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The GATOR2-GATOR1 signaling axis is essential for amino-acid-dependent mTORC1 activation. However, the molecular function of the GATOR2 complex remains unknown. Here, we report that disruption of the Ring domains of Mios, WDR24, or WDR59 completely impedes amino-acid-mediated mTORC1 activation. Mechanistically, via interacting with Ring domains of WDR59 and WDR24, the Ring domain of Mios acts as a hub to maintain GATOR2 integrity, disruption of which leads to self-ubiquitination of WDR24. Physiologically, leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. As such, WDR24 ablation or Ring deletion prevents mTORC1 activation, leading to severe growth defects and embryonic lethality at E10.5 in mice. Hence, our findings demonstrate that Ring domains are essential for GATOR2 to transmit amino acid availability to mTORC1 and further reveal the essentiality of nutrient sensing during embryonic development.
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Complexos Multiproteicos , Serina-Treonina Quinases TOR , Animais , Camundongos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Transdução de SinaisRESUMO
Background: Rheumatoid arthritis (RA) remains one of the most prevalent chronic joint diseases. However, due to the heterogeneity among RA patients, there are still no robust diagnostic and therapeutic biomarkers for the diagnosis and treatment of RA. Methods: We retrieved RA-related and pan-cancer information datasets from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. Six gene expression profiles and corresponding clinical information of GSE12021, GSE29746, GSE55235, GSE55457, GSE77298, and GSE89408 were adopted to perform differential expression gene analysis, enrichment, and immune component difference analyses of RA. Four machine learning algorithms, including LASSO, RF, XGBoost, and SVM, were used to identify RA-related biomarkers. Unsupervised cluster analysis was also used to decipher the heterogeneity of RA. A four-signature-based nomogram was constructed and verified to specifically diagnose RA and osteoarthritis (OA) from normal tissues. Consequently, RA-HFLS cell was utilized to investigate the biological role of CRTAM in RA. In addition, comparisons of diagnostic efficacy and biological roles among CRTAM and other classic biomarkers of RA were also performed. Results: Immune and stromal components were highly enriched in RA. Chemokine- and Th cell-related signatures were significantly activated in RA tissues. Four promising and novel biomarkers, including CRTAM, PTTG1IP, ITGB2, and MMP13, were identified and verified, which could be treated as novel treatment and diagnostic targets for RA. Nomograms based on the four signatures might aid in distinguishing and diagnosing RA, which reached a satisfactory performance in both training (AUC = 0.894) and testing (AUC = 0.843) cohorts. Two distinct subtypes of RA patients were identified, which further verified that these four signatures might be involved in the immune infiltration process. Furthermore, knockdown of CRTAM could significantly suppress the proliferation and invasion ability of RA cell line and thus could be treated as a novel therapeutic target. CRTAM owned a great diagnostic performance for RA than previous biomarkers including MMP3, S100A8, S100A9, IL6, COMP, LAG3, and ENTPD1. Mechanically, CRTAM could also be involved in the progression through immune dysfunction, fatty acid metabolism, and genomic instability across several cancer subtypes. Conclusion: CRTAM, PTTG1IP, ITGB2, and MMP13 were highly expressed in RA tissues and might function as pivotal diagnostic and treatment targets by deteriorating the immune dysfunction state. In addition, CRTAM might fuel cancer progression through immune signals, especially among RA patients.
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Artrite Reumatoide , Neoplasias , Humanos , Silício , Metaloproteinase 13 da Matriz , Biomarcadores , AlgoritmosRESUMO
PURPOSE: Prolonged mechanical ventilation (PMV) and reintubation are among the most serious postoperative adverse events associated with malignant cervical tumors. In this study, we aimed to clarify the incidence, characteristics, and risk factors for PMV and reintubation in target patients. METHODS: This retrospective nested case-control study was performed between January 2014 and January 2020 at a large spinal tumor center in China. Univariate analysis was used to identify the possible risk factors associated with PMV and reintubation. Logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) with covariates of a probability < 0.05 in univariate analysis. RESULTS: From a cohort of 560 patients with primary malignant (n = 352) and metastatic (n = 208) cervical tumors, 27 patients required PMV and 20 patients underwent reintubation. The incidence rates of PMV and reintubation were 4.82% and 3.57%, respectively. Three variables (all p < 0.05) were independently associated with an increased risk of PMV: Karnofsky Performance Status < 50 compared to ≥ 80, operation duration ≥ 8 h compared to < 6 h, and C4 nerve root encased by the tumor. Longer operative duration and preoperative hypercapnia (all p < 0.05) were independent risk factors for postoperative reintubation, both of which led to longer length of stay (32.6 ± 30.8 vs. 10.7 ± 5.95 days, p < 0.001), with an in-hospital mortality of 17.0%. CONCLUSION: Our results demonstrate the risk factors for PMV or reintubation after surgery for malignant cervical tumors. Adequate assessment, early detection, and prevention are necessary for this high-risk population.
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Intubação Intratraqueal , Respiração Artificial , Humanos , Feminino , Pessoa de Meia-Idade , Respiração Artificial/estatística & dados numéricos , Masculino , Estudos de Casos e Controles , Fatores de Risco , Idoso , Estudos Retrospectivos , Intubação Intratraqueal/estatística & dados numéricos , Intubação Intratraqueal/efeitos adversos , Adulto , Vértebras Cervicais/cirurgia , Neoplasias da Coluna Vertebral/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreasing tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGγ KO mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation, we found with REGγ-deficiency, neuron loss, dendrite reduction, tau filament accumulation, and microglial activation are much more prominent in the REGγ KO;PS19 than the PS19 model. Moreover, we observed that the degenerative neuronal lesions and aberrant behaviors were alleviated in REGγ OE;PS19 mice. Memory and other behavior analysis substantiate the role of REGγ in prevention of tauopathy-like symptoms. In addition, we investigated the potential mechanism underlying aging-related REGγ decline. This study provides valuable insights into the novel regulatory mechanisms and potential therapeutic targets for tau-related neurodegenerative diseases.
Assuntos
Complexo de Endopeptidases do Proteassoma , Tauopatias , Humanos , Animais , Camundongos , Lactente , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Tauopatias/genética , Autoantígenos/metabolismo , Citoplasma/metabolismo , Envelhecimento/genéticaRESUMO
PURPOSE: Although total en bloc spondylectomy (TES) is strongly recommended for spinal giant cell tumor (GCT), it is extremely difficult to excise a L5 neoplasm intactly through the single-stage posterior approach. Given the risk of neurological and vascular injury, intralesional curettage (IC) is usually recommended for the treatment of L5 GCT. In this study, we presented our experience with the use of an improved TES to treat L5 GCT through the single-stage posterior approach. METHODS: This study included 20 patients with L5 GCT who received surgical treatment in our department between September 2010 and April 2021. Of them, seven patients received improved TES without iliac osteotomy, and the other 13 patients received IC (n = 8), sagittal en bloc resection (n = 1), TES with iliac osteotomy (n = 3), and TES with radicotomy (n = 1) as control. RESULTS: The mean operative time was 331.43 ± 92.95 min for improved TES group and 365.77 ± 85.17 min for the control group (p = 0.415), with the mean blood loss of 1142.86 ± 340.87 ml vs. 1969.23 ± 563.30 ml (p = 0.002). Postoperative treatment included bisphosphonates in nine patients and denosumab in 12 patients including one patient who changed from bisphosphonates to denosumab. Three patients who received IC experienced local recurrence, and no relapse was observed in improved TES group. CONCLUSION: Single-stage posterior TES for L5 GCT was previously considered impossible. In this study, we presented our experience with the use of an improved surgical technique for L5 TES through the single-stage posterior approach, which has proved to be superior to the conventional procedures in terms of blood loss control and complication and recurrence rates. LEVEL OF EVIDENCE: IV.
Assuntos
Tumor de Células Gigantes do Osso , Neoplasias da Coluna Vertebral , Humanos , Denosumab , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgia , Neoplasias da Coluna Vertebral/patologia , Recidiva Local de Neoplasia/cirurgia , Vértebras Lombares/cirurgia , Vértebras Lombares/patologia , Tumor de Células Gigantes do Osso/diagnóstico por imagem , Tumor de Células Gigantes do Osso/cirurgia , Tumor de Células Gigantes do Osso/patologia , Difosfonatos , Resultado do TratamentoRESUMO
BACKGROUND: The surgical efficacy and prognostic outcomes of patients with unspecific malignant bone tumors (UMBTs) remain unclear. The study is to address: 1) What are the clinicopathological features and prognostic determinants for patients with UMBTs? 2) Can a nomogram be developed for clinicians to predict the short and long-term outcomes for individuals with UMBTs? 3) Does surgery improve outcomes for UMBT patients who received radiotherapy or chemotherapy after balancing the confounding bias? METHODS: 400 UMBT patients were filtrated from the Surveillance, Epidemiology, and End Results database to assess the clinicopathological features, treatments, and factors affecting prognosis. The optimal cutoff values of continuous variables were identified by the x-tile software. Kaplan-Meier method and multivariate Cox proportional hazard modeling were performed to evaluate the independent prognostic factors. Nomogram was further developed by using R software with rms package. The surgical efficacy was further assessed for patients receiving radiotherapy or chemotherapy after performing propensity score matching. RESULTS: The enrolled cohort included 195 (48.8%) female and 205 (51.2%) male patients. The 2- and 5-year cancer-specific survival (CSS) and overall survival (OS) rate were 58.2 ± 3.0%, 46.8 ± 3.2%, and 46.5 ± 2.6%, 34.4 ± 2.5%, respectively. Nomogram was finally developed for CSS and OS according to the identified independent factors: age, tumor extent, primary tumor surgery, tumor size, and pathology grade. For UMBT patients who received radiotherapy or chemotherapy, surgical intervention was associated with better CSS (pr = 0.003, pc = 0.002) and OS (pr = 0.035, pc = 0.002), respectively. CONCLUSIONS: Nomogram was developed for individual UMBT patient to predict short and long-term CSS and OS rate, and more external patient cohorts are warranted for validation. Surgery improves outcomes for UMBT patients who received either radiotherapy or chemotherapy.
Assuntos
Neoplasias Ósseas , Nomogramas , Humanos , Masculino , Feminino , Programa de SEER , Estadiamento de Neoplasias , Prognóstico , Neoplasias Ósseas/cirurgiaRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized as chronic inflammation of joint. Both genetic and environmental factors play important roles in RA progression. G protein-coupled receptor 54 (GPR54) and Kisspeptins (KPs), the natural GRP54 ligands encoded by Kiss-1 gene are known to play important roles in immune regulation but the precise role of KP-10/GPR54 in RA remains elusive. Kiss1/Gpr54 expression was determined by immunohistochemistry on protein and real-time PCR on RNA from isolated RA-patient synovial tissue and PBMC. Collagen-induced arthritis (CIA) mouse models were used to investigate the effect of KP-10/Gpr54 on the rheumatic arthritis severity in the mice. The signaling pathway involved in KP-10/GPR54 was assessed by western blot and immunofluorescence.In the present study, we demonstrated that GPR54 upregulation in bone marrow-derived macrophages (BMDM) was associated with the severity of RA. In addition, Gpr54-/- increased the inflammatory cytokines induced by lipopolysaccharide (LPS) in BMDM and diseased severity of CIA (n = 10), while KP-10 reduced the LPS-induced inflammatory cytokines in vitro and ameliorated the CIA symptoms in vivo. Furthermore, we demonstrated that KP-10/GPR54 binds to PP2A-C to suppressed LPS induced NF-κB and MAPK signaling in BMDM. All these findings suggest that KP-10/GPR54 may be a novel therapeutic target for the diagnosis and treatment of RA.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Kisspeptinas/uso terapêutico , Osteoartrite/genética , Receptores de Kisspeptina-1/genética , Febre Reumática/genética , Animais , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Anti-Inflamatórios/farmacologia , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/imunologia , Artrite Experimental/patologia , Células Cultivadas , Citocinas/genética , Humanos , Kisspeptinas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos DBA , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Osteoartrite/imunologia , Receptores de Kisspeptina-1/imunologia , Febre Reumática/imunologia , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: To increase our knowledge of the characteristics of rare gastrointestinal stromal tumors (GISTs) spinal metastatic diseases and share our experience of dealing with these diseases. METHODS: A total of 6 patients with spinal cord compression caused by GISTs spinal metastases operated in our department were identified from Oct, 2010 to Oct, 2018. The clinical and operative notes, radiographic images, and pathological reports with histochemistry of all these patients were reviewed. RESULTS: Among these six, four were male. The average age was 57.2 ± 9.0 years-old. The average duration between GISTs resections and diagnosis of spinal metastases was 80.8 ± 91.9 months. Four patients died from their disease during follow-up. The average duration between operation and death was 8.5 ± 4.4 months. CONCLUSIONS: Generally, patients with GISTs spinal metastatic diseases had a poor prognosis. The average survival of these patients did not exceed 12 months. Palliative treatments are recommended mainly to control symptoms.
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Tumores do Estroma Gastrointestinal , Compressão da Medula Espinal , Neoplasias da Coluna Vertebral , Idoso , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgiaRESUMO
BACKGROUND: No standard treatment exists for advanced chordoma. Apatinib has been found to have promising efficacy and manageable adverse effects for the treatment of solid tumours. We aimed to investigate the safety and antitumour activity of apatinib in patients with advanced chordoma. METHODS: We did a single-arm, phase 2 study at one tertiary hospital in Shanghai, China. Eligible patients were aged 18-75 years, with histologically confirmed advanced chordoma that was unresectable or resectable only through demolitive surgery, who had previously received surgical treatment, with at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, evidence of tumour progression on enhanced CT or MRI in the previous 6 months, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received oral 500 mg apatinib once daily until disease progression or unacceptable toxicity. The co-primary endpoints were progression-free survival and objective response rate according to RECIST 1.1 and Choi criteria by investigator assessment. Progression-free survival was assessed in the intention-to-treat population. Objective response rate was assessed in the per-protocol population, which included all enrolled patients who were compliant with the protocol and had at least one post-baseline assessment. Safety was analysed in all patients with complete safety data. This study is ongoing, but recruitment is complete. This study is registered with Chictr.org.cn, ChiCTR-OIC-17013586. FINDINGS: Between Aug 21, 2017, and May 31, 2019, we screened 32 patients, of whom 30 were enrolled. Median follow-up was 14·2 months (IQR 9·4-19·7). Of the 27 patients included in the per-protocol population, one patient (3·7%; 95% CI 0-11·3) achieved an objective response according to RECIST, and seven patients (25·9%; 8·3-43·6) achieved an objective response according to Choi criteria. Median progression-free survival was 18 months (95% CI 3-34) according to RECIST and 18 months (3-33) according to Choi criteria. The most common treatment-related grade 3 adverse events were hypertension (seven [24%] of 29 patients) and proteinuria (two [7%]). No treatment-related grade 4 adverse events or treatment-related deaths were observed. INTERPRETATION: To our knowledge, this is the first trial of apatinib for the treatment of advanced chordoma. Apatinib shows promising activity and manageable toxicity and thus might be an option for the treatment of advanced chordoma. FUNDING: None.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cordoma/tratamento farmacológico , Piridinas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , China/epidemiologia , Cordoma/epidemiologia , Cordoma/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Critérios de Avaliação de Resposta em Tumores Sólidos , Adulto JovemRESUMO
An amendment to this paper has been published and can be accessed via the original article.
RESUMO
Numerous nanomedicines have been developed to improve the efficiency and safety of conventional anticancer drugs; however, the complexities in carrier materials and functional integration make it challenging to promote these candidates for clinical translation. In this study, a facile method to prepare carrier-free anticancer nanodrug with inherent bone targeting and osteoclastogenesis inhibition capabilities is reported. Phytic acid, a naturally occurring and nontoxic product, is reacted with cisplatin to form uniform nanoparticles of different sizes. The prepared nanoparticles possess high drug loading and pH-responsive drug release behaviors. Phytic acid in the nanomedicine ensures high bone targeting and osteoclastogenesis inhibition, and the released platinum drugs triggered by tumor extracellular acidity eradicate tumor cells. The nanomedicine around 100 nm shows high anticancer activity and much reduced side effects in a subcutaneous breast cancer model when compared with cisplatin. In addition, it shows high accumulation at osteolytic lesions, and efficiently inhibits tumor growth and tumor-associated osteolysis in a bone metastatic breast cancer model. Here, a facile and efficient strategy to prepare carrier-free nanomedicines with high anticancer drug loading, inherent bone targeting, and osteoclast inhibitory activities for cancer therapy is provided.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Nanomedicina , Neoplasias/tratamento farmacológico , PlatinaRESUMO
The tumor-initiating cells (TICs) are a cell population that can initiate tumor occurrence, mediate drug resistance, and give rise to metastasis. FOXD3 is a forkhead box (Fox) transcription factor family that regulates the pluripotency of embryonic stem cell and tumorigenicity. However, it is unclear whether FOXD3 plays any role in TIC and tumor metastasis. The functional analysis of FOXD3 was performed by oncospheres formation and redifferentiation, drug resistance assay, and cell migration. Global genomic RNA-Seq and ChIP-Seq analysis were used to identify the direct target of FOXD3 in lung cancer. We demonstrated that downregulation of FOXD3 in TICs was positively correlated with higher histologic grades and positive lymph node metastasis. FOXD3 repressed TIC expansion and cell migration, drug resistance, and osteoclasts in vitro and in vivo. Mechanically, we found that FOXD3 represses WDR5, which regulates TIC-related signaling pathway. Moreover, WDR5 were positively correlated with the TIC abundance and tumor progression. Besides, patients with high expression of WDR5 presented a poorer overall survival. FOXD3 may suppress TIC accumulation by repressing the expression of WDR5 in lung cancer. Stem Cells 2019;37:582-592.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Transcrição Forkhead/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Paclitaxel/farmacologiaRESUMO
PURPOSE: Primary cancer patients may have some symptoms and develop spinal metastases in their disease progression. This study was to report the distribution and predictive value of specific initial presenting symptoms in patients with spine metastatic disease. METHODS: The clinical information about patients with primary cancers was retrospectively collected and analyzed at their initial diagnosis from January 2008 to December 2017. The distribution and specific value of initial presenting symptoms were analyzed in predicting spinal metastases. RESULTS: A total of 14,603 cancer patients were finally included, of whom 1665 (11.4%) cases were confirmed with spinal metastases. 41.55% (6067/14,603) patients had initial presenting symptoms, while 92.19% (1535/1665) patients with spinal metastases presented at least one initial presenting symptoms. Among 6269 patients with symptoms, 1535 (24.49%) were diagnosed with spinal metastases. Factors including primary tumor type, local pain, night-aggravating pain, limb numbness, limb weakness, unstable gait, claudication, loss of sphincter control, and weight loss are associated with the distribution of spinal metastases. The pooled sensitivity, specificity, positive predictive value, and negative predictive value were 90.9% (89.4-92.2%), 64.9% (64.0-65.7%), 24.99% (23.91-26.11%), and 98.23% (97.92-98.50%), respectively. Positive likelihood ratio of "night-aggravating pain" was 33.25 (12.65-87.36) and 17.26 (12.25-24.32) in patients < 45 and 45-64 years old, respectively. CONCLUSIONS: The distribution of spinal metastases is associated with primary tumor type and initial presenting symptoms. The predictive value of initial presenting symptoms differs in age groups, but resembles in cancer types. The presence of night-aggravating pain had relative high value in predicting metastases in cancer patients under 65 years old.
Assuntos
Neoplasias da Coluna Vertebral , Humanos , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/diagnóstico , Neoplasias da Coluna Vertebral/secundárioRESUMO
OBJECTIVE: To verify whether the pedicle screw placement (PSP) skills of young surgeons receiving immersive virtual reality surgical simulator (IVRSS) training could be improved effectively and whether the IVRSS-PSP training mode could produce a real clinical value in clinical surgery. METHODS: Twenty-four young surgeons were equally randomized to a VR group and a NON-VR group. Participants in VR group received IVRSS-PSP training, and those in NON-VR group used the conventional model of observing a spinal model first and then watching a teaching video of spinal surgery for 40 minutes x five. The nailing outcome of the participants before and after training was evaluated by statistical analysis in both groups. RESULTS: Post-training data analysis showed that the success rate and accuracy rate of screw placement in VR group and NON-VR group were 82.9% and 69.6% vs. 74.2% and 55.4%, respectively, showing statistically significant differences between the two groups by chi-square test (P < 0.05). CONCLUSION: The present study demonstrated that IVRSS-PSP was helpful to improve the success rate of PSP for young surgeons, and may provide valuable reference for PSP training of young surgeons. In addition, our study also showed a promising potential of the VR technology in surgical simulation training.
Assuntos
Internato e Residência , Parafusos Pediculares , Treinamento por Simulação , Realidade Virtual , Competência Clínica , HumanosRESUMO
BACKGROUND: The extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES). However, the regulatory and prognostic roles of tenascin-C (TNC) in ES remain unclear. METHODS: TNC expression was examined in specimens by immunohistochemistry, and the association of TNC expression with ES patient survival was also analysed. TNC-knockout cell lines were constructed using CRISPR/Cas9 methods. In vitro experiments and in vivo bioluminescent imaging using BALB/c nude mice were conducted to evaluate the effect of TNC on ES tumour progression. RNA sequencing was performed, and the underlying mechanism of TNC was further explored. RESULTS: TNC was overexpressed in ES tissue and cell lines, and TNC overexpression was associated with poor survival in ES patients. TNC enhanced cell proliferation, migration and angiogenesis in vitro and promoted ES metastasis in vivo. The oncoprotein EWS-FLI1 profoundly increased TNC expression by directly binding to the TNC promoter region. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) upregulation induced by Yes-associated protein (YAP) activation was responsible for TNC-regulated ES tumour progression. Activated integrin α5ß1 signalling might be correlated with YAP dephosphorylation and nuclear translocation. CONCLUSIONS: TNC may promote ES tumour progression by targeting MALAT1 through integrin α5ß1-mediated YAP activation.
Assuntos
Carcinogênese/metabolismo , Proteínas de Ciclo Celular/metabolismo , Integrina alfa5beta1/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , RNA Longo não Codificante/metabolismo , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/metabolismo , Tenascina/metabolismo , Fatores de Transcrição/metabolismo , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Feminino , Células HEK293 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Sarcoma de Ewing/patologia , Tenascina/genética , Transfecção , Adulto JovemRESUMO
Developing novel therapeutic agents against chondrosarcoma is important. SF2523 is a PI3K-Akt-mTOR and bromodomain-containing protein 4 (BRD4) dual inhibitor. Its activity in human chondrosarcoma cells is tested. Our results show that SF2523 potently inhibited survival, proliferation and migration, and induced apoptosis activation in SW1353â¯cells and primary human chondrosarcoma cells. The dual inhibitor was yet non-cytotoxic to the primary human osteoblasts and OB-6 osteoblastic cells. SF2523 blocked Akt-mTOR activation and downregulated BRD4-regulated genes (Bcl-2 and c-Myc) in chondrosarcoma cells. It was more efficient in killing chondrosarcoma cells than other established PI3K-Akt-mTOR and BRD4 inhibitors, including JQ1, perifosine and OSI-027. In vivo, intraperitoneal injection of SF2523 (30â¯mg/kg) potently inhibited subcutaneous SW1353 xenograft tumor growth in severe combined immunodeficient mice. Akt-mTOR inhibition as well as Bcl-2 and c-Myc downregulation were detected in SF2523-treated SW1353 tumor tissues. In conclusion, targeting PI3K-Akt-mTOR and BRD4 by SF2523 potently inhibited chondrosarcoma cell growth in vitro and in vivo.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Condrossarcoma/tratamento farmacológico , Morfolinas/farmacologia , Piranos/farmacologia , Adulto , Animais , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Humanos , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Morfolinas/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Piranos/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidoresRESUMO
For quite a long time, the 11S proteasome activator REGÉ and REGß, but not REGγ, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REGγ functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REGγ promotes MHC class I-restricted presentation to prime CD8+ T cells in vitro and in vivo. Mice deficient for REGγ have elevation of CD8+ T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REGγ specifically interacts with phosphorylated STAT3 and promotes its degradation in vitro and in cells. Inhibition of STAT3 dramatically attenuates levels of LMP2/LMP7 and antigen presentation in cells lacking REGγ. Importantly, treatment with STAT3 or LMP2/7 inhibitor prevented accumulation of immune complex in REGγ-/- kidney. Moreover, REGγ-/- mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REGγ with enhanced expression of phosphorylated STAT3, LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REGγ is a new regulator of immunoproteasome to balance autoimmunity.
Assuntos
Envelhecimento/imunologia , Autoantígenos/metabolismo , Doenças Autoimunes/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/metabolismo , Envelhecimento/genética , Animais , Apresentação de Antígeno , Autoantígenos/genética , Doenças Autoimunes/genética , Células Cultivadas , Cisteína Endopeptidases/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Camundongos , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/genética , Fator de Transcrição STAT3/metabolismoRESUMO
BACKGROUND: Spinal malignant melanoma (SMM) is a rare type of tumor that can cause nerve roots or spinal cord compression. Patients often suffer from fierce pain and paralyzation. And the estimated survival time were less than 6 months. Surgical interventions to remove the tumor and decompress the nearby nerve roots and spinal cord are effective management. Unfortunately, there lack a thorough and persuasive surgical guideline that specifically aims for this disease. It is necessary to obtain some clinical prognostic factors that predict the recurrence rate and overall survival (OS) of patients with SMM who underwent surgical interventions. METHODS: 21 patients with SMM who underwent surgical intervention were retrospectively reviewed. Related patients factors, treatment factors and tumor factors were acquired and subjected into survive analyses using Kaplan-Meier method and the log-rank test. Further Cox proportional hazards model was used to identify independent prognostic factors. Literature regarding surgical interventions on SMM patients were reviewed and summarized as well. RESULTS: Surgical approach total en-bloc spondylectomy (TES/Piecemeal) (p = 0.015, B 0.029, 95%CI 0.002-0.508), preoperative Frankel grade (A-C/D-E) (p = 0.021, B 15.041, 95%CI 1.492-151.669) and tumor metastases (Yes/No) (p = 0.013, B 16.667, 95%CI 1.805-153.897) are independent prognostic factors for recurrence free survival (RFS). Preoperative Frankel grade (A-C/D-E) (p = 0.031, B 10.676, 95%CI 1.241-91.877) is independent prognostic factors for OS. 12 literatures have been reviewed, including 11 case reports and one retrospective study. CONCLUSIONS: Surgical interventions for patients with SMM are beneficial. Surgical approach (TES/piecemeal), tumor origin (primary/metastasis) and preoperative Frankel grade (A-C/D-E) are independent risk factors in predicting RFS. Preoperative Frankel grade (A-C/D-E) is independent prognostic factor in predicting OS.
Assuntos
Melanoma/patologia , Neoplasias da Coluna Vertebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/cirurgia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/mortalidade , Neoplasias da Coluna Vertebral/cirurgia , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The aim of the study was to report the long-term outcomes and analyze the potential prognostic factors that may contribute to symptomatic patients with aneurysmal bone cyst (ABC) of the spine undergoing surgical treatments. METHODS: A retrospective analysis of consecutive patients with ABCs of the spine was performed. The clinical features were reviewed, and the disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. Factors with p values ≤ 0.05 were subjected to multivariate analysis by Cox proportional hazards model to identify the independent prognostic contributors. p values < 0.05 were considered statistically significant. RESULTS: A total of 42 patients with ABCs of the spine were included in the study. All patients received surgical treatments. The mean follow-up period was 41.3 months (median 39.5, range 24-64). Local recurrence was detected in eight patients after surgery in our center, whereas death occurred in three patients. The estimated 5-year DFS and OS rate was 54.1% and 76.8%, respectively. The statistical analyses indicated that both en bloc resection and primary/secondary tumor status were independent prognostic factors for DFS. CONCLUSIONS: Secondary ABC status may be associated with worse prognosis, and en bloc resection remains the treatment of choice for ABCs with neurologic deficits or spinal instability of the spine, which is correlated with better prognosis for local tumor control. These slides can be retrieved under Electronic Supplementary Material.
Assuntos
Cistos Ósseos Aneurismáticos/mortalidade , Cistos Ósseos Aneurismáticos/cirurgia , Doenças da Coluna Vertebral/mortalidade , Doenças da Coluna Vertebral/cirurgia , Adolescente , Adulto , Criança , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To develop a novel nomogram for predicting survival of patients with spine metastasis from colorectal cancer (SMCRC) based on the clinical characteristics and prognostic factors. METHODS: Included in this study were 93 SMCRC patients who received treatments in our institute between 2006 and 2017, whose clinical data were analyzed retrospectively by univariate and multivariate analysis to identify independent variables that could predict prognosis. A nomogram for survival prediction was established on the basis of preoperative independent factors, and then subjected to bootstrap re-samples for internal validation. The discrimination was measured by concordance index (C-index). We used ROC analysis with the corresponding AUROC to compare the prediction accuracy of Changzheng Nomogram with three existing prognostic systems (Tomita, Tokuhashi and Bauer). RESULTS: The high and median degrees of primary tumor differentiation, primary tumor surgery, carcinoembryonic antigen ≤ 5 ng/ml, no visceral metastases and ECOG-PS (0-2) were favorable prognostic factors for CRC metastases in the spine. These five preoperative independent factors were identified and entered into the nomogram with the C-index of 0.786 (0.739-0.833). The calibration curves for probability of 12- and 24-month overall survival (OS) showed good agreement between the predictive risk and the actual risk, and calibration was assessed. Compared with the previous prognostic systems, Changzheng Nomogram reported in this study showed higher accuracy in predicting OS of patients with SMCRC spinal metastases (p < 0.05). CONCLUSION: By using this novel predictive model, clinicians could more precisely estimate the survival outcome of individual patients by evaluating clinical characteristics and identify subgroups of patients who are in need of a specific individual treatment strategy. These slides can be retrieved under Electronic Supplementary Material.