RESUMO
Intervertebral disc degeneration (IVDD) severely affects the work and the quality of life of people. We previously demonstrated that silencing activation transcription factor 3 (ATF3) blocked the IVDD pathological process by regulating nucleus pulposus cell (NPC) ferroptosis, apoptosis, inflammation, and extracellular matrix (ECM) metabolism. Nevertheless, whether miR-874-3p mediated the IVDD pathological process by targeting ATF3 remains unclear. We performed single-cell RNA sequencing (scRNA-seq) and bioinformatics analysis to identify ATF3 as a key ferroptosis gene in IVDD. Then, Western blotting, flow cytometry, ELISA, and animal experiments were performed to validate the roles and regulatory mechanisms of miR-874-3p/ATF3 signalling axis in IVDD. ATF3 was highly expressed in IVDD patients and multiple cell types of IVDD rat, as revealed by scRNA-seq and bioinformatics analysis. GO analysis unveiled the involvement of ATF3 in regulating cell apoptosis and ECM metabolism. Furthermore, we verified that miR-874-3p might protect against IVDD by inhibiting NPC ferroptosis, apoptosis, ECM degradation, and inflammatory response by targeting ATF3. In vivo experiments displayed the protective effect of miR-874-3p/ATF3 axis on IVDD. These findings propose the potential of miR-874-3p and ATF3 as biomarkers of IVDD and suggest that targeting the miR-874-3p/ATF3 axis may be a therapeutic target for IVDD.
Assuntos
Fator 3 Ativador da Transcrição , Ferroptose , Degeneração do Disco Intervertebral , MicroRNAs , Núcleo Pulposo , Fator 3 Ativador da Transcrição/metabolismo , Fator 3 Ativador da Transcrição/genética , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Humanos , Ratos , Ferroptose/genética , Masculino , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Análise de Célula Única/métodos , Apoptose/genética , Transdução de Sinais , Feminino , Pessoa de Meia-Idade , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos , Matriz Extracelular/metabolismo , Adulto , Regulação da Expressão Gênica , Modelos Animais de Doenças , Biologia Computacional/métodosRESUMO
Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult but not paediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues. Here we present a pan-cancer study of somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number alterations, gene fusions and internal tandem duplications in 1,699 paediatric leukaemias and solid tumours across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data processed under a uniform analytical framework. We report 142 driver genes in paediatric cancers, of which only 45% match those found in adult pan-cancer studies; copy number alterations and structural variants constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet-light exposure in eight aneuploid leukaemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele-specific expression. These data provide a comprehensive genomic architecture for paediatric cancers and emphasize the need for paediatric cancer-specific development of precision therapies.
Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Leucemia/genética , Mutação/genética , Neoplasias/genética , Alelos , Aneuploidia , Criança , Variações do Número de Cópias de DNA , Exoma/genética , Humanos , Mutação/efeitos da radiação , Taxa de Mutação , Oncogenes/genética , Medicina de Precisão/tendências , Raios Ultravioleta/efeitos adversosRESUMO
PURPOSE: To evaluate outcomes of choosing different Roussouly shapes and improving in Schwab modifiers for surgical Roussouly type 1 patients. METHODS: Baseline (BL) and 2-year (2Y) clinical data of adult spinal deformity (ASD) patients presenting with Roussouly type 1 sagittal spinal alignment were isolated in the single-center spine database. Patients were grouped into Roussouly type 1, 2 and 3 with anteverted pelvis (3a) postoperatively. Schwab modifiers at BL and 2Y were categorized as follows: no deformity (0), moderate deformity (+), and severe deformity (++) for pelvic tilt (PT), sagittal vertical axis (SVA), and pelvic incidence and lumbar lordosis mismatch (PI-LL). Improvement in SRS-Schwab was defined as a decrease in the severity of any modifier at 2Y. RESULTS: A total of 96 patients (69.9 years, 72.9% female, 25.2 kg/m2) were included. At 2Y, there were 34 type 1 backs, 60 type 2 backs and only 2 type 3a. Type 1 and type 2 did not differ in rates of reaching 2Y minimal clinically important difference (MCID) for health-related quality of life (HRQOL) scores (all P > 0.05). Two patients who presented with type 3a had poor HRQOL scores. Analysis of Schwab modifiers showed that 41.7% of patients improved in SVA, 45.8% in PI-LL, and 36.5% in PT. At 2Y, patients who improved in SRS-Schwab PT and SVA had lower Oswestry disability index (ODI) scores and significantly more of them reached MCID for ODI (all P < 0.001). Patients who improved in SRS-Schwab SVA and PI-LL had more changes of VAS Back and Short Form-36 (SF-36) outcomes questionnaire physical component summary (SF-36 PCS), and significantly more reached MCID (all P < 0.001). By 2Y, type 2 patients who improved in SRS-Schwab grades reached MCID for VAS back and ODI at the highest rate (P = 0.003, P = 0.001, respectively), and type 1 patients who improved in SRS-Schwab grades reached MCID for SF-36 PCS at the highest rate (P < 0.001). CONCLUSION: For ASD patients classified as Roussouly type 1, postoperative improvement in SRS-Schwab grades reflected superior patient-reported outcomes while type 1 and type 2 did not differ in clinical outcomes at 2Y. However, development of type 3a should be avoided at the risk of poor functional outcomes. Utilizing both classification systems in surgical decision-making can optimize postoperative outcomes.
Assuntos
Diferença Mínima Clinicamente Importante , Humanos , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Fusão Vertebral/métodos , Lordose/cirurgia , Lordose/diagnóstico por imagem , Escoliose/cirurgia , Qualidade de VidaRESUMO
PURPOSE: This study aimed to evaluate the cervical sagittal profile after the spontaneous compensation of global sagittal imbalance and analyze the associations between the changes in cervical sagittal alignment and spinopelvic parameters. METHODS: In this retrospective radiographic study, we analyzed 90 patients with degenerative lumbar stenosis (DLS) and sagittal imbalance who underwent short lumbar fusion (imbalance group). We used 60 patients with DLS and sagittal balance as the control group (balance group). Patients in the imbalance group were also divided into two groups according to the preoperative PI: low PI group (≤ 50°), high PI group (PI > 50°). We measured the spinal sagittal alignment parameters on the long-cassette standing lateral radiographs of the whole spine. We compared the changes of spinal sagittal parameters between pre-operation and post-operation. We observed the relationships between the changes in cervical profile and spinopelvic parameters. RESULTS: Sagittal vertical axis (SVA) occurred spontaneous compensation (p = 0.000) and significant changes were observed in cervical lordosis (CL) (p = 0.000) and cervical sagittal vertical axis (cSVA) (p = 0.023) after surgery in the imbalance group. However, there were no significant differences in the radiographic parameters from pre-operation to post-operation in the balance group. The variations in CL were correlated with the variations in SVA (R = 0.307, p = 0.041). The variations in cSVA were correlated with the variations in SVA (R=-0.470, p = 0.001). CONCLUSION: Cervical sagittal profile would have compensatory changes after short lumbar fusion. The spontaneous decrease in CL would occur in patients with DLS after the spontaneous compensation of global sagittal imbalance following one- or two-level lumbar fusion. The changes of cervical sagittal profile were related to the extent of the spontaneous compensation of SVA.
Assuntos
Vértebras Cervicais , Lordose , Vértebras Lombares , Fusão Vertebral , Estenose Espinal , Humanos , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Masculino , Feminino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Vértebras Lombares/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Estenose Espinal/cirurgia , Estenose Espinal/diagnóstico por imagem , Lordose/diagnóstico por imagem , Lordose/cirurgia , Equilíbrio Postural/fisiologia , RadiografiaRESUMO
ß-FeOOH nanorods were prepared via the urea hydrolysis process with the average length of 289.1 nm and average diameter of 61.2 nm, while magneticα-Fe2O3/Fe3O4heterostructure nanorods were prepared via the urea calcination process withß-FeOOH nanorods as precursor, and the optimum conditions were the calcination temperature of 400 °C, the calcination time of 2 h, theß-FeOOH/urea mass ratio of 1:6. The average length, diameter, and the saturation magnetization of the heterostructure nanorods prepared under the optimum conditions were 328.8 nm, 63.4 nm and 42 emu·g-1, respectively. The Prussian blue test demonstrated that the heterostructure nanorods could be taken up by HepG2 cells, and cytotoxicity tests proved that the heterostructure nanorods had no significant effect on the viabilities of LO2 and HepG2 cells within 72 h in the range of 100-1600µg·ml-1. Therefore, magneticα-Fe2O3/Fe3O4heterostructure nanorods had better biocompatibility with LO2 and HepG2 cells.
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PURPOSE: Previous animal studies have discovered dysregulation of the local inflammatory state as a novel mechanism to explain structural changes in paraspinal muscles in association with disc degeneration. This study aimed to determine whether the expression of inflammatory genes in the multifidus muscle (MM) differs between individuals with disc degeneration and non-degeneration, which may cause changes in the cross-sectional area (CSA) of paraspinal muscles and clinical outcomes. METHODS: Muscles were procured from 60 individuals undergoing percutaneous endoscopic lumbar discectomy for lumbar disc herniation (LDH). Total and functional CSAs and fatty degeneration of paraspinal muscles on ipsilateral and unilateral sides were measured. Gene expression was quantified using qPCR assays. Paired t-test and Pearson's correlation analysis were used to compare the mean difference and associations, respectively. RESULTS: There were significant differences in total CSAs of paraspinal muscles and functional CSA and fatty degeneration of MM between ipsilateral and unilateral sides. Participants in the disc degeneration group displayed higher fat infiltration in MM. The expression of TNF was moderately correlated with total CSAs of paraspinal muscles and functional CSA and fatty degeneration of MM. The expression of IL-1ß was strongly correlated with the total and functional CSA of MM. The expression of TGF-ß1 was moderately correlated with the functional CSA of MM. The expression of TNF, IL-1ß, and TGF-ß1 was moderate to strongly correlated with clinical outcomes. CONCLUSION: The results show that there were differences in the characteristics of paraspinal muscles between the ipsilateral and unilateral sides, which were affected by disc degeneration and the degree of fat infiltration. High-fat filtration and reduction of CSA of MM are associated with inflammatory dysfunction. There was evidence of a dysregulated inflammatory profile in MM in individuals with poor clinical outcomes.
Assuntos
Discotomia Percutânea , Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Humanos , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/cirurgia , Degeneração do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Deslocamento do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/complicações , Fator de Crescimento Transformador beta1 , Citocinas , Imageamento por Ressonância Magnética , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Músculos Paraespinais/diagnóstico por imagem , Músculos Paraespinais/cirurgiaRESUMO
OBJECTIVE: To identify factors associated with T1 slope (T1S). METHODS: A total of 215 patients over 18 years old who underwent whole-spine X-rays to evaluate lower back pain were enrolled in this study. T1S, pelvic tilt (PT), sacral slope (SS), pelvic incidence (PI), thoracic kyphosis (TK), lumbar lordosis (LL), cervical lordosis (CL), thoracolumbar kyphosis (TLK), and sagittal vertical axis (SVA) were measured. Patients were divided into balance, compensatory balance, thoracic compensation, and thoracic decompensation groups. RESULTS: TK (p < 0.001), SVA (p < 0.001), and CL (p = 0.020) were significantly related to high T1S. The balance group had the smallest PT, largest SS and largest LL of the four groups (p < 0.001). The thoracic compensation group had the smallest TK of all groups (p < 0.001). There was no significant difference in T1S between the balance and thoracic compensation groups (p = 0.099). The thoracic decompensation group had a larger T1S than the balance group (p = 0.023). CONCLUSIONS: Caudal spine segments had a sequential effect on cranial spine segments. T1S reflected the compensation ability of the spine. The absence of balance tended to increase the T1S. Pelvic posterior rotation and thoracic compensation were two crucial factors protecting against increased T1S in patients with ASD.
Assuntos
Cifose , Lordose , Humanos , Adolescente , Lordose/diagnóstico por imagem , Cifose/diagnóstico por imagem , Sacro , Radiografia , Pelve/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Estudos RetrospectivosRESUMO
To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.
Assuntos
Biomarcadores Tumorais/genética , Metotrexato/uso terapêutico , Mutagênese/efeitos dos fármacos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , 5'-Nucleotidase/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Análise Mutacional de DNA , Feminino , Seguimentos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Receptores de Glucocorticoides/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
Patients with advanced gastric cancer experience rapid disease progression with limited survival, high mortality, and a lack of surgical options. Thus, radiochemotherapy or a combination of chemotherapeutics with targeted therapy is the mainstay of treatment. In comparison to the treatment of other malignant tumors, in gastric cancer, the development of molecularly targeted drugs has been relatively slow. Currently, there are two major classes of molecularly targeted drug regimens that have achieved a certain efficacy in clinical practice: anti-vascular endothelial growth factor (anti-VEGF) therapy and anti-epidermal growth factor receptor (anti-EGFR) therapy. Trastuzumab has been approved as the standard of care for first-line treatment in advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer. Ramucirumab in combination with paclitaxel is the recommended regimen for second-line treatment, and apatinib is recommended as third-line treatment. This review summarizes the current status of targeted therapies in the treatment of gastric cancer and gives a perspective on the future.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Trastuzumab/uso terapêutico , Paclitaxel , Terapia de Alvo MolecularRESUMO
BACKGROUND: Kinetic parameters estimated with dynamic 18F-FDG PET/CT can help to characterize hepatocellular carcinoma (HCC). We aim to evaluate the feasibility of the gravitational search algorithm (GSA) for kinetic parameter estimation and to propose a dynamic chaotic gravitational search algorithm (DCGSA) to enhance parameter estimation. METHODS: Five-minute dynamic PET/CT data of 20 HCCs were prospectively enrolled, and the kinetic parameters k1 ~ k4 and the hepatic arterial perfusion index (HPI) were estimated with a dual-input three-compartment model based on nonlinear least squares (NLLS), GSA and DCGSA. RESULTS: The results showed that there were significant differences between the HCCs and background liver tissues for k1, k4 and the HPI of NLLS; k1, k3, k4 and the HPI of GSA; and k1, k2, k3, k4 and the HPI of DCGSA. DCGSA had a higher diagnostic performance for k3 than NLLS and GSA. CONCLUSIONS: GSA enables accurate estimation of the kinetic parameters of dynamic PET/CT in the diagnosis of HCC, and DCGSA can enhance the diagnostic performance.
Assuntos
Algoritmos , Carcinoma Hepatocelular/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Compostos RadiofarmacêuticosRESUMO
For better use of solar energy, the development of efficient broadband photocatalyst has attracted extraordinary attention. In this study, a ternary composite consisting of Sr2LaF7:Yb3+,Er3+ upconversion (UC) nanocrystals and Bi nanoparticles loaded BiOBr nanosheets with oxygen vacancies (OVs, SLFBB) was designed and synthesized by multistep solvent-thermal method. Mechanisms of in-situ formation of Bi nanoparticles and OVs in BiOBr/Sr2LaF7:Yb3+,Er3+ composites (SFLB) are clarified. The Bi metal and OVs enhanced the light-harvesting capacity in the region of visible-near-infrared (Vis-NIR), and promoted the separation of electron-hole (e-/h+) pairs. Furthermore, the surface plasmon resonance (SPR) effect of Bi metal can improve the energy transfer from Sr2LaF7:Yb3+,Er3+ to BiOBr via nonradiative energy transfer process, resulting in enhancing the light utilization from upconverting NIR into Vis light. Due to the synergistic effects of UC function, SPR and OVs, the SFLBB exhibited obviously enhanced photocatalytic ability for the degradation of BPA with a rate of 8.9 × 10-3 min-1, which is about 2.78 times higher than 3.2 × 10-3 min-1 of BiOBr (BOB) under UV-Vis-NIR light irradiation. This work provides a novel strategy for the project of high-efficiency Bismuth-based broadband photocatalysts, which is helpful to further understand the mechanism of enhanced photocatalysis by UC function and plasmonic effect.
Assuntos
Bismuto , Oxigênio , Catálise , LuzRESUMO
BACKGROUND: Traumatic spinal cord injury (SCI) is a severely disabling disease that leads to loss of sensation, motor, and autonomic function. As exosomes have great potential in diagnosis, prognosis, and treatment of SCI because of their ability to easily cross the blood-brain barrier, the function of Schwann cell-derived exosomes (SCDEs) is still largely unknown. METHODS: A T10 spinal cord contusion was established in adult female mice. SCDEs were injected into the tail veins of mice three times a week for 4 weeks after the induction of SCI, and the control group was injected with PBS. High-resolution transmission electron microscope and western blot were used to characterize the SCDEs. Toll-like receptor 2 (TLR2) expression on astrocytes, chondroitin sulfate proteoglycans (CSPGs) deposition and neurological function recovery were measured in the spinal cord tissues of each group by immunofluorescence staining of TLR2, GFAP, CS56, 5-HT, and ß-III-tublin, respectively. TLR2f/f mice were crossed to the GFAP-Cre strain to generate astrocyte specific TLR2 knockout mice (TLR2-/-). Finally, western blot analysis was used to determine the expression of signaling proteins and IKKß inhibitor SC-514 was used to validate the involved signaling pathway. RESULTS: Here, we found that TLR2 increased significantly on astrocytes post-SCI. SCDEs treatment can promote functional recovery and induce the expression of TLR2 on astrocytes accompanied with decreased CSPGs deposition. The specific knockout of TLR2 on astrocytes abolished the decreasing CSPGs deposition and neurological functional recovery post-SCI. In addition, the signaling pathway of NF-κB/PI3K involved in the TLR2 activation was validated by western blot. Furthermore, IKKß inhibitor SC-514 was also used to validate this signaling pathway. CONCLUSION: Thus, our results uncovered that SCDEs can promote functional recovery of mice post-SCI by decreasing the CSPGs deposition via increasing the TLR2 expression on astrocytes through NF-κB/PI3K signaling pathway.
Assuntos
Astrócitos/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Exossomos/metabolismo , Células de Schwann/metabolismo , Traumatismos da Medula Espinal/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Camundongos , Camundongos Knockout , Recuperação de Função Fisiológica/fisiologia , Serotonina/metabolismo , Medula Espinal/metabolismo , Receptor 2 Toll-Like/genética , Tubulina (Proteína)/metabolismoRESUMO
Osteoporosis (OP) is an increasingly important public health issue, women constitute approximately 80% of those diagnosed with OP. Improved risk perception regarding OP is important for early prevention. This study aimed to examine the association among socio-demographic, communication related variables and risk perception regarding OP. An online survey with 950 participants was conducted. The survey comprised 19 questions pertaining to lifestyle, general health, bone fracture awareness and demographics. Bivariate analyses were used to examine unadjusted relations among socio-demographic, communication related variables and comparative perceived risk of OP. Ordinary least squares (OLS) regression analysis was used to analyze the association between communication media exposure, information processing mode, educational level, self-efficacy and risk perception for OP. Results suggest that some socio-demographic variables (gender, educational level, income) and some communication relevant variables (communication media exposure, the ability to acquire information and systematic information processing) were positively associated with higher OP risk perception, while self-efficacy was negative factor. The study also showed that heuristic-systematic processing and self-efficacy were found to moderate the impact of communication media on risk perceptions. Improved understanding of the impact of communication on risk perception may aid in the development of effective intervention strategies to reduce the burden of OP.
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Conhecimentos, Atitudes e Prática em Saúde , Osteoporose , China/epidemiologia , Comunicação , Escolaridade , Feminino , Humanos , Estilo de Vida , Osteoporose/epidemiologiaRESUMO
A strategy is proposed to stabilize the polymeric interface by using the irregular Janus nanosheet (JNS). The poly(vinylidene fluoride) (PVDF)/poly(l-lactic acid) (PLLA) at 60/40 (wt/wt) with a bi-continuous structure is selected as the model melt blend, and the PMMA/epoxy JNS is synthesized and used as the compatibilizer. The JNS is preferentially located at the interface. The interfacial coverage by the JNS reaches a saturated state forming the interconnected jamming structure at 0.5 wt% of the JNS. The interface is thus stabilized which is well preserved after annealing at high temperature. After selectively etching PLLA, the robust PVDF porous material is derived with the JNS armored at the pore skeleton surface. The porous material provides a universal scaffold to achieve stable functional materials after filling the pores.
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Materiais Biocompatíveis , Polímeros , PorosidadeRESUMO
Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
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Transformação Celular Neoplásica , Ependimoma/genética , Ependimoma/metabolismo , NF-kappa B/metabolismo , Proteínas/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Sequência de Bases , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 11/genética , Ependimoma/patologia , Feminino , Humanos , Camundongos , Modelos Genéticos , Dados de Sequência Molecular , NF-kappa B/genética , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas/genética , Fator de Transcrição RelA/genética , Fatores de Transcrição , Translocação Genética/genética , Proteínas de Sinalização YAPRESUMO
Oxaliplatin is a first-line clinical drug in cancer treatment and its side effects of peripheral neuropathic pain have also attracted much attention. Neuroinflammation induced by oxidative stress-mediated activation of nuclear factor-kappa B (NF-κB) plays an important role in the course. Current studies have shown that curcumin has various biological activities like antioxidant, anti-inflammatory, antitumor and so on, while few studies were conducted about its role in oxaliplatin-induced peripheral neuropathic pain. The aim of this study is to verify the mechanism of curcumin alleviating oxaliplatin-induced peripheral neuropathic pain. Intraperitoneal injection with oxaliplatin (4 mg/kg body weight) was given to the rats twice a week and last for four weeks to establish the model rats. Gavage administration of curcumin (12.5, 25, and 50 mg/kg body weight, respectively) was conducted for consecutive 28 d to explore the effects and potential mechanism. Our results showed that curcumin administration could increase mechanical withdrawal threshold and decrease the paw-withdrawal times of cold allodynia significantly; meanwhile, motor nerve conduction velocity (MNCV) and sense nerve conduction velocity (SNCV) were both increased and the injured neurons of the spinal cord were repaired. In addition, curcumin administration increased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and reduced malondialdehyde (MDA). Moreover, the curcumin operation inhibited the activated of NF-κB and level of inflammatory factors like tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). In conclusion, these findings suggested that curcumin could alleviate oxaliplatin-induced peripheral neuropathic pain; the mechanism might be inhibiting oxidative stress-mediated activation of NF-κB and mitigating neuroinflammation.
Assuntos
Curcumina/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Hiperalgesia/tratamento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Malondialdeído/metabolismo , Condução Nervosa/efeitos dos fármacos , Neuralgia/induzido quimicamente , Oxaliplatina , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Maternal feeding anxiety (FA) was prevalent during puerperium and might affect infant feeding practices. This study was aimed to investigate the FA status in Chinese postpartum women and its relationship with infant feeding practices (FPs). METHODS: Participants were from the Mother-Infant Cohort Study of China, in which the dietary and feeding practices, physical and psychiatric health for both mothers and infants were followed up from childbirth to next 2 years. In this study the maternal feeding anxiety (FA) status at 0-3 months postpartum was assessed by Li's Self-rating Feeding Anxiety Scale (SFAS). Infant feeding practices (FPs) at 0-3 months, including breastfeeding-related behaviors, responsive feeding and infant food refusal were investigated by self-designed questionnaire. RESULTS: In total 456 mothers the average feeding anxiety scores (FAS) was 41.02 ± 8.02 (mean ± SD), and maternal FA prevalence were 61.4% (FAS>38) with severe FA being 8.6% (FAS>52) at 0-3 months postpartum. The FAS was related with infant FPs, and lower maternal FAS was significantly related with infant colostrum feeding (40.86 ± 8.02 vs 44.74 ± 11.33, P < 0.05), but higher FAS was related with bottle feeding (41.95 ± 8.28 vs 39.69 ± 7.92, P < 0.05). The mothers with severe feeding anxiety (FAS > 53) were more likely to feed infants with bottle (ORs, 95%CI: 2.41, 1.11 ~ 5.19). There were not significant association between FAS and exclusive breastfeeding and responsive feeding practices (P > 0.05). The higher FAS was associated with infant food refusal behaviors, the maternal scores whose infant "never", "rarely", "sometimes" and "often" spat out food when feeding were 39.86 ± 8.02, 41.47 ± 8.18, 41.36 ± 7.44 and 42.14 ± 12.03 increasingly (P > 0.05), and the FA prevalence was significantly different among groups (P < 0.05). The infants whose mother was identified as feeding anxiety were more likely to refuse opening the mouth when feeding (P < 0.05). Multivariate analysis indicated maternal FAS was positively related to infant bottle feeding (ßi = 2.487, P < 0.05) and outdoor sunshine exposure practice (ßi = 1.787, P < 0.05), and negatively related to household income level (ßi = - 0.118, P < 0.05). CONCLUSIONS: Maternal postpartum feeding anxiety was associated with some infant feeding practices, including bottle feeding and infant food refusal behaviors.
Assuntos
Ansiedade/epidemiologia , Alimentação com Mamadeira/psicologia , Aleitamento Materno/psicologia , Comportamento Alimentar/psicologia , Mães/psicologia , Adulto , Ansiedade/diagnóstico , Atitude Frente a Saúde , Alimentação com Mamadeira/estatística & dados numéricos , Aleitamento Materno/estatística & dados numéricos , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Período Pós-Parto/psicologia , Prevalência , Inquéritos e QuestionáriosRESUMO
Number of well-known contagious diseases exist around the world that mainly include HIV, Hepatitis B, influenzas etc., among these, a recently contested coronavirus (COVID-19) is a serious class of such transmissible syndromes. Abundant scientific evidence the wild animals are believed to be the primary hosts of the virus. Majority of such cases are considered to be human-to-human transmission, while a few are due to wild animals-to-human transmission and substantial burdens on healthcare system following this spread. To understand the dynamical behavior such diseases, we fitted a susceptible-infectious-quarantined model for human cases with constant proportions. We proposed a model that provide better constraints on understanding the climaxes of such unseen disastrous spread, relevant consequences, and suggesting future imperative strategies need to be adopted. The main features of the work include the positivity, boundedness, existence and uniqueness of solution of the model. The conditions were derived under which the COVID-19 may extinct or persist in the population. Sensitivity and estimation of those important parameters have been carried out that plays key role in the transmission mechanism. To optimize the spread of such disease, we present a control problem for further analysis using two control measures. The necessary conditions have been derived using the Pontryagin's maximum principle. Parameter values have been estimated from the real data and experimental numerical simulations are presented for comparison as well as verification of theoretical results. The obtained numerical results also present the verification, accuracy, validation, and robustness of the proposed scheme.
RESUMO
Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of BCR-ABL1 (n = 46) or ETV6-RUNX1 (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of CRLF2 (IGH-CRLF2 or P2RY8-CRLF2) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients (50.8% of those with CRLF2 rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (ABL1, ABL2, CSF1R, and PDGFRB) in 14.1%, EPOR rearrangements or JAK2 fusions in 8.8%, alterations activating other JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6%, and mutations involving the Ras pathway (KRAS, NRAS, NF1, PTPN11) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.
Assuntos
Fusão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Quinases/genética , Criança , Feminino , Proteínas de Fusão bcr-abl/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Janus Quinase 2/genética , Masculino , Mutação , Cromossomo Filadélfia , Receptores de Citocinas/genética , Estudos Retrospectivos , TranscriptomaRESUMO
BACKGROUND: On September 4, 2018, a boarding school in the Shunyi District of Beijing, China reported an outbreak of acute gastroenteritis. At least 209 suspected students caused of diarrhea and vomiting. The case was investigated, and control measures were taken to prevent further spread. METHODS: A retrospective cohort study was conducted among the school students and staff in order to test hypothesis that high risk of food served at the school canteen. We collected information on demographics, refectory records, person to person transmission by uniform epidemiological questionnaire. Risk ratios (RR) and 95% confidence intervals (CI) were calculated. Stool specimens of cases and canteen employees, retained food, water, and environmental swabs were investigated by laboratory analysis. RESULTS: We identified 209 cases (including 28 laboratory-confirmed cases) which occurred from August 29 to September 10. All cases were students, and the average age was 20, 52% were male. The outbreak lasted for 13 days, and peaked on September 5. Consumption of Drinks stall and Rice flour stall on September 1 (RR:3.4, 95%CI:1.5-7.8, and RR:7.6, 95%CI:2.8-20.2), Rice flour stall and Fish meal stall on September 2 (RR:4.0, 95%CI:1.2-13.6, and RR:4.6, 95%CI:1.7-12.5), muslim meal stall on September 4 (RR:2.7, 95%CI:1.3-5.4), Barbeque stall on September 5 (RR:3.0, 95%CI:1.2-7.0) were independently associated with increased risk of disease within the following 2 days. Among 35 specimens of rectal swabs or feces from students, 28 specimens were positive. Norovirus GI.6 alone was detected in 23 specimens, Bacillus cereus alone in 3 specimens and both norovirus GI.6 and Bacillus cereus in 2 specimens. Ten specimens of rectal swabs from canteen employees were positive for norovirus GI, and 2 specimens were positive for Bacillus cereus. Four retained food specimens were positive for Bacillus cereus, and environmental samples were negative for any viruses or bacteria. CONCLUSION: Our investigation indicated that canteen employees were infected by two pathogens (norovirus and Bacillus cereus) and transmission may have been possible due to unhygienic practices. Student consumption of food or drink at high-risk stalls was determined as the probable cause of the outbreak.