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CRISPR/Cas9, presently the most widely used genome editing technology, has provided great potential for functional studies and plant breeding. However, the strict requirement for a protospacer adjacent motif (PAM) has hindered the application of the CRISPR/Cas9 system because the number of targetable genomic sites is limited. Recently, the engineered variants Cas9-NG, SpG, and SpRY, which recognize non-canonical PAMs, have been successfully tested in plants (mainly in rice, a monocot). In this study, we evaluated the targeted mutagenesis capabilities of these Cas9 variants in two important Brassica vegetables, Chinese cabbage (Brassica rapa spp. pekinensis) and cabbage (Brassica oleracea var. capitata). Both Cas9-NG and SpG induced efficient mutagenesis at NGN PAMs, while SpG outperformed Cas9-NG at NGC and NGT PAMs. SpRY achieved efficient editing at almost all PAMs (NRN > NYN), albeit with some self-targeting activity at transfer (T)-DNA sequences. And SpRY-induced mutants were detected in cabbage plants in a PAM-less fashion. Moreover, an adenine base editor was developed using SpRY and TadA8e deaminase that induced A-to-G conversions within target sites using non-canonical PAMs. Together, the toolboxes developed here induced successful genome editing in Chinese cabbage and cabbage. Our work further expands the targeting scope of genome editing and paves the way for future basic research and genetic improvement in Brassica. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00155-7.
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Stroke, the second leading cause of death and disability, causes massive cell death in the brain followed by secondary inflammatory injury initiated by disease associated molecular patterns released from dead cells. Nonetheless, the evidence regarding the causal relationship between inflammatory cytokines and stroke subtypes is obscure. To leverage large scale genetic association data to investigate the interplay between circulating cytokines and stroke, we adopted a two-sample bi-directional Mendelian randomization (MR) analysis. Firstly, we performed a forward MR analysis to examine the associations of genetically determined 31 cytokines with 6 stroke subtypes. Secondly, we conducted a reverse MR analysis to check the associations of 6 stroke subtypes with 31 cytokines. In the forward MR analysis, genetic evidence suggests that 21 cytokines were significantly associated with certain stroke subtype risk with |ß| ranging from 1.90 × 10-4 to 0.74. In the reverse MR analysis, our results found that five stroke subtypes (intracerebral hemorrhage (ICH), large artery atherosclerosis ischemic stroke (LAAS), lacunar stroke (LS), cardioembolic ischemic stroke (CEI), small-vessel ischemic stroke (SV)) caused significantly changes in 16 cytokines with |ß| ranging from 1.08 × 10-4 to 0.69. In particular, those five stroke subtypes were statistically significantly associated with C-reactive protein (CRP). In addition, ICH, LAAS, LS and SV were significantly correlated with vascular endothelial growth factor (VEGF), while LAAS, LS, CEI and SV were significantly related to fibroblast growth factor (FGF). Moreover, integrated bi-directional MR analysis, these factors (IL-3Rα, IL-6R, IL-6Rα, IL-1Ra, insulin-like growth factor-1(IGF-1), IL-12Rß2) can be used as predictors of some specific stroke subtypes. As well as, IL-16 and C-C motif chemokine receptor 7 (CCR7) can be used as prognostic factors of stroke. Our findings prognostic identify potential pharmacological opportunities, including perturbation of circulating cytokines for both predicting stroke risk and post stroke treatment effects. As we conducted a comprehensive search and analysis of stroke subtype and cytokines in the existing publicly available GWAS database, the results have good population-generalizability.
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Citocinas , Análisis de la Aleatorización Mendeliana , Accidente Cerebrovascular , Humanos , Citocinas/sangre , Citocinas/metabolismo , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/sangre , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Predisposición Genética a la Enfermedad , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/sangreRESUMEN
BACKGROUND AND OBJECTIVES: Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. METHODS: In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. RESULTS: The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. CONCLUSIONS: No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.
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Major depressive disorder (MDD) is a debilitating mental health condition that poses significant risks and burdens. Resting-state functional magnetic resonance imaging (fMRI) has emerged as a promising tool in investigating the neural mechanisms underlying MDD. However, a comprehensive bibliometric analysis of resting-state fMRI in MDD is currently lacking. Here, we aimed to thoroughly explore the trends and frontiers of resting-state fMRI in MDD research. The relevant publications were retrieved from the Web of Science database for the period between 1998 and 2022, and the CiteSpace software was employed to identify the influence of authors, institutions, countries/regions, and the latest research trends. A total of 1501 publications met the search criteria, revealing a gradual increase in the number of annual publications over the years. China contributed the largest publication output, accounting for the highest percentage among all countries. Particularly, the University of Electronic Science and Technology of China, Capital Medical University, and Harvard Medical School were identified as key institutions that have made substantial contributions to this growth. Neuroimage, Biological Psychiatry, Journal of Affective Disorders, and Proceedings of the National Academy of Sciences of the United States of America are among the influential journals in the field of resting-state fMRI research in MDD. Burst keywords analysis suggest the emerging research frontiers in this field are characterized by prominent keywords such as dynamic functional connectivity, cognitive control network, transcranial brain stimulation, and childhood trauma. Overall, our study provides a systematic overview into the historical development, current status, and future trends of resting-state fMRI in MDD, thus offering a useful guide for researchers to plan their future research.
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Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).
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Citometría de Flujo , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Adulto , Masculino , Femenino , Citometría de Flujo/métodos , Persona de Mediana Edad , Adulto Joven , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , AdolescenteRESUMEN
Immunotherapy has shown promising clinical results in clear cell renal cell carcinoma (ccRCC), but low clinical target response rates due to dysfunction of the major histocompatibility complex (MHC) and an inhibitory tumor immune microenvironment (TIME) have largely limited the associated clinical benefits. In the present study, we explored the feasibility of enhancing tumor-specific-MHC-II-HLA-DRA expression, counteracting the TIME's suppressive effects, thereby improving the sensitivity of immune checkpoint inhibitor (ICI) therapy from the standpoint of cuproptosis. Immunohistochemical staining and in vitro experiments validated the expression of HLA-DRA in ccRCC and its positive impact on ICI therapy. Subsequently, we observed that cuproptosis upregulated HLA-DRA expression in a dose-dependent manner, further confirming the link between cuproptosis and HLA-DRA. In vivo experiments showed that cuproptosis increased the sensitivity to ICI treatment, and implementing cuproptosis alongside anti-PD-1 treatment curtailed tumor growth. Mechanistically, cuproptosis upregulates HLA-DRA expression at the transcriptional level in a dose-dependent manner by inducing the production of reactive oxygen species; high levels of HLA-DRA promote the expression of chemokines CCL5, CXCL9, and CXCL10 in the TIME, inhibiting the development of a pro-tumor microenvironment by promoting the infiltration of CD4+T and CD8+T cells, thereby synergizing ICI therapy and exerting anti-tumor effects. Taken together, this work highlights the role of cuproptosis in mediating TIME remodeling and synergistic immunotherapy, providing new evidence that cuproptosis can evoke effective anti-tumor immune responses.
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Accurate segmentation of polyp regions in gastrointestinal endoscopic images is pivotal for diagnosis and treatment. Despite advancements, challenges persist, like accurately segmenting small polyps and maintaining accuracy when polyps resemble surrounding tissues. Recent studies show the effectiveness of the pyramid vision transformer (PVT) in capturing global context, yet it may lack detailed information. Conversely, U-Net excels in semantic extraction. Hence, we propose the bilateral fusion enhanced network (BFE-Net) to address these challenges. Our model integrates U-Net and PVT features via a deep feature enhancement fusion module (FEF) and attention decoder module (AD). Experimental results demonstrate significant improvements, validating our model's effectiveness across various datasets and modalities, promising advancements in gastrointestinal polyp diagnosis and treatment.
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The ever-increasing demand for safety has thrust all-solid-state batteries (ASSBs) into the forefront of next-generation energy storage technologies. However, the atomic mechanisms underlying the failure of layered cathodes in ASSBs, as opposed to their counterparts in liquid electrolyte-based lithium-ion batteries (LIBs), have remained elusive. Here, leveraging artificial intelligence-enhanced super-resolution electron microscopy, we unravel the atomic origins dictating the chemomechanical degradation of technologically crucial high-Ni layered oxide cathodes in ASSBs. We reveal that the coupling of surface frustration and interlayer-shear-induced phase transformation exacerbates the chemomechanical breakdown of layered cathodes. Surface frustration, a phenomenon previously unobserved in liquid electrolyte-based LIBs, emerges through electrochemical processes involving surface nanocrystallization coupled with rock salt transformation. Simultaneously, delithiation-induced interlayer shear yields the formation of chunky O1 phases and intricate interfaces/transition motifs, distinct from scenarios observed in liquid electrolyte-based LIBs. Bridging the knowledge gap between the failure mechanisms of layered cathodes in solid-state electrolytes and conventional liquid electrolytes, our study provides unprecedented atomic-scale insights into the degradation pathways of layered cathodes in ASSBs.
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Anti-inflammatory and angiogenesis are two important factors in wound healing. Wound dressings with anti-inflammation and vascularization are essential to address complex interventions, expensive treatments, and uncontrolled release mechanisms. Based on the above considerations, we designed a near-infrared (NIR)-responsive hydrogel dressing, which is composed of mPDA-DFO@LA nanoparticles (mPDA: dopamine hydrochloride nanoparticles, DFO: deferoxamine, LA: lauric acid), valsartan (abbreviated as Va), and dopamine-hyaluronic acid hydrogel. The hydrogel dressing demonstrated injectability, bioadhesive, and photothermal properties. The results indicated the obtained dressing by releasing Va can appropriately regulate macrophage phenotype transformation from M1 to M2, resulting in an anti-inflammatory environment. In addition, DFO encapsulated by LA can be sustainably released into the wound site by NIR irradiation, which further prevents excessive neovascularization. Notably, the results in vivo indicated the mPDA-DFO@LA/Va hydrogel dressing significantly enhanced wound recovery, achieving a healing rate of up to 96% after 11 days of treatment. Therefore, this NIR-responsive hydrogel dressing with anti-inflammation, vascularization, and on-demand programmed drug release will be a promising wound dressing for wound infection.
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Antiinflamatorios , Vendajes , Hidrogeles , Nanocompuestos , Cicatrización de Heridas , Animales , Ratones , Angiogénesis/efectos de los fármacos , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Deferoxamina/química , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Dopamina/química , Dopamina/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Rayos Infrarrojos , Ácidos Láuricos/química , Ácidos Láuricos/farmacología , Nanocompuestos/química , Nanocompuestos/uso terapéutico , Células RAW 264.7 , Cicatrización de Heridas/efectos de los fármacosRESUMEN
How to simultaneously utilize photogenerated electrons and holes still remains a critical challenge in the field of artificial photosynthesis, especially in the process of photocatalytic hydrogen (H2) evolution coupled with biomass oxidation to value-added chemicals. Herein, a series-parallel photocatalyst (Cu NPs/CdS/In2O3) that can intrinsically regulate the transfer of photogenerated carriers is ingeniously designed for photocatalytic H2 evolution synergized with furfural alcohol (FFA) selective oxidation to furfural (FF). Accordingly, the desired H2 and FF evolution rates with near 100% selectivity toward FF are achieved on Cu NPs/CdS/In2O3 in a sealed atmospheric system. Experimental and theoretical analyses confirm that the localized surface plasmon resonance (LSPR) effect induced by Cu NPs accelerates the reduction of protons (H+) to H2 efficiently, while the photogenerated holes from In2O3 preferentially activate the α-C-H bond of FFA adsorbed on Lewis acid sites to generate FF. This work provides a reference for regulating the transfer of photogenerated carriers for H2 evolution coupled with FF synthesis.
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Anaprazole sodium enteric-coated tablet is a novel proton pump inhibitor which has been approved for the treatment of duodenal ulcer. The aim of this study is to provide reliable information for the design of an optimal dosage regimen. Population pharmacokinetics and exposure-response models were integrated to evaluate the pharmacokinetic parameters and covariates of Anaprazole and its metabolite M21-1, and subsequently provided dosage suggestions based on clinical trials and simulation data. A pharmacokinetic model incorporating two-compartment for the parent drug and one-compartment for the metabolite, with both first-order and zero-order mixed absorption was used to describe the pharmacokinetics of Anaprazole and M21-1. Age emerged as a significant covariate affecting the elimination rate constant of M21-1, with clearance decreasing as age advances. No correlation was observed between the pharmacokinetics of Anaprazole or M21-1 and the adverse reactions under the current dosages. BMI might be the influence factor of the mild gastrointestinal adverse reactions. Meanwhile, Anaprazole had a good healing rate (94.0 %) in duodenal ulcer patients and the exposure-response analysis indicated that the cured results were not influenced by the exposure parameters of parent drug or metabolite. In conclusion, the drug is safe when dosing between 20 and 100 mg once a day.
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Úlcera Duodenal , Modelos Biológicos , Humanos , Úlcera Duodenal/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Adulto , Femenino , Anciano , 2-Piridinilmetilsulfinilbencimidazoles/farmacocinética , 2-Piridinilmetilsulfinilbencimidazoles/administración & dosificación , Inhibidores de la Bomba de Protones/farmacocinética , Inhibidores de la Bomba de Protones/administración & dosificación , Adulto Joven , Adolescente , Relación Dosis-Respuesta a DrogaRESUMEN
This study reports a protocol for the highly regioselective photocatalyzed C-H nitrosylation of imidazo[1,2-a]pyridine scaffolds at the C3 position under a combination of visible-light irradiation and continuous flow without any external photocatalyst. This protocol involves mild and safe conditions and shows good tolerance to air and water along with excellent functional group compatibility and site selectivity, generating various 3-nitrosoimidazo[1,2-a]pyridines in excellent yields under photocatalyst-, oxidant-, and additive-free conditions.Notably, the proposed nitrosylation reaction, which introduces the chromophore NO into imidazo[1,2-a]pyridine scaffolds, occurs efficiently under visible-light irradiation without any additional photocatalyst owing to the intense light-absorption characteristics of the nitrosylation products. This study could guide future studies on the development of green organic-synthesis strategies with a wide variety of potential applications.
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Many countries attach great importance to the green, low-carbon, and circular development of industrial parks. China is one of them and has entered an exploration journey of national demonstration eco-industrial parks (NDEIPs). However, the impact of the transformation of industrial parks into NDEIPs on local economic development still remains a mystery. To address this issue, we develop an empirical study using a combination of the multi-period difference-in-differences method and the propensity score matching method based on the panel data for 266 cities in China from 2001 to 2021. The results show that industrial parks becoming NDEIPs promotes cities' economic development. This conclusion still holds after a series of robustness tests, such as the reverse causality test and the placebo test. Moreover, the park heterogeneity tests show that the economic consequences vary according to differences in levels, industry types, life cycle phases, and the degree of foreign firm agglomeration. The city heterogeneity tests show that the economic consequences differ based on administrative levels, innovation capabilities, technology industrialization, and environmental friendliness. The spatial heterogeneity tests show that the economic consequences differ according to geographical location and whether situated in the Yangtze River Economic Belt. The policy upgrading heterogeneity tests show that the economic consequences differ during the process of policy upgrading and transformation. In addition, the mechanism tests reveal that green innovation, human capital level, and firm attractiveness mediate the relationship between industrial parks becoming NDEIPs and cities' economic development. This study provides a new perspective for understanding the economic effects of the transformation of industrial parks into NDEIPs, and provides a reference for the government on how to maximize these economic effects.
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Parques Recreativos , China , Desarrollo Económico , Ciudades , Industrias , Conservación de los Recursos Naturales , HumanosRESUMEN
BACKGROUND Wünderlich syndrome (WS) is a rare diagnosis of nontraumatic spontaneous renal hemorrhage into the subcapsular, perirenal, or pararenal spaces. Prompt and effective intervention is necessary for an accurate pathological diagnosis and preservation of life. In the current literature, open surgery is the primary option when conservative treatment fails, but there can be serious trauma and corresponding consequences. Herein, we present 3 cases of Wünderlich syndrome managed by robot-assisted laparoscopic nephrectomy via a retroperitoneal approach. CASE REPORT Patient 1 was a 44-year-old woman with right flank pain for 6 h. Patient 2 was a 53-year-old woman with a history of diabetes who had pain in her right flank pain and nausea for 1 day. Patient 3 was a 45-year-old man with left flank pain for 1 day. All cases of WS were confirmed by CT. All 3 patients were treated with retroperitoneal robot-assisted nephrectomy after conservative treatment failed. Pathological examination confirmed that patient 1 had angiomyolipoma, and patients 2 and 3 had renal clear cell carcinoma. At the 9-month follow-up, renal function was good and no evidence of recurrence or metastasis has been detected. CONCLUSIONS These cases have highlighted the importance of the clinical history and imaging findings in the diagnosis of Wünderlich syndrome, and show that rapid management can be achieved using robot-assisted laparoscopic nephrectomy. However, it is crucial to have a skilled surgical team and adequate preoperative preparation.
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Laparoscopía , Nefrectomía , Procedimientos Quirúrgicos Robotizados , Humanos , Nefrectomía/métodos , Persona de Mediana Edad , Masculino , Femenino , Adulto , Síndrome , Enfermedades Renales/cirugía , Hemorragia/cirugía , Hemorragia/etiología , Neoplasias Renales/cirugía , Neoplasias Renales/complicaciones , Angiomiolipoma/cirugía , Angiomiolipoma/complicaciones , Angiomiolipoma/diagnóstico por imagen , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/complicacionesRESUMEN
Realizing room-temperature, efficient, and reversible fluoride-ion redox is critical to commercializing the fluoride-ion battery, a promising post-lithium-ion battery technology. However, this is challenging due to the absence of usable electrolytes, which usually suffer from insufficient ionic conductivity and poor (electro)chemical stability. Herein we report a water-in-salt (WIS) electrolyte based on the tetramethylammonium fluoride salt, an organic salt consisting of hydrophobic cations and hydrophilic anions. The new WIS electrolyte exhibits an electrochemical stability window of 2.47 V (2.08-4.55 V vs Li+/Li) with a room-temperature ionic conductivity of 30.6 mS/cm and a fluoride-ion transference number of 0.479, enabling reversible (de)fluoridation redox of lead and copper fluoride electrodes. The relationship between the salt property, the solvation structure, and the ionic transport behavior is jointly revealed by computational simulations and spectroscopic analysis.
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The limited excitation efficiency of quantum dots in the detection of subsurface defects in optical elements by quantum dot fluorescence gives rise to insufficient accuracy. To enhance the excitation efficiency of quantum dots, we studied the modulation of the polarization direction of linearly polarized incident light on quantum dot fluorescence. We first apply density matrix evolution theory to study the quantum dots interacting with linearly polarized incident light and emitting fluorescence. The fluorescence intensity exhibits cosine oscillations versus modulated laser polarization. It reaches a maximum value at the polarization angle zero, and then decreases as the angle becomes larger until π/2. The experimental results for the quantum dot in both solutions and subsurface defect of optical elements confirmed these results. For optical elements tagged with CdSe/ZnS quantum dots, the fluorescence intensity increases by 61.7%, and the area for the detected subsurface defects increases by 142.9%. Similarly, for C and InP/ZnS quantum dots, there are also increases in both the fluorescence intensity and the area of subsurface defects. Our study suggests that the subsurface defect detection in optical elements by the linearly polarized incident light could enhance the detection accuracy of subsurface defects in optical elements, and potentially achieve super-resolution imaging of subsurface defects.
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BACKGROUND: Over 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy. METHODS: Longitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL. RESULTS: The study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA-) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA- at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (<170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, including TP53, IGLL5, PIM1, BTG1, CD79B, GNA13, and P2RY8. Notably, we observed a significant correlation between IGLL5 mutation and inferior PFS (p=0.008) and OS (p=0.014). CONCLUSIONS: Our study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.
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ADN Tumoral Circulante , Linfoma de Células B Grandes Difuso , Humanos , ADN Tumoral Circulante/genética , Inmunoterapia Adoptiva , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Genómica , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/terapiaRESUMEN
Calpain and PARP-NF-κB signaling are reported to participate in the ischemic brain injury. In this study, it was investigated whether calpain was contributed to the neurovascular unit (NVU) damage through up-regulating PARP-NF-κB signaling during experimental ischemic stroke. Male Sprague-Dawley rats were suffered from 90 min of middle cerebral artery occlusion, followed by reperfusion. The NVU damage was evaluated by the permeability of blood-brain barrier (BBB), the degradation of proteins in extracellular matrix and tight junctions, and ultrastructural changes. The inflammatory response was determined by the expression of inflammatory genes driven by PARP-NF-κB signaling and the activities of myeloperoxidase (MPO). Treatment with MDL 28,170, a calpain inhibitor, improved neurological functions, reduced TUNEL staining index, lessened brain swelling, and decreased infarct volume in ischemic rats. Moreover, it reduced the BBB permeability, enhanced the levels of laminin, collagen IV and occludin, and attenuated the ultrastructural damage of NVU in penumbra and core after induction of ischemia. Meanwhile, it enhanced the levels of cytosolic IκBα, lessened the levels of nuclear PARP and NF-κB p65, reduced the levels of ICAM-1, TNF-α, IL-1ß, MMP-9, and MMP-2,and suppressed the activities of MPO in penumbra and core. These data showed that calpain inhibition suppressed PARP-NF-κB signaling-mediated inflammatory response, reduced NVU damage, and protected brain against ischemic stroke, suggesting the involvement of calpain in the NVU damage through up-regulating PARP-NF-κB signaling during brain ischemia.
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This study reports the surgical technique and outcomes of tendon ball arthroplasty combined with proximal carpal stabilization using the extensor carpi radialis longus tendon for treating advanced Kienbock's disease. The collapsed lunate is excised and a tendon ball inserted as a spacer. A distally based extensor carpi radials longus graft is passed through the scaphoid, tendon ball and triquetrum, reconstructing the proximal carpal row. In total, 16 patients were included and the mean follow-up was 25 months. Pain improved from 5.6 preoperatively to 1.3 postoperatively on a 10-point visual analogue scale. Mean wrist motion improved by 17.8° and grip strength compared with the non-operative side increased by 22.1% on average. Radiographic outcomes demonstrated correction of scaphoid flexion and carpal height ratio. The modified tendon ball arthroplasty may be an alternative wrist salvage procedure for the treatment of advanced Kienbock's disease.Level of evidence: IV.
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Solid polymer electrolytes based on plastic crystals are promising for solid-state sodium metal (Na0) batteries, yet their practicality has been hindered by the notorious Na0-electrolyte interface instability issue, the underlying cause of which remains poorly understood. Here, by leveraging a model plasticized polymer electrolyte based on conventional succinonitrile plastic crystals, we uncover its failure origin in Na0 batteries is associated with the formation of a thick and non-uniform solid electrolyte interphase (SEI) and whiskery Na0 nucleation/growth. Furthermore, we design a new additive-embedded plasticized polymer electrolyte to manipulate the Na0 deposition and SEI formulation. For the first time, we demonstrate that introducing fluoroethylene carbonate (FEC) additive into the succinonitrile-plasticized polymer electrolyte can effectively protect Na0 against interfacial corrosion by facilitating the growth of dome-like Na0 with thin, amorphous, and fluorine-rich SEIs, thus enabling significantly improved performances of Na//Na symmetric cells (1,800â h at 0.5â mA cm-2) and Na//Na3V2(PO4)3 full cells (93.0 % capacity retention after 1,200 cycles at 1â C rate in coin cells and 93.1 % capacity retention after 250 cycles at C/3 in pouch cells at room temperature). Our work provides valuable insights into the interfacial failure of plasticized polymer electrolytes and offers a promising solution to resolving the interfacial instability issue.