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BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer, and chemoresistance poses a significant challenge to the survival and prognosis of GBM. Although numerous regulatory mechanisms that contribute to chemoresistance have been identified, many questions remain unanswered. This study aims to identify the mechanism of temozolomide (TMZ) resistance in GBM. METHODS: Bioinformatics and antibody-based protein detection were used to examine the expression of E2F7 in gliomas and its correlation with prognosis. Additionally, IC50, cell viability, colony formation, apoptosis, doxorubicin (Dox) uptake, and intracranial transplantation were used to confirm the role of E2F7 in TMZ resistance, using our established TMZ-resistance (TMZ-R) model. Western blot and ChIP experiments provided confirmation of p53-driven regulation of E2F7. RESULTS: Elevated levels of E2F7 were detected in GBM tissue and were correlated with a poor prognosis for patients. E2F7 was found to be upregulated in TMZ-R tumors, and its high levels were linked to increased chemotherapy resistance by limiting drug uptake and decreasing DNA damage. The expression of E2F7 was also found to be regulated by the activation of p53. CONCLUSIONS: The high expression of E2F7, regulated by activated p53, confers chemoresistance to GBM cells by inhibiting drug uptake and DNA damage. These findings highlight the significant connection between sustained p53 activation and GBM chemoresistance, offering the potential for new strategies to overcome this resistance.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Factor de Transcripción E2F7/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Pronóstico , Temozolomida/farmacología , Temozolomida/uso terapéutico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Detecting mutations related to tumors holds immense clinical significance for cancer diagnosis and treatment. However, the presence of highly redundant wild DNA poses a challenge for the advancement of low-copy mutant ctDNA genotyping in cancer cases. To address this, a Taqman qPCR strategy to identify rare mutations at low variant allele fractions (VAFs) has been developed. This strategy combines mutant-specific primers with wild-specific blockers. Diverging from other blocker-mediated PCRs, which rely on primer-induced strand displacement or the use of modified oligos resistant to Taq polymerase, our innovation is built upon the cleavage of specific blockers by Taq polymerase. Given its unique design, which does not hinge on strand displacement or base modification, we refer to this novel method as unmodified-blocker cleavage PCR (UBC-PCR). Multiple experiments consistently confirmed that variant distinction was improved significantly by introduction of 5' unmatched blockers into the reaction. Moreover, UBC-PCR successfully detected mutant DNA at VAFs as low as 0.01% across six different variant contexts. Multiplex UBC-PCR was also performed to identify a reference target and three mutations with a sensitivity of 0.01% VAFs in one single tube. In profiling the gene status from 12 lung cancer ctDNA samples and 22 thyroid cancer FNA DNA samples, UBC-PCR exhibited a 100% concordance rate with ddPCR and a commercial ARMS kit, respectively. Our work demonstrates that UBC-PCR can identify low-abundance variants with high sensitivity in multiplex reactions, independent of strand displacement and base modification. This strategy holds the potential to significantly impact clinical practice and precision medicine.
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OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have increased risk of premature atherosclerosis but the exact mechanisms remains unclear. Flow-mediated dilatation (FMD) is an established non-invasive assessment of vascular endothelial function. Lipoprotein subfractions may be better predictors of FMD than conventional cholesterol measurements. We tested the hypothesis that lipoprotein subfractions are independently associated with FMD. METHODS: Forty-one consecutive adult patients with SLE without known cardiovascular risk factors or disease were recruited in this cross-sectional study. Endothelial function and early atherosclerosis were assessed by brachial FMD and common carotid artery (CCA) intima-media thickness (IMT). High-density lipoprotein (HDL)/low-density lipoprotein (LDL) subfractions were measured. Machine learning models were also constructed to predict FMD and CCA IMT. RESULTS: Median FMD was 4.48% (IQR 5.00%) while median IMT was 0.54 mm (IQR 0.12 mm). Univariate analysis showed lower LDL1 (r=-0.313, p<0.05) and higher HDL2 subfractions (r=0.313, p<0.05) were significantly associated with higher log-transformed FMD. In a multiple linear regression model, HDL2 (ß=0.024, SE=0.012, p<0.05) remained an independent predictor of higher FMD after adjusting for age, body mass index, LDL1 and systolic blood pressure. The machine learning model included parameters such as HDL2 (positive association), prednisolone dose, LDL cholesterol and LDL1 for prediction of FMD (r=0.433, p<0.01). Age, LDL cholesterol and systolic blood pressure were independently associated with higher CCA IMT after adjusting for body mass index and HDL2. CONCLUSIONS: HDL 2, a large HDL particle, was independently associated with greater FMD and may be a biomarker of vascular health in SLE.
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Aterosclerosis , Lupus Eritematoso Sistémico , Adulto , Humanos , Lipoproteínas HDL2 , LDL-Colesterol , Grosor Intima-Media Carotídeo , Estudios Transversales , Colesterol , Lipoproteínas HDLRESUMEN
OBJECTIVE: To assess the cost and effectiveness of percutaneous endoscopic interlaminar discectomy (PEID) and microscope-assisted tubular discectomy (MATD) for patients with L5/S1 lumbar disc herniation (LDH). METHODS: The medical and financial records of patients diagnosed with L5/S1 LDH and who underwent either PEID or MATD from April 2021 to April 2022 were retrospectively collected. Demographic and baseline information, perioperative observational index, clinical outcomes, and inpatient costs were analyzed. RESULTS: Sixty patients were included, with 30 patients in the PEID group and 30 patients in the MATD group. No significant difference was found in demographic and baseline information between the 2 groups (P > 0.05). The PEID group showed significantly shorter incision length, less intraoperative blood loss, shorter hospital stays, and higher intraoperative fluoroscopy frequency compared with the MATD group (P < 0.05). There were no significant differences in visual analog scale back/leg score, Oswestry Disability Index, and 36-Item Short-Form Survey score between PEID and MATD groups before the surgery and at any follow-up time points (P > 0.05). The total cost, surgery cost, and surgical instruments/materials cost were significantly higher in the PEID group compared with the MATD group (P < 0.05). In contrast, the drug and nursing costs were significantly higher in the MATD group than in the PEID group (P < 0.05). CONCLUSIONS: PEID and MATD provide equivalent clinical efficacy and safety in treating LDH at L5/S1 segment within a 1-year follow-up. However, PEID is less invasive and MATD is less costly. No one surgical technique is superior in all aspects and patients should make decisions according to their top concern.
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Discectomía Percutánea , Desplazamiento del Disco Intervertebral , Humanos , Desplazamiento del Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Estudios Retrospectivos , Discectomía Percutánea/métodos , Discectomía/métodos , Endoscopía/métodos , Resultado del TratamientoRESUMEN
TP53 mutations are ubiquitous with tumorigenesis in non-small cell lung cancers (NSCLC). By analyzing the TCGA database, we reported that TP53 missense mutations are correlated with chromosomal instability and tumor mutation burden in NSCLC. The inability of wild-type nor mutant p53 expression can't predict survival in lung cancer cohorts, however, an examination of primary NSCLC tissues found that acetylated p53 did yield an association with improved survival outcomes. Molecularly, we demonstrated that acetylation drove the ubiquitination and degradation of mutant p53 but enhanced stability of wild-type p53. Moreover, acetylation of a missense p53 mutation prevented the gain of oncogenic function observed in typical TP53 mutant-expressing cells and enhanced tumor suppressor functions. Consequently, acetylation inducer targeting of missense mutant p53 may be a viable therapeutic goal for NSCLC treatment and may improve the accuracy of current efforts to utilize p53 mutations in a prognostic manner.
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BACKGROUND: The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction > 50%. METHODS: LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk. RESULTS: Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr < 20%, LAScd < 6%, and LASct < 12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr < 20% was associated with the primary outcome and secondary outcome 1, LAScd < 6% with all clinical outcomes, and LASct < 12% with secondary outcome 2. LAScd < 6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd < 6% had the best discriminative value. CONCLUSIONS: In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd < 6%, LASr < 20%, and LASct < 12% identified patients at higher risk for adverse outcomes.
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Estenosis de la Válvula Aórtica , Fibrilación Atrial , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Pronóstico , Volumen Sistólico , Función Ventricular Izquierda , Péptido Natriurético Encefálico , Atrios Cardíacos , Medición de Riesgo , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/complicacionesRESUMEN
Temozolomide (TMZ) resistance is a major clinical challenge for glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) mediated DNA damage repair is a key mechanism for TMZ resistance. However, MGMT-null GBM patients remain resistant to TMZ, and the process for resistance evolution is largely unknown. Here, we developed an acquired TMZ resistant xenograft model using serial implantation of MGMT-hypermethylated U87 cells, allowing the extraction of stable, TMZ resistant (TMZ-R) tumors and primary cells. The derived tumors and cells exhibited stable multidrug resistance both in vitro and in vivo. Functional experiments, as well as single-cell RNA sequencing (scRNA-seq), indicated that TMZ treatment induced cellular heterogeneity including quiescent cancer stem cells (CSCs) in TMZ-R tumors. A subset of these were labeled by NES+/SOX2+/CADM1+ and demonstrated significant advantages for drug resistance. Further study revealed that Epidermal Growth Factor Receptor (EGFR) deficiency and diminished downstream signaling may confer this triple positive CSCs subgroup's quiescent phenotypes and chemoresistance. Continuous EGF treatment improved the chemosensitivity of TMZ-R cells both in vitro and in vivo, mechanically reversing cell cycle arrest and reduced drug uptake. Further, EGF treatment of TMZ-R tumors favorably normalized the response to TMZ in combination therapy. Here, we characterize a unique subgroup of CSCs in MGMT-null experimental glioblastoma, identifying EGF + TMZ therapy as a potential strategy to overcome cellular quiescence and TMZ resistance, likely endowed by deficient EGFR signaling.
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Previous studies have demonstrated that glucocorticoid receptor ß (GRß) functions as an oncoprotein, regulating the malignant phenotypes and stem-like cell maintaining in human glioblastoma (GBM). Of the glucocorticoid receptor (GR) isoforms, GRß and GRα are highly homologous, though the mechanism underlying the distinct functions of these two isoforms in GBM has not been clarified. Here by establishing a carboxyl-terminal (COOH-terminal) deletion mutant, we determined that GRß can be ubiquitinated. We also found that its COOH terminal is essential for this ubiquitination. The mutation of a lysine to arginine at residue 733 (K733R) blocked the ubiquitination of GRß, indicating that K733 is a key site for ubiquitination. Using K733R to establish nonubiquitinated GRß, we demonstrated that ubiquitination not only regulates the stability and nuclear translocation of GRß, but is also a vital mechanism for its oncogenic functions in vitro and in vivo. Protein interaction assay further indicated that ubiquitin-specific protease 49 (USP49) is a GRß-binding protein and the interaction depends on GRß ubiquitination. USP49 knockdown resulted in a decrease of cell proliferation, invasion, and an increase of cell apoptosis. More importantly, USP49 knockdown increased ubiquitination and amplified the oncogenic effects of GRß, confirming the decisive role of ubiquitination on GRß carcinogenicity. Taken together, these findings established that ubiquitination is a vial process for GRß the execution of oncogenic functions in GBM and that the K733 site is crucial for ubiquitination of GRß. IMPLICATIONS: This work is the first identify of the activation GRß by a single lysine point-mediated ubiquitination and proteasome degradation, which determines its oncogenic functions in GBM.
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Glioblastoma/genética , Receptores de Glucocorticoides/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinación/genética , Animales , Apoptosis , Glioblastoma/patología , Humanos , Masculino , Ratones , Ratones DesnudosRESUMEN
Background Carotid artery stiffness is associated with cognitive impairment and dementia, but the underlying mechanisms remain unknown. We examined the associations of carotid artery stiffness with cerebral small-vessel disease markers, cognition, and dementia subtypes in a memory clinic cohort. Methods and Results A total of 272 participants underwent carotid ultrasonography, 3 Tesla brain magnetic resonance imaging, and neuropsychological assessment. Carotid ultrasonography was used to assess ß-index, pressure-strain elastic modulus, and pulse-wave velocity-ß. Brain magnetic resonance images were graded for cerebral small-vessel disease markers, including white matter hyperintensities, lacunes, and cerebral microbleeds. Participants were classified as having no cognitive impairment, cognitive impairment and no dementia, or dementia subtyped as Alzheimer disease and vascular dementia. Cognition was assessed using National Institute of Neurological Disorders and Stroke-Canadian Stroke Network harmonization battery. After adjusting for age, sex, cardiovascular risk factors, and diseases, multivariable models showed that ß-index (ß=0.69; P=0.002), elastic modulus (ß=0.78; P<0.001), and pulse-wave velocity-ß (ß=0.80; P<0.001) were associated with white matter hyperintensities, and elastic modulus (odds ratio [OR], 1.39 [95% CI, 1.04-1.85]) and pulse-wave velocity-ß (OR, 1.47 [95% CI, 1.10-1.98]) were independently associated with lacunes. Similarly, ß-index (OR, 2.04 [95% CI, 1.14-4.13]), elastic modulus (OR, 2.22 [95% CI, 1.25-4.42]), and pulse-wave velocity-ß (OR, 2.50 [95% CI, 1.36-5.18]) were independently associated with vascular dementia. Carotid stiffness measures were independently associated with worse performance in global cognition, visuomotor speed, visuospatial function, and executive function. These associations became largely nonsignificant after further adjusting for cerebral small-vessel disease markers. Conclusions In memory clinic patients, carotid artery stiffness was associated with white matter hyperintensities and lacunes, impairment in global and domain-specific cognition, and causative subtypes of dementia, particularly vascular. The effects of carotid stiffness on cognition were not independent of, and were partially mediated by, cerebral small-vessel disease.
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Demencia Vascular , Humanos , Demencia Vascular/diagnóstico por imagen , Canadá , Arterias Carótidas/diagnóstico por imagenRESUMEN
BACKGROUND: NF-κB signaling is widely linked to the pathogenesis and treatment resistance in cancers. Increasing attention has been paid to its anti-oncogenic roles, due to its key functions in cellular senescence and the senescence-associated secretory phenotype (SASP). Therefore, thoroughly understanding the function and regulation of NF-κB in cancers is necessary prior to the application of NF-κB inhibitors. METHODS: We established glioblastoma (GBM) cell lines expressing ectopic TCF4N, an isoform of the ß-catenin interacting transcription factor TCF7L2, and evaluated its functions in GBM tumorigenesis and chemotherapy in vitro and in vivo. In p65 knock-out or phosphorylation mimic (S536D) cell lines, the dual role and correlation of TCF4N and NF-κB signaling in promoting tumorigenesis and chemosensitivity was investigated by in vitro and in vivo functional experiments. RNA-seq and computational analysis, immunoprecipitation and ubiquitination assay, minigene splicing assay and luciferase reporter assay were performed to identify the underlying mechanism of positive feedback regulation loop between TCF4N and the p65 subunit of NF-κB. A eukaryotic cell-penetrating peptide targeting TCF4N, 4N, was used to confirm the therapeutic significance. RESULTS: Our results indicated that p65 subunit phosphorylation at Ser 536 (S536) and nuclear accumulation was a promising prognostic marker for GBM, and endowed the dual functions of NF-κB in promoting tumorigenesis and chemosensitivity. p65 S536 phosphorylation and nuclear stability in GBM was regulated by TCF4N. TCF4N bound p65, induced p65 phosphorylation and nuclear translocation, inhibited its ubiquitination/degradation, and subsequently promoted NF-κB activity. p65 S536 phosphorylation was essential for TCF4N-led senescence-independent SASP, GBM tumorigenesis, tumor stem-like cell differentiation and chemosensitivity. Activation of p65 was closely connected to alterative splicing of TCF4N, a likely positive feedback regulation loop between TCF4N and p65 in GBM. 4N increased chemosensitivity, highlighting a novel anti-cancer strategy. CONCLUSION: Our study defined key roles of TCF4N as a novel regulator of NF-κB through mutual regulation with p65 and provided a new avenue for GBM inhibition.
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Neoplasias del Sistema Nervioso Central , Glioblastoma , Proteína 2 Similar al Factor de Transcripción 7 , Factor de Transcripción ReIA , Carcinogénesis/genética , Línea Celular Tumoral , Transformación Celular Neoplásica , Péptidos de Penetración Celular , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/metabolismo , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Luciferasas , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína 2 Similar al Factor de Transcripción 7/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , beta CateninaRESUMEN
Sustained activation of signal transducer and activator of transcription 3 (STAT3) is a critical contributor in tumorigenesis and chemoresistance, thus making it an attractive cancer therapeutic target. Here, SH2 domain-containing adapter protein F (SHF) is identified as a tumor suppressor in glioblastoma Multiforme (GBM) and its negative regulation of STAT3 activity is characterized. Mechanically, SHF selectively binds and inhibits acetylated STAT3 dimerization without affecting STAT3 phosphorylation or acetylation. Additionally, by blocking STAT3-DNMT1 (DNA Methyltransferase 1) interaction, SHF relieves methylation of tumor suppressor genes. The SH2 domain is documented to be essential for SHF's actions on STAT3, and almost entirely replaces the functions of SHF on STAT3 independently. Moreover, the peptide C16 a peptide derived from the STAT3-binding sites of SHF inhibits STAT3 dimerization and STAT3/DNMT1 interaction, and achieves remarkable growth inhibition in GBM cells in vitro and in vivo. These findings strongly identify targeting of the SHF/STAT3 interaction as a promising strategy for developing an optimal STAT3 inhibitor and provide early evidence of the potential clinical efficacy of STAT3 inhibitors such as C16 in GBM.
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Glioblastoma , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Dimerización , Genes Supresores de Tumor , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Fosforilación , Multimerización de Proteína , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
OBJECTIVE: We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS). METHODS: N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses. RESULTS: Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker. CONCLUSION: MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS.
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Estenosis de la Válvula Aórtica , Insuficiencia Cardíaca , Adrenomedulina , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/diagnóstico , Factor Natriurético Atrial , Biomarcadores , Femenino , Humanos , Proteína 1 Similar al Receptor de Interleucina-1 , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Pronóstico , Precursores de Proteínas , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults, characterized by diffuse infiltration, dysplasia, and resistance to therapy. Metabolic remodeling and immunosuppression are typical events which contribute to GBM progression, but the molecular link between these two events remains largely undetermined. Studies have shown that high levels of transforming growth factor-ß (TGF-ß) and its receptors are associated with glioma malignancy and a poor prognosis. TGF-ß plays an important role in cell metabolism and immunity. During tumorigenesis, TGF-ß induces a shift in cell metabolism from oxidative phosphorylation to aerobic glycolysis, providing a favorable environment for tumor growth. Locally, TGF-ß creates an immunosuppressive microenvironment and promotes the malignant phenotype of GBM. In this review, we aim to link GBM aerobic glycolysis and immunosuppression through TGF-ß to provide new ideas for the study of GBM.
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Neoplasias Encefálicas/patología , Glioblastoma/patología , Glucólisis/inmunología , Terapia de Inmunosupresión , Factor de Crecimiento Transformador beta/metabolismo , HumanosRESUMEN
Frailty is associated with future cardiovascular events in older adults. This cross-sectional study examined the relationship between subclinical vasculopathy with measures of skeletal muscle mass and function. Asymptomatic community-dwelling Asians ≥55 years underwent assessments for subclinical vasculopathy (carotid intima-media thickness (cIMT), aortic and carotid stiffness, and endothelial function), muscle mass (calf circumference adjusted for body mass index) and function (knee extension strength, 6-meter fast gait speed). Multivariable regression analyses for associates of muscle mass/function controlled for demographics and cardiometabolic risk factors. Among 336 participants (median age 62 years, 55.1% male, 3.6% sarcopenia), cIMT, aortic and carotid stiffness inversely correlated with muscle mass, strength and gait speed; cIMT remained independently associated with gait speed (ß=-0.26) in multivariable analyses. Age and sex significantly modified the relationship between subclinical vasculopathy and muscle mass/function. Associations, only found in those aged ≥70, included cIMT with gait speed (ß=-0.48) and knee strength (ß=-9.33), and aortic augmentation index and aortic stiffness composite z-score with gait speed (ß=-0.11 and ß=-0.19 respectively). Among males, cIMT correlated with gait speed (ß=-0.31). The association of subclinical vasculopathy with skeletal muscle mass and function in asymptomatic adults ≥55 years is best reflected by cIMT. The roles of mediating pathways deserve further evaluation.
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Envejecimiento/patología , Músculo Esquelético/patología , Enfermedades Vasculares/patología , Anciano , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , SingapurRESUMEN
Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF.
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BACKGROUND: Highly trained athletes running 42 km or more demonstrate elevated cardiac biomarkers, ventricular dysfunction, and decreased glomerular filtration rate (GFR). Whether similar changes occur in the much larger population of recreational runners following half-marathon distance running is unclear. HYPOTHESIS: Recreational runners exhibit changes in myocardial and renal biomarkers, including ventricular strain, after a half-marathon treadmill run. METHODS: 10 recreational subjects (mean age 36.5 ± 6.5 years) ran 21 km on a treadmill (mean completion time 121.6 ± 16.1 minutes). Serum high-sensitivity troponin T (hsTnT), amino-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) were measured prior to, 1 hour post-, and 24 hours post-exercise. Pre- and post-exercise echocardiograms were performed. RESULTS: All biomarkers increased 1 hour post-exercise: hsTnT by 8.5 ± 8.5 pg/ml (P < .05), NT-ProBNP by 26.2 ± 22.8 pg/ml (P < .05) and NGAL by 29.5 ± 37.7 ng/ml (P=NS). By 24 hours post-run, these biomarkers declined toward baseline levels. Right ventricle (RV) free wall and left ventricle global longitudinal strain decreased by 5.5% and 1.8%, respectively (P < .001). Changes in NGAL correlated well with changes in serum creatinine (R = 0.79, P < .01) and GFR (R = -0.73, P < .05). Faster 21 km completion times, and a larger reduction in post-exercise RV strain, were associated with higher NGAL levels: (R = -0.75, P = .01) and (R = 0.66, P < .05), respectively. CONCLUSION: A 21 km run in recreational runners is associated with transient ventricular stunning and reversible changes in myocardial and renal biomarkers. Whether repeated bouts of similar activity contributes to chronic cardiac or kidney dysfunction deserves further evaluation.
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Creatinina/sangre , Ventrículos Cardíacos/diagnóstico por imagen , Riñón/metabolismo , Lipocalina 2/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Carrera/fisiología , Troponina T/sangre , Adulto , Biomarcadores/sangre , Ecocardiografía , Prueba de Esfuerzo , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Masculino , Adulto JovenRESUMEN
Traumatic brain injury (TBI) is a common cause of death and disability. Enhancing the midline-crossing of the contralateral corticospinal tract (CST) to the denervated side of spinal cord facilitates functional recovery after TBI. Activation of the gamma isoform of PKC (PKCγ) in contralateral CST implicates its roles in promoting CST remodeling after TBI. In this study, we deployed loss and gain of function strategies in N2a cells and primary cortical neurons in vitro, and demonstrated that PKCγ is not only important but necessary for neuronal differentiation, neurite outgrowth and axonal branching but not for axonal extension. Mechanically, through the phosphorylation of GSK3ß, PKCγ stabilizes the expression of cytosolic ß-catenin and increase GAP43 expression, thus promoting axonal outgrowth. Further, rAAV2/9-mediated delivery of constitutive PKCγ in the corticospinal tract after unilateral TBI in vivo additionally showed that specifically delivery of active PKCγ mutant to cortical neuron promotes midline crossing of corticospinal fibers from the uninjured side to the denervated cervical spinal cord. This PKCγ-mediated injury response promoted sensorimotor functional recovery. In conclusion, PKCγ mediates stability of ß-catenin through the phosphorylation of GSK3ß to facilitate neuronal differentiation, neurite outgrowth and axonal branching, and PKCγ maybe a novel therapeutic target for physiological and functional recovery after TBI.
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Axones/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/fisiopatología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Neuronas/citología , Proteína Quinasa C/farmacología , Tractos Piramidales/citología , beta Catenina/metabolismo , Animales , Axones/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Regeneración Nerviosa , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/metabolismo , Recuperación de la Función , Transducción de Señal , beta Catenina/genéticaRESUMEN
STUDY OBJECTIVES: Sleep apnea is often newly diagnosed in patients presenting with ST-segment elevation myocardial infarction (STEMI). We assessed longitudinal changes in apnea-hypopnea index (AHI) and sleep apnea phenotype after STEMI and determined its association with changes in the left ventricular ejection fraction (LVEF). METHODS: A total of 101 eligible patients with STEMI underwent consecutive sleep studies and echocardiographic studies within 5 days of admission and at 6-month follow-up. Sleep apnea (AHI ≥ 15 events/h) was further divided into obstructive sleep apnea (OSA) or central sleep apnea (CSA). RESULTS: Both AHI (mean difference -6.4 events/h, 95% confidence interval [CI] -9.6 to 3.3, P < .001) and LVEF (mean difference 2.6%, 95% CI 1.3 to 4.0, P < .001) improved from baseline to 6 months. The improvement in AHI was associated with an increase in LVEF (ß = -.47, 95% CI -.86 to -.07, P = .023) and a decrease in left ventricular end-systolic volume (LVESV) (ß = .25, 95% CI .07 to .43, P = .007). Of the patients with OSA at baseline (46%), resolution of OSA was seen in 48% at 6 months. Of those with CSA at baseline (12%), conversion to OSA was seen in 83%. In contrast, among those with no sleep apnea (42%) at baseline, the diagnosis remained the same in 93% at 6 months. CONCLUSIONS: Concurrent changes in AHI, LVEF, and LVESV were seen after STEMI. Sleep studies performed on admission are reliable in excluding sleep apnea. However, patients with OSA or CSA on admission warrant re-evaluation due to evolution of the sleep apnea phenotype.
Asunto(s)
Infarto del Miocardio/cirugía , Intervención Coronaria Percutánea , Síndromes de la Apnea del Sueño/etiología , Función Ventricular Izquierda , Ecocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Síndromes de la Apnea del Sueño/fisiopatología , Apnea Central del Sueño/etiología , Apnea Central del Sueño/fisiopatología , Apnea Obstructiva del Sueño/etiología , Apnea Obstructiva del Sueño/fisiopatologíaRESUMEN
The reticulon family has been found to induce apoptosis, inhibit axon regeneration and regulate protein trafficking. However, little is known about the mechanisms of how reticulon proteins are involved in neuronal death-promoting processes during ischemia. Here, we report that the expression of Reticulon Protein 1-C (RTN1-C) was associated with the progression of cerebral ischemia/reperfusion (I/R) injury. Using a combination of rat middle cerebral artery occlusion (MCAO) stroke and oxygen-glucose deprivation followed by reoxygenation (OGD/R) models, we determined that the expression of RTN1-C was significantly increased during cerebral ischemic/reperfusion. RTN1-C overexpression induced apoptosis and increased the cell vulnerability to ischemic injury, whereas RTN1-C knockdown reversed ischemia-induced apoptosis and attenuated the vulnerability of OGD/R-treated neural cells. Mechanistically, we demonstrated that RTN1-C mediated OGD/R-induced apoptosis through ER stress and mitochondria-associated pathways. RTN1-C interacted with Bcl-xL and increased its localization in the ER, thus reducing the anti-apoptotic activity of Bcl-xL. Most importantly, knockdown of Rtn1-c expression in vivo attenuated apoptosis in MCAO rats and reduced the extent of I/R-induced brain injury, as assessed by infarct volume and neurological score. Collectively, these data support for the first time that RTN1-C may represent a novel candidate for therapies against cerebral ischemia/reperfusion injury.