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Background: Prior research suggests a potential link between ABO blood types and susceptibility to various malignancies. The correlation between ABO blood types and hematological myeloid neoplasms, however, remains inadequately explored. Objective: This study investigates the association between ABO blood groups and the incidence of hematological myeloid neoplasms in adolescents and adults. Methods: In this retrospective clinical study, 1,022 adolescent and adult cases of myeloid neoplasms diagnosed at our institution were initially considered. After excluding conditions potentially linked to ABO blood types from prior studies, 792 eligible cases were analyzed. These cases were categorized based on disease subtypes and compared with a control group for blood type distribution. Results: Our findings reveal a significantly higher prevalence of blood type A in patients with myeloid neoplasms compared to the control group, except for chronic myelocytic leukemia and myeloproliferative neoplasms. Conversely, the prevalence of blood type AB in myeloid neoplasms was notably lower than in the control group. Conclusion: The study suggests a potential association between ABO blood types and the risk of developing hematological myeloid neoplasms in adolescents and adults. Further research is warranted to elucidate the underlying mechanisms of this relationship.
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Deep learning-based predictive models, leveraging Electronic Health Records (EHR), are receiving increasing attention in healthcare. An effective representation of a patient's EHR should hierarchically encompass both the temporal relationships between historical visits and medical events, and the inherent structural information within these elements. Existing patient representation methods can be roughly categorized into sequential representation and graphical representation. The sequential representation methods focus only on the temporal relationships among longitudinal visits. On the other hand, the graphical representation approaches, while adept at extracting the graph-structured relationships between various medical events, fall short in effectively integrate temporal information. To capture both types of information, we model a patient's EHR as a novel temporal heterogeneous graph. This graph includes historical visits nodes and medical events nodes. It propagates structured information from medical event nodes to visit nodes and utilizes time-aware visit nodes to capture changes in the patient's health status. Furthermore, we introduce a novel temporal graph transformer (TRANS) that integrates temporal edge features, global positional encoding, and local structural encoding into heterogeneous graph convolution, capturing both temporal and structural information. We validate the effectiveness of TRANS through extensive experiments on three real-world datasets. The results show that our proposed approach achieves state-of-the-art performance.
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Aims: Cerebral ischemic preconditioning is a neuroprotective therapy against cerebral ischemia and ischemia-reperfusion injury. This study aims to demonstrate the alternation of gene expression in exosomes from brain tissue of mice after ischemic preconditioning and their potential functions. Methods: Ten mice were divided into the sham and the cerebral ischemic preconditioning groups. Their brain tissues were harvested, from which the exosomes were extracted. The characteristics and protective effects of exosomes were evaluated. Whole transcriptome sequencing was used to demonstrate the gene expression discrepancy between the exosomes from the two groups of mice brains. Volcano graphs and heatmaps were used to picture the difference in expression quantity of mRNA, lncRNA, and circRNA. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to demonstrate the functions of differentially expressed RNAs. Results: Exosomes were successfully extracted, and those from the cerebral ischemic preconditioning group had better protective effects on cells that received oxygen-glucose deprivation and restoration injury. A total of 306 mRNAs and 374 lncRNAs were significantly upregulated, and 320 mRNAs and 405 lncRNAs were significantly downregulated in the preconditioning group. No circRNAs were differentially expressed between the two groups. GO and KEGG pathway analysis indicated that the functions of differentially expressed RNAs were related to both neural protective and injurious effects. Conclusion: The brain-derived exosomes may participate in the neuroprotective effect of cerebral ischemic preconditioning. Thorough research is necessary to investigate exosome functions derived from the ischemic preconditioned brain.
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BACKGROUND: When considering hepatectomy for elderly HCC patients, it's essential to assess surgical safety and survival benefits. This study investigated the impact of preoperative frailty, assessed with the Clinical Frailty Scale (CFS), on outcomes for octogenarians undergoing HCC hepatectomy. METHODS: A retrospective cohort study of octogenarians who had hepatectomy for HCC between 2010 and 2022 at 16 hepatobiliary centers was conducted. Patients were categorized as frail or non-frail based on preoperative CFS, with frailty defined as CFS ≥5. The primary endpoints were overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS), with perioperative outcomes as secondary endpoints. RESULTS: Among 240 octogenarians, 105 were characterized as being frail. Frail patients had a higher incidence of postoperative 30-day morbidity and postoperative 30-day and 90-day mortality versus non-frail patients. Meanwhile, 5-year OS, RFS and CSS among frail patients were lower compared with non-frail patients. Univariable and multivariable analysis revealed that preoperative frailty was an independent risk factor of postoperative 30-day morbidity (OR: 2.060), OS (HR: 2.384), RFS (HR: 2.190) and CSS (HR: 2.203). CONCLUSION: Preoperative frailty, as assessed by the CFS, was strongly associated with both short-term outcomes and long-term survival among octogenarians undergoing hepatectomy for HCC. Incorporating frailty assessment into the preoperative evaluation may help optimize patient selection and perioperative care.
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This study aims to elucidate the pivotal role of aldolase A (ALDOA) in retinoblastoma (RB) and evaluate the potential of the ALDOA inhibitor itaconate in impeding RB progression. Utilizing single-cell RNA sequencing, ALDOA consistently exhibits overexpression across diverse cell types, particularly in cone precursor cells, retinoma-like cells, and retinoblastoma-like cells. This heightened expression is validated in RB tissues and cell lines. ALDOA knockdown significantly diminishes RB cell viability, impedes colony formation, and induces notable metabolic alterations. RNA-seq analysis identifies SUSD2, ARHGAP27, and CLK2 as downstream genes associated with ALDOA. The application of itaconate demonstrates efficacy in inhibiting RB cell proliferation, validated through in vitro and in vivo models. This study emphasizes ALDOA as a promising target for innovative RB therapies, with potential implications for altering tumor energy metabolism.
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Background: Congenital tufting enteropathy (CTE) is a rare cause of intractable congenital diarrhea in children, always resulting in parenteral nutrition (PN) dependency. We aimed to report novel mutations in Chinese patients and to illustrate the clinical, histopathological, and molecular features of CTE in China. Case Description: We report three cases of CTE diagnosed with whole-exome sequencing (WES) and MOC31 [a monoclonal antibody of epithelial cell adhesion molecule (EPCAM)] immunohistochemistry. The main manifestations in the three patients were watery diarrhea and growth retardation. Upper endoscopy in three patients revealed villous atrophy of the duodenal mucosa. Histological examination revealed villus abnormalities and two patients with focal tufting. All of the three patients revealed a complete absence of EPCAM expression through MOC31 immunohistochemistry. Five novel mutations, including c.319delG, c.505_507delGAG, c.491+1G>C, c.60del (p.F20Lfs*17), and c.353G>A, in EPCAM were identified through molecular analysis. In our review, there were 18 different mutations in 11 patients from nine studies, with 12 mutations reported only once. In China, 73% of the patients were compound heterozygotes, and most of the pathogenic variants were in exon 3. All patients presented with congenital diarrhea and needed PN because of growth retardation, even when diarrhea was improved. Of the 11 patients, 3 (27%) died. Conclusions: CTE is rare and fatal, and lacks characteristic changes during endoscopy. Patients with CTE require early diagnosis via histological examination and genetic detection to improve survival.
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BACKGROUND: Few studies have been conducted on the dynamic survival rates of follicular thyroid cancer (FTC). This study aimed to ascertain how the survival probability of patients with FTC changes over time. METHODS: In this retrospective analysis, 10,617 patients diagnosed with FTC between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) database were included. Actuarial disease-specific survival (DSS) was estimated using the Kaplan-Meier method, and the log-rank test was used for comparisons. The annual hazard of mortality was determined using the hazard function, and the conditional survival (CS) was calculated using the life table method. RESULTS: A total of 459 (4.3%) patients died of FTC, and the 5-year and 10-year DSS rates were 96.6 ± 0.2% and 94.6 ± 0.3%, respectively. There was a statistically significant difference in the DSS rate between patients with different SEER combined summary stages (P < 0.001). The annual hazard curve for cancer mortality in the entire study cohort displayed a steep downward trend with a slight peak at 2.5 years after diagnosis, followed by a gradual decline. Patients with distant metastases exhibited a higher mortality hazard curve and more notable declining trend. CS demonstrated an upward trend across the entire study population, with the most pronounced trend in patients with distant metastases. CONCLUSION: Prognosis improved over time in a stage-dependent manner in patients with FTC after diagnosis. The most significant improvement was observed in the patients with distant metastases. Notably, dynamic survival estimations, such as death hazard and conditional survival analysis, provide more precise survival projections than traditional survival analysis for FTC survivors.
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BACKGROUND: Branch atheromatous disease (BAD)-related stroke has emerged as a meaningful subtype of ischemic stroke yet remained understudied. We aimed to investigate the demographic, clinical, therapeutic, and prognostic characteristics of BAD-related stroke. METHODS: The BAD-study was a nationwide, multicenter, prospective, observational cohort study in 20 Chinese hospitals from June 2021 to June 2023, enrolling patients aged 18 to 80 years with BAD-related stroke within 72 hours of onset. Eligible single subcortical infarct in the territory of lenticulostriate artery and paramedian pontine artery was included. Clinical, laboratory, and treatment data were collected at baseline. The primary outcome was a proportion of good outcomes (modified Rankin Scale score, 0-2) at 90 days. Main secondary outcomes included early neurological deterioration (END), cerebrovascular event, major bleeding, and excellent outcome (modified Rankin Scale score, 0-1) during 90-day follow-up. RESULTS: We finally enrolled 476 patients, with a median age of 60 (interquartile range, 53-68) years, and 70.2% were male. The median National Institutes of Health Stroke Scale score was 3 (interquartile range, 2-6) at enrollment. Involvement of the lenticulostriate artery was more common than the paramedian pontine artery (60.7% versus 39.3%). END occurred in 14.7% of patients, with a median time from onset of 38 (interquartile range, 22-62) hours. The rates of good and excellent outcomes were 86.5% and 72%, respectively. Its 90-day stroke recurrence rate was 1.9%. Acute-phase therapy (from onset to 7 days of enrollment) showed heterogeneity and was not associated with prognosis. Multivariable logistic regression analysis identified the National Institutes of Health Stroke Scale score ≥4 at admission and END as negative predictors and extracranial artery stenosis as a positive predictor of good outcomes. Age ≥60 years, National Institutes of Health Stroke Scale score ≥4 at admission, and END were negative predictors of excellent outcomes. CONCLUSIONS: With distinct demographic, clinical, and prognostic characteristics, along with a high incidence of END and a low risk of stroke recurrence, BAD-related stroke could be categorized as a separate disease entity. Moreover, its acute-phase treatment strategies were undetermined, awaiting further high-quality studies.
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AVC Isquêmico , Imageamento por Ressonância Magnética , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Estudos Prospectivos , Prognóstico , AVC Isquêmico/diagnóstico por imagem , Adulto , Idoso de 80 Anos ou mais , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/epidemiologiaRESUMO
The innovation of synthetic strategies for selective B-H functionalization is a pivotal objective in the realm of boron cluster chemistry. However, the precise, efficient, and rapid functionalization of a B-H bond of carboranes that is distant from the existing functional groups remains intractable owing to the limited approaches for site-selective control from the established methods. Herein, we report a dative bonding activation strategy for the selective functionalization of a nonclassical remote B-H site of nido-carboranes. By leveraging the electronic effects brought by the exopolyhedral B(9)-dative bond, a cross-nucleophile B-H/S-H coupling protocol of the distal B(5)-H bond has been established. The dative bond not only amplifies the subtle reactivity difference among B-H bonds but also significantly changes the reactive sites, further infusing nido-carboranes with additional structural diversity. This reaction paradigm features mild conditions, rapid conversion, efficient production, broad scope, and excellent group tolerance, thus enabling the applicability to an array of complex bioactive molecules. The efficient and scalable reaction platform is amenable to the modular construction of photofunctional molecules and boron delivery agents for boron neutron capture therapy. This work not only provides an unprecedented solution for the selective diversification of distal B-H sites in nido-carboranes but also holds the potential for expediting the discovery of novel carborane-based functional molecules.
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Ofloxacin (OFL), one of the most widely used fluoroquinolone antibiotics, has been frequently detected in marine environments. Nonetheless, researchers are yet to focus on the effects of OFL on the benthos. In the present study, marine clams (Ruditapes philippinarum) were exposed to OFL (0.5, 50, and 500 µg/L) for 14 d, followed by a 7 d depuration period. The accumulation of OFL, antioxidative defense responses, neurotoxicity, burrowing behavior, and metabolomic changes in clams were evaluated. The results indicated that OFL could accumulate in clams, albeit with a low bioaccumulation capacity. The intermediate (50 µg/L) and high (500 µg/L) levels of OFL induced significant antioxidative responses in the gills and digestive glands of clams, mainly manifesting as the inhibition of catalase activities and the induction of superoxide dismutase and glutathione S-transferase activities, which ultimately elevated the content of malondialdehyde, causing oxidative damage. Furthermore, the significant induction of acetylcholinesterase activities was observed, coinciding with a significant increase in burrowing rates of clams. The high level of OFL affected glycerophospholipid, arachidonic acid, steroid hormone biosynthesis, unsaturated fatty acids biosynthesis, and glycolysis/glycogenesis metabolism. In conclusion, this study has contributed to the understanding of the physiological and biochemical effects and molecular toxicity mechanisms of OFL to marine bivalves.
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The study aims to investigate the effects of nano-alumina (AlNPs) on the early development and neurobehavior of zebrafish and the role of mTOR in this process. After embryos and grown-up larvae exposed to AlNPs from 0 to 200 µg/mL, we examined the development, neurobehavior, AlNPs content, and mTOR pathway genes. Moreover, embryos were randomly administered with control, negative control, mTOR knockdown, AlNPs, and mTOR knockdown + AlNPs, then examined for development, neurobehavior, oxidative stress, neurotransmitters, and development genes. As AlNPs increased, swimming speed and distance initially increased and then decreased; thigmotaxis and panic-avoidance reflex substantially decreased in the high-dose AlNPs group; aluminum and nanoparticles considerably accumulated in the 100 µg/mL AlNPs group; AlNPs at high dose decreased mTOR gene and protein levels, stimulating autophagy via increasing ULK1 and ULK2. mTOR knockdown exacerbated the harm to normal development rate, eye and body length, and neurobehavior induced by AlNPs through raising ROS, SOD, and ACH levels but decreasing AchE activity and development genes. Therefore, AlNPs suppress neurobehavior through downregulating mTOR, and mTOR knockdown further aggravates their early development and neurobehavior loss, suggesting mTOR could be a potential target for the toxicity of AlNPs.
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RESEARCH QUESTION: Can day 3 embryo morphology serve as an independent criterion for optimal single blastocyst selection? DESIGN: This retrospective, single-centre cohort study included 1517 single vitrified-warmed blastocyst transfer (SVBT) cycles conducted between October 2019 and July 2022. The live birth rate (LBR) and other clinical outcomes of SVBT cycles were evaluated, considering both good-quality and non-good-quality day 3 embryos. The associations of day 3 morphological characteristics, encompassing number of blastomeres and embryo grade, were assessed. Multivariable analyses were undertaken using multiple models adjusted for day of blastocyst development and blastocyst grade. RESULTS: Blastocysts from good-quality day 3 embryos had significantly higher LBR compared with those from non-good-quality embryos for both day 5 (51.5% versus 42.9%; Pâ¯=â¯0.013) and day 6 (25.1% versus 17.6%; Pâ¯=â¯0.018) blastocysts. LBR did not differ significantly with number of blastomeres on day 3, regardless of day of blastocyst development (day 5/6) or blastocyst grade. LBR varied significantly by day 3 embryo grade for both day 5 (48.0%, 51.5%, 46.6% and 32.7% for grades I, II, III and IV-V; Pâ¯=â¯0.005) and day 6 (41.5%, 23.6%, 15.9% and 16.1% for grades I, II, III and IV-V; Pâ¯=â¯0.001) blastocysts. Multivariable logistic regression revealed that non-good-quality embryos and lower morphological grade (IV-V) on day 3 were significantly and negatively correlated with LBR, while the number of blastomeres on day 3 was not an independent factor. CONCLUSIONS: When selecting blastocysts of equal quality for SVBT cycles, those with higher day 3 morphological scores are preferred. Day 3 morphological evaluation is a valuable supplement to conventional selection methods.
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BACKGROUND: Past research has shown an inverse correlation between high-density lipoprotein (HDL) and coronary heart disease (CHD), while recent studies have shown that extremely high or low HDL levels increase the risk of cardiovascular death. OBJECTIVE: To explore the relationships between HDL subtypes and the degree of coronary artery stenosis in patients with acute myocardial infarction (AMI). METHODS: This was a single-center cross-sectional study. Ultimately, we included 1,200 adult participants with AMI hospitalized from 2017 to 2023. Patients were classified into mild and moderate-severe groups according to their Gensini score. Restricted cubic spline and multivariate logistic regression models were used to explore the associations between HDL subclasses and the severity of coronary stenosis. RESULTS: The adjusted odds ratios (ORs), 95 % confidence intervals (CIs), and p values for HDL subclasses in the multivariate logistic model (adjusted for age, gender, hypertension status, diabetes status, stroke status, and kidney disease status) were as follows: HDL-2b: 0.97 (0.95-1.00, p= 0.018) and HDL-3: 0.98 (0.97-0.99, p= 0.008). Subgroup analysis revealed that HDL-3 exhibited a statistically significant impact on the severity of coronary stenosis among individuals aged <75 years of age and among men, and the influence of HDL-2b on the severity of coronary stenosis was statistically significant only in individuals aged ≥75 years. CONCLUSION: The relationship between reduced levels of HDL-2b and HDL-3 and the risk of coronary stenosis exhibited a linear pattern and was significantly modified by age. Subgroup analysis identified specific populations that warrant attention regarding HDL-2b and HDL-3.
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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with a median survival of less than 5 years. In recent years, glutamine has been reported to be involved in the regulation of collagen deposition and cell proliferation in fibroblasts, thereby influencing the progression of IPF. However, the relationships between glutamine and the incidence, progression, and treatment response of IPF remain unclear. Our study aimed to investigate the relationship between circulating glutamine levels and IPF, as well as its potential as a therapeutic target. METHODS: We performed a comprehensive Mendelian Randomization (MR) analysis using the most recent genome-wide association study summary-level data. A total of 32 single nucleotide polymorphisms significantly correlated to glutamine levels were identified as instrumental variables. Eight MR analysis methods, including inverse variance weighted, MR-Egger, weighted median, weighted mode, constrained maximum likelihood, contamination mixture, robust adjusted profile score, and debiased inverse-variance weighted method, were used to assess the relationship between glutamine levels with IPF. RESULTS: The inverse variance weighted analysis revealed a significant inverse correlation between glutamine levels and IPF risk (Odds Ratio = 0.750; 95% Confidence Interval : 0.592-0.951; P = 0.017). Sensitivity analyses, including MR-Egger regression and MR-PRESSO global test, confirmed the robustness of our findings, with no evidence of horizontal pleiotropy or heterogeneity. CONCLUSION: Our study provides novel evidence for a causal relationship between lower circulating glutamine levels and increased risk of IPF. This finding may contribute to the early identification of high-risk individuals for IPF, disease monitoring, and development of targeted therapeutic strategies.
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Estudo de Associação Genômica Ampla , Glutamina , Fibrose Pulmonar Idiopática , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Glutamina/sangue , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/sangueRESUMO
Purkinje-related ventricular arrhythmias have been increasingly reported, and with the development of catheter ablation techniques, intervention for Purkinje-related arrhythmias has been shown to be effective. The characteristics of Purkinje fibres orientation in the 12 canine left ventricles were observed at a gross level by staining the endocardium with Lugol's solution. Purkinje fibres were observed microscopically by HE, Masson's, PAS glycogen, and Cx40 immunohistochemical staining. Staining was successful, and the transverse orientation characteristics of Purkinje fibres were observed by Lugol's staining, and the longitudinal distribution was observed microscopically. The distribution of Purkinje fibres in the canine left ventricle is 'graded', 'layered', and 'networked', which can guide catheter ablation of Purkinje-related ventricular arrhythmia.
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Ventrículos do Coração , Ramos Subendocárdicos , Animais , Cães , Ventrículos do Coração/metabolismo , Conexinas/metabolismo , Conexinas/genética , Masculino , Proteína alfa-5 de Junções Comunicantes , FemininoRESUMO
Background: Hemoglobin (HGB) was the most important factors which could cause dysmenorrhea in women. Metals exposure and hemoglobin level in dysmenorrhea female was unclear. We aimed to explore the associations of multi-metal exposure and HGB level in female college students with dysmenorrhea. Methods: 253 female students who had dysmenorrhea was included in our study. The Last Absolute Shrinkage and Selection Operator (LASSO) regression, generalized linear model (GLM), and Bayesian Kernel Machine Regression (BKMR) models were used to explore the associations of multi-metal exposure and HGB levels in female college students with dysmenorrhea. Results: GLM results showed that plasma Fe, Ni and Rb was positively associated with HGB and plasma Co was negatively associated with HGB. In menarche age ≤13 years old group, plasma Co and Rb only was negatively and positively associated with HGB level, respectively, and plasma Ni had positive association with HGB level in menarche age >13 years old group. BKMR results showed the reverse U-shaped relationship between the five metals mixture (Co, Fe, Ni, Cu and Rb) and HGB levels in overall and menarche age ≤13 years old group. However, there were positive association between the five metals mixture and HGB levels in menarche age >13 years old group. Conclusion: Our present study revealed that metals (Fe, Ni, Co, Rb, Cu) mixture exposure could effect HGB levels in female college students with dysmenorrhea. And the relationships were different during different menarche age in female college students.
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Devices under semi-on-state stress often suffer from more severe current collapse than when they are in the off-state, which causes an increase in dynamic on-resistance. Therefore, characterization of the trap states is necessary. In this study, temperature-dependent transient recovery current analysis determined a trap energy level of 0.08 eV under semi-on-state stress, implying that interface traps are responsible for current collapse. Multi-frequency capacitance-voltage (C-V) testing was performed on the MIS diode, calculating that interface trap density is in the range of 1.37×1013 to 6.07×1012cm-2eV-1 from EC-ET=0.29 eV to 0.45 eV.
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Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3-8, but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases.
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Núcleo Arqueado do Hipotálamo , Matriz Extracelular , Resistência à Insulina , Neurônios , Obesidade , Animais , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Camundongos , Masculino , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Neurônios/metabolismo , Neurônios/patologia , Obesidade/metabolismo , Obesidade/patologia , Insulina/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Feminino , Camundongos Obesos , Camundongos Endogâmicos C57BL , Hipotálamo/metabolismo , Hipotálamo/patologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , HumanosRESUMO
Non-small cell lung cancer (NSCLC) is a primary cause of cancer-related mortality on a global scale. Research increasingly shows that long non-coding RNAs (lncRNAs) play crucial regulatory roles and serve as biomarkers for diagnosis, prognosis, therapy monitoring, and druggable targets in NSCLC. We previously identified HAR1A as a tumor-suppressing lncRNA in NSCLC, with its loss also observed in oral and hepatocellular carcinoma. This study aimed to expand the understanding of the functional role of HAR1A in NSCLC and uncover its underlying mechanisms. Our results demonstrated that elevating HAR1A levels impeded NSCLC cell proliferation and migration but promoted apoptosis, thereby boosting their susceptibility to cisplatin. Subsequently, we discovered that HAR1A enhanced cisplatin's cytotoxicity in NSCLC cells by curbing adaptive autophagy through the downregulation of MYC. Further analysis revealed that HAR1A suppresses MYC by both lowering its transcript levels and promoting protein ubiquitination and degradation, thereby restricting tumor cell proliferation, migration, and adaptive autophagy. In exploring MYC's targets, we observed that MYC upregulated the transcription of heat shock protein 90 alpha family class B member 1 (HSP90AB1/HSP90ß) gene. Rescue experiments verified that HAR1A mitigated NSCLC cell proliferation and migration and induced apoptosis through the MYC/HSP90ß axis. Finally, we confirmed that HAR1A overexpression increased cisplatin efficacy in nude mouse NSCLC xenograft models.In conclusion, the findings suggest that HAR1A could be a promising therapeutic target in treating NSCLC and biomarkers for predicting chemotherapy outcomes. This study provides new insights into the molecular mechanisms of chemoresistance in NSCLC and underscores the potential of lncRNA-based strategies in cancer therapy.
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Nickel (Ni) is an important micronutrient, but excess Ni is toxic to many plant species. Currently, relatively little is known about the genetic basis of the plant responses to Ni toxicity. Here, we demonstrate that NAC32 transcription factor functions as a core genetic hub to regulate the Ni toxicity responses in Arabidopsis. NAC32 negatively regulates root-Ni concentration through the IREG2 (IRON REGULATED2) encoding a transporter. NAC32 also induces local auxin biosynthesis in the root-apex transition zone by upregulating YUCCA 7 (YUC7)/8/9 expression, which results in a local enhancement of auxin signaling in root tips, especially under Ni toxicity, thereby impaired primary root growth. By analyses of various combinations of nac32 and ireg2 mutants, as well as nac32 and yuc7/8/9 triple mutants, including high-order quadruple mutant, we demonstrated that NAC32 negatively regulates Ni stress tolerance by acting upstream of IREG2 and YUC7/8/9 to modulate their function in Ni toxicity responses. ChIPqPCR, EMSA (electrophoretic mobility shift assay) and transient dual-LUC reporter assays showed that NAC32 transcriptionally represses IREG2 expression but activates YUC7/8/9 expression by directly binding to their promoters. Our work demonstrates that NAC32 coordinates Ni compartmentation and developmental plasticity in roots, providing a conceptual framework for understanding Ni toxicity responses in plants.