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Designing highly active and cost-effective electrocatalysts for the alkaline hydrogen oxidation reaction (HOR) is critical for advancing anion-exchange membrane fuel cells (AEMFCs). While dilute metal alloys have demonstrated substantial potential in enhancing alkaline HOR performance, there has been limited exploration in terms of rational design, controllable synthesis, and mechanism study. Herein, we developed a series of dilute Pd-Ni alloys, denoted as x% Pd-Ni, based on a trace-Pd decorated Ni-based coordination polymer through a facile low-temperature pyrolysis approach. The x% Pd-Ni alloys exhibit efficient electrocatalytic activity for HOR in alkaline media. Notably, the optimal 0.5% Pd-Ni catalyst demonstrates high intrinsic activity with an exchange current density of 0.055 mA cm-2, surpassing that of many other alkaline HOR catalysts. The mechanism study reveals that the strong synergy between Pd single atoms (SAs)/Pd dimer and Ni substrate can modulate the binding strength of proton (H)/hydroxyl (OH), thereby significantly reducing the activation energy barrier of a decisive reaction step. This work offers new insights into designing advanced dilute metal or single-atom-alloys (SAAs) for alkaline HOR and potentially other energy conversion processes.
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INTRODUCTION: The urgency and complexity of emergency room (ER) settings require precise and swift decision-making processes for patient care. Ensuring the timely execution of critical examinations and interventions is vital for reducing diagnostic errors, but the literature highlights a need for innovative approaches to optimize diagnostic accuracy and patient outcomes. In response, our study endeavors to create predictive models for timely examinations and interventions by leveraging the patient's symptoms and vital signs recorded during triage, and in so doing, augment traditional diagnostic methodologies. METHODS: Focusing on four key areas-medication dispensing, vital interventions, laboratory testing, and emergency radiology exams, the study employed Natural Language Processing (NLP) and seven advanced machine learning techniques. The research was centered around the innovative use of BioClinicalBERT, a state-of-the-art NLP framework. RESULTS: BioClinicalBERT emerged as the superior model, outperforming others in predictive accuracy. The integration of physiological data with patient narrative symptoms demonstrated greater effectiveness compared to models based solely on textual data. The robustness of our approach was confirmed by an Area Under the Receiver Operating Characteristic curve (AUROC) score of 0.9. CONCLUSION: The findings of our study underscore the feasibility of establishing a decision support system for emergency patients, targeting timely interventions and examinations based on a nuanced analysis of symptoms. By using an advanced natural language processing technique, our approach shows promise for enhancing diagnostic accuracy. However, the current model is not yet fully mature for direct implementation into daily clinical practice. Recognizing the imperative nature of precision in the ER environment, future research endeavors must focus on refining and expanding predictive models to include detailed timely examinations and interventions. Although the progress achieved in this study represents an encouraging step towards a more innovative and technology-driven paradigm in emergency care, full clinical integration warrants further exploration and validation.
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AIMS: To systematically evaluate and analyse literature concerning the factors influencing the implementation of clinical practice guidelines related to enteral nutrition in the adult intensive care unit. BACKGROUND: Guidelines serve as crucial tools for guiding clinical practice. However, a significant gap persists between current clinical practice and guidelines pertaining to enteral nutrition. It is essential to identify the reasons behind this disparity to foster clinical transformation. METHODS: A mixed-methods systematic review. DATA SOURCES: A systematic search was conducted across PubMed, Embase, Medline, Cochrane, PsycINFO and CNKI databases to identify impediments and facilitators to the implementation of ICU clinical practice guidelines related to enteral nutrition. The types of studies included quantitative, qualitative and mixed-methods studies. The search spanned from January 2003 to January 2024 and was updated in May 2024. The quality assessment of the included literature was conducted using the Mixed-Methods Study Evaluation Tool (MMAT). Data analysis was performed using a data-based convergent integration approach. The protocol for this study was prospectively registered (PROSPERO2023, CRD42023483287). RESULTS: Twenty papers were finally included, and 65 findings were extracted, integrating a total of three categories, Category 1: healthcare provider factors, including three sub-themes: knowledge of guideline-related knowledge and awareness of guideline application; social/professional roles and identity domains; beliefs, attitudes and self-efficacy; collaboration, Category 2: practice environments, including two sub-themes: environmental factors and resource areas; systems and behavioural norms, Category 3: patient values and nutritional support preferences including two sub-themes: patient disease status and value orientation. CONCLUSION: Healthcare professionals should analyse obstacles and facilitators to guideline implementation from multiple perspectives, strengthen healthcare collaboration, improve education and training systems, correct misperceptions and increase awareness of evidence-based practice.
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Gratitude expressions have received growing attention from scholars, with research emphasizing its many positive effects on expressers, recipients, and witnesses. Although our knowledge of gratitude expressions' benefits is accumulating, our understanding of its limits is less developed. In this article, we ask when employees' expressions of gratitude toward their leaders positively influence witnesses' perceptions of them, and when they do not. Across three studies including two multiwave surveys and an experiment, we find that expressed gratitude strengthens witnesses' perceptions of expressers' prosocial identities, especially when the leader is believed to be deserving of gratitude. Study 1 examines leader competence as an indicator of deservingness in a sample of leaders and employees in a manufacturing context. Studies 2 and 3 use survey and experimental methods to directly establish leader deservingness as a mechanism of the competence moderator and explore warmth as an additional component of employees' deservingness perceptions. All three studies show how gratitude expression ultimately shapes witnesses' tendencies to help expressers and seek feedback from them. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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PURPOSES: Mono-focal papillary thyroid carcinoma (PTC) patients with encapsulated tumor have traditionally been considered as low central lymph node metastasis (CLNM) risk subgroup. The aim of the research was to quantitatively predict the probability of CLNM for mono-focal PTC patients with encapsulated tumor as confirmed by preoperative ultrasound based on pre- and post-operative indexes respectively to guide the selection of prophylactic central lymph node dissection (CLND) and follow-up strategies. METHODS: A total of 1014 mono-focal PTC patients with encapsulated tumor as confirmed by preoperative ultrasound from three medical centers were retrospectively analyzed, with 534 patients served as Training group and 480 patients as Validation group. RESULTS: Multivariate analyses showed that age < 55 years old, male, clinical maximum tumor diameter (cMTD) > 0.5 cm, pathological maximum tumor diameter (pMTD) > 0.5 cm, and the presence of microscopic thyroid capsular invasion (mTCI) were independent CLNM risk factors. These were used to construct two nomograms that can effectively predict the central neck involvement in mono-focal PTC patients with encapsulated tumor. The first nomogram (pre-model) provides quantitative assessment on the necessity of prophylactic CLND, while the second nomogram (post-model) informs postoperative follow-up strategies. CONCLUSIONS: Meticulous and comprehensive stratification flow charts that quantitatively evaluate the risk of central lymph node metastasis both pre- and post-operatively were constructed for mono-focal PTC patients with encapsulated tumor as confirmed by preoperative ultrasound, which may benefit both clinical decision-making of prophylactic CLND and postoperative follow-up strategies for the management of neck regions.
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INTRODUCTION: The objective of this study was to identify relevant aspects for disability evaluation used in scientific literature for older adults. EVIDENCE ACQUISITION: We employed a systematic review methodology as outlined by the ICF Research Branch. The methodology consists of four steps: 1) identifying studies that focus on disability evaluation among older adults; 2) identifying disability measures used in these studies; 3) linking the concepts contained in these measures to ICF categories; 4) conducting frequency analysis. EVIDENCE SYNTHESIS: A total of 1942 concepts contained in disability measures from 137 studies were extracted. About 97.7% of the concepts could be linked, and 1862 concepts were linked to 52 second-level ICF categories. Of these, 44 categories found in at least 5% of the studies (range 5.1-85.4%) were selected to develop an outcome set that represents the relevant categories, including five categories in the Body Functions component and 39 categories from the Activities and Participation component. CONCLUSIONS: The relevant categories identified in our study reflect the essential areas that measure disability for older adults, providing a scientific basis for developing an ICF Core Set for disability evaluation, in combination with further empirical study and expert survey. Information from the outcome set is also valuable for providing a standardized minimal set for disability measurement, which can be used for data comparison across different studies and the development of an ICF-based disability measurement tool.
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Designing highly efficient orally administrated nanotherapeutics with specific inflammatory site-targeting functions in the gastrointestinal tract for ulcerative colitis (UC) management is a noteworthy challenge. Here, we focused on exploring a specific targeting oral nanotherapy, serving as "one stone," for the directed localization of inflammation and the regulation of redox homeostasis, thereby achieving effects against "two birds" for UC treatment. Our designed nanotherapeutic agent OPNs@LMWH (oxidation-sensitive ε-polylysine nanoparticles at low-molecular weight heparin) exhibited specific active targeting effects and therapeutic efficacy simultaneously. Our results indicate that OPNs@LMWH had high integrin αM-mediated immune cellular uptake efficiency and preferentially accumulated in inflamed tissues. We also confirmed its effectiveness in the treatment experiment of colitis in mice by ameliorating oxidative stress and inhibiting the activation of inflammation-associated signaling pathways while simultaneously bolstering the protective mechanisms of the colonic epithelium. Overall, these findings underscore the compelling dual functionalities of OPNs@LMWH, which enable effective oral delivery to inflamed sites, thereby facilitating precise UC management.
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Colitis, Ulcerative , Homeostasis , Integrins , Nanoparticles , Oxidation-Reduction , Animals , Mice , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/metabolism , Nanoparticles/chemistry , Administration, Oral , Integrins/metabolism , Oxidative Stress/drug effects , Humans , Disease Models, Animal , Drug Delivery SystemsABSTRACT
DDB1-Cullin-4-associated factor-2 (DCAF2, also known as DTL or CDT2), a conserved substrate recognition protein of Cullin-RING E3 ligase 4 (CRL4), recognizes and degrades several substrate proteins during the S phase to maintain cell cycle progression and genome stability. Dcaf2 mainly expressed in germ cells of human and mouse. Our study found that Dcaf2 was expressed in mouse spermatogonia and spermatocyte. The depletion of Dcaf2 in germ cells by crossing Dcaf2fl/fl mice with stimulated by retinoic acid gene 8(Stra8)-Cre mice caused a reduction in progenitor spermatogonia and differentiating spermatogonia, eventually leading to the failure of meiosis initiation and male infertility. Further studies showed that depletion of Dcaf2 in germ cells caused abnormal accumulation of the substrate proteins, cyclin-dependent kinase inhibitor 1A (p21) and thymine DNA glycosylase (TDG), decreasing of cell proliferation, increasing of DNA damage and apoptosis. Overexpression of p21 or TDG attenuates proliferation and increases DNA damage and apoptosis in GC-1 cells, which is exacerbated by co-overexpression of p21 and TDG. The findings indicate that DCAF2 maintains the proliferation and differentiation of progenitor spermatogonia by targeting the substrate proteins p21 and TDG during the S phase.
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This phase II trial aimed to determine the efficacy and safety of induction chemoimmunotherapy of camrelizumab plus modified TPF in locally advanced hypopharyngeal squamous cell carcinoma (LA HSCC) (NCT04156698). The primary endpoint was objective response rate (ORR), and secondary endpoints were 3-year overall survival (OS), progression-free survival (PFS), larynx preservation rate (LPR), and metastasis-free survival (MFS). Patients (cT3-4aN0-2M0), regardless of sex, received induction chemoimmunotherapy for three cycles: camrelizumab 200 mg d1, docetaxel 75 mg/m2 d1, cisplatin 25 mg/m2 d1-3, and capecitabine 800 mg/m2 bid d1-14, q21d. Patients were assigned to radioimmunotherapy if they had a complete or partial response, those with stable or progressive disease underwent surgery and adjuvant (chemo)radiotherapy. Camrelizumab was maintained post-radioimmunotherapy. Fifty-one patients were enrolled with a median follow-up duration of 23.7 months. After induction therapy, the ORR was 82.4% (42/51), meeting the prespecified endpoint. Grade 3/4 adverse events occurred in 26 patients, and no treatment-related death occurred. As three-year outcomes were immature, two-year OS, PFS and LPR were reported. As no distant metastatic event had occurred, MFS was not reported here. The two-year OS, PFS, and LPR rates were 83.0%, 77.1%, and 70.0%, respectively. The induction chemoimmunotherapy of camrelizumab plus TPF showed a high ORR rate with an acceptable safety profile in LA HSCC.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Hypopharyngeal Neoplasms , Humans , Male , Female , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Aged , Hypopharyngeal Neoplasms/therapy , Hypopharyngeal Neoplasms/pathology , Hypopharyngeal Neoplasms/mortality , Hypopharyngeal Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Adult , Immunotherapy/methods , Neoplasm Staging , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Cisplatin/adverse effects , Progression-Free Survival , Induction Chemotherapy , Treatment OutcomeABSTRACT
Hungatella xylanolytica X5-1T is an anaerobic, xylan-fermenting bacterium first isolated from methane-producing cattle manure. Initially identified as Bacteroides xylanolyticus, this species was later reclassified as H. xylanolytica in 2019. Although this reclassification found support through Genome blast Distance Phylogeny analysis which placed H. xylanolytica X5-1T into the same clade as Hungatella effluvii DSM 24995T, it was contradicted by 16S rRNA gene phylogenetic analysis, which associated it with a set of misnamed Clostridium species later reassigned into the genus Lacrimispora. To ascertain its taxonomic position, comparative analyses were performed to re-examine the relationship between H. xylanolytica X5-1T and all species of the genera Hungatella and Lacrimispora. The ranges of 16S rRNA gene sequence similarity, average amino acid identity, and percentage of conserved protein prediction values were higher between H. xylanolytica X5-1T and species of the genus Lacrimispora than Hungatella. In addition, H. xylanolytica X5-1T was found to harbour genes and pathways conserved and exclusive to species within the genus Lacrimispora but not Hungatella. Essentially, in both the 16S rRNA gene phylogenetic tree and the core-genome phylogenomic tree, H. xylanolytica X5-1T clustered into the same clade as species of the genus Lacrimispora, distinct from species of the genus Hungatella. It is thus clear that H. xylanolytica X5-1T represents a species within the genus Lacrimispora, which we propose to reclassify as Lacrimispora xylanisolvens nom. nov. Finally, based on the results from the phylogenetic and comparative analyses, the genus Hungatella was transferred to the family Lachnospiraceae.
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Bacterial Typing Techniques , DNA, Bacterial , Phylogeny , RNA, Ribosomal, 16S , Sequence Analysis, DNA , RNA, Ribosomal, 16S/genetics , DNA, Bacterial/genetics , Clostridiales/classification , Clostridiales/genetics , Clostridiales/isolation & purification , Genome, Bacterial , Animals , CattleABSTRACT
[This corrects the article DOI: 10.3892/ol.2022.13554.].
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The preparation of atom-thick porous lattice hosting Å-scale pores is attractive to achieve a large ion-ion selectivity in combination with a large ion flux. Graphene film is an ideal selective layer for this if high-precision pores can be incorporated, however, it is challenging to avoid larger non-selective pores at the tail-end of the pore size distribution which reduces ion-ion selectivity. Herein, we develop a strategy to overcome this challenge using an electrochemical repair strategy that successfully masks larger pores in large-area graphene. 10-nm-thick electropolymerized conjugated microporous polymer (CMP) layer is successfully deposited on graphene, thanks to a strong π-π interaction in these two materials. While the CMP layer itself is not selective, it effectively masks graphene pores, leading to a large Li+/Mg2+ selectivity from zero-dimensional pores reaching 300 with a high Li+ ion permeation rate surpassing the performance of reported materials for ion-ion separation. Overall, this scalable repair strategy enables the fabrication of monolayer graphene membranes with customizable pore sizes, limiting the contribution of nonselective pores, and offering graphene membranes a versatile platform for a broad spectrum of challenging separations.
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Mammalian oocyte development depends on the temporally controlled translation of maternal transcripts, particularly in the coordination of meiotic and early embryonic development when transcription has ceased. The translation of mRNA is regulated by various RNA-binding proteins. We show that the absence of cytoplasmic polyadenylation element-binding protein 3 (CPEB3) negatively affects female reproductive fitness. CPEB3-depleted oocytes undergo meiosis normally but experience early embryonic arrest due to a disrupted transcriptome, leading to aberrant protein expression and the subsequent failure of embryonic transcription initiation. We found that CPEB3 stabilizes a subset of mRNAs with a significantly longer 3'UTR that is enriched in its distal region with cytoplasmic polyadenylation elements. Overall, our results suggest that CPEB3 is an important maternal factor that regulates the stability and translation of a subclass of mRNAs that are essential for the initiation of embryonic transcription and thus for embryonic development.
Subject(s)
Oocytes , RNA-Binding Proteins , Oocytes/metabolism , Animals , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Female , Mice , Meiosis/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Embryonic Development/genetics , Gene Expression Regulation, Developmental , 3' Untranslated Regions/genetics , Polyadenylation , RNA Stability/geneticsABSTRACT
OBJECTIVE: The characteristics of cervical lymph node involvement in papillary thyroid carcinoma (PTC) patients with different degree of capsular invasion remains unclear, especially for those with mono-focal lesion who have traditionally been considered as low neck metastasis risk subgroup. STUDY DESIGN: Retrospective cohort study. SETTING: Three academic teaching hospital. METHODS: A total of 1276 mono-focal PTC patients were retrospectively analyzed. RESULTS: Mono-focal PTC patients with extrathyroidal extension (ETE) showed significantly higher central lymph node metastasis (CLNM) rate than those without. For patients with no gross ETE (gETE), those with minimal ETE (mETE) also showed more commonly CLNM than those with encapsulated lesions. However, the lateral lymph node metastasis (LLNM) rates of patients with mETE and encapsulated tumors were comparable, both lower than that of patients with gETE. Age ≥40, male, and MTD ≥0.5 cm were identified as independent risk factors of CLNM for those with encapsulated tumors and were enrolled for creating a prediction model. In terms of LLNM, only MTD ≥1.0 cm was confirmed as independent risk factors of LLNM for patients with positive gETE. CONCLUSIONS: The presence and degree of ETE may have different effects on the risk of central and lateral lymph node metastasis. gETE demonstrates a strong correlation with both CLNM and LLNM while mETE is only associated with CLNM in mono-focal PTC patients. A comprehensive model is established in the aim of predicting neck involvement according to the capsular status and the corresponding stratified risk factors, which may aid clinical decision-making for the management of neck regions.
Subject(s)
Lymph Nodes , Lymphatic Metastasis , Neck , Thyroid Cancer, Papillary , Thyroid Neoplasms , Humans , Male , Female , Thyroid Neoplasms/pathology , Thyroid Cancer, Papillary/pathology , Thyroid Cancer, Papillary/secondary , Retrospective Studies , Middle Aged , Adult , Neck/pathology , Lymph Nodes/pathology , Risk Factors , Neoplasm Invasiveness , Aged , Age Factors , Cohort StudiesABSTRACT
Based on the background of urbanization in China, we used the dynamic spatial panel Durbin model to study the driving mechanism of ozone pollution empirically. We also analyzed the spatial distribution of ozone driving factors using the GTWR. The results show that: i) The average annual increase of ozone concentration in ambient air in China from 2015 to 2019 was 1.68µg/m3, and 8.39µg/m3 elevated the year 2019 compared with 2015. ii) The Moran's I value of ozone in ambient air was 0.027 in 2015 and 0.209 in 2019, showing the spatial distribution characteristics of "east heavy and west light" and "south low and north high". iii) Per capita GDP industrial structure, population density, land expansion, and urbanization rate have significant spillover effects on ozone concentration, and the regional spillover effect is greater than the local effect. R&D intensity and education level have a significant negative impact on ozone concentration. iv) There is a decreasing trend in the inhibitory effect of educational attainment and R&D intensity on ozone concentration, and an increasing trend in the promotional effect of population urbanization rate, land expansion, and economic development on ozone concentration. Empirical results suggest a twofold policy meaning: i) to explore the causes behind the distribution of ozone from the new perspective of urbanization, and to further the atmospheric environmental protection system and ii) to eliminate the adverse impacts of ozone pollution on nature and harmonious social development.
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Air Pollutants , Air Pollution , Ozone , Urbanization , Ozone/analysis , China , Air Pollutants/analysis , Air Pollution/analysis , Air Pollution/adverse effects , Humans , Spatio-Temporal Analysis , Environmental MonitoringABSTRACT
Large amount of polyethylene terephthalate (PET) plastics waster and emerging contaminants in water, including fluoroquinolone antibiotics, pose challenges to human survival. In this work, a green synthesis scheme is proposed in which the defective UiO-66 (d-UiO-66) is fabricated via a solvent-free routine by using PET plastics waster as raw materials for lomefloxacin (LOM) removal. In comparison with defect-free UiO-66, the created defect imparts d-UiO-66 with higher porosity and abundant defective Zr sites, which are beneficial to boost LOM adsorption. As expected, d-UiO-66 exhibited excellent LOM adsorption performances, showcasing a saturation adsorption capacity of 588 mg g-1 and a kinetic rate constant of 0.204 g mg-1 h-1, which are 3.5 and 2.0 times higher than those of the pristine UiO-66, respectively. Remarkably, the LOM saturation adsorption capacity of d-UiO-66 surpasses that of all reported adsorbents. Mechanism study reveals that this outstanding adsorption performance of d-UiO-66 is mainly ascribed to the abundant defective sites, high porosity, together with the strong hydrogen bonding interaction and π-π stacking interaction between d-UiO-66 and LOM. Therefore, the d-UiO-66 obtained by the solvent-free method can not only effectively upcycle PET plastic waster, but also efficiently remove LOM, demonstrating a potential routine to simultaneous address the solid PET waster and wastewater.
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The DNA methylation is gradually acquired during oogenesis, a process sustained by successful follicle development. However, the functional roles of methyl-CpG-binding protein 2 (MeCP2), an epigenetic regulator displaying specifical binding with methylated DNA, remains unknown in oogenesis. In this study, we found MeCP2 protein was highly expressed in primordial and primary follicle, but was almost undetectable in secondary follicles. However, in aged ovary, MeCP2 protein is significantly increased in both oocyte and granulosa cells. Overexpression of MeCP2 in growing oocyte caused transcription dysregulation, DNA hypermethylation, and genome instability, ultimately leading to follicle growth arrest and apoptosis. MeCP2 is targeted by DCAF13, a substrate recognition adaptor of the Cullin 4-RING (CRL4) E3 ligase, and polyubiquitinated for degradation in both cells and oocytes. Dcaf13-null oocyte exhibited an accumulation of MeCP2 protein, and the partial rescue of follicle growth arrest induced by Dcaf13 deletion was observed following MeCP2 knockdown. The RNA-seq results revealed that large amounts of genes were regulated by the DCAF13-MeCP2 axis in growing oocytes. Our study demonstrated that CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to ensure normal DNA methylome and transcription in growing oocytes. Moreover, in aged ovarian follicles, deceased DCAF13 and DDB1 protein were observed, indicating a potential novel mechanism that regulates ovary aging.
Subject(s)
Methyl-CpG-Binding Protein 2 , Ubiquitin-Protein Ligases , Female , Humans , Cullin Proteins/genetics , Cullin Proteins/metabolism , DNA/metabolism , DNA Methylation , Methyl-CpG-Binding Protein 2/genetics , Methyl-CpG-Binding Protein 2/metabolism , Oocytes/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Background: The aim of this study was to investigate the effect of DNA methylation of Fork Head Box O3 (FOXO3a) on the process of epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Methods: The expressions of FOXO3a, DNA methyltransferase 1 (DNMT1), METTL3, and EMT-related proteins (E-cadherin and N-cadherin) were measured. The influence of 5-Aza-dC and DNMT1 on the methylation level in the promoter region of FOXO3a was examined through the application of methylation-specific PCR (MSP). Chromatin immunoprecipitation (ChIP) was employed to detect binding between DNMT1 and the FOXO3a promoter. Methylated RNA immunoprecipitation (MeRIP) was utilized to evaluate the level of DNMT1 N6-methyladenosine (m6A) methylation. The assessment of cell viability and invasion abilities of A549 cells was performed using Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. NSCLC xenograft mouse models were established by subcutaneously injected treated A549 cells into nude mice. Results: The expression levels of DNMT1 and DNA methylation level FOXO3a were found to be significantly increased, whereas FOXO3a expression was considerably decreased in NSCLC cell lines and NSCLC tumor tissues. Both 5-Aza-dC treatment and DNMT1 knockdown resulted in the down-regulation of DNA methylation levels of FOXO3a while simultaneously up-regulating the expression of FOXO3a. A ChIP assay demonstrated that DNMT1 has the ability to bind to the promoter region of FOXO3a. Furthermore, the knockdown of DNMT1 promoted E-cadherin expression, but inhibited expression of N-cadherin, cell viability, and invasion ability. However, the knockdown of FOXO3a hindered the effect of DNMT1 knockdown on EMT, cell viability, and invasion ability of A549 cells. This was evidenced by decreased E-cadherin expression and increased N-cadherin expression, as well as increased cell viability and invasion ability. Increased expression of DNMT1 resulted from m6A methylation of DNMT1, which was mediated by METTL3. Overexpression of DNMT1 decreased of E-cadherin expression while increased N-cadherin expression, cell viability, and invasion ability in METTL3-shRNA treated A549 cells. In xenograft mouse models, DNMT1 knockdown significantly reduced tumor volumes and tumor weight. DNMT1 knockdown upregulated the expression of FOXO3a and E-cadherin, while downregulated N-cadherin expression in vivo. Conclusion: METTL3-mediated m6A methylation of DNMT1 up-regulates FOXO3a promoter methylation, thereby promoting the progression of NSCLC.
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OBJECTIVES: To explore the predictive significance of baseline absolute peripheral lymphocyte counts (ALC) in the effectiveness of radiation in hypopharyngeal squamous cell carcinoma (HPSCC) patients. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study of pathologically confirmed HPSCC patients who had definitive radiation between January 2020 and January 2022 at Fudan University Eye and ENT Hospital. The routine blood results of patients were obtained to determine if the baseline ALC was connected with the response to radiation. The receiver operator characteristic (ROC) curve and LASSO-based Cox regression were employed to assess the predictive value of ALC for the efficacy of radiotherapy (RT). MAIN OUTCOME MEASURES AND RESULTS: RT induced a considerable drop in ALC and the level of ALC did not revert to the baseline values 1 year after radiation. The baseline level of ALC was higher in patients who met complete response after RT. The baseline ALC and monocyte counts demonstrated the predictive value of radiation effectiveness and ALC was an independent predictor. CONCLUSION: In HPSCC, lymphocytes were sensitive to radiation and reduced significantly during RT. The baseline ALC might be regarded as a predictive indicator of the effectiveness of RT.
Subject(s)
Hypopharyngeal Neoplasms , Humans , Male , Lymphocyte Count , Retrospective Studies , Female , Hypopharyngeal Neoplasms/radiotherapy , Hypopharyngeal Neoplasms/blood , Hypopharyngeal Neoplasms/pathology , Middle Aged , Aged , Squamous Cell Carcinoma of Head and Neck/radiotherapy , Squamous Cell Carcinoma of Head and Neck/blood , Squamous Cell Carcinoma of Head and Neck/pathology , Treatment Outcome , Predictive Value of Tests , Adult , Carcinoma, Squamous Cell/radiotherapy , Carcinoma, Squamous Cell/blood , Carcinoma, Squamous Cell/pathology , ROC CurveABSTRACT
The infiltration and prognostic significance of tumor-infiltrating plasmacytoid dendritic cells (TI-pDC) have been elucidated in various human solid cancers. However, the infiltrating patterns and functional importance of TI-pDC in laryngeal squamous cell carcinoma (LSCC) remain unknown. In this study, flow cytometric analyses were conducted to characterize the infiltration of dendritic cells and T lymphocytes, along with their respective subgroups in tumor tissues (TT), para-carcinoma tissues (PT), and peripheral blood (PB) from LSCC patients. Immunohistochemical staining for CD4 and CD8, as well as immunofluorescence staining for CD123, were performed on serial tissue sections to investigate the co-localization of TI-pDC and tumor-infiltrating T lymphocytes (TIL) within the tumor microenvironment (TME). Our results demonstrated significantly lower percentages of all three DC subsets in PB compared to TT and PT. Notably, the pDC percentage was markedly higher in TT than in PT. Moreover, TI-pDC percentage was significantly elevated in N+ stage patients compared to those with N0 stage. The results of survival analysis consistently demonstrated that high levels of TI-pDC infiltration were indicative of a poor prognosis. Further investigation revealed a significant negative correlation between TI-pDC and CD8+ TILs; notably, pDCs expressed an inhibitory surface molecule PD-L2 rather than PD-L1 within PT. Collectively, our findings suggest that increased TI-pDC is associated with adverse outcomes in LSCC patients while exhibiting an inhibitory phenotype that may play a crucial role in suppressing CD8+ TILs within LSCC tumors. These results highlight the potential therapeutic strategy targeting PD-L2+ pDCs for immunotherapies against LSCC.