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The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.
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BACKGROUND: Given the global shifts in environmental conditions and dietary habits, understanding the potential impact of dietary factors and body mass index (BMI) on respiratory diseases, including asthma, is paramount. Investigating these relationships can contribute to the formulation of more effective prevention strategies. The Planetary Health Diet Index (PHDI), a dietary scoring system that balances human health with environmental sustainability, underscores the importance of increasing the consumption of plant-based foods while reducing the intake of red meat, sugar, and highly processed foods. The objective of this study was to assess the association between PHDI and the prevalence of asthma and the mediation effect of BMI in a US general population. METHODS: This study utilized data from 32,388 participants in the National Health and Nutrition Examination Survey (NHANES) spanning from 2005 to 2018. Multivariate logistic regression and weighted quantile sum (WQS) regressions were employed to investigate the association between PHDI, individual nutrients, and asthma. Restricted cubic spline (RCS) analysis explored the linear or non-linear relationship between PHDI and asthma. Interaction analyses were conducted on subgroups to validate the findings. Mediation analysis was performed to examine the effect of BMI on the relationship between PHDI and asthma. RESULTS: There was a significant negative association between PHDI and asthma. After adjusting for covariates, for every 10-point increase in PHDI, there was a 4% decrease in the prevalence of asthma (P = 0.025). Moreover, as PHDI increased, there was a trend towards lower asthma prevalence (P for trend < 0.05). WQS analyses showed consistent associations (OR = 0.93, 95%CI: 0.88, 0.98), with Fiber, Vitamin C, and Protein significant factors. The dose-response curve indicated a linear association between PHDI and asthma, with higher PHDI associated with lower asthma prevalence. Additionally, BMI is significantly positively associated with asthma (P < 0.001), and BMI decreases as the PHDI increases (ß = -0.64, P < 0.001). Mediation analysis indicates that BMI significantly mediates the relationship between PHDI and asthma, with a mediation proportion of 33.85% (P < 0.001). CONCLUSION: The results of this study show a strong negative correlation between PHDI and the prevalence of asthma. In addition, BMI mediated this negative relationship.
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Asma , Índice de Masa Corporal , Encuestas Nutricionales , Humanos , Asma/epidemiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estados Unidos/epidemiología , Adulto Joven , Adolescente , Prevalencia , Dieta Saludable/estadística & datos numéricos , Dieta/estadística & datos numéricos , Anciano , Estudios TransversalesRESUMEN
BACKGROUND: In recent years, there has been a growing trend in the utilization of observational studies that make use of routinely collected healthcare data (RCD). These studies rely on algorithms to identify specific health conditions (e.g. diabetes or sepsis) for statistical analyses. However, there has been substantial variation in the algorithm development and validation, leading to frequently suboptimal performance and posing a significant threat to the validity of study findings. Unfortunately, these issues are often overlooked. METHODS: We systematically developed guidance for the development, validation, and evaluation of algorithms designed to identify health status (DEVELOP-RCD). Our initial efforts involved conducting both a narrative review and a systematic review of published studies on the concepts and methodological issues related to algorithm development, validation, and evaluation. Subsequently, we conducted an empirical study on an algorithm for identifying sepsis. Based on these findings, we formulated specific workflow and recommendations for algorithm development, validation, and evaluation within the guidance. Finally, the guidance underwent independent review by a panel of 20 external experts who then convened a consensus meeting to finalize it. RESULTS: A standardized workflow for algorithm development, validation, and evaluation was established. Guided by specific health status considerations, the workflow comprises four integrated steps: assessing an existing algorithm's suitability for the target health status; developing a new algorithm using recommended methods; validating the algorithm using prescribed performance measures; and evaluating the impact of the algorithm on study results. Additionally, 13 good practice recommendations were formulated with detailed explanations. Furthermore, a practical study on sepsis identification was included to demonstrate the application of this guidance. CONCLUSIONS: The establishment of guidance is intended to aid researchers and clinicians in the appropriate and accurate development and application of algorithms for identifying health status from RCD. This guidance has the potential to enhance the credibility of findings from observational studies involving RCD.
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Algoritmos , Estado de Salud , Estudios Observacionales como Asunto , Humanos , Estudios Observacionales como Asunto/métodos , Estudios Observacionales como Asunto/normas , Reproducibilidad de los Resultados , Recolección de Datos/métodos , Recolección de Datos/normas , Recolección de Datos/estadística & datos numéricosRESUMEN
Aneuploidy generally has severe phenotypic consequences. However, the molecular basis for this has been focused on single chromosomal dosage changes. It is not clear how the karyotype of complex aneuploidies affects gene expression. Here, we identified six different double-trisomy loquat strains from Q24 progenies of triploid loquat. The differences and similarities of the transcriptional responses of different double trisomy loquat strains were studied systematically via RNA-seq. The global modulation of gene expression indicated that both cis and trans-effects coordinately regulated gene expression in aneuploid loquat to some extent, and this coordinated regulation was determined by different gene functional groups. Aneuploidy can induce specific transcriptional responses on loquat chromosomes. The differentially expressed genes exhibited regional gene expression dysregulation domains along chromosomes. Furthermore, Aneuploidy could also promote the expression of genes with moderate and high in loquats. Our results provide new insights into the genome-wide transcriptional effects of karyotypes with complex aneuploidies.
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Small molecule/polymer semiconductor blends are promising solutions for the development of high-performing organic electronics. They are able to combine ease in solution processability, thanks to the tunable rheological properties of polymeric inks, with outstanding charge transport properties thanks to high crystalline phases of small molecules. However, because of charge injection issues, so far such good performances are only demonstrated in ad-hoc device architectures, not suited for high-frequency applications, where transistor dimensions require downscaling. Here, the successful integration of the most performing blend reported to date, based on 2,7-dioctyl[1] benzothieno[3,2-b][1]benzothiophene (C8-BTBT) and poly(indacenodithiophene-co-benzothiadiazole) (C16IDT-BT), in OFETs characterized by channel and overlap lengths equal to 1.3 and 1.9 µm, respectively, is demonstrated, enabling a transition frequency of 23 MHz at -8 V. Two key aspects allowed such result: molecular doping, leading to width-normalized contact resistance of only 260 Ωcm, allowing to retain an apparent field-effect mobility as high as 3 cm2/(Vs) in short channel devices, and the implementation of a high capacitance dielectric stack, enabling the reduction of operating voltages below 10 V and the overcoming of self-heating issues. These results represent a fundamental step for the future development of low-cost and high-speed printed electronics for IoT applications.
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Parthenocarpy is an important way for seedless fruit production in citrus. However, the molecular mechanism(s) of parthenocarpy in pomelo is still unknown. Our initial study found significantly different parthenocarpic abilities in Guanximiyou (G) and Shatianyou (S) pomelo following emasculation, and an endogenous hormone content assay revealed that indole-3-acetic acid (IAA), gibberellic acid (GA3) and zeatin (ZT) jointly promoted fruit expansion and cell division in parthenocarpic pomelo (G pomelo). To unravel the underlying molecular mechanism(s), we conducted the first transcriptome analysis on the two pomelo accessions at these two critical stages: the fruit initiation stage and the rapid expansion stage, in order to identify genes associated with parthenocarpy. This analysis yielded approximately 7.86 Gb of high-quality reads, and the subsequent de novo assembly resulted in the identification of 5,792 DEGs (Differentially Expressed Genes). Among these, a range of transcription factor families such as CgERF, CgC2H2, CgbHLH, CgNAC and CgMYB, along with genes like CgLAX2, CgGH3.6 and CgGH3, emerged as potential candidates contributing to pomelo parthenocarpy, as confirmed by qRT-PCR analysis. The present study provides comprehensive transcriptomic profiles of both parthenocarpic and non-parthenocarpic pomelos, reveals several metabolic pathways linked to parthenocarpy, and highlights the significant role of plant hormones in its regulation. These findings deepen our understanding of the molecular mechanisms underlying parthenocarpy in pomelo.
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Conducting polymers are mixed ionic-electronic conductors that are emerging candidates for neuromorphic computing, bioelectronics and thermoelectrics. However, fundamental aspects of their many-body correlated electron-ion transport physics remain poorly understood. Here we show that in p-type organic electrochemical transistors it is possible to remove all of the electrons from the valence band and even access deeper bands without degradation. By adding a second, field-effect gate electrode, additional electrons or holes can be injected at set doping states. Under conditions where the counterions are unable to equilibrate in response to field-induced changes in the electronic carrier density, we observe surprising, non-equilibrium transport signatures that provide unique insights into the interaction-driven formation of a frozen, soft Coulomb gap in the density of states. Our work identifies new strategies for substantially enhancing the transport properties of conducting polymers by exploiting non-equilibrium states in the coupled system of electronic charges and counterions.
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This study aimed to elucidate the effects of long day and night shifts on immune cells in a population of nurses. This cross-sectional study in December 2019 was based on a group of nurses. 1568 physically healthy caregivers were included, including 1540 women and 28 men. 1093 nurses had long-term shift work (working in a rotating system for > 1 year). The receiver operating characteristic curve, Ensemble Learning, and Logistic regression analyses were used to evaluate factors related to long-term shift work. The night shift group nurses had significantly higher MPV, PLCR, and WBC and significantly lower BASO%, ELR, MCHC, PLR, RDW-CV, and RDW-SD (P < 0.01). ROC curves showed that WBC, PLR, ELR, RDW_CV, and BASO% were more related to the night shift. Ensemble Learning, combined with the LASSO model, finally filtered out three indicators of night shifts related to ELR, WBC, and RDW_SD. Finally, logistic regression analysis showed that the nurses' night shift situation greatly influenced two peripheral blood ELR and WBC indicators (ELR: log (OR) = - 3.9, 95% CI: - 5.8- - 2.0; WBC: log (OR) = 0.25, 95% CI: 0.18-0.32). Finally, we showed that, unlike WBC, the relative riskiness of ELR showed opposite results among junior nurses and middle-senior nurses (log (OR) 6.5 (95% CI: 1.2, 13) and - 7.1 (95% CI: - 10, - 3.8), respectively). Our study found that prolonged night shifts were associated with abnormal WBC and ELR, but after strict age matching, WBC remained significantly different. These findings help to confirm that COVID-19 and tumorigenesis (e.g., breast cancer) are significantly associated with circadian rhythm disruption. However, more detailed studies are needed to confirm this.
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Enfermeras y Enfermeros , Horario de Trabajo por Turnos , Humanos , Femenino , Masculino , Estudios Transversales , Adulto , China , Leucocitos , Recuento de Leucocitos , Persona de Mediana Edad , Tolerancia al Trabajo Programado , COVID-19/sangre , COVID-19/epidemiologíaRESUMEN
Objective: To identify subclasses of acute pancreatitis (AP) patients in the intensive care unit (ICU) by analyzing blood urea nitrogen (BUN) trajectories. Methods: AP patients in West China Hospital System (development cohort) and three public databases in the United States (validation cohort) were included. Latent class trajectory modelling was used to identify subclasses based on BUN trajectories within the first 21 days after ICU admission. Clinical characteristics and outcomes were compared, and results were externally validated. Results: The study comprised 2971 and 930 patients in the development and validation cohorts, respectively, with five subclasses: Class 1 ("Moderate-azotemia, slow decreasing"), Class 2 ("Non-azotemia"), Class 3 ("Severe-azotemia, slow decreasing"), Class 4 ("Moderate-azotemia, rapid increasing"), and Class 5 ('Moderate-azotemia, slow increasing) identified. Azotemia patients showed significantly higher 30-day mortality risk in development and validation cohorts. Specifically, Class 4 patients exhibited notably highest mortality risk in both the development cohort (HR 5.32, 95% CI 2.62-10.82) and validation cohort (HR 6.23, 95% CI 2.93-13.22). Regarding clinical characteristics, AP patients in Class 4 showed lower mean arterial pressure and a higher proportion of renal disease. We also created an online early classification model to further identify Class 4 patients among all patients with moderate azotemia at baseline. Conclusion: This multinational study uncovers heterogeneity in BUN trajectories among AP patients. Patients with "Moderate-azotemia, rapid increasing" trajectory, had a higher mortality risk than patients with severe azotemia at baseline. This finding complements studies that solely rely on baseline BUN for risk stratification and enhanced our understanding of longitudinal progression of AP.
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BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver disease-related deaths worldwide. Unfortunately, approved medications for the treatment of this condition are quite limited. One promising candidate is the anthocyanin, Cyanidin-3-O-glucoside (C3G), which has been reported to protect mice against hepatic lipid accumulation, as well as fibrosis in different animal models. However, the specific effects and mechanisms of C3G on ALD remain to be investigated. EXPERIMENTAL APPROACH: In this report, a Gao-binge mouse model of ALD was used to investigate the effects of C3G on ethanol-induced liver injury. The mechanisms of these C3G effects were assessed using AML12 hepatocytes. RESULTS: C3G administration ameliorated ethanol-induced liver injury by suppressing hepatic oxidative stress, as well as through reducing hepatic lipid accumulation and inflammation. Mechanistically, C3G activated the AMPK pathway and enhanced mitophagy to eliminate damaged mitochondria, thus reducing mitochondria-derived reactive oxidative species in ethanol-challenged hepatocytes. CONCLUSIONS: The results of this study indicate that mitophagy plays a potentially important role underlying the hepatoprotective action of C3G, as demonstrated in a Gao-binge mouse model of ALD. Accordingly, C3G may serve as a promising, new therapeutic drug candidate for use in ALD.
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Antocianinas , Modelos Animales de Enfermedad , Etanol , Glucósidos , Hepatopatías Alcohólicas , Mitofagia , Estrés Oxidativo , Animales , Antocianinas/farmacología , Mitofagia/efectos de los fármacos , Ratones , Glucósidos/farmacología , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/prevención & control , Etanol/toxicidad , Etanol/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Masculino , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Especies Reactivas de Oxígeno/metabolismo , Metabolismo de los Lípidos/efectos de los fármacosRESUMEN
Vocal communication plays an important role in survival, reproduction, and animal social association. Birds and mammals produce complex vocal sequence to convey context-dependent information. Vocalizations are conspicuous features of the behavior of most anuran species (frogs and toads), and males usually alter their calling strategies according to ecological context to improve the attractiveness/competitiveness. However, very few studies have focused on the variation of vocal sequence in anurans. In the present study, we used both conventional method and network analysis to investigate the context-dependent vocal repertoire, vocal sequence, and call network structure in serrate-legged small treefrogs Kurixalus odontotarsus. We found that male K. odontotarsus modified their vocal sequence by switching to different call types and increasing repertoire size in the presence of a competitive rival. Specifically, compared with before and after the playback of advertisement calls, males emitted fewer advertisement calls, but more aggressive calls, encounter calls, and compound calls during the playback period. Network analysis revealed that the mean degree, mean closeness, and mean betweenness of the call networks significantly decreased during the playback period, which resulted in lower connectivity. In addition, the increased proportion of one-way motifs and average path length also indicated that the connectivity of the call network decreased in competitive context. However, the vocal sequence of K. odontotarsus did not display a clear small-world network structure, regardless of context. Our study presents a paradigm to apply network analysis to vocal sequence in anurans and has important implications for understanding the evolution and function of sequence patterns.
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Chemical doping is an important approach to manipulating charge-carrier concentration and transport in organic semiconductors (OSCs)1-3 and ultimately enhances device performance4-7. However, conventional doping strategies often rely on the use of highly reactive (strong) dopants8-10, which are consumed during the doping process. Achieving efficient doping with weak and/or widely accessible dopants under mild conditions remains a considerable challenge. Here, we report a previously undescribed concept for the photocatalytic doping of OSCs that uses air as a weak oxidant (p-dopant) and operates at room temperature. This is a general approach that can be applied to various OSCs and photocatalysts, yielding electrical conductivities that exceed 3,000 S cm-1. We also demonstrate the successful photocatalytic reduction (n-doping) and simultaneous p-doping and n-doping of OSCs in which the organic salt used to maintain charge neutrality is the only chemical consumed. Our photocatalytic doping method offers great potential for advancing OSC doping and developing next-generation organic electronic devices.
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Conjugated polymers are promising materials for thermoelectric applications, however, at present few effective and well-understood strategies exist to further advance their thermoelectric performance. Here a new model system is reported for a better understanding of the key factors governing their thermoelectric properties: aligned, ribbon-phase poly[2,5-bis(3-dodecylthiophen-2-yl)thieno[3,2-b]thiophene] (PBTTT) doped by ion-exchange doping. Using a range of microstructural and spectroscopic methods, the effect of controlled incorporation of tie-chains between the crystalline domains is studied through blending of high and low molecular weight chains. The tie chains provide efficient transport pathways between crystalline domains and lead to significantly enhanced electrical conductivity of 4810 S cm-1, which is not accompanied by a reduction in Seebeck coefficient or a large increase in thermal conductivity. Respectable power factors of 173 µW m-1 K-2 are demonstrated in this model system. The approach is generally applicable to a wide range of semicrystalline conjugated polymers and could provide an effective pathway for further enhancing their thermoelectric properties and overcome traditional trade-offs in optimization of thermoelectric performance.
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Background: In contemporary study, the death of esophageal squamous cell carcinoma (ESCC) patients need precise and expedient prognostic methodologies. Objective: To develop and validate a prognostic model tailored to ESCC patients, leveraging the power of machine learning (ML) techniques and drawing insights from comprehensive datasets of laboratory-derived blood parameters. Methods: Three ML approaches, including Gradient Boosting Machine (GBM), Random Survival Forest (RSF), and the classical Cox method, were employed to develop models on a dataset of 2521 ESCC patients with 27 features. The models were evaluated by concordance index (C-index) and time receiver operating characteristics (Time ROC) curves. We used the optimal model to evaluate the correlation between features and prognosis and divide patients into low- and high-risk groups by risk stratification. Its performance was analyzed by Kaplan-Meier curve and the comparison with AJCC8 stage. We further evaluate the comprehensive effectiveness of the model in ESCC subgroup by risk score and KDE (kernel density estimation) plotting. Results: RSF's C-index (0.746) and AUC (three-year AUC 0.761, five-year AUC 0.771) had slight advantage over GBM and the classical Cox method. Subsequently, 14 features such as N stage, T stage, surgical margin, tumor length, age, Dissected LN number, MCH, Na, FIB, DBIL, CL, treatment, vascular invasion, and tumor grade were selected to build the model. Based on these, we found significant difference for survival rate between low-(3-year OS 81.8%, 5-year OS 69.8%) and high-risk (3-year OS 25.1%, 5-year OS 11.5%) patients in training set, which was also verified in test set (all P < 0.0001). Compared with the AJCC8th stage system, it showed a greater discriminative ability which is also in good agreement with its staging ability. Conclusion: We developed an ESCC prognostic model with good performance by clinical features and laboratory blood parameters.
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CD80 is a transmembrane glycoprotein belonging to the B7 family, which has emerged as a crucial molecule in T cell modulation via the CD28 or CTLA4 axes. CD80-involved regulation of immune balance is a finely tuned process and it is important to elucidate the underlying mechanism for regulating CD80 function. In this study we investigated the post-translational modification of CD80 and its biological relevance. By using a metabolic labeling strategy, we found that CD80 was S-palmitoylated on multiple cysteine residues (Cys261/262/266/271) in both the transmembrane and the cytoplasmic regions. We further identified zDHHC20 as a bona fide palmitoyl-transferase determining the S-palmitoylation level of CD80. We demonstrated that S-palmitoylation protected CD80 protein from ubiquitination degradation, regulating the protein stability, and ensured its accurate plasma membrane localization. The palmitoylation-deficient mutant (4CS) CD80 disrupted these functions, ultimately resulting in the loss of its costimulatory function upon T cell activation. Taken together, our results describe a new post-translational modification of CD80 by S-palmitoylation as a novel mechanism for the regulation of CD80 upon T cell activation.
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Aciltransferasas , Antígeno B7-1 , Lipoilación , Activación de Linfocitos , Humanos , Antígeno B7-1/metabolismo , Aciltransferasas/metabolismo , Células HEK293 , Linfocitos T/metabolismo , Linfocitos T/inmunología , Procesamiento Proteico-Postraduccional , UbiquitinaciónRESUMEN
OBJECTIVE: Time-varying treatments are common in observational studies. However, when assessing treatment effects, the methodological framework has not been systematically established for handling time-varying treatments. This study aimed to examine the current methods for dealing with time-varying treatments in observational studies and developed practical recommendations. METHODS: We searched PubMed from 2000 to 2021 for methodological articles about time-varying treatments, and qualitatively summarized the current methods for handling time-varying treatments. Subsequently, we developed practical recommendations through interactive internal group discussions and consensus by a panel of external experts. RESULTS: Of the 36 eligible reports (22 methodological reviews, 10 original studies, 2 tutorials and 2 commentaries), most examined statistical methods for time-varying treatments, and only a few discussed the overarching methodological process. Generally, there were three methodological components to handle time-varying treatments. These included the specification of treatment which may be categorized as three scenarios (i.e., time-independent treatment, static treatment regime, or dynamic treatment regime); definition of treatment status which could involve three approaches (i.e., intention-to-treat, per-protocol, or as-treated approach); and selection of analytic methods. Based on the review results, a methodological workflow and a set of practical recommendations were proposed through two consensus meetings. CONCLUSIONS: There is no consensus process for assessing treatment effects in observational studies with time-varying treatments. Previous efforts were dedicated to developing statistical methods. Our study proposed a stepwise workflow with practical recommendations to assist the practice.
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To explores the effect and mechanism of quiet eye training on the accuracy of golfers´ putts in pressure situations and provides methods and basis for targeted attention training and control. 22 young golfers in China golf team aged from 13 to 18 were randomly assigned to the experimental group (quiet eye training group) and the control group (technical guidance group) according to gender. Both groups of participants underwent two consecutive weeks of push training (3 sets per day, 20 golf putts per set, rest for 3 min between sets) separately in accordance with the guidance of a professional psychological research group and an expert coach. Eye tracking technology, biofeedback technology, and subjective evaluation methods were used to test and analyze the push process of the two groups of participants before and after training under pressure situations (Eye movement behaviors and the heart rate were recorded by ASL Mobile Eye-XG and NeXus-2 biofeedback, pressure and state anxiety were evaluated by self-rating pressure scale and S-AI. Golf putting performance was recorded by a research graduate assistant). A higher hit ratio as well as lower pressure and SAI level was founded in quiet eye training group in the pressure situation, the quiet eye movement time and total fixation time was longer than technical group. The quiet eye training group has a better putting performance. Quiet eye training can improve the golf putting performance in pressure situations. After quiet eye training, the state anxiety decreased, the quiet eye movement time and the total fixation time increased in pressure situations.
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Golf , Desempeño Psicomotor , Humanos , Desempeño Psicomotor/fisiología , Golf/fisiología , Movimientos Oculares , Ansiedad , Trastornos de AnsiedadRESUMEN
Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.