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Atherosclerosis treatments by gene regulation are garnering attention, yet delivery of gene cargoes to atherosclerotic plaques remains inefficient. Here, we demonstrate that assembly of therapeutic oligonucleotides into a three-dimensional spherical nucleic acid nanostructure improves their systemic delivery to the plaque and the treatment of atherosclerosis. This noncationic nanoparticle contains a shell of microRNA-146a oligonucleotides, which regulate the NF-κB pathway, for achieving transfection-free cellular entry. Upon an intravenous injection into apolipoprotein E knockout mice fed with a high-cholesterol diet, this nanoparticle naturally targets class A scavenger receptor on plaque macrophages and endothelial cells, contributing to elevated delivery to the plaques (â¼1.2% of the injected dose). Repeated injections of the nanoparticle modulate genes related to immune response and vascular inflammation, leading to reduced and stabilized plaques but without inducing severe toxicity. Our nanoparticle offers a safe and effective treatment of atherosclerosis and reveals the promise of nucleic acid nanotechnology for cardiovascular disease.
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Aterosclerosis , MicroARNs , Nanopartículas , Placa Aterosclerótica , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Células Endoteliales/metabolismo , Ratones , Ratones Noqueados , MicroARNs/genética , MicroARNs/uso terapéutico , FN-kappa B/genética , FN-kappa B/metabolismo , Nanopartículas/química , Nanopartículas/uso terapéutico , Oligonucleótidos/uso terapéutico , Placa Aterosclerótica/metabolismo , Receptores Depuradores/metabolismoRESUMEN
OBJECTIVE: To identify the main risk factors for metachronous metastatic nasopharyngeal carcinoma (NPC) in different periods after radiotherapy and estimate the weight of various factors in the early or late metachronous metastasis (EMM/LMM) groups. METHODS: This retrospective registry consists of 4434 patients with newly diagnosed NPC. Cox regression analysis was used to assess the independent significance of various risk factors. The Interactive Risk Attributable Program (IRAP) was used to calculate the attributable risks (ARs) for metastatic patients during different periods. RESULTS: Among 514 metastatic patients, 346 (67.32%) patients diagnosed with metastasis within 2 years after treatment were classified into the EMM group, while other 168 patients were classified into the LMM group. The ARs of T-stage, N-stage, pre-Epstein-Barr virus (EBV) DNA, post-EBV DNA, age, sex, pre-neutrophil-to-lymphocyte ratio, pre-platelet-to-lymphocyte ratio, pre-hemoglobin (HB), and post-HB were 20.19, 67.25, 2.81, 14.28, 18.50, - 11.17%, 14.54, 9.60, 3.74% and - 9.79%, respectively, in the EMM group. In the LMM group, the corresponding ARs were 3.68, 49.11, - 18.04%, 2.19, 6.11, 0.36, 4.62, 19.77, 9.57 and 7.76%, respectively. After multivariable adjustment, the total AR for tumor-related factors was 78.19%, and that for patient-related factors was 26.07% in the EMM group. In the LMM group, the total AR of tumor-related factors was 43.85%, while the weights of patient-related factors was 39.97%. In addition, except for these identified tumor- and patient-related factors, other unevaluated factors played a more important role in patients with late metastasis, with the weight increasing by 15.77%, from 17.76% in the EMM group to 33.53% in the LMM group. CONCLUSION: Most metachronous metastatic NPC cases occurred in the first 2 years after treatment. Early metastasis was mainly affected by tumor-related factors, which accounted for a declining percentage in the LMM group.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Estudios Retrospectivos , Herpesvirus Humano 4/genética , Factores de Riesgo , Pronóstico , ADN ViralRESUMEN
Nanosubstrate engineering is an established approach for modulating cellular responses, but it remains infrequently exploited to facilitate the intracellular delivery of nanoparticles (NPs). We report nanoscale roughness of the extracellular environment as a critical parameter for regulating the cellular uptake of NPs. After seeding cells atop a substrate that contains randomly immobilized gold NPs (termed AuNP-S) with sub-10 nm surface roughness, we demonstrate that such cells internalize up to â¼100-fold more poly(ethylene glycol)-coated AuNPs (Au@PEG NPs) than those cells seeded on a conventional flat culture plate. Our result is generalizable to 4 different cell types and Au@PEG NPs modified with 13 different hydrocarbyl functional groups. Conditioning cells to AuNP-S not only leads to upregulation of clathrin- and integrin-related genes, but also supports elevated uptake of Au@PEG NPs via clathrin-mediated endocytosis. Our data suggest a simple and robust method for boosting the intracellular delivery of nanomedicines by nanosubstrate engineering.
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Nanopartículas del Metal , Nanopartículas , Clatrina , Endocitosis , Oro , PolietilenglicolesRESUMEN
Ppardδ, one of the lipid-activated nuclear receptor expressed in many cell types to activate gene transcription, also regulates cellular functions other than lipid metabolism. The mechanism regulating the function of antigen-presenting cells during the development of atherosclerosis is not fully understood. Here we aimed to study the involvement of PPARδ in CD11c+ cells in atherosclerosis. We used the Cre-loxP approach to make conditional deletion of Ppard in CD11c+ cells in mice on Apoe-/- background, which were fed with high cholesterol diet to develop atherosclerosis. Ppard deficiency in CD11c+ cells attenuated atherosclerotic plaque formation and infiltration of myeloid-derived dendritic cells (DCs) and T lymphocytes. Reduced lesion was accompanied by reduced activation of dendritic cells, and also a reduction of activation and differentiation of T cells to Th1 cells. In addition, DC migration to lymph node was also attenuated with Ppard deletion. In bone marrow-derived DCs, Ppard deficiency reduced palmitic acid-induced upregulation of co-stimulatory molecules and pro-inflammatory cytokine IL12 and TNFα. Our results indicated PPARδ activation by fatty acid resulted in the activation of myeloid DCs and subsequent polarization of T lymphocytes, which contributed to atherosclerosis in Apoe-/- mice. These findings also reveal the potential regulatory role of PPARδ in antigen presentation to orchestrate the immune responses during atherosclerosis.
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Aterosclerosis/metabolismo , Células Dendríticas/metabolismo , Eliminación de Gen , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Antígenos CD11/genética , Antígenos CD11/metabolismo , Células Cultivadas , Interleucina-12/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptores Citoplasmáticos y Nucleares/genética , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Polyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion of an unstable CAG repeat in the coding region of the affected genes. Hallmarks of polyQ diseases include the accumulation of misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ diseases are currently incurable, highlighting the urgent need for approaches that inhibit the formation of disaggregate cytotoxic polyQ protein inclusions. Here, we screened for bisamidine-based inhibitors that can inhibit neuronal polyQ protein inclusions. We demonstrated that one inhibitor, AQAMAN, prevents polyQ protein aggregation and promotes de-aggregation of self-assembled polyQ proteins in several models of polyQ diseases. Using immunocytochemistry, we found that AQAMAN significantly reduces polyQ protein aggregation and specifically suppresses polyQ protein-induced cell death. Using a recombinant and purified polyQ protein (thioredoxin-Huntingtin-Q46), we further demonstrated that AQAMAN interferes with polyQ self-assembly, preventing polyQ aggregation, and dissociates preformed polyQ aggregates in a cell-free system. Remarkably, AQAMAN feeding of Drosophila expressing expanded polyQ disease protein suppresses polyQ-induced neurodegeneration in vivo In addition, using inhibitors and activators of the autophagy pathway, we demonstrated that AQAMAN's cytoprotective effect against polyQ toxicity is autophagy-dependent. In summary, we have identified AQAMAN as a potential therapeutic for combating polyQ protein toxicity in polyQ diseases. Our findings further highlight the importance of the autophagy pathway in clearing harmful polyQ proteins.
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Autofagia , Modelos Animales de Enfermedad , Furanos/farmacología , Cuerpos de Inclusión/patología , Enfermedades Neurodegenerativas/prevención & control , Neuronas/patología , Péptidos/metabolismo , Animales , Citoprotección , Drosophila melanogaster/fisiología , Furanos/química , Humanos , Cuerpos de Inclusión/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Péptidos/química , RatasRESUMEN
Macrophage is one of the important players in immune response which perform many different functions during tissue injury, repair, and regeneration. Studies using animal models of cardiovascular diseases have provided a clear picture describing the effect of macrophages and their phenotype during injury and regeneration of various vascular beds. Many data have been generated to demonstrate that macrophages secrete many important factors including cytokines and growth factors to regulate angiogenesis and arteriogenesis, acting directly or indirectly on the vascular cells. Different subsets of macrophages may participate at different stages of vascular repair. Recent findings also suggest a direct interaction between macrophages and other cell types during the generation and repair of vasculature. In this short review, we focused our discussion on how macrophages adapt to the surrounding microenvironment and their potential interaction with other cells, in the context of vascular repair supported by evidences mostly from studies using hindlimb ischemia as a model for studying post-ischemic vascular repair.
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Isquemia/complicaciones , Macrófagos/citología , Neovascularización Patológica/terapia , Regeneración , Ingeniería de Tejidos , Animales , Humanos , Neovascularización Patológica/etiología , FenotipoRESUMEN
Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated ß-galactosidase (ß-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3ß/C/EBPα signaling pathway. These results suggest that the mTORC2/Akt/GSK-3ß/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.
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Senescencia Celular/fisiología , Células Endoteliales/fisiología , Diana Mecanicista del Complejo 2 de la Rapamicina/fisiología , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Asthma is the chronic pulmonary inflammatory response that could lead to respiratory failure when allergic reactions exacerbate. It is featured by type 2 immunity with eosinophilic inflammation, mucus, and IgE production, and Th2 cytokine secretion upon repeated challenge of allergens. The symptom severity of asthma displays an apparent circadian rhythm with aggravated airway resistance in the early morning in patients. Bmal1 is the core regulator of the circadian clock, while the regulatory role of Bmal1 in asthma remains unclear. Here, we investigate whether the myeloid Bmal1 is involved in the pathogenesis of house dust mite (HDM)-induced lung allergy. We found that knockdown of Bmal1 in macrophages suppressed the time-of-day variance of the eosinophil infiltration in the alveolar spaces in chronic asthmatic mice. This was accompanied by decreased bronchial mucus production, collagen deposition, and HDM-specific IgE production. However, the suppression effects of myeloid Bmal1 deletion did not alter the allergic responses in short-term exposure to HDM. The transcriptome profile of alveolar macrophages (AMs) showed that Bmal1-deficient AMs have enhanced phagocytosis and reduced production of allergy-mediating prostanoids thromboxane A2 and prostaglandin F2α synthesis. The attenuated thromboxane A2 and prostaglandin F2α may lead to less induction of the eosinophil chemokine Ccl11 expression in bronchial epithelial cells. In summary, our study demonstrates that Bmal1 ablation in macrophages attenuates eosinophilic inflammation in HDM-induced chronic lung allergy, which involves enhanced phagocytosis and reduced prostanoid secretion.
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Asma , Eosinofilia , Hipersensibilidad , Humanos , Ratones , Animales , Pyroglyphidae , Dinoprost/metabolismo , Tromboxano A2/metabolismo , Pulmón , Alérgenos , Eosinofilia/metabolismo , Eosinofilia/patología , Inmunoglobulina E/metabolismo , Inflamación/patología , Modelos Animales de EnfermedadRESUMEN
Atherosclerosis is initiated with endothelial cell (EC) dysfunction and vascular inflammation under hyperlipidemia. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase. However, the specific role of endothelial SIRT3 during atherosclerosis remains poorly understood. The present study aims to study the role and mechanism of SIRT3 in EC function during atherosclerosis. Wild-type Sirt3f/f mice and endothelium-selective SIRT3 knockout Sirt3f/f; Cdh5Cre/+ (Sirt3EC-KO) mice are injected with adeno-associated virus (AAV) to overexpress PCSK9 and fed with high-cholesterol diet (HCD) for 12 weeks to induce atherosclerosis. Sirt3EC-KO mice exhibit increased atherosclerotic plaque formation, along with elevated macrophage infiltration, vascular inflammation, and reduced circulating L-arginine levels. In human ECs, SIRT3 inhibition resulted in heightened vascular inflammation, reduced nitric oxide (NO) production, increased reactive oxygen species (ROS), and diminished L-arginine levels. Silencing of SIRT3 results in hyperacetylation and deactivation of Argininosuccinate Synthase 1 (ASS1), a rate-limiting enzyme involved in L-arginine biosynthesis, and this effect is abolished in mutant ASS1. Furthermore, L-arginine supplementation attenuates enhanced plaque formation and vascular inflammation in Sirt3EC-KO mice. This study provides compelling evidence supporting the protective role of endothelial SIRT3 in atherosclerosis and also suggests a critical role of SIRT3-induced deacetylation of ASS1 by ECs for arginine synthesis.
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Aterosclerosis , Sirtuina 3 , Humanos , Ratones , Animales , Proproteína Convertasa 9 , Argininosuccinato Sintasa , Arginina , Endotelio , InflamaciónRESUMEN
Background: Coronavirus disease 2019 (COVID-19) has placed a tremendous burden on the world's healthcare systems, prompting medical professionals worldwide to diligently research and experiment with treatment methods to prevent infection and alleviate symptoms. Previous studies have shown the potential of nasal irrigation in reducing viral clearance time and alleviating local symptoms of COVID-19. However, views differ regarding its efficacy in improving systemic symptoms. Thus, we sought to examine whether saline nasal irrigation might play a role in treatment and self-care after COVID-19 infection, but further validation is still necessary. Methods: We conducted a retrospective analysis of 468 patients and 51 healthcare personnel concurrently. The participants were grouped based on whether they received saline nasal irrigation. We used χ2 tests and Fisher's exact tests to assess the differences in the rates of COVID-19 infection and the rates of developing a fever after COVID-19 infection among different groups. Additionally, we used independent samples t-tests and Mann-Whitney U tests to evaluate differences in the maximum fever temperature and fever duration among participants with fever in different groups. Results: The rate of developing a fever after COVID-19 infection was lower (37.7%) in the patients who underwent saline nasal irrigation. Among all febrile patients, there was no difference in the highest fever temperature, but patients who underwent saline nasal irrigation had a shorter fever duration (1.72±1.05 days). Additionally, the rate of COVID-19 infection and the rate of developing a fever were higher, and fever symptoms were more severe in the healthcare worker group than in the patient group. Conclusions: Saline nasal irrigation can alleviate symptoms caused by COVID-19 infection.
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OBJECTIVES: Current guidelines recommend universal PET/CT screening for metastases staging in newly diagnosed nasopharyngeal carcinoma (NPC) despite the low rate of synchronous distant metastasis (SDM). The study aims to achieve individualized screening recommendations of NPC based on the risk of SDM. METHODS AND MATERIALS: 18 pre-treatment peripheral blood indicators was retrospectively collected from 2271 primary NPC patients. A peripheral blood risk score (PBRS) was constructed by indicators associated with SDM on least absolute shrinkage and selection operator (LASSO) regression. The PBRS-based distant metastases (PBDM) model was developed from features selected by logistic regression analyses in the training cohort and then validated in the validation cohort. Receiver operator characteristic curve analysis, calibration curves, and decision curve analysis were applied to evaluate PBDM model performance. RESULTS: Pre-treatment Epstein-Barr viral DNA copy number, percentage of total lymphocytes, serum lactate dehydrogenase level, and monocyte-to-lymphocyte ratio were most strongly associated with SDM in NPC and used to construct the PBRS. Sex (male), T stage (T3-4), N stage (N2-3), and PBRS (≥1.076) were identified as independent risk factors for SDM and applied in the PBDM model, which showed good performance. Through the model, patients in the training cohort were stratified into low-, medium-, and high-risk groups. Individualized screening recommendations were then developed for patients with differing risk levels. CONCLUSION: The PBDM model offers individualized recommendations for applying PET/CT for metastases staging in NPC, allowing more targeted screening of patients with greater risk of SDM compared with current recommendations.
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Carcinoma Nasofaríngeo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Carcinoma Nasofaríngeo/diagnóstico por imagen , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/diagnóstico , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Adulto , Estudios Retrospectivos , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/diagnóstico , Anciano , Metástasis de la Neoplasia , Factores de Riesgo , Adulto Joven , Medicina de Precisión/métodosRESUMEN
BACKGROUND: To develop a common follow-up strategy for appropriate imaging examination at an appropriate time for nasopharyngeal carcinoma (NPC). METHODS: Independent prognostic factors were identified by Cox regression analysis, and a nomogram model was developed. Random survival forest (RSF) model was constructed to depict probability of disease failure during a 5-year follow-up and establish a reasonable risk-based follow-up strategy. RESULTS: The nomogram model finally categorized the patients into three risk groups. RSF model demonstrated distribution trends for local and regional recurrences, bone metastasis, liver metastasis, and lung metastasis of NPC. Adequate imaging at follow-up should be considered between 10 and 21 months for patients at moderate-risk of recurrence or metastasis and 7-36 months for those at high-risk. CONCLUSIONS: The temporal distribution of incidence rates of recurrence or metastasis varied among different risk groups. We recommend implementing a focused and targeted imaging surveillance intervention at appropriate times to improve its efficiency and reduce costs.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo , Pronóstico , Estudios de Seguimiento , Estadificación de Neoplasias , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: This study inventively combines epidermal growth factor receptor (EGFR) expression of the primary lesion and standardized uptake value (SUV) of positron emission tomography and computed tomography (PET/CT) to predict the prognosis of nasopharyngeal carcinoma (NPC). This study aimed to evaluate the predictive efficacy of maximum standard uptake value (SUVmax) and EGFR for treatment failure in patients with NPC. METHODS: This retrospective study reviewed the results of EGFR expression and pretreatment 18F-FDG PET/CT of 313 patients with NPC. Time-dependent receiver operator characteristics was used for analyzing results and selecting the optimal cutoff values. Cox regression was used to screen out multiple risk factors. Cumulative survival rate was calculated by Kaplan-Meier. RESULTS: The selected cutoff value of SUVmax-T was 8.5. The patients were categorized into four groups according to EGFR expression and SUVmax-T. There were significant differences in the 3-year local recurrence-free survival (LRFS) (p = 0.0083), locoregional relapse-free survival (LRRFS) (p = 0.0077), distant metastasis-free survival (DMFS) (p = 0.013), and progression-free survival (PFS) (p = 0.0018) among the four groups. Patients in the EGFR-positive and SUVmax-T > 8.5 group had the worst survival, while patients in the EGFR-negative and SUVmax-T ≤ 8.5 group had the best prognosis. Subsequently, patients with only positive EGFR expression or high SUVmax-T were classified as the middle-risk group. There were also a significant difference in 3-year overall survival among the three risk groups (p = 0.034). SUVmax-T was associated with regional recurrence-free survival and LRRFS in multivariate analysis, whereas EGFR was an independent prognostic factor for LRRFS, DMFS, and PFS. CONCLUSION: The combination of SUVmax-T and EGFR expression can refine prognosis and indicate clinical therapy.
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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Receptores ErbB/metabolismo , Fluorodesoxiglucosa F18 , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/terapia , Recurrencia Local de Neoplasia/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , Pronóstico , Radiofármacos , Estudios Retrospectivos , Insuficiencia del TratamientoRESUMEN
PURPOSE: To assess whether the high metabolic region of fluorine-18-fluorode-oxyglucose (18F-FDG) in the primary lesion is the crux for recurrence in patients with nasopharyngeal carcinoma (NPC), to assess the feasibility and rationale for use of biological target volume (BTV) based on 18F-FDG positron emission tomography/computed tomography (18F-FDG-PET/CT). METHODS: The retrospective study included 33 patients with NPC who underwent 18F-FDG-PET/CT at the time of initial diagnosis as well as the time of diagnosis of local recurrence. Paired 18F-FDG-PET/CT images for primary and recurrent lesion were matched by deformation coregistration method to determine the cross-failure rate between two lesions. RESULTS: The median volume of the Vpri (primary tumor volume using the SUV thresholds of 2.5), the Vhigh (the volume of high FDG uptake using the SUV50%max isocontour), and the Vrecur (the recurrent tumor volume using the SUV thresholds of 2.5) were 22.85, 5.57, and 9.98 cm3, respectively. The cross-failure rate of Vrecurâ©high showed that 82.82% (27/33) of local recurrent lesions had < 50% overlap volume with the region of high FDG uptake. The cross-failure rate of Vrecurâ©pri showed that 96.97% (32/33) of local recurrent lesions had > 20% overlap volume with the primary tumor lesions and the median cross rate was up to 71.74%. CONCLUSION: 18F-FDG-PET/CT may be a powerful tool for automatic target volume delineation, but it may not be the optimal imaging modality for dose escalation radiotherapy based on applicable isocontour. The combination of other functional imaging could delineate the BTV more accurately.
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Neoplasias Nasofaríngeas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18 , Estudios Retrospectivos , Flúor , Recurrencia Local de Neoplasia , Tomografía de Emisión de Positrones , Carcinoma Nasofaríngeo , RadiofármacosRESUMEN
INTRODUCTION: This study aimed to evaluate the survival and prognosis of older patients with nasopharyngeal carcinoma (NPC) who received intensity-modulated radiotherapy (IMRT) alone versus IMRT plus chemotherapy using propensity score matching (PSM). MATERIALS AND METHODS: We enrolled 841 older patients with NPC aged 60 years and above without metastasis receiving IMRT alone or chemoradiotherapy from 2012 to 2019. The comorbidity was assessed by adult comorbidity evaluation (ACE-27). PSM (1:3 ratio) was conducted between the two treatment groups based on four clinical factors including age, T-stage, N-stage, and ACE-27. Differences in overall survival (OS) and cancer-specific survival (CSS) were analyzed by the Kaplan-Meier method and Cox proportional hazard model. RESULTS: A total of 841 patients with NPC were included in the study, there were 94 patients in the IMRT alone group and 747 patients in the chemoradiotherapy (CRT) group. After a 1:3 ratio PSM, 89 patients underwent IMRT alone and 223 patients underwent CRT. The baseline analysis showed an insignificant difference after PSM (P > 0.05). In multivariate analysis, we found that ACE-27 (≥2) was associated with worse five-year OS and CSS (HR = 1.994, 95%CI: 1.276-3.116, P = 0.002; HR = 1.849, 95%CI: 1164-2.935, P = 0.009, respectively). Chemotherapy was an independent prognosticator of better five-year OS and CSS (HR = 0.333, 95%CI: 0.213-0.552, P < 0.001; HR = 0.327, 95%CI: 0.204-0.524, P < 0.001, respectively). In terms of subgroup analysis, chemotherapy was a statistically beneficial predictor for stage III-IV patients (P < 0.05), but no significant difference in stage II patients (P > 0.05). About the adverse events, the incidence of hepatotoxicity (P = 0.002), neutropenia (P < 0.001), anemia (P < 0.001), and thrombocytopenia (P < 0.001) were significantly higher in the CRT group. DISCUSSION: Combined modality therapy was associated with improved five-year OS and CSS in older adults with stage III-IV NPC, but was not associated with improved survival over IMRT alone in patients with stage II disease. Risk factors including T3-4 disease, positive lymph nodes, ACE-27 score ≥ 2, and IMRT alone were were associated with worse OS and CSS. There was a significantly higher incidence of hepatotoxicity and blood toxicity in the CRT group.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Neoplasias Nasofaríngeas , Radioterapia de Intensidad Modulada , Humanos , Anciano , Carcinoma Nasofaríngeo/tratamiento farmacológico , Radioterapia de Intensidad Modulada/efectos adversos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Puntaje de Propensión , Estudios Retrospectivos , Quimioradioterapia/métodos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Estadificación de NeoplasiasRESUMEN
BACKGROUND: To identify patients at low risk of synchronous bone metastasis who should not receive bone scans when initially diagnosed with nasopharyngeal carcinoma (NPC). METHODS: In total, 6652 patients were enrolled in the training cohort and 1919 patients in the multicenter external validation cohort. Logistic regression analyses were performed to assess independent predictors of synchronous bone metastasis for the nomogram model. RESULTS: After risk stratification, 46.3% (3081/6652) patients were separated into the low-risk group with an incidence of 0.71% for synchronous bone metastasis. The odds ratio of the intermediate and high-risk groups was 5.61 and 23.82 times that of the low-risk group, respectively. For patients with high EBV DNA, we recommend routine screening for N2-3 female patients, but that all male subgroups are screened. CONCLUSIONS: Bone scans should not be routine. Patients in the low-risk group should not be screened, which would avoid excessive radiation and economize iatrical resource.
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Neoplasias Nasofaríngeas , Humanos , Masculino , Femenino , Carcinoma Nasofaríngeo/patología , Estudios Retrospectivos , Neoplasias Nasofaríngeas/patología , Estadificación de Neoplasias , Nomogramas , Factores de Riesgo , PronósticoRESUMEN
Atherosclerosis is initiated by endothelial cell dysfunction and vascular inflammation under the condition of hyperlipidemia. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial deacetylase, which plays a key role in maintaining normal mitochondrial function. The present study tested whether endothelial-selective SIRT3 deletion accelerates vascular inflammation and oxidative stress, and assessed the protective effect of NAD+ to alleviate these changes in endothelial cells and in mouse models of atherosclerosis. We found that the selective deletion of SIRT3 in endothelial cells further impaired endothelium-dependent vasodilatation in the aorta treated with IL-1ß, which was accompanied by upregulation of vascular inflammation markers and mitochondrial superoxide overproduction. Excepting the dysfunction of endothelium-dependent vasodilatation, such effects could be attenuated by treatment with NAD+. In human umbilical vein endothelial cells, SIRT3 silencing potentiated the induction of inflammatory factors by IL-1ß, including VCAM-1, ICAM-1, and MCP1, and the impairment of mitochondrial respiration, both of which were alleviated by NAD+ treatment. In ApoE-deficient mice fed with a high-cholesterol diet, supplementation with nicotinamide riboside, the NAD+ precursor, reduced plaque formation, improved vascular function, and diminished vascular inflammation. Our results support the SIRT3-dependent and -independent of NAD+ to improve endothelial function in atherosclerosis.
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AIMS: In addition to its involvement of inflammatory responses, limited information is available on the phenotype and behaviour of vascular macrophages during hypertensive vascular remodelling. Here, we aim at studying the contribution of BMAL1 to the pro-fibrotic macrophage phenotype in the vasculature during hypertension, which leads to enhanced vascular remodelling and promoted blood pressure increase. METHODS AND RESULTS: Wild type Bmal1f/f and myeloid cell selective Bmal1 knockout Bmal1f/f; LysMCre/+ mice were infused with AngII for 4 weeks to induce hypertension. AngII-induced blood pressure increase, vascular media thickness and vascular dysfunction were enhanced in Bmal1f/f; LysMCre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1f/f; LysMCre/+ mice also have more up-regulations of MMP9 and MMP13 expression in the vascular wall, accompanied by enhanced collagen deposition after AngII infusion. Loss of Bmal1 in bone marrow-derived macrophages enhanced STAT6 activation induced by IL4, and the subsequent MMP13 up-regulation and activity. In macrophages, loss of Bmal1 enhanced the phosphorylation and nuclear translocation of STAT6 triggered by IL4, through possibly a direct interaction between BMAL1 and STAT6. To further determine whether IL4-induced signalling in macrophage contributes to enhanced vascular remodelling in hypertensive mice, we showed that deletion of myeloid IL4Rα in Il4raf/f; LysMCre/+ mice attenuated blood pressure increase and hypertensive vascular remodelling after AngII infusion. CONCLUSIONS: Our results suggested a tonic effect of BMAL1 deletion on hypertensive vascular remodelling. BMAL1 might inhibit IL4-STAT6 signalling in macrophages through the interaction with STAT6 to reduce STAT6 activation and target gene transcription, especially MMP9 and MMP13, contributing to vascular remodelling.
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Factores de Transcripción ARNTL , Hipertensión , Factor de Transcripción STAT6 , Remodelación Vascular , Animales , Ratones , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Hipertensión/metabolismo , Interleucina-4/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismoRESUMEN
Diabetic vasculopathy is a major health problem worldwide. Peripheral arterial disease (PAD), and in its severe form, critical limb ischemia is a major form of diabetic vasculopathy with limited treatment options. Existing literature suggested an important role of PPARδ in vascular homeostasis. It remains elusive for using PPARδ as a potential therapeutic target due to mostly the side effects of PPARδ agonists. To explore the roles of PPARδ in endothelial homeostasis, endothelial cell (EC) selective Ppard knockout and controlled mice were subjected to hindlimb ischemia (HLI) injury. The muscle ECs were sorted for single-cell RNA sequencing (scRNA-seq) analysis. HLI was also performed in high fat diet (HFD)-induced obese mice to examine the function of PPARδ in obese mice with delayed vascular repair. Adeno-associated virus type 1 (AAV1) carrying ICAM2 promoter to target endothelium for overexpressing PPARδ was injected into the injured muscles of normal chow- and HFD-fed obese mice before HLI surgery was performed. scRNA-seq analysis of ECs in ischemic muscles revealed a pivotal role of PPARδ in endothelial homeostasis. PPARδ expression was diminished both after HLI injury, and also in obese mice, which showed further delayed vascular repair. Endothelium-targeted delivery of PPARδ by AAV1 improved perfusion recovery, increased capillary density, restored endothelial integrity, suppressed vascular inflammation, and promoted muscle regeneration in ischemic hindlimbs of both lean and obese mice. Our study indicated the effectiveness of endothelium-targeted PPARδ overexpression for restoring functional vasculature after ischemic injury, which might be a promising option of gene therapy to treat PAD and CLI.
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Diabetes Mellitus , PPAR delta , Lesiones del Sistema Vascular , Animales , Dependovirus/genética , Dependovirus/metabolismo , Diabetes Mellitus/genética , Modelos Animales de Enfermedad , Endotelio , Miembro Posterior/metabolismo , Isquemia/complicaciones , Isquemia/metabolismo , Isquemia/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Músculo Esquelético/metabolismo , Neovascularización Fisiológica , PPAR delta/genética , PPAR delta/metabolismo , SerogrupoRESUMEN
Rationale: Restoration of vascular perfusion in peripheral arterial disease involves a combination of neovessel formation and the functional restoration of vascular endothelium. Previous studies indicated that ligand-dependent PPARδ activation enhances angiogenesis. However, how PPARδ is triggered by hypoxia and its downstream effects during post-ischemic vascular repair was not well understood. Methods: We induced experimental hindlimb ischemia in endothelial cell selective Ppard knockout induced by Cdh5-Cre mediated deletion of floxed Ppard allele in mice and their wild type control and observed blood perfusion, capillary density, vascular relaxation, and vascular leakage. Results: Deletion of endothelial Ppard delayed perfusion recovery and tissue repair, accompanied by delayed post-ischemic angiogenesis, impaired restoration of vascular integrity, more vascular leakage and enhanced inflammatory responses. At the molecular level, hypoxia upregulated and activated PPARδ in endothelial cells, whereas PPARδ reciprocally stabilized HIF1α protein to prevent its ubiquitin-mediated degradation. PPARδ directly bound to the oxygen-dependent degradation domain of HIF1α at the ligand-dependent domain of PPARδ. Importantly, this HIF1α-PPARδ interaction was independent of PPARδ ligand. Adeno-associated virus mediated endothelium-targeted overexpression of stable HIF1α in vivo improved perfusion recovery, suppressed vascular inflammation, and enhanced vascular repair, to counteract with the effect of Ppard knockout after hindlimb ischemia in mice. Conclusions: In summary, hypoxia-induced, ligand-independent activation of PPARδ in ECs stabilizes HIF1α and serves as a critical regulator for HIF1α activation to facilitate the post-ischemic restoration of vascular homeostasis.