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Nano zero-valent iron (nZVI) is widely used in soil remediation due to its high reactivity. However, the easy agglomeration, poor antioxidant ability and passivation layer of Fe-Cr coprecipitates of nZVI have limited its application scale in Cr-contaminated soil remediation, especially in high concentration of Cr-contaminated soil. Herein, we found that the carboxymethyl cellulose on nZVI particles could increase the zeta potential value of soil and change the phase of nZVI. Along with the presence of biochar, 97.0% and 96.6% Cr immobilization efficiency through CMC-nZVI/BC were respectively achieved in high and low concentrations of Cr-contaminated soils after 90-days remediation. In addition, the immobilization efficiency of Cr(VI) only decreased by 5.1% through CMC-nZVI/BC treatment after 10 weeks aging in air, attributing to the strong antioxidation ability. As for the surrounding Cr-contaminated groundwater, the Cr(VI) removal capacity of CMC-nZVI/BC was evaluated under different reaction conditions through column experiments and COMSOL Multiphysics. CMC-nZVI/BC could efficiently remove 85% of Cr(VI) in about 400 hr when the initial Cr(VI) concentration was 40 mg/L and the flow rate was 0.5 mL/min. This study demonstrates that uniformly dispersed CMC-nZVI/BC has an excellent remediation effect on different concentrations of Cr-contaminated soils.
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Carboximetilcelulosa de Sodio , Carbón Orgánico , Cromo , Restauración y Remediación Ambiental , Hierro , Contaminantes del Suelo , Contaminantes del Suelo/química , Carbón Orgánico/química , Restauración y Remediación Ambiental/métodos , Hierro/química , Cromo/química , Carboximetilcelulosa de Sodio/química , Suelo/química , Nanopartículas del Metal/químicaRESUMEN
BACKGROUND: Antipsychotic and other psychotropic medication use is prevalent among community-dwelling older adults with dementia despite the potential for adverse effects. Two Centers for Medicare & Medicaid Services (CMS) initiatives, the National Partnership to Improve Dementia Care ("the Partnership") and the Five Star Quality Rating System for antipsychotic use reporting, have been successful in reducing antipsychotic use in nursing home residents. We assessed if these initiatives had a spillover effect in antipsychotic and other psychotropic medication use among community dwellers with dementia due to potential overlap in prescribers across settings. METHODS: Among community-dwelling older adults with dementia, we examined psychotropic medication class use (i.e., antipsychotics, antidepressants, anxiolytics, anticonvulsants/mood stabilizers, antidementia) in 2010-2017 Medicare fee-for-service claims using interrupted time series analyses across three periods ("Pre-Partnership": July 1, 2010 to March 31, 2012; "Post-Partnership": April 1, 2012 to January 31, 2015; "Five Star Quality Rating": February 1, 2015 to December 31, 2017). RESULTS: We included 1,289,401 community dwellers with dementia contributing 26,609,697 person-months. The mean age was 80 years, most were female (70%), approximately 80% were non-Hispanic Whites, 10% were non-Hispanic Blacks, and 5% were Hispanic ethnicity. Antipsychotic use was declining pre-Partnership (ß = -0.06, 95% CI: -0.08, -0.05) and post-Partnership (ß = -0.02, 95% CI: -0.02, -0.01). Post-Five Star Quality Rating, antipsychotic use remained stable with a nearly flat slope (ß = -0.01, 95% CI: -0.01, 0.00). Anticonvulsant and antidepressant use increased and anxiolytic and antidementia medication use decreased among community-dwelling older adults with dementia. CONCLUSIONS: These two CMS policies on antipsychotic use for nursing home residents were not associated with a spillover effect to community-dwelling older adults with dementia. Strategies to monitor the appropriateness of psychotropic medication use may be warranted for community-dwellers with dementia.
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The impact of tensile biaxial strain on the thermal transport properties of hydrogen (HD), fluorine (FD), and chlorine (ClD) functionalized diamane is investigated by using the Boltzmann transport equation. Our results reveal ClD as an exceptionally strain-sensitive material for thermal transport applications, exhibiting a 70% reduction in thermal conductivity at a 5% strain-outperforming HD and FD. The strain-induced modifications in phonon dispersion and phonon scattering rates result in the unique responsiveness of ClD. This discovery positions ClD as a promising candidate for applications demanding highly tunable thermal conductivity. The ability to precisely control thermal properties makes ClD an ideal candidate for the development of thermal smart metamaterials, opening avenues for innovations in thermal management and diverse applications in the field of advanced materials.
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Prostate cancer (PCa) is a highly heterogeneous disease, encompassing various molecular and clinical pathological subtypes. Fusion genes play a facilitating role in the occurrence and progression of PCa. We categorized PCa samples into the ETS family of transcription factors fusion positive and fusion negative subtypes based on fusion genes. This subtyping method is closely related to the epigenomic DNA methylation profiles of PCa, with each sample cluster including more than 85% of the patients. We conducted an analysis of the distribution of the ETS family fusion genes on chromosomes, fusion modes within reading frames, and predictions of structural domains. Among these, the highest frequency of the ETS family related fusion genes occurred on chromosome 21. Compared to the parental genes, fusion genes exhibited new structural domains, such as IG_like, and the most common fusion mode was out-of-frame fusion. The correlation between the methylation levels of hypermethylated CpG sites and the expression levels of their corresponding mRNAs indicates that CD8A and B3GNT5 (with correlations of - 0.388 and - 0.253, respectively) could serve as potential prognostic markers for PCa.
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Metilación de ADN , Proteínas de Fusión Oncogénica , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-ets , Humanos , Neoplasias de la Próstata/genética , Masculino , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas de Fusión Oncogénica/genética , Regulación Neoplásica de la Expresión Génica , Islas de CpG/genética , Biomarcadores de Tumor/genética , PronósticoRESUMEN
Bioenergy decline occurs with reperfusion following acute ischemic stroke. However, the molecular mechanisms that limit energy metabolism and their impact on post-stroke cognitive and emotional complications are still unclear. In the present study, we demonstrate that the p53 transcriptional response is responsible for neuronal adenosine triphosphate (ATP) deficiency and progressively neuropsychiatric disturbances, involving the downregulation of mitochondrial voltage-dependent anion channels (VDACs). Neuronal p53 transactivated the promoter of microRNA-183 (miR-183) cluster, thereby upregulating biogenesis of miR-183-5p (miR-183), miR-96-5p (miR-96), and miR-182-5p. Both miR-183 and miR-96 directly targeted and post-transcriptionally suppressed VDACs. Neuronal ablation of p53 protected against ATP deficiency and neurological deficits, whereas post-stroke rescue of miR-183/VDAC signaling reversed these benefits. Interestingly, cyclin-dependent kinase 9 (CDK9) was found to be enriched in cortical neurons and upregulated the p53-induced transcription of the miR-183 cluster in neurons after ischemia. Post-treatment with the CDK9 inhibitor oroxylin A promoted neuronal ATP production mainly through suppressing the miR-183 cluster/VDAC axis, further improved long-term sensorimotor abilities and spatial memory, and alleviated depressive-like behaviors in mice following stroke. Our findings reveal an intrinsic CDK9/p53/VDAC pathway that drives neuronal bioenergy decline and underlies post-stroke cognitive impairment and depression, thus highlighting the therapeutic potential of oroxylin A for better outcomes.
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Metabolismo Energético , Ratones Endogámicos C57BL , MicroARNs , Neuronas , Transducción de Señal , Accidente Cerebrovascular , Proteína p53 Supresora de Tumor , Animales , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ratones , Neuronas/metabolismo , Neuronas/patología , MicroARNs/genética , MicroARNs/metabolismo , Masculino , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/complicaciones , Adenosina Trifosfato/metabolismoRESUMEN
BACKGROUND: To assess predictive value of short-term choroidal changes for future myopic shift in children. METHODS: 577 eyes of 289 primary school children were prospectively followed for 2 years. Cycloplegic refractions at baseline, 1 year and 2 years, and choroidal measurements by optical coherence tomography at baseline and 3 months, were used for analyses. Myopic shift was defined as refraction change of at least -0.50 dioptre/year, at 2 years compared with baseline. RESULTS: 228 participants (455 eyes) completed 2-year follow-up. Approximately 37.6% of 311 initially non-myopic eyes and 73.6% of 144 initially myopic eyes developed a myopic shift. Notably, at 3 months greater reductions were found in initially myopic eyes with myopic shift, than in those without myopic shift-in choroidal thickness (ChT), luminal area (LA), stromal area (SA) and total choroidal area (TCA), but no significant differences in any choroidal parameters were observed between non-myopic eyes, with and without myopic shift. Multivariable analyses showed that in myopic eyes, each percentage increase in ChT, LA, SA and TCA was associated with reduced odds of myopic shift (all p<0.001). Similar associations were observed in non-myopic eyes, with smaller effects than in myopic eyes. Adding a 3-month percentage change of each choroidal parameter to a basic model including age, gender, parental myopia and baseline refraction significantly improved the predictive performance in myopic eyes (area under the receiver operating characteristic curves increasing from 0.650 to approximately 0.800, all p<0.05), but not in non-myopic eyes. CONCLUSION: Short-term choroidal changes could act as early indicators for future myopic shift in children.
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Triptophenolide, a major diterpenoid extracted from Tripterygium wilfordii Hook. f., has been reported to possess significant anti-tumour, anti-androgen and anti-inflammatory activities. However, the metabolic fate of triptophenolide remains unknown. Therefore, this study focused on the metabolic profiling of triptophenolide in rat plasma, urine, bile and faeces following intragastric administration. An ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry with combination of extracted ion chromatogram strategy based on 71 typical metabolic reactions was established to comprehensively profile the metabolites of triptophenolide. This strategy allowed for the identification of 17 metabolites from the biosamples. Reduction, oxidation, glucuronide conjugation, and hydroxylation were considered as its main metabolic pathways in vivo. The present study will be greatly helpful for the further pharmacological studies on triptophenolide and would provide valuable information for its clinical application.
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INTRODUCTION: Advanced chronic kidney disease (CKD) is common among patients with coronary artery disease (CAD), and angiotensinconverting enzyme inhibitors (ACEI) or angiotensinreceptor blockers (ARB) can improve cardiac and renal function, but whether ACEI/ARB therapy improves long-term prognosis remains unclear among these high-risk patients. Therefore, this research aimed to investigate the relationship between ACEI/ARB therapy and long-term prognosis among CAD patients with advanced CKD. METHODS: CAD patients with advanced CKD were included in five hospitals. Advanced CKD was defined as estimated glomerular filtration rate (eGFR)<30 ml/min per 1.73 m2. Cox regression models and competing risk Fine and Gray models were used to examine the relationship between ACEI/ARB therapy and all-cause and cardiovascular death, respectively. RESULTS: Of 2527 patients, 47.6% population of our cohort was discharged on ACEI/ARB. The overall all-cause and cardiovascular mortality were 38.6% and 24.7%, respectively. Multivariate Cox regression analyses indicated that ACEI/ARB therapy was found to be associated with lower rates of both all-cause mortality (hazard ratio (HR)=0.836, 95% confidence interval (CI): 0.738-0.948, p = 0.005) and cardiovascular mortality (HR = 0.817, 95%CI: 0.699-0.956, p = 0.011). In the propensity-matched cohort, the survival benefit was consistent, and significantly better survival was observed for all-cause mortality (HR = 0.856, 95%CI: 0.752-0.974, p = 0.019) and cardiovascular mortality (HR = 0.830, 95%CI: 0.707-0.974, p = 0.023) among patients treated with ACEI/ARB. CONCLUSION: ACEI/ARB therapy showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up, which manifested that strategies to maintain ACEI/ARB treatment may improve clinical outcomes among these high-risk populations.
What is the current knowledge on the topic? Advanced CKD is highly prevalent and strongly associated with higher mortality risk and worse outcomes among CAD patients, and patients with advanced CKD have often been excluded from randomized controlled trials, creating an evidence gap for these high-risk CAD patients. ACEI/ARB are beneficial for greater survival among CAD patients, but the effect of ACEI/ARB therapy on long-term prognosis is unclear among CAD patients with advanced CKD.What does this study add to our knowledge? ACEI/ARB treatment showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up.How might this change clinical pharmacology or translational science? CAD patients with advanced CKD are not only have worse outcomes but also limited in their choice of therapy strategies. Our study may prompt an important reference for the subsequent improvement of long-term prognosis among these high-risk populations.
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Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Enfermedad de la Arteria Coronaria , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica , Humanos , Masculino , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Femenino , Antagonistas de Receptores de Angiotensina/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/mortalidad , Persona de Mediana Edad , Anciano , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Estudios Longitudinales , Modelos de Riesgos Proporcionales , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Causas de MuerteRESUMEN
Seven fatty acids were detected by GC-MS in Xanthoceras sorbifolium Bunge seed oil extracted at different temperatures, including Palmitic acid C16:0, Stearic acid C18:0, Oleic acid C18:1, Eicosenoic acid C20:1, Docosenoic acid C22:1, Tetracosenoic acid C24:1, and Linoleic acid C18:2. The highest content of nervonic acid (NA) was found in Xanthoceras sorbifolium Bunge seed oil extracted at 70 °C. Three methods were selected to analyze the extraction rate of nervonic acid in Xanthoceras sorbifolium Bunge seed oil, including urea complexation, low-temperature solvent crystallization, and a combined treatment using these two methods. The final content of nervonic acid obtained was 14.07%, 19.66%, and 40.17%, respectively. The combined treatment method increased the purity of nervonic acid in Xanthoceras sorbifolium Bunge seed oil by 12.62 times. Meanwhile, thermogravimetric behavior analysis of samples extracted using different methods was conducted by thermogravimetric analyzer, which suggested that the thermal stability of the samples extracted by the combined treatment was enhanced. These results can provide a new process parameter and scientific basis for the extraction of NA. At the same time, FTIR and NMR were also used to characterize the combined extraction sample, and the structure of the samples was proved.
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BACKGROUND: Acute myeloid leukemia (AML) is a hematological malignancy. The aim of this research was to develop a ferroptosis and cuproptosis related novel prognostic signature associated with AML. METHODS: The ferroptosis and cuproptosis related genes correlated with the prognosis of AML were identified by univariate Cox analysis. The consistent cluster analysis was performed for 150 AML patients in TCGA dataset. The key module genes associated with GSVA score of ferroptosis and cuproptosis were identified by WGCNA. univariate Cox and LASSO regression analysis were adopted to build a ferroptosis and cuproptosis AML prognostic signature. Finally, the expression of five prognostic genes in clinical tissue samples were verified by RT-qPCR. RESULTS: A grand total of 27 FCRGs associated with AML prognosis were identified.Then, two AML sub-types with significantly different survival were obtained. We found 3 significantly differential expressed immune cells (naive CD4 cells, regulatory T cells and resting mast cells) between two risk sub-groups. Meanwhile, 'IL6 JAK STAT3 signaling' and 'P53 pathway' were enriched in low-risk group. A ferroptosis and cuproptosis related prognostic signature was build based on 8 prognostic genes. RT-qPCR results indicated that there was no significant difference in the expression of OLFML2A and CD109 between AML and normal samples. However, compared to the control group, LGALS1, SOCS1, and RHOC showed significantly lower expression in the AML group. CONCLUSION: The prognostic signature comprised of OLFML2A, LGALS1, ABCB11, SOCS1, RHOC, CD109, RD3L and PTPN13 based on ferroptosis and cuproptosis was established, which provided theoretical basis for the research of AML.
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BACKGROUND: The long-term impact of drug-coated balloon (DCB) angioplasty for the treatment of patients with de novo coronary artery lesions remains uncertain. We aimed to assess the non-inferiority of DCB angioplasty with rescue stenting to intended drug-eluting stent (DES) deployment for patients with de novo, non-complex coronary artery lesions. METHODS: REC-CAGEFREE I was an open-label, randomised, non-inferiority trial conducted at 43 sites in China. After successful lesion pre-dilatation, patients aged 18 years or older with de novo, non-complex coronary artery disease (irrespective of target vessel diameter) and an indication for percutaneous coronary intervention were randomly assigned (1:1), via a web-based centralised system with block randomisation (block size of two, four, or six) and stratified by site, to paclitaxel-coated balloon angioplasty with the option of rescue stenting due to an unsatisfactory result (DCB group) or intended deployment of second-generation thin-strut sirolimus-eluting stents (DES group). The primary outcome was the device-oriented composite endpoint (DoCE; including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularisation) assessed at 24 months in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Non-inferiority was established if the upper limit of the one-sided 95% CI for the absolute risk difference was smaller than 2·68%. Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT04561739. It is closed to accrual and extended follow-up is ongoing. FINDINGS: Between Feb 5, 2021, and May 1, 2022, 2272 patients were randomly assigned to the DCB group (1133 [50%]) or the DES group (1139 [50%]). Median age at the time of randomisation was 62 years (IQR 54-69), 1574 (69·3%) of 2272 were male, 698 (30·7%) were female, and all patients were of Chinese ethnicity. 106 (9·4%) of 1133 patients in the DCB group received rescue DES after unsatisfactory DCB angioplasty. As of data cutoff (May 1, 2024), median follow-up was 734 days (IQR 731-739). At 24 months, the DoCE occurred in 72 (6·4%) of 1133 patients in the DCB group and 38 (3·4%) of 1139 in the DES group, with a risk difference of 3·04% in the cumulative event rate (upper boundary of the one-sided 95% CI 4·52; pnon-inferiority=0·65; two-sided 95% CI 1·27-4·81; p=0·0008); the criterion for non-inferiority was not met. During intervention, no acute vessel closures occurred in the DCB group and one (0·1%) of 1139 patients in the DES group had acute vessel closure. Periprocedural myocardial infarction occurred in ten (0·9%) of 1133 patients in the DCB group and nine (0·8%) in the DES group. INTERPRETATION: In patients with de novo, non-complex coronary artery disease, irrespective of vessel diameter, a strategy of DCB angioplasty with rescue stenting did not achieve non-inferiority compared with the intended DES implantation in terms of the DoCE at 2 years, which indicates that DES should remain the preferred treatment for this patient population. FUNDING: Xijing Hospital and Shenqi Medical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Angioplastia Coronaria con Balón , Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Paclitaxel , Humanos , Masculino , Femenino , Persona de Mediana Edad , Angioplastia Coronaria con Balón/métodos , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Enfermedad de la Arteria Coronaria/terapia , Anciano , Sirolimus/uso terapéutico , Sirolimus/administración & dosificación , Resultado del Tratamiento , Materiales Biocompatibles Revestidos , China/epidemiología , Intervención Coronaria Percutánea/métodosRESUMEN
BACKGROUND: The relationship between long-term outcomes and operator experience for left atrial appendage occlusion (LAAO) is still unknown. OBJECTIVES: This study sought to explore the association between operator LAAO experience and one-year clinical outcomes. METHODS: The RECORD study (Registry to Evaluate Chinese Real-World Clinical Outcomes in Patients With AF Using the WATCHMAN Left Atrial Appendage Closure Technology; NCT03917563) was a multicenter, prospective registry that included patients with the WATCHMAN LAAO device (Boston Scientific) in China from April 1, 2019, to October 31, 2020. The current analyses included patients with solely LAAO from the registry; those who had concomitant LAAO and ablation/other procedures were excluded. The primary outcome was a composite endpoint of death, stroke, systemic embolism, and Bleeding Academic Research Consortium (BARC)-defined type 3 or 5 bleeding at 1 year. RESULTS: A total of 1,547 LAAO patients and 111 operators were included. The mean ± SD CHA2DS2-VASc and HAS-BLED scores of patients were 4.0 ± 1.8 and 2.5 ± 1.1, respectively. The mean ± SD age of operators was 47.0 ± 7.2 years, 15 (13.5%) were female, and 52 (46.8%) were electrophysiologists. Utilizing maximally selected log-rank statistics, the thresholds to categorize an experienced operator were performing ≥32 LAAOs annually or ≥134 LAAOs in total. Performing ≥32 LAAOs annually is the better criterion than ≥134 LAAOs in total (absolute net reclassification index: 25.79%; P < 0.001). Compared with the ≥32 LAAO annually group, the <32 group was associated with a 1.8-fold (HRadjusted: 1.79; 95% CI: 1.16-2.78; P = 0.009) increase in the risk of the primary endpoint, and such risk in the <32 group can be reduced by â¼12% after performing each additional 5 cases (HRadjusted per 5 cases: 0.88; 95% CI: 0.78-0.99; P = 0.033). CONCLUSIONS: Performing ≥32 LAAOs annually could be a threshold to categorize an experienced operator. Before reaching this threshold, the risk of death, stroke, systemic embolism, and BARC-defined type 3 or 5 bleeding decreased by 12% after every 5 cases performed.
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Background: Older patients are at high risk of falling, and regular assessments of their concerns about falling (CaF) are often recommended. The present study aimed to investigate the association between CaF and personality traits among older patients as well as to elucidate the mediating role of subjective age. Method: A cross-sectional study was conducted among 407 patients aged over 60 years in a tertiary hospital located in Chengdu, Sichuan Province, from March 2023 to May 2023. Predesigned electronic questionnaires were distributed to collect relevant data. Four different models (both crude and adjusted weighted linear regression models) were constructed based on the confounders. Confounders were gradually put into the models to control for bias and to examine the stability of the correlations. Bootstrap sampling was employed to examine the mediating role of subjective age. Result: According to the fully adjusted model, neuroticism (ß = 0.17, 95% CI: 0.02 to 0.31, p for trend = 0.02), extraversion (ß = -0.07, 95% CI: -0.15 to 0.001, p for trend = 0.05), and subjective age (ß = 2.02, 95% CI: 1.28 to 2.78, p for trend <0.001) were consistently correlated with CaF. Mediating analysis revealed that extraversion was negatively related with CaF both directly and indirectly, via subjective age [23.2% partial effect, bootstrap 95%CI: -0.024(-0.080, -0.000)]. Higher neuroticism was consistently related to older subjective age (ß = 0.002, 95% CI: 0.001 to 0.004, p for trend = 0.006), while higher levels of conscientiousness, openness, and extraversion were consistently correlated with younger subjective age(ß = -0.002, p for trend = 0.04; ß = -0.003, p for trend = 0.003; ß = -0.002, p for trend = 0.0, respectively). Conclusion: Extraversion and neuroticism were significantly correlated with CaF. Moreover, subjective age partially mediated the relationship between extraversion and CaF. Furthermore, subjective age was found to be associated with both CaF and personality traits. These findings highlighted the important roles of personality traits and subjective age in assessments of CaF and in the development of strategies for preventing falls among older patients.
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Accidentes por Caídas , Personalidad , Humanos , Masculino , Femenino , Anciano , Estudios Transversales , Accidentes por Caídas/estadística & datos numéricos , Persona de Mediana Edad , Encuestas y Cuestionarios , China/epidemiología , Factores de Edad , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. METHODS: Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. RESULTS: Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). CONCLUSIONS: Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient's quality of life.
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Supervivientes de Cáncer , Neoplasias , Medición de Resultados Informados por el Paciente , Piridinas , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Supervivientes de Cáncer/psicología , Neoplasias/tratamiento farmacológico , Anciano , Adulto , Encuestas y Cuestionarios , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Depresión/inducido químicamente , Satisfacción del Paciente , Calidad de VidaRESUMEN
BACKGROUND: Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC); however, almost 20% of patients experience treatment failure due to radioresistance. Therefore, understanding the mechanisms of radioresistance is imperative. HOTAIRM1 is deregulated in various human cancers, yet its role in NPC radioresistance are largely unclear. METHODS: This study investigated the association between HOTAIRM1 and radioresistance using CCK8, flow cytometry, and comet assays. Additionally, xenograft mice and patient-derived xenografts (PDX) models were employed to elucidate the biological functions of HOTAIRM1, and transcriptomic RNA sequencing was utilized to identify its target genes. RESULTS: Our study revealed an upregulation of HOTAIRM1 levels in radioresistant NPC cell lines and tissues. Furthermore, a positive correlation was noted between high HOTAIRM1 expression and increased NPC cell proliferation, reduced apoptosis, G2/M cell cycle arrest, and diminished cellular DNA damage following radiotherapy. HOTAIRM1 modulates the acetylation and stability of the FTO protein, and inhibiting FTO elevates the m6A methylation level of CD44 precursor transcripts in NPC cells. Additionally, silencing the m6A reading protein YTHDC1 was found to increase the expression of CD44V. HOTAIRM1 enhances NPC cell resistance to ferroptosis and irradiation through the HOTAIRM1-FTO-YTHDC1-CD44 axis. Mechanistically, HOTAIRM1 interacts with the FTO protein and induces m6A demethylation of the CD44 transcript. The absence of m6A modification in the CD44 transcript prevents its recognition by YTHDC1, resulting in the transition from CD44S to CD44V. An abundance of CD44V suppresses ferroptosis induced by irradiation and contributes to NPC radioresistance. CONCLUSIONS: In conclusion, the results in this study support the idea that HOTAIRM1 stimulates CD44 alternative splicing via FTO-mediated demethylation, thereby attenuating ferroptosis induced by irradiation and promoting NPC radioresistance.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Empalme Alternativo , Regulación Neoplásica de la Expresión Génica , Receptores de Hialuranos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Tolerancia a Radiación , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Ratones , Tolerancia a Radiación/genética , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Animales , Línea Celular Tumoral , Acetilación , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/metabolismo , Proliferación Celular , Apoptosis/genética , Ensayos Antitumor por Modelo de Xenoinjerto , MicroARNsRESUMEN
Background: Radiation-induced pulmonary fibrosis (RIPF) is a common complication after radiotherapy in thoracic cancer patients, and effective treatment methods are lacking. The purpose of this study was to investigate the protective effect of rosmarinic acid (RA) on RIPF in mice as well as the mechanism involved. Methods: m7G-tRNA-seq and tRNA-seq analyses were conducted to identify m7G-modified tRNAs. Western blotting, immunohistochemistry, northwestern blotting, northern blotting, immunofluorescence, wound-healing assays and EdU experiments were performed to explore the molecular mechanism by which RA regulates fibroblast-to-myofibroblast transformation (FMT) by affecting the exosomes of lung epithelial cells. Ribo-seq and mRNA-seq analyses were used to explore the underlying target mRNAs. Seahorse assays and immunoprecipitation were carried out to elucidate the effects of RA on glycolysis and FMT processes via the regulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) acetylation. Results: We found that RA had an antifibrotic effect on the lung tissues of RIPF model mice and inhibited the progression of FMT through exosomes derived from lung epithelial cells. Mechanistically, RA reduced the transcription and translation efficiency of sphingosine kinase 1 in lung fibroblasts by decreasing N7-methylguanosine modification of tRNA, downregulating the expression of tRNAs in irradiated lung epithelial cell-derived exosomes, and inhibiting the interaction between sphingosine kinase 1 and the N-acetyltransferase 10 protein in fibroblasts. Furthermore, the acetylation and cytoplasmic translocation of PFKFB3 were reduced by exosomes derived from irradiated lung epithelial cells, which following RA intervention. This suppression of the FMT process, which is triggered by glycolysis, and ultimately decelerating the progression of RIPF. Conclusion: These findings suggest that RA is a potential therapeutic agent for RIPF.
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CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell-mediated antitumor effects.
Asunto(s)
Linfocitos T CD8-positivos , Proteínas Facilitadoras del Transporte de la Glucosa , Glucosa , Ácido Láctico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Ácido Láctico/metabolismo , Animales , Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Activación de Linfocitos/efectos de los fármacos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glucólisis/efectos de los fármacosRESUMEN
Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re â LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re â LS â LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.
Asunto(s)
Ansiedad , Neuronas GABAérgicas , Área Hipotalámica Lateral , Prurito , Animales , Ratones , Neuronas GABAérgicas/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Núcleos Talámicos de la Línea Media/metabolismo , Masculino , Conducta Animal , Vías Nerviosas , Plasticidad Neuronal , Núcleos SeptalesRESUMEN
Patulin (PAT) is a widespread fruit toxin. Trace-level PAT exposure can cause serious harm to human health. Herein, a multimodal PAT aptasensor was designed based on Ru(bpy)32+-based metal organic framework composited hydrogel (RuMOF@hydrogel) and versatile banana peel-derived carbonized polymer dots (BPPDs). RuMOF@hydrogel modified magnetic-electrode exhibited excellent anodic and cathodic electrochemiluminescence (ECL) emission and stability. Meanwhile, the BPPDs could enhance anodic ECL of RuMOF@hydrogel, and also show excellent fluorescence (FL) and photothermal (PT) properties. With the aid of PAT-triggered hybridization chain reaction and magnetic separation, ECL, FL, and PT responses could be recorded concurrently. The detection limit can reach as low as 0.25 fg mL-1. The ratiometric ECL quantitation ensured the sensitivity and accuracy of this assay. And visual FL and portable PT modes contributed to the utility. Furthermore, this aptasensor demonstrated better performances than HPLC in fruit products and the protocol can be extended to determine various contaminants in foods.
Asunto(s)
Técnicas Biosensibles , Contaminación de Alimentos , Frutas , Patulina , Polímeros , Frutas/química , Patulina/análisis , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodos , Contaminación de Alimentos/análisis , Polímeros/química , Hidrogeles/química , Aptámeros de Nucleótidos/química , Límite de Detección , Estructuras Metalorgánicas/química , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos , Puntos Cuánticos/química , Musa/química , Mediciones Luminiscentes/instrumentación , Mediciones Luminiscentes/métodosRESUMEN
OBJECTIVE: Colorectal cancer progression involves complex cellular mechanisms. This study examines the effects of Lactobacillus plantarum-derived extracellular vesicles (LEVs) on the SIRT5/p53 axis, focusing on glycolytic metabolic reprogramming and abnormal proliferation in intestinal epithelial cells. METHODS: LEVs were isolated from Lactobacillus plantarum and incubated with Caco-2 cells. Differential gene expression was analyzed through RNA sequencing and compared with TCGA-COAD data. Key target genes and pathways were identified using PPI network and pathway enrichment analysis. Various assays, including RT-qPCR, EdU staining, colony formation, flow cytometry, and Western blotting, were used to assess gene expression, cell proliferation, and metabolic changes. Co-immunoprecipitation confirmed the interaction between SIRT5 and p53, and animal models were employed to validate in vivo effects. RESULTS: Bioinformatics analysis indicated the SIRT5/p53 axis as a critical pathway in LEVs' modulation of colorectal cancer. LEVs were found to inhibit colorectal cancer cell proliferation and glycolytic metabolism by downregulating SIRT5, influencing p53 desuccinylation. In vivo, LEVs regulated this axis, reducing tumor formation in mice. Clinical sample analysis showed that SIRT5 and p53 succinylation levels correlated with patient prognosis. CONCLUSION: Lactobacillus-derived extracellular vesicles play a pivotal role in suppressing colonic tumor formation by modulating the SIRT5/p53 axis. This results in decreased glycolytic metabolic reprogramming and reduced proliferation in intestinal epithelial cells.