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Biological networks serve a crucial role in elucidating intricate biological processes. While interspecies environmental interactions have been extensively studied, the exploration of gene interactions within species, particularly among individual microorganisms, is less developed. The increasing amount of microbiome genomic data necessitates a more nuanced analysis of microbial genome structures and functions. In this context, we introduce a complex structure using higher-order network theory, "Solid Motif Structures (SMS)", via a hierarchical biological network analysis of genomes within the same genus, effectively linking microbial genome structure with its function. Leveraging 162 high-quality genomes of Microcystis, a key freshwater cyanobacterium within microbial ecosystems, we established a genome structure network. Employing deep learning techniques, such as adaptive graph encoder, we uncovered 27 critical functional subnetworks and their associated SMSs. Incorporating metagenomic data from seven geographically distinct lakes, we conducted an investigation into Microcystis' functional stability under varying environmental conditions, unveiling unique functional interaction models for each lake. Our work compiles these insights into an extensive resource repository, providing novel perspectives on the functional dynamics within Microcystis. This research offers a hierarchical network analysis framework for understanding interactions between microbial genome structures and functions within the same genus.
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Genoma Bacteriano , Microcystis , Microcystis/genética , Lagos/microbiologia , Redes Reguladoras de Genes , Metagenômica/métodos , Metagenoma , Genoma Microbiano , Genômica/métodos , Aprendizado ProfundoRESUMO
BACKGROUND: Transcatheter mitral valve replacement (TMVR) has become an alternative for high-risk patients with severe mitral regurgitation (MR). The aim of this study was to evaluate the safety and feasibility of the Mi-thos TMVR system (NewMed Medical) for high-risk patients with severe MR. METHODS: This was a prospective, two-center, single-arm early feasibility study. Baseline characteristics, procedural data and 30-day follow-up outcomes were collected and analyzed. The primary endpoint was intraoperative success rate of device implantation. The second endpoints were all-cause mortality and major post-procedural complications. Echocardiographic data were evaluated by an independent core laboratory. Clinical events were adjudicated by a clinical events committee. RESULTS: Ten high-risk patients with severe MR were enrolled at two sites from August 2021 to November 2022. The median age was 70.5 years, and 60% of patients were female. The median Society of Thoracic Surgeons Predicted Risk of Mortality was 9.5%. The Mi-thos TMVR system was successfully implanted via transapical access in all patients. There was no pericedural mortality or major postpericedural complications during the 30-day follow-up. All implanted prosthetic valves had no or trace valvular or paravalvular MR, and the median mitral valve gradient at 30 days was 2.0 mmHg (IQR: 2.0-3.0 mmHg). There was one mild left ventricular outflow tract obstruction. CONCLUSIONS: The favorable short-term outcomes of the Mi-thos TMVR system demonstrated that it might be a feasible and safe therapeutic alternative for high-risk patients with severe MR. Nevertheless, further evaluation of the Mi-thos TMVR system is warranted.
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Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Insuficiência da Valva Mitral , Humanos , Feminino , Idoso , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Insuficiência da Valva Mitral/etiologia , Próteses Valvulares Cardíacas/efeitos adversos , Estudos Prospectivos , Cateterismo Cardíaco , Resultado do TratamentoRESUMO
Transapical beating-heart mitral repair with chordal implantation system has been considered as an alternative treatment for degenerative mitral regurgitation. This study aimed to assess the feasibility and safety of the E-Chord system (Med-Zenith Medical, Beijing, China) for transapical beating-heart mitral valve repair in a porcine model. Artificial chordae were transapically implanted on the mitral valves of 12 anesthetized pigs under epicardial echocardiographic guidance and secured outside the left ventricular apex. The study endpoints included procedural success, device durability, and tissue response to the device. The procedural success rate was 100% (12/12). All animals were implanted with E-Chord in the anterior and posterior leaflets, respectively, and survived uneventfully until euthanized as planned. During the 180-day follow-up, no animal had significant mitral valve dysfunction. The gross observation showed no evidence of anchor detachment and chordal rupture, and there was no obvious damage or changes to mitral leaflets. Microscopic evaluation revealed that the endothelialization of anchor and chordae was completed 90 days after implantation and there was no evidence of chordal rupture, thrombosis, or infection during the 180-day follow-up. The E-Chord system was found to be feasible and safe for heart-beating mitral chordal implantation in a porcine model. The findings of this study suggest that the E-Chord system may be a potential alternative for the treatment of degenerative mitral regurgitation in humans.
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Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Mitral , Prolapso da Valva Mitral , Humanos , Suínos , Animais , Insuficiência da Valva Mitral/cirurgia , Estudos de Viabilidade , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Cordas Tendinosas/cirurgia , Resultado do TratamentoRESUMO
It has been recognized that wall shear stress plays an important role in the development of Bicuspid Aortopathy (BA), but the intrinsic mechanism is not well elucidated. This study aims to explore the underlying relationship between hemodynamical forces and pathological phenomenon. Total RNA was prepared from aortic wall tissues collected from 20 BA patients. RNA sequencing, bioinformatic analysis and quantitative reverse-transcription PCR validation identified nine miRNAs that were up-regulated in the aortic part exposed to high wall shear stress compared to the low wall shear stress control, and six miRNAs that were down-regulated. Among these candidates, miR-34a and miR-125a, both down-regulated in the high wall shear stress parts, were shown to be potential inhibitors of the metalloproteinase 2 gene. Luciferase reporter assays confirmed that both miRNAs could inhibit the expression of metalloproteinase 2 mRNA in CRL1999 by complementing with its 3' untranslated region. Conversely, immunofluorescence assays showed that inhibition of miR-34a or miR-125a could lead to increased metalloproteinase 2 protein level. On the other hand, both miR-34a and miR-125a were shown to alleviate stretch-induced stimulation of metalloproteinase 2 expression in CRL1999 cells. The results suggested that miR-34a and miR-125a might be implicated in wall shear stress induced aortic pathogenesis due to their apparent regulatory roles in metalloproteinase 2 expression and extracellular matrix remodeling, which are key events in the weakening of aortic walls among BA patients.
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Doenças das Valvas Cardíacas , MicroRNAs , Regiões 3' não Traduzidas , Valva Aórtica , Proliferação de Células , Humanos , Metaloproteinase 2 da Matriz/genética , MicroRNAs/genéticaRESUMO
Patients with aortic stenosis and low left ventricular ejection fraction (LVEF) would benefit from transcatheter aortic valve replacement. However, the safety and efficacy of transcatheter aortic valve replacement in patients with aortic regurgitation and left ventricular dysfunction remains unknown.We defined LVEF < 50% as left ventricular dysfunction. A total of 27 symptomatic patients with aortic regurgitation and ejection fraction < 50% underwent transcatheter aortic valve replacement using the J-Valve™ system (JieCheng Medical Technology Co, Ltd, Suzhou, China) in Zhongshan Hospital, Fudan University, from May 2014 to June 2019. Procedural and postoperative clinical outcomes were analyzed according to Valve Academic Research Consortium-2 (VARC-2) criteria.All patients (eight females; 70.6 ± 7.1 years) were considered to be at least intermediate surgical risk and/or severe comorbidity precluding for surgical aortic valve replacement (logistic European System for Cardiac Operative Risk Evaluation, 16.8 ± 9.5%, range 4.6% to 37.9%) by a multidisciplinary heart team. Transapical implantations were successful in 26 (96.3%) patients. All-cause mortality was 3.7% in the latest follow-up (25-590 days, median 369 days). Significant improvements in LVEF, left ventricular end-diastolic, and systolic dimensions were observed after procedure (from 40.3 ± 6.7% to 50.8 ± 10.5%, P < 0.001; from 65.1 ± 8.9 mm to 56.0 ± 9.6 mm, P = 0.002; from 52.2 ± 9.8 mm to 35.9 ± 13.4 mm, P < 0.001, respectively). No patient had aortic stenosis and paravalvular leak more than moderate and heart function improvement was obtained in the majority of patients at 1-year follow-up.Transcatheter aortic valve replacement using the J-Valve™ system is a reasonable alternative for patients with aortic regurgitation and left ventricular dysfunction regarding promising short-term outcomes.
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Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/cirurgia , Substituição da Valva Aórtica Transcateter , Disfunção Ventricular Esquerda/complicações , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume Sistólico , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: The occiput-axis crossing translaminar screw (C2LAM) fixation technique can help avoid vertebral injury, while the inclusion of offset connectors can facilitate implantation. This three-dimensional finite element (FE) study compared the stability of C2LAM using offset connectors (C2LAM + OF) with other methods. MATERIALS AND METHODS: Occipital and cervical spine computed tomography images of a healthy 30-year-old man were selected to build the FE model. Four internal fixation instruments including occiput plate-C2 pedicle (C2P) and pars (C2Pars) screws, as well as C2LAM and C2LAM + OF were applied consecutively to the model respectively to establish four new models, which were subjected to all states of motion and physiological loads to simulate normal movement, including the four kinds of basic activities of human such as flexion, extension, lateral bending, and axial rotation. Physiological measures and comparison included the range of motion (ROM) and stress distribution in the model. RESULTS: ROM between the fixation techniques was comparable, and the stability of the C2LAM + OF fixation technique was similar to that of C2P. Screw entry points, offset connectors and rods were the main stress distribution regions in the C2LAM + OF system. The mean von Mises stress of the inner wall was significantly smaller than that of the outer wall in flexion, extension, and rotation (p < 0.05); however, lateral bending was comparable, indicating a relatively small risk of damage to the inner wall. CONCLUSIONS: The results of this study indicate that the C2LAM + OF fusion technique can provide sufficient stability and can be used as an alternative to C2P under special circumstances.
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In this study, a versatile dual-functional polydimethylsiloxane (PDMS) sponge Surface Enhanced Raman Scattering (SERS) substrate has been fabricated for the on-site detection of pesticide residues both on the surface and in solution with minimum or no sample pretreatment. The PDMS sponge was fabricated using white granulated sugar and soft white sugar as pore-forming reagents. Later, multiple rounds of Ag NP deposition were performed by incubating the PDMS sponge in the Ag NP solution with the help of 3-mercaptopropyltrimethoxysilane (APTMS). The highest SERS enhancement was achieved through 2 rounds of Ag NP deposition. Under optimum conditions, with Rhodamine 6G (R6G) as the probe molecule, the limit of detection (LOD) reached 2 femtomoles (20 µL at a concentration of 100 pM). The analytical performance for potential on-site applications of the substrate has been demonstrated with pesticide-spiked agricultural products taken as examples. Without sample pretreatment, the pesticide triazophos and methyl parathion were successfully detected by swabbing on the fruit surface with LODs of 0.79 ng and 1.58 ng, respectively. In addition, the lowest detected concentrations of triazophos and methyl parathion in fruit juice were found to be 100 ppb and 1 ppm. More importantly, the PDMS sponge SERS substrate can be safely stored for 36 days without affecting its SERS activity.
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PURPOSE: Craniopharyngioma is a common pediatric brain tumor, with a high rate of recurrence after primary treatment. This retrospective study investigated the effect of various primary treatments on surgical strategies and outcomes for recurrent craniopharyngiomas. METHODS: The study population comprised 35 children (mean age 8.77 years, range 1-16 years) with recurrent craniopharyngioma re-operated from January 1990 to January 2009. The recurrent craniopharyngiomas were excised whenever possible. For analysis, the patients were divided into four groups according to the primary treatment: radical tumor resection (A), incomplete tumor resection (B), radiotherapy + incomplete tumor resection (C), and Ommaya reservoir placement + incomplete tumor resection (D). RESULTS: Group B had a significantly shorter recurrence-free interval than groups A, C, or D. Outcomes were significantly different among the four groups. The hypothalamic status scores of groups A (2.38 ± 0.27) and C (2.28 ± 0.42) were significantly higher than that of group B (1.64 ± 0.20). There were no statistical differences between any two other groups. CONCLUSIONS: In children, the primary treatments for craniopharyngioma should be considered when choosing the surgical strategy for recurrence. Radiotherapy before repeated surgery can result in a worse functional outcome and hypothalamic-pituitary function.
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Craniofaringioma/terapia , Recidiva Local de Neoplasia , Neoplasias Hipofisárias/terapia , Adolescente , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Craniofaringioma/complicações , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/complicações , Radioterapia , Reoperação/mortalidadeRESUMO
OBJECTIVE: To investigate the morphometric characteristics of the lateral bone window (LBW) of the sella turica. METHODS: A descriptive anatomical study of LBW was performed in 530 cases of dry skull base specimens with relatively complete sella turcica. Detailed morphometric characteristics such as dimensions and classification of the LBW was studied. All data analysis was performed using SPSS 17.0 statistical software. RESULTS: LBW is located in the lateral bony structures of sella turcica. The mean area sizes of the LBW were 75.99 ± 25.81 mm(2) (left) and 76.00 ± 25.53 mm(2) (right). There was no significant difference and there was a ââgood positive correlation between bilateral areas of the LBWs. The area size of the LBWs is graded as follows: Grade A (< 60 mm(2)), B (60~90 mm(2)) and C (> 90 mm(2)). LBW morphology was typed as follows: Type I, II, III, IV. And Tpye III includes Type IIIa and IIIb; Type IV includes Type IVa, IVb, IVc, IVd. CONCLUSIONS: The lateral bone window of sella turcica is an important structure located between pituiary fossa and parasellar region. The morphological measurements and variations of LBW in this study will provide preliminary data for further anatomical study of sella turcica. Moreover, knowing detailed anatomy of this region is essential for neurosurgeons who make surgery on cranial base or for teaching about the sella turcica in the neuroanatomy lab.
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Osso e Ossos/anatomia & histologia , Sela Túrcica/anatomia & histologia , Base do Crânio/anatomia & histologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefalometria , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To explore the clinical efficacies of bevacizumab (BEV) for high-grade glioma (HGG) in Chinese patients and evaluate its profiles of adverse events and usage safety. METHODS: A total of 15 HGG cases, including glioblastoma multiform (GBM) (n = 12) and anaplastic astrocytoma (AA) (n = 3), were selected to receive the treatments of BEV (10 mg/kg, q2w) and temozolomide (TMZ, 150 mg/m(2), 5 d/28 d). Their radiological responses, clinical status, progression-free survival (PFS) and overall survival (OS) were evaluated. Also their adverse events and severity were recorded and analyzed. RESULTS: According to the RANO criteria, during the short period (<3 months), 11 cases had significant radiological and clinical responses. However, only 4 cases responded during a follow-up period of beyond 3 months. Three cases had retrogression after BEV chemotherapy. At 6 months post-treatment, 8 cases (53.3%) survived without lesion progression and the median PFS was 8 ± 5 months. During a longer follow-up (>6 months), 8 patients had tumor retrogression, including 5 deaths. The median overall survival period was 24 ± 10 months. The adverse events included hypertension (n = 2), wound-healing complication (n = 1), vomiting (n = 2) and cerebro-spinal fluid leakage (n = 1). All complications were cured by activate supportive measures. CONCLUSION: After BEV treatment, most patients obtain more significant short-term responses with good toleration. For re-operative cases, the usage of BEV should be deferred to one month post-operation so as to avoid the occurrence of wound-healing complications.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Glioma/tratamento farmacológico , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Bevacizumab , Intervalo Livre de Doença , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Background: The improvement rate and predictors of secondary mitral regurgitation in patients with aortic regurgitation undergoing transcatheter aortic valve replacement (TAVR) remain unclear. This study aimed to identify predictors of persistent moderate to severe secondary mitral regurgitation after TAVR in patients with aortic regurgitation by assessing mitral valve geometry with computed tomography (CT). Methods: This retrospective cohort study reviewed 242 consecutive patients with aortic regurgitation who underwent TAVR between May 2014 and December 2022. Patients with primary or less than moderate mitral regurgitation were excluded. Mitral annular dimensions (area, perimeter, anteroposterior, intercommissural, and trigone-to-trigone diameter), mitral valve tenting geometry (mitral valve tenting area [MVTA] and mitral valve tenting height [MVTH]), and papillary muscle displacement were systematically measured at CT. Mitral regurgitation improvement was assessed at 3 months after TAVR by echocardiography. Logistic regression was performed to explore the association of mitral valve geometry with mitral regurgitation improvement after TAVR. Results: A total of 75 patients (mean age, 74 ± 7 years; 32.0% female) with moderate to severe secondary mitral regurgitation were included in the final analysis. Mitral regurgitation improved in 49 patients and remained unchanged in 26 patients. Mitral annular dimensions, including area, perimeter, anteroposterior, and intercommissural diameter, were associated with mitral regurgitation improvement. MVTA and MVTH were risk factors for sustained mitral regurgitation. In addition, QRS duration > 120 ms and atrial fibrillation had an impact on the mitral regurgitation improvement. Mitral annular area (odds ratio [OR], 1.41; 95% confidence interval [CI]: 1.05, 1.90; p = 0.02) and MVTA (OR, 7.24; 95% CI: 1.72, 30.44; p = 0.007) were independent predictors of persistent secondary mitral regurgitation after TAVR. Conclusions: Mitral annular area and MVTA were independent predictors of persistent secondary mitral regurgitation after TAVR.
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The inflammation-related tumor microenvironment (TME) is one of the major driving forces of hepatocarcinogenesis. We aimed to investigate cell-to-cell communication among Hepatocellular Carcinoma (HCC) through re-analyzing HCC single-cell RNA-seq data, and to confirm such cellular interaction through in vitro and in vivo study. We found a subset of Regulatory B cells with PD-L1 expression (PD-L1+ Bregs), mainly located in adjacent HCC tissues. In co-localization with PD-L1+ Bregs, a subset of Tumor Associated Macrophages with high expression of CXCL12 (CXCL12+ TAMs) was also mainly located in adjacent HCC tissues. Moreover, CXCL12+ TAMs can be stimulated in vitro using an HCC conditional medium. Using CellChat analysis and Multiplex Immunohistochemistry staining (mIHC), CXCL12+ TAMs were found to be first recruited by Cancer-Associated Fibroblasts (CAFs) through a CD74/macrophage migration inhibitory factor (MIF) pattern, and further differentiated into TGF-ß-enriched tissues. Furthermore, CXCL12+ TAMs recruited PD-L1+ Bregs via the CXCL12/CXCR4 axis, and CXCR4 expression was significantly positively correlated to PD-L1 expression in PD-L1+ Bregs. At last, we confirmed the communications among CAFs, Macrophages and B cells and their tumor-promoting effects by using an orthotopic mouse model of HCC. Immunosuppressive HCC TME involving cell-to-cell communications comprised MIF-secreting CAFs, CXCL12-secreting TAMs, and PD-L1-producing Bregs, and their regulation could be promising therapeutic targets in future immunotherapy for human HCC.
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Figla is one of the earliest expressed genes in the oocyte during ovarian development. In this study, Figla was characterized in C. maculata, one of the main aquaculture species in China, and designated as CmFigla. The length of CmFigla cDNA was 1303 bp, encoding 197 amino acids that contained a conserved bHLH domain. CmFigla revealed a female-biased expression patterns in the gonads of adult fish, and CmFigla expression was far higher in ovaries than that in testes at all gonadal development stages, especially at 60~180 days post-fertilization (dpf). Furthermore, a noteworthy inverse relationship was observed between CmFigla expression and the methylation of its promoter in the adult gonads. Gonads at 90 dpf were used for in situ hybridization (ISH), and CmFigla transcripts were mainly concentrated in oogonia and the primary oocytes in ovaries, but undetectable in the testes. These results indicated that Figla would play vital roles in the ovarian development in C. maculata. Additionally, the frame-shift mutations of CmFigla were successfully constructed through the CRISPR/Cas9 system, which established a positive foundation for further investigation on the role of Figla in the ovarian development of C. maculata. Our study provides valuable clues for exploring the regulatory mechanism of Figla in the fish ovarian development and maintenance, which would be useful for the sex control and reproduction of fish in aquaculture.
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AIM: Our aim was to conduct a systematic review and meta-analysis to examine the efficacy and safety of oliceridine in patients with postoperative pain. METHODS: Four databases were searched from the beginning of the database to the present. We included all randomized controlled trials (RCT) that evaluated the efficacy and safety of oliceridine in patients with postoperative pain. Our endpoints were the proportion of treatment responders to the oliceridine regimen and the incidence of adverse effects such as nausea and vomiting. RESULTS: The analysis showed that more patients responded significantly with oliceridine compared to placebo. The proportion of treatment responders to oliceridine was comparable to that of morphine. Oliceridine had analgesia effects similar to morphine compared to placebo. The incidence of respiratory safety events was significantly lower with oliceridine compared to morphine. Oliceridine was significantly associated with more adverse events such as nausea and vomiting compared to placebo. The safety profile of oliceridine was superior to morphine compared to morphine. CONCLUSIONS: Our systematic review and meta-analysis showed that oliceridine is an effective and safe intravenous analgesic in patients with postoperative pain, producing rapid postoperative analgesic and usually well tolerated, and reducing incidence of adverse events compared to morphine. PROSPERO REGISTRATION: CRD42023391581.
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Analgésicos Opioides , Morfina , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Morfina/efeitos adversos , Analgésicos/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Vômito/induzido quimicamente , Náusea/induzido quimicamenteRESUMO
BACKGROUND: Our previous study suggested that atlanto-occipital instability (AOI) is common in patients with type II basilar invagination (II-BI). OBJECTIVE: To further understand the pathogenesis of AOI in Chiari malformations (CM) and CM + II-BI through systematic measurements of the bone structure surrounding the craniocervical junction. METHODS: Computed tomography data from 185 adults (80 controls, 63 CM, and 42 CM + II-BI) were collected, and geometric models were established for parameter measurement. Canonical correlation analysis was used to evaluate the morphological and positional relationships of the atlanto-occipital joint (AOJ). RESULTS: Among the 3 groups, the length and height of the condyle and superior portion of the lateral masses of the atlas (C1-LM) were smallest in CM + II-BI cases; the AOJ had the shallowest depth and the lowest curvature in the same group. AOJs were divided into 3 morphological types: type I, the typical ball-and-socket joint, mainly in the control group (100%); type II, the shallower joint, mainly in the CM group (92.9%); and type III, the abnormal flat-tilt joint, mainly in the CM + II-BI group (89.3%). Kinematic computed tomography revealed AOI in all III-AOJs (100%) and some II-AOJs (1.5%) but not in type I-AOJs (0%). Morphological parameters of the superior portion of C1-LM positively correlated with those of C0 and the clivus and significantly correlated with AOI. CONCLUSION: Dysplasia of the condyle and superior portion of C1-LM exists in both CM and II-BI cases yet is more obvious in type II-BI. Unstable movement caused by AOJ deformation is another pathogenic factor in patients with CM + II-BI.
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Malformação de Arnold-Chiari , Articulação Atlantoaxial , Articulação Atlantoccipital , Instabilidade Articular , Adulto , Humanos , Articulação Atlantoaxial/diagnóstico por imagem , Articulação Atlantoaxial/anormalidades , Malformação de Arnold-Chiari/complicações , Malformação de Arnold-Chiari/diagnóstico por imagem , Malformação de Arnold-Chiari/patologia , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/etiologia , Tomografia Computadorizada por Raios X , Fossa Craniana Posterior , Articulação Atlantoccipital/diagnóstico por imagem , Articulação Atlantoccipital/patologiaRESUMO
Background: Acute Stanford type A aortic dissection (ATAAD) is characterized by intimal tearing and false lumen formation containing large amounts of erythrocytes with heme. Heme oxygenase 1 (HO-1) is the key enzyme to degrade heme for iron accumulation and further ferroptosis. The current study aimed at investigating the role of HO-1 in the dissection progression of ATAAD. Methods: Bioinformatic analyses and experimental validation were performed to reveal ferroptosis and HO-1 expression in ATAAD. Human aortic vascular smooth muscle cell (HA-VSMC) was used to explore underlying molecular mechanisms and the role of HO-1 overexpression in ATAAD. Results: Ferroptosis was identified as a critical manner of regulated cell death in ATAAD. HO-1 was screened as a key signature of ferroptosis in ATAAD, which was closely associated with oxidative stress. Single cell/nucleus transcriptomic analysis and histological staining revealed that HO-1 and HIF-1α were upregulated in vascular smooth muscle cell (VSMC) of ATAAD. Further in vitro experiments showed that H2O2-induced oxidative stress increased VSMC ferroptosis with the overexpression of HO-1, which could be suppressed by HIF-1α inhibitor PX-478. HIF-1α could transcriptionally regulate the expression of HO-1 through binding to its promoter region. Pharmacological inhibition of HO-1 by zinc protoporphyrin (ZnPP) did not reduce H2O2-induced HA-VSMC damage without heme co-incubation. However, H2O2-induced HA-VSMC damage was worsened when heme was added into the medium, and ZnPP could reduce HA-VSMC damage in this condition. Conclusion: HO-1 is a key signature of VSMC ferroptosis in ATAAD. HIF-1α/HO-1 mediated ferroptosis might participate in oxidative stress induced VSMC damage.
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Accurate anatomical matching for patient-specific electromyographic (EMG) mapping is crucial yet technically challenging in various medical disciplines. The fixed electrode construction of multielectrode arrays (MEAs) makes it nearly impossible to match an individual's unique muscle anatomy. This mismatch between the MEAs and target muscles leads to missing relevant muscle activity, highly redundant data, complicated electrode placement optimization, and inaccuracies in classification algorithms. Here, we present customizable and reconfigurable drawn-on-skin (DoS) MEAs as the first demonstration of high-density EMG mapping from in situ-fabricated electrodes with tunable configurations adapted to subject-specific muscle anatomy. The DoS MEAs show uniform electrical properties and can map EMG activity with high fidelity under skin deformation-induced motion, which stems from the unique and robust skin-electrode interface. They can be used to localize innervation zones (IZs), detect motor unit propagation, and capture EMG signals with consistent quality during large muscle movements. Reconfiguring the electrode arrangement of DoS MEAs to match and extend the coverage of the forearm flexors enables localization of the muscle activity and prevents missed information such as IZs. In addition, DoS MEAs customized to the specific anatomy of subjects produce highly informative data, leading to accurate finger gesture detection and prosthetic control compared with conventional technology.
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For treatment of glioblastoma (GBM), temozolomide (TMZ) and radiotherapy (RT) exert antitumor effects by inducing DNA double-strand breaks (DSBs), mainly via futile DNA mismatch repair (MMR) and inducing apoptosis. Here, we provide evidence that RBBP4 modulates glioblastoma resistance to chemotherapy and radiotherapy by recruiting transcription factors and epigenetic regulators that bind to their promoters to regulate the expression of the Mre11-Rad50-NBS1(MRN) complex and the level of DNA-DSB repair, which are closely associated with recovery from TMZ- and radiotherapy-induced DNA damage in U87MG and LN229 glioblastoma cells, which have negative MGMT expression. Disruption of RBBP4 induced GBM cell DNA damage and apoptosis in response to TMZ and radiotherapy and enhanced radiotherapy and chemotherapy sensitivity by the independent pathway of MGMT. These results displayed a possible chemo-radioresistant mechanism in MGMT negative GBM. In addition, the RBBP4-MRN complex regulation axis may provide an interesting target for developing therapy-sensitizing strategies for GBM.
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Quebras de DNA de Cadeia Dupla , Glioblastoma , Humanos , Glioblastoma/patologia , Enzimas Reparadoras do DNA/genética , Proteína Homóloga a MRE11/genética , Reparo do DNA , Temozolomida/uso terapêutico , Fatores de Transcrição/genética , DNA , Quimiorradioterapia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Hidrolases Anidrido Ácido/metabolismo , Proteína 4 de Ligação ao Retinoblastoma/genética , Proteína 4 de Ligação ao Retinoblastoma/metabolismoRESUMO
PURPOSE: Temozolomide resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of temozolomide with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance. EXPERIMENTAL DESIGN: Haloperidol/temozolomide synergism was assessed in GBM cell lines with different dopamine D2 receptor (DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) were used to validate the specific mechanisms by which haloperidol and temozolomide induce ferroptosis in GBM cells. RESULTS: In the present work, we demonstrate that the DRD2 level is increased by temozolomide in a time-dependent manner and is inversely correlated with temozolomide sensitivity in GBM. The DRD2 antagonist haloperidol, a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances temozolomide efficacy in vivo and in vitro. Mechanistically, haloperidol suppressed the effect of temozolomide on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered ER stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis. CONCLUSIONS: Our results provide experimental evidence for repurposing haloperidol as an effective adjunct therapy to inhibit adaptive temozolomide resistance to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.
Assuntos
Neoplasias Encefálicas , Ferroptose , Glioblastoma , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/farmacologia , Linhagem Celular Tumoral , Autofagia , Estresse do Retículo Endoplasmático , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptores de Dopamina D2/genéticaRESUMO
OBJECTIVES: Data on many predictors of hypothalamic-pituitary axis dysfunction associated with childhood craniopharyngioma (CP) are rather inconsistent, probably reflecting the variable but as yet unclarified growth pattern of these tumours. The aim of this study was to define the determinative role of tumour growth pattern on hypothalamic-pituitary axis function and outcomes for childhood CPs. PATIENTS AND METHODS: The authors retrospectively analysed the records of 81 consecutive children with primary CP who underwent a uniform treatment paradigm of attempted radical resection performed by a single surgeon. The patients were divided into two subgroups based on tumour location and growth patterns: group A (infra-diaphragmatic sellar tumours: 34 cases) and group B [third ventricular floor (3rd VF) tumours: 47 cases]. The children's pre- and postsurgical endocrinological and hypothalamic disturbances were compared. Pituitary function and hypothalamic statues were quantitatively assessed using classification systems proposed in the previous studies. RESULTS: Preoperative pituitary function was more severely compromised in patients in group A than those in group B and deteriorated significantly following resection in both groups. (Average pituitary function scores increased from 2·19 ± 0·83 to 3·31 ± 0·74, P < 0·001). At the last follow-up, children with 3rd VF tumours had more prevalent weight gain (median body mass index: 23·1 kg/m(2) in group B vs 19·7 kg/m(2) in group A, P < 0·001) and increased hypothalamic dysfunction (average hypothalamic status scores: 2·04 ± 0·97 in group B vs 1·29 ± 0·57 in group A, P < 0·001). Children with 3rd VF tumours had a significantly lower probability of recurrence-free survival than those with sellar tumours (at 5 years: 74%vs 49%, respectively; at 10 years: 66%vs 32%, respectively; P = 0·02). CONCLUSIONS: Substantial differences in the outcome of childhood CP with different tumour growth patterns and locations were found, which suggested that diverse therapeutic considerations, especially endocrinological substitution, might be emphasized.