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Endometrial cancer is considered to be the second most common tumor of the female reproductive system, and patients diagnosed with advanced endometrial cancer have a poor prognosis. The influence of fatty acid metabolism in the prognosis of patients with endometrial cancer remains unclear. We constructed a prognostic risk model using transcriptome sequencing data of endometrial cancer and clinical information of patients from The Cancer Genome Atlas (TCGA) database via least absolute shrinkage and selection operator regression analysis. The tumor immune microenvironment was analyzed using the CIBERSORT algorithm, followed by functional analysis and immunotherapy efficacy prediction by gene set variation analysis. The role of model genes in regulating endometrial cancer in vitro was verified by CCK-8, colony formation, wound healing, and transabdominal invasion assays, and verified in vivo by subcutaneous tumor transplantation in nude mice. A prognostic model containing 14 genes was constructed and validated in 3 cohorts and clinical samples. The results showed differences in the infiltration of immune cells between the high-risk and low-risk groups, and that the high-risk group may respond better to immunotherapy. Experiments in vitro confirmed that knockdown of epoxide hydrolase 2 (EPHX2) and acyl-CoA oxidase like (ACOXL) had an inhibitory effect on EC cells, as did overexpression of hematopoietic prostaglandin D synthase (HPGDS). The same results were obtained in experiments in vivo. Prognostic models related to fatty acid metabolism can be used for the risk assessment of endometrial cancer patients. Experiments in vitro and in vivo confirmed that the key genes HPGDS, EPHX2, and ACOXL in the prognostic model may affect the development of endometrial cancer.
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Neoplasias Endometriales , Ácidos Grasos , Femenino , Neoplasias Endometriales/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/inmunología , Humanos , Ratones , Ácidos Grasos/metabolismo , Animales , Pronóstico , Ratones Desnudos , Microambiente Tumoral/inmunología , Línea Celular TumoralRESUMEN
BACKGROUND: Sepsis-associated encephalopathy (SAE) impairs hippocampal microglial efferocytosis, causing cognitive deficits. Previous research found that milk fat globule epidermal growth factor 8 protein (MFGE8) stimulates efferocytosis, reducing hippocampal inflammation in SAE rats. In this study, we explore MFGE8's role in alleviating cognitive impairment and its impact on neural activity using functional magnetic resonance imaging (fMRI). METHODS: Sixty male Sprague Dawley rats were divided into four groups: Sham, cecal ligation and puncture (CLP), CLP+MFGE8, and CLP+MFGE8+CGT (Cilengitide). After CLP, CLP+MFGE8 rats received intracerebroventricular MFGE8 (3.3 µg), while CLP+MFGE8+CGT rats received intraperitoneal Cilengitide (10 mg/kg). We assessed cognitive function with the Morris water maze and open field test over five days. Eight days post-surgery, rats underwent T2-weighted magnetic resonance imaging (MRI) and resting state (rs)-fMRI scans. Brain tissues were collected for western blot, hematoxylin-eosin (HE) staining, and immunofluorescence. Statistical analysis employed one-way analysis of variance (ANOVA) followed by Tukey's post-test for multiple comparisons. RESULTS: MFGE8 improved neurobehavioral performance in open field task (OFT) and morris water maze (MWM) tests. fMRI indicated a significant reduction in abnormal neural activity in the right hippocampal CA1, CA3, and dentate gyrus of SAE rats following MFGE8 treatment. Voxel-based morphometry (VBM) analysis revealed decreased high-signal areas in the hippocampus, along with reduced hippocampal volume due to alleviated neural edema. Western blot analysis demonstrated that MFGE8 enhanced ras-related C3 botulinum toxin substrate 1 (Rac1) and microtubule-associated protein 1A/1B-light chain 3 (LC3) expression in the rat hippocampus, while CGT reduced these protein levels. Behavioral experiments and fMRI results confirmed that CGT reversed the cognitive effects of MFGE8 by inhibiting microglial αVß3/αVß5 integrin receptors. CONCLUSIONS: Our findings show that MFGE8 reduced amplitude of low-frequency fluctuations (ALFF) values in the right hippocampal CA1, CA3, and the dentate gyrus, mitigating abnormal neural activity and decreasing hippocampal volume. This led to an improvement in cognitive dysfunction in SAE rats. These results suggest that MFGE8 enhances microglial efferocytosis by activating αVß3 and αVß5 integrin receptors on microglial surfaces, ultimately improving cognitive function in SAE rats.
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Disfunción Cognitiva , Imagen por Resonancia Magnética , Encefalopatía Asociada a la Sepsis , Animales , Masculino , Ratas , Antígenos de Superficie/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/diagnóstico por imagen , Proteínas de la Leche/farmacología , Proteínas de la Leche/administración & dosificación , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Metabolic reprogramming is one of hallmarks of cancer progression and is of great importance for the tumor microenvironment (TME). As an abundant metabolite, lactate has been found to play a critical role in cancer development and immunosuppression of TME. However, the potential role of lactate metabolism-related genes in endometrial cancer (EC) remains obscure. METHODS: RNA sequencing data and clinical information of EC were obtained from The Cancer Genome Atlas (TCGA) database. Lactate metabolism-related genes (LMRGs) WERE from Molecular Signature Database v7.4 and then compared the candidate genes from TCGA to obtain final genes. Univariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression were performed to screen prognostic genes. A lactate metabolism-related risk profile was constructed using multivariate Cox regression analysis. The signature was validated by time-dependent ROC curve analysis and Kaplan-Meier analysis. The relationship between the risk score and age, grade, stage, tumor microenvironmental characteristics, and drug sensitivity was as well explored by correlation analyses. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional analysis between the high and low-risk groups were performed. CCK8, EdU, and clone formation assays were applied to detect the proliferation ability of EC cells, Transwell assay was performed to detect the migration ability of EC cells, and intracellular lactate and glucose content was used to asses lactate metabolism. RESULTS: We constructed a risk signature based on 18 LMRGs. Kaplan-Meier curves confirmed that the high-risk group had poorer prognosis compared to the low-risk group. A nomogram was then constructed to predict the probability of EC survival. We also performed GO enrichment analysis and KEGG pathway functional analysis between the high and low-risk groups, and the outcome revealed that the features were significantly associated with energy metabolism. There was a significant correspondence between LMRGs and tumor mutational load, checkpoints and immune cell infiltration. C1, C2, and C4 were the most infiltrated in the high-risk group. The high-risk group showed increased dendritic cell activation, while the low-risk group showed increased plasma cells and Treg cells. Drug sensitivity analysis showed LMRGs risk was more resistant to Scr kinase inhibitors. We further proved that one of the lactate metabolism related genes, TIMM50 could promote EC cell proliferation, migration and lactate metabolism. CONCLUSION: In conclusion, we have established an effective prognostic signature based on LMRG expression patterns, which may greatly facilitate the assessment of prognosis, molecular features and treatment modalities in EC patients and may be useful in the future translation to clinical applications. TIMM50 was identified as a novel molecule that mediates lactate metabolism in vitro and in vivo, maybe a promising target for EC prognosis.
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Neoplasias Endometriales , Humanos , Femenino , Neoplasias Endometriales/genética , Metabolismo Energético , Factores de Riesgo , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: To adequately utilize patient reported outcome scores in the clinical setting, accurate determination of a cohort-specific minimal clinically important differences (MCID) is necessary. The purpose of this study was to assess MCID for Patient Reported Outcome Information System Physical Function Scores (PROMIS®) Physical Function (PF) in a sample of patients who have undergone operative fixation for femur fractures. METHODS: All patients at a single Level 1 trauma center who were treated for operative femur fractures were identified by Current Procedural Terminology (CPT) codes (27,244, 27,245, 27,506, 27,507). PROMIS PF was collected as part of routine clinical care via computer adaptive testing (CAT). MCID calculations were performed using both anchor-based and distribution-based methods. RESULTS: A total of 182 patients with 723 score observations were included in the overall distribution-based analysis and 131 patients with 309 score observations were included in the anchor-based analysis. In the overall cohort, the average age was 53.1 (SD 22.3), and 45% of participants were female. MCID for PROMIS PF scores was 5.43 in the distribution-based method and 5.18 in the anchor-based method. Overall scores in the distribution group improved from mean of 27.4 (SD 7.0) at the first postoperative visit to a mean of 36.7 (SD 10.0) at a subsequent follow up visit. Overall scores in the anchor group improved from mean of 26.7 (SD 7.3) at the first postoperative visit to a mean of 37.5 (SD 9.3) at a subsequent follow up visit. CONCLUSIONS: This study identifies two MCID values (5.18, 5.43) based on two calculation methods for PROMIS physical function scores in the operative femur fracture population. This data could be helpful in targeting postoperative patients who fall below expected norms or in allowing clinical correlation with changes in surgical practice.
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Relevancia Clínica , Diferencia Mínima Clínicamente Importante , Femenino , Masculino , Animales , Examen Físico , Medición de Resultados Informados por el Paciente , Fémur , Resultado del TratamientoRESUMEN
BACKGROUND: We aimed to measure patient-reported outcomes (PROs) and costs associated with same-day discharge (SDD) for atrial fibrillation (AF) ablation and vascular closure device implantation in clinical practice. METHODS: PROs were prospectively measured in 50 AF ablation patients, comparing complete vascular device closure (n = 25) versus manual compression hemostasis (n = 25). Health-system costs for SDD patients receiving vascular device closure were compared to matched controls with one-night stays who did not receive any closure device. RESULTS: Prospectively enrolled patients receiving vascular device closure for AF ablation had a mean age of 65 years, 17% were female, with a mean CHA2 DS2 -VASc score of 3. The mean number of venous sheaths was higher among patients receiving vascular device closure (3.8 vs. 3.1, p < 0.001), and there was one case of rebleeding in a patient receiving a vascular closure device (no other complications). Same-day discharge rates (76% vs. 8.3%, p < 0.001), patient satisfaction with bedrest time (8.5 vs. 6, p = 0.004) and with pain (8 vs. 5.1, p = 0.009) were significantly better among patients receiving vascular closure. In matched analyses of health-system costs, patients with vascular closure had mean age 66, 32% were female, and the mean CHA2 DS2 -VASc score was 2 (p = NS vs. controls). SDD with vascular closure was associated with the significantly lower facility, pharmacy, and disposable costs, but higher implant costs. Overall costs for ablation were not significantly different (mean difference 1.10%, 95% confidence interval [CI] -3.03 to 5.42). CONCLUSIONS: Vascular closure for AF ablation improves patient experience in routine care. The use of vascular closure and SDD after AF ablation reduces several components of healthcare system costs, without an overall increase.
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Fibrilación Atrial , Ablación por Catéter , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/cirugía , Ablación por Catéter/efectos adversos , Femenino , Hemostasis , Humanos , Masculino , Alta del Paciente , Medición de Resultados Informados por el Paciente , Resultado del TratamientoRESUMEN
BACKGROUND: In this study we sought to explore the possibility of using patient centered care (PCC) documentation as a measure of the delivery of PCC in a health system. METHODS: We first selected 6 VA medical centers based on their scores for a measure of support for self-management subscale from a national patient satisfaction survey (the Survey for Healthcare Experience-Patients). We accessed clinical notes related to either smoking cessation or weight management consults. We then annotated this dataset of notes for documentation of PCC concepts including: patient goals, provider support for goal progress, social context, shared decision making, mention of caregivers, and use of the patient's voice. We examined the association of documentation of PCC with patients' perception of support for self-management with regression analyses. RESULTS: Two health centers had < 50 notes related to either tobacco cessation or weight management consults and were removed from further analysis. The resulting dataset includes 477 notes related to 311 patients total from 4 medical centers. For a majority of patients (201 out of 311; 64.8%) at least one PCC concept was present in their clinical notes. The most common PCC concepts documented were patient goals (patients n = 126; 63% clinical notes n = 302; 63%), patient voice (patients n = 165, 82%; clinical notes n = 323, 68%), social context (patients n = 105, 52%; clinical notes n = 181, 38%), and provider support for goal progress (patients n = 124, 62%; clinical notes n = 191, 40%). Documentation of goals for weight loss notes was greater at health centers with higher satisfaction scores compared to low. No such relationship was found for notes related to tobacco cessation. CONCLUSION: Providers document PCC concepts in their clinical notes. In this pilot study we explored the feasibility of using this data as a means to measure the degree to which care in a health center is patient centered. PRACTICE IMPLICATIONS: clinical EHR notes are a rich source of information about PCC that could potentially be used to assess PCC over time and across systems with scalable technologies such as natural language processing.
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Documentación , Registros Electrónicos de Salud , Humanos , Satisfacción del Paciente , Atención Dirigida al Paciente , Proyectos PilotoRESUMEN
PURPOSE: Although the pain visual analog scale (VAS-pain) is a ubiquitous patient-reported outcome instrument, it remains unclear how to interpret changes or differences in scores. Therefore, our purpose was to calculate the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) for the VAS-pain instrument in a nonshoulder hand and upper extremity postoperative population. METHODS: Adult postoperative patients treated by 1 of 5 fellowship-trained orthopedic hand surgeons at a single tertiary academic medical center were identified. Inclusion required VAS-pain scores at baseline (up to 3 months before surgery) and follow-up (up to 4 months after surgery), in addition to a response to a pain-specific anchor question at follow-up. The MCID estimates were calculated with (1) the 1/2 standard deviation method; and (2) an anchor-based approach. The SCB estimates were calculated with (1) an anchor-based approach; and (2) a receiver operator curve method that maximized the sensitivity and specificity for detecting a "much improved" pain status. RESULTS: There were 667 and 148 total patients included in the MCID and SCB analyses, respectively. The 1/2 standard deviation MCID estimate was 1.6, and the anchor-based estimate was 1.9. The anchor-based SCB estimate was 2.2. The receiver operator curve analysis yielded an SCB estimate of 2.6, with an area under the curve of 0.72, consistent with acceptable discrimination. CONCLUSIONS: We propose MCID values in the range of 1.6 to 1.9 and SCB values in the range of 2.2 to 2.6 for the VAS-pain instrument in a nonshoulder hand and upper extremity postoperative population. CLINICAL RELEVANCE: These MCID and SCB estimates may be useful for powering clinical studies and when interpreting VAS-pain score changes or differences reported in the hand surgery literature. These values are to be applied at a population level, and should not be applied to assess the improvement, or lack thereof, for individual patients.
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Mano , Diferencia Mínima Clínicamente Importante , Adulto , Mano/cirugía , Humanos , Dolor , Resultado del Tratamiento , Escala Visual AnalógicaRESUMEN
BACKGROUND: Cognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits. METHODS: Sepsis was induced in adult male C57BL/6 J and CXCR5-/- mice by cecal ligation and puncture (CLP). At 14-18 days after surgery, animals were tested in a Morris water maze, followed by a fear conditioning test. Transmission electron microscopy of hippocampal sections was used to assess levels of autophagy. Primary microglial cultures challenged with lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting CXCR5, and to investigate the possible involvement of the p38MAPK/NF-κB/STAT3 signaling pathway. RESULTS: CLP impaired learning and memory and up-regulated CXCR5 in hippocampal microglia. CLP activated hippocampal autophagy, as reflected by increases in numbers of autophagic vacuoles, conversion of microtubule-associated protein 1 light chain 3 (LC3) from form I to form II, accumulation of beclin-1 and autophagy-related gene-5, and a decrease in p62 expression. CLP also shifted microglial polarization to the M1 phenotype, and increased levels of IL-1ß, IL-6 and phosphorylated p38MAPK. CXCR5 knockout further enhanced autophagy but partially reversed all the other CLP-induced effects, including cognitive deficits. Similar effects on autophagy and cytokine expression were observed after knocking down CXCR5 in LPS-challenged primary microglial cultures; this knockdown also partially reversed LPS-induced up-regulation of phosphorylated NF-κB and STAT3. The p38MAPK agonist P79350 partially reversed the effects of CXCR5 knockdown in microglial cultures. CONCLUSIONS: CXCR5 may act via p38MAPK/NF-κB/STAT3 signaling to inhibit hippocampal autophagy during sepsis and thereby contribute to cognitive dysfunction. Down-regulating CXCR5 can restore autophagy and mitigate the proinflammatory microenvironment in the hippocampus.
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Disfunción Cognitiva/metabolismo , FN-kappa B/metabolismo , Receptores CXCR5/deficiencia , Factor de Transcripción STAT3/metabolismo , Encefalopatía Asociada a la Sepsis/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Autofagia/fisiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/prevención & control , Regulación hacia Abajo/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , FN-kappa B/genética , Receptores CXCR5/genética , Factor de Transcripción STAT3/genética , Encefalopatía Asociada a la Sepsis/genética , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND: Oncotype DX (ODx) is a 12-gene assay assessing the recurrence risk (high, intermediate, and low) of ductal carcinoma in situ (pre-invasive breast cancer), which guides clinicians regarding prescription of radiotherapy. However, ODx is expensive, time-consuming, and tissue-destructive. In addition, the actual prognostic meaning for the intermediate ODx risk category remains unclear. METHODS: In this work, we evaluated the ability of quantitative nuclear histomorphometric features extracted from hematoxylin and eosin-stained slide images of 62 ductal carcinoma in situ (DCIS) patients to distinguish between the corresponding ODx risk categories. The prognostic value of the identified image signature was further evaluated on an independent validation set of 30 DCIS patients in its ability to distinguish those DCIS patients who progressed to invasive carcinoma versus those who did not. Following nuclear segmentation and feature extraction, feature ranking strategies were employed to identify the most discriminating features between individual ODx risk categories. The selected features were then combined with machine learning classifiers to establish models to predict ODx risk categories. The model performance was evaluated using the average area under the receiver operating characteristic curve (AUC) using cross validation. In addition, an unsupervised clustering approach was also implemented to evaluate the ability of nuclear histomorphometric features to discriminate between the ODx risk categories. RESULTS: Features relating to spatial distribution, orientation disorder, and texture of nuclei were identified as most discriminating between the high ODx and the intermediate, low ODx risk categories. Additionally, the AUC of the most discriminating set of features for the different classification tasks was as follows: (1) high vs low ODx (0.68), (2) high vs. intermediate ODx (0.67), (3) intermediate vs. low ODx (0.57), (4) high and intermediate vs. low ODx (0.63), (5) high vs. low and intermediate ODx (0.66). Additionally, the unsupervised clustering resulted in intermediate ODx risk category patients being co-clustered with low ODx patients compared to high ODx. CONCLUSION: Our results appear to suggest that nuclear histomorphometric features can distinguish high from low and intermediate ODx risk category patients. Additionally, our findings suggest that histomorphometric features for intermediate ODx were more similar to low ODx compared to high ODx risk category.
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Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Núcleo Celular/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Carcinoma Intraductal no Infiltrante/diagnóstico , Femenino , Humanos , Aprendizaje Automático , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Curva ROC , Factores de RiesgoRESUMEN
PURPOSE: Both developmental language disorder (DLD) and attention-deficit/hyperactivity disorder (ADHD) represent relatively common and chronic neurodevelopmental conditions associated with increased risk for poor academic and interpersonal outcomes. Reports of common co-occurrence suggest these neurodevelopmental disruptions might also be linked. Most of the data available on the issue have been based on case-control studies vulnerable to ascertainment and other biases. METHOD: Seventy-eight children, representing four neurodevelopmental profiles (DLD, ADHD, co-occurring ADHD + DLD, and neurotypical development), were administered a battery of psycholinguistic tests. Parents provided standardized ratings of the severity of their children's inattention, hyperactivity/impulsivity, and executive function symptoms. Examiners were blinded to children's clinical status. Group differences, correlations, and best subset regression analyses were used to examine potential impacts of children's ADHD symptoms on their psycholinguistic abilities. RESULTS: For children with DLD, significant links between their ADHD symptoms and psycholinguistic abilities were limited to the contributions of elevated hyperactivity/impulsivity symptoms to lower pragmatic abilities. For children without DLD, inattention symptoms contributed to lower levels of performance in pragmatic, sentence recall, receptive vocabulary, and narrative abilities. DISCUSSION: Links among children's ADHD symptoms and their psycholinguistic abilities were different for children with and without DLD. Implications for the provision of clinical services are discussed.
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Glutathione (GSH) is commonly used as a diagnostic biomarker for many diseases. In this study, based on carbon quantum dots prepared from dragon fruit peel (D-CQDs) and the T-Hg(II)-T mismatch, a dual-mode biosensor was developed for the detection of GSH. This system consists of two single-stranded DNA (ssDNA). DNA1 was the T-rich sequence; DNA2 was attached to streptavidin-coated magnetic beads and consisted of T-rich and G-rich fragments. Due to the presence of Hg(II), the T-Hg(II)-T mismatch was formed between T-rich fragments of two ssDNA. In the presence of GSH, Hg(II) detached from dsDNA and bound with GSH to form a new complex. The G-rich fragment assembled with the hemin shed from D-CQDs to form the G-quadruplex/hemin complex. At this time, in fluorescence mode, the fluorescence of D-CQDs quenched by hemin could be restored. In colorimetric mode, after the magnetic beads separate, a visual signal could be produced by catalyzing the oxidation of ABTS using the peroxide-like activity of the G-quadruplex/hemin complex. This biosensor in both fluorescence mode and colorimetric mode had excellent selectivity and sensitivity, and the limit of detection was 0.089 µM and 0.26 µM for GSH, respectively. Moreover, the proposed dual-mode biosensor had good application prospects for detection of GSH.
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Técnicas Biosensibles , Carbono , Frutas , Glutatión , Puntos Cuánticos , Puntos Cuánticos/química , Técnicas Biosensibles/métodos , Glutatión/química , Glutatión/análisis , Carbono/química , Frutas/química , ADN de Cadena Simple/química , Mercurio/análisis , Mercurio/química , Límite de Detección , Disparidad de Par Base , Humanos , G-Cuádruplex , CactaceaeRESUMEN
BACKGROUND: Observational studies have suggested an association between endometriosis and glycemic traits, but causality remains unclear. We used bidirectional and multivariate Mendelian randomization (MR) to examine the causal effect of glycemic traits on endometriosis and vice versa. METHODS: We obtained genome-wide association studies summary data of endometriosis and glycemic traits in our study. Inverse variance weighted (IVW), Weighted median, MR-Egger and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were applied in bidirectional two-sample MR analyses. MVMR was implemented to estimate the causal effect for fasting insulin (FI), fasting glucose (FG), and glycosylated hemoglobin A1c (HbA1c) on endometriosis. To test the validity of our findings, a number of sensitivity analyses were conducted. RESULTS: The risk of endometriosis was significantly increased by genetically predicted T1DM (OR = 1.02, 95% CI 1.00-1.04, p = 0.0171, q = 0.0556) and GDM (OR = 1.01, 95% CI 1.01-1.02, p = 1.34 × 10- 8, q = 1.74 × 10- 7). Endometriosis had a suggestive association with HbA1c (Beta = 0.04, 95% CI 0.00-0.08, p = 0.0481, q = 0.1251). Using multivariate Mendelian randomization (MVMR), a significant causal effect of FI on genetically predicted endometriosis was found (OR = 2.18, 95% CI 1.16-4.09, p = 0.0154, q = 0.0547). Moreover, no causal associations between endometriosis and other glycemic traits were detected. CONCLUSION: Our findings supported the significant causal associations of T1DM, GDM and FI with endometriosis, respectively. Additionally, a suggestive association was found of endometriosis on HbA1c. Importantly, our study may shed light on etiology studies and clinical management of endometriosis.
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BACKGROUND: Emerging clinical evidence has been discovered associating Inflammatory bowel disease (IBD) with Henoch-Schönlein purpura (HSP) and immune thrombocytopenia (ITP). However, it is unclear whether a cause-effect relationship exists between them. We aimed to examine the casual effect of IBD on the risk of HSP and ITP. METHODS: Based on summary statistics from International IBD Genetics (IIBDG) Consortium and FinnGen study, a two-sample Mendelian randomization study was carried out to determine whether IBD including ulcerative colitis (UC) and Crohn's disease (CD) is causally related to HSP, ITP or secondary thrombocytopenia. To support the results, a variety of sensitivity analyses were performed. RESULTS: Significant causal relationships between IBD and HSP (odds ratios = 1.20, 95% confidence interval: 1.07-1.36, adjusted P = 0.006) and ITP (odds ratios =1.22, 95% confidence interval: 1.08-1.38, adjusted P = 0.006) were found. Both genetically predicted UC and CD were positively related with ITP, while CD alone may be responsible for the higher risk of HSP. Besides, no significant association was observed between IBD and secondary thrombocytopenia. CONCLUSIONS: The results of this Mendelian randomization study supported the causal association of IBD with HSP and ITP. Taken together, our findings may present implications for management of IBD.
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Colitis Ulcerosa , Enfermedad de Crohn , Vasculitis por IgA , Enfermedades Inflamatorias del Intestino , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopénica Idiopática/genética , Análisis de la Aleatorización Mendeliana , Vasculitis por IgA/complicaciones , Vasculitis por IgA/genética , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/genética , Enfermedad de Crohn/genética , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/genéticaRESUMEN
Background: Endometrial carcinoma (EC) is one of the most prevalent gynecologic malignancies and requires further classification for treatment and prognosis. Long non-coding RNAs (lncRNAs) and immunogenic cell death (ICD) play a critical role in tumor progression. Nevertheless, the role of lncRNAs in ICD in EC remains unclear. This study aimed to explore the role of ICD related-lncRNAs in EC via bioinformatics and establish a prognostic risk model based on the ICD-related lncRNAs. We also explored immune infiltration and immune cell function across prognostic groups and made treatment recommendations. Methods: A total of 552 EC samples and clinical data of 548 EC patients were extracted from The Cancer Genome Atlas (TCGA) database and University of California Santa Cruz (UCSC) Xena, respectively. A prognostic-related feature and risk model was developed using the least absolute shrinkage and selection operator (LASSO). Subtypes were classified with consensus cluster analysis and validated with t-Distributed Stochastic Neighbor Embedding (tSNE). Kaplan-Meier analysis was conducted to assess differences in survival. Infiltration by immune cells was estimated by single sample gene set enrichment analysis (ssGSEA), Tumor IMmune Estimation Resource (TIMER) algorithm. Quantitative polymerase chain reaction (qPCR) was used to detect lncRNAs expression in clinical samples and cell lines. A series of studies was conducted in vitro and in vivo to examine the effects of knockdown or overexpression of lncRNAs on ICD. Results: In total, 16 ICD-related lncRNAs with prognostic values were identified. Using SCARNA9, FAM198B-AS1, FKBP14-AS1, FBXO30-DT, LINC01943, and AL161431.1 as risk model, their predictive accuracy and discrimination were assessed. We divided EC patients into high-risk and low-risk groups. The analysis showed that the risk model was an independent prognostic factor. The prognosis of the high- and low-risk groups was different, and the overall survival (OS) of the high-risk group was lower. The low-risk group had higher immune cell infiltration and immune scores. Consensus clustering analysis divided the samples into four subtypes, of which cluster 4 had higher immune cell infiltration and immune scores. Conclusions: A prognostic signature composed of six ICD related-lncRNAs in EC was established, and a risk model based on this signature can be used to predict the prognosis of patients with EC.
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BACKGROUND: Antimicrobial resistance poses a major threat to public health. There are few comprehensive nationwide studies that quantify long-term trends in infection incidence and antimicrobial resistance for multiple pathogens. We aimed to analyse trends in inpatient infection incidence and antimicrobial resistance for nine pathogens over the past 15 years across the USA. METHODS: In this US nationwide retrospective cohort study, we analysed clinical microbiology data from electronic health records from all patients admitted to all 138 Veterans Affairs (VA) Medical Centers with acute care wards across the USA from Feb 1, 2007, to March 31, 2022. We quantified inpatient antibiotic use as days of therapy (DOT) per 1000 patient-days and antimicrobial resistance by resistance proportion (proportion of incident isolates identified as resistant) and phenotypic incidence (incidence of infections per 1000 admissions classified as resistant, susceptible, or missing). To analyse trends before the COVID-19 pandemic and during the COVID-19 pandemic, we used generalised estimating equation models and reported average annual percentage changes (AAPC). FINDINGS: We collected 991 527 30-day incident isolates from 507 760 patients in 138 VA Medical Centers and 50 states in the USA. Between Feb 1, 2007, and Dec 31, 2019, infection incidence and antimicrobial resistance declined for many pathogens and pathogen-drug combinations. The proportion of methicillin resistance in Staphylococcus aureus decreased from 57·7% (11 876 of 20 584 incident isolates) to 44·6% (5916 of 13 257) over these 13 years (AAPC -1·8%; 95% CI -2·4 to -1·2; p<0·0001), and vancomycin-resistant Enterococcus faecium infections decreased from 77·8% (2555 of 3285) to 65·1% (893 of 1371; AAPC -1·2%; 95% CI -2·5 to 0·0; p=0·052). Fluoroquinolone resistance declined in both proportion and incidence for most pathogens. These trends correlated with substantial reductions in fluoroquinolone use, from 125 DOT per 1000 patient-days to 20 DOT per 1000 patient-days. Third generation cephalosporin resistance increased steeply in Escherichia coli infections from 6·7% (942 of 14 042) in 2007 to 15·3% (2153 of 14 053) in 2019 (AAPC 8·5%; 95% CI 6·2 to 10·7; p<0·0001). Carbapenem resistance proportion increased in Enterobacter cloacae infections from 1·1% (30 of 2852) in 2007 to 7·3% (212 of 2919) in 2019 (AAPC 19·8%; 95% CI 13·7 to 26·2; p<0·0001), but remained low for Klebsiella pneumoniae and E coli. During the COVID-19 pandemic between Jan 1, 2020, and March 31, 2022, several pathogen-drug combinations increased in both incidence and resistance for hospital-associated infections. For some pathogen-drug combinations, trends in incidence of resistant and susceptible infections were divergent, whereas for other combinations, these trends were in the same direction. INTERPRETATION: Significant reductions in methicillin resistance in S aureus, vancomycin-resistant E faecium, and fluoroquinolone resistance across multiple pathogens suggest that control efforts have had an effect on resistance. The rise in extended-spectrum ß-lactamases-producing Enterobacterales and recent surge in hospital-associated infections emphasise the need for ongoing surveillance and interventions. Our study highlights how coupling the analysis of phenotypic incidence with resistance proportion can enhance interpretation of antimicrobial resistance data. FUNDING: US Centers for Disease Control and Prevention.
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BACKGROUND: The density of tumour-infiltrating lymphocytes (TILs) could be prognostic in ductal carcinoma in situ (DCIS). However, manual TIL quantification is time-consuming and suffers from interobserver and intraobserver variability. In this study, we developed a TIL-based computational pathology biomarker and evaluated its association with the risk of recurrence and benefit of adjuvant treatment in a clinical trial cohort. METHODS: In this retrospective cohort study, a computational pathology pipeline was developed to generate a TIL-based biomarker (CPath TIL categories). Subsequently, the signature underwent a masked independent validation on H&E-stained whole-section images of 755 patients with DCIS from the UK/ANZ DCIS randomised controlled trial. Specifically, continuous biomarker CPath TIL score was calculated as the average TIL density in the DCIS microenvironment and dichotomised into binary biomarker CPath TIL categories (CPath TIL-high vs CPath TIL-low) using the median value as a cutoff. The primary outcome was ipsilateral breast event (IBE; either recurrence of DCIS [DCIS-IBE] or invasive progression [I-IBE]). The Cox proportional hazards model was used to estimate the hazard ratio (HR). FINDINGS: CPath TIL-score was evaluable in 718 (95%) of 755 patients (151 IBEs). Patients with CPath TIL-high DCIS had a greater risk of IBE than those with CPath TIL-low DCIS (HR 2·10 [95% CI 1·39-3·18]; p=0·0004). The risk of I-IBE was greater in patients with CPath TIL-high DCIS than those with CPath TIL-low DCIS (3·09 [1·56-6·14]; p=0·0013), and the risk of DCIS-IBE was non-significantly higher in those with CPath TIL-high DCIS (1·61 [0·95-2·72]; p=0·077). A significant interaction (pinteraction=0·025) between CPath TIL categories and radiotherapy was observed with a greater magnitude of radiotherapy benefit in preventing IBE in CPath TIL-high DCIS (0·32 [0·19-0·54]) than CPath TIL-low DCIS (0·40 [0·20-0·81]). INTERPRETATION: High TIL density is associated with higher recurrence risk-particularly of invasive recurrence-and greater radiotherapy benefit in patients with DCIS. Our TIL-based computational pathology signature has a prognostic and predictive role in DCIS. FUNDING: National Cancer Institute under award number U01CA269181, Cancer Research UK (C569/A12061; C569/A16891), and the Breast Cancer Research Foundation, New York (NY, USA).
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Neoplasias de la Mama , Carcinoma Intraductal no Infiltrante , Linfocitos Infiltrantes de Tumor , Humanos , Femenino , Carcinoma Intraductal no Infiltrante/patología , Neoplasias de la Mama/patología , Estudios Retrospectivos , Pronóstico , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Biomarcadores de Tumor , Reino Unido , Anciano , AdultoRESUMEN
Increasing evidence indicates that peripheral blood vessels play a pivotal role in regulating tumor growth with the presence of new blood vessels facilitating tumor growth and metastasis. Nevertheless, the impact of specific molecule-mediated angiogenesis on the tumor immune microenvironment (TIME) and individual prognosis of uterine corpus endometrial carcinoma (UCEC) remains uncertain. The transcriptome information on 217 prognostic angiogenesis-related genes was integrated, and the angiogenesis patterns of 506 UCEC patients in The Cancer Genome Atlas (TCGA) cohort were comprehensively evaluated. We identified five angiogenic subtypes, namely, EC1, EC2, EC3, EC4, and EC5, which differed significantly in terms of prognosis, clinicopathological features, cancer hallmarks, genomic mutations, TIME patterns, and immunotherapy responses. Additionally, an angiogenesis-related prognostic risk score (APRS) was constructed to enable an individualized comprehensive evaluation. In multiple cohorts, APRS demonstrated a powerful predictive ability for the prognosis of UCEC patients. Likewise, APRS was confirmed to be associated with clinicopathological features, genomic mutations, cancer hallmarks, and TIME patterns in UCEC patients. The predictability of APRS for immune checkpoint inhibitor (ICI) therapy was also salient. Subsequently, the expression levels of four angiogenesis-related hub genes were verified by qRT-PCR, immunohistochemistry, and single-cell sequencing data analysis. The effects of four representative genes on angiogenesis were validated by Wound-Healing and Transwell assays, tube formation assay in vitro, and tumor xenograft model in vivo. This study proffered a new classification of UCEC patients based on angiogenesis. The established APRS may contribute to individualized prognosis prediction and immunotherapy selections that are better suited for UCEC patients.
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Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has been associated with increased morbidity and mortality. Nuclear factor of activated T cells (NFATs) 1, a transcriptional factor that regulates T cell development, activation and differentiation, has been implicated in neuronal plasticity. Here we examined the potential role of NFAT1 in sepsis-associated encephalopathy in mice. Adult male C57BL/6J mice received intracerebroventricular injections of short interfering RNA against NFAT1 or sex-determining region Y-box 2 (SOX2), or a scrambled control siRNA prior to cecal ligation and perforation (CLP). A group of mice receiving sham surgery were included as an additional control. CLP increased escape latency and decreased the number of crossings into, and total time spent within, the target quadrant in the Morris water maze test. CLP also decreased the freezing time in context-dependent, but not context-independent, fear conditioning test. Knockdown of either NFAT1 or SOX2 attenuated these behavioral deficits. NFAT1 knockdown also attenuated CLP-induced upregulation of SOX2, increased the numbers of nestin-positive cells and newborn astrocytes, reduced the number of immature newborn neurons, and promoted the G1 to S transition of neural stem cells in hippocampus. These findings suggest that NFAT1 may contribute to sepsis-induced behavioral deficits, possibly by promoting SOX2 signaling and neurogenesis.
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Disfunción Cognitiva , Encefalopatía Asociada a la Sepsis , Sepsis , Masculino , Ratones , Animales , Ratones Endogámicos C57BL , Sepsis/complicaciones , Hipocampo , Cognición , Neurogénesis , Linfocitos TRESUMEN
Histone lactylation has been reported to involve in tumorigenesis and development. However, its biological regulatory mechanism in endometrial carcinoma (EC) is yet to be reported in detail. In the present study, we evaluated the modification levels of global lactylation in EC tissues by immunohistochemistry and western blot, and it was elevated. The non-metabolizable glucose analog 2-deoxy-d-glucose (2-DG) and oxamate treatment could decrease the level of lactylation so as to inhibit the proliferation and migration ability, induce apoptosis significantly, and arrest the cell cycle of EC cells. Mechanically, histone lactylation stimulated USP39 expression to promote tumor progression. Moreover, USP39 activated PI3K/AKT/HIF-1α signaling pathway via interacting with and stabilizing PGK1 to stimulate glycolysis. The results of present study suggest that histone lactylation plays an important role in the progression of EC by promoting the malignant biological behavior of EC cells, thus providing insights into potential therapeutic strategies for endometrial cancer.
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Neuromorphic vision sensors or event cameras have made the visual perception of extremely low reaction time possible, opening new avenues for high-dynamic robotics applications. These event cameras' output is dependent on both motion and texture. However, the event camera fails to capture object edges that are parallel to the camera motion. This is a problem intrinsic to the sensor and therefore challenging to solve algorithmically. Human vision deals with perceptual fading using the active mechanism of small involuntary eye movements, the most prominent ones called microsaccades. By moving the eyes constantly and slightly during fixation, microsaccades can substantially maintain texture stability and persistence. Inspired by microsaccades, we designed an event-based perception system capable of simultaneously maintaining low reaction time and stable texture. In this design, a rotating wedge prism was mounted in front of the aperture of an event camera to redirect light and trigger events. The geometrical optics of the rotating wedge prism allows for algorithmic compensation of the additional rotational motion, resulting in a stable texture appearance and high informational output independent of external motion. The hardware device and software solution are integrated into a system, which we call artificial microsaccade-enhanced event camera (AMI-EV). Benchmark comparisons validated the superior data quality of AMI-EV recordings in scenarios where both standard cameras and event cameras fail to deliver. Various real-world experiments demonstrated the potential of the system to facilitate robotics perception both for low-level and high-level vision tasks.