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1.
Front Physiol ; 12: 731762, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630148

RESUMO

Objectives: To evaluate the effect of extreme weight loss programs on circulating metabolites and their relationship with cardiometabolic health in children with metabolic syndrome. Methods: This study was a quasi-experimental design with a pretest and post-test. Thirty children with metabolic syndrome and aged 10-17years were recruited to an extreme weight loss program (i.e., exercise combined with diet control). The primary outcomes included plasma metabolites, body composition, and cardiometabolic risk factors. A total of 324 metabolites were quantitatively detected by an ultra-performance liquid chromatography coupled to tandem mass spectrometry system, and the variable importance in the projection (VIP) value of each metabolite was calculated by the orthogonal projection to latent structures discriminant analysis. The fold change (FC) and p value of each metabolite were used to screen differential metabolites with the following values: VIP>1, p value<0.05, and |log2FC|>0.25. Pathway enrichment and correlation analyses between metabolites and cardiometabolic risk factors were also performed. Result: A large effect size was observed, presenting a weight loss of -8.9kg (Cohen's d=1.00, p<0.001), body mass index reduction of -3.3kg/m2 (Cohen's d=1.47, p<0.001), and body fat percent reduction of -4.1 (%) (Cohen's d=1.22, p<0.001) after the intervention. Similar improvements were found in total cholesterol (Cohen's d=2.65, p<0.001), triglycerides (Cohen's d=2.59, p<0.001), low-density lipoprotein cholesterol (Cohen's d=2.81, p<0.001), glucose metabolism, and blood pressure. A total of 59 metabolites were changed after the intervention (e.g., aminoacyl-tRNA biosynthesis, glycine, serine, and threonine metabolism; nitrogen metabolism, tricarboxylic acid cycle, and phenylalanine, tyrosine, and tryptophan biosynthesis). The changes in metabolites (e.g., amino acids, fatty acids, organic acids, and carnitine) were related to lipid metabolism improvement (p<0.05). Organic acids and carnitines were associated with changes in the body composition (p<0.05). Conclusion: Exercise combined with dietary control improved the body composition and cardiometabolic health in children with metabolic syndrome, and these changes may be related to plasma metabolites.

2.
Front Endocrinol (Lausanne) ; 12: 736906, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603212

RESUMO

Female moths use sex pheromones to attract males, and corresponding regulatory mechanism underlying sex pheromone biosynthesis is species-dependent. However, the detailed mechanism involved in sex pheromone biosynthesis in Ostrinia furnacalis has not yet been fully addressed. In the present study, transcriptome sequencing of O. furnacalis pheromone glands screened a serials of candidate genes involved in sex pheromone biosynthesis. Our analysis showed that sex pheromone release in O. furnacalis females arrives its peak at the 2nd scotophase, consistent with its mating behavior. Pheromone biosynthesis-activating neuropeptide (PBAN) was confirmed to regulate sex pheromone biosynthesis, and Ca2+ is the secondary messenger of PBAN signaling in O. furnacalis. The functional analysis of candidate genes demonstrated that the decreased mRNA levels or activities of calcineurin (CaN) and acetyl-CoA carboxylase (ACC) led to significant decrease in sex pheromone production and female capability to attract males, as demonstrated by RNAi-mediated knockdown and pharmacological inhibitor assay. Most importantly, the activities of CaN and ACC depend on the activation of PBAN/PBANR/Ca2+. Furthermore, fatty-acyl reductase 14 was involved in PBAN-mediated sex pheromone biosynthesis. Altogether, our results demonstrated that PBAN regulates sex pheromone biosynthesis through PBANR/Ca2+/CaN/ACC pathway to promote sex pheromone biosynthesis in O. furnacalis and provided a reference for non-model organism to study neuropeptide signal transduction.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34615452

RESUMO

Hepatic disease negatively impacts liver function and metabolism. Primary human hepatocytes are the gold standard for the prediction and successful treatment of liver disease. However, the sources of hepatocytes for drug toxicity testing and disease modeling are limited. To overcome this issue, pluripotent stem cells (PSCs) have emerged as an alternative strategy for liver disease therapy. Human PSCs, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) can self-renew and give rise to all cells of the body. Human PSCs are attractive cell sources for regenerative medicine, tissue engineering, drug discovery, and developmental studies. Several recent studies have shown that mesenchymal stem cells (MSCs) can also differentiate (or trans-differentiate) into hepatocytes. Differentiation of human PSCs and MSCs into functional hepatocyte-like cells (HLCs) opens new strategies to study genetic diseases, hepatotoxicity, infection of hepatotropic viruses, and analyze hepatic biology. Numerous in vitro and in vivo differentiation protocols have been established to obtain human PSCs/MSCs-derived HLCs and mimic their characteristics. It was recently discovered that microRNAs (miRNAs) play a critical role in controlling the ectopic expression of transcription factors and governing the hepatocyte differentiation of human PSCs and MSCs. In this review, we focused on the role of miRNAs in the differentiation of human PSCs and MSCs into hepatocytes.

4.
Chin Med J (Engl) ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34653079

RESUMO

BACKGROUND: Finding an optimal treatment strategy for adolescent idiopathic scoliosis (AIS) patients remains challenging because of its intrinsic complexity. For mild to moderate scoliosis patients with lower skeletal growth potential (Risser 3-5), most clinicians agree with observation treatment; however, the curve progression that occurs during puberty, the adolescent period, and even in adulthood, remains a challenging issue for clinicians. The aim of the study is to investigate the efficacy of Schroth exercise in AIS patients with lower skeletal growth potential (Risser 3-5) and moderate scoliosis (Cobb angle 20°-40°). METHODS: From 2015 to 2017, data of 64 patients diagnosed with AIS in Peking University Third Hospital were reviewed. Forty-three patients underwent Schroth exercise were classified as Schroth group, and 21 patients underwent observation were classified as observation group. Outcomes were measured by health-related quality of life (HRQOL) and radiographic parameters. HRQOL was assessed using the visual analog scale (VAS) scores for back, Scoliosis Research Society-22 (SRS-22) patient questionnaire. Radiographic spinopelvic parameters were obtained from anteroposterior and lateral X-rays. The pre-treatment and post-treatment HRQOL and radiographic parameters were tested to validate Schroth exercise efficacy. The inter-rater reliability of the radiographic parameters was tested using the interclass correlation coefficient (ICC). The paired t test was used to examine HRQOL and radiographic parameters. Clinical relevance between C2-C7 sagittal vertical axis (SVA) and thoracic kyphosis was analyzed using Spearman correlation. RESULTS: In Schroth group, VAS back score, SRS-22 pain, and SRS-22 self-image domain were significantly improved from pre-treatment 3.0 ±â€Š0.8, 3.6 ±â€Š0.5, and 3.5 ±â€Š0.7 to post-treatment 1.6 ±â€Š0.6 (t = 5.578, P = 0.013), 4.0 ±â€Š0.3 (t = -3.918, P = 0.001), and 3.7 ±â€Š0.4 (t = -6.468, P < 0.001), respectively. No significant improvements of SRS-22 function domain (t = -2.825, P = 0.088) and mental health domain (t = -3.174, P = 0.061) were observed. The mean Cobb angle decreased from 28.9 ±â€Š5.5° to 26.3 ±â€Š5.2° at the final follow-up, despite no statistical significance was observed (t = 1.853, P = 0.102). The mean C2-C7 SVA value decreased from 21.7 ±â€Š8.4 mm to 17.0 ±â€Š8.0 mm (t = -1.224 P = 0.049) and mean T1 tilt decreased from 4.9 ±â€Š4.2 ° to 3.5 ±â€Š3.1° (t = 2.913, P = 0.011). No significant improvement of radiographic parameters and HRQOL were observed in observation group. CONCLUSIONS: For AIS patients with a Risser 3-5 and a Cobb angle 20°-40°, Schroth exercises improved HRQOL and halted curve progression during the follow-up period. Both cervical spine alignment and shoulder balance were also significantly improved after Schroth exercises. We recommend Schroth exercises for patients with AIS.

5.
Glob Food Sec ; 28: 100463, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34513581

RESUMO

The outbreak and wide spread of COVID-19 poses a new threat to global food security. This paper aims to address two important policy related issues, that is which agricultural subsector suffers more under zoonotic diseases and how do zoonotic diseases affect these subsectors. Using provincial panel data of 24 main farm commodities in China from 2002 to 2017, this paper identifies the impacts of zoonotic diseases and projects the potential disruption of COVID-19 to agricultural output in China under three scenarios. The main findings are as follows. First, zoonotic diseases have adverse impacts on almost all the farm commodities, while livestock on average suffers more than crops. Second, zoonotic diseases affect these subsectors mainly through the channel of adverse shocks on total factor productivity (TFP). Third, while a few subsectors can find a way to offset part of the TFP loss by applying more input, most subsectors suffer from both input reduction and TFP loss. Fourth, the spread of COVID-19 is projected to lower the growth rates of China's crop and livestock sector by 1.1%-2.3% and 1.3%-2.6%, with TFP loss by 1.1%-2.0% and 1.4%-2.7%, respectively, in 2020. This paper then discusses several policy implications for mitigating the negative impacts of COVID-19 on agricultural production in China and elsewhere.

6.
ACS Appl Mater Interfaces ; 13(38): 45375-45384, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34529410

RESUMO

Herein, we propose a new concept of energy storage system composed of a nonpolarized electrode and a polarized electrode (PPE) with an impressive energy density. It offered nearly 4 times higher energy density than that of carbon-based supercapacitor. Among the suggested potential PPE system, we introduced an electrodeposited nanozinc on the copper foam as the nearly nonpolarized electrode and a Zn-2,5-dihydroxyterephthalic acid (DHTA) metal-organic framework (MOF)-derived activated porous carbon as a nearly polarized electrode in KOH-ZnO electrolyte to constitute the C|Zn PPE system prototype. The C|Zn system achieved an impressive energy density of 84.5 Wh kg-1 at 1000 W kg-1, 4 times higher than that of the C|C supercapacitor. It also shows a high capacitance retention rate of 94.5% at 10 A g-1 after 10 000 cycles. Therefore, the amazing results indicate that the PPE energy system integrates the advantages of supercapacitors and secondary batteries. It will be a promising and effective energy device for higher-performance electric vehicles.

7.
Metabolites ; 11(9)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34564439

RESUMO

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer's disease (AD) and Parkinson's disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.

8.
Genes Dis ; 8(6): 731-745, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34522704

RESUMO

Cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT) plays a key role in antioxidant defense by mediating cystine uptake, promoting glutathione synthesis, and maintaining cell survival under oxidative stress conditions. Recent studies showed that, to prevent toxic buildup of highly insoluble cystine inside cells, cancer cells with high expression of SLC7A11 (SLC7A11high) are forced to quickly reduce cystine to more soluble cysteine, which requires substantial NADPH supply from the glucose-pentose phosphate pathway (PPP) route, thereby inducing glucose- and PPP-dependency in SLC7A11high cancer cells. Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH "debt", redox "bankruptcy", and subsequent cell death. This review summarizes our current understanding of NADPH-generating and -consuming pathways, discusses the opposing role of SLC7A11 in protecting cells from oxidative stress-induced cell death such as ferroptosis but promoting glucose starvation-induced cell death, and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation. A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.

9.
Front Neurosci ; 15: 750936, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34566576

RESUMO

As a common neurophysiological phenomenon, voluntary muscle fatigue is accompanied by changes in both the central nervous system and peripheral muscles. Considering the effectiveness of the muscle network and the functional corticomuscular coupling (FCMC) in analyzing motor function, muscle fatigue can be analyzed by quantitating the intermuscular coupling and corticomuscular coupling. However, existing coherence-based research on muscle fatigue are limited by the inability of the coherence algorithm to identify the coupling direction, which cannot further reveal the underlying neural mechanism of muscle fatigue. To address this problem, we applied the time-delayed maximal information coefficient (TDMIC) method to quantitate the directional informational interaction in the muscle network and FCMC during a right-hand stabilized grip task. Eight healthy subjects were recruited to the present study. For the muscle networks, the beta-band information flow increased significantly due to muscle fatigue, and the information flow between the synergist muscles were stronger than that between the synergist and antagonist muscles. The information flow in the muscle network mainly flows to flexor digitorum superficialis (FDS), flexor carpi ulnar (FCU), and brachioradialis (BR). For the FCMC, muscle fatigue caused a significant decrease in the beta- and gamma-band bidirectional information flow. Further analysis revealed that the beta-band information flow was significantly stronger in the descending direction [electroencephalogram (EEG) to surface electromyography (sEMG)] than that in the ascending direction (sEMG to EEG) during pre-fatigue tasks. After muscle fatigue, the beta-band information flow in the ascending direction was significantly stronger than that in the descending direction. The present study demonstrates the influence of muscle fatigue on information flow in muscle networks and FCMC. We proposes that beta-band intermuscular and corticomuscular informational interaction plays an adjusting role in autonomous movement completion under muscle fatigue. Directed information flow analysis can be used as an effective method to explore the neural mechanism of muscle fatigue on the macroscopic scale.

10.
J Colloid Interface Sci ; 606(Pt 2): 1364-1373, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34492472

RESUMO

In this paper, a new hexagonal prismatic Zn-MOF is rapidly synthesized at room temperature through a one-step precipitation method as precursor for the preparation of porous carbon. The SEM and GCD tests indicate that the pre-ionization process of BTC greatly accelerates the reaction speed between BTC and Zn ions, and only 0.5 h is required for the preparation of Zn-MOF with orderly morphology at room temperature, far less than 3-24 h of the existing hydrothermal synthesis. The derived porous carbon (BTCC) is provided with a considerable specific surface area of 1,464 m2 g-1 and suitable pores of 3.9 nm in size. Its richly porous structure offers a superior supercapacitor performance. The BTCC electrode offered a high specific capacitance and an excellent cycle stability. Furthermore, the assembled two symmetrical supercapacitors, C|1 M Na2SO4|C and C|6 M KOH|C, provide high energy density of 22.4 Wh kg-1 and 13.7 Wh kg-1, respectively. Their energy retention rates were 80.0% and 89.4%, respectively after 10,000 cycles at 20 A g-1. The proposed pre-ionization strategy is a facile, convenient and easy-to-industrial method for the preparation of new MOFs, thereby significantly reducing the manufacturing cost of porous carbon for energy storage.

11.
Sci Total Environ ; 799: 149403, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364287

RESUMO

Interaction between flow and cylindrical-shaped structures generates coherent and periodic turbulent flow that is frequently experienced by fish in natural environments, influencing fish maneuvering and swimming stability. The current study evaluated the behavioral responses of hybrid sturgeon (Acipenser dabryanus ♀ × Acipenser baerii ♂) when interacting with the wake flows induced by a D-shaped cylinder, with diameter ranging from 2 to 6 cm. A two dimensional Particle Image Velocimetry (PIV) was used to measure the wake flows hydrodynamics induced by D-shaped cylinders, and the fish behavior was recorded by camera. Hydrodynamic space occupancy together with swimming behaviors were analyzed, and the result shows that due to the presence of lowest velocity and relatively low turbulence, the regions behind cylinder were characterized by the preferred station holding zone for fish. Sturgeon adopted distinctive swimming gaits (Kármán gaiting or spill) in response to the cylinder wake flow and the associated fish swimming kinematics differed from each other. Kármán gaiting and spill significantly depended on velocity, vorticity and Reynolds shear stress, and varied according to the ratio of turbulence length scale to standard fish length (Lu/Lfish), which highlights the importance of cylinder vortex structure in influencing fish holding station and swimming stability. It is envisioned that these results can provide insights into the positions where fish may prefer to occupy in natural habitats and recommendations for the design and optimization of fish-friendly projects.


Assuntos
Laboratórios , Oncorhynchus mykiss , Animais , Fenômenos Biomecânicos , Hidrodinâmica , Natação
12.
Eur Spine J ; 30(9): 2427-2433, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34414472

RESUMO

PURPOSE: To explore the normal distribution of cervical sagittal alignment and the relationship between cervical alignment and global spine balance in asymptomatic young adults. METHODS: A total of 67 males and 59 females aged from 18 to 30 years old were recruited from 11/2011 to 12/2014. The C0-C2 angle, disk angles from C2-C3 to C6-C7, vertebral angles from C3 to C7, T1 slope, thoracic kyphosis (TK), lumbar lordosis, pelvic incidence, sacral slope, C2-C7 sagittal vertical axis (SVA), center of gravity of head to C7 SVA (CGH-C7SVA), C7-S1SVA were measured and statistically analyzed. The Roussouly classification was utilized. RESULTS: Mean value of C0-C7 was 26.0° ± 12.8°, composed of 15.2° ± 6.7° for C0-C2, 9.1° ± 12.1° for sum of disk angles from C2-C3 to C6-C7, and 1.4° ± 10.2° for sum of vertebral angles from C3 to C7. C2-C7SVA (18.6 mm ± 7.9 mm) and CGH-C7SVA (22.9 mm ± 12.3 mm) were offset ideally by C7-S1SVA (-21.6 mm ± 31.0 mm). Significant difference was found between cervical alignment of different Roussouly types (p < 0.01). There was significant correlation between cervical alignment and T1 slope (p < 0.01), TK (p < 0.01). There was significant correlation between adjacent segmental angles from T1 slope up to C0-C2 angle (p < 0.05). CONCLUSION: Normative values of each vertebral angle and disk angle were established. The cervical lordosis occurred mainly at C0-C2 and disk levels, which was influenced by parameters of other parts of the spine, such as T1 slope, TK and the Roussouly classification. There was significant correlation between adjacent disk angles. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

14.
Ann Transl Med ; 9(13): 1060, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34422972

RESUMO

Background: The surgical outcomes of individual patient with ossification of the posterior longitudinal ligament (OPLL) can vary depending on various patient-related factors. Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) is a well-developed tool for outcome measurement and considers both disease-specific and general health aspects. This study aimed to investigate the reliability, validity, and responsiveness of the JOACMEQ in patients with OPLL in mainland China and to compare post-operative outcomes of OPLL patients between mainland China and Japan. Methods: This multicenter trial was performed between July 2009 and June 2019. The procedure for the JOACMEQ translation followed Beaton's guidelines. All patients enrolled were diagnosed with OPLL and had completed the JOACMEQ, the modified Japanese Orthopaedic Association (mJOA) scale, and the 36-Item Short Form Health Survey (SF-36) before and after surgery. The reliability (Cronbach's α and Pearson's correlation), construct validity (factor analysis), concurrent validity (Spearman's correlation with SF-36) and responsiveness (effect sizes) of JOACMEQ were evaluated. A mixed-model analytic approach was used to analyze differences in postoperative outcomes between the 2 countries. Results: Ninety-one patients from mainland China and ninety-one patients from Japan were recruited. JOACMEQ showed satisfactory internal consistency (Cronbach's α=0.75). In test-retest reliability evaluation, except for the bladder function domain, the JOACMEQ domains had good test-retest reliability (0.89-0.96). In factor analysis, most of the items (19/24) were well clustered. Regarding clinical validity, all 5 domains were found to have moderate correlations with the physical component summary (PCS) of SF-36 (r=0.25-0.50), and the bladder function and quality of life domains also had moderate correlations (r=0.25-0.50) with the mental component summary (MCS) of SF-36. JOACMEQ showed a variable responsiveness in different domains (effect size =0.17-0.84; standardized response means =0.15-0.85). Regarding postoperative improvements in the JOACMEQ score, mixed-model analysis revealed a significant difference in the quality of life domain between Chinese and Japanese patients (16.0±18.7 vs. 7.8±17.7, P<0.05). Conclusions: JOACMEQ generally shows good reliability, good validity and mild responsiveness, and can identify the post-operative improvements in patients with OPLL in mainland China. Chinese OPLL patients showed a significantly larger improvement in postoperative quality of life compared to their Japanese counterparts.

15.
J Magn Reson Imaging ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425037

RESUMO

BACKGROUND: Diffusion-weighted imaging (DWI) can quantify the microstructural changes in the spinal cord. It might be a substitute for T2 increased signal intensity (ISI) for cervical spondylotic myelopathy (CSM) evaluation and prognosis. PURPOSE: The purpose of the study is to investigate the relationship between DWI metrics and neurologic function of patients with CSM. STUDY TYPE: Retrospective. POPULATION: Forty-eight patients with CSM (18.8% females) and 36 healthy controls (HCs, 25.0% females). FIELD STRENGTH/SEQUENCE: 3 T; spin-echo echo-planar imaging-DWI; turbo spin-echo T1/T2; multi-echo gradient echo T2*. ASSESSMENT: For patients, conventional MRI indicators (presence and grades of T2 ISI), DWI indicators (neurite orientation dispersion and density imaging [NODDI]-derived isotropic volume fraction [ISOVF], intracellular volume fraction, and orientation dispersion index [ODI], diffusion tensor imaging [DTI]-derived fractional anisotropy [FA] and mean diffusivity [MD], and diffusion kurtosis imaging [DKI]-derived FA, MD, and mean kurtosis), clinical conditions, and modified Japanese Orthopaedic Association (mJOA) were recorded before the surgery. Neurologic function improvement was measured by the 3-month follow-up recovery rate (RR). For HCs, DWI, and mJOA were measured as baseline comparison. STATISTICAL TESTS: Continuous (categorical) variables were compared between patients and HCs using Student's t-tests or Mann-Whitney U tests (chi-square or Fisher exact tests). The relationships between DWI metrics/conventional MRI findings, and the pre-operative mJOA/RR were assessed using correlation and multivariate analysis. P < 0.05 was considered statistically significant. RESULTS: Among patients, grades of T2 ISI were not correlated with pre-surgical mJOA/RR (P = 0.717  and 0.175, respectively). NODDI ODI correlated with pre-operative mJOA (r = -0.31). DTI FA, DKI FA, and NODDI ISOVF were correlated with the recovery rate (r = 0.31, 0.41, and -0.34, respectively). In multivariate analysis, NODDI ODI (DTI FA, DKI FA, NODDI ISOVF) significantly contributed to the pre-operative mJOA (RR) after adjusting for age. DATA CONCLUSION: DTI FA, DKI FA, and NODDI ISOVF are predictors for prognosis in patients with CSM. NODDI ODI can be used to evaluate CSM severity. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 5.

16.
Cancers (Basel) ; 13(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34359650

RESUMO

Triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Standard cytotoxic chemotherapies are currently the main treatment options, but their clinical efficacies are limited and patients usually suffer from severe side effects. The goal of this study was to develop and evaluate targeted liposomes-delivered combined chemotherapies to treat TNBCs. Specifically, the IC50 values of the microtubule polymerization inhibitor mertansine (DM1), mitotic spindle assembly defecting taxane (paclitaxel, PTX), DNA synthesis inhibitor gemcitabine (GC), and DNA damage inducer doxorubicin (AC) were tested in both TNBC MDA-MB-231 and MDA-MB-468 cells. Then we constructed the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) tagged liposomes and confirmed its TNBC cell surface binding using flow cytometry, internalization with confocal laser scanning microscopy, and TNBC xenograft targeting in NSG female mice using In Vivo Imaging System. The safe dosage of anti-EGFR liposomal chemotherapies, i.e., <20% body weight change, was identified. Finally, the in vivo anti-tumor efficacy studies in TNBC cell line-derived xenograft and patient-derived xenograft models revealed that the targeted delivery of chemotherapies (mertansine and gemcitabine) can effectively inhibit tumor growth. This study demonstrated that the targeted liposomes enable the new formulations of combined therapies that improve anti-TNBC efficacy.

17.
19.
Vaccines (Basel) ; 9(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34452008

RESUMO

Triple-negative breast cancers (TNBCs) are frequently recurrent due to the development of drug resistance post chemotherapy. Both the existing literature and our study found that surface receptor CD47 (cluster of differentiation 47) was upregulated in chemotherapy-treated TNBC cells. The goal of this study was to develop a monoclonal antibody (mAb)-based targeting strategy to treat TNBC after standard treatment. Specifically, a new mAb that targets the extracellular domain of receptor CD47 was developed using hybridoma technology and produced in fed-batch culture. Flow cytometry, confocal microscopy, and in vivo imaging system (IVIS) showed that the anti-CD47 mAb effectively targeted human and mouse TNBC cells and xenograft models with high specificity. The antibody-drug conjugate (ADC) carrying mertansine was constructed and demonstrated higher potency with reduced IC50 in TNBC cells than did the free drug and significantly inhibited tumor growth post gemcitabine treatment in MDA-MB-231 xenograft NSG model. Finally, whole blood analysis indicated that the anti-CD47 mAb had no general immune toxicity, flow cytometry analysis of lymph nodes revealed an increase of CD69+ NK, CD11c+ DC, and CD4+ T cells, and IHC staining showed tumoral infiltration of macrophage in the 4T1 xenograft BALB/cJ model. This study demonstrated that targeting CD47 with ADC has great potential to treat TNBCs as a targeted therapy.

20.
World Neurosurg ; 154: e529-e535, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34314912

RESUMO

BACKGROUND: Discontinuous thoracic ossification of the ligamentum flavum (TOLF) is diagnosed according to the number and distribution of involved segments seen on magnetic resonance images. When TOLF causes thoracic myelopathy, surgical intervention for these lesions becomes unavoidable. However, there are few reports on the outcomes of surgery for discontinuous TOLF. METHODS: The study included 26 patients of mean age 55.0 years who underwent simultaneous (n = 16) or staged (n = 10) decompression of discontinuous TOLF between July 2006 and June 2016. Final neurologic status was evaluated using the modified Japanese Orthopaedic Association (JOA) score. The surgical data and incidence of complications were compared. The mean follow-up duration was 73.3 months. RESULTS: There was no between-group difference in number of levels decompressed or the amount of intraoperative blood loss. There was a significant improvement in the JOA score from 4.0 before surgery to 8.0 postoperatively, with an average recovery rate of 58.3%. The JOA recovery rate was significantly better in the staged group than simultaneous group (68.4% vs. 52.0%, P < 0.05). However, the incidence of complications was similar between the staged and simultaneous groups including for dural tear (1 vs. 6, P = 0.19), cerebrospinal fluid leak (4 vs. 6, P = 1.00), and transient neurologic deterioration (0 vs. 2, P = 0.51). CONCLUSIONS: The surgical outcome of staged decompression for discontinuous TOLF seems to be better than that of simultaneous decompression. The complication rates of these 2 strategies are similar.

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