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Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Crizotinib , Ferroptosis , Factor 2 Relacionado con NF-E2 , Factor de Transcripción STAT1 , Ferroptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Animales , Crizotinib/farmacología , Crizotinib/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Ratones , Transducción de Señal/efectos de los fármacos , Masculino , Fenilendiaminas/farmacología , Ratones Endogámicos C57BL , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Fosforilación/efectos de los fármacosRESUMEN
A three-dimensional (3D) microstructural volume is reconstructed from a stack of two-dimensional sections which was obtained by serial sectioning coupled with electron back scattering diffraction (EBSD) mapping of a 316L austenitic stainless steel. A new alignment algorithm named linear translation by minimising the indicator (LTMI) is proposed to reduce the translational misalignments between adjacent sections by referencing to coherent twin boundaries which are flat and lying on {111} planes. The angular difference between the measured orientation of a flat twin boundary and that of the {111} plane is used as an indicator of the accuracy of the alignment operations. This indicator is minimised through linear translations of the centroids of triangular facets, which constitute grain boundaries at a distance not restricted by the in-plane step size of the EBSD maps. And hence the systematic trend in the translational misalignments can be effectively reduced. The LTMI alignment procedure proposed herein effectively corrects the misalignments remained by other methods on a 3D-EBSD data prepared using serial sectioning methods. The accuracy in distinguishing between coherent and incoherent twin boundaries is significantly improved.
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Background and Objectives: The Alberta Stroke Program CT Score (ASPECTS) is a widely used rating system for assessing infarct extent and location. We aimed to investigate the prognostic value of ASPECTS subregions' involvement in the long-term functional outcomes of acute ischemic stroke (AIS). Materials and Methods: Consecutive patients with AIS and anterior circulation large-vessel stenosis and occlusion between January 2019 and December 2020 were included. The ASPECTS score and subregion involvement for each patient was assessed using posttreatment magnetic resonance diffusion-weighted imaging. Univariate and multivariable regression analyses were conducted to identify subregions related to 3-month poor functional outcome (modified Rankin Scale scores, 3-6) in the reperfusion and medical therapy cohorts, respectively. In addition, prognostic efficiency between the region-based ASPECTS and ASPECTS score methods were compared using receiver operating characteristic curves and DeLong's test. Results: A total of 365 patients (median age, 64 years; 70% men) were included, of whom 169 had poor outcomes. In the reperfusion therapy cohort, multivariable regression analyses revealed that the involvement of the left M4 cortical region in left-hemisphere stroke (adjusted odds ratio [aOR] 5.39, 95% confidence interval [CI] 1.53-19.02) and the involvement of the right M3 cortical region in right-hemisphere stroke (aOR 4.21, 95% CI 1.05-16.78) were independently associated with poor functional outcomes. In the medical therapy cohort, left-hemisphere stroke with left M5 cortical region (aOR 2.87, 95% CI 1.08-7.59) and caudate nucleus (aOR 3.14, 95% CI 1.00-9.85) involved and right-hemisphere stroke with right M3 cortical region (aOR 4.15, 95% CI 1.29-8.18) and internal capsule (aOR 3.94, 95% CI 1.22-12.78) affected were related to the increased risks of poststroke disability. In addition, region-based ASPECTS significantly improved the prognostic efficiency compared with the conventional ASPECTS score method. Conclusion: The involvement of specific ASPECTS subregions depending on the affected hemisphere was associated with worse functional outcomes 3 months after stroke, and the critical subregion distribution varied by clinical management. Therefore, region-based ASPECTS could provide additional value in guiding individual decision making and neurological recovery in patients with AIS.
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This study took a novel approach to address the dual challenges of enhancing the ethanol content and aroma complexity in Laiyang pear wine. It focused on sorbitol as a pivotal element in the strategic selection of yeasts with specific sorbitol-utilization capabilities and their application in co-fermentation strategies. We selected two Saccharomyces cerevisiae strains (coded as Sc1, Sc2), two Metschnikowia pulcherrima (coded as Mp1, Mp2), and one Pichia terricola (coded as Tp) due to their efficacy as starter cultures. Notably, the Sc2 strain, alone or with Mp2, significantly increased the ethanol content (30% and 16%). Mixed Saccharomyces cerevisiae and Pichia terricola fermentation improved the ester profiles and beta-damascenone levels (maximum of 150%), while Metschnikowia pulcherrima addition enriched the phenethyl alcohol content (maximum of 330%), diversifying the aroma. This study investigated the efficacy of strategic yeast selection based on sorbitol utilization and co-fermentation methods in enhancing Laiyang pear wine quality and aroma.
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Fermentación , Aromatizantes , Odorantes , Pyrus , Saccharomyces cerevisiae , Sorbitol , Gusto , Vino , Vino/análisis , Vino/microbiología , Pyrus/química , Pyrus/microbiología , Pyrus/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/química , Aromatizantes/metabolismo , Aromatizantes/química , Sorbitol/metabolismo , Sorbitol/análisis , Odorantes/análisis , Etanol/metabolismo , Etanol/análisis , Pichia/metabolismo , Metschnikowia/metabolismo , Frutas/química , Frutas/microbiología , Frutas/metabolismoRESUMEN
Introduction: Cognitive impairment (CI) is a common complication of end-stage renal disease (ESRD) that is associated with structural and functional changes in the brain. However, whether a joint structural and functional alteration pattern exists that is related to CI in ESRD is unclear. Methods: In this study, instead of looking at brain structure and function separately, we aim to investigate the covariant characteristics of both functional and structural aspects. Specifically, we took the fusion analysis approach, namely, multimodal canonical correlation analysis and joint independent component analysis (mCCA+jICA), to jointly study the discriminative features in gray matter volume (GMV) measured by T1-weighted (T1w) MRI, fractional anisotropy (FA) in white matter measured by diffusion MRI, and the amplitude of low-frequency fluctuation (ALFF) measured by blood oxygenation-level-dependent (BOLD) MRI in 78 ESRD patients versus 64 healthy controls (HCs), followed by a mediation effect analysis to explore the relationship between neuroimaging findings, cognitive impairments and uremic toxins. Results: Two joint group-discriminative independent components (ICs) were found to show covariant abnormalities across FA, GMV, and ALFF (all p < 0.05). The most dominant joint IC revealed associative patterns of alterations of GMV (in the precentral gyrus, occipital lobe, temporal lobe, parahippocampal gyrus, and hippocampus), alterations of ALFF (in the precuneus, superior parietal gyrus, and superior occipital gyrus), and of white matter FA (in the corticospinal tract and inferior frontal occipital fasciculus). Another significant IC revealed associative alterations of GMV (in the dorsolateral prefrontal and orbitofrontal cortex) and FA (in the forceps minor). Moreover, the brain changes identified by FA and GMV in the above-mentioned brain regions were found to mediate the negative correlation between serum phosphate and mini-mental state examination (MMSE) scores (all p < 0.05). Conclusion: The mCCA+jICA method was demonstrated to be capable of revealing covariant abnormalities across neuronal features of different types in ESRD patients as contrasted to HCs, and joint brain changes may play an important role in mediating the relationship between serum toxins and CIs in ESRD. Our results show the mCCA+jICA fusion analysis approach may provide new insights into similar neurobiological studies.
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Background: This study analyzed the laboratory diagnosis results and drug resistance of patients infected with non-tuberculous mycobacterium (NTM). Methods: We collected information on patients with positive indicators of NTM infection at the Henan Provincial Chest Hospital from 2020 to 2022. Acid-fast smear, mycobacterium culture, QB-SPOT assay, GeneXpert MTB/RIF assay, immunoglobulin E test, tuberculosis antibody test, and microplate method for drug sensitivity test were analyzed using strain identification as the gold standard. Results: The 242 cases of NTM infection were predominantly detected with slow-growing mycobacteria (a detection rate of 87.19%), among which Mycobacterium intracellulare (66.53%), Mycobacterium avium (15.70%), and Mycobacterium chelonei/abscessus complex (11.16%) ranked the top three in terms of the isolation rate. Males patients accounted for a higher proportion (58.26%) than females (41.74%), and the majority of them were over 60 years (50.83%). Among laboratory tests for patients with NTM infection, mycobacterium culture showed a highest detected rate (87.20%) among laboratory tests. The results of the drug sensitivity test demonstrated that the resistance rate of NTM was generally high. Moreover, the Mycobacterium avium complex with the highest isolation rate showed 100% resistant to doxycycline and minocycline, but exhibited relatively high sensitivity to moxifloxacin (a resistance rate of 7.89%) and rifabutin (a resistance rate of 13.16%). The Mycobacterium chelonei/abscessus complex was 100% resistant to doxycycline and relatively sensitive to cefoxitin (29.17%) and clarithromycin (37.50%). Conclusion: The NTM species isolated by the Henan Provincial Chest Hospital is dominated by Mycobacterium intracellulare and the highest positive rate is detected by mycobacterium culture among laboratory tests. NTM infection generally exhibits a high rate of drug resistance. Accordingly, the accurate diagnosis of NTM diseases requires enhanced drug sensitivity testing to provide patients with targeted combination drug treatment.
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Importance: In the face of an emerging heart failure (HF) epidemic, describing the association between perceived economic burden (PEB) and health care outcomes is an important step toward more equitable and achievable care. Objectives: To examine the association between PEB and risk of 1-year clinical outcomes and HF-specific health status in patients with acute decompensated HF. Design, Setting, and Participants: This prospective, multicenter, hospital-based cohort study prospectively enrolled adult patients hospitalized for acute decompensated HF at 52 hospitals in China from August 2016 to May 2018, with 1-year follow-up. Data were analyzed on June 17, 2022. Exposure: Perceived economic burden, categorized as severe (cannot undertake expenses), moderate (can almost undertake expenses), or little (can easily undertake expenses). Main Outcomes and Measures: The clinical outcomes of the study were 1-year all-cause death and rehospitalization for HF. Heart failure-specific health status was assessed by the 12-Item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results: Among 3386 patients, median age was 67 years (IQR, 58-75 years) and 2116 (62.5%) were men. Of these patients, 404 (11.9%) had severe PEB; 2021 (59.7%), moderate PEB; and 961 (28.4%), little PEB. Compared with patients with little PEB, those with severe PEB had increased risk of 1-year mortality (hazard ratio [HR], 1.61; 95% CI, 1.21-2.13; P < .001) but not 1-year HF rehospitalization (HR, 1.21; 95% CI, 0.98-1.49; P = .07). The mean (SD) adjusted KCCQ-12 score was lowest in patients with severe PEB and highest in patients with little PEB at baseline (40.0 [1.7] and 50.2 [1.0] points, respectively; P < .001) and at each visit (eg, 12 months: 61.5 [1.6] and 75.5 [0.9] points respectively; P < .001). Patients reporting severe PEB had a clinically significant lower 1-year KCCQ-12 score compared with those reporting little PEB (mean difference, -11.3 points; 95% CI, -14.9 to -7.6 points; P < .001). Conclusions and Relevance: In this cohort study of patients with acute decompensated HF, greater PEB was associated with higher risk of mortality and poorer health status but not with risk of HF rehospitalization. The findings suggest that PEB may serve as a convenient tool for risk estimation and as a potential target for quality-improvement interventions for patients with HF.
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Estrés Financiero , Insuficiencia Cardíaca , Adulto , Masculino , Humanos , Anciano , Femenino , Estudios de Cohortes , Estudios Prospectivos , Pacientes Internos , Insuficiencia Cardíaca/epidemiología , Estado de SaludRESUMEN
BACKGROUND: The aim of this study was to investigate the clinical features of Nocardia infections, antibiotic resistance profile, choice of antibiotics and treatment outcome, among others. In addition, the study compared the clinical and microbiological characteristics of nocardiosis in bronchiectasis patients and non-bronchiectasis patients. METHODS: Detailed clinical data were collected from the medical records of 71 non-duplicate nocardiosis patients from 2017 to 2023 at a tertiary hospital in Zhengzhou, China. Nocardia isolates were identified to the species level using MALDI-TOF MS and 16S rRNA PCR sequencing. Clinical data were collected from medical records, and drug susceptibility was determined using the broth microdilution method. RESULTS: Of the 71 cases of nocardiosis, 70 (98.6%) were diagnosed as pulmonary infections with common underlying diseases including bronchiectasis, tuberculosis, diabetes mellitus and chronic obstructive pulmonary disease (COPD). Thirteen different strains were found in 71 isolates, the most common of which were N. farcinica (26.8%) and N. cyriacigeorgica (18.3%). All Nocardia strains were 100% susceptible to both TMP-SMX and linezolid, and different Nocardia species showed different patterns of drug susceptibility in vitro. Pulmonary nocardiosis is prone to comorbidities such as bronchiectasis, diabetes mellitus, COPD, etc., and Nocardia is also frequently accompanied by co-infection of the body with pathogens such as Mycobacterium and Aspergillus spp. Sixty-one patients underwent a detailed treatment regimen, of whom 32 (52.5%) received single or multi-drug therapy based on TMP-SMX. Bronchiectasis was associated with a higher frequency of Nocardia infections, and there were significant differences between the bronchiectasis and non-bronchiectasis groups in terms of age distribution, clinical characteristics, identification of Nocardia species, and antibiotic susceptibility (P < 0.05). CONCLUSIONS: Our study contributes to the understanding of the species diversity of Nocardia isolates in Henan, China, and the clinical characteristics of patients with pulmonary nocardiosis infections. Clinical and microbiologic differences between patients with and without bronchiectasis. These findings will contribute to the early diagnosis and treatment of patients.
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Bronquiectasia , Diabetes Mellitus , Nocardiosis , Nocardia , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Nocardia/genética , ARN Ribosómico 16S/genética , Combinación Trimetoprim y Sulfametoxazol , Nocardiosis/tratamiento farmacológico , China , Bronquiectasia/tratamiento farmacológico , Resistencia a MedicamentosRESUMEN
Objective: This study aimed to investigate the potential association between biological disease-modifying antirheumatic drugs (bDMARDs) and pericarditis and uncover relevant clinical characteristics in ankylosing spondylitis (AS). Methods: Reports of pericarditis recorded in the FDA Adverse Event Reporting System (FAERS) (January 2004-December 2022) were identified through the preferred term "pericarditis." Demographic and clinical characteristics were described, and disproportionality signals were assessed through the reporting odds ratio (ROR) and information component (IC). A significant signal was detected if the lower bound of IC (IC025) was more than zero. Results: We found 1,874 reports of pericarditis with bDMARDs (11.3% of cases with fatal outcomes). Adalimumab (IC025 3.24), infliximab (IC025 4.90), golimumab (IC025 5.40), certolizumab (IC025 5.43), etanercept (IC025 3.24), secukinumab (IC025 3.97), and ustekinumab (IC025 7.61) exhibit significant disproportionality signals compared to other medications in the FAERS database. After excluding pre-existing diseases and co-treated drugs that may increase the susceptibility of pericarditis, the disproportionality signal associated with infliximab, certolizumab, etanercept, secukinumab, and ustekinumab remained strong. Pericarditis cases associated with all bDMARDs were predominantly recorded in women aged 25-65 years. Conclusion: More reports of pericarditis were detected with AS patients on bDMARDs than with other drugs in the overall database. Further studies are warranted to investigate the underlying mechanisms and identify patient-related susceptibility factors, thus supporting timely diagnosis and safe(r) prescribing of bDMARDs.
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Natural structural materials often possess unique combinations of strength and toughness resulting from their complex hierarchical assembly across multiple length scales. However, engineering such well-ordered structures in synthetic materials via a universal and scalable manner still poses a grand challenge. Herein, a simple yet versatile approach is proposed to design hierarchically structured hydrogels by flow-induced alignment of nanofibrils, without high time/energy consumption or cumbersome postprocessing. Highly aligned fibrous configuration and structural densification are successfully achieved in anisotropic hydrogels under ambient conditions, resulting in desired mechanical properties and damage-tolerant architectures, for example, strength of 14 ± 1 MPa, toughness of 154 ± 13 MJ m-3, and fracture energy of 153 ± 8 kJ m-2. Moreover, a hydrogel mesoporous framework can deliver ultra-fast and unidirectional water transport (maximum speed at 65.75 mm s-1), highlighting its potential for water purification. This scalable fabrication explores a promising strategy for developing bioinspired structural hydrogels, facilitating their practical applications in biomedical and engineering fields.
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Solid-state electrolytes (SSEs) play a crucial role in developing lithium metal batteries (LMBs) with high safety and energy density. Exploring SSEs with excellent comprehensive performance is the key to achieving the practical application of LMBs. In this work, the great potential of Li0.95 Na0.05 FePO4 (LNFP) as an ideal SSE due to its enhanced ionic conductivity and reliable stability in contact with lithium metal anode is demonstrated. Moreover, LNFP-based composite solid electrolytes (CSEs) are prepared to further improve electronic insulation and interface stability. The CSE containing 50 wt% of LNFP (LNFP50) shows high ionic conductivity (3.58 × 10-4 S cm-1 at 25 °C) and good compatibility with Li metal anode and cathodes. Surprisingly, the LMB of Li|LNFP50|LiFePO4 cell at 0.5 C current density shows good cycling stability (151.5 mAh g-1 for 500 cycles, 96.5% capacity retention, and 99.3% Coulombic efficiency), and high-energy LMB of Li|LNFP50|Li[Ni0.8 Co0.1 Mn0.1 ]O2 cell maintains 80% capacity retention after 170 cycles, which are better than that with traditional liquid electrolytes (LEs). This investigation offers a new approach to commercializing SSEs with excellent comprehensive performance for high-performance LMBs.
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OBJECTIVE: To develop and validate an iodine maps-based radiomics nomogram for preoperatively predicting cervical lymph node metastasis (LNM) in head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: A total of 278 patients who pathologically confirmed as HNSCC were retrospectively recruited from two medical centers between June 2012 and July 2022. The training set (n = 152) and internal set (n = 67) were randomly selected from medical center A, and the patients from medical center B were enrolled as the external set (n = 69). The minority group in the training set was balanced by the adaptive synthetic sampling (ADASYN) approach. Radiomics features were extracted from dual-energy CT-derived iodine maps at arterial phase (AP) and venous phase (VP), respectively. Three radiomics signatures were constructed to predict the LNM by using a random forest algorithm. The independent clinical predictors for LNM were identified by multivariate analysis and combined with radiomics signatures to establish a radiomic-clinical nomogram. The performance of radiomic-clinical nomogram was evaluated with respect to its discrimination and clinical usefulness. RESULTS: The AP-VP-incorporated radiomics model exhibited a great predictive performance for LNM prediction with an area under curve (AUC) of 0.885 (95% CI, 0.836-0.933) in ADASYN-training set and confirmed in all validation sets. The nomogram that incorporated AP-VP radiomics signatures, CT-reported LN status, and histological grades yielded AUCs of 0.920 (95% CI, 0.881-0.959) in ADASYN-training set, 0.858 (95% CI, 0.771-0.944) in internal validation, and 0.849 (95% CI, 0.752-0.946) in external validation, with good calibration in all cohorts (p > 0.05). Decision curve analyses indicated the nomogram was clinically useful. In addition, the predictive performance of clinical-radiomics nomogram was also validation in combing cohorts. Stratified analysis confirmed the stability of nomogram, particularly in group negative for CT-reported LNM. CONCLUSION: Clinical-radiomics nomogram based on iodine maps exhibited promising performance in predicting LNM and providing valuable information for making individualized therapy decisions.
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Neoplasias de Cabeza y Cuello , Tomografía Computarizada por Rayos X , Humanos , Metástasis Linfática/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Estudios Retrospectivos , Radiómica , Ganglios Linfáticos/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/diagnóstico por imagenRESUMEN
BACKGROUND: The International Myeloma Working Group (IMWG) consensus criteria for response assessment in multiple myeloma (MM) has methodological limitations. Whole-body diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) histogram analysis may be complementary to response assessment of MM. PURPOSE: To explore the role of histogram analysis of the ADC based on the total tumor volume (ttADC) in response assessment in patients with newly diagnosed MM (NDMM). STUDY TYPE: Retrospective. POPULATION: Thirty-six patients with NDMM. FIELD STRENGTH/SEQUENCE: 3.0T/single-shot DWI echo planar imaging (EPI) sequence with an integrated slice-by-slice shimming (iShim) technique. ASSESSMENT: Baseline (median: 1 day before treatment) and post-treatment (median: five cycles of therapy) whole-body DWI were analyzed. A region of interest (ROI) containing lesions on every section of baseline image was drawn to derive the per-patient total tumor data. Post-treatment image analysis was based on the same ROI as the corresponding baseline. Histogram metrics were extracted from both ROIs. Patients were categorized into the very good partial response or better (VGPR+) group and the less than VGPR group per the IMWG response criteria for response assessment. Progression-free survival (PFS) was also calculated. STATISTICAL TESTS: Mann-Whitney test and Fisher's exact or Chi-squared tests, Receiver operating characteristic (ROC) analysis and DeLong test, Kaplan-Meier analysis and Cox proportional hazards model. A two-tailed P-value <0.05 was considered statistically significant. RESULTS: Thirty patients were categorized into the VGPR+ group and six into the less than VGPR group. The ttADC histogram changes between post-treatment and baseline metrics (ΔttADC) revealed significant differences in all percentile values between the VGPR+ and less than VGPR groups. For distinguishing VGPR+, ΔttADC_5th percentile had the largest area under the curve (AUC) (0.950, 95% CI 0.821-0.995). Patients with lower ΔttADC_5th percentile values (cutoff point, 188.193) showed significantly longer PFS (HR = 34.911, 95% CI 6.392-190.677). DATA CONCLUSION: ttADC histogram may facilitate response assessment in patients with NDMM. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 4.
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Liver disease has emerged as a significant worldwide health challenge due to its diverse causative factors and therapeutic complexities. The majority of liver diseases ultimately progress to end-stage liver disease and liver transplantation remains the only effective therapy with the limitations of donor organ shortage, lifelong immunosuppressants and expensive treatment costs. Numerous pre-clinical studies have revealed that extracellular vesicles released by mesenchymal stem cells (MSC-EV) exhibited considerable potential in treating liver diseases. Although natural MSC-EV has many potential advantages, some characteristics of MSC-EV, such as heterogeneity, uneven therapeutic effect, and rapid clearance in vivo constrain its clinical translation. In recent years, researchers have explored plenty of ways to improve the therapeutic efficacy and rotation rate of MSC-EV in the treatment of liver disease. In this review, we summarized current strategies to enhance the therapeutic potency of MSC-EV, mainly including optimization culture conditions in MSC or modifications of MSC-EV, aiming to facilitate the development and clinical application of MSC-EV in treating liver disease.
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Introduction: The etiology and pathophysiology of major depressive disorders (MDDs) remain unclear. Increasing evidence has demonstrated that essential trace elements (ETEs), such as iodine (I), zinc (Zn), copper (Cu), selenium (Se), cobalt (Co), and molybdenum (Mo), play vital roles in MDDs. Methods: In total, 72 patients with MDD and 75 healthy controls (HCs) in the Zhumadian Second People's Hospital, Henan Province, China were recruited in our study. The levels of different ETEs were examined in both serum and urine, using an inductively coupled plasma mass spectrometer (ICP-MS), for both the MDD patients and HCs. Results: The serum levels of I, Se, Cu, and Mo were significantly lower in the MDD patients compared to the HCs (p < 0.05), and the urinary levels of I and Zn were significantly higher in the MDD patients compared to the HCs (p < 0.05). The serum concentration of I (Q3: OR = 0.210, Q4: OR = 0.272) was negatively associated with MDD after adjusting for potential confounders, including age, gender, and BMI, and the urinary concentration of I (Q4: OR = 2.952) was positively associated. Conclusions: The higher levels of I, Se, Cu, and Mo in serum might be protective against the development of MDD, and the excess I and Zn in urine may be associated with MDD pathogenesis. Future research needs to gain a deeper understanding of the metabolic pathways of ETEs, especially I, Se, Zn, Cu, and Mo, in MDD, and their role in the pathogenesis of depression.
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Sistema Cardiovascular , Insuficiencia Cardíaca , Masculino , Femenino , Humanos , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/complicaciones , Hospitalización , Corazón , Sistema de Registros , Volumen Sistólico , Pronóstico , Función Ventricular IzquierdaRESUMEN
OBJECTIVE: To measure the relative T1 (rT1) value in different hypo-perfused regions after ischemic stroke using T1 mapping derived by Strategically Acquired Gradient Echo (STAGE) and assess its relationship with onset time and severity of ischemia. MATERIALS AND METHODS: Sixty-three patients with acute anterior circulation ischemic stroke from 2017 to 2022 who underwent STAGE, diffusion weighted imaging (DWI) and dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI) within 7 days were retrospectively enrolled. The areas with reduced diffusion and hypo-perfusion were segmented based on apparent diffusion coefficient (ADC) value < 0.62 × 10-3mm2/s and time-to-maximum (Tmax) thresholds (4, 6, 8, and 10 seconds). We measured the T1 value in the diffusion reduced and every 2 s Tmax strata regions and calculated rT1 (T1ipsi/T1contra) to explore the relationship between rT1 value, Tmax, and onset time. RESULTS: rT1 value was increased in diffusion reduced (1.42) and hypo-perfused regions (1.02, 1.06, 1.12, 1.27, Tmax 4-6 s, 6-8 s, 8-10 s, > 10 s, respectively; all different from 1, P < 0.001). rT1 value was positively correlated with Tmax (rs = 0.61, P < 0.001) and onset time in area with reduced diffusion (rs = 0.39, P = 0.014). CONCLUSIONS: Increased rT1 value in different hypo-perfused brain regions using T1 mapping derived by STAGE may reflect the edema; it was associated with the severity of Tmax and showed a weak correlation with the onset time in diffusion reduced areas.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico por imagen , Estudios Retrospectivos , Encéfalo/diagnóstico por imagen , Isquemia Encefálica/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodosRESUMEN
BACKGROUND AND OBJECTIVE: Although tumor lysis syndrome was reported with obinutuzumab and rituximab, the association with CD20 monoclonal antibodies for chronic lymphocytic leukemia is unclear. METHODS: A disproportionality analysis was conducted to investigate the link between CD20 monoclonal antibodies and tumor lysis syndrome by accounting for known confounders and comparing with other anticancer drugs, using data from the US Food and Drug Administration Adverse Event Reporting System. Reporting odds ratios and the information component were calculated as disproportionality measures. A stepwise sensitivity analysis was conducted to test the robustness of disproportionality signals. Bradford Hill criteria were adopted to globally assess the potential causal relationship. RESULTS: From 2004 to 2022, 197, 368, 41, and 14 tumor lysis syndrome reports were detected for obinutuzumab, rituximab, ofatumumab, and alemtuzumab (CD52 monoclonal antibody), respectively. Disproportionality signals were found for the above four monoclonal antibodies when compared with other anticancer drugs. Sensitivity analyses confirmed robust disproportionality signals for obinutuzumab, rituximab, and ofatumumab. The median onset time was 4.5, 1.5, and 2.5 days for rituximab, obinutuzumab, and ofatumumab, respectively. A potential causal relationship was fulfilled by assessing Bradford Hill criteria. CONCLUSIONS: This pharmacovigilance study on the FDA Adverse Event Reporting System detected a plausible association between CD20 monoclonal antibodies (but not CD52) and tumor lysis syndrome by assessing the adapted Bradford Hill criteria. Urgent clarification of drug- and patient-related risk factors is needed through large comparative population-based studies.
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Gold nanoparticles (AuNPs) with localized surface plasmon resonance effect have been widely used for colorimetric detection based on the interparticle plasmon coupling during AuNPs aggregation. However, it is still challenging to develop portable and quantitative methods with good sensitivity and excellent selectivity. In this study, a smartphone-based colorimetric assay is developed on the principle of surfactant-mediated AuNPs aggregation assisted with rolling circle amplification (RCA) on magnetic beads (MBs). The detection of adenosine is demonstrated as an example. The cetyl trimethyl ammonium bromide (CTAB) causes the negatively charged AuNPs to aggregate, which results in the color change from red to blue. When adenosine is in solution, the RCA process is triggered on the MBs because of specific adenosine-aptamer recognition, resulting in prolongation of single-stranded nucleic acid (ssDNA). The solution color remains red due to the electrostatic interaction between CTAB and ssDNA. Using this method, the limit of detection (LOD) for adenosine can be as low as 16 pM. Besides, it also works well in human serum. In addition, a portable device integrated with in-situ RGB analysis software is developed for the detection with a smartphone. This study offers a new strategy to improve the sensitivity and selectivity for the AuNPs-based colorimetric assay, taking advantages of specific aptamer recognition, in-situ RCA on MBs, magnetic separation, and smartphone-based portable device.
Asunto(s)
Nanopartículas del Metal , Ácidos Nucleicos , Humanos , Tensoactivos , Colorimetría , Oro , Cetrimonio , Lipoproteínas , Adenosina , Oligonucleótidos , Fenómenos MagnéticosRESUMEN
We present a facile chemical method for fabricating bioinspired microadhesives with significant improved reversible adhesion strength. Four kinds of polysiloxane with gradient varying phenyl contents were synthesized and used to fabricate microadhesives. The chemical structures and mechanical properties, as well as surface properties of the four microadhesives, were confirmed and characterized by ATR-FTIR, DSC, XPS, low-field NMR, tensile tests, and SEM, respectively. The macroadhesion test results revealed that phenyl contents showed remarkable and positive impacts on the macroadhesion performance of microadhesives. The pull-off adhesion strength of microadhesives with 90% phenyl content (0.851 N/cm2) was nearly 300% higher than that of pure PDMS (0.309 N/cm2). The macroadhesion mechanism analysis demonstrates that a larger bulk energy dissipation caused by massive π-π interaction, as well as the hydrophobic interaction and van der Waals forces at the interface synergistically resulted in a significant enhancement of the adhesion performance. Our results demonstrate the remarkable impact of chemical structures on the adhesion of microadhesives, and it is conducive to the further improvement of adhesion properties of bioinspired microadhesives.