RESUMO
Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.
Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP , Subunidades alfa de Proteínas de Ligação ao GTP , Humanos , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Animais , Camundongos , Feminino , Masculino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Mutação , Adulto , Pessoa de Meia-Idade , Transdução de Sinais , Hemangioma Cavernoso/genética , Hemangioma Cavernoso/patologia , Adolescente , Sequenciamento do Exoma , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genéticaRESUMO
BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).
Assuntos
Arteriopatias Oclusivas , Artéria Basilar , Procedimentos Endovasculares , Acidente Vascular Cerebral , Trombectomia , Humanos , Arteriopatias Oclusivas/complicações , Arteriopatias Oclusivas/tratamento farmacológico , Arteriopatias Oclusivas/mortalidade , Arteriopatias Oclusivas/cirurgia , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/cirurgia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/mortalidade , Isquemia Encefálica/cirurgia , Avaliação da Deficiência , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/etiologia , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/cirurgia , Trombectomia/efeitos adversos , Trombectomia/métodos , Fatores de Tempo , Resultado do TratamentoRESUMO
Although some pyroptosis-related (PR) prognostic models for cancers have been reported, pyroptosis-based features have not been fully discovered at the single-cell level in hepatocellular carcinoma (HCC). In this study, by deeply integrating single-cell and bulk transcriptome data, we systematically investigated significance of the shared pyroptotic signature at both single-cell and bulk levels in HCC prognosis. Based on the pyroptotic signature, a robust PR risk system was constructed to quantify the prognostic risk of individual patient. To further verify capacity of the pyroptotic signature on predicting patients' prognosis, an attention mechanism-based deep neural network classification model was constructed. The mechanisms of prognostic difference in the patients with distinct PR risk were dissected on tumor stemness, cancer pathways, transcriptional regulation, immune infiltration and cell communications. A nomogram model combining PR risk with clinicopathologic data was constructed to evaluate the prognosis of individual patients in clinic. The PR risk could also evaluate therapeutic response to neoadjuvant therapies in HCC patients. In conclusion, the constructed PR risk system enables a comprehensive assessment of tumor microenvironment characteristics, accurate prognosis prediction and rational therapeutic options in HCC.
Assuntos
Carcinoma Hepatocelular , Aprendizado Profundo , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Transcriptoma , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Comunicação Celular , Microambiente Tumoral/genéticaRESUMO
Arteriovenous malformations (AVMs) are fast-flow vascular malformations and refer to important causes of intracerebral haemorrhage in young adults. Getting deep insight into the genetic pathogenesis of AVMs is necessary. Herein, we identified two vital missense variants of G protein-coupled receptor (GPCR) associated sorting protein 1 (GPRASP1) in AVM patients for the first time and congruously determined to be loss-of-function variants in endothelial cells. GPRASP1 loss-of-function caused endothelial dysfunction in vitro and in vivo. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral haemorrhage, AVMs and exhibited vascular anomalies in multiple organs. GPR4 was identified to be an effective GPCR binding with GPRASP1 to develop endothelial disorders. GPRASP1 deletion activated GPR4/cAMP/MAPK signalling to disturb endothelial functions, thus contributing to vascular anomalies. Mechanistically, GPRASP1 promoted GPR4 degradation. GPRASP1 enabled GPR4 K63-linked ubiquitination, enhancing the binding of GPR4 and RABGEF1 to activate RAB5 for conversions from endocytic vesicles to endosomes, and subsequently increasing the interactions of GPR4 and ESCRT members to package GPR4 into multivesicular bodies or late endosomes for lysosome degradation. Notably, the GPR4 antagonist NE 52-QQ57 and JNK inhibitor SP600125 effectively rescued the vascular phenotype caused by endothelial Gprasp1 deletion. Our findings provided novel insights into the roles of GPRASP1 in AVMs and hinted at new therapeutic strategies.
Assuntos
Malformações Arteriovenosas , Malformações Arteriovenosas Intracranianas , Animais , Humanos , Camundongos , Malformações Arteriovenosas/genética , Células Endoteliais/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Malformações Arteriovenosas Intracranianas/genética , Malformações Arteriovenosas Intracranianas/metabolismo , Camundongos Knockout , Receptores Acoplados a Proteínas GRESUMO
Current treatments of brain arteriovenous malformation (BAVM) are associated with considerable risks and at times incomplete efficacy. Therefore, a clinically consistent animal model of BAVM is urgently needed to investigate its underlying biological mechanisms and develop innovative treatment strategies. Notably, existing mouse models have limited utility due to heterogenous and untypical phenotypes of AVM lesions. Here we developed a novel mouse model of sporadic BAVM that is consistent with clinical manifestations in humans. Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions. This strategy successfully induced BAVMs in mice across different age groups and within various brain regions. Pathological features of BAVM were primarily dilated blood vessels with reduced vascular wall stability, accompanied by spontaneous hemorrhage and neuroinflammation. Single-cell sequencing revealed differentially expressed genes that were related to the cytoskeleton, cell motility, and intercellular junctions. Early administration of Dabrafenib was found to be effective in slowing the progression of BAVMs; however, its efficacy in treating established BAVM lesions remained uncertain. Taken together, our proposed approach successfully induced BAVM that closely resembled human BAVM lesions in mice, rendering the model suitable for investigating the pathogenesis of BAVM and assessing potential therapeutic strategies.
Assuntos
Malformações Arteriovenosas Intracranianas , Proteínas Proto-Oncogênicas B-raf , Animais , Malformações Arteriovenosas Intracranianas/genética , Malformações Arteriovenosas Intracranianas/patologia , Malformações Arteriovenosas Intracranianas/metabolismo , Camundongos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Mutação/genética , Modelos Animais de Doenças , Humanos , Oximas/farmacologia , Imidazóis/farmacologia , Encéfalo/patologia , Encéfalo/metabolismo , Encéfalo/irrigação sanguínea , Endotélio Vascular/patologia , Endotélio Vascular/metabolismo , Camundongos Transgênicos , Camundongos Endogâmicos C57BLRESUMO
Single-cell RNA sequencing (scRNA-seq) data scale surges with high-throughput sequencing technology development. However, although single-cell data analysis is a powerful tool, various issues have been reported, such as sequencing sparsity and complex differential patterns in gene expression. Statistical or traditional machine learning methods are inefficient, and the accuracy needs to be improved. The methods based on deep learning can not directly process non-Euclidean spatial data, such as cell diagrams. In this study, we have developed graph autoencoders and graph attention network for scRNA-seq analysis based on a directed graph neural network named scDGAE. Directed graph neural networks cannot only retain the connection properties of the directed graph but also expand the receptive field of the convolution operation. Cosine similarity, median L1 distance, and root-mean-squared error are used to measure the gene imputation performance of different methods with scDGAE. Furthermore, adjusted mutual information, normalized mutual information, completeness score, and Silhouette coefficient score are used to measure the cell clustering performance of different methods with scDGAE. Experiment results show that the scDGAE model achieves promising performance in gene imputation and cell clustering prediction on four scRNA-seq data sets with gold-standard cell labels. Furthermore, it is a robust framework that can be applied to general scRNA-Seq analyses.
Assuntos
Redes Neurais de Computação , Análise da Expressão Gênica de Célula Única , Análise de Sequência de RNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Célula Única/métodos , Análise de Dados , Análise por Conglomerados , Perfilação da Expressão Gênica/métodosRESUMO
Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the CNS that can lead to seizure, haemorrhage and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analysed whole-exome sequencing data for patients with CCM and found that â¼40% of them have a single, specific MAP3K3 mutation [c.1323C>G (p.Ile441Met)] but not any other known mutations in CCM-related genes. We developed a mouse model of CCM with MAP3K3I441M uniquely expressed in the endothelium of the CNS. We detected pathological phenotypes similar to those found in patients with MAP3K3I441M. The combination of in vivo imaging and genetic labelling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood-brain barrier. Experiments with our MAP3K3I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1/2/3 and/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs.
Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central , Proteínas Proto-Oncogênicas , Animais , Camundongos , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Mutação/genética , Fenótipo , Medula Espinal/patologiaRESUMO
In this work, a THz stereo inverse synthetic aperture radar scheme based on photonics is proposed, and proof-of-concept experimentally demonstrated, achieving high resolution and fast three-dimensional (3D) positioning of multiple targets. An optical frequency comb and a uni-traveling carrier photodiode are employed to photonically generate a linear frequency-modulation signal at 300-320 GHz. By two incoherent measurements at different angles with one pair of antennas, 3D positioning of plane reflectors over a distance of 0.6 m is successfully accomplished, achieving a resolution of 7.5 mm for both range and azimuth dimensions, and a maximum experimental height error of 4 mm.
RESUMO
Non-cavernous sinus (CS) dural arteriovenous fistulas (DAVFs) involving the sphenoid bone are rare entities that are easily confused with one another due to the complex structure and high variability of the venous system around the middle cranial fossa. We present a large retrospective study on middle cranial fossa non-CS DAVFs and review the literature on DAVF treatment in this location as well as relative anatomy. 15 patients had DAVFs involving the lesser sphenoid wing and 11 patients had DAVFs involving the greater sphenoid wing. Six patients presented with intracranial hemorrhage or subarachnoid hemorrhage (23.1%, 6/26). The most common symptoms were eye symptoms (38.5%, 10/26). Nineteen patients were treated with trans-arterial embolization (TAE) using liquid embolic agents and two patients were treated with transvenous embolization (TVE) using Onyx or in combination with coils. Surgical disconnection of the drainage veins was performed in five patients, with three cases experiencing unsuccessful TAE. Anatomic cure was achieved in 92.3% of the patients (24/26). Twelve patients had DSA and clinical follow-up from 3 to 27 months. There was one recurrence (8.3%) of the fistula in the patient two months after the initial complete occlusion. The majority of patients can be cured endovascularly. Laterocavernous sinus DAVFs may not be embolized by transvenous approach via the cavernous sinus because there is often no connection between them in most patients. A small percentage of patients may require surgical ligation to be cured.
Assuntos
Malformações Vasculares do Sistema Nervoso Central , Embolização Terapêutica , Humanos , Fossa Craniana Média/cirurgia , Estudos Retrospectivos , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Procedimentos Cirúrgicos Vasculares , Resultado do TratamentoRESUMO
Dural arteriovenous fistulas (DAVFs) within the falx cerebri are infrequently documented and may be linked with the falcine sinus/venous plexus. The falcine sinus/venous plexus, often regarded as a normal venous structure, can exhibit pathological characteristics, differing from the persistent fetal falcine sinus. A retrospective analysis was conducted at a single center to identify all cases of DAVFs within the falx cerebri spanning from 2002 to 2022. Demographic data, fistula features, treatment modalities, clinical outcomes, and fistula closure were collected and analyzed. Additionally, relevant literature on DAVFs in this location was reviewed. Ten cases were identified at our center, supplemented by 13 cases reported in the literature. In our cohort, patients had an average age of 49.4 ± 8.1 years, with a male predominance of 90%. Trans-arterial embolization (TAE) alone achieved immediate complete occlusion in eight cases, while conservative treatment was pursued in two cases. No treatment-related complications or fistula recurrences were observed. In the literature, seven patients underwent direct surgery, three underwent TAE, and one underwent both direct surgery and radiosurgery for complete fistula closure. No instances of fistula recurrence or treatment complications were reported. Dural arteriovenous fistulas within the falx cerebri are rare, with limited literature available. They typically present as aggressive lesions. Treatment options include direct surgery or TAE. However, due to a lack of long-term DSA follow-up, the cure and recurrence rates are unknown for endovasdcular therapy. Further investigation is warranted to elucidate the involvement of the falcine sinus/venous plexus in falx cerebri DAVFs.
Assuntos
Malformações Vasculares do Sistema Nervoso Central , Dura-Máter , Embolização Terapêutica , Humanos , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Malformações Vasculares do Sistema Nervoso Central/terapia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Embolização Terapêutica/métodos , Estudos Retrospectivos , Resultado do Tratamento , IdosoRESUMO
BACKGROUND: Presently, a consistent strategy for determining the stability of unruptured intracranial aneurysms (UIAs) in elderly patients is lacking, primarily due to the unique characteristics of this demographic. Our objective was to assess the risk factors contributing to aneurysm instability (growth or rupture) within the elderly population. METHODS: In this study, we compiled data from follow-up patients with UIAs spanning from November 2016 to August 2021. We specifically focused on patients aged ≥ 60 years. Clinical histories were gathered, and morphological parameters of aneurysms were measured. The growth of aneurysms was determined using the computer-assisted semi-automated measurement (CASAM). Growth and rupture rates of UIAs were calculated, and both univariate and multivariate Cox regression analyses were conducted. Additionally, Kaplan-Meier survival curves were plotted. RESULTS: A total of 184 patients with 210 aneurysms were enrolled in the study. The follow-up period encompasses 506.6 aneurysm-years and 401.4 patient-years. Among all the aneurysms, 23 aneurysms exhibited growth, with an annual aneurysm growth rate of 11.0%, and 1 (4.5%) experienced rupture, resulting in an annual aneurysm rupture rate of 0.21%. Multivariate Cox analysis identified poorly controlled hypertension (P = 0.011) and high-risk aneurysms (including anterior cerebral artery (ACA), anterior communicating artery (AcoA), posterior communicating artery aneurysm (PcoA), posterior circulation (PC) > 4 mm or distal internal carotid artery (ICAd), middle cerebral artery (MCA), and PC > 7 mm) (P = 0.006) as independent risk factors for the development of unstable aneurysms. CONCLUSIONS: In the elderly, poorly controlled hypertension and high-risk aneurysms emerge as significant risk factors for aneurysm instability. This underscores the importance of rigorous surveillance or timely intervention in patients presenting with these risk factors.
Assuntos
Aneurisma Roto , Hipertensão , Aneurisma Intracraniano , Humanos , Idoso , Adulto , Criança , Aneurisma Intracraniano/epidemiologia , Fatores de Risco , Aneurisma Roto/epidemiologia , Artéria Cerebral AnteriorRESUMO
BACKGROUND: Isolated sinus dural arteriovenous fistulas (DAVFs) constitute a rare and distinctive subtype of DAVF, typically found in small case numbers or case reports. The optimal treatment for this DAVF type remains unclear. OBJECTIVE: This study aims to further detail the treatment outcomes of isolated sinus DAVFs in a sizable cohort from a single center. METHODS: A retrospective study was undertaken on a consecutive series of patients with isolated sinus DAVFs treated at a single institution from 2002 to 2022. The article delineates the clinical presentation, angiographic features, treatment strategy, clinical and angiographic outcomes, and complications. RESULTS: The cohort consisted of 31 males and 13 females, with an average age of 52.0 ± 15.5 years (range, 16-83). The success rate for trans-arterial embolization (TAE) was 97.3% (36/37). Transvenous embolization (TVE) with the reopening technique was successful in 3 of 4 patients (75.0%). Two open burr-hole TVE cases (66.7%, 2/3) and one surgery (100%) resulted in immediate complete closure of the fistula. Immediate complete occlusion was achieved in 93.2% (41/44) of cases. There was one major complication (2.3%, 1/44) and two fistulas recurred (9.5%, 2/21). CONCLUSIONS: The majority of isolated sinus DAVFs can be effectively treated with TAE using Onyx. TVE and surgery serve as alternative techniques when arterial access is deemed inappropriate or when complete occlusion cannot be attained with TAE. Complete embolization of isolated sinus DAVFs by TAE can typically be achieved without delay.
Assuntos
Malformações Vasculares do Sistema Nervoso Central , Embolização Terapêutica , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Resultado do Tratamento , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Procedimentos Cirúrgicos Vasculares , Angiografia , Embolização Terapêutica/efeitos adversosRESUMO
This study investigated the effect of trametenolic acid(TA) on the migration and invasion of human hepatocellular carcinoma HepG2.2.15 cells by using Ras homolog gene family member C(RhoC) as the target and probed into the mechanism, aiming to provide a basis for the utilization of TA. The methyl thiazolyl tetrazolium(MTT) assay was employed to examine the proliferation of HepG2.2.15 cells exposed to TA, and scratch and Transwell assays to examine the cell migration and invasion. The pull down assay was employed to determine the impact of TA on RhoC GTPase activity. Western blot was employed to measure the effect of TA on the transport of RhoC from cytoplasm to cell membrane and the expression of RhoC/Rho-associated kinase 1(ROCK1)/myosin light chain(MLC)/matrix metalloprotease 2(MMP2)/MMP9 pathway-related proteins. RhoC was over-expressed by transient transfection of pcDNA3.1-RhoC. The changes of F-actin in the cytoskeleton were detected by Laser confocal microscopy. In addition, the changes of cell migration and invasion, expression of proteins in the RhoC/ROCK1/MLC/MMP2/MMP9 pathway, and RhoC GTPase activity were detected. The subcutaneously transplanted tumor model of BALB/c nude mice and the low-, medium-, and high-dose(40, 80, and 120 mg·kg~(-1), respectively) TA groups were established and sorafenib(20 mg·kg~(-1)) was used as the positive control. The tumor volume and weight in each group were measured, and the expression of related proteins in the tumor tissue was determined by Western blot. The results showed that TA inhibited the proliferation of HepG2.2.15 cells in a concentration-dependent manner, with the IC_(50) of 66.65 and 23.09 µmol·L~(-1) at the time points of 24 and 48 h, respectively. The drug administration groups had small tumors with low mass. The tumor inhibition rates of sorafenib and low-, medium-and high-dose TA were 62.23%, 26.48%, 55.45%, and 62.36%, respectively. TA reduced migrating and invading cells and inhibited RhoC protein expression and RhoC GTPase activity in a concentration-dependent manner, dramatically reducing RhoC and membrane-bound RhoC GTPase. The expression of ROCK1, MLC, p-MLC, MMP2, and MMP9 downstream of RhoC can be significantly inhibited by TA, as confirmed in both in vitro and in vivo experiments. After HepG2.2.15 cells were transfected with pcDNA3.1-RhoC to overexpress RhoC, TA down-regulated the protein levels of RhoC, ROCK1, MLC, p-MLC, MMP2, and MMP9 and decreased the activity of RhoC GTPase, with the inhibition level comparable to that before overexpression. In summary, TA can inhibit the migration and invasion of HepG2.2.15 cells. It can inhibit the RhoC/ROCK1/MLC/MMP2/MMP9 signaling pathway by suppressing RhoC GTPase activity and down-regulating RhoC expression. This study provides a new idea for the development of autophagy modulators targeting HSP90α to block the proliferation and inhibit the invasion and migration of hepatocellular carcinoma cells via multiple targets of active components in traditional Chinese medicines.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Proteína de Ligação a GTP rhoC/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Metaloproteinase 9 da Matriz/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Sorafenibe , Camundongos Nus , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Movimento Celular , Proliferação de CélulasRESUMO
Adolescent idiopathic scoliosis (AIS) is a common pediatric musculoskeletal disorder worldwide, characterized by atypical spine curvatures in otherwise healthy children. Human genetic studies have identified candidate genes associated with AIS, however, only a few of these have been shown to recapitulate adult-viable scoliosis in animal models. Using an F0 CRISPR screening approach in zebrafish, we demonstrate that disruption of the dynein axonemal heavy chain 10 (dnah10) gene results in recessive adult-viable scoliosis in zebrafish. Using a stably segregating dnah10 mutant zebrafish, we showed that the ependymal monocilia lining the hindbrain and spinal canal displayed reduced beat frequency, which was correlated with the disassembly of the Reissner fiber and the onset of body curvatures. Taken together, these results suggest that monocilia function in larval zebrafish contributes to the polymerization of the Reissner fiber and straightening of the body axis.
Assuntos
Dineínas do Axonema , Cílios , Escoliose , Coluna Vertebral , Peixe-Zebra , Animais , Dineínas do Axonema/genética , Movimento Celular/genética , Cílios/genética , Cílios/metabolismo , Modelos Animais de Doenças , Morfogênese/genética , Escoliose/genética , Escoliose/fisiopatologia , Coluna Vertebral/embriologia , Coluna Vertebral/fisiologia , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Adolescent idiopathic scoliosis (AIS) is a common spinal deformity in young women, but its pathogenesis remains unclear. The primary pathogenic factors contributing to its development include genetics, abnormal bone metabolism, and endocrine factors. Bone marrow stem cells (BMSCs) play a crucial role in the pathogenesis of AIS by regulating its occurrence and progression. Noncoding RNAs (ncRNAs) are also involved in the pathogenesis of AIS, and their role in regulating BMSCs in patients with AIS requires further evaluation. In this review, we discuss the relevant literature regarding the osteogenic, chondrogenic, and lipogenic differentiation of BMSCs. The corresponding mechanisms of ncRNA-mediated BMSC regulation in patients with AIS, recent advancements in AIS and ncRNA research, and the importance of ncRNA translation profiling and multiomics are highlighted.
RESUMO
Adolescent idiopathic scoliosis (AIS) is a complex disease characterized by three-dimensional structural deformities of the spine. Its pathogenesis is associated with osteopenia. Bone-marrow-derived mesenchymal stem cells (BMSCs) play an important role in bone metabolism. We detected 1919 differentially expressed mRNAs and 744 differentially expressed lncRNAs in BMSCs from seven patients with AIS and five patients without AIS via high-throughput sequencing. Multiple analyses identified bone morphogenetic protein-6 (BMP6) as a hub gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS. BMP6 expression was found to be decreased in AIS and its knockdown in human BMSCs significantly altered the degree of osteogenic differentiation. Additionally, CAP1-217 has been shown to be a potential upstream regulatory molecule of BMP6. We showed that CAP1-217 knockdown downregulated the expression of BMP6 and the osteogenic differentiation of BMSCs. Simultaneously, knockout of BMP6 in zebrafish embryos significantly increased the deformity rate. The findings of this study suggest that BMP6 is a key gene that regulates the abnormal osteogenic differentiation of BMSCs in AIS via the CAP1-217/BMP6/RUNX2 axis.
Assuntos
Doenças Ósseas Metabólicas , Escoliose , Humanos , Adolescente , Animais , Escoliose/genética , Escoliose/patologia , Osteogênese/genética , Peixe-Zebra/genética , Coluna Vertebral/metabolismo , Diferenciação Celular/genética , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/metabolismo , Células Cultivadas , Células da Medula Óssea/metabolismo , Proteína Morfogenética Óssea 6/genéticaRESUMO
The prevalence of idiopathic scoliosis (IS) is 2-3% worldwide and is more common in girls. Estrogen receptors (ERs) is supposed to be related to sex differences and development of IS. Meanwhile, paravertebral muscle (PVM) abnormalities play important roles in the pathogenesis of IS. But the changes of ERs between the PVMs from IS patients and controls, and the mechanism by which ERs may affect IS patients remain unclear. Thus, the expression levels of ERs, myogenesis regulator (MYOG) and adipogenesis related factors (CEBPA, PPARγ, FABP4), as well as morphological changes in the PVMs and primary skeletal muscle mesenchymal progenitor cells (hSM-MPCs) of IS patients and controls were investigated. Increased expression levels of ERs and CEBPA, PPARγ, FABP4, together with severe myofiber necrosis and fat infiltration, were found in the PVMs of IS patients. Meanwhile, upregulated ERs, FABP4 and CEBPA, downregulated MYOG and impaired myogenesis were also revealed in the hSM-MPCs of IS patients compared with those of controls. Upregulation of ERs inhibited myogenesis but increased expression of CEBPA and FABP4 in C2C12 myoblasts. Nevertheless, treatment of ER antagonist increased expression of MYOG, enhanced myogenesis and decreased expression of CEBPA and FABP4 in skeletal muscle cells of IS patients. Therefore, our study suggested that PVMs specific upregulation of ERs could impair myogenesis and increase the expression of adipogenesis related factors, further leading to PVMs abnormalities in IS patients.
Assuntos
Adipogenia , Escoliose , Humanos , Masculino , Feminino , Receptores de Estrogênio/metabolismo , Escoliose/metabolismo , PPAR gama/metabolismo , Músculo Esquelético/metabolismo , Desenvolvimento Muscular/fisiologiaRESUMO
Cavernous malformations (CM) have long been considered congenital of central nervous system, while the mechanism of CMs detailed development process associated with genetic factors remains unclear. We reported an uncommon case which suffered spinal cord cavernous malformations. In this work, representative samples were obtained, and the sequenced results were described for the first time. A 9-year-old boy was found oblique shoulder with slightly weakness of left limbs; MRI indicated spinal cord cavernous malformations (CMs) located at the C4-C6 vertebral level. On genetic analysis, a shared mutation of PIK3CA (p.H1047R) in CMs and associated developmental venous anomalies (DVAs) was detected, with a different abundance (2% and 7%, respectively), and a somatic mutation of MAP3K3 (p.I441M) was detected in the CM tissue samples. This case provides better knowledge of the formation history and genetic triggers of the DVA-associated CMs. This evidence allows us to speculate the developmental history of the CM lesion: The DVA with PIK3CA mutation might be genetic precursor, and then the associated CM could be derived from terminal cell population of the DVA by acquiring a somatic mutation in MAP3K3.
Assuntos
Malformações Vasculares do Sistema Nervoso Central , Hemangioma Cavernoso do Sistema Nervoso Central , Malformações do Sistema Nervoso , Masculino , Humanos , Criança , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/genética , Malformações Vasculares do Sistema Nervoso Central/complicações , Imageamento por Ressonância Magnética , Malformações do Sistema Nervoso/complicações , Medula Espinal/diagnóstico por imagemRESUMO
Cavernous malformations (CM) that arise in the central nervous system have long been considered congenital, while there are many reports of de novo non-familial-type CM adjacent to developmental venous anomalies (DVA) or after radiation. The mechanisms that cause de novo formations of sporadic cavernous malformation (CM) still remain unknown and purely speculative. We report a case of de novo cerebral CM in a child with multiple developmental venous anomalies and cutaneous vascular malformations. Histological examination and whole-exome sequencing (WES) was performed on a fresh-frozen tissue sample of the CM. WES revealed 2 missense non-synonymous variants in two genes, EPHB4 and PIK3CA. The mutant allele of EPHB4 (NM_004444.4: c.1840 T > C, p.Y614H) appeared in 248/469 WES reads (allele frequency, 52.88%), which suggested the mutation a germline one. PIK3CA (NM_006218.2) somatic mutations were found in exon 9: c.1624G > A (p.Glu542Lys) with variant frequency of 2.2% (2/89 WES reads). We did not find any non-synonymous mutations of the three CCM genes (KRIT1, CCM2, and PDCD10) in this patient. Our findings suggested that the combination of gain of function in PIK3CA and loss of function in EPHB4 may play an important role in the pathogenesis of CM, which can develop in acquired form like tumorigenesis.
Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central , Criança , Humanos , Proteínas de Transporte/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação em Linhagem Germinativa , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas/genéticaRESUMO
This study aimed to investigate the therapeutic efficacy of three different surgical approaches for the treatment of intraventricular craniopharyngiomas (IVCs). The three surgical approaches investigated in this study were the endoscopic endonasal approach (EEA), pterional trans-lamina terminalis approach (PTA), and interhemispheric trans-lamina terminalis approach (ITA). Patient demographics, preoperative symptoms, endocrine and hypothalamic status, tumor characteristics, and surgical outcomes were analyzed and compared among the different surgical groups. A total of 31 patients with IVCs were included in the analysis, with 12 patients in the EEA group, 8 patients in the ITA group, and 11 patients in the PTA group. The mean follow-up time was 39 ± 23 months. Statistical analysis of the data revealed significant differences in the gross total resection (GTR) rate among the three surgical groups (P = 0.033). The GTR rate for the EEA group was 100%, that for the ITA group was 88%, and that for the PTA group was 64%, which was the lowest rate observed. After surgery, only 8.3% of the patients in the EEA group did not experience new postoperative hypopituitarism, while the percentages in the ITA and PTA groups were 75% and 73%, respectively (P = 0.012). Finally, we found that postoperative hypopituitarism may be related to the transection of the pituitary stalk during the operation (P = 0.020). Based on the results of this study, we recommend using the EEA and the ITA instead of the PTA for the surgical resection of IVCs. Furthermore, the appropriate surgical approach should be selected based on the tumor's growth pattern.