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1.
Cell Mol Life Sci ; 81(1): 179, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38602536

RESUMO

Extracellular vesicles (EVs) have recently received increasing attention as essential mediators of communication between tumor cells and their microenvironments. Tumor-associated macrophages (TAMs) play a proangiogenic role in various tumors, especially head and neck squamous cell carcinoma (HNSCC), and angiogenesis is closely related to tumor growth and metastasis. This research focused on exploring the mechanisms by which EVs derived from TAMs modulate tumor angiogenesis in HNSCC. Our results indicated that TAMs infiltration correlated positively with microvascular density in HNSCC. Then we collected and identified EVs from TAMs. In the microfluidic chip, TAMs derived EVs significantly enhanced the angiogenic potential of pHUVECs and successfully induced the formation of perfusable blood vessels. qPCR and immunofluorescence analyses revealed that EVs from TAMs transferred miR-21-5p to endothelial cells (ECs). And targeting miR-21-5p of TAMs could effectively inhibit TAM-EVs induced angiogenesis. Western blot and tube formation assays showed that miR-21-5p from TAM-EVs downregulated LATS1 and VHL levels but upregulated YAP1 and HIF-1α levels, and the inhibitors of YAP1 and HIF-1α could both reduce the miR-21-5p enhanced angiogenesis in HUVECs. The in vivo experiments further proved that miR-21-5p carried by TAM-EVs promoted the process of tumor angiogenesis via YAP1/HIF-1α axis in HNSCC. Conclusively, TAM-derived EVs transferred miR-21-5p to ECs to target the mRNA of LATS1 and VHL, which inhibited YAP1 phosphorylation and subsequently enhanced YAP1-mediated HIF-1α transcription and reduced VHL-mediated HIF-1α ubiquitination, contributing to angiogenesis in HNSCC. These findings present a novel regulatory mechanism of tumor angiogenesis, and miR-21-5p/YAP1/HIF-1α might be a potential therapeutic target for HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , MicroRNAs , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , 60489 , Células Endoteliais , Macrófagos Associados a Tumor , Neoplasias de Cabeça e Pescoço/genética , Proteínas Serina-Treonina Quinases , MicroRNAs/genética , Microambiente Tumoral
2.
Nat Commun ; 15(1): 3163, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605025

RESUMO

The transcription and replication processes of non-segmented, negative-strand RNA viruses (nsNSVs) are catalyzed by a multi-functional polymerase complex composed of the large protein (L) and a cofactor protein, such as phosphoprotein (P). Previous studies have shown that the nsNSV polymerase can adopt a dimeric form, however, the structure of the dimer and its function are poorly understood. Here we determine a 2.7 Å cryo-EM structure of human parainfluenza virus type 3 (hPIV3) L-P complex with the connector domain (CD') of a second L built, while reconstruction of the rest of the second L-P obtains a low-resolution map of the ring-like L core region. This study reveals detailed atomic features of nsNSV polymerase active site and distinct conformation of hPIV3 L with a unique ß-strand latch. Furthermore, we report the structural basis of L-L dimerization, with CD' located at the putative template entry of the adjoining L. Disruption of the L-L interface causes a defect in RNA replication that can be overcome by complementation, demonstrating that L dimerization is necessary for hPIV3 genome replication. These findings provide further insight into how nsNSV polymerases perform their functions, and suggest a new avenue for rational drug design.


Assuntos
Nucleotidiltransferases , Vírus de RNA , Humanos , Dimerização , Domínio Catalítico , Replicação Viral
3.
BMC Pediatr ; 24(1): 232, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566089

RESUMO

BACKGROUND: Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome) is a severe multi-systemic developmental disorder, caused by variants in the SON gene. A patient diagnosed with ZTTK syndrome who carried a de novo SON mutation and exhibited recurrent myocardial injury was described in this case. CASE PRESENTATION: A 7-year-old girl was admitted to the Cardiology Department of Beijing Children's Hospital in November 2019 due to myocardial injury following respiratory infection. She displayed elevated myocardial enzymes and severe T-wave changes on electrocardiogram. Over the past three years, she had experienced myocardial injury on three occasions. Additionally, she exhibited intellectual disability, congenital amblyopia, and dysmorphic facial features. Genetic analysis revealed a de novo heterozygous mutation c.3852_3856delGGTAT in the SON gene, which was confirmed by Sanger sequencing of her parents. She received anti-infection treatment and was administered metoprolol orally. Her condition was stable at the time of discharge. Over a 42-month follow-up period at the outpatient clinic, she complained intermittent fatigue and palpitation. CONCLUSIONS: The identified SON mutation, which plays a crucial role in heart development and mitochondrial function, may be associated with an increased susceptibility to myocardial injury or cardiomyopathy. This case report contributes novel insights into this rare condition and suggests the expansion of the ZTTK syndrome phenotype.


Assuntos
Anormalidades do Olho , Deficiência Intelectual , Criança , Feminino , Humanos , Deficiência Intelectual/genética , Mutação , Heterozigoto , Fenótipo , Arritmias Cardíacas
4.
Cardiol Young ; : 1-6, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38572563

RESUMO

AIM: Malignant vasovagal syncope in children seriously affects their physical and mental health. Our study aimed to explore the efficacy of catheter ablation in ganglionated plexus with malignant vasovagal syncope children. CONCLUSION: Catheter ablation of ganglionated plexus was safe and effective in children with malignant vasovagal syncope and can be used as a treatment option for these children. METHODS: A total of 20 children diagnosed with malignant vasovagal syncope were enrolled in Beijing Children's Hospital, affiliated with Capital Medical University. All underwent catheter ablation treatment of ganglionated plexus. Ganglionated plexuses of the left atrium were identified by high-frequency stimulation and/or anatomic landmarks being targeted by radiofrequency catheter ablation. The efficacy of the treatment was evaluated by comparing the remission rate of post-operative syncopal symptoms and the rate of negative head-up tilt results. Safety and adverse events were evaluated. RESULTS: After follow-up for 2.5 (0.6-5) years, the syncope symptom scores were decreased significantly compared with before treatment [3 (2-4) versus 5 (3-8) scores, P < 0.01]. Eighty-five per cent (17/20) children no longer experienced syncope, whilst 80% (16/20) children showed negative head-up tilt test after treatment. No adverse effects such as cardiac arrhythmia occurred in the children.

5.
medRxiv ; 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38585975

RESUMO

Introduction: Lung cancer leads in cancer-related deaths. Disparities are observed in lung cancer rates, with African Americans (AAs) experiencing disproportionately higher incidence and mortality compared to other ethnic groups. Non-coding RNAs (ncRNAs) play crucial roles in lung tumorigenesis. Our objective was to identify ncRNA biomarkers associated with the racial disparity in lung cancer. Methods: Using droplet digital PCR, we examined 93 lung-cancer-associated ncRNAs in the plasma and sputum samples from AA and White American (WA) participants, which included 118 patients and 92 cancer-free smokers. Subsequently, we validated our results with a separate cohort comprising 56 cases and 72 controls. Results: In the AA population, plasma showed differential expression of ten ncRNAs, while sputum revealed four ncRNAs when comparing lung cancer patients to the control group. In the WA population, the plasma displayed eleven ncRNAs, and the sputum had five ncRNAs showing differential expression between the lung cancer patients and the control group. For AAs, we identified a three-ncRNA panel (plasma miRs-147b, 324-3p, 422a) diagnosing lung cancer in AAs with 86% sensitivity and 89% specificity. For WAs, a four-ncRNA panel was developed, comprising sputum miR-34a-5p and plasma miRs-103-3p, 126-3p, 205-5p, achieving 88% sensitivity and 87% specificity. These panels remained effective across different stages and histological types of lung tumors and were validated in the independent cohort. Conclusions: The ethnicity-related ncRNA signatures have promise as biomarkers to address the racial disparity in lung cancer.

6.
Bioorg Chem ; 147: 107315, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38604017

RESUMO

Seven new meroterpenoids, paraphaeones A-G (1-7), and two new polyketides, paraphaeones H-I (8-9), along with eight known compounds (10-17), were isolated from the endophytic fungus Paraphaeosphaeria sp. C-XB-J-1. The structures of 1-9 were identified through the analysis of 1H, 13C, and 2D NMR spectra, assisted by HR-ESI-MS data. Compounds 1 and 7 exhibited a dose-dependent decrease in lactate dehydrogenase levels, with IC50 values of 1.78 µM and 1.54 µM, respectively. Moreover, they inhibited the secretion of IL-1ß and CASP-1, resulting in a reduction in the activity levels of NLRP3 inflammasomes. Fluorescence microscopy results indicated that compound 7 concentration-dependently attenuated cell pyroptosis. Additionally, compounds 4 and 7 showed potential inhibitory effects on the severe acute respiratory syndrome coronavirus-2 main protease (SARS-CoV-2 Mpro), with IC50 values of 10.8 ± 0.9 µM and 12.9 ± 0.7 µM, respectively.

7.
Foods ; 13(6)2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38540826

RESUMO

Green huajiao has a unique flavor and is widely used in cooking as an edible spice. In this study, the intensity of overall aroma and aroma attributes of seven green huajiao samples from the Sichuan and Chongqing regions were evaluated using a dynamic dilution olfactometer and ranking descriptive analysis (RDA) technology. The volatile compounds and major aroma components were determined by GC-MS in combination with odor activity value (OAV) analysis. The partial least squares regression (PLSR) model was further used to identify the key aromas contributing to the aroma sensory attributes. Seven green huajiao samples were categorized into three groups: (1) huajiao samples from Liangshan have a strong intensity of pungent, floral and herbal aromas and a medium-high intensity of sweet aroma, and the key contributing aroma compounds were α-pinene, sabinene, ß-pinene, myrcene, ocimene and linalool; (2) huajiao samples from Panzhihua and Hongya have a strong intensity of citrusy, lemony and minty aromas, and the key contributing aroma compound was linalool; and (3) the huajiao sample from the Chongqing region was categorized into a separate group and was characterized by a medium-high intensity of green, minty and sweet aromas, and the main aroma compounds are ocimene, citronellal and α-terpineol. These results provide useful basic data for evaluating the aroma quality and analyzing the key aroma characteristics of green huajiao in the Sichuan and Chongqing regions.

8.
Heliyon ; 10(5): e25982, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38434381

RESUMO

Fermented rose petals are a traditional delicacy of the Dali Bai community in Yunnan, China. Fermentation enhances the quality and nutritional value of roses, as well as their efficacy, by increasing the levels of phenolic compounds. This study aimed to investigate the significant variations in four active compounds throughout the traditional fermentation process. Four compounds in Rosa rugosa 'Mohong' were examined, and significant variations among polyphenols and antioxidant and anti-inflammatory activities were observed. These variations were studied during fermentation by Saccharomyces rouxii at varying temperatures and durations. Moreover, the results showed that gallic acid and syringic acid content significantly increased (P < 0.05) with a rise in temperature from 20°C-35 °C during fermentation. Simultaneously, rutin and quercetin levels significantly decreased (P < 0.05) at all four temperatures throughout the five periods. The antioxidant and anti-inflammatory activities of fermented R. rugosa 'Mohong' methanol extracts were dose-dependent. Our results provide valuable insights into optimizing the processing scale and quality control of fermented rose products.

9.
Mol Plant Pathol ; 25(3): e13442, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38476100

RESUMO

The type VI secretion system (T6SS) of many gram-negative bacteria injects toxic effectors into adjacent cells to manipulate host cells during pathogenesis or to kill competing bacteria. However, the identification and function of the T6SS effectors remains only partly known. Pantoea ananatis, a gram-negative bacterium, is commonly found in various plants and natural environments, including water and soil. In the current study, genomic analysis of P. ananatis DZ-12 causing brown stalk rot on maize demonstrated that it carries three T6SS gene clusters, namely, T6SS-1, T6SS-2, and T6SS-3. Interestingly, only T6SS-1 secretion systems are involved in pathogenicity and bacterial competition. The study also investigated the T6SS-1 system in detail and identified an unknown T6SS-1-secreted effector TseG by using the upstream T6SS effector chaperone TecG containing a conserved domain of DUF2169. TseG can directly interact with the chaperone TecG for delivery and with a downstream immunity protein TsiG for protection from its toxicity. TseG, highly conserved in the Pantoea genus, is involved in virulence in maize, potato, and onion. Additionally, P. ananatis uses TseG to target Escherichia coli, gaining a competitive advantage. This study provides the first report on the T6SS-1-secreted effector from P. ananatis, thereby enriching our understanding of the various types and functions of type VI effector proteins.


Assuntos
Pantoea , Sistemas de Secreção Tipo VI , Sistemas de Secreção Tipo VI/metabolismo , Pantoea/genética , Sistemas de Secreção Bacterianos/genética , Virulência/genética , Antibacterianos , Chaperonas Moleculares , Proteínas de Bactérias/metabolismo
10.
Heliyon ; 10(6): e27562, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38515728

RESUMO

Purpose: To determine the differences in myopia control efficiency and corneal reshaping between three different brands of orthokeratology (OK) lenses (Lucid, Euclid, and Alpha). Method: We retrospectively reviewed subjects who started simultaneously using different brands of OK lenses. For each participant, every 6 months in the 19 months of following, the changes in axial length (AL), horizontal and vertical maximum distances of the treatment zone (HMDTZ and VMDTZ), width of the high convex zone (WHCZ), distance of decentration, and horizontal and vertical components of the decentration vector were measured. The average values of the above data, the average value of the decentration vector (ADV), and the average value of decentration calculated algebraically (ADA) were calculated. Results: All the three pairs (Lucid (n = 46) vs. Euclid (n = 46): groups Lucid-versus-Euclid-Lucid (LE-L) and LE-E), Lucid (n = 50) vs. Alpha (n = 50): groups LA-L and LA-A), and Euclid (n = 17) vs. Alpha (n = 17): groups EA-E and EA-A) showed good comparability. Regarding the change in AL during 19 months, none of the pairs showed significant differences (LE-L:0.27 ± 0.24 mm, LE-E:0.31 ± 0.24 mm (p = 0.68); LA-L:0.36 ± 0.26 mm, LA-A:0.36 ± 0.27 mm (p = 0.85); EA-E:0.34 ± 0.27 mm, EA-A:0.41 ± 0.28 mm (p = 0.63)). Regarding treatment zone, Lucid showed the largest HMDTZ and VMDTZ (both p < 0.05). Regarding the WHCZ, none of the pairs showed significant differences. For the ADV and ADA, Lucid had more ADV and ADA than Euclid (ADV: LE-L:0.73 ± 0.44 mm, LE-E:0.55 ± 0.45 mm, p < 0.05; ADA: LE-L:0.80 ± 0.41 mm, LE-E:0.63 ± 0.44 mm, p < 0.05), and the remaining pairs showed no significant difference. For the overall cohort with 113 eyes, the change in AL was weakly correlated with both ADV and ADA (both p < 0.05). Regarding the ADV/ADA, all pairs showed no significant differences, indicating equal lens position stability. Conclusion: After OK, there were no significant differences between the different pairs of the three brands in AL growth, WHCZ, or lens position stability, although Lucid had a larger treatment zone than Euclid and Alpha, and Lucid had more decentration than Euclid. A larger lens decentration were weakly related to less AL growth.

11.
Artigo em Inglês | MEDLINE | ID: mdl-38547512

RESUMO

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. CVD and kidney disease are closely related, with kidney injury increasing CVD mortality. The pathogenesis of cardiovascular and renal diseases involves complex and diverse interactions between multiple extracellular and intracellular signaling molecules, among which transient receptor potential vanilloid 1 (TRPV1)/ transient receptor potential ankyrin 1(TRPA1) channels have received increasing attention. TRPV1 belongs to the vanilloid receptor subtype family of transient receptor potential (TRP) ion channels, and TRPA1 belongs to the TRP channel superfamily. TRPV1/TRPA1 are jointly involved in the management of cardiovascular and renal diseases, and play important roles in regulating vascular tension, promoting angiogenesis, anti-fibrosis, anti-inflammation, and anti-oxidation. The mechanism of TRPV1 / TRPA1 is mainly related to regulation of intracellular calcium influx and release of nitric oxide (NO) and calcitonin gene-related peptide (CGRP). Therefore, this study takes TRPV1 / TRPA1 channel as the research object, analyzes and summarizes the process and mechanism of TRPV1 / TRPA1 affecting cardiovascular and renal diseases, and lays a foundation for the treatment of cardio-renal diseases.

12.
Oral Oncol ; 152: 106755, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38547780

RESUMO

OBJECT: Previous studies suggest BRAFV600E mutation is a marker for poor prognosis in papillary thyroid cancer, however, its ability to further risk stratify papillary thyroid microcarcinoma (PTMC) remains controversial. We aimed to explore the association between BRAFV600E mutation and the clinicopathological features and recurrence in Chinese PTMC patients. METHODS: We retrospectively reviewed 2094 PTMC patients who underwent surgery and had a valid BRAFV600E mutation test result. Among them, 1292 patients had complete follow-up data. The mutation incidence was determined. Moreover, the clinicopathological characteristics, disease-free survival (DFS), and response to therapy distribution were compared between the mutation and non-mutation groups. RESULTS: BRAFV600E mutation was observed in 90.6 % of all patients and 89.2 % of patients with complete follow-up data. No significant difference was observed in lymph node metastases (LNM) number categories between the mutation and non-mutation groups among all patients (P = 0.329) and 1292 patients (P = 0.408). Neither the 3-year DFS (97.9 % vs. 98.0 %, P = 0.832) nor the response to therapy distribution (P > 0.05) indicated a significant difference between the mutation and non-mutation groups. The 3-year DFS differs among patients having different LNM number categories (99.8 % vs. 98.5 % vs. 77.3 %, P < 0.001). Multivariate analysis revealed that high-volume (over 5) LNM (Total thyroidectomy (TT): OR = 4.000, 95 % CI 2.390-6.694, P < 0.001; Unilateral thyroidectomy (UT): OR = 4.183, 95 % CI 1.565-11.190, P = 0.004), rather than BRAFV600E mutation (P > 0.05), was an independent risk factor of response to therapy. CONCLUSIONS: Our results suggested that BRAFV600E mutation could not accurately predict LNM or the recurrence of Chinese PTMC patients. Moreover, high-volume LNM is significantly associated with PTMC prognosis.

13.
BMC Med Genomics ; 17(1): 77, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515109

RESUMO

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment of lung adenocarcinoma (LUAD) and are often associated with poorer clinical outcomes. This study aimed to screen for CAF-specific genes that could serve as promising therapeutic targets for LUAD. METHODS: We established a single-cell transcriptional profile of LUAD, focusing on genetic changes in fibroblasts. Next, we identified key genes associated with fibroblasts through weighted gene co-expression network analysis (WGCNA) and univariate Cox analysis. Then, we evaluated the relationship between glutathione peroxidase 8 (GPX8) and clinical features in multiple independent LUAD cohorts. Furthermore, we analyzed immune infiltration to shed light on the relationship between GPX8 immune microenvironment remodeling. For clinical treatment, we used the tumor immune dysfunction and exclusion (TIDE) algorithm to assess the immunotherapy prediction efficiency of GPX8. After that, we screened potential therapeutic drugs for LUAD by the connectivity map (cMAP). Finally, we conducted a cell trajectory analysis of GPX8+ CAFs to show their unique function. RESULTS: Fibroblasts were found to be enriched in tumor tissues. Then we identified GPX8 as a key gene associated with CAFs through comprehensive bioinformatics analysis. Further analysis across multiple LUAD cohorts demonstrated the relationship between GPX8 and poor prognosis. Additionally, we found that GPX8 played a role in inducing the formation of an immunosuppressive microenvironment. The TIDE method indicated that patients with low GPX8 expression were more likely to be responsive to immunotherapy. Using the cMAP, we identified beta-CCP as a potential drug-related to GPX8. Finally, cell trajectory analysis provided insights into the dynamic process of GPX8+ CAFs formation. CONCLUSIONS: This study elucidates the association between GPX8+ CAFs and poor prognosis, as well as the induction of immunosuppressive formation in LUAD. These findings suggest that targeting GPX8+ CAFs could potentially serve as a therapeutic strategy for the treatment of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Fibroblastos Associados a Câncer , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Fibroblastos , Imunoterapia , Neoplasias Pulmonares/genética , Microambiente Tumoral , Prognóstico , Peroxidases
14.
Nanoscale ; 16(13): 6748-6760, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38497195

RESUMO

Compounding of suitable fillers with PEO-based polymers is the key to forming high-performance electrolytes with robust network structures and homogeneous Li+-transport channels. In this work, we innovatively and efficiently prepared Al2O3 nanofibers and deposited an aqueous dispersion of Al2O3 into a membrane via vacuum filtration to construct a nanofiber membrane with a three-dimensional (3D) network structure as the backbone of a PEO-based solid-state electrolyte. The supporting effect of the nanofiber network structure improved the mechanical properties of the reinforced composite solid-state electrolyte and its ability to inhibit the growth of Li dendrites. Meanwhile, interconnected nanofibers in the PEO-based electrolyte and the strong Lewis acid-base interactions between the chemical groups on the surface of the inorganic filler and the ionic species in the PEO matrix provided facilitated pathways for Li+ transport and regulated the uniform deposition of Li+. Moreover, the interaction between Al2O3 and lithium salts as well as the PEO polymer increased free Li+ concentration and maintained its stable electrochemical properties. Hence, assembled Li/Li symmetric cells achieved a cycle life of more than 2000 h. LFP/Li and NMC811/Li cells provided high discharge specific capacities of up to 146.9 mA h g-1 (0.5C and 50 °C) and 166.9 mA h g-1 (0.25C and 50 °C), respectively. The prepared flexible self-supporting 3D nanofiber network structure construction can provide a simple and efficient new strategy for the exploitation of high-performance solid-state electrolytes.

15.
bioRxiv ; 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38464122

RESUMO

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, and CRC detection through screening improves survival rates. A promising avenue to improve patient screening compliance is the development of minimally-invasive liquid biopsy assays that target CRC biomarkers on circulating cell-free DNA (cfDNA) in peripheral plasma. In this report, we identify cfDNA biomarker candidate genes bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that diagnose occult CRC up to 36 months prior to clinical diagnosis using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial samples. Methods: Archived PLCO Trial plasma samples containing cfDNA were obtained from the National Cancer Institute (NCI) biorepositories. Study subjects included those who were diagnosed with CRC within 36 months of blood collection (i.e., case, n = 201) and those who were not diagnosed with any cancer during an average of 16.3 years of follow-up (i.e., controls, n = 402). Following the extraction of 3 - 8 ng cfDNA from less than 300 microliters plasma, we employed the sensitive 5hmC-Seal chemical labeling approach, followed by next-generation sequencing (NGS). We then conducted association studies and machine-learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio. Results: Despite the technical challenges associated with the PLCO samples (e.g., limited plasma volumes, low cfDNA amounts, and long archival times), robust genome-wide 5hmC profiles were successfully obtained from these samples. Association analyses using the Cox proportional hazards models suggested several epigenetic pathways relevant to CRC development distinguishing cases from controls. A weighted Cox model, comprised of 32-associated gene bodies, showed predictive detection value for CRC as early as 24-36 months prior to overt tumor presentation, and a trend for increased predictive power was observed for blood samples collected closer to CRC diagnosis. Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and self-reported race/ethnicity, and significantly outperformed risk factors such as age and obesity according to BMI (body mass index). Additionally, further improvement of predictive performance was achieved by combining the 5hmC-based model and risk factors for CRC. Conclusions: An assay of 5hmC epigenetic signals on cfDNA revealed candidate biomarkers with the potential to predict CRC occurrence despite the absence of clinical symptoms or the availability of effective predictors. Developing a minimally-invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient survival through higher compliance screening and earlier intervention. Future investigation to expand this strategy to prospectively collected samples is warranted.

16.
Cancer ; 130(S8): 1449-1463, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38482921

RESUMO

BACKGROUND: Clinical studies on programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors for treating triple-negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor-infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin-dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies. METHODS: The authors tested three CDK inhibitors on the TNBC cell lines MDA-MB-231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune-related mechanisms of different combination therapy experiments in a 4T1 cell-transplanted BALB/c mouse model. RESULTS: Treatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell-cycle arrest and induced apoptosis in human breast cancer MDA-MB-231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD-L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels. CONCLUSIONS: Combination therapy with CDK and PD-L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Antígeno B7-H1 , Quinases Ciclina-Dependentes , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos
17.
Expert Rev Clin Immunol ; : 1-6, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38315096

RESUMO

OBJECTIVE: Coronary artery lesions (CALs) are a major complication of Kawasaki disease (KD); however, data on CAL incidence and risk factors in recurrent KD are limited. METHODS: Ninety-seven children with recurrent KD were retrospectively enrolled from 2013 to 2022, and CAL incidence was tracked during admission, discharge, and during follow-up. RESULTS: Initially, 27.8% had CAL at admission and discharge, declining to 7.2% at 12 months post-discharge. Most patients (66 of 97, 68.0%) did not exhibit CAL at any of the time points, 7 cases presented CAL at all time points, indicating a persistent CAL. The remaining 20 cases presented CAL at admission but recovered at discharge or during follow-up. Notably, transient CALs had presented at discharge, or during the follow-up, but finally resolved at 12 months after discharge. Notably, prior IVIG resistance and increased prothrombin time seemed associated with CAL in recurrent KD, suggesting they could help identify patients needing close monitoring. CONCLUSION: The study highlights decreasing CAL incidence over time in recurrent KD but with diverse patterns, emphasizing the importance of monitoring and further investigations to confirm these findings.

18.
Aging (Albany NY) ; 16(3): 2273-2298, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38319706

RESUMO

BACKGROUND: Methods for predicting the outcome of lung adenocarcinoma (LUAD) in the clinic are limited. Anoikis is an important route to programmed cell death in LUAD, and the prognostic value of a model constructed with anoikis-related lncRNAs (ARlncRNAs) in LUAD is unclear. METHODS: Transcriptome and basic information for LUAD patients was obtained from the Cancer Genome Atlas. Coexpression and Cox regression analyses were utilized to identify prognostically significant ARlncRNAs and construct a prognostic signature. Furthermore, the signature was combined with clinical characteristics to create a nomogram. Finally, we performed principal component, enrichment, tumor mutation burden (TMB), tumor microenvironment (TME) and drug sensitivity analyses to evaluate the basic research and clinical merit of the signature. RESULTS: The prognostic signature developed with eleven ARlncRNAs can accurately predict that high-risk group patients have a worse prognosis, as proven by the receiver operating characteristic (ROC) curve (AUC: 0.718). Independent prognostic analyses indicated that the risk score is a significant independent prognostic element for LUAD (P<0.001). In the high-risk group, enrichment analysis demonstrated that glucose metabolism and DNA replication were the main enrichment pathways. TMB analysis indicated that the high-risk group had a high TMB (P<0.05). Drug sensitivity analyses can recognize drugs that are sensitive to different risk groups. Finally, 11 ARlncRNAs of this signature were verified by RT-qPCR analysis. CONCLUSIONS: A novel prognostic signature developed with 11 ARlncRNAs can accurately predict the OS of LUAD patients and offer clinical guidance value for immunotherapy and chemotherapy treatment.


Assuntos
Adenocarcinoma , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Anoikis/genética , Prognóstico , RNA Longo não Codificante/genética , Pulmão , Neoplasias Pulmonares/genética , Microambiente Tumoral/genética
19.
ACS Nano ; 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38343106

RESUMO

Lithium metal batteries (LMBs) employing high-voltage nickel-rich cathodes represent a promising strategy to enable higher energy density storage systems. However, instability at the electrolyte-electrode interfaces (EEIs) currently impedes the translation of these advanced systems into practical applications. Herein, 1,3-dimethyl-1H-imidazol-2(3H)-one (DMIO), integrating structural features of vinylene carbonate (VC) while substituting oxygen with electron-donating nitrogen, has been synthesized and validated as a multifunctional electrolyte additive for high-voltage LMBs. Theoretical calculations and experimental results demonstrate that the potent electron-donating nitrogen in DMIO enables preferential DMIO oxidation at the cathode while preserving its carbon-carbon double bond for a concomitant reduction on the anode. Thereby, robust DMIO-derived EEIs are generated, reinforcing cycling in the full cells. Additionally, DMIO leverages Lewis acid-based interactions to coordinate and sequester protons from acidic LiPF6 decomposition byproducts, concurrently retarding LiPF6 hydrolysis while attenuating parasitic consumption of EEIs by acidic species. Consequently, incorporating DMIO into conventional carbonate electrolytes enables an improved capacity retention of Li||NCM622 cells to 81% versus 26% in the baseline electrolyte after 600 cycles. Similarly, DMIO improves Li anode cycling performance, displaying extended life spans over 200 h in Li||Li symmetric cells and enhancing Coulombic efficiency from 76% to 88% in Li||Cu cells. The synergistic effects of DMIO on both the cathode and anode lead to substantially improved cell lifetime. This rationally designed, multifunctional electrolyte additive paradigm provides vital insights that can be translatable to further electrolyte molecular engineering strategies.

20.
Food Funct ; 15(4): 2115-2130, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38305469

RESUMO

Akt acts as a central protein influencing multiple pathologies in neurodegenerative diseases including AD and PD, and using Akt activators is a promising management strategy. The current study characterized the effects of an Akt-activating peptide (Glu-Pro-Glu-Val-Leu-Pro, EPEVLR) obtained from walnut protein degradation on D-gal-induced memory impairment in mice. EPEVLR was obtained by hydrolysis of walnut proteins, identification of peptide sequences, and screening for molecular docking sequentially. The MWM test in mice indicated that the oral administration of EPEVLR (80, 200 and 400 mg per kg per day) significantly (p < 0.05) reversed D-gal-induced memory impairment. WB tests of the mouse hippocampus confirmed that EPEVLR could activate Akt by promoting its phosphorylation. In addition, further characterization (including TEM, ELISA, and immunohistochemistry) related to Akt phosphorylation showed lower Aß and p-tau levels, as well as more autophagosomes than those in the model group. Moreover, the EPEVLR treatment significantly increased Lactobacillus abundance and reduced Helicobacter abundance in the gut microbiome and caused up-regulation of SCFAs and down-regulation of LPS of serum metabolites. Therefore, EPEVLR ingestion reversed cognitive impairment symptoms, possibly related to the activation of Akt and regulation of the intestinal flora pathway. Consumption of an EPEVLR-containing diet is beneficial for treating cognitive dysfunction.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Juglans , Camundongos , Animais , Doença de Alzheimer/metabolismo , Juglans/química , Peptídeos beta-Amiloides/metabolismo , Proteólise , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simulação de Acoplamento Molecular , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Modelos Animais de Doenças
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