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2.
Gene Ther ; 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534612

RESUMO

With the development of basic research, some genetic-based methods have been found to treat Duchenne muscular dystrophy (DMD) with large deletion mutations and nonsense mutations. Appropriate therapeutic approaches for repairing multiple duplications are limited. We used the CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 system with patient-derived primary myoblasts to correct multiple duplications of the dystrophin gene. Muscle tissues from a patient carrying duplications of dystrophin were obtained, and tissue-derived primary cells were cultured. Myoblasts were purified with an immunomagnetic sorting system using CD56 microbeads. After transduction by lentivirus with a designed single guide RNA (sgRNA) targeting a duplicated region, myoblasts were allowed to differentiate for 7 days. Copy number variations in the exons of the patient's myotubes were quantified by real-time PCR before and after genetic editing. Western blot analysis was performed to detect the full-length dystrophin protein before and after genetic editing. The ten sequences predicted to be the most likely off-targets were determined by Sanger sequencing. The patient carried duplications of exon 18-25, dystrophin protein expression was completely abrogated. Real-time PCR showed that the copy number of exon 25 in the patient's myotubes was 2.015 ± 0.079 compared with that of the healthy controls. After editing, the copy number of exon 25 in the patient's modified myotubes was 1.308 ± 0.083 compared with that of the healthy controls (P < 0.001). Western blot analysis revealed no expression of the dystrophin protein in the patient's myotubes before editing. After editing, the patient's myotubes expressed the full-length dystrophin protein at a level that was ~6.12% of that in the healthy control samples. Off-target analysis revealed no abnormal editing at the ten sites predicted to be the most likely off-target sites. The excision of multiple duplications by the CRISPR/Cas9 system restored the expression of full-length dystrophin. This study provides proof of evidence for future genome-editing therapy in patients with DMD caused by multiple duplication mutations.

3.
Front Vet Sci ; 9: 837882, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35350432

RESUMO

Cefquinome, the fourth-generation cephalosporin applied solely for veterinary medicine, is commonly used for bovine mastitis caused by Staphylococcus aureus. The present study aims to establish an optimal dose and provide a PK/PD Cutoff value (COPD) for cefquinome against S. aureus based on ex vivo pharmacokinetics and pharmacodynamics (PK/PD) integration. This study investigated the pharmacokinetics (PK) of cefquinome when administered as three consecutive intramammary (IMM) doses of cefquinome in three healthy dairy cows at 75 mg/gland. Drug concentration was determined by HPLC-MS/MS assay. The ex vivo pharmacodynamics (PD) of cefquinome were evaluated by using a milk sample from a PK experiment. The relationship between the AUC/ MIC of cefquinome and bacterial loading reduction was simulated using a Sigmoid Emax model. The cefquinome concentration in milk attained a maximum level of 1.55 ± 0.21 mg/mL at 1.8 h after the third administration. The mean value of the area under the concentration-time curve (AUC0-24) was 26.12 ± 2.42 mg·h/mL after the third administration. The elimination half-life was 10.6 h. For PD profile, the MICs of cefquinome in milk were 2-4 times higher than those in the broth. In vitro time-killing curve shows that initial bacterial concentration has a huge impact on antibacterial effect on three strains. The antibacterial effect was weakened with the initial bacterial concentration increasing from 106 to 108 CFU/mL. The AUC0-24h/MIC index correlated well with ex vivo efficacy both for the initial inoculum of 106 CFU/mL and 108 CFU/mL (R 2 > 0.84). According to the inhibitory sigmoid Emax model analysis, the PK/PD surrogate (AUC0-24/MIC) values were 8,638, 1,397, and 3,851 for bactericidal effect (E = -3) with an initial inoculum of 106 CFU/mL, while the corresponding values were 12,266, 2,295, and 5,337, respectively, with the initial inoculum of 108 CFU/mL. The ex vivo PK/PD based population dose prediction indicated a target attainment rate (TAR) of 90% of 55 mg/gland/12 h. The COPD for cefquinome against S. aureus was 2 µg/mL under the recommended dose of 55 mg/gland/12 h. However, it should be validated in clinical practice in future investigations. These results contribute to the rational use of cefquinome for mastitis treatment in clinical veterinary medicine.

4.
Ying Yong Sheng Tai Xue Bao ; 33(2): 405-414, 2022 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-35229514

RESUMO

Light simplified cultivation and high quality rice are the main directions of rice production in China. Meteorological factors are the most important environmental factors affecting rice growth and yield. Few studies examined the relationship between rice yield and microclimate under different light simplified cultivation modes. To explore the relationship between rice yield and climatic factors (temperature, sunshine and water) at different growth stages of hybrid rice under different forecrops in southwest China, we carried out a split-plot design experiment in 2019 and 2020, with two forecrops of green cabbage and rape as the main plot, and three planting methods, direct-seeding, blanket-transplanting, and artificial transplanting as the subplots, taking Yixiangyou 2115 as the experimental variety. Results showed that compared with rape-paddy cropping system, cabbage-paddy cropping system significantly improved the accumulated temperature and precipitation production efficiency and consequently improved the effective panicles, setting rate, and 1000-grain weight. The yield was increased by 12.7% and 8.3% under cabbage-paddy and rape-paddy cropping system, respectively. Compared with manual transplanting, mechanical transplanting improved effective panicles, production efficiency of radiation, accumulated temperature and precipitation, and the radiation use efficiency of grain during the whole growth period. The mean yield was increased by 4.6% in 2019 and 2020. However, the above parameters of direct-seeding significantly decreased, but the yield decreased by 8.7%. Compared with 2019, mechanical transplanting and artificial transplanting were sown one month earlier in 2020 under the same stubble, which shortened growth period, reduced air temperature, and increased precipitation after flowering, leading to a significant decrease in effective accumulated temperature and light radiation; production efficiency of accumulated temperature, light energy, and precipitation; and utilization efficiency of light energy of grain, spikelets per panicle, setting rate, and 1000-grain weight. However, the yield was significantly reduced. Partial least squares regression analysis was used to establish the production forecast equation of standardized regression coefficients of meteorological factors. There was a positive correlation between rice yield and effective accumulated temperature and total radiation during the growth stage or the whole growth period. In addition, there was a significant negative correlation between rice yield and precipitation during the whole growth period. In conclusion, mechanical transplanting under cabbage-paddy cropping system was a rice planting method that optimised the seasonal sunshine and temperature resources in southwest China. The method facilitated the full utilization of temperature and sunshine resources, resulting in high yield. However, it was not advisable to sow or transplant too early.


Assuntos
Agricultura , Brassica , Oryza , Agricultura/métodos , Brassica/crescimento & desenvolvimento , China , Grão Comestível , Oryza/crescimento & desenvolvimento , Temperatura
5.
Neuroscience ; 490: 250-263, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35339646

RESUMO

Spinal cord injury (SCI) is a common disease of the nervous system, including primary and secondary injuries. Neuronal inflammation after SCI is the most important pathological process of SCI and a chemical barrier to nerve function recovery after injury. Ski, an evolutionarily conserved functional transcriptional regulator protein, is upregulated in reactive astrocytes after SCI and regulates the biological characteristics of astrocytes. However, its role in the glial inflammatory response triggered by reactive astrocytes after spinal cord ischemia and its exact mechanism remains unclear. This study investigated the role and mechanism of Ski in the inflammatory response triggered by reactive astrocytes induced by oxygen and sugar deprivation/reoxygenation (OGD/R) model in vitro. In the ODG/R model, Ski expression was upregulated. In contrast, Ski upregulation was accompanied by increased levels of iNOS, IL-1ß, IL-6, TNF-α, and other inflammation-related factors. These results indicated that the inflammatory response triggered by astrocytes was significantly enhanced in OGD/R-stimulated astrocytes. Astrocytes were transfected with Ski specific siRNA to knock out Ski and subsequently attenuate OGD-induced astrocyte-triggered inflammation. Our results also suggest that Ski downregulation downregulates the expression of iNOS, IL-1ß, IL-6, and TNF-α in OGD/R-induced reactive astrocytes by inhibiting the activity of the NF-κB signaling pathway. In conclusion, downregulation of Ski can effectively inhibit glial inflammation in SCI by inhibiting the activity of the NF-κB pathway. These findings suggest that Ski is a promising therapeutic target for inflammatory responses after SCI.In conclusion, Ski downregulation can effectively inhibit glial inflammation in SCI by inhibiting the activity of the NF-κB pathway. These findings suggest that Ski might serve as a promising target for the treatment of inflammatory responses after SCI.


Assuntos
NF-kappa B , Proteínas Proto-Oncogênicas , Traumatismos da Medula Espinal , Animais , Astrócitos/metabolismo , Glucose/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Oxigênio/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Apoptosis ; 27(1-2): 133-148, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35147801

RESUMO

This study aimed to determine the effects of SKI on interleukin (IL)-1ß-induced apoptosis of nucleus pulposus (NP) cells, intervertebral disc degeneration (IDD), and the Wnt signaling pathway. NP tissue specimens of different Pfirrmann grades (II-V) were collected from patients with different grades of IDD. Real-time polymerase chain reaction and western blotting were used to compare SKI mRNA and protein expression in NP tissues from patients. Using the IL-1ß-induced IDD model, NP cells were infected with lentivirus-coated si-SKI to downregulate the expression of SKI and treated with LiCl to evaluate the involvement of the Wnt/ß-catenin signaling pathway. Western blotting, immunofluorescence, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect NP cell apoptosis, extracellular matrix (ECM) metabolism, and related protein expression changes in the Wnt/ß-catenin signaling pathway. To investigate the role of SKI in vivo, a rat IDD model was established by needle puncture of the intervertebral disc. Rats were injected with lentivirus-coated si-SKI and evaluated by magnetic resonance imaging (MRI), and hematoxylin and eosin (HE) and safranin O staining. SKI expression positively correlated with the severity of human IDD. In the IL-1ß-induced NP cell degeneration model, SKI expression increased significantly and reached a peak at 24 h. SKI knockdown protected against IL-1ß-induced NP cell apoptosis and ECM degradation. LiCl treatment reversed the protective effects of si-SKI on NP cells. Furthermore, lentivirus-coated si-SKI injection partially reversed the NP tissue damage in the IDD model in vivo. SKI knockdown reduced NP cell apoptosis and ECM degradation by inhibiting the Wnt/ß-catenin signaling pathway, ultimately protecting against IDD. Therefore, SKI may be an effective target for IDD treatment.


Assuntos
Degeneração do Disco Intervertebral , Núcleo Pulposo , Animais , Apoptose/genética , Células Cultivadas , Matriz Extracelular/metabolismo , Humanos , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/terapia , Núcleo Pulposo/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
7.
J Neuroimmunol ; 364: 577807, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35007896

RESUMO

Spinal cord injury (SCI) is a leading cause of disability and death worldwide. Reactive astrogliosis, a typical feature of SCI, undergoes various molecular and morphological changes and contributes to glial scar formation, which impedes axonal regeneration. Ski is a novel molecule that regulates the biological characteristics of astrocytes after spinal cord injury, but its function and the exact mechanism of its overexpression in reactive astrocyte proliferation and migration after SCI remain unclear. The purpose of this study was to elucidate the effect and mechanism of Ski on the proliferation and migration of reactive astrocytes, and to regulate the spatiotemporal formation of glial scars after SCI. In an in vitro lipopolysaccharide (LPS)-induced astrocyte injury model, the expression of Ski was upregulated in a time-dependent manner in LPS-induced astrocytes, and the upregulation of Ski was accompanied by that of PCNA, CDK4, CyclinD1, and other proliferation-related proteins. Our findings suggest that Ski promotes the proliferation and migration of reactive astrocytes. Next, astrocytes were transfected with a specific lentivirus to cause the overexpression of Ski, which significantly enhanced the proliferation and migration of reactive astrocytes and LPS-induced activation of the PI3K/Akt pathway. The PI3K/Akt pathway inhibitor LY294002 significantly inhibited the proliferation and migration of LPS-induced reactive astrocytes after Ski overexpression. In conclusion, Ski regulates LPS-induced astrocyte proliferation and migration through the PI3K/Akt pathway, making Ski a promising target for strategies to combat glial scarring after SCI.


Assuntos
Astrócitos/metabolismo , Gliose/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/fisiologia , Traumatismos da Medula Espinal/patologia , Animais , Astrócitos/patologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Gliose/patologia , Lipopolissacarídeos/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo
8.
Otolaryngol Head Neck Surg ; 166(3): 490-497, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34182810

RESUMO

OBJECTIVE: Salvage endoscopic nasopharyngectomy (ENPG) is a reasonable choice for resectable recurrent nasopharyngeal carcinoma (rNPC). However, in past decades, complete removal of the tumor was not feasible when the recurrent lesion was adjacent to the internal carotid artery (ICA). The present article introduces innovative strategies to ensure sufficient surgical margins while avoiding accidental injury to the ICA. STUDY DESIGN: Retrospective study. SETTING: Tertiary care center. METHODS: We retrospectively reviewed rT2-3 rNPC patients with tumor lesions adjacent to the ICA (<5 mm) who underwent ENPG at the Sun Yat-sen University Cancer Center between January 2015 and June 2020. Thirty-seven patients were selected for this study. Seventeen patients underwent ENPG using direct dissection, 10 patients underwent endoscopic-assisted transcervical protection of the parapharyngeal ICA combined with ENPG, and 10 patients underwent ICA embolization followed by ENPG. RESULTS: With a median follow-up duration of 31 months (range, 5 to 53 months), the 2-year overall survival, progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates of salvage ENPG for rNPC adjacent to the ICA were 88.7%, 72.0%, 72.0%, and 97.3%, respectively. The incidences of grade 1-2 and grade 3-5 postoperative complications were 16.2% and 13.5%, respectively. Two patients experienced ICA rupture during direct dissection but were out of danger after vascular embolization therapy. One patient had a positive margin. Two patients had severe nasopharyngeal wound infections with mucosal flap necrosis. CONCLUSION: ENPG combined with ICA pretreatment allows the feasible and effective resection of rNPC lesions adjacent to the ICA.


Assuntos
Artéria Carótida Interna , Neoplasias Nasofaríngeas , Artéria Carótida Interna/patologia , Artéria Carótida Interna/cirurgia , Doença Crônica , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos
9.
Environ Res ; 203: 111873, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34411548

RESUMO

A series of rare earth complexes containing (α-PW12O40)3- and PO ligand are synthesized by water bath in 70 °C, [Ln(OPPh3)4(H2O)3](PW12O40)·4CH3CN (Ln = La, Pr, Nd, Sm, Gd, Tb, Ho 1-7) (OPPh3 = Triphenylphosphine oxide, {PW12} = phosphotungstic acid). The precise structures are confirmed by X-ray single crystal diffraction and the result shows all complexes are isostructural. Complexes 1-7 are fully characterized by PXRD, FT-IR, TGA, UV diffuse reflectance spectra and terahertz time-domain spectroscopy (THz-TDS). Complex 3 exhibits the highest photocatalytic degradation efficiency for methylene blue (MB) in this series of complexes. The experimental results showed that the photodegradation efficiency can remain constant at the level of 95% after five consecutive cycles. The photocatalytic reaction kinetics and mechanism of complexes were investigated. Additionally, complexes also exhibit photocatalytic hydrogen evolution activity. THz-TDS was used to characterize the complexes and its raw materials, the characteristic peaks of OPPh3 (broad peak at 1.20 THz) and phosphotungstic acid (sharp peaks at 0.23, 0.32 THz) were obtained.


Assuntos
Elementos da Série dos Lantanídeos , Óxidos , Fosfinas , Sorbitol/análogos & derivados , Espectroscopia de Infravermelho com Transformada de Fourier , Tiramina/análogos & derivados
10.
Cancer Med ; 11(4): 1109-1118, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34953045

RESUMO

PURPOSE: We aimed to develop and prospectively validate a risk score model to guide individualized concurrent chemoradiotherapy (CCRT) for patients with stage II nasopharyngeal carcinoma (NPC) in intensity-modulated radiotherapy (IMRT) era. MATERIALS AND METHODS: In total, 1220 patients who received CCRT or IMRT alone were enrolled in this study, including a training cohort (n = 719), a validation cohort (n = 307), and a prospective test cohort (n = 194). Patients were stratified into different risk groups by a risk score model based on independent prognostic factors, which were developed in the training cohort. Survival rates were compared by the log-rank test. The validation and prospective test cohorts were used for validation. RESULTS: Total tumor volume, Epstein-Barr virus DNA, and lactate dehydrogenase were independent risk factors for failure-free survival (FFS, all p < 0.05). A risk score model based on these three risk factors was developed to classify patients into low-risk group (no risk factor, n = 337) and high-risk group (one or more factors, n = 382) in the training cohort. In the high-risk group, CCRT had better survival rates than IMRT alone (5-year FFS: 82.6% vs. 74.0%, p = 0.028). However, there was no survival difference between CCRT and IMRT alone either in the whole training cohort (p = 0.15) or in the low-risk group (p = 0.15). The results were verified in the validation and prospective test cohorts. CONCLUSION: A risk score model was developed and prospectively validated to precisely select high-risk stage II NPC patients who can benefit from CCRT, and thus guided individualized treatment in IMRT era.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Herpesvirus Humano 4 , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Fatores de Risco
11.
Front Immunol ; 12: 763791, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34880862

RESUMO

Ovarian cancer (OC) is a devastating malignancy with a poor prognosis. The complex tumor immune microenvironment results in only a small number of patients benefiting from immunotherapy. To explore the different factors that lead to immune invasion and determine prognosis and response to immune checkpoint inhibitors (ICIs), we established a prognostic risk scoring model (PRSM) with differential expression of immune-related genes (IRGs) to identify key prognostic IRGs. Patients were divided into high-risk and low-risk groups according to their immune and stromal scores. We used a bioinformatics method to identify four key IRGs that had differences in expression between the two groups and affected prognosis. We evaluated the sensitivity of treatment from three aspects, namely chemotherapy, targeted inhibitors (TIs), and immunotherapy, to evaluate the value of prediction models and key prognostic IRGs in the clinical treatment of OC. Univariate and multivariate Cox regression analyses revealed that these four key IRGs were independent prognostic factors of overall survival in OC patients. In the high-risk group comprising four genes, macrophage M0 cells, macrophage M2 cells, and regulatory T cells, observed to be associated with poor overall survival in our study, were higher. The high-risk group had a high immunophenoscore, indicating a better response to ICIs. Taken together, we constructed a PRSM and identified four key prognostic IRGs for predicting survival and response to ICIs. Finally, the expression of these key genes in OC was evaluated using RT-qPCR. Thus, these genes provide a novel predictive biomarker for immunotherapy and immunomodulation.


Assuntos
Neoplasias Ovarianas/imunologia , Biologia Computacional , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Prognóstico , Modelos de Riscos Proporcionais
13.
Cell Rep Med ; 2(9): 100383, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34622226

RESUMO

This is a phase Ib/II study of regorafenib plus toripalimab for colorectal cancer. The objective response rate (ORR) is 15.2% and the disease control rate is 36.4% in evaluable patients with recommended phase II dose (80 mg regorafenib plus toripalimab). The median progression-free survival (PFS) and the median overall survival are 2.1 months and 15.5 months, respectively. Patients with liver metastases have lower ORR than those without (8.7% versus 30.0%). All patients (3/3) with lung-only metastasis respond, whereas no patients (0/4) with liver-only metastasis respond. 94.9% and 38.5% of patients have grade 1 and grade 3 treatment-related adverse events, respectively. Gut microbiome analysis of the baseline fecal samples shows significantly increased relative abundance and positive detection rate of Fusobacterium in non-responders than responders. Patients with high-abundance Fusobacterium have shorter PFS than those with low abundance (median PFS = 2.0 versus 5.2 months; p = 0.002).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Resultado do Tratamento
14.
Biomolecules ; 11(9)2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34572480

RESUMO

The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22-0.98; p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months; HR: 0.11, 95% CI: 0.01-1.22; p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04-0.68; p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21-1.05; p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Modelos de Riscos Proporcionais
15.
Biomed Pharmacother ; 143: 112170, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536759

RESUMO

Intervertebral disc degeneration (IDD) is a chronic skeletal muscle degenerative disease, which is considered the main cause of low back pain. It seriously affects the quality of life of patients and consequently brings a heavy economic burden to their families and the society. Although IDD is considered a natural process in degenerative lesions, it is mainly caused by aging, trauma, genetic susceptibility and other factors. It is closely related to changes in the tissue structure and function, including the progressive destruction of extracellular matrix, cell aging, cell death of the intervertebral disc (IVD), inflammation, and impairment of tissue biomechanical function. Currently, the treatment of IDD is aimed at alleviating symptoms rather than at targeting pathological changes in the IVD. Furthermore, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway is closely related to various pathological processes in IDD, and the activation of the MAPK/ERK pathway promotes the degradation of the IVD extracellular matrix, cell aging, apoptosis, and inflammatory responses. It also induces autophagy and oxidative stress that accelerate the IVD process. In our current review, we summarize the latest developments in the negative regulation of IDD after activation of the MAPK/ERK signaling pathway and emphasize on its influence on IDD. Targeting this pathway may become an attractive treatment strategy for IDD in the near future.


Assuntos
Anti-Inflamatórios/uso terapêutico , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Degeneração do Disco Intervertebral/tratamento farmacológico , Disco Intervertebral/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/enzimologia , Matriz Extracelular/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Disco Intervertebral/enzimologia , Disco Intervertebral/patologia , Disco Intervertebral/fisiopatologia , Degeneração do Disco Intervertebral/enzimologia , Degeneração do Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/fisiopatologia , Terapia de Alvo Molecular , Transdução de Sinais
16.
Adv Mater ; 33(43): e2103472, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34463380

RESUMO

Malus' law regulating the intensity of light when passed through a polarizer, forms the solid basis for image steganography based on orthogonal polarizations of light to convey hidden information without adverse perceptions, which underpins important practices in information encryptions, anti-counterfeitings, and security labels. Unfortunately, the restriction to orthogonal states being taken for granted in the common perceptions fails to advance cryptoinformation to upgraded levels of security. By introducing a vectorial compound metapixel design, arbitrary nonorthogonal polarization multiplexing of independent grayscale images with high fidelity and strong concealment is demonstrated. The Jones matrix treatment of compound metapixels consisting of double atoms with tailored in-plane orientation sum and difference allows point-by-point configuring of both the amplitude and polarization rotations of the output beam in an analytical and linear form. With this, both multiplexing two continuous grayscale images in arbitrary nonorthogonal polarization angles and concealing grayscale image on another in an arbitrary disclosure angle window are experimentally demonstrated in the visible TiO2 metasurface platform. The methods shed new light on multifarious metaoptics by harnessing the new degree of freedom and unlock the full potential of metasurface polarization optics.

17.
Oral Oncol ; 121: 105494, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34425533

RESUMO

BACKGROUND: Our previous trial confirmed that induction chemotherapy (IC) improved long-term survival outcomes in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). In this study, we investigated the impact of IC on long-term quality of life (QoL) in this cohort. METHODS: Our trial was a randomised, open-label phase 3 trial comparing IC followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in patients with stage III-IVB (except T3N0-1) NPC. All participants completed two self-administered questionnaires, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (H&N35). As per protocol, the questionnaires had to be completed before knowledge of treatment allocation by the patient (baseline). Patients were then approached to enroll at the time of the present study period. RESULTS: Ultimately, QoL data from 228 patients were included in the analysis. Most scales were both statistically and clinically decreased in both groups between baseline and the latest follow-up. The IC followed by CCRT group had significantly better outcome in role functioning, cognitive functioning, social functioning, fatigue, pain, and constipation in QLQ-C30 scales at the last follow-up. Similarly, in H&N35 scales, a significantly better result was observed in pain, sexuality, sticky saliva, pain killers use, nutritional supplements, and weight loss, but a poorer result in senses problems, for those treated by IC followed by CCRT. CONCLUSION: IC followed by CCRT seemed to have better long-term QoL outcomes compared with CCRT alone in patients with locoregionally advanced NPC.


Assuntos
Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica , Quimiorradioterapia , Humanos , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Dor
18.
Curr Med Sci ; 41(4): 770-776, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34403102

RESUMO

OBJECTIVE: Donor-derived carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has recently emerged as a critical early complication after renal transplantation. Although CRKP is usually sensitive to tigecycline, monotherapy with this drug is often less than effective. We investigated the efficacy of a combined regimen of tigecycline with high-dose, extended-infusion meropenem in the treatment of donor-derived CRKP infection after kidney transplantation. METHODS: From Jan. 2016 to Dec. 2017, a total of 12 CRKP isolates were detected from cultures of the organ preservation solution used for soaking the donor kidneys at our institute. Probable or possible donor-derived infection (DDI) was identified in 8 transplant recipients. Clinical data were retrospectively analyzed. RESULTS: Klebsiella pneumoniae carbapenemase-2 (KPC-2)-producing CRKP was reported to be positive in organ preservation solution cultures at 3.5±0.9 days after transplantation, leading to surgical site (n=3), urinary tract (n=4), and/or bloodstream (n=2) infections in 8 recipients. The drug susceptibility tests showed that CRKP was sensitive to tigecycline, but resistant to meropenem. In 7 patients who received tigecycline combined with high-dose extended-infusion meropenem, DDIs were successfully cured. The length of hospital stay was 31 (18-129) days, and the serum creatinine at discharge was 105.8±16.7 µmol/L. The one remaining patient who received tigecycline combined with intravenous-drip meropenem died of septic shock. A median follow-up of 43 months (33-55) showed no recurrence of new CRKP infection in the 7 surviving recipients. CONCLUSION: It was suggested that a prompt and appropriate combination therapy using tigecycline with high-dose extended-infusion meropenem is effective in treating donor-derived KPC-2-producing CRKP infection after renal transplantation.


Assuntos
Proteínas de Bactérias/genética , Infecções por Klebsiella/tratamento farmacológico , Meropeném/farmacologia , Tigeciclina/farmacologia , beta-Lactamases/genética , Adolescente , Adulto , Carbapenêmicos/efeitos adversos , Carbapenêmicos/farmacologia , Criança , Farmacorresistência Bacteriana/genética , Feminino , Humanos , Lactente , Transplante de Rim/efeitos adversos , Infecções por Klebsiella/etiologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/patogenicidade , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Doadores de Tecidos , Adulto Jovem
19.
J Cancer ; 12(14): 4424-4432, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093843

RESUMO

Introduction: Biopsy is essential for some patients with suspected distant metastasis, so we aim to figure out whether biopsy of distant metastasis is associated with impaired survival in NPC. Methods: A total of 743 synchronous metastatic NPC patients from 2004 to 2016 were analyzed from the population-based Surveillance, Epidemiology, and End Results program. Propensity score matching was used to control confounders and create a well-balanced cohort. Five-year survival rate estimates and Kaplan-Meier survival curves were calculated. Cox proportional hazard ratios (HRs) were used to identify independent prognostic factors for survival. Results: Of 743 eligible patients, 194 (26.11%) underwent biopsy of distant metastasis. After control for demographic and clinicopathologic characteristics, patients with biopsy of distant metastasis achieved comparable 5-year overall survival (OS) (20.3% vs 24.7%; P = 0.41) and 5-year cancer specific survival (CSS) (31.0% vs 33.6%; P = 0.35) with patients without biopsies. Multivariate analysis further confirmed that biopsy of distant metastasis was not associated with impaired OS (HR = 1.03, 95% CI = 0.84-1.25; P = 0.80) or CSS (HR = 1.07, 95% CI = 0.86-1.34; P = 0.54). Conclusions: Biopsy of distant metastasis was not associated with impaired survival outcomes for synchronous metastatic NPC patients. Biopsy of distant metastasis could be another diagnosed choice for patients with suspected distant metastasis.

20.
ACS Appl Mater Interfaces ; 13(25): 29654-29663, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34148341

RESUMO

The surface reconstruction of iridium-based derivatives (AxIryOz) was extensively demonstrated to have an excellent oxygen evolution reaction (OER) performance in an acidic medium. It is urgent to use various spectroscopy and computational methods to explore the electronic state changes in the surface reconstruction process. Herein, the underestimated Lu2Ir2O7 was synthesized and investigated. Four typical forms of electrochemistry impedance spectra involved in the reconstruction process revealed three dominating forms of reconstructed pyrochlore in the OER stage, including the inner intact pyrochlore, mid metastable [IrO6]-[IrO6] framework, and the outer collapse amorphous layer. The enhancing electron transport efficiency of the corner-shared [IrO6]-[IrO6] framework was revealed as a critical role in acidic systems. The density of state (DOS) for the constructed [IrO6]-[IrO6] framework corroborated the enhancement of Ir-O hybridization and the downshift of the d-band center. Additionally, we contrast the pristine and reconstruction properties of the Pr2Ir2O7, Eu2Ir2O7, and Lu2Ir2O7 in alkaline and acidic media. The DOS and the XANES results reveal the scale relationship between the O 2p band center and the intrinsic activity for bulk pyrochlore in alkaline media. The highest O 2p center and the highest Ir-O hybridization of Lu2Ir2O7 exhibited the best OER performance among the Ir-based pyrochlore, up to a ninefold improvement in Ir-mass activity compared to IrO2. Our findings emphasize the electrochemical behavior of the reconstruction process for activated water-splitting performance.

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