RÉSUMÉ
In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.
Sujet(s)
Vieillissement de la cellule , Cellules endothéliales de la veine ombilicale humaine , Jonctions intercellulaires , Facteur-2 apparenté à NF-E2 , Transduction du signal , Humains , Facteur-2 apparenté à NF-E2/métabolisme , Vieillissement de la cellule/physiologie , Cellules endothéliales de la veine ombilicale humaine/métabolisme , Jonctions intercellulaires/métabolisme , Facteurs de transcription à motif basique hélice-boucle-hélice/métabolisme , Stress oxydatif , Diabète/métabolisme , Glucose/métabolismeRÉSUMÉ
In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the formation of microspeckles. However, our understanding, largely learned from morphological observations, lacks insight into the mechanisms behind PML/RARα-mediated microspeckle formation and its role in APL leukemogenesis. This study presents evidence uncovering liquid-liquid phase separation (LLPS) as a key mechanism in the formation of PML/RARα-mediated microspeckles. This process is facilitated by the intrinsically disordered region containing a large portion of PML and a smaller segment of RARα. We demonstrate the coassembly of bromodomain-containing protein 4 (BRD4) within PML/RARα-mediated condensates, differing from wild-type PML-formed NBs. In the absence of PML/RARα, PML NBs and BRD4 puncta exist as two independent phases, but the presence of PML/RARα disrupts PML NBs and redistributes PML and BRD4 into a distinct phase, forming PML/RARα-assembled microspeckles. Genome-wide profiling reveals a PML/RARα-induced BRD4 redistribution across the genome, with preferential binding to super-enhancers and broad-promoters (SEBPs). Mechanistically, BRD4 is recruited by PML/RARα into nuclear condensates, facilitating BRD4 chromatin binding to exert transcriptional activation essential for APL survival. Perturbing LLPS through chemical inhibition (1, 6-hexanediol) significantly reduces chromatin co-occupancy of PML/RARα and BRD4, attenuating their target gene activation. Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.
Sujet(s)
Protéines du cycle cellulaire , Leucémie aiguë promyélocytaire , Protéines de fusion oncogènes , Facteurs de transcription , Humains , Leucémie aiguë promyélocytaire/métabolisme , Leucémie aiguë promyélocytaire/génétique , Leucémie aiguë promyélocytaire/anatomopathologie , Facteurs de transcription/métabolisme , Facteurs de transcription/génétique , Protéines du cycle cellulaire/métabolisme , Protéines du cycle cellulaire/génétique , Protéines de fusion oncogènes/métabolisme , Protéines de fusion oncogènes/génétique , Lignée cellulaire tumorale , Régulation de l'expression des gènes dans la leucémie , Protéines nucléaires/métabolisme , Protéines nucléaires/génétique , Protéine de la leucémie promyélocytaire/métabolisme , Protéine de la leucémie promyélocytaire/génétique , , Protéines contenant un bromodomaineRÉSUMÉ
Background: MicroRNAs (miRNAs) have been widely recognized as crucial regulators in the development and progression of various cancers, including colorectal cancer (CRC). Previous studies have highlighted the involvement of several miRNAs in CRC, such as miR-145, miR-29a-3p, and miR-196. However, the specific role and clinical significance of miR-411-5p in CRC have not been thoroughly investigated, representing a significant gap in the current understanding of CRC biology. While miR-411-5p has been implicated in the pathogenesis of other human malignancies, its precise mechanisms and impact on CRC development and prognosis remain largely unexplored. Understanding the functional relevance of miR-411-5p in CRC and elucidating its molecular interactions can provide valuable insights into the underlying mechanisms of CRC progression and potentially identify novel therapeutic targets. Therefore, this study aims to investigate the clinical value and level of miR-411-5p in colorectal cancer, shedding light on its potential as a diagnostic and prognostic biomarker. Additionally, we aim to explore the molecular mechanisms underlying the effects of miR-411-5p on CRC cells, particularly its interaction with the target gene NFE2L3. By filling this knowledge gap, our research contributes to a deeper understanding of the role of miR-411-5p in CRC and opens avenues for developing targeted therapies for this prevalent malignancy. Methods: Colorectal cancer (CRC) tissue samples and corresponding normal paracancerous tissue samples were collected from 60 CRC patients treated at the Affiliated Hospital of Hebei University. Normal paracancerous tissue refers to the healthy tissue adjacent to the cancerous region. These tissue samples were obtained through biopsies, and the patients provided informed consent for their use in the study. To investigate the expression levels of miR-411-5p and NFE2L3, we employed quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. This technique allowed us to measure the levels of miR-411-5p and NFE2L3 mRNA in both CRC and normal tissue samples. Additionally, we validated the protein levels of NFE2L3 using Western blot analysis. Furthermore, we assessed the functional impact of miR-411-5p on CRC cells through various assays. The MTT assay determined cell viability, the transwell migration assay evaluated cell migration and invasion abilities, and flow cytometry measured the rate of apoptosis in CRC cells. To confirm the molecular interaction between miR-411-5p and its target gene NFE2L3, we conducted dual-luciferase reporter assays. These assays enabled us to validate the binding between miR-411-5p and the 3' untranslated region (3'UTR) of the NFE2L3 mRNA. To investigate the potential therapeutic role of NFE2L3 in CRC, we transfected CRC cells with pcDNA3.0-NFE2L3, a plasmid overexpressing NFE2L3. This allowed us to assess the impact of NFE2L3 restoration on the behavior of CRC cells. Results: Overexpression of miR-411-5p in CRC cells significantly reduced cell viability, inhibited migration and invasion, and increased the rate of apoptosis. Conversely, inhibition of miR-411-5p expression exerted the opposite effects on the biological behavior of CRC cells. Furthermore, our study revealed that NFE2L3 is a downstream target of miR-411-5p. Dual-luciferase reporter assays confirmed the binding between miR-411-5p and the 3'UTR of NFE2L3 mRNA, indicating a direct interaction between them. To investigate the therapeutic potential of targeting NFE2L3 in CRC, we transfected CRC cells with pcDNA3.0-NFE2L3, resulting in the restoration of NFE2L3 levels. This restoration effectively reversed the effects induced by miR-411-5p mimics on the behavior of CRC cells. Conclusion: Our study provides compelling evidence for the tumor-suppressive role of miR-411-5p in CRC. The overexpression of miR-411-5p resulted in reduced cell viability, inhibited migration and invasion, and increased apoptosis in CRC cells. Importantly, we identified NFE2L3 as a downstream target of miR-411-5p and demonstrated its involvement in mediating the effects of miR-411-5p on CRC cell behavior. These findings not only confirm the tumor-suppressive role of miR-411-5p in CRC but also highlight NFE2L3 as a promising target for novel therapeutic strategies. Targeting NFE2L3 to modulate the biological function of CRC cells may hold therapeutic potential and serve as a basis for the development of targeted drugs. Further investigations are warranted to fully elucidate the underlying molecular mechanisms of miR-411-5p-NFE2L3 interaction and its impact on CRC progression. Additionally, future studies could explore the clinical implications of miR-411-5p as a diagnostic or prognostic biomarker in CRC patients. By advancing our understanding of the intricate regulatory networks involved in CRC, we can pave the way for personalized therapeutic approaches and improve patient outcomes.
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Background: Cardiac ultrasound is one of the most important examinations in cardiovascular medicine, but the technical requirements for the operator are relatively high, which to some extent affects the scope of its use. This study was dedicated to investigating the agreement of ejection fraction between coronary computed tomography (CT) and cardiac ultrasound and diagnostic performance in evaluating the clinical diagnosis of patients with chronic heart failure. Methods: We conducted a single-center-based retrospective study including 343 consecutive patients enrolled between January 2019 to April 2020, all of whom presented with suspected symptoms of heart failure within one month. All enrolled cases performed cardiac ultrasound and coronary CT scans. The CT images were analyzed using accurate left ventricle (AccuLV) artificial intelligence (AI) software to calculate the ejection fraction-computed tomography (EF-CT) and it was compared with the ejection fraction (EF) obtained based on ultrasound. Cardiac insufficiency was determined if the EF measured by ultrasound was below 50%. Diagnostic performance analysis, correlation analysis and Bland-Altman plot were used to compare agreement between EF-CT and CT. Results: Of the 319 successfully performed patients, 220 (69%) were identified as cardiac insufficiency. Quantitative consistency analysis showed a good correlation between EF-CT and EF values in all cases (R square =0.704, r=0.837). Bland-Altman analysis showed mean bias of 6.6%, mean percentage error of 27.5% and 95% limit of agreement of -17% to 30% between EF and EF-CT. The results of the qualitative diagnostic study showed that the sensitivity and specificity of EF measured by coronary CT reached a high level of 91% [95% confidence interval (CI): 86-94%], and the positive diagnostic value was up to 96% (95% CI: 92-98%). Conclusions: The EF-CT and EF have excellent agreement, and AccuLV-based AI left ventricular function analysis software perhaps can be used as a clinical diagnostic reference.
RÉSUMÉ
Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFß::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFß::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.
Sujet(s)
Sous-unité alpha 2 du facteur CBF , Leucémie aigüe myéloïde , Protéines de fusion oncogènes , Humains , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/métabolisme , Leucémie aigüe myéloïde/traitement médicamenteux , Leucémie aigüe myéloïde/anatomopathologie , Sous-unité alpha 2 du facteur CBF/génétique , Sous-unité alpha 2 du facteur CBF/métabolisme , Protéines de fusion oncogènes/génétique , Protéines de fusion oncogènes/métabolisme , Animaux , Sous-unités bêta du facteur CBF/génétique , Sous-unités bêta du facteur CBF/métabolisme , Souris , Régulation de l'expression des gènes dans la leucémie , Lignée cellulaire tumoraleRÉSUMÉ
Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.
Sujet(s)
Résistance aux médicaments antinéoplasiques , Leucémie aigüe myéloïde , Mutation , Facteur d'épissage U2AF , Humains , Facteur d'épissage U2AF/génétique , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/traitement médicamenteux , Leucémie aigüe myéloïde/anatomopathologie , Résistance aux médicaments antinéoplasiques/génétique , Biosynthèse des protéines/effets des médicaments et des substances chimiques , ARN messager/génétique , Épissage des ARN/génétique , Animaux , Études rétrospectives , Souris , Lignée cellulaire tumorale , Facteur-4A d'initiation eucaryote/génétique , Facteur-4A d'initiation eucaryote/métabolismeRÉSUMÉ
[This retracts the article DOI: 10.3892/ol.2018.8999.].
RÉSUMÉ
BACKGROUND: It's difficult to treat segmental tibial fractures (STFs), which are intricate injuries associated with significant soft tissue damage. The aim of this study was to compare the clinical effect of hexaxial external fixator (HEF) and intramedullary nail (IMN) in treatment of STFs. METHODS: A total of 42 patients with STFs were finally recruited between January 2018 and June 2022. There were 25 males and 17 females with age range of 20 to 60 years. All fractures were classified as type 42C2 using the Arbeitsgemeinschaftfür Osteosythese/Orthopaedic Trauma Association (AO/OTA) classification. 22 patients were treated with HEF and 20 patients were treated with IMN. The condition of vascular and neural injuries, time of full weight bearing, bone union time and infection rate were documented and analyzed between the two groups. The mechanical medial proximal tibial angle (mMPTA), mechanical posterior proximal tibial angle (mPPTA), mechanical lateral distal tibial angle (mLDTA), mechanical anterior distal tibial angle (mADTA), hospital for special surgery (HSS) knee joint score, American Orthopaedic Foot and Ankle Society (AOFAS) ankle joint score, range of motion (ROM) of flexion of keen joint and ROM of plantar flexion and dorsal flexion of ankle joint were compared between the two groups at the last clinical visit. RESULTS: There were no vascular and neural injuries or other severe complications in both groups. All 22 patients in HEF group underwent closed reduction but 3 patients in IMN group were treated by open reduction. The time of full weight bearing was (11.3 ± 3.2) days in HEF group and (67.8 ± 5.8) days in IMN group(P < 0.05), with bone union time for (6.9 ± 0.8) months and (7.7 ± 1.4) months, respectively(P < 0.05). There was no deep infection in both groups. In the HEF group and IMN group, mMPTA was (86.9 ± 1.5)° and (89.7 ± 1.8)°(P < 0.05), mPPTA was (80.8 ± 1.9)° and (78.6 ± 2.0)°(P < 0.05), mLDTA was (88.5 ± 1.7)° and (90.3 ± 1.7)°(P < 0.05), while mADTA was (80.8 ± 1.5)° and (78.4 ± 1.3)°(P < 0.05). No significant differences were found between the two groups at the last clinical visit concerning HSS knee joint score and AOFAS ankle joint score, ROM of flexion of keen joint and ROM of plantar flexion of ankle joint (P > 0.05). The ROM of dorsal flexion of ankle joint in IMN group was (30.4 ± 3.5)°, better than (21.6 ± 2.8)° in HEF group (P < 0.05). CONCLUSION: In terms of final clinical outcomes, the use of either HEF or IMN for STFs can achieve good therapeutic effects. While HEF is superior to IMN in terms of completely closed reduction, early full weight bearing, early bone union and alignment. Nevertheless, HEF has a greater impact on the ROM of dorsal flexion of the ankle joint, and much more care and adjustment are needed for the patients than IMN.
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Fractures du tibia , Mâle , Femelle , Humains , Jeune adulte , Adulte , Adulte d'âge moyen , Études rétrospectives , Résultat thérapeutique , Fractures du tibia/chirurgie , Fixateurs externes , Plaques orthopédiquesRÉSUMÉ
Perianal/perineal rhabdomyosarcomas (PRMS) is rare, and the outcome is poor. A 29-year-old female presented with perineal rhabdomyosarcomas revealed metastases to inguinal lymph nodes on the bilateral side. Disease progression was discovered when the patient got adjuvant epirubicin, ifosfamide, and bevacizumab for 2 cycles. After 3 cycles of nivolumab, dacarbazine, cisplatin, and vinblastine therapy, a partial response was identified in the patient. The surgical resection was performed. The patient received neoadjuvant chemotherapy before surgery and was weak after surgery, so he did not receive chemoradiotherapy. The patient succumbed after 11 months postoperatively due to widespread intraabdominal metastasis.
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Rhabdomyosarcome , Mâle , Femelle , Humains , Adulte , Rhabdomyosarcome/diagnostic , Rhabdomyosarcome/thérapie , Rhabdomyosarcome/anatomopathologie , Traitement néoadjuvant , Noeuds lymphatiques/anatomopathologie , Ifosfamide , Évolution de la maladie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Stress hyperglycemia ratio (SHR), associated with adverse outcomes in patients with ST-segment elevation myocardial infarction (STEMI), has several definitions. This study aims to assess the prognostic value of SHR, derived from hemoglobin A1c (HbA1c) or glycated albumin (GA), to mortality. METHODS: The study comprised 1,643 STEMI patients who underwent percutaneous coronary intervention (PCI) in two centers. SHR1 was calculated using fasting blood glucose (FBG)/GA, while SHR2 was calculated using the formula FBG/(1.59*HbA1c-2.59). The primary endpoints were in-hospital death and all-cause mortality, with a median follow-up duration of 1.56 years. RESULTS: Higher SHR1 and SHR2 values are associated with increased risks of in-hospital death and all-cause mortality. Each standard deviation increase in SHR1 corresponded to a 39% and 22% escalation in in-hospital death and all-cause mortality, respectively. The respective increases for SHR2 were 51% and 26%. Further examinations validated these relationships as linear. Additionally, the areas under the curve (AUC) for in-hospital death were not significantly different between SHR1 and SHR2 (p > 0.05). Incorporating SHR1 or SHR2 into the base model significantly improved the discrimination and risk reclassification for in-hospital and all-cause mortality. A subgroup analysis revealed that the effects of SHR1 and SHR2 were more pronounced in patients with hypercholesteremia. CONCLUSION: SHR1 and SHR2 have emerged as robust and independent prognostic markers for STEMI patients undergoing PCI. The SHR calculation based on either HbA1c or GA can provide additional predictive value for mortality beyond traditional risk factors, helping to identify high-risk STEMI patients.
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Hyperglycémie , Intervention coronarienne percutanée , Infarctus du myocarde avec sus-décalage du segment ST , Humains , Hémoglobine glyquée , Infarctus du myocarde avec sus-décalage du segment ST/diagnostic , Infarctus du myocarde avec sus-décalage du segment ST/thérapie , Intervention coronarienne percutanée/effets indésirables , Glycémie , Mortalité hospitalière , Résultat thérapeutique , Marqueurs biologiques , Hyperglycémie/diagnostic , Pronostic , Facteurs de risque , AlbuminesRÉSUMÉ
BACKGROUND: Colorectal cancer (CRC) is a common malignancy in the gastrointestinal tract. Keloid refers to abnormal scar tissue that forms on the skin or mucous membrane. The relationship between RRP9 and DDX21 and the two diseases is unclear. METHODS: Download the colorectal cancer dataset GSE134834, GSE206800, GSE209892 and keloid dataset GSE44270 from the GEO database. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis (WGCNA) was performed. The construction and analysis of protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis (GSEA). Gene expression heat map was drawn. The comparative toxicogenomics database (CTD) analysis was performed to find diseases most related to core genes. TargetScan screened miRNAs that regulated central DEGs. We conducted experimental validation using Western blotting and Polymerase Chain Reaction (PCR). RESULTS: In the colorectal cancer dataset and the scar tissue dataset, we identified 1380 DEGs and 1000 DEGs, respectively. The enrichment pattern for scar tissue was similar to that of colorectal cancer. We identified two core genes, RRP9 and DDX21. CTD analysis indicated that RRP9 and DDX21 are associated with proliferation, scar tissue, colorectal tumors, scleroderma, and inflammation. We found that the core genes (RRP9 and DDX21) were highly expressed in colorectal cancer and scar tissue samples, while their expression was lower in normal samples. This was further validated through Western blotting (WB) and Polymerase Chain Reaction (PCR). CONCLUSIONS: The higher the expression of RRP9 and DDX21 in colorectal cancer and keloid, the worse the prognosis.
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Tumeurs colorectales , Chéloïde , microARN , Humains , Chéloïde/génétique , Cartes d'interactions protéiques/génétique , Analyse de profil d'expression de gènes , Tumeurs colorectales/anatomopathologie , microARN/métabolisme , Biologie informatique , DEAD-box RNA helicases/génétique , DEAD-box RNA helicases/métabolismeRÉSUMÉ
Colorectal cancer originates from the epithelium of the large intestine and is a common malignant tumor in the gastrointestinal tract. However, the relationship between RRP9 and DDX21 and colorectal cancer (CRC) remains unclear. GSE134834, GSE206800, and GSE209892 profiles for CRC were downloaded from the gene expression omnibus database generated using GPL20115 and GPL23126. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis was performed. The construction and analysis of protein-protein interaction network. Functional enrichment analysis and gene set enrichment analysis were performed. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to the core gene. TargetScan was used to screen miRNAs regulating central DEGs. One thousand three hundred eighty DEGs were identified. According to gene ontology analysis, they were mainly concentrated in signal receptor activity regulation and metal titanase activity. Kyoto encyclopedia of gene and genome analysis showed that they mainly focused on IL17 signal pathway, PPAR signal pathway, protein digestion, and absorption, and the interaction of viral proteins with cytokines and cytokine receptors. The intersection of enrichment items and GOKEGG enrichment items of differentially expressed genes is mainly concentrated in PPAR signal pathway and the interaction of viral proteins with cytokines and cytokine receptors. The protein-protein interaction network obtained 16 core genes (MAD2L1, MELK, TPX2, UBE2C, RFC4, PLK1, RACGAP1, DKC1, DDX21, L Y AR, WDR3, RRP9, WDR43, NOLC1, BRIX1, and GTPBP4). Heat map of gene expression showed that core genes (TPX2, UBE2C, RFC4, PLK1, DKC1, LYAR, WDR3, NOLC1, and BRIX1) were not significantly differentially expressed between CRC and normal tissue samples. Core genes (MAD2L1, MELK, RACGAP1, RRP9, WDR43, DDX21, and GTPBP4) were highly expressed in CRC tissue samples and lowly expressed in normal tissue samples. Comparative toxicogenomics database analysis showed that 7 genes (MAD2L1, MELK, RACGAP1, RRP9, WDR43, DDX21, and GTPBP4) were related to necrosis, inflammation, tumor, precancerous symptoms, hemorrhage, and weightlessness. RRP9 and DDX21 are highly expressed in CRC. The higher the expression level of RRP9 and DDX21, the worse the prognosis.
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Tumeurs colorectales , Récepteurs activés par les proliférateurs de peroxysomes , Humains , Récepteurs activés par les proliférateurs de peroxysomes/génétique , Cartes d'interactions protéiques/génétique , Analyse de profil d'expression de gènes , Protéines du cycle cellulaire/métabolisme , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Tumeurs colorectales/anatomopathologie , Cytokines/métabolisme , Récepteurs aux cytokines/génétique , Récepteurs aux cytokines/métabolisme , Protéines virales/métabolisme , Biologie informatique , Régulation de l'expression des gènes tumoraux , Réseaux de régulation génique , Protéines nucléaires/génétiqueRÉSUMÉ
BACKGROUND: A recent randomized trial reported fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) strategy was noninferior to the intracoronary ultrasound (IVUS)-guided PCI strategy with respect to clinical outcomes with fewer revascularizations. OBJECTIVES: This study sought to investigate the sex differences in treatment and clinical outcomes according to physiology- or imaging-guided PCI strategies. METHODS: In this secondary analysis of the FLAVOUR (Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI) trial, the impact of sex on procedural characteristics, PCI rate, and outcomes according to different strategies and treatment types (PCI vs deferral of PCI) was analyzed. The primary outcome was target vessel failure (TVF) at 24 months, defined as a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization. RESULTS: Of 1,619 patients, 30% were women. Compared with men, women had a smaller minimal lumen area, smaller plaque burden, and higher FFR. They had a lower PCI rate (40.8% vs 47.9%; P = 0.008), which was mainly contributed by FFR guidance. Overall, women showed a lower TVF rate (2.4% vs 4.5%). According to the treatment type, the cumulative incidence of TVF was lower in women than in men among those with the deferral of PCI (1.7% vs 5.2%). However, this trend was not observed in patients who underwent PCI. In both women and men, there were no differences in clinical outcomes between the FFR- and IVUS-guided strategies. CONCLUSIONS: In cases of intermediate stenosis, despite receiving fewer interventions, women had more favorable outcomes than men. The use of FFR led to a lower PCI rate but had a similar prognostic value compared with IVUS in both women and men.
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Maladie des artères coronaires , Fraction du flux de réserve coronaire , Intervention coronarienne percutanée , Femelle , Humains , Mâle , Coronarographie , Maladie des artères coronaires/imagerie diagnostique , Maladie des artères coronaires/thérapie , Intervention coronarienne percutanée/effets indésirables , Intervention coronarienne percutanée/méthodes , Caractères sexuels , Résultat thérapeutique , Échographie interventionnelle/méthodesRÉSUMÉ
BACKGROUND: In recent years, several studies have demonstrated that stress hyperglycemia is significantly associated with poor prognosis in patients diagnosed with acute coronary syndrome (ACS). In the present study, we aimed to investigate the potential associations between various markers of stress hyperglycemia, such as admission blood glucose (ABG), fasting blood sugar (FBS), and stress hyperglycemia ratio (SHR) with different definitions, and the occurrence of adverse cardiovascular events in patients diagnosed with ST-elevation myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI). METHODS: Our study enrolled a total of 1099 patients diagnosed with STEMI who underwent PCI from 2016 to 2021. The primary outcomes of this study were in-hospital death and all-cause mortality. RESULTS: Stress hyperglycemia was associated with a higher incidence of in-hospital death (ABG OR: 1.27 95% CI 1.19-1.36; FBS OR: 1.25 95% CI 1.16-1.35; SHR1 OR: 1.61 95% CI 1.21-2.14; SHR2 OR: 1.57, 95%CI 1.22-2.01; SHR3 OR: 1.59, 95%CI 1.24-2.05) and all-cause mortality (ABG HR: 1.10, 95% CI 1.07-1.14; FBS HR: 1.12, 95 CI 1.07-1.17; SHR1 HR: 1.19 95% CI 1.03-1.39; SHR2 HR: 1.28, 95%CI 1.14-1.44; SHR3 HR: 1.29, 95%CI 1.14-1.45) after adjusting for ischemic time, age, gender, BMI, hypertension, hyperlipidemia, diabetes mellitus (DM), current smoking history, chronic kidney disease (CKD), previous history of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, cancer, culprit vessel, multi-vessel disease. These associations exhibited a non-linear, J-shaped pattern, wherein the risk significantly increased when the ABG and FBS levels exceeded 5mmol/L. Moreover, the inflection point for SHR was estimated to be 1.2. CONCLUSIONS: Stress hyperglycemia was significantly associated with an increased risk of in-hospital death and all-cause mortality in STEMI patients treated with PCI. Stress hyperglycemia should be considered a high-risk prognostic marker in all STEMI patients, regardless of with or without diabetes.
Sujet(s)
Diabète , Hyperglycémie , Intervention coronarienne percutanée , Infarctus du myocarde avec sus-décalage du segment ST , Humains , Infarctus du myocarde avec sus-décalage du segment ST/diagnostic , Infarctus du myocarde avec sus-décalage du segment ST/thérapie , Études de cohortes , Mortalité hospitalière , Intervention coronarienne percutanée/effets indésirables , Résultat thérapeutique , Hyperglycémie/diagnostic , Diabète/diagnostic , Glycémie , Facteurs de risqueRÉSUMÉ
BACKGROUND: Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract with high incidence and mortality. Exosomal circular RNA (circRNA) has been shown to be associated with the malignant progression of cancers, including CRC. Circ_0005100 (named as circ_FMN2) has been shown to promote CRC cell proliferation and migration. However, whether exosomal circ_FMN2 participated in CRC progression remains unclear. METHODS: Exosomes were isolated from the serum of CRC patients and then identified using transmission electron microscope. Western blot assay was used to test the protein levels of exosome markers, proliferation-related marker, metastasis-related markers and musashi-1 (MSI1). The expression levels of circ_FMN2, microRNA (miR)-338-3p and MSI1 were detected by qPCR. Flow cytometry, colony formation assay, MTT assay, and transwell assay were employed to measure cell cycle, apoptosis, colony formation ability, viability, migration and invasion. Dual-luciferase reporter assay was performed to assess the interaction between miR-338-3p and circ_FMN2 or MSI1. BALB/c nude mice was used to conduct animal experiments. RESULTS: Circ_FMN2 was overexpressed in the exosomes of CRC patient's serums and CRC cells. Overexpressed exosomal circ_FMN2 could promote CRC cell proliferation, metastasis, and suppress apoptosis. Circ_FMN2 acted as miR-338-3p sponge. MiR-338-3p overexpression reversed the promotion effect of circ_FMN2 on CRC progression. MSI1 was found to be a target of miR-338-3p, and its overexpression revoked the inhibitory effect of miR-338-3p on CRC progression. Furthermore, exosomal circ_FMN2 overexpression also could facilitate CRC tumor growth in vivo. CONCLUSION: Exosomal circ_FMN2 accelerated CRC progression through miR-338-3p/MSI1 axis, revealing that exosomal circ_FMN2 might be a target for CRC treatment.
Sujet(s)
Tumeurs colorectales , microARN , Animaux , Humains , Souris , Apoptose , Bandages , Lignée cellulaire tumorale , Prolifération cellulaire/génétique , Tumeurs colorectales/génétique , Souris nude , microARN/génétique , Protéines de tissu nerveux , Protéines de liaison à l'ARN/génétiqueRÉSUMÉ
Aiming at the problem of the low accuracy of projector calibration in a structured light system, an improved projector calibration method is proposed in this paper. One of the key ideas is to estimate the sub-pixel coordinates in the projector image plane using local random sample consensus (RANSAC). A bundle adjustment (BA) algorithm is adopted to optimize the calibration parameters to further improve the accuracy and robustness of the projector calibration. After system calibration and epipolar rectification, the mapping relationship between the pixel coordinates and the absolute phase in the projector image plane is established by using cubic polynomial fitting, and the disparity is rapidly solved by using the mapping relationship, which not only ensures the measurement accuracy, but also improves the measurement efficiency. The experimental results demonstrated that the average re-projection error after optimization is reduced to 0.03 pixels, and the proposed method is suitable for high-speed 3D reconstruction without the time-consuming homogenous point searching.
Sujet(s)
Leucémie aiguë promyélocytaire , Thrombocytémie essentielle , Humains , Thrombocytémie essentielle/génétique , Leucémie aiguë promyélocytaire/diagnostic , Leucémie aiguë promyélocytaire/traitement médicamenteux , Leucémie aiguë promyélocytaire/génétique , Translocation génétique , Évolution clonale/génétiqueRÉSUMÉ
BACKGROUND: Colorectal cancer is a common gastrointestinal malignancy worldwide. Many studies have proved that long noncoding RNA alterations participate in colorectal cancer development. This study sought to probe the regulatory mechanism of lncRNA IGF-like family member 2 antisense RNA 1 (IGFL2-AS1) in colorectal cancer cell malignant proliferation. METHODS: LncRNA IGFL2-AS1 expression in colorectal cancer cancer and para-cancerous tissues and colorectal cancer cell lines was detected via quantitative real-time polymerase chain reaction. HCT116 cells were transfected with si-IGFL2-AS1, microRNA (miR)- 433-3p inhibitor or p21 (RAC1)-activated kinase 4, PAK4 and IGFL2-AS1 overexpression vector, followed by assessment of cell proliferation and clone formation using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay and colony formation assay. The subcellular localization of lncRNA IGFL2-AS1 was predicted and testified via the nuclear/cytosol fractionation assay. The downstream miRNA of lncRNA IGFL2-AS1 and downstream target of miRNA were predicted, and their binding relationships were testified using dualluciferase assay and RNA immunoprediction experiment. RESULTS: LncRNA IGFL2-AS1 was abundantly expressed in colorectal cancer tissues and cells. Silencing lncRNA IGFL2-AS1 discouraged HCT116 cell malignant proliferation, while lncRNA IGFL2-AS1 overexpression played an opposite role. LncRNA IGFL2-AS1 was mainly expressed in the cytoplasm of HCT116 cells. LncRNA IGFL2-AS1 bound to miR-433-3p and inhibited its expression. miR-433-3p tar geted PAK4. Silencing lncRNA IGFL2-AS1 facilitated miR-433-3p to suppress PAK4 transcription. miR-433-3p inhibition or PAK4 overexpression partly reversed the inhibition of lncRNA IGFL2-AS1 on HCT116 cell malignant proliferation. CONCLUSION: LncRNA IGFL2-AS1 was abundantly expressed in colorectal cancer tissues and cells, and comparatively bound to miR433-3p to facilitate PAK4 transcription, thus promoting HCT116 cell malignant proliferation.