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BACKGROUND: Cyclic Nucleotide-Binding Domain (CNBD)-family channels display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, the human Ether-a-go-go Related Gene (hERG) channel and the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel share high amino acid sequence similarity and identical domain structures. hERG conducts outward current and is activated by positive membrane potentials (depolarization), whereas HCN conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the "opposite" voltage-sensing properties of hERG and HCN remains unknown. RESULTS: We found the voltage-sensing domain (VSD) involves in modulating the gating polarity of hERG. We identified that a long-QT syndrome type 2-related mutation within the VSD, K525N, mediated an inwardly rectifying non-deactivating current, perturbing the channel closure, but sparing the open state and inactivated state. K525N rescued the current of a non-functional mutation in the pore helix region (F627Y) of hERG. K525N&F627Y switched hERG into a hyperpolarization-activated channel. The reactivated inward current induced by hyperpolarization mediated by K525N&F627Y can be inhibited by E-4031 and dofetilide quite well. Moreover, we report an extracellular interaction between the S1 helix and the S5-P region is crucial for modulating the gating polarity. The alanine substitution of several residues in this region (F431A, C566A, I607A, and Y611A) impaired the inward current of K525N&F627Y. CONCLUSIONS: Our data provide evidence that a potential cooperation mechanism in the extracellular vestibule of the VSD and the PD would determine the gating polarity in hERG.
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Canal de Potássio ERG1 , Ativação do Canal Iônico , Humanos , Sequência de Aminoácidos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Ativação do Canal Iônico/genética , Mutação , Nucleotídeos Cíclicos , Canal de Potássio ERG1/genéticaRESUMO
Accurate and sensitive analysis of circulating tumor cells (CTCs) in human blood provides a non-invasive approach for the evaluation of cancer metastasis and early cancer diagnosis. Herein, we demonstrate the controllable assembly of a quantum dot (QD)-based aptasensor guided by CRISPR/Cas12a for direct measurement of CTCs in human blood. We introduce a magnetic bead@activator/recognizer duplex core-shell structure to construct a multifunctional platform for the capture and direct detection of CTCs in human blood, without the need for additional CTC release and re-identification steps. Notably, the introduction of magnetic separation ensures that only a target-induced free activator can initiate the downstream catalysis, efficiently avoiding the undesired catalysis triggered by inappropriate recognition of the activator/recognizer duplex structure by crRNAs. This aptasensor achieves high CTC-capture efficiency (82.72%) and sensitive detection of CTCs with a limit of detection of 2 cells mL-1 in human blood, holding great promise for the liquid biopsy of cancers.
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Células Neoplásicas Circulantes , Pontos Quânticos , Humanos , Células Neoplásicas Circulantes/patologia , Pontos Quânticos/química , Sistemas CRISPR-Cas/genética , Biópsia LíquidaRESUMO
Delafloxacin, a fluoroquinolone antibiotic to treat skin infections, exhibits a broad-spectrum antimicrobial activity. The first randomized, open-label phase I clinical trial was conducted to assess the safety and pharmacokinetics (PK) of intravenous delafloxacin in the Chinese population. A population pharmacokinetic (PopPK) model based on the clinical trial was conducted by NONMEM software. Monte Carlo simulation was performed to evaluate the antibacterial effects of delafloxacin at different doses in different Chinese populations. The PK characteristics of delafloxacin were best described by a three-compartment model with mixed linear and nonlinear clearance. Body weight was included as a covariate in the model. We simulated the AUC0-24h in a steady state at five doses in patient groups of various weights. The results indicated that for patients weighing 70 kg and treated with methicillin-resistant Staphylococcus aureus (MRSA) infections, a minimum dose of 300 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, suggesting an ideal bactericidal effect. For patients weighing less than 60 kg, a dose of 200 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, also suggesting an ideal bactericidal effect. Additionally, this trial demonstrated the high safety of delafloxacin in single-dose and multiple-dose groups of Chinese. Delafloxacin (300 mg, q12h, iv) was recommended for achieving optimal efficacy in Chinese bacterial skin infections patients. To ensure optimal efficacy, an individualized dose of 200 mg (q12h, iv) could be advised for patients weighing less than 60 kg, and 300 mg (q12h, iv) for those weighing more than 60 kg.
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Antibacterianos , Fluoroquinolonas , Voluntários Saudáveis , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Humanos , Fluoroquinolonas/farmacocinética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Adulto , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Administração Intravenosa , Adulto Jovem , Área Sob a Curva , Peso Corporal/efeitos dos fármacosRESUMO
Chromoplasts are plant organelles with a unique ability to sequester and store massive carotenoids. Chromoplasts have been hypothesized to enable high levels of carotenoid accumulation due to enhanced sequestration ability or sequestration substructure formation. However, the regulators that control the substructure component accumulation and substructure formation in chromoplasts remain unknown. In melon (Cucumis melo) fruit, ß-carotene accumulation in chromoplasts is governed by ORANGE (OR), a key regulator for carotenoid accumulation in chromoplasts. By using comparative proteomic analysis of a high ß-carotene melon variety and its isogenic line low-ß mutant that is defective in CmOr with impaired chromoplast formation, we identified carotenoid sequestration protein FIBRILLIN1 (CmFBN1) as differentially expressed. CmFBN1 expresses highly in melon fruit tissue. Overexpression of CmFBN1 in transgenic Arabidopsis (Arabidopsis thaliana) containing ORHis that genetically mimics CmOr significantly enhances carotenoid accumulation, demonstrating its involvement in CmOR-induced carotenoid accumulation. Both in vitro and in vivo evidence showed that CmOR physically interacts with CmFBN1. Such an interaction occurs in plastoglobules and results in promoting CmFBN1 accumulation. CmOR greatly stabilizes CmFBN1, which stimulates plastoglobule proliferation and subsequently carotenoid accumulation in chromoplasts. Our findings show that CmOR directly regulates CmFBN1 protein levels and suggest a fundamental role of CmFBN1 in facilitating plastoglobule proliferation for carotenoid sequestration. This study also reveals an important genetic tool to further enhance OR-induced carotenoid accumulation in chromoplasts in crops.
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Arabidopsis , Cucurbitaceae , beta Caroteno/metabolismo , Cucurbitaceae/metabolismo , Fibrilinas/metabolismo , Proteômica , Carotenoides/metabolismo , Plastídeos/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Frutas/genéticaRESUMO
PURPOSE: To identify the biodistribution and diagnostic performance of a novel fibroblast activation protein (FAP) targeted positron emission tomography (PET) tracer, [68Ga]Ga-DOTA-GPFAPI-04, in patients with solid tumors in a head-to-head comparison with [18F]F-FDG. METHODS: Twenty-six patients histologically proven with cancers of nasopharyngeal (n = 5), esophagus (n = 5), gastro-esophagus (n = 1), stomach (n = 7), liver (n = 3), and colorectum (n = 5) were recruited for [68Ga]Ga-DOTA-GPFAPI-04 and [18F]F-FDG PET/CT scans on consecutive days. The primary endpoint was the diagnostic efficacy, with the histological diagnosis and the follow-up results selected as the gold standard. The secondary endpoint was the background uptake pattern. Two experienced nuclear medicine physicians who were blinded to the gold standard results while having essential awareness of the clinical context reviewed the images and labeled lesions by consensus for subsequent software-assisted lesion segmentation. Additionally, background organs were automatically segmented, assisted by artificial intelligence. Volume, mean, and maximum standard uptake values (SUVmean and SUVmax) of all segmentations were recorded. P < 0.05 was deemed as statistically significant. RESULTS: Significant glandular uptake of [68Ga]Ga-DOTA-GPFAPI-04 was detected in the thyroid, pancreas, and submandibular glands, while moderate uptake was observed in the parotid glands. The myocardium and myometrium exhibited 2-3 times higher uptake of the radiotracer than that of the background levels in blood and liver. A total of 349 targeted lesions, consisting of 324 malignancies and 25 benign lesions, were segmented. [68Ga]Ga-DOTA-GPFAPI-04 is more sensitive than [18F]F-FDG, especially for abdominopelvic dissemination (1.000 vs. 0.475, P < 0.001). Interestingly, [18F]F-FDG demonstrated higher sensitivity for lung metastasis compared to [68Ga]Ga-DOTA-GPFAPI-04 (0.845 vs. 0.682, P = 0.003). The high glandular uptake made it difficult to delineate lesions in close proximity and masked two metastatic lesions in these organs. CONCLUSION: Despite prominent glandular uptake, [68Ga]Ga-DOTA-GPFAPI-04 demonstrates favorable diagnostic performance. It is a promising probe scaffold for further development of FAP-targeted tumor theranostic agents.
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Copper is widely used in everyday life and industrial production because of its good electrical and thermal conductivity. To overcome copper oxidation and maintain its good physical properties, small organic molecules adsorbed on the surface of copper make a passivated layer to further avoid copper corrosion. In this work, we have investigated thioglycolic acid (TGA, another name is mercaptoacetic acid) adsorbed on copper surfaces by using density functional theory (DFT) calculations and a periodical slab model. We first get five stable adsorption structures, and the binding interaction between TGA and Cu(111) surfaces by using density of states (DOS), indicating that the most stable configuration adopts a triple-end binding model. Then, we analyze the vibrational Raman spectra of TGA adsorbed on the Cu(111) surface and make vibrational assignments according to the vibrational vectors. Finally, we explore the temperature effect of the thermodynamically Gibbs free energy of TGA on the Cu(111) surface and the antioxidant ability of the small organic molecular layer of copper oxidation on the copper surface. Our calculated results further provide evidences to interpret the stability of adsorption structures and antioxidant properties of copper.
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AIMS: Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. METHODS: Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). RESULTS: A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. CONCLUSIONS: Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.
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For designing conductive polymer composites (CPCs), understanding how the fiber curvature affects the percolation behavior of curved conductive fibers is essential for determining the effective electrical conductivity σeff of the CPCs. In this work, CPCs were considered as a polymer matrix filled with the random packing of overlapped curved spherocylinders. The geometries of the curved spherocylinders were defined, and inter-curved spherocylinder contact-detecting and system-spanning fiber cluster searching algorithms were developed. The finite-size-scaling method was used to explore how the aspect ratio α and bending central angle θ of a curved spherocylinder affect the percolation threshold Ïc of an overlapped curved spherocylinder system in 3D space. The findings suggest that Ïc decreases as α increases and increases initially before declining as θ increases. An empirical approximation formula was proposed to quantify the effect of the curved spherocylinder's morphology, characterized by the dimensionless excluded volume Vdex of the curved spherocylinder, on Ïc. The new rigorous bound for Ïc of the soft-curved spherocylinder system was further proposed. A random resistor network model was constructed, and the reliability of this model was validated by comparing the simulations and published data. Finally, a fitting formula was developed to assess the impacts of the normalized reduced density (η - ηc)/ηc and Vdex on the σeff of CPCs. A distinct linear correlation between σeff and (η - ηc)/ηc was constructed, denoted as σeff â¼ [(η - ηc)/ηc]t(α,θ). An empirical approximation model was proposed to establish the relationship between the fiber shape and conductivity exponent t. Our study may provide a theoretical hint for the design of CPCs.
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In forensic practice, determining the postmortem submersion interval (PMSI) and cause-of-death of cadavers in aquatic ecosystems has always been challenging task. Traditional approaches are not yet able to address these issues effectively and adequately. Our previous study proposed novel models to predict the PMSI and cause-of-death based on metabolites of blood from rats immersed in freshwater. However, with the advance of putrefaction, it is hardly to obtain blood samples beyond 3 days postmortem. To further assess the feasibility of PMSI estimation and drowning diagnosis in the later postmortem phase, gastrocnemius, the more degradation-resistant tissue, was collected from drowned rats and postmortem submersion model in freshwater immediately after death, and at 1 day, 3 days, 5 days, 7 days, and 10 days postmortem respectively. Then the samples were analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the dynamic changes of the metabolites. A total of 924 metabolites were identified. Similar chronological changes of gastrocnemius metabolites were observed in the drowning and postmortem submersion groups. The difference in metabolic profiles between drowning and postmortem submersion groups was only evident in the initial 1 day postmortem, which was faded as the PMSI extension. Nineteen metabolites representing temporally-dynamic patterns were selected as biomarkers for PMSI estimation. A regression model was built based on these biomarkers with random forest algorithm, which yielded a mean absolute error (± SE) of 5.856 (± 1.296) h on validation samples from an independent experiment. These findings added to our knowledge of chronological changes in muscle metabolites from submerged vertebrate remains during decomposition, which provided a new perspective for PMSI estimation.
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Afogamento , Água Doce , Imersão , Metabolômica , Modelos Animais , Músculo Esquelético , Mudanças Depois da Morte , Animais , Músculo Esquelético/metabolismo , Afogamento/diagnóstico , Afogamento/metabolismo , Masculino , Cromatografia Líquida , Espectrometria de Massas em Tandem , Ratos , Ratos Sprague-Dawley , Biomarcadores/metabolismoRESUMO
OBJECTIVES: The aim of this study was to investigate the predictive value of uric acid (UA) in prognosis of pulmonary artery involvement (PAI) in patients with Takayasu's arteritis (TAK). METHODS: A total of 166 TAK patients were enrolled in the study, including 76 with PAI and 90 without. Outcomes of 144 TAK patients were followed up and recorded. The possible associations between serum UA levels and incidence of PAI in TAK and PAI-related prognosis of TAK patients were examined using different statistical models. RESULTS: The serum UA levels were significantly higher in TAK patient with PAI than TAK patients without PAI. Multivariate logistic regression analysis indicated that serum UA level ≥284.5 umol/L was associated with an increasing incidence of PAI in TAK (OR: 2.108, 95% CI: 1.063 to 4.180; p=0.033). Kaplan-Meier survival analysis showed that TAK patients with serum UA level ≥328.1 umol/L had a significantly higher cumulative incidence of PAI-related adverse events compared to TAK patients with serum UA level <328.1 umol/L (p=0.008). Multivariate Cox proportional hazard regression analysis revealed that serum UA level ≥328.1 umol/L (HR: 2.595, 95% CI: 1.198 to 5.622; p=0.016) was a PAI-related prognostic risk factor for TAK. CONCLUSIONS: Elevation of serum UA level was associated with an increasing risk of PAI and PAI-related adverse event in patients with TAK, indicating its potential as a predictor for identification of PAI onset and worsening in TAK patients.
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Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.
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Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of the chemotherapeutic agents in cancer. Chronic inflammation provides a favorable environment for tumorigenesis by inducing immunosuppression, whereas acute inflammation prompts tumor suppression by generating anti-tumor immune responses. Inflammatory factors derived from interstitial cells or tumor cells can stimulate cell proliferation and survival by modulating oncogenes and/or tumor suppressors. Recently, a new class of RNAs, i.e., circular RNAs (circRNAs), has been implicated in inflammatory diseases. Although there are reports on circRNAs imparting functions in inflammatory insults, whether these circularized transcripts hold the potential to regulate inflammation-induced cancer or tumor-related inflammation, and modulate the interactions between tumor microenvironment (TME) and the inflammatory stromal/immune cells, awaits further elucidation. Contextually, the current review describes the molecular association between inflammation and cancer, and spotlights the regulatory mechanisms by which circRNAs can moderate TME in response to inflammatory signals/triggers. We also present comprehensive information about the immune cell(s)-specific expression and functions of the circRNAs in TME, modulation of inflammatory signaling pathways to drive tumorigenesis, and their plausible roles in inflammasomes and tumor development. Moreover, the therapeutic potential of these circRNAs in harnessing inflammatory responses in cancer is also discussed.
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Neoplasias , RNA Circular , Humanos , RNA Circular/genética , RNA/genética , RNA/metabolismo , Transformação Celular Neoplásica/genética , Neoplasias/genética , Inflamação/genética , Microambiente Tumoral/genéticaRESUMO
Extracellular vesicles are small lipid bilayer particles that resemble the structure of cells and range in size from 30 to 1000 nm. They transport a variety of physiologically active molecules, such as proteins, lipids, and miRNAs. Insulin resistance (IR) is a pathological disease in which insulin-responsive organs or components become less sensitive to insulin's physiological effects, resulting in decreased glucose metabolism in target organs such as the liver, muscle, and adipose tissue. Extracellular vesicles have received a lot of attention as essential intercellular communication mediators in the setting of IR. This review looks at extracellular vesicles' role in IR from three angles: signaling pathways, bioactive compounds, and miRNAs. Relevant publications are gathered to investigate the induction, inhibition, and bidirectional regulation of extracellular vesicles in IR, as well as their role in insulin-related illnesses. Furthermore, considering the critical function of extracellular vesicles in regulating IR, the study analyzes the practicality of employing extracellular vesicles for medication delivery and the promise of combination therapy for IR.
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Vesículas Extracelulares , Resistência à Insulina , MicroRNAs , Humanos , Vesículas Extracelulares/metabolismo , Insulina/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de SinaisRESUMO
Self-renewing, damage-repair and differentiation of mammalian stratified squamous epithelia are subject to tissue homeostasis, but the regulation mechanisms remain elusive. Here, we investigate the esophageal squamous epithelial tissue homeostasis in vitro and in vivo. We establish a rat esophageal organoid (rEO) in vitro system and show that the landscapes of rEO formation, development and maturation trajectories can mimic those of rat esophageal epithelia in vivo. Single-cell RNA sequencing (scRNA-seq), snapshot immunostaining and functional analyses of stratified "matured" rEOs define that the epithelial pluripotent stem cell determinants, p63 and Sox2, play crucial but distinctive roles for regulating mammalian esophageal tissue homeostasis. We identify two cell populations, p63+Sox2+ and p63-Sox2+, of which the p63+Sox2+ population presented at the basal layer is the cells of origin required for esophageal epithelial stemness maintenance and proliferation, whereas the p63-Sox2+ population presented at the suprabasal layers is the cells of origin having a dual role for esophageal epithelial differentiation (differentiation-prone fate) and rapid tissue damage-repair responses (proliferation-prone fate). Given the fact that p63 and Sox2 are developmental lineage oncogenes and commonly overexpressed in ESCC tissues, p63-Sox2+ population could not be detected in organoids formed by esophageal squamous cell carcinoma (ESCC) cell lines. Taken together, these findings reveal that the tissue homeostasis is maintained distinctively by p63 and/or Sox2-dependent cell lineage populations required for the tissue renewing, damage-repair and protection of carcinogenesis in mammalian esophagi.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Ratos , Animais , Neoplasias Esofágicas/genética , Mamíferos , Homeostase , CarcinogêneseRESUMO
This study aims to investigate the causal relationship between primary Sjögren's syndrome (SS) and multiple sclerosis (MS) using a two-sample Mendelian randomization (MR) analysis to provide insights into their common mechanisms and implications for therapeutic strategies. We utilized data from Genome-Wide Association Studies (GWAS) for primary SS (1,290 cases and 213,145 controls) and MS (4,888 cases and 10,395 controls), restricted to European ancestry. Instrumental variables (IVs) were selected based on genetic variants associated with primary SS. The primary MR method was Inverse Variance Weighted (IVW), supplemented by MR Egger, Weighted Median, Simple Mode, and Weighted Mode algorithms to assess the bidirectional causal relationships between MS and primary SS. Sensitivity analyses, including MR-PRESSO and leave-one-out analysis, were conducted to ensure the robustness of our findings. After excluding SNPs with pleiotropic effects, 42 and 5 SNPs were identified as robust IVs for primary SS and MS, respectively. Our analysis revealed a significant protective effect of MS on primary SS, with IVW showing an OR of 0.896 (95% CI: 0.841-0.954, P = 0.001). No significant heterogeneity or horizontal pleiotropy was detected, supporting the reliability of the results. Our findings suggest a potential protective effect of MS against primary SS, indicating a negative causal association between these two autoimmune diseases. This adds valuable genetic evidence to the understanding of the complex interplay between primary SS and MS, offering new avenues for research and therapeutic interventions.
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BACKGROUND: For patients with multilevel degenerative cervical myelopathy, laminectomy and posterior cervical fusions (PCF) with instrumentation are widely accepted techniques for symptom relief. However, hardware failure is not rare and results in neck pain or even permanent neurological lesions. There are no in-depth studies of hardware-related complications following laminectomy and PCF with instrumentation. METHODS: The present study was a retrospective, single centre, observational study. Patients who underwent laminectomy and PCF with instrumentation in a single institution between January 2019 and January 2021 were included. Patients were divided into hardware failure and no hardware failure group according to whether there was a hardware failure. Data, including sex, age, screw density, end vertebra (C7 or T1), cervical sagittal alignment parameters (C2-C7 cervical lordosis, C2-C7 sagittal vertical axis, T1 slope, Cervical lordosis correction), regional Hounsfield units (HU) of the screw trajectory and osteoporosis status, were collected and compared between the two groups. RESULTS: We analysed the clinical data of 56 patients in total. The mean overall follow-up duration was 20.6 months (range, 12-30 months). Patients were divided into the hardware failure group (n = 14) and no hardware failure group (n = 42). There were no significant differences in the general information (age, sex, follow-up period) of patients between the two groups. The differences in fusion rate, fixation levels, and screw density between the two groups were not statistically significant (p > 0.05). The failure rate of fixation ending at T1 was lower than that at C7 (9% vs. 36.3%) (p = 0.019). The regional HU values of the pedicle screw (PS) and lateral mass screw (LMS) in the failure group were lower than those in the no failure group (PS: 267 ± 45 vs. 368 ± 43, p = 0.001; LMS: 308 ± 53 vs. 412 ± 41, p = 0.001). The sagittal alignment parameters did not show significant differences between the two groups before surgery or at the final follow-up (p > 0.05). The hardware failure rate in patients without osteoporosis was lower than that in patients with osteoporosis (14.3% vs. 57.1%) (p = 0.001). CONCLUSIONS: Osteoporosis, fixation ending at C7, and low regional HU value of the screw trajectory were the independent risk factors of hardware failure after laminectomy and PCF. Future studies should illuminate if preventive measures targeting these factors can help reduce hardware failure and identified more risk factors, and perform long-term follow-up.
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Lordose , Osteoporose , Parafusos Pediculares , Fusão Vertebral , Humanos , Laminectomia/efeitos adversos , Laminectomia/métodos , Lordose/diagnóstico por imagem , Lordose/etiologia , Lordose/cirurgia , Estudos Retrospectivos , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Vértebras Cervicais/patologia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Parafusos Pediculares/efeitos adversos , Osteoporose/complicaçõesRESUMO
BACKGROUND: To find out if three-dimensional printing (3DP) off-the-shelf (OTS) prosthesis is superior to titanium mesh cages in anterior cervical corpectomy and fusion (ACCF) when treating single-segment degenerative cervical spondylotic myelopathy (DCSM). METHODS: DCSM patients underwent ACCF from January 2016 to January 2019 in a single center were included. Patients were divided into the 3DP group (28) and the TMC group (23). The hospital stays, operation time, intraoperative blood loss, and the cost of hospitalization were compared. The Japanese Orthopedic Association (JOA) scores and Neck Disability Index (NDI) were recorded pre-operatively, 1 day, 3, 6, 12, and 24 months post-operatively. Radiological data was measured to evaluate fusion, subsidence, and cervical lordosis. Patients were sent with SF-36 to assess their health-related quality of life (HRQoL). RESULTS: The differences in operative time, intraoperative blood loss, and hospital stay were not statistically significant between groups (p > 0.05). Postoperative dysphagia occurred in 2 cases in the 3DP group and 3 cases in the TMC group, which all relieved one week later. The difference in improvement of JOA and NDI between the two groups was not statistically significant (p > 0.05). No hardware failure was found and bony fusion was achieved in all cases except one in the 3DP group. The difference in cervical lordosis (CL), fused segmental angle (FSA), mean vertebral height (MVH), and subsidence rates between groups at each follow-up time point was not statistically significant and the results of the SF-36 were similar (p > 0.05). The total cost was higher in the 3DP group with its higher graft cost (p < 0.05). CONCLUSION: In treating single-segment DCSM with ACCF, both 3DP OTS prosthesis and TMC achieved satisfactory outcomes. However, the more costly 3DP OTS prosthesis was not able to reduce subsidence as it claimed.
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Membros Artificiais , Lordose , Doenças da Medula Espinal , Fusão Vertebral , Humanos , Perda Sanguínea Cirúrgica , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Lordose/cirurgia , Impressão Tridimensional , Qualidade de Vida , Doenças da Medula Espinal/cirurgia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Telas Cirúrgicas , Titânio , Resultado do TratamentoRESUMO
BACKGROUND: Intervertebral disc degeneration and sarcopenia are both age-related diseases without effective treatments. Their comorbidities may worsen the prognosis, and further studies on interaction and therapy are needed. The purpose of the study was to investigate the prevalence of sarcopenia in intervertebral disc degeneration, and to compare the characteristics of intervertebral disc degeneration with and without sarcopenia and effects of interferential current. METHODS: One hundred twenty disc degeneration patients were included from 2021 to 2022 in a single institute. Medical records, examination results and radiological reports were reviewed. Patients with sarcopenia were screened and grouped according to Asian Working Group for Sarcopenia 2019. VAS, ODI, SARC-F, SMI, gait speed (GS), grip strength, disc Pfirrmann grading, standard cross-sectional area (SCSA), degree of fatty infiltration (DFF), and nerve conduction velocity (NCV) were assessed before and after treatment. RESULTS: The prevalence of sarcopenia in intervertebral disc degeneration was 28.3%. The difference of VAS, ODI, disc Pfirrmann grading, SCSA, DFF and NCV between two groups were significant before intervention (P < 0.05), SCSA and DFF were related to the degree of disc degeneration. The improvement of SMI, GS, grip strength, VAS, SARC-F and ODI in intervertebral disc degeneration with sarcopenia group was significant after intervention, as well as SMI, GS, grip strength, VAS and ODI in those without sarcopenia (P < 0.05). The improvement of grip strength, GS, ODI and SARC-F in intervertebral disc degeneration with sarcopenia group were greater than the one without sarcopenia (P < 0.05), whereas there was no significance in improvement degree of other indicators between the two groups (P > 0.05). CONCLUSION: The prevalence of sarcopenia was high in intervertebral disc degeneration, and paravertebral muscles degeneration correlated with the degree of disc degeneration. Compared to those without sarcopenia, intervertebral disc degeneration patients with sarcopenia have more severe pain, poorer mobility and neurological function. Interferential current is effective in intervertebral disc degeneration patients and sarcopenia patients.
Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Sarcopenia , Humanos , Idoso , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/epidemiologia , Estudos Retrospectivos , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Vértebras Lombares , Resultado do TratamentoRESUMO
PURPOSE: To develop a deep learning model to accurately detect anterior cruciate ligament (ACL) ruptures on magnetic resonance imaging (MRI) and to evaluate its effect on the diagnostic accuracy and efficiency of clinicians. METHODS: A training dataset was built from MRIs acquired from January 2017 to June 2021, including patients with knee symptoms, irrespective of ACL ruptures. An external validation dataset was built from MRIs acquired from January 2021 to June 2022, including patients who underwent knee arthroscopy or arthroplasty. Patients with fractures or prior knee surgeries were excluded in both datasets. Subsequently, a deep learning model was developed and validated using these datasets. Clinicians of varying expertise levels in sports medicine and radiology were recruited, and their capacities in diagnosing ACL injuries in terms of accuracy and diagnosing time were evaluated both with and without artificial intelligence (AI) assistance. RESULTS: A deep learning model was developed based on the training dataset of 22,767 MRIs from 5 centers and verified with external validation dataset of 4,086 MRIs from 6 centers. The model achieved an area under the receiver operating characteristic curve of 0.987 and a sensitivity and specificity of 95.1%. Thirty-eight clinicians from 25 centers were recruited to diagnose 3,800 MRIs. The AI assistance significantly improved the accuracy of all clinicians, exceeding 96%. Additionally, a notable reduction in diagnostic time was observed. The most significant improvements in accuracy and time efficiency were observed in the trainee groups, suggesting that AI support is particularly beneficial for clinicians with moderately limited diagnostic expertise. CONCLUSIONS: This deep learning model demonstrated expert-level diagnostic performance for ACL ruptures, serving as a valuable tool to assist clinicians of various specialties and experience levels in making accurate and efficient diagnoses. LEVEL OF EVIDENCE: Level III, retrospective comparative case series.
Assuntos
Lesões do Ligamento Cruzado Anterior , Aprendizado Profundo , Humanos , Lesões do Ligamento Cruzado Anterior/diagnóstico por imagem , Lesões do Ligamento Cruzado Anterior/cirurgia , Ligamento Cruzado Anterior , Estudos Retrospectivos , Inteligência Artificial , Imageamento por Ressonância Magnética/métodosRESUMO
Membrane protein engineering exhibits great potential for cell functionalization. Although genetic strategies are sophisticated for membrane protein engineering, there still exist some issues, including transgene insertional mutagenesis, laborious, complicated procedures, and low tunability. Herein, we report a DNA-templated anchoring of exogenous proteins on living cell membranes to realize programmable functionalization of living cells. Using DNA as a scaffold, the model cell membranes are readily modified with proteins, on which the density and ratio of proteins as well as their interactions can be precisely controlled through predictable DNA hybridization. Then, the natural killer (NK) cells were engineered to gain the ability to eliminate the immune checkpoint signaling at the NK-tumor synapse, which remarkably promoted NK cell activation in immunotherapy. Given the versatile functions of exogenous proteins and flexible designs of programmable DNA, this method has the potential to facilitate membrane-protein-based cell engineering and therapy.