95% CI, 0.36-1.65; P = .50) was demonstrated as no significant difference as well. CONCLUSION: The overall efficacy of the decompression combined with fusion is not revealed to be superior to decompression alone. At the same time, more evidence-based performance is needed to supplement this opinion.

11.
Sci Adv ; 7(14)2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33811079

RESUMEN

Proper immune responses are critical for successful biomaterial implantation. Here, four scales of honeycomb-like TiO2 structures were custom made on titanium (Ti) substrates to investigate cellular behaviors of RAW 264.7 macrophages and their immunomodulation on osteogenesis. We found that the reduced scale of honeycomb-like TiO2 structures could significantly activate the anti-inflammatory macrophage phenotype (M2), in which the 90-nanometer sample induced the highest expression level of CD206, interleukin-4, and interleukin-10 and released the highest amount of bone morphogenetic protein-2 among other scales. Afterward, the resulting immune microenvironment favorably triggered osteogenic differentiation of murine mesenchymal stem cells in vitro and subsequent implant-to-bone osteointegration in vivo. Furthermore, transcriptomic analysis revealed that the minimal scale of TiO2 honeycomb-like structure (90 nanometers) facilitated macrophage filopodia formation and up-regulated the Rho family of guanosine triphosphatases (RhoA, Rac1, and CDC42), which reinforced the polarization of macrophages through the activation of the RhoA/Rho-associated protein kinase signaling pathway.

12.
Liver Int ; 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33794040

RESUMEN

BACKGROUND & AIMS: During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB). METHODS: 80 CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes. RESULTS: Compared to the healthy controls, a reshaping of NK cell pool towards more CD56bright NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/ml) displayed an activated phenotype with increased expression of activation makers CD38, Granzyme B and proliferation marker Ki-67 while presenting with defective functional responses (MIP-1ß, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age. CONCLUSIONS: The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance.

13.
Theranostics ; 11(8): 3710-3724, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664857

RESUMEN

Nanoparticle drug delivery system (NDDS) is quite different from the widely studied traditional chemotherapy which suffers from drug resistance and side effect. NDDS offers the straightforward solution to the chemotherapy problem and provides an opportunity to monitor the drug delivery process in real time. In this vein, we developed one NDDS, namely Py-TPE/siRNA@PMP, to relieve resistance and side effects during chemotherapy against ovarian cancer. The Py-TPE/siRNA@PMP is a multifunctional polymeric nanoparticle contained several parts as follows: (1) a nanoparticle (NP) self-assembled by reduction-sensitive paclitaxel polymeric prodrug (PMP); (2) the glutathione (GSH)-responsive release of paclitaxel (PTX) for the suppression of ovarian cancer cells; (3) the P-glycoprotein (P-gp) siRNA for restoring the sensitivity of chemo-resistant tumor cells to chemotherapy; (4) the positively charged aggregation-induced emission fluorogen (AIEgen) Py-TPE for tumor imaging and promoting encapsulation of siRNA into the nanoparticle. Methods: The Py-TPE/siRNA@PMP nanoparticles were prepared by self-assembly method and characterized by the UV-Vis absorption spectra, zeta potentials, TEM image, stability assay and hydrodynamic size distributions. The combinational therapeutic effects of Py-TPE/siRNA@PMP on overcoming chemotherapy resistance were explored both in vitro and in vivo. Result: The Py-TPE/siRNA@PMP exhibited an average hydrodynamic size with a good stability. Meanwhile they gave rise to the remarkable chemotoxicity performances in vitro and suppressed the tumors growth in both SKOV-3/PTX (PTX resistance) subcutaneous and intraperitoneal metastasis tumor models. The investigations on ovarian cancer patient-derived xenografts (PDX) model revealed that Py-TPE/siRNA@PMP was able to effectively overcome their chemo-resistance with minimal side effects. Conclusion: Our findings demonstrated the Py-TPE/siRNA@PMP as a promising agent for the highly efficient treatment of PTX-resistant cells and overcoming the shortage of chemotherapy in ovarian cancer.

14.
Theranostics ; 11(8): 3948-3960, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33664872

RESUMEN

Background: Pacemaker implantation is currently used in patients with symptomatic bradycardia. Since a pacemaker is a lifetime therapeutic device, its energy consumption contributes to battery exhaustion, along with its voltage stimulation resulting in local fibrosis and greater resistance, which are all detrimental to patients. The possible resolution for those clinical issues is an injection of a conductive hydrogel, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), to reduce the myocardial threshold voltage for pacemaker stimulation. Methods: PAMB-G is synthesized by covalently linking PAMB to gelatin, and its conductivity is measured using two-point resistivity. Rat hearts are injected with gelatin or PAMB-G, and pacing threshold is evaluated using electrocardiogram and cardiac optical mapping. Results: PAMB-G conductivity is 13 times greater than in gelatin. The ex vivo model shows that PAMB-G significantly enhances cardiac tissue stimulation. Injection of PAMB-G into the stimulating electrode location at the myocardium has a 4 times greater reduction of pacing threshold voltage, compared with electrode-only or gelatin-injected tissues. Multi-electrode array mapping reveals that the cardiac conduction velocity of PAMB-G group is significantly faster than the non- or gelatin-injection groups. PAMB-G also reduces pacing threshold voltage in an adenosine-induced atrial-ventricular block rat model. Conclusion: PAMB-G hydrogel reduces cardiac pacing threshold voltage, which is able to enhance pacemaker efficacy.

15.
PLoS One ; 16(3): e0249356, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33770149

RESUMEN

Aloe vera has been widely used in health and nutritional supplements in Chinese herbal medicine. Furthermore, Aloe vera production has been an emerging industry for making cosmetics and functional food. However, the reported adverse effects raised questions as to whether Aloe vera and its products were safe enough to be used in medicine and health care. In view of this, the safety evaluation of Aloe vera products before marketing is very important. The present study aimed to assess the toxicological profile of Aloe vera soft capsule (ASC), through acute, subacute toxicity and genotoxicity tests. Male and female ICR mice were received by oral gavage 15000 mg/kg bodyweight of ASC in the acute toxicity test. Male and female SD rats were fed on diet blended with different doses of ASC (equivalent to 832.5, 1665 and 3330 mg/kg bodyweight of ASC) for the subacute toxicity test. In the acute toxicity study, no mortality or behavioral changes were observed, indicating the LD50 was higher than 15000 mg/kg bodyweight. In the subacute toxicity test, no significant changes were observed in bodyweight, food consumption, hematological, biochemical or histopathological parameters in the rats exposed. These data suggested that ASC used in this study did not produce any marked subacute toxic effects up to a maximum concentration of 3330 mg/kg bodyweight. In the genotoxicity study, ASC showed no mutagenic activity in the Ames test and no evidence of potential to induce bone marrow micronucleus or testicular chromosome aberrations in ICR mice exposed to 10000 mg/kg bodyweight. Collectively, ASC could be considered safe before it was marketed as a laxative and moistening health food.

16.
ACS Biomater Sci Eng ; 7(4): 1640-1650, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33719394

RESUMEN

Head and neck squamous cell carcinomas (HNSCCs) are one of the most common cancers with poor survival rates, which is attributed to the difficulty in the early detection of disease. However, conventional imaging methods lack accuracy and sensitivity in the early diagnosis of HNSCCs. Thus, there is an urgent need to develop an effective and sensitive approach for HNSCC imaging. As known, the cMet receptor is overexpressed in HNSCC tumor cells CAL27 and tumor tissues. Herein, we synthesize the dual-modal near-infrared II (NIR II) imaging of luminescence and T1 magnetic resonance imaging (MRI)-based nanoprobes with the cMet targeting binding peptide (NaGdF4-PEG-cMBP), which has strong upconversion/NIR II luminescence and higher R1 relaxivity compared with the commercially used gadolinium acid (5.871 vs 3.471 mM-1 s-1). Additionally, the luminescence imaging of Yb,Er,Ce-doped probes showed that the material can efficiently accumulate in HNSCC tumors with the cMet-targeted. It can be clearly visualized in both subcutaneous and orthotopic HNSCC tumor models by dual-modal T1-weighted MRI and NIR II luminescence imaging methods. The results demonstrate that our cMBP-conjugated nanoplatform may provide a novel and very efficient noninvasive diagnostic approach for HNSCC in the near future.

17.
Int J Nanomedicine ; 16: 1361-1376, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33658777

RESUMEN

Object: High targeting and efficient cytotoxicity toward tumor cells endow NPs excellent anti-tumor activity. Herein, a peptide polymer possessing dual-targeting ability and double therapeutic activity was developed and named TGMF, which can form NPs through self-assembly. It is composed of four functional modules: 1) Active targeting peptide TMTP1 (T) deliver NPs to tumors specifically; 2) Therapeutic peptide GO-203 (G), which can significantly inhibit tumor growth by disrupting the redox balance in cells; 3) A passively targeted enzyme-responsive peptide PLGLGA (M), which can be cleaved specifically by metalloproteinase-2 (MMP-2) highly expressed in the tumor microenvironment (TME); and 4) Hexadecyl (F), which has strong hydrophobicity, can promote the self-assembly of TGMF NPs. Methods: Five modular peptide probes, namely, TGF, TMF, TGM, GMF, and TGMF were synthesized and self-assembled into NPs in solution. The characterization, enzyme reactivity, and cytotoxicity of NPs were evaluated in vitro, and the pharmacokinetics, bio-distribution, anti-tumor activity of NPs were investigated in vivo. In addition, transcriptome sequencing identified the intracellular signaling pathway-related genes involved in the anti-tumor effect of TGMF. Results: Upon enzyme cleavage, two types of nanostructure, NPs and nanofibers (NFs), were detected under TEM. Moreover, the cytotoxicity and anti-invasion activity of TGMF against tumor cells used were strongest among the five modular probes examined in vitro. TGMF increased reactive oxygen species (ROS) levels in cytoplasm and produced numerous NFs in extracellular interval and intracellular space. Transcriptome sequencing revealed that TGMF caused 446 genes' down-regulation and 270 genes' up-regulation in HeLa cells. In vivo, TGMF has a good anti-tumor effect, effectively prolonging the survival time of HeLa-tumor-bearing mice without systemic side effects. Conclusion: Integration of multiple functional modules into NPs could be a promising strategy for the future of nanomedicine design towards tumor treatment.


Asunto(s)
Antineoplásicos/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Femenino , Células HeLa , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Nanofibras/química , Nanofibras/ultraestructura , Nanopartículas/ultraestructura , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias/genética , Péptidos/química , Polímeros/química , Análisis de Componente Principal , Especies Reactivas de Oxígeno/metabolismo , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Microambiente Tumoral/efectos de los fármacos
18.
Ecotoxicol Environ Saf ; 214: 112112, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33714140

RESUMEN

Sole biochar addition or microbial inoculation as a soil amendment helps to reduce cadmium (Cd) toxicity in polluted agricultural soils. Yet the synergistic effects of microorganisms and biochar application on Cd absorption and plant productivity remain unclear. Therefore, a pot experiment was conducted to investigate the combined effect of microorganisms (Trichoderma harzianum L. and Bacillus subtilis L.), biochar (maize straw, cow manure, and poultry manure), and Cd (0, 10, and 30 ppm) on plant physiology and growth to test how biochar influences microbial growth and plant nutrient uptake, and how biochar ameliorates under Cd-stressed soil. Results showed that in comparison to non-Cd polluted soil, the highest reduction in chlorophyll content, photosynthetic rate, transpiration rate, stomatal conductance, water use efficiency, and intercellular CO2 were observed in Cd2 (30 ppm), which were 9.34%, 22.95%, 40.45%, 29.07%, 20.67%, and 22.55% respectively less than the control Cd0 (0 ppm). Among sole inoculation of microorganisms, highest stomatal conductance, water use efficiency, and intercellular CO2 were recorded with combined inoculation of both microorganisms (M3), which were 5.92%, 7.65%, and 7.28% respectively higher than the control, and reduced the Cd concentration in soil, root, and shoot by 21.34%, 28.36%, and 20.95%, respectively, compared to the control. Similarly, co-application of microorganisms and biochar ameliorated the adverse effect of Cd in soybean as well as significantly improved plant biomass, photosynthetic activity, nutrient contents, and antioxidant enzyme activities, and minimized the production of reactive oxygen species and Cd content in plants. Soil amended with poultry manure biochar had significantly improved the soil organic carbon, total nitrogen, total phosphorous, and available potassium by 43.53%, 36.97%, 22.28%, and 4.24%, respectively, and decreased the concentration of Cd in plant root and shoot by 34.68% and 47.96%, respectively, compared to the control. These findings indicate that the combined use of microorganisms and biochar as an amendment have important synergistic effects not only on the absorption of nutrients but also on the reduction of soybean Cd intake, and improve plant physiology of soybean cultivated in Cd-polluted soils as compared to sole application of microorganisms or biochar.


Asunto(s)
Bacillus subtilis , Cadmio/análisis , Carbón Orgánico , Hypocreales , Contaminantes del Suelo/análisis , Soja/crecimiento & desarrollo , Soja/metabolismo , Cadmio/metabolismo , Estiércol , Nitrógeno/metabolismo , Fósforo/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Brotes de la Planta/crecimiento & desarrollo , Brotes de la Planta/metabolismo , Potasio/metabolismo , Contaminantes del Suelo/metabolismo , Zea mays
19.
Nat Commun ; 12(1): 1813, 2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753738

RESUMEN

Long-term antibody responses and neutralizing activities in response to SARS-CoV-2 infection are not yet clear. Here we quantify immunoglobulin M (IgM) and G (IgG) antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) of the spike (S) or the nucleocapsid (N) protein, and neutralizing antibodies during a period of 6 months from COVID-19 disease onset in 349 symptomatic COVID-19 patients who were among the first be infected world-wide. The positivity rate and magnitude of IgM-S and IgG-N responses increase rapidly. High levels of IgM-S/N and IgG-S/N at 2-3 weeks after disease onset are associated with virus control and IgG-S titers correlate closely with the capacity to neutralize SARS-CoV-2. Although specific IgM-S/N become undetectable 12 weeks after disease onset in most patients, IgG-S/N titers have an intermediate contraction phase, but stabilize at relatively high levels over the 6 month observation period. At late time points, the positivity rates for binding and neutralizing SARS-CoV-2-specific antibodies are still >70%. These data indicate sustained humoral immunity in recovered patients who had symptomatic COVID-19, suggesting prolonged immunity.


Asunto(s)
/inmunología , /inmunología , Adulto , Anciano , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Femenino , Humanos , Inmunidad Humoral/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus
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