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Tumor spread through air spaces (STAS) is a distinctive metastatic pattern affecting prognosis in lung adenocarcinoma (LUAD) patients. Several challenges are associated with STAS detection, including misdetection, low interobserver agreement, and lack of quantitative analysis. In this research, a total of 489 digital whole slide images (WSIs) were collected. The deep learning-based STAS detection model, named STASNet, was constructed to calculate semi-quantitative parameters associated with STAS density and distance. STASNet demonstrated an accuracy of 0.93 for STAS detection at the tiles level and had an AUC of 0.72-0.78 for determining the STAS status at the WSI level. Among the semi-quantitative parameters, T10S, combined with the spatial location information, significantly stratified stage I LUAD patients on disease-free survival. Additionally, STASNet was deployed into a real-time pathological diagnostic environment, which boosted the STAS detection rate and led to the identification of three easily misidentified types of occult STAS.
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Intensity-modulated radiation therapy (IMRT) has been widely used in treating head and neck tumors. However, due to the complex anatomical structures in the head and neck region, it is challenging for the plan optimizer to rapidly generate clinically acceptable IMRT treatment plans. A novel deep learning multi-scale Transformer (MST) model was developed in the current study aiming to accelerate the IMRT planning for head and neck tumors while generating more precise prediction of the voxel-level dose distribution. The proposed end-to-end MST model employs the shunted Transformer to capture multi-scale features and learn a global dependency, and utilizes 3D deformable convolution bottleneck blocks to extract shape-aware feature and compensate the loss of spatial information in the patch merging layers. Moreover, data augmentation and self-knowledge distillation are used to further improve the prediction performance of the model. The MST model was trained and evaluated on the OpenKBP Challenge dataset. Its prediction accuracy was compared with three previous dose prediction models: C3D, TrDosePred, and TSNet. The predicted dose distributions of our proposed MST model in the tumor region are closest to the original clinical dose distribution. The MST model achieves the dose score of 2.23 Gy and the DVH score of 1.34 Gy on the test dataset, outperforming the other three models by 8%-17%. For clinical-related DVH dosimetric metrics, the prediction accuracy in terms of mean absolute error (MAE) is 2.04% for D 99 , 1.54% for D 95 , 1.87% for D 1 , 1.87% for D mean , 1.89% for D 0.1 c c , respectively, superior to the other three models. The quantitative results demonstrated that the proposed MST model achieved more accurate voxel-level dose prediction than the previous models for head and neck tumors. The MST model has a great potential to be applied to other disease sites to further improve the quality and efficiency of radiotherapy planning.
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PPM1F has been shown to play diverse biological functions in the progression of multiple tumors. PPM1F controls the T788/T789 phosphorylation switch of ITGB1 and regulates integrin activity. However, the impacts of PPM1F and ITGB1 on ovarian cancer (OV) progression remain unclear. Whether there is such a regulatory relationship between PPM1F and ITGB1 in ovarian cancer has not been studied. Therefore, the purpose of this study is to elucidate the function and the mechanism of PPM1F in ovarian cancer. The expression level and the survival curve of PPM1F were analyzed by databases. Gain of function and loss of function were applied to explore the function of PPM1F in ovarian cancer. A tumor formation assay in nude mice showed that knockdown of PPM1F inhibited tumor formation. We tested the effect of PPM1F on ITGB1 dephosphorylation in ovarian cancer cells by co-immunoprecipitation and western blotting. Loss of function was applied to investigate the function of ITGB1 in ovarian cancer. ITGB1-mut overexpression promotes the progression of ovarian cancer. Rescue assays showed the promoting effect of ITGB1-wt on ovarian cancer is attenuated due to the dephosphorylation of ITGB1-wt by PPM1F. PPM1F and ITGB1 play an oncogene function in ovarian cancer. PPM1F regulates the phosphorylation of ITGB1, which affects the occurrence and development of ovarian cancer.
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Previous studies revealed that MIR155HG possessed an oncogenic role in many types of tumors including lung adenocarcinoma (LUAD), along with higher expression in tumors. However, in our study, we observed a positive correlation between MIR155HG expression and overall survival across different cohorts. The transferred PBMC on the NCG mouse model abrogated the tumor intrinsic oncogenic role of MIR155HG in LUAD. Upregulation of MIR155HG positively correlated with CD8+ T cell infiltration both in vitro and in vivo, as well as LUAD tissues. Mechanistically, we revealed that MIR155HG increased the cytokine CCL5 expression at the transcriptional level, which depended on the interaction between MIR155HG and YBX1 protein, a novel transcription factor of CCL5, resulting in the more protein stability of YBX1 through dampening ubiquitination. Additionally, we also observed that MIR155 could increase PD-L1 expression to hamper the activity of recruited CD8+ T cells, which could be rescued through PD-L1 mAb addition. Finally, we uncovered that patients with high MIR155HG expression had a higher response rate to immunotherapy, and the combination of MIR155HG overexpression and PD-L1 mAb increased the efficacy of PD-L1 mAb. Together, our study provides a novel biomarker and potential combination treatment strategy for patients who received immunotherapy.
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Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.
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Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Receptores ErbB , Ferritinas , Neoplasias Pulmonares , Animales , Humanos , Ratones , Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Cobre/metabolismo , Receptores ErbB/antagonistas & inhibidores , Ferritinas/metabolismo , Indoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones Desnudos , Coactivadores de Receptor Nuclear/metabolismo , Coactivadores de Receptor Nuclear/genética , Fosforilación Oxidativa/efectos de los fármacos , Pirimidinas/farmacología , /farmacologíaRESUMEN
Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.
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Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Animales , Ratones , Línea Celular Tumoral , Movimiento Celular , Vía de Señalización Wnt , Pronóstico , Carcinogénesis/genéticaRESUMEN
PURPOSE: Patient setup errors have been a primary concern impacting the dose delivery accuracy in radiation therapy. A robust treatment plan might mitigate the effects of patient setup errors. In this reported study, we aimed to evaluate the impact of translational and rotational errors on the robustness of linac-based, single-isocenter, coplanar, and non-coplanar volumetric modulated arc therapy treatment plans for multiple brain metastases. METHODS: Fifteen patients were retrospectively selected for this study with a combined total of 49 gross tumor volumes (GTVs). Single-isocenter coplanar and non-coplanar plans were generated first with a prescribed dose of 40 Gy in 5 fractions or 42 Gy in 7 fractions to cover 95% of planning target volume (PTV). Next, four setup errors (+1 and +2 mm translation, and +1° and +2° rotation) were applied individually to generate modified plans. Different plan quality evaluation metrics were compared between coplanar and non-coplanar plans. 3D gamma analysis (3%/2 mm) was performed to compare the modified plans (+2 mm and +2° only) and the original plans. Paired t-test was conducted for statistical analysis. RESULTS: After applying setup errors, variations of all plan evaluation metrics were similar (p > 0.05). The worst case for V100% to GTV was 92.07% ± 6.13% in the case of +2 mm translational error. 3D gamma pass rates were > 90% for both coplanar (+2 mm and +2°) and the +2 mm non-coplanar groups but was 87.40% ± 6.89% for the +2° non-coplanar group. CONCLUSION: Translational errors have a greater impact on PTV and GTV dose coverage for both planning methods. Rotational errors have a greater negative impact on gamma pass rates of non-coplanar plans. Plan evaluation metrics after applying setup errors showed that both coplanar and non-coplanar plans were robust and clinically acceptable.
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Neoplasias Encefálicas , Órganos en Riesgo , Aceleradores de Partículas , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Errores de Configuración en Radioterapia , Radioterapia de Intensidad Modulada , Humanos , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Radioterapia de Intensidad Modulada/métodos , Errores de Configuración en Radioterapia/prevención & control , Estudios Retrospectivos , Aceleradores de Partículas/instrumentación , Órganos en Riesgo/efectos de la radiación , Pronóstico , Posicionamiento del PacienteRESUMEN
Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), which functions as a robust co-activator of POU2F3, the master transcription factor which is critical for both normal and neoplastic tuft cell identity and viability. Here, we demonstrate that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements. Loss of POU2AF2 leads to an inhibition of active enhancer nearby genes, such as tuft cell identity genes, and a derepression of Polycomb-dependent poised enhancer nearby genes, which are critical for cell viability and differentiation. Mechanistically, depletion of POU2AF2 results in a global redistribution of the chromatin occupancy of the SWI/SNF complex, leading to a significant 3D genome structure change and a subsequent transcriptional reprogramming. Our genome-wide CRISPR screen further demonstrates that POU2AF2 depletion or SWI/SNF inhibition leads to a PTEN-dependent cell growth defect, highlighting a potential role of POU2AF2-SWI/SNF axis in small cell lung cancer (SCLC) pathogenesis. Additionally, pharmacological inhibition of SWI/SNF phenocopies POU2AF2 depletion in terms of gene expression alteration and cell viability decrease in SCLC-P subtype cells. Therefore, impeding POU2AF2-mediated transcriptional regulation represents a potential therapeutic approach for human SCLC therapy.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Regulación de la Expresión Génica , Factores de Transcripción/metabolismo , Neoplasias Pulmonares/genética , Diferenciación Celular , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
BACKGROUND: Previous studies have confirmed the separate effect of arterial stiffness and obesity on type 2 diabetes; however, the joint effect of arterial stiffness and obesity on diabetes onset remains unclear. OBJECTIVE: This study aimed to propose the concept of arterial stiffness obesity phenotype and explore the risk stratification capacity for diabetes. METHODS: This longitudinal cohort study used baseline data of 12,298 participants from Beijing Xiaotangshan Examination Center between 2008 and 2013 and then annually followed them until incident diabetes or 2019. BMI (waist circumference) and brachial-ankle pulse wave velocity were measured to define arterial stiffness abdominal obesity phenotype. The Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% CI. RESULTS: Of the 12,298 participants, the mean baseline age was 51.2 (SD 13.6) years, and 8448 (68.7%) were male. After a median follow-up of 5.0 (IQR 2.0-8.0) years, 1240 (10.1%) participants developed diabetes. Compared with the ideal vascular function and nonobese group, the highest risk of diabetes was observed in the elevated arterial stiffness and obese group (HR 1.94, 95% CI 1.60-2.35). Those with exclusive arterial stiffness or obesity exhibited a similar risk of diabetes, and the adjusted HRs were 1.63 (95% CI 1.37-1.94) and 1.64 (95% CI 1.32-2.04), respectively. Consistent results were observed in multiple sensitivity analyses, among subgroups of age and fasting glucose level, and alternatively using arterial stiffness abdominal obesity phenotype. CONCLUSIONS: This study proposed the concept of arterial stiffness abdominal obesity phenotype, which could improve the risk stratification and management of diabetes. The clinical significance of arterial stiffness abdominal obesity phenotype needs further validation for other cardiometabolic disorders.
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Diabetes Mellitus Tipo 2 , Rigidez Vascular , Masculino , Humanos , Persona de Mediana Edad , Femenino , Estudios Longitudinales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Obesidad Abdominal/complicaciones , Obesidad Abdominal/epidemiología , Índice Tobillo Braquial , Análisis de la Onda del Pulso , Estudios de Cohortes , Obesidad/complicaciones , Obesidad/epidemiologíaRESUMEN
Gasdermin D (GSDMD) is a key executor which triggers pyroptosis as well as an attractive checkpoint in various inflammatory and autoimmune diseases but it has yet to prove its function in Graves'orbitopathy (GO). Our aim was to investigate GSDMD levels in orbital connective tissue and serum of GO patients and then assess the association between serum levels and patients' clinical activity score (CAS). Further, GSDMD-mediated pyroptosis and the underlying mechanism in inflammatory pathogenesis in the cultured orbital fibroblasts (OFs) of GO patients were examined. OFs were collected after tumor necrosis factor (TNF)-α or interferon (IFN)-γ treatment or combination treatment at different times, and the expression of GSDMD and related molecular mechanisms were analyzed. Then, we constructed the GSDMD knockout system with siRNA and the system was further exposed to the medium with or without IFN-γ and TNF-α for a specified time. Finally, we evaluated the production of interleukin (IL)-1ß and IL-18. We found that serum GSDMD levels were elevated and positively correlated with the CAS in GO patients. Meanwhile, the expression of GSDMD and N-terminal domain (NT-GSDMD) in orbital connective tissue of GO patients was augmented. Also, increased expression of GSDMD and related pyroptosis factors was observed in vitro model of GO. We further demonstrated that GSDMD-mediated pyroptosis induced inflammation via the nuclear factor kB (NF-κB)/absent in melanoma-2 (AIM-2)/caspase-1 pathway. In addition, blocking GSDMD suppressed proinflammatory cytokine production in GO. We concluded that GSDMD may be a biomarker as well as a potential target for the evaluation and treatment of inflammation related with GO.
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Oftalmopatía de Graves , Humanos , Oftalmopatía de Graves/metabolismo , FN-kappa B/metabolismo , Piroptosis , Caspasa 1/metabolismo , Células Cultivadas , Inflamación/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión al ADN/metabolismo , Gasderminas , Proteínas de Unión a Fosfato/metabolismoRESUMEN
PURPOSE: This study aimed to evaluate corneal morphological and biomechanical changes in patients with thyroid-associated ophthalmopathy (TAO) and their correlations with activity and severity. METHODS: Patients diagnosed with TAO were recruited and divided into groups by activity and severity. All subjects underwent a complete ophthalmic examination, including magnetic resonance imaging. Corneal topography was measured using a Pentacam device, and biomechanical parameters were obtained using a CorVis ST tonometer. Correlations among the corneal parameters, clinical activity score, and NOSPECS score were analyzed. Areas under the receiver operating characteristic curves were calculated to evaluate the diagnostic accuracy of corneal changes for active and severe TAO. RESULTS: Fifty-three eyes with TAO and 16 healthy eyes were enrolled in our study. The back elevation, CorVis biomechanical index, tomographic and biomechanical index, stiffness parameter at the first applanation, deviation from normality in back elevation, relational thickness, and overall deviation from normality were significantly increased in patients with TAO (all P <0.05), whereas the smallest corneal thickness, maximum Ambrósio relational thickness, and deformation amplitude (DA) ratio were significantly decreased (all P <0.05). The clinical activity score was strongly positively correlated with back elevation (γ = 0.515, P <0.001). The NOSPECS score was strongly positively correlated with relational thickness and tomographic and biomechanical index (γ = 0.429 and 0.515, P <0.001) and negatively correlated with maximum Ambrósio relational thickness (γ = -0.53, P <0.001). Moreover, maximum Ambrósio relational thickness and the Ambrósio relational thickness through the horizontal meridian showed desirable diagnostic capacity in distinguishing mild TAO from moderate-severe TAO (areas under the receiver operating characteristic curve, 0.799 and 0.769). CONCLUSIONS: Corneal morphological and biomechanical changes were found in patients with TAO, which might be related to the presence of inflammation. Measurements of corneal morphological and biomechanical parameters could serve as references in evaluating TAO.
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Oftalmopatía de Graves , Queratocono , Humanos , Oftalmopatía de Graves/diagnóstico , Queratocono/diagnóstico , Córnea/patología , Topografía de la Córnea/métodos , Curva ROC , Fenómenos Biomecánicos , Paquimetría Corneal/métodosRESUMEN
Oxaliplatin-induced peripheral nerve pain (OIPNP) is a common chemotherapy-related complication, but the mechanism is complex. Mitochondria are vital for cellular homeostasis and regulating oxidative stress. Parkin-mediated mitophagy is a cellular process that removes damaged mitochondria, exhibiting a protective effect in various diseases; however, its role in OIPNP remains unclear. In this study, we found that Parkin-mediated mitophagy was decreased, and reactive oxygen species (ROS) was upregulated in OIPNP rat dorsal root ganglion (DRG) in vivo and in PC12 cells stimulated with oxaliplatin (OXA) in vitro. Overexpression of Parkin indicated that OXA might cause mitochondrial and cell damage by inhibiting mitophagy. We also showed that salidroside (SAL) upregulated Parkin-mediated mitophagy to eliminate damaged mitochondria and promote PC12 cell survival. Knockdown of Parkin indicated that mitophagy is crucial for apoptosis and mitochondrial homeostasis in PC12 cells. In vivo study also demonstrated that SAL enhances Parkin-mediated mitophagy in the DRG and alleviates peripheral nerve injury and pain. These results suggest that Parkin-mediated mitophagy is involved in the pathogenesis of OIPNP and may be a potential therapeutic target for OIPNP.NEW & NOTEWORTHY This article discusses the effects and mechanisms of Parkin-mediated mitophagy in oxaliplatin-induced peripheral nerve pain (OIPNP) from both in vivo and in vitro. We believe that our study makes a significant contribution to the literature because OIPNP has always been the focus of clinical medicine, and mitochondrial quality regulation mechanisms especially Parkin-mediated mitophagy, have been deeply studied in recent years. We use a variety of molecular biological techniques and animal experiments to support our argument.
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Mitofagia , Enfermedades del Sistema Nervioso Periférico , Ratas , Animales , Mitofagia/fisiología , Oxaliplatino/farmacología , Especies Reactivas de Oxígeno , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Dolor , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Background: Arterial stiffness is a major contributor to morbidity and mortality worldwide. Although several metabolic markers associated with arterial stiffness have been developed, there is limited data regarding whether glycemic control modifies the association between diabetes and arterial stiffness. For these reasons, identification of traits around diabetes will directly contribute to arterial stiffness and atherosclerosis management in the context of predictive, preventive, and personalized medicine (PPPM). Thus, this study aimed to explore the relationship of diabetes and glycemic control status with arterial stiffness in a real-world setting. Methods: Data of participants from Beijing Xiaotangshan Examination Center (BXEC) with at least two surveys between 2008 and 2019 were used. Cumulative hazards were presented by inverse probability of treatment weighted (IPTW) Kaplan-Meier curves. Cox models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI). Arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s. Results: Of 5837 participants, the mean baseline age was 46.5±9.3 years, including 3791 (64.9%) males. During a median follow-up of 4.0 years, 1928 (33.0%) cases of incident arterial stiffness were observed. People with diabetes at baseline had a 48.4% (HR: 1.484, 95% CI: 1.250-1.761) excessive risk of arterial stiffness. Adherence to good glycemic control attenuated the relationship between diabetes and arterial stiffness (HR: 1.264, 95% CI: 0.950-1.681); while uncontrolled diabetes was associated with the highest risk of arterial stiffness (HR: 1.629, 95% CI: 1.323-2.005). Results were consistent using IPTW algorithm and multiple imputed data. Conclusion: Our study quantified that diabetes status is closely associated with an increased risk of arterial stiffness and supported that adherence to good glycemic control could attenuate the adverse effect of diabetes on arterial stiffness. Therefore, glucose monitoring and control is a cost-effective strategy for the predictive diagnostics, targeted prevention, patient stratification, and personalization of medical services in early vascular damages and arterial stiffness. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00347-z.
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Background and aims: Dyslipidemia is known to contribute to arterial stiffness, while the inverse association remains unknown. This study aimed to explore the association of baseline arterial stiffness and its changes, as determined by brachial-ankle pulse wave velocity (baPWV), with dyslipidemia onset in the general population. Methods: This study enrolled participants from Beijing Health Management Cohort using measurements of the first visit from 2012 to 2013 as baseline, and followed until the dyslipidemia onset or the end of 2019. Unadjusted and adjusted Cox proportional regression models were used to evaluate the associations of baseline baPWV and baPWV transition (persistent low, onset, remitted and persistent high) with incident dyslipidemia. Results: Of 4362 individuals (mean age: 55.5 years), 1490 (34.2%) developed dyslipidemia during a median follow-up of 5.9 years. After adjusting for potential confounders, participants with elevated arterial stiffness at baseline had an increased risk of dyslipidemia (HR, 1.194; 95% CI, 1.050-1.358). Compared with persistent low baPWV, new-onset and persistent high baPWV were associated with a 51.2% and 37.1% excess risk of dyslipidemia. Conclusion: The findings indicated that arterial stiffness is an early risk factor of dyslipidemia, suggesting a bidirectional association between arterial stiffness and lipid metabolism.
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Dislipidemias , Rigidez Vascular , Humanos , Persona de Mediana Edad , Estudios de Cohortes , Índice Tobillo Braquial , Análisis de la Onda del Pulso , Dislipidemias/epidemiologíaRESUMEN
Purpose: Thyroid hormones sensitivity is a newly proposed clinical entity closely related with metabolic health. Prior studies have reported the cross-sectional relationship between thyroid hormones sensitivity and diabetes; however, the longitudinal association is unclear to date. We aimed to explore the relationship between impaired thyroid hormone sensitivity at baseline and diabetes onset using a cohort design. Methods: This study enrolled 7283 euthyroid participants at the first visit between 2008 and 2009, and then annually followed until diabetes onset or 2019. Thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were measured to calculate thyroid hormone sensitivity by thyroid feedback quantile-based index (TFQI), Chinese-referenced parametric thyroid feedback quantile-based index (PTFQI), thyrotropin index (TSHI), thyrotroph thyroxine resistance index (TT4RI) and FT3/FT4 ratio. Cox proportional hazard model and cross-lagged panel analysis were used. Results: The mean baseline age was 44.2 ± 11.9 years, including 4170 (57.3%) male. During a median follow-up of 5.2 years, 359 cases developed diabetes. There was no significant association between thyroid hormones sensitivity indices and diabetes onset, and adjusted hazard ratios per unit (95% CIs) were 0.89 (0.65-1.23) for TFQI, 0.91 (0.57-1.45) for PTFQI, 0.95 (0.70-1.29) for TSHI, 0.98 (0.70-1.01) for TT4RI and 2.12 (0.17-5.78) for FT3/FT4 ratio. Cross-lagged analysis supported the temporal association from fasting glucose to impaired thyroid hormones sensitivity indices. Conclusions: Our findings could not demonstrate that thyroid hormones sensitivity status is a predictor of diabetes onset in the euthyroid population. Elevated fasting glucose (above 7.0 mmol/L) appeared to precede impaired sensitivity indices of thyroid hormones.
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Diabetes Mellitus , Glándula Tiroides , Humanos , Masculino , Adulto , Persona de Mediana Edad , Femenino , Glándula Tiroides/metabolismo , Tiroxina/metabolismo , Hormonas Tiroideas/metabolismo , Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Tirotropina/metabolismo , Glucosa/metabolismoRESUMEN
BACKGROUND: The triglyceride-glucose (TyG) index is a predictor of cardiovascular diseases; however, to what extent the TyG index is associated with cardiovascular diseases through renal function is unclear. This study aimed to evaluate the complex association of the TyG index and renal function with cardiovascular diseases using a cohort design. METHODS: This study included participants from the China Health and Retirement Longitudinal Study (CHARLS) free of cardiovascular diseases at baseline. We performed adjusted regression analyses and mediation analyses using Cox models. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Renal function was defined by the estimated glomerular filtration rate (eGFR). RESULTS: A total of 6 496 participants were included in this study. The mean age of the participants was 59.6 ± 9.5 years, and 2996 (46.1%) were females. During a maximum follow-up of 7.0 years, 1 996 (30.7%) people developed cardiovascular diseases, including 1 541 (23.7%) cases of heart diseases and 651 (10.0%) cases of stroke. Both the TyG index and eGFR level were significantly associated with cardiovascular diseases. Compared with people with a lower TyG index (median level) and eGFR ≥ 60 ml/minute/1.73 m2, those with a higher TyG index and decreased eGFR had the highest risk of cardiovascular diseases (HR, 1.870; 95% CI 1.131-3.069). Decreased eGFR significantly mediated 29.6% of the associations between the TyG index and cardiovascular diseases. CONCLUSIONS: The combination of a higher TyG index and lower eGFR level was associated with the highest risk of cardiovascular diseases. Renal function could mediate the association between the TyG index and cardiovascular risk.
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Enfermedades Cardiovasculares , Glucosa , Femenino , Humanos , Persona de Mediana Edad , Anciano , Masculino , Estudios de Cohortes , Estudios Longitudinales , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo , Triglicéridos , Medición de Riesgo , Glucemia/análisis , Biomarcadores , Riñón/fisiologíaRESUMEN
Background: The profile of immune-related adverse events (irAEs) due to programmed death-1 (PD-1) inhibitors-based combination therapy in advanced non-small cell lung cancer (NSCLC) and its relationship with survival have not been fully described. Objective: Designed to capture the spectrum of irAEs and explore the association between irAEs and clinical outcomes in patients with NSCLC. Design: This retrospective single-center study included patients with advanced NSCLC treated with PD-1 inhibitors (mainly in combination with chemotherapy) at Jiangsu Cancer Hospital. Methods: The relationship between irAEs and survival was explored using landmark analysis and time-dependent Cox regression. The subgroup analyses focused on investigating the effects of organ-specific irAE, irAE grade, and steroid dose used to treat irAE. Results: This study included 301 patients, 199 of whom received PD-1 inhibitors plus chemotherapy. The most common irAEs were skin toxicity (19.3%), endocrinopathy (21.3%), and pneumonitis (17.6%). In the entire cohort, the median progression-free survival (PFS) for patients developing and not developing irAE was 12.3 and 10.7 months (p < 0.001), and the median overall survival (OS) was 23.5 months and 20.1 months (p = 0.137), respectively. Subgroup analyses indicated that grade 3 or higher irAE, high steroid dose, and immune-related pneumonitis were detrimental to OS, whereas skin toxicity was beneficial to survival. These findings were further corroborated by both landmark analyses and Cox regression models conducted over four time points (1, 3, 6, and 12 months). Conclusion: In the real world, NSCLC patients receiving PD-1 inhibitor-based combination therapy (particularly combined with chemotherapy) experience longer PFS with irAE, though not necessarily OS. Immune-related skin toxicity is associated with a better prognosis, whereas pneumonitis grade ⩾3 irAE and high steroid dose compromise survival. Clinicians should remain cognizant of the organ-specific manifestations of irAE and take proactive measures to mitigate the progression of irAE.
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Background: We aimed to explore the frequencies of islet ß-cell autoantibodies and insulin resistance (IR) in thyroid-associated ophthalmopathy (TAO) and identify specific diabetes mellitus (DM) indicators as early predictors for dysthyroid optic neuropathy (DON). Methods: Ninety-eight TAO patients (57 DON and 41 non-DON patients) and 48 healthy control (HC) participants were recruited for this prospective cross-sectional study. Serum thyroxine, serum thyroid autoantibodies, serum humoral immune markers against islet ß-cell, fasting plasma glucose (FPG), fasting serum insulin (FINS), fasting c-peptide (FCP), and glycosylated hemoglobin A1 (HbA1c) were measured. Logistic regression analysis was used to evaluate the correlation of patients' age, body mass index (BMI), FPG, HbA1c, and related indexes of islet ß-cell function to the occurrence of DON. Results: The DON group had higher FPG (P<0.001, 0.016) and HbA1c (P<0.0001, P<0.001) levels than the HC and non-DON groups. The homeostasis model assessment (HOMA)-IR level was the highest in the DON group (HC 2.15 ± 0.89, non-DON 2.41 ± 1.24, and DON 2.82 ± 2.65), while the HOMA-ß level was the lowest (HC 101.8 ± 44.75%, non-DON 102.9 ± 54.61%, and DON 88.29 ± 52.75%), with no significant differences (P=1, P>0.05). On univariate analysis, age (P=0.006), BMI (P=0.022), history of steroid use (P=0.014), FPG (P=0.013), and HbA1c (P=0.001) levels were significantly associated with the presence/absence of DON. In addition, after adjusting for potential confounds, the HbA1c level was an independent factor associated with DON (P=0.009, OR=4.012). Conclusions: HbA1c is an independent risk factor for DON. Given the interconnected link between thyroid dysfunction and DM, the use of HbA1c as a potential biomarker for DON warrants further investigation.
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Diabetes Mellitus , Oftalmopatía de Graves , Resistencia a la Insulina , Enfermedades del Nervio Óptico , Humanos , Hemoglobina Glucada , Estudios Transversales , Estudios Prospectivos , Factores de Riesgo , AutoanticuerposRESUMEN
Numerous studies have focused on the classification of N6-methyladenosine (m6A) modification sites in RNA sequences, treating it as a multi-feature extraction task. In these studies, the incorporation of physicochemical properties of nucleotides has been applied to enhance recognition efficacy. However, the introduction of excessive supplementary information may introduce noise to the RNA sequence features, and the utilization of sequence similarity information remains underexplored. In this research, we present a novel method for RNA m6A modification site recognition called M6ATMR. Our approach relies solely on sequence information, leveraging Transformer to guide the reconstruction of the sequence similarity matrix, thereby enhancing feature representation. Initially, M6ATMR encodes RNA sequences using 3-mers to generate the sequence similarity matrix. Meanwhile, Transformer is applied to extract sequence structure graphs for each RNA sequence. Subsequently, to capture low-dimensional representations of similarity matrices and structure graphs, we introduce a graph self-correlation convolution block. These representations are then fused and reconstructed through the local-global fusion block. Notably, we adopt iteratively updated sequence structure graphs to continuously optimize the similarity matrix, thereby constraining the end-to-end feature extraction process. Finally, we employ the random forest (RF) algorithm for identifying m6A modification sites based on the reconstructed features. Experimental results demonstrate that M6ATMR achieves promising performance by solely utilizing RNA sequences for m6A modification site identification. Our proposed method can be considered an effective complement to existing RNA m6A modification site recognition approaches.
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Adenosina , Nucleótidos , Secuencia de Bases , ARN/genéticaRESUMEN
BACKGROUND: Lung cancer is the leading cause of cancer related to mortality worldwide, and the main pathological type is lung adenocarcinoma (LUAD). Circular RNAs (circRNAs) have been reported to be modified by N6 -methyladenosine (m6A), which is involved in the progression of diverse tumors. However, the crosstalk between circRNAs and m6A modification has not been well elucidated in LUAD. METHODS: MeRIP-seq and YTHDF2-RIP-seq datasets were explored to identify candidate circRNAs modified by YTHDF2. Dual-luciferase reporter assay, RIP, and rescue assays were performed to explore the relationship between circFUT8 and its parent mRNA of FUT8. In vitro and in vivo experiments were utilized to uncover the function of circFUT8. RESULTS: In this study, we identified a novel m6A-modified circFUT8, derived from exon 3 of FUT8, which was elevated in tumor tissues compared with adjacent noncancerous tissues. The m6A reader YTHDF2 recognized and destabilized circFUT8 in an m6A-dependent manner. YTHDF2 also combined with the line form of FUT8 (mFUT8), and circFUT8 competitively interacted with YTHDF2, blunting its binding to mFUT8, to stabilize the mRNA level of FUT8. Additionally, circFUT8 sponged miR-186-5p to elevate the expression of mFUT8. Finally, we revealed that circFUT8 promoted the malignant progression of LUAD dependent on the oncogenic function of FUT8. CONCLUSIONS: These findings identified a novel m6A-modified circFUT8 recognized and destabilized by YTHDF2, which competitively interacted with YTHDF2 and miR-186-5p to stabilize FUT8 mRNA to promote malignant progression in LUAD.