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1.
Nano Lett ; 24(19): 5894-5903, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38709593

RESUMO

The combination of radiotherapy (RT) and immunotherapy shows promise in improving the clinical treatment of solid tumors; however, it faces challenges of low response rates and systemic toxicity. Herein, an implantable alginate/collagen hydrogel encapsulating C-C motif ligand 21 (CCL21)-expressing dendritic cells (CCL21-DCs@gel) was developed to potentiate the systemic antitumor effects of RT. The hydrogel functioned as a suitable reservoir for in vivo culture and proliferation of CCL21-DCs, thereby enabling sustained CCL21 release. The local CCL21 gradient induced by CCL21-DCs@gel significantly enhanced the efficacy of RT in suppressing primary tumor growth and inhibiting distant metastasis across several mouse models. Furthermore, the combination of RT with CCL21-DCs@gel provided complete prophylactic protection to mice. Mechanistic investigations revealed that CCL21-DCs@gel potentiated RT by promoting tumor lymphangiogenesis and attracting immune cell infiltration into the tumor. Collectively, these results suggest that CCL21-DCs@gel is a promising adjunct to RT for effectively eradicating tumors and preventing tumor recurrence.


Assuntos
Quimiocina CCL21 , Células Dendríticas , Hidrogéis , Animais , Hidrogéis/química , Camundongos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Linhagem Celular Tumoral , Humanos , Alginatos/química , Neoplasias/radioterapia , Neoplasias/patologia , Neoplasias/imunologia , Colágeno/química , Imunoterapia/métodos
2.
Am J Physiol Cell Physiol ; 326(1): C294-C303, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38047300

RESUMO

Forkhead box protein 3 (FOXP3), traditionally recognized as a specific transcription factor for regulatory T cells (Tregs), has also been identified in various tumor epithelial cells (named as cancer-FOXP3, c-FOXP3). However, the natural state and functional role of FOXP3 positive tumor epithelial cells remain unknown. Monoclonal cells expressing varying levels of c-FOXP3 were isolated from established PANC-1 cells using limited dilution. Whole transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) were conducted on these subsets, followed by in vitro and in vivo functional investigations. In addition, we identified c-FOXP3+E-cadherin- epithelial cells in human pancreatic cancer tissues after radical resection by immunofluorescence co-staining. We also investigated the connection between c-FOXP3+E-cadherin- epithelial cells and their clinicopathological features. Our study uncovered a distinct subset of c-FOXP3+ tumor epithelial cells characterized by reduced E-cadherin expression. C-FOXP3+E-cadherin- cells displayed significant proliferation potential and pro-angiogenic effect through the expression of chemokines, including C-X-C motif ligand 1 (CXCL1), C-X-C motif ligand 5 (CXCL5), and C-X-C motif ligand 8 (CXCL8). Notably, higher counts of c-FOXP3+E-Cadherin- cells correlated with poorer prognosis, lower tumor differentiation, lymph node metastasis, and vascular invasion in pancreatic ductal adenocarcinoma (PDAC). In conclusion, this work revealed the stable expression of FOXP3 in tumor epithelial cells, marking a distinct subset. C-FOXP3+E-cadherin- epithelial cells exhibit active proliferation and promote angiogenesis in a vascular endothelial growth factor A (VEGFA) independent manner. These findings provide novel insights into PDAC prognosis and therapeutic avenues.NEW & NOTEWORTHY In this study, we revealed a novel c-FOXP3+ tumor epithelial cell subset marked by diminished E-cadherin and stable FOXP3 expression. These subpopulations not only show robust proliferation and drive angiogenesis via CXCL1, CXCL5, and CXCL8, bypassing VEGFA pathways, but their heightened presence also correlates with adverse PDAC outcomes. By challenging traditional epithelial cell definitions and extending lymphocyte markers to these cells, our findings present innovative targets for PDAC treatment and enrich our understanding of cell biology.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Fator A de Crescimento do Endotélio Vascular , Angiogênese , Ligantes , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Caderinas/genética , Células Epiteliais/metabolismo , Proliferação de Células
3.
Small ; 20(1): e2304824, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37653618

RESUMO

Mesenchymal stem cells (MSCs) are becoming hotspots for application in disease therapies recently, combining with biomaterials and drug delivery system. A major advantage of MSCs applied in drug delivery system is that these cells enable specific targeting and releasing of cargos to the disease sites. However, the potential tumor tropic effects of MSCs raised concerns on biosafety. To solve this problem, there are emerging methods of isolating cell membranes and developing nanoformulations to perform drug delivery, which avoids concerns on biosafety without disturbing the membrane functions of specific polarizing and locating. These cargoes are so called "nanoghosts." This review article summarizes the current applications of nanoghosts, the promising potential of MSCs to be applied in membrane isolation and nanoghost construction, and possible approaches to develop better drug delivery system harnessing from MSC ghost cell membranes.


Assuntos
Células-Tronco Mesenquimais , Neoplasias , Humanos , Biomimética , Neoplasias/metabolismo , Sistemas de Liberação de Medicamentos , Membrana Celular , Células-Tronco Mesenquimais/metabolismo
4.
Electrophoresis ; 45(5-6): 480-488, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38037297

RESUMO

In paternity testing, short tandem repeats (STRs) allele mismatches are often detected. Nowadays, polymerase chain reaction- and capillary electrophoresis (CE)-based STR genotyping is the most commonly used method to distinguish alleles based on their length. However, it could not detect alleles of the same size with sequence differences. Massively parallel sequencing (MPS) can determine not only allele sizes but also sequences, which could explain the causes of allele mismatches. Additionally, more types of genetic markers can be detected in a single assay, which increases the discriminatory power and facilitates the analysis of paternity tests. In this study, we analyzed 11 cases with homozygous allele mismatches from routine DNA trio paternity tests using the CE platform. Samples were sequenced using the ForenSeq DNA Signature Prep Kit and the MiSeq FGx Sequencing System. The results show that of the eight father-child mismatch cases and three mother-child mismatch cases, five cases with D5S818 and D8S1179 and one case at D13S317 were classified as non-amplification. The other three cases and two cases could be defined as mutations. This study suggests that MPS-based STR genotyping can provide additional information that allows more accurate interpretation of allelic mismatches in paternity testing.


Assuntos
Impressões Digitais de DNA , Paternidade , Humanos , Impressões Digitais de DNA/métodos , Alelos , Análise de Sequência de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Repetições de Microssatélites/genética , DNA
5.
Environ Res ; 247: 118392, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38307178

RESUMO

Intensive anthropogenic activities have led to drastic changes in land use/land cover (LULC) and impacted the carbon storage in high-groundwater coal basins. In this paper, we conduct a case study on the Yanzhou Coalfield in Shandong Province of China. We further classify waterbodies by using the Google Earth Engine (GEE) to better investigate the process of LULC transformation and the forces driving it in four periods from 1985 to 2020 (i.e., 1985-1995, 1995-2005, 2005-2015, and 2015-2020). We modeled the spatiotemporal dynamics of carbon storage by using InVEST based on the transformation in LULC and its drivers, including mining (M), reclamation (R), urbanization and village relocation (U), and ecological restoration (E). The results indicate that carbon storage had depleted by 19.69 % (321099.06 Mg) owing to intensive transformations in LULC. The area of cropland shrank with the expansion of built-up land and waterbodies, and 56.31 % of the study area underwent transitions in land use in the study period. U was the primary driver of carbon loss while E was the leading driver of carbon gain. While the direct impact of M on carbon loss accounted for only 5.23 % of the total, it affected urbanization and led to village relocation. R led to the recovery of cropland and the reclamation of water for aquaculture, which in turn improved the efficiency of land use. However, it contributed only 2.09 % to the total increase in carbon storage. Numerous complicated and intertwined processes (211) drove the changes in carbon storage in the study area. The work here provides valuable information for decision-makers as well as people involved in reclamation and ecological restoration to better understand the link between carbon storage and the forces influencing it. The results can be used to integrate the goals of carbon sequestration into measures for land management.


Assuntos
Minas de Carvão , Água Subterrânea , Humanos , Carbono , China , Carvão Mineral , Ecossistema , Conservação dos Recursos Naturais
6.
BMC Med Inform Decis Mak ; 24(1): 158, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840126

RESUMO

BACKGROUND: Allogeneic Blood transfusion is common in hip surgery but is associated with increased morbidity. Accurate prediction of transfusion risk is necessary for minimizing blood product waste and preoperative decision-making. The study aimed to develop machine learning models for predicting perioperative blood transfusion in hip surgery and identify significant risk factors. METHODS: Data of patients undergoing hip surgery between January 2013 and October 2021 in the Peking Union Medical College Hospital were collected to train and test predictive models. The primary outcome was perioperative red blood cell (RBC) transfusion within 72 h of surgery. Fourteen machine learning algorithms were established to predict blood transfusion risk incorporating patient demographic characteristics, preoperative laboratory tests, and surgical information. Discrimination, calibration, and decision curve analysis were used to evaluate machine learning models. SHapley Additive exPlanations (SHAP) was performed to interpret models. RESULTS: In this study, 2431 hip surgeries were included. The Ridge Classifier performed the best with an AUC = 0.85 (95% CI, 0.81 to 0.88) and a Brier score = 0.21. Patient-related risk factors included lower preoperative hemoglobin, American Society of Anesthesiologists (ASA) Physical Status > 2, anemia, lower preoperative fibrinogen, and lower preoperative albumin. Surgery-related risk factors included longer operation time, total hip arthroplasty, and autotransfusion. CONCLUSIONS: The machine learning model developed in this study achieved high predictive performance using available variables for perioperative blood transfusion in hip surgery. The predictors identified could be helpful for risk stratification, preoperative optimization, and outcomes improvement.


Assuntos
Transfusão de Sangue , Aprendizado de Máquina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Artroplastia de Quadril , Fatores de Risco , Medição de Risco
7.
Genomics ; 115(3): 110639, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37187255

RESUMO

Interleukin (IL)-35, a new member of the IL-12 family, exerts immunosuppressive effects in the hepatic microenvironment. Innate immune cells, such as γδ T cells, have vital roles in hepatic diseases, including acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). In the current study, we focused on the effects and mechanisms of IL-35 on the local immune status of γδ T cells, especially in liver tumors. Based on CCK8 assay and immunofluorescence results, we showed that exogenous IL-35 stimulation of γδ T cells attenuated proliferative ability and killing functions against Hepa1-6 or H22 cells. Flow cytometry results showed that exogenous IL-35 stimulated the expression of programmed cell death 1 (PDCD1) and lymphocyte activation gene 3 (LAG3) in γδ T cells. The exogenous IL-35 stimulated group also showed impairment of cytotoxic cytokine secretion. In addition, stat5a revealed a significant increase after IL-35 stimulation of γδ T cells screened via transcription factor based on PCR array analysis. Furthermore, bioinformatics analysis revealed that stat5a-related tumor-specific genes were mainly involved in immune regulatory pathways. Correlation analysis indicated that stat5a expression was significantly and positively correlated with tumor immune cell infiltration, and pdcd1 and lag3 expression. Finally, bioinformatics analysis using the TCGA and GSE36376 HCC datasets corroborated the significant positive correlation between IL-35 and stat5a. Taken together, overexpressed IL-35 promoted exhaustion and impaired the anti-tumor function of γδ T cells in HCC. Targeting IL-35 might be a promising means to enhance the antitumor therapy of γδ T cells, which would significantly improve prognosis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Linfócitos T , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Exaustão das Células T , Interleucinas , Carcinogênese , Microambiente Tumoral
8.
J Craniofac Surg ; 35(1): 168-171, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37815293

RESUMO

OBJECTIVE: The aim of this study was to conclude the safety and effectiveness of hybrid surgery for revascularization of chronic occlusion of internal carotid artery (COICA). METHODS: A total of 56 COCIA patients underwent hybrid surgery (carotid endarterectomy+carotid artery stenting) from September 2017 to September 2021 in our department. The clinical material and radiology data (preoperation and postoperation) were retrospectively analyzed to conclude the safety and effectiveness of hybrid surgery for revascularization of COICA. RESULTS: All 56 patients underwent hybrid surgery got revascularization successfully (with a successful rate of 100%) and improved intracranial blood flow. The computed tomography perfusion results indicate that the postoperative cerebral blood flow perfusion of the patient is significantly improved compared with before surgery. In 1 patient, postoperative brain magnetic resonance imaging within 24 hours showed spotted fresh infarction with head magnetic resonance imaging, without any clinical symptoms; 3 patients developing symptoms of ipsilateral neural-functional defect (hypoglossal nerve, superior laryngeal nerve, and mandibular branch of facial nerve, respectively), 2 weeks later the symptoms were disappeared. Imaging study at 3 and 6 months during the follow-up showed no abnormalities. CONCLUSION: Hybrid surgery is safe and effective for revascularization of COICA.


Assuntos
Estenose das Carótidas , Revascularização Cerebral , Endarterectomia das Carótidas , Humanos , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/cirurgia , Endarterectomia das Carótidas/métodos , Estudos Retrospectivos , Stents , Resultado do Tratamento
9.
J Cell Mol Med ; 27(12): 1697-1707, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37165726

RESUMO

The skin harbours transcriptionally and functionally heterogeneous mesenchymal cells that participate in various physiological activities by secreting biochemical cues. In this study, we aimed to identify a new subpopulation of dermal mesenchymal cells that enhance hair follicle regeneration through a paracrine mechanism. Integrated single-cell RNA sequencing (scRNA-seq) data analysis revealed epidermal growth factor receptor (EGFR) as a marker of distinct fibroblast subpopulation in the neonatal murine dermis. Immunofluorescence staining and fluorescence-activated cell sorting (FACS) were used to validate the existence of the cell population in Krt14-rtTA-H2BGFP mouse. The difference of gene expression between separated cell subpopulation was examined by real-time PCR. Potential effect of the designated factor on hair follicle regeneration was observed after the application on excisional wounds in Krt14-rtTA-H2BGFP mouse. Immunofluorescence staining demonstrated the existence of dermal EGFR+ cells in neonatal and adult mouse dermis. The EGFR+ mesenchymal population, sorted by FACS, displayed a higher expression level of Igf1 (insulin-like growth factor 1). Co-localisation of IGF1 with EGFR in the mouse dermis and upregulated numbers of hair follicles in healed wounds following the application of exogenous IGF1 illustrated the contribution of EGFR+ cells in promoting wound-induced hair follicle neogenesis. Our results indicate that EGFR identifies a subpopulation of dermal fibroblasts that contribute to IGF1 promotion of hair follicle neogenesis. It broadens the understanding of heterogeneity and the mesenchymal cell function in skin and may facilitate the potential translational application of these cells.


Assuntos
Derme , Folículo Piloso , Animais , Camundongos , Derme/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Folículo Piloso/fisiologia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Pele
10.
Immunology ; 168(2): 248-255, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35689826

RESUMO

The tumour microenvironment (TME) is a complex system composed of cancer cells, stromal cells and immune cells. Regulatory T cells (Tregs) in the TME impede immune surveillance of tumours and suppress antitumor immune responses. Transcription factor forkhead box protein 3 (FOXP3) is the main marker of Tregs, which dominates the function of Tregs. FOXP3 was originally thought to be a Tregs-specific expression molecule, and recent studies have found that FOXP3 is expressed in a variety of tumours with inconsistent functional roles. This review summarizes the recent progress of infiltrating Treg-FOXP3 and tumour-FOXP3 in TME, discusses the communication mechanism between FOXP3+ cells and effector T cells in TME, the relationship between FOXP3 and clinical prognosis, and the potential of FOXP3-targeted therapy.


Assuntos
Fatores de Transcrição Forkhead , Neoplasias , Humanos , Fatores de Transcrição Forkhead/genética , Microambiente Tumoral , Linfócitos do Interstício Tumoral , Neoplasias/patologia , Prognóstico , Linfócitos T Reguladores
11.
Anal Chem ; 95(48): 17467-17476, 2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-38009238

RESUMO

Glycosylation of proteins is an essential feature of extracellular vesicles (EVs). However, while the glycosylation heterogeneity focusing on specific EV subtypes and proteins will better reveal the functions of EVs, the determination of their specific glycans remains highly challenging. Herein, we report a method of protein-specific glycan recognition using DNA-encoded affinity ligands to label proteins and glycans. Manipulating the sequences of DNA tags and employing a DNA logic gate to trigger a spatial proximity-induced DNA replacement reaction enabled the release of glycan-representative DNA strands for the quantitative detection of multiple glycoforms. After size-dependent isolation of EV subgroups and decoding of three typical glycoforms on the epithelial growth factor receptor (EGFR), we found that the different EV subgroups of the EGFR glycoprotein varied with respect to glycan types and abundance. The distinctive glycoforms of the EV subgroups could interfere with the EGFR-related EV functions. Furthermore, the sialylation of small EVs possessed the potential as a cancer biomarker. This method provides new insights into the role of protein-specific glycoforms in EV functions.


Assuntos
Vesículas Extracelulares , Glicoproteínas , Glicosilação , Glicoproteínas/metabolismo , Polissacarídeos/metabolismo , Vesículas Extracelulares/metabolismo , Receptores ErbB/metabolismo
12.
Small ; 19(17): e2206981, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36693779

RESUMO

CRISPR/Cas9-based gene therapy and photodynamic therapy both show promise for cancer treatment but still have their drawbacks limited by tumor microenvironment and long treatment duration. Herein, CRISPR/Cas9 genome editing and photodynamic strategy for a synergistic anti-tumor therapeutic modality is merged. Chlorophyll (Chl) extracted from natural green vegetables is encapsulated in Pluronic F127 (F127) micelles and Histidine-tagged Cas9 can be effectively chelated onto micelles via metal coordination by simple incubation, affording Cas9-Chl@F127 micelles. Mg2+ acts as an enzyme cofactor to correlatively enhance Cas9 gene-editing activity. Upon laser irradiation, Chl as an effective photosensitizer generates reactive oxygen species (ROS) to kill tumor cells. Meanwhile, CRISPR/Cas9, mediated by dual deliberately designed gRNAs of APE1 and NRF2, can reprogram the tumor microenvironment by increasing the intracellular oxygen accumulation and impairing the oxidative defense system of tumor cells. Cas9-Chl@F127 micelles can responsively release Cas9 in the presence of abundant ATP or low pH in tumor cells. In a murine tumor model, Cas9-Chl@F127 complexed with dual gRNAs including APE1 and NRF2 significantly inhibits the tumor growth. Taken together, Cas9-Chl@F127 micelles, representing the first Chl-based green biomaterial for the delivery of Cas9, show great promise for the synergistic anti-tumor treatment by PDT and gene editing.


Assuntos
Neoplasias , Fotoquimioterapia , Camundongos , Animais , Micelas , Edição de Genes , Clorofila , Sistemas CRISPR-Cas/genética , Fator 2 Relacionado a NF-E2 , Neoplasias/genética , Neoplasias/terapia
13.
Small ; 19(50): e2304023, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37728188

RESUMO

The use of orally-administered therapeutic proteins for treatment of inflammatory bowel disease (IBD) has been limited due to the harsh gastrointestinal environment and low bioavailability that affects delivery to diseased sites. Here, a nested delivery system, termed Gal-IL10-EVs (C/A) that protects interleukin 10 (IL-10) from degradation in the stomach and enables targeted delivery of IL-10 to inflammatory macrophages infiltrating the colonic lamina propria, is reported. Extracellular vesicles (EVs) carrying IL-10 are designed to be secreted from genetically engineered mammalian cells by a plasmid system, and EVs are subsequently modified with galactose, endowing the targeted IL-10 delivery to inflammatory macrophages. Chitosan/alginate (C/A) hydrogel coating on Gal-IL10-EVs enables protection from harsh conditions in the gastrointestinal tract and favorable delivery to the colonic lumen, where the C/A hydrogel coating is removed at the diseased sites. Gal-IL10-EVs control the production of reactive oxygen species (ROS) and inhibit the expression of proinflammatory cytokines. In a murine model of colitis, Gal-IL10-EVs (C/A) alleviate IBD symptoms including inflammatory responses and disrupt colonic barriers. Taken together, Gal-IL10-EVs (C/A) features biocompatibility, pH-responsive drug release, and macrophage-targeting as a therapeutic platform for oral delivery of bioactive proteins for treating intestinal diseases.


Assuntos
Quitosana , Vesículas Extracelulares , Doenças Inflamatórias Intestinais , Camundongos , Animais , Citocinas , Interleucina-10 , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Vesículas Extracelulares/metabolismo , Hidrogéis , Mamíferos
14.
Small ; 19(50): e2302756, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37603007

RESUMO

Cancer vaccines generally are limited by insufficient tumor-specific cellular immunogenicity. Herein, a potent "ABC" ternary membrane-derived vaccine system blended from antigen-presenting mature dendritic cell membranes ("A"), bacterial E. coli cytoplasmic membranes ("B"), and cancer cell membranes ("C") is developed using a block-copolymer micelle-enabled approach. The respective ABC membrane components provide for a source of cellular immune communication/activation and enhanced accumulation in lymph nodes (A), immunological adjuvant (B), and tumor antigens (C). The introduction of dendritic cell (DC) membranes enables multiple cell-to-cell communication and powerful immune activation. ABC activates dendritic cells and promotes T-cell activation and proliferation in vitro. In vivo, ABC is 14- and 304-fold more immunogenic than binary (BC) and single (C) membrane vaccines, and immunization with ABC enhances the frequency of tumor-specific cytotoxic T lymphocytes, leading to an 80% cure rate in tumor-bearing mice. In a surgical resection and recurrence model, ABC prevents recurrence with vaccination from autologous cancer membranes, and therapeutic effects are observed in a lung metastasis model even with heterologous cancer cell membranes. ABCs formed from human cancer patient-derived tumor cells activate human monocyte-derived dendritic cells (moDC). Taken together, the ternary ABC membrane system provides the needed functional components for personalized cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Neoplasias , Humanos , Animais , Camundongos , Escherichia coli , Células Dendríticas , Neoplasias/tratamento farmacológico , Linfócitos T Citotóxicos , Antígenos de Neoplasias , Imunoterapia
15.
Ann Surg Oncol ; 30(9): 5843-5853, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37219654

RESUMO

INTRODUCTION: The study investigated the synergistic effect of the micropapillary (MIP) component and consolidation-to-tumor ratio (CTR) on the recurrence and survival of patients with pathologic stage IA3 lung adenocarcinoma. METHODS: We enrolled 419 patients confirmed pathological stage IA3 adenocarcinoma from four institutions. Kaplan-Meier analysis was performed to examine the value of the MIP component and CTR on relapse-free survival (RFS) and overall survival (OS). The cumulative recurrence between different stages was analyzed by using cumulative event curves. RESULTS: RFS (P < 0.0001) and OS (P = 0.008) in the presence of the MIP group were significantly lower than those in the absence of the MIP group, and CTR > 5 only reduced RFS (P = 0.0004), but not OS (P = 0.063), in the patients. In addition, the prognosis of patients with both the MIP component and CTR > 5 was worse than that of those without the MIP component or CTR ≤ 5. Therefore, we established new subtypes of the stage IA3: IA3a, IA3b, and IA3c. RFS and OS for IA3c staging were significantly lower than those for IA3a and IA3b. For IA3c, the cumulative incidence of local recurrence (P < 0.001) and that of distant metastasis (P = 0.004) were significantly higher than those for IA3a and IA3b. CONCLUSIONS: The MIP component combined with CTR > 0.5 can effectively predict the prognosis of patients with pathological stage IA3 lung adenocarcinoma and may offer more detailed recurrence and survival information according to the established subtype stage of IA3.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/patologia , Adenocarcinoma de Pulmão/patologia , Prognóstico , Estudos Retrospectivos
16.
Eur Radiol ; 33(12): 9038-9051, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37498380

RESUMO

OBJECTIVES: Hepatic arterial infusion chemotherapy (HAIC) using the FOLFOX regimen (oxaliplatin plus fluorouracil and leucovorin) is a promising option for advanced hepatocellular carcinoma (Ad-HCC). As identifying patients with Ad-HCC who would obtain objective response (OR) to HAIC preoperatively remains a challenge, we aimed to develop an automatic and non-invasive model for predicting HAIC response. METHODS: A total of 458 patients with Ad-HCC who underwent HAIC were retrospectively included from three hospitals (310 for training, 77 for internal validation, and 71 for external validation). The deep learning and radiomic features were extracted from the automatically segmented liver region on contrast-enhanced computed tomography images. Then, a deep learning radiomic nomogram (DLRN) was constructed by integrating deep learning scores, radiomic scores, and significant clinical variables with multivariate logistic regression. Model performance was assessed by AUC and Kaplan-Meier estimator. RESULTS: After automatic segmentation, only a few modifications were needed (less than 30 min for 458 patients). The DLRN achieved an AUC of 0.988 in the training cohort, 0.915 in the internal validation cohort, and 0.896 in the external validation cohort, respectively, outperforming other models in HAIC response prediction. Moreover, survival risk stratification was also successfully performed by the DLRN. The overall survival (OS) of the predictive OR group was significantly longer than that of the predictive non-OR group (median OS: 26.0 vs. 12.3 months, p < 0.001). CONCLUSIONS: The DLRN provided a satisfactory performance for predicting HAIC response, which is essential to identify Ad-HCC patients for HAIC and may potentially benefit personalized pre-treatment decision-making. CLINICAL RELEVANCE STATEMENT: This study presents an accurate and automatic method for predicting response to hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma, and therefore help in defining the best candidates for this treatment. KEY POINTS: • Deep learning radiomic nomogram (DLRN) based on automatic segmentation of CECT can accurately predict hepatic arterial infusion chemotherapy (HAIC) response of advanced HCC patients. • The proposed prediction model can perform survival risk stratification and is an easy-to-use tool for personalized pre-treatment decision-making for advanced HCC patients.


Assuntos
Carcinoma Hepatocelular , Aprendizado Profundo , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Nomogramas , Estudos Retrospectivos , Cisplatino , Resultado do Tratamento , Infusões Intra-Arteriais
17.
Macromol Rapid Commun ; 44(22): e2300416, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37712327

RESUMO

Solvated electron (esol - ) is highly reducing species and apt to initiate monomers via one-electron transfer reaction. Herein, utilizing the esol - solution of Na/hexamethylphosphoramide, radical and anionic initiations are observed respectively, which heavily depend on Na concentrations. Interestingly, this initiation system, in states of lower Na concentrations, higher molar conductivities and less paired esol - , give rise to a controlled radical polymerization (CRP) to yield polymers with predictable molecular weights and narrow molecular weight distributions (the lowest Ð = 1.25). This CRP presents unique behaviors, like solvent effect, electric field effect, and unusual copolymerization phenomenon. A semi-conjugated radical carrying a negative charge is proposed to be responsible for the CRP. This system gives a distinct way to regulate CRP from current CRPs, and offers new insights into the monomer initiation by esol - .


Assuntos
Elétrons , Polímeros , Polimerização , Peso Molecular
18.
Lipids Health Dis ; 22(1): 156, 2023 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-37736721

RESUMO

Lipid metabolism disorders are considerably involved in the pathology of atherosclerosis; nevertheless, the fundamental mechanism is still largely unclear. This research sought to examine the function of lipophagy in lipid metabolism disorder-induced atherosclerosis and its fundamental mechanisms. Previously, Sirt6 has been reported to stimulate plaque stability by promoting macrophage autophagy. However, its role in macrophage lipophagy and its relationship with Wnt1 remains to be established. In this study, ApoE-/-: Sirt6-/- and ApoE-/-: Sirt6Tg mice were used and lipid droplets were analysed via transmission electron microscopy and Bodipy 493/503 staining in vitro. Atherosclerotic plaques in ApoE-/-: Sirt6-/- mice showed greater necrotic cores and lower stability score. Reconstitution of Sirt6 in atherosclerotic mice improved lipid metabolism disorder and prevented the progression of atherosclerosis. Furthermore, macrophages with Ac-LDL intervention showed more lipid droplets and increased expression of adipophilin and PLIN2. Reconstitution of Sirt6 recruited using SNF2H suppressed Wnt1 expression and improved lipid metabolism disorder by promoting lipophagy. In addition, downregulation of Sirt6 expression in Ac-LDL-treated macrophages inhibited lipid droplet degradation and stimulated foam cell formation. Innovative discoveries in the research revealed that atherosclerosis is caused by lipid metabolism disorders due to downregulated Sirt6 expression. Thus, modulating Sirt6's function in lipid metabolism might be a useful therapeutic approach for treating atherosclerosis.


Assuntos
Aterosclerose , Transtornos do Metabolismo dos Lipídeos , Placa Aterosclerótica , Sirtuínas , Animais , Camundongos , Metabolismo dos Lipídeos/genética , beta Catenina , Aterosclerose/genética , Placa Aterosclerótica/genética , Macrófagos , Apolipoproteínas E/genética , Autofagia/genética , Sirtuínas/genética
19.
Proc Natl Acad Sci U S A ; 117(19): 10378-10387, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32332162

RESUMO

Barrier-to-autointegration factor (BAF) is a highly conserved protein in metazoans that has multiple functions during the cell cycle. We found that BAF is SUMOylated at K6, and that this modification is essential for its nuclear localization and function, including nuclear integrity maintenance and DNA replication. K6-linked SUMOylation of BAF promotes binding and interaction with lamin A/C to regulate nuclear integrity. K6-linked SUMOylation of BAF also supports BAF binding to DNA and proliferating cell nuclear antigen and regulates DNA replication. SENP1 and SENP2 catalyze the de-SUMOylation of BAF at K6. Disrupting the SUMOylation and de-SUMOylation cycle of BAF at K6 not only disturbs nuclear integrity, but also induces DNA replication failure. Taken together, our findings demonstrate that SUMOylation at K6 is an important regulatory mechanism that governs the nuclear functions of BAF in mammalian cells.


Assuntos
Replicação do DNA/fisiologia , Proteínas de Ligação a DNA/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Núcleo Celular/metabolismo , Chlorocebus aethiops , DNA/metabolismo , Proteínas de Ligação a DNA/genética , Células HEK293 , Células HeLa , Humanos , Lamina Tipo A/metabolismo , Lisina/metabolismo , Proteínas de Membrana/metabolismo , Sinais de Localização Nuclear/genética , Proteínas Nucleares/metabolismo , Ligação Proteica/fisiologia , Sumoilação/fisiologia
20.
BMC Med Inform Decis Mak ; 23(1): 179, 2023 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-37697312

RESUMO

Addressing the current complexities, costs, and adherence issues in the detection of forward head posture (FHP), our study conducted an exhaustive epidemiologic investigation, incorporating a comprehensive posture screening process for each participant in China. This research introduces an avant-garde, machine learning-based non-contact method for the accurate discernment of FHP. Our approach elevates detection accuracy by leveraging body landmarks identified from human images, followed by the application of a genetic algorithm for precise feature identification and posture estimation. Observational data corroborates the superior efficacy of the Extra Tree Classifier technique in FHP detection, attaining an accuracy of 82.4%, a specificity of 85.5%, and a positive predictive value of 90.2%. Our model affords a rapid, effective solution for FHP identification, spotlighting the transformative potential of the convergence of feature point recognition and genetic algorithms in non-contact posture detection. The expansive potential and paramount importance of these applications in this niche field are therefore underscored.


Assuntos
Pontos de Referência Anatômicos , População do Leste Asiático , Postura , Adolescente , Humanos , Povo Asiático , Aprendizado de Máquina , Postura/fisiologia , Algoritmos
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