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Low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6), a member of the LDLR superfamily of cell surface receptors, is most widely known as a crucial co-receptor in the activation of canonical Wnt/ß-catenin signaling. This signaling pathway is implicated in multiple biological processes, such as lipoprotein metabolism, protease regulation, cell differentiation, and migration. LRP6 is frequently overexpressed in a variety of tumors, including liver cancer, colorectal cancer, and prostate cancer, and is generally considered an oncogene that promotes tumor proliferation, migration, and invasion. However, there are exceptions; some studies have reported that LRP6 inhibits lung metastasis of breast cancer through its ectodomain (LRP6N), and patients with low LRP6 expression tend to have a poor prognosis. Thus, the role of LRP6 in tumors remains controversial. Although limited studies have shown that LRP6 is associated with the expression and roles of a variety of immune cells in tumors, the interaction of LRP6 with the tumor microenvironment (TME) is not fully understood. Furthermore, it is crucial to acknowledge that LRP6 can engage with alternative pathways, including the mTORC1, CXCL12/CXCR4, and KRAS signaling pathways mentioned earlier, resulting in the regulation of biological functions independent of canonical Wnt/ß-catenin signaling. Due to the potential of LRP6 as a molecular target for cancer therapy, various treatment modalities have been developed to directly or indirectly inhibit LRP6 function, demonstrating promising anti-cancer effects across multiple cancer types. This review will concentrate on exploring the expression, function, and potential therapeutic applications of LRP6 in different cancer types, along with its influence on the TME.
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Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Terapia de Alvo Molecular , Neoplasias , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Terapia de Alvo Molecular/métodos , Microambiente Tumoral/imunologia , Via de Sinalização Wnt , AnimaisRESUMO
Chemotherapy failure and resistance are the leading causes of mortality in patients with acute myeloid leukemia (AML). However, the role of m6A demethylase FTO and its inhibitor rhein in AML and AML drug resistance is unclear. Therefore, this study aimed to investigate the antileukemic effect of rhein on AML and explore its potential mechanisms underlying drug resistance. Bone marrow fluid was collected to assess FTO expression in AML. The Cell Counting Kit 8 reagent was used to assess cell viability. Migration assays were conducted to assess the cell migration capacity. Flow cytometry was used to determine the apoptotic effects of rhein and western blot analysis was used to detect protein expression. Online SynergyFinder software was used to calculate the drug synergy scores. The in-vivo antileukemic effect of rhein was assessed in an AML xenograft mouse model. We analyzed different types of AML bone marrow specimens to confirm that FTO is overexpressed in AML, particularly in cases of multidrug resistance. Subsequently, we conducted in-vivo and in-vitro investigations to explore the pharmacological activity and mechanism of rhein in AML and AML with multidrug resistance. The findings demonstrated that rhein effectively suppressed the proliferation and migration of AML cells in a time- and dose-dependent manner and induced apoptosis. Rhein targets FTO, inhibits the AKT/mTOR pathway, and exhibits synergistic antitumor effects when combined with azacitidine. This study elucidates the significant role of FTO and its inhibitor rhein in AML and AML with multidrug resistance, providing new insights for overcoming multidrug resistance in AML.
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Dioxigenase FTO Dependente de alfa-Cetoglutarato , Antraquinonas , Apoptose , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Animais , Camundongos , Antraquinonas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Masculino , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Nus , Pessoa de Meia-Idade , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: The purpose of this study was to investigate the learning curve of percutaneous endoscopic transforaminal discectomy (PETD) and interlaminar unilateral biportal endoscopic discectomy (UBED) in the treatment of lumbar disc herniation (LDH). METHODS: Between 2018 and 2023, 120 consecutive patients with lumbar disc herniation (LDH) treated by endoscopic lumbar discectomy were retrospectively included. The PETD group comprised 87 cases, and the UBED group comprised 33 cases. Cumulative sum analysis was used to evaluate the learning curve, with the occurrence of complications or unresolved symptoms defined as surgical failure, and variables of different phases of the learning curve being compared. RESULTS: The learning curve analysis identified the cutoff point at 40 cases in the PETD group and 15 cases in the UBED group. In the mastery phase, both PETD and UBED demonstrated a significant reduction in operation times (approximately 38 min for PTED and 49 min for UBED). In both PETD and UBED groups, the surgical failure rates during the learning and mastery phases showed no statistically significant differences. The visual analogue scale at the last follow-up was significantly lower than before surgery in both the PETD and UBED groups. CONCLUSION: PETD and UBED surgery are effective in the treatment of LDH with a low incidence of complications. However, achieving mastery in PETD necessitates a learning curve of 40 cases, while UBED requires a minimum of 15 cases to reach proficiency.
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Discotomia Percutânea , Endoscopia , Deslocamento do Disco Intervertebral , Curva de Aprendizado , Vértebras Lombares , Humanos , Deslocamento do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Discotomia Percutânea/métodos , Discotomia Percutânea/educação , Masculino , Feminino , Pessoa de Meia-Idade , Vértebras Lombares/cirurgia , Vértebras Lombares/diagnóstico por imagem , Adulto , Endoscopia/métodos , Endoscopia/educação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Acute myeloid leukemia(AML) is a malignant tumor of the blood system that is highly heterogeneous in terms of pathogenesis, genetic background and prognostic outcome, with an extremely high fatality rate and recurrence rate. Therefore, exploring new treatment methods and diagnostic strategies is one of the ways to improve the survival rate of patients with acute myeloid leukemia. Circular RNA (circRNA) is a special kind of nonîcoding RNA, which plays an important role in gene transcription, translation and epigenetic modification, and participates in the disease progression and prognosis of multiple solid tumors. At present, it has found that the abnormal expression of circRNA is closely related to the occurrence, development, drug resistance and prognosis of acute myeloid leukemia.Clinically, it can be used as a new biomarker and potential therapeutic target for AML. This article briefly reviews the research progress of circRNA in acute myeloid leukemia, aiming to provide new strategies for optimizing the diagnosis, treatment and prognosis of leukemia.
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Leucemia Mieloide Aguda , RNA Circular , Humanos , Progressão da Doença , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Prognóstico , RNA/genética , RNA/uso terapêutico , RNA Circular/genéticaRESUMO
High-quality protein-ligand complex structures provide the basis for understanding the nature of noncovalent binding interactions at the atomic level and enable structure-based drug design. However, experimentally determined complex structures are scarce compared with the vast chemical space. In this study, we addressed this issue by constructing the BindingNet data set via comparative complex structure modeling, which contains 69,816 modeled high-quality protein-ligand complex structures with experimental binding affinity data. BindingNet provides valuable insights into investigating protein-ligand interactions, allowing visual inspection and interpretation of structural analogues' structure-activity relationships. It can also be used for evaluating machine-learning-based scoring functions. Our results indicate that machine learning models trained on BindingNet could reduce the bias caused by buried solvent-accessible surface area, as we previously found for models trained on the PDBbind data set. We also discussed strategies to improve BindingNet and its potential utilization for benchmarking the molecular docking methods and ligand binding free energy calculation approaches. The BindingNet complements PDBbind in constructing a sufficient and unbiased protein-ligand binding data set and is freely available at http://bindingnet.huanglab.org.cn.
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Desenho de Fármacos , Proteínas , Simulação de Acoplamento Molecular , Ligantes , Proteínas/química , Ligação ProteicaRESUMO
In recent years, notable headway has been made in augmenting supercapacitor functioning through employment of pioneering components, exceptional nanostructures and additional investigation of electrolytes. Nonetheless, achieving superior performance with straightforward techniques remains a significant hurdle. In order to surmount this, an experimental three-dimensional nanospherical pore structure (TPB-20@Ni(OH)2) was designed and prepared. TPB-1 was obtained through carbonisation and activation. TPB-20@Ni(OH)2nanoparticles were synthesized using TPB-1 as the carbon source and nickel chloride hexahydrate as the nickel source. Furthermore, the TPB-20@Ni(OH)2//AC supercapacitor displayed an impressive energy density of 22.1 Wh kg-1. The TPB-20@Ni(OH)2composites exhibited a specific capacity of 978 F-1, which is noteworthy. The exceptional output exhibited by the TPB-20@Ni(OH)2composite derives from its innovative structure, presenting an extensive specific surface area of 237.4 m2g-1and porosity of roughly 4.0 nm. Following 20 000 cycles (at a current density of 1 A g-1), asymmetric supercapacitors assembled from TPB-20@Ni(OH)2//AC retained 80.0% of its initial specific electrostatic capacity, indicating superior electrochemical stability and high electrochemical reversibility.
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This study aimed to present a special case of treatment of a patient with multisegmental vertebral compression fracture, burst fracture, and sandwich vertebra and to review the literature on this condition. An 85 year-old female presented with severe low back pain but no radiating pain in the lower extremities. The patient was diagnosed with T12 and L5 vertebral compression fractures, fresh vertebral burst fractures in L2 and L3, and osteoporosis. The focus was on formulating a surgical treatment strategy. At the 12 month follow-up, no neurological deficits were observed, and the chosen surgical treatment approach yielded favorable clinical outcomes. A comprehensive literature review indicates that percutaneous kyphoplasty (PKP) can effectively alleviate pain and ensure safety in managing osteoporotic vertebral burst fractures. While complications remain a theoretical risk, they can be mitigated through meticulous assessment, careful surgical procedures, and appropriate preventive measures. PKP is an effective and safe treatment modality for osteoporotic vertebral burst fractures. Conservative management of sandwich vertebrae can yield positive clinical outcomes, but regular anti-osteoporosis treatment is necessary.
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BACKGROUND CONTEXT: Standard partial facetectomies, (Smith-Petersen Osteotomy, (SPO), (Schwab-grade-I) and complete facet resection also known as Ponte osteotomy, (PO), (Schwab-grade-II) are narrowly akin and collectively appreciated as posterior column shortening osteotomies (PCOs). The former is considered a gentler osteotomy grade than the latter. The spine literature provides very little information on their comparison regarding perioperative complications and major curve correction rate outcomes. PURPOSE: To determine whether Schwab-grade-I PCO (SPO) and Schwab-grade-II PCO (PO) are comparably safe in the surgical management of severe rigid scoliosis or kyphoscoliosis patients. STUDY DESIGN/SETTING: Retrospective single-center comparative clinical study. PATIENT SAMPLE: A total of 38 patients with severe rigid scoliosis or kyphoscoliosis were propensity score matched in this study, (SPO-treated); n=21 (55.30%) and (PO-treated); n=17 (44.70%), who underwent primary spinal deformity corrective surgery, respectively. OUTCOME MEASURES: Outcomes included demographics, baseline pulmonary functional outcomes, perioperative complications incidence, hospital costs, Oswestry disability index (ODI), and the Scoliosis Research Society-22 (SRS-22) questionnaire scores. METHODS: Following approval by the Institutional Review Board (IRB) of Beijing Chaoyang Hospital-Affiliated Capital Medical University in Beijing, out of a total of 82 consecutive surgical patients with complete data demonstrating severe and/or rigid spinal deformity, a pool of 38 of the 82 (46.3%) propensity-matched adult (≥18 years) patients with severe rigid scoliosis or kyphoscoliosis defined with a preoperative major curve magnitude of ≥80° on anteroposterior plain radiographs, and flexibility of <25% on bending plain radiographs who underwent primary spinal deformity corrective surgery were retrospectively evaluated. The patients were dichotomized into two osteotomy groups: standard (partial) facetectomy (SPO-treated), n=21 with an average age of 24.67 years, (Schwab-grade-I PCO) and complete facet excision, (PO-treated), (ie, Schwab-grade-II PCO), n=17 with an average age of 23.12 years. The minimum follow-up period was 2 years. Primary outcomes included baseline demographics and clinical features. Secondary outcomes included perioperative [intraoperative, immediate, and 2-year postoperative] complication rates. Tertiary outcomes included perioperative ODI and SRS-22 scores. Statistical analyses were carried out by Student t-test and Pearson's Chi-square test (Fisher's Exact Test), through Python statistical software package. Statistical significance was set at (p<.05). RESULTS: Of the 38 matched severe rigid scoliosis or kyphoscoliosis patients, 55.30% (n=21) were SPO-treated and 44.70% (n=17) were PO-treated patients, respectively. The overall average age of patients was 23.97 years, with a female incidence of 76.32%. Major curve correction rates were 49.19% and 57.40% in SPO-treated and PO-treated patients, respectively, (p>.05). Immediately following surgery, comparable overall complication rates of 28.57% (n=6/21) versus 29.41% (n=5/17) were observed in the SPO-treated and PO-treated patients, respectively, (p=.726). We observed incidences of 9.52%, (n=2/21) versus 5.88%, (n=1/17) for surgical intensive care unit (SICU) admission, and incidences of 4.76%, (n=1/21) versus 5.88%, (n=1/17) for cardiopulmonary events in SPO-treated versus PO-treated patients following corrective surgery, respectively, (p>.05). The incidences of neurological deficits in the SPO-treated and PO-treated patients were respectively, 14.29%, (n=3/21) versus 17.65%, (n=3/17) immediately following surgery, (p>.05), and 0.00%, (n=0/21) in SPO-treated versus 14.28%, (n=3/21) in PO-treated patients at ≥2 years postoperative, (p<.05). Among the three patients that reported neurological deficits in the PO-treated group at ≥2 years postoperative, two patients had pre-existing baseline neurological deficits. The ODI score in the PO-treated group was significantly inferior at a minimum 2-year follow-up, (p<.05). CONCLUSIONS: In the current study, both SPO-treated and PO-treated patients demonstrated statistically comparable surgical complications immediately following corrective surgery. Severe rigid kyphoscoliosis patients with preexisting baseline neurological deficits were more inclined to sustain neurological morbidity following corrective surgery. PCO corrective techniques are warranted as safe options for treating patients with severe rigid spine deformity phenotypes.
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Cifose , Escoliose , Adulto , Humanos , Feminino , Adulto Jovem , Escoliose/cirurgia , Escoliose/complicações , Estudos Retrospectivos , Seguimentos , Resultado do Tratamento , Cifose/diagnóstico por imagem , Cifose/cirurgia , Cifose/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
Background: We aimed to propose the apical vertebras distribution modifier to supplement the coronal balance (CB) classification for adult idiopathic scoliosis (AdIS). An algorithm to predict postoperative coronal compensation and avoid postoperative coronal imbalance (CIB) was proposed. Methods: Patients were categorized into CB and CIB groups according to the preoperative coronal balance distance (CBD). The apical vertebras distribution modifier was defined as negative (-) if the centers of the apical vertebras (CoAVs) were on either side of the central sacral vertical line (CSVL) and positive (+) if the CoAVs were on the same side of the CSVL. Results: A total of 80 AdIS patients, with an average age of 25.97 ± 9.20 years, who underwent posterior spinal fusion (PSF) were prospectively recruited. The mean Cobb angle of the main curve was 107.25 ± 21.11 degrees at preoperation. The mean follow-up time was 3.76 ± 1.38 (2-8) years. At postoperation and follow-up, CIB occurred in 7 (70%) and 4 (40%) CB- patients, 23 (50%) and 13 (28.26%) CB+ patients, 6 (60%) and 6 (60%) CIB- patients, and 9 (64.29%) and 10 (71.43%) CIB+ patients. Health-related quality of life (HRQoL) was significantly better in the CIB- group compared with that of the CIB+ group in the dimension of back pain. To avoid postoperative CIB, the correction rate of the main curve (CRMC) should match the compensatory curve for CB-/+ patients; the CRMC should be greater than the compensatory curve for CIB- patients; and the CRMC should be less than the compensatory curve for CIB+ patients, and the inclination of the LIV needs to be reduced. Conclusions: CB+ patients have the least postoperative CIB rate and the best coronal compensatory ability. CIB+ patients are at a high risk of postoperative CIB and have the poorest coronal compensatory capacity in the event of postoperative CIB. The proposed surgical algorithm facilitates the handling of each type of coronal alignment.
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PURPOSE: The study aims to investigate the impact of m6A modulators on drug resistance and the immune microenvironment in acute myeloid leukemia (AML). The emergence of drug resistance is a significant factor that contributes to relapse and refractory AML, leading to a poor prognosis. METHODS: The AML transcriptome data were retrieved from the TCGA database. The "oncoPredict" R package was utilized to assess the sensitivity of each sample to cytarabine (Ara-C) and classify them into distinct groups. Differential expression analysis was performed to identify m6A modulators differentially expressed between the two groups. Select Random Forest (RF) to build a predictive model. Model performance was evaluated using calibration curve, clinical decision curve, and clinical impact curve. The impacts of METTL3 on Ara-C sensitivity and immune microenvironment in AML were examined using GO, KEGG, CIBERSORT, and GSEA analyses. RESULTS: Seventeen out of 26 m6A modulators exhibited differential expression between the Ara-C-sensitive and resistant groups, with a high degree of correlation. We selected the 5 genes with the highest scores in the RF model to build a reliable and accurate prediction model. METTL3 plays a vital role in m6A modification, and further analysis shows its impact on the sensitivity of AML cells to Ara-C through its interaction with 7 types of immune-infiltrating cells and autophagy. CONCLUSION: This study utilizes m6A modulators to develop a prediction model for the sensitivity of AML patients to Ara-C, which can assist in treating AML drug resistance by targeting mRNA methylation.
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Citarabina , Leucemia Mieloide Aguda , Humanos , Citarabina/farmacologia , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Recidiva , Microambiente Tumoral , Metiltransferases/genética , Metiltransferases/uso terapêuticoRESUMO
Acute myeloid leukemia (AML) has a high rate of treatment failure due to increased prevalence of therapy resistance. Mesenchymal stem cells (MSCs) in the leukemia microenvironment contribute to chemoresistance in AML, but the specific mechanism remains unclear. The critical role of the epithelial-mesenchymal transition (EMT)-like profile in AML chemoresistance has been gradually recognized. However, there is no research to suggest that the AML-derived bone marrow mesenchymal stem cells (AML-MSCs) induce the EMT program in AML thus far. We isolated AML-MSCs and cocultured them with AML cells. We found that AML-MSCs induced a significant mesenchymal-like morphology in drug-resistant AML cells, but it was scarce in parental AML cells. The AML-MSCs promoted growth of AML cells in the presence or absence of chemotherapeutics in vitro and in vivo. Acute myeloid leukemia MSCs also induced EMT marker expression in AML cells, especially in chemoresistant AML cells. Mechanistically, AML-MSCs secreted abundant interleukin-6 (IL-6) and upregulated IL-6 expression in AML cells. Acute myeloid leukemia cells upregulated IL-6 expression in AML-MSCs in turn. Meanwhile, AML-MSCs activated the JAK2/STAT3 pathway in AML cells. Two JAK/STAT pathway inhibitors counteracted the AML-MSCs induced morphology change and EMT marker expression in AML cells. In conclusion, AML-MSCs not only promote the emergence of chemoresistance but also enhance it once AML acquires chemoresistance. AML-MSCs induce EMT-like features in AML cells; this phenotypic change could be related to chemoresistance progression. AML-MSCs induce the EMT-like program in AML cells through IL-6/JAK2/STAT3 signaling, which provides a therapeutic target to reverse chemoresistance in AML.
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Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Humanos , Transição Epitelial-Mesenquimal , Interleucina-6/metabolismo , Transdução de Sinais , Resistencia a Medicamentos Antineoplásicos , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Mesenquimais/metabolismo , Microambiente Tumoral , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
BACKGROUND: Posterior cervical decompression and fusion (PCF) is a common procedure for treating patients with multilevel degenerative cervical spine disease. The selection of lower instrumented vertebra (LIV) relative to the cervicothoracic junction (CTJ) remains controversial. This study aimed to compare the outcomes of PCF construct terminating at the lower cervical spine and crossing the CTJ. METHODS: A comprehensive literature search was performed for relevant studies in the PubMed, EMBASE, Web of Science, and Cochrane Library database. Complications, rate of reoperation, surgical data, patient-reported outcomes (PROs), and radiographic outcomes were compared between PCF construct terminating at or above C7 (cervical group) and at or below T1 (thoracic group) in patients with multilevel degenerative cervical spine disease. A subgroup analysis based on surgical techniques and indications was performed. RESULTS: Fifteen retrospective cohort studies comprising 2071 patients (1163 in the cervical group and 908 in the thoracic group) were included. The cervical group was associated with a lower incidence of wound-related complications (RR, 0.58; 95% CI 0.36 to 0.92, p = 0.022; 831 patients in cervical group vs. 692 patients in thoracic group), a lower reoperation rate for wound-related complications (RR, 0.55; 95% CI 0.32 to 0.96, p = 0.034; 768 vs. 624 patients), and less neck pain at the final follow-up (WMD, -0.58; 95% CI -0.93 to -0.23, p = 0.001; 327 vs. 268 patients). However the cervical group also developed a higher incidence of overall adjacent segment disease (ASD, including distal ASD and proximal ASD) (RR, 1.87; 95% CI 1.27 to 2.76, p = 0.001; 1079 vs. 860 patients), distal ASD (RR, 2.18; 95% CI 1.36 to 3.51, p = 0.001; 642 vs. 555 patients), overall hardware failure (including hardware failure of LIV and hardware failure occurring at other instrumented vertebra) (RR, 1.48; 95% CI 1.02 to 2.15, p = 0.040; 614 vs. 451 patients), and hardware failure of LIV (RR, 1.89; 95% CI 1.21 to 2.95, p = 0.005; 380 vs. 339 patients). The operating time was reasonably shorter (WMD, -43.47; 95% CI -59.42 to -27.52, p < 0.001; 611 vs. 570 patients) and the estimated blood loss was lower (WMD, -143.77; 95% CI -185.90 to -101.63, p < 0.001; 721 vs. 740 patients) when the PCF construct did not cross the CTJ. CONCLUSIONS: PCF construct crossing the CTJ was associated with a lower incidence of ASD and hardware failure but a higher incidence of wound-related complications and a small increase in qualitative neck pain, without difference in neck disability on the NDI. Based on the subgroup analysis for surgical techniques and indications, prophylactic crossing of the CTJ should be considered for patients with concurrent instability, ossification, deformity, or a combination of anterior approach surgeries as well. However, long-term follow-up outcomes and patient selection-related factors such as bone quality, frailty, and nutrition status should be addressed in further studies.
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Low-density lipoprotein receptor-related protein-6 (LRP6) is overexpressed in various cancers. The small molecule salinomycin sodium inhibits LRP6. We observed a higher proportion of subjects with non-germinal center B (non-GCB) subtypes having high LRP6 expression than those with GCB subtypes by immunohistochemistry. The PCR and Western blot assays demonstrated increased LRP6 expression in non-GCB subtype cells. In addition, CCK-8 assays and transwell cell migration assays revealed that salinomycin sodium exhibited dose- and time-dependent inhibition of proliferation and migration in non-GCB subtype cells. Furthermore, Western blot assays showed that salinomycin sodium decreased the expression of Bcl2, while increasing the expression of Bax. Additionally, salinomycin sodium suppressed LRP6 expression, blocked LRP6 phosphorylation, and inhibited the Wnt/ß-catenin and mTORC1 signaling pathways. Our results suggest that LRP6 is highly expressed in non-GCB subtype. Furthermore, salinomycin sodium inhibited LRP6 expression and the Wnt/ß-catenin and mTORC1 signaling in non-GCB subtype cells, and displayed potent anticancer activity.
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Linfoma de Células B , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Sódio , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genéticaRESUMO
Background: Dual traditional growing rod (dTGR) implantation may not always be feasible for patients with severe early-onset scoliosis (EOS). The concave single traditional growing rod (sTGR) can serve as a starting construct. Distal foundation augmentation (DFA) with four pedicle screws with a cross-link can increase the spinal control provided by a dTGR. However, DFA has yet to be used with a sTGR. This study investigated the efficiency of DFA in patients with severe EOS who underwent sTGR implantation. Methods: From 2010 to 2021, 74 consecutive patients with severe EOS (major curve ≥80°) who underwent traditional growing rod implantation (48 sTGR and 26 dTGR) with a minimum 24-month follow-up were recruited. The sTGR cohort was further divided into two groups by whether or not DFA was performed. In our center, patients who were admitted for sTGR implantation after 2018 routinely underwent DFA. The implantation of a dTGR was based on the severity of thoracic torsion and BMI. Baseline clinical characteristics, complications, and radiographic parameters preoperatively, postoperatively, and at the last follow-up before conversion to a dual rod instrumentation were compared between the three groups. Results: There was no significant difference in baseline clinical characteristics between the three groups (P>0.05). Twenty-four patients in the sTGR cohort underwent DFA. There was no significant difference in preoperative radiographic parameters between the DFA and non-DFA group (P>0.05). Compared with the non-DFA group, the DFA group had superior results at the last follow-up in terms of maintaining the correction of the major curve (P=0.001), maximal kyphosis correction (P=0.001), the distance between the C7 plumb line and the central sacral vertical line (P=0.036), and distracting the growing thorax (P=0.032) and trunk (P=0.044). Furthermore, the incidence of implant-related complications (P=0.019), especially at the distal foundation (P=0.033), was significantly lower in the DFA group. There was no significant difference between the DFA and dTGR groups in radiographic outcomes or complications at the final follow-up (P>0.05). Conclusions: For patients with severe EOS who undergo sTGR implantation, DFA might better maintain the deformity correction, distract the growing spine, preserve balance, and decrease the incidence of implant-related complications. The efficiency of sTGR with DFA was comparable to that of the gold-standard dTGR treatment. Further multicenter randomized controlled trials are needed for more convincing conclusions.
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BACKGROUND: We evaluated long-term outcomes (radiographic parameters and pulmonary function) at a minimum follow-up of 5 years after use of dual growing rods (DGRs) to treat severe early-onset scoliosis (sEOS). METHODS: Among a total of 112 patients who were diagnosed with early-onset scoliosis (EOS) and were treated with DGRs between 2006 and 2015, 52 patients had sEOS, with a major Cobb angle of >80°. Of these patients, 39 with a minimum follow-up of 5 years had complete radiographic and pulmonary function test results and were included. The Cobb angle of the major curve, T1-S1 height, T1-T12 height, and maximum kyphosis angle in the sagittal plane were measured on radiographs. Pulmonary function test results were collected in all patients before the initial operation (preoperatively), 12 months after the initial operation (postoperatively), and at the last follow-up. The changes in pulmonary function and complications during treatment were analyzed. RESULTS: The mean age of patients before the initial operation was 7.7 ± 1.2 years, and the mean follow-up period was 75.0 ± 14.1 months. The mean number of lengthenings was 4.5 ± 1.3, and the mean interval between lengthenings was 11.2 ± 2.1 months. The Cobb angle improved from 104.5° ± 18.2° preoperatively to 38.1° ± 10.1° after the initial surgical procedure (postoperatively) and 21.9° ± 8.6° at the final follow-up. The T1-S1 height increased from 25.1 ± 4.0 cm preoperatively to 32.4 ± 3.5 cm postoperatively and to 39.5 ± 4.0 cm at the final follow-up. However, no significant difference was detected between the increased pulmonary function parameters at 1 year and those before the operation (p > 0.05), except for residual volume, whereas pulmonary function parameters had significantly increased at the final follow-up (p < 0.05). During the treatment period, 17 complications occurred in 12 patients. CONCLUSIONS: DGRs are effective in treating sEOS in the long term. They allow longitudinal growth of the spine, and the correction of the spinal deformity can provide conditions that make improving pulmonary function possible in patients with sEOS. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.
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Cifose , Escoliose , Fusão Vertebral , Humanos , Criança , Escoliose/diagnóstico por imagem , Escoliose/cirurgia , Escoliose/etiologia , Estudos Retrospectivos , Coluna Vertebral/cirurgia , Cifose/cirurgia , Pulmão/diagnóstico por imagem , Fusão Vertebral/métodos , Resultado do Tratamento , SeguimentosRESUMO
BACKGROUND: The lack of randomized evidence makes it difficult to establish reliable treatment recommendations for patients with M2 occlusion. This study aims to compare the efficacy and safety of endovascular treatment (EVT) with best medical management (BMM) in patients with M2 occlusion, and to investigate whether the optimal treatment varies according to stroke severity. METHODS: Comprehensive literature retrieval was conducted to identify studies that directly compared the outcomes of EVT and BMM. According to stroke severity, the study population were classified into those with moderate-severe stroke and those with mild stroke. National Institute of Health Stroke Scale (NIHSS) scores ≥ 6 was defined as moderate-severe stroke, and NIHSS scores 0-5 as mild stroke. Random-effects meta-analyses were performed to measure the symptomatic intracranial hemorrhage (sICH) within 72 h, and the modified Rankin Scale (mRS) scores 0-2 and the mortality at 90 days. RESULTS: Totally, 20 studies were identified, including 4358 patients. In the moderate-severe stroke population, the EVT had 82% higher odds for mRS scores 0-2 (OR 1.82, 95% CI 1.34-2.49) and a 43% lower odds for mortality (OR 0.57, 95% CI 0.39-0.82) compared with the BMM. However, no difference was found in the sICH rate (OR 0.88, 95% CI 0.44-1.77). In the mild stroke population, no differences were observed in the mRS scores 0-2 (OR 0.81, 95% CI 0.59-1.10) or mortality (OR 1.23, 95% CI 0.72-2.10) between EVT and BMM, whereas EVT was associated with higher sICH rate (OR 4.21, 95% CI 1.86-9.49). CONCLUSION: EVT may be only beneficial for patients with M2 occlusion and high stroke severity, but not for those with NIHSS scores 0-5.
Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Resultado do Tratamento , Procedimentos Endovasculares/efeitos adversos , Acidente Vascular Cerebral/etiologia , Hemorragias Intracranianas/etiologia , Trombectomia/efeitos adversos , Isquemia Encefálica/terapiaRESUMO
BACKGROUND: Frailty is a state of cumulative degeneration of bodily functions that is consistently associated with poor outcomes in older people following illness. Combined stroke intervention and frailty may yield additive and synergistic effects adults with stroke. OBJECTIVE: To evaluate the safety and efficacy of endovascular therapy (EVT) in frail patients. METHODS: We conducted a systematic review of the relationship between debilitation and acute ischemic stroke (AIS) after EVT. Until August 2022, researchers have searched three databases (Pubmed, EMBASE and Cochrane). Random-effects meta-analysis, combined ratio (OR) and 95% confidence interval (95%CI) were used to assess efficacy values. The I2 statistic was used to assess heterogeneity. Comprehensive meta-analysis software was used for meta-analysis. RESULTS: We ultimately included eight studies including 3662 non-overlapping participants. Four studies used the Clinical Frailty Scale (CFS), two studies used the Hospital Frailty Risk Score (HFRS), a study used frailty index and a study used the comprehensive geriatric assessment (CGA). Frailty prevalence: 35%; 95% CI, 0.27-0.43; low quality evidence, downgraded due to heterogeneity, bias. Random effects showed that poor functional outcome (5 studies, OR 1.956, 95% CI 1.256-3.048) and mortality (9 studies, OR 2.320, 95% CI 1.680-3.205) was significantly associated with frailty. In adjusted analyses, poor functional outcome (4 studies, ORadj 1.189, 95% CI 1.043-1.357), and mortality (3 studies, ORadj 1.036, 95% CI 1.008-1.065) were significantly associated with frailty. CONCLUSION: Pre-stroke frailty is an important predictor of poor prognosis assessed by EVT and can be added to the classical predictors of stroke outcome. Routine assessment of pre-stroke frailty can help patients to make decisions about the efficacy of their choice of EVT.
Assuntos
Procedimentos Endovasculares , Fragilidade , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Idoso , Fragilidade/complicações , Procedimentos Endovasculares/efeitos adversos , Acidente Vascular Cerebral/terapia , Fatores de Risco , Resultado do TratamentoRESUMO
STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: This study aimed to compare the radiographical and clinical outcomes between anterior spinal fusion (ASF) and posterior spinal fusion (PSF) in Lenke type 5 adolescence idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: PSF has been the standard operation for adolescence idiopathic scoliosis. ASF can also achieve a good curve correction effect with fewer fusion segments and minor invasion of paraspinal structures. MATERIALS AND METHODS: A systematic literature research was conducted in PubMed, Embase, Cochrane Library, and Web of Science. Use meta-analysis to compare the changes of thoracolumbar/lumbar and thoracic curves and other important outcomes between ASF and PSF. RESULTS: A total of 427 ASF and 392 PSF patients from 12 studies were included. There was no significant difference in the correction degree of thoracolumbar/lumbar and thoracic curve between ASF and PSF ( P >0.05), except for PSF had more compensatory correction degree of thoracic curve at postoperation ( P <0.05). Besides, the loss of correction in thoracic curve in PSF at the last follow-up was significantly less than that in ASF ( P <0.05). PSF presented larger change values of thoracic kyphosis and lumbar lordosis at the last follow-up ( P <0.05). PSF showed a better effect in correcting trunk shift distance at the postoperation ( P <0.05) but less trunk shift distance correction from postoperation to last follow-up ( P <0.05). There was no significant difference in the incidence of proximal junctional kyphosis and estimated blood loss between the two approaches ( P >0.05). Moreover, ASF showed fewer fusion segments, but longer operation and hospital stay time ( P <0.05). CONCLUSION: ASF is capable of achieving similar correction in coronal curve and balance as PSF with fewer fusion segments. Spine surgeons should select an appropriate approach tailored to individual patients needs while considering procedural risks and benefits. LEVEL OF EVIDENCE: Level II.
Assuntos
Cifose , Lordose , Escoliose , Fusão Vertebral , Adolescente , Humanos , Escoliose/diagnóstico por imagem , Escoliose/cirurgia , Escoliose/etiologia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Resultado do Tratamento , Cifose/cirurgia , Fusão Vertebral/efeitos adversos , Estudos Retrospectivos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgiaRESUMO
Argument mining (AM), an emerging field in natural language processing (NLP), aims to automatically extract arguments and the relationships between them in texts. In this study, we propose a new method for argument mining of argumentative essays. The method generates dynamic word vectors with BERT (Bidirectional Encoder Representations from Transformers), encodes argumentative essays, and obtains word-level and essay-level features with BiLSTM (Bi-directional Long Short-Term Memory) and attention training, respectively. By integrating these two levels of features we obtain the full-text features so that the content in the essay is annotated according to Toulmin's argument model. The proposed method was tested on a corpus of 180 argumentative essays, and the precision of automatic annotation reached 69%. The experimental results show that our model outperforms existing models in argument mining. The model can provide technical support for the automatic scoring system, particularly on the evaluation of the content of argumentative essays.
RESUMO
PURPOSE: The aim of this study was to compare the clinical and radiographical outcomes between OLIF and ALIF in treating lumbar degenerative diseases. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library for relevant studies. Changes in disc height (DH), segmental lordosis angle (SLA), lumbar lordosis (LL), visual analogue scale (VAS) score, and Oswestry disability index (ODI) between baseline and final follow-up, along with other important surgical outcomes, were assessed and analysed. Data on the global fusion rate and main complications were collected and compared. RESULTS: Approximately, 2041 patients from 36 studies were included, consisting of 1057 patients who underwent OLIF and 984 patients who underwent ALIF. The results reveal no significant difference in DH, SLA, VAS score, and ODI between the two groups (all P > 0.05). The operation time, estimated blood loss, and length of hospital stay were also comparable between the two groups. Over 90% of the fusion rate was achieved in both groups. The OLIF group showed a higher complication rate than the ALIF group (OLIF 18.83% vs ALIF 7.32%). CONCLUSIONS: OLIF leads to a higher complication rate, with the most notable complication being cage subsidence. Both OLIF and ALIF are effective treatments for degenerative lumbar diseases and have similar therapeutic effects. ALIF was expected to be more expensive for patients because of the necessity of involving vascular surgeons.