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Major advances have been made in utilizing human-induced pluripotent stem cells (hiPSCs) for regenerative medicine. Nevertheless, the delivery and integration of hiPSCs into target tissues remain significant challenges, particularly in the context of retinal ganglion cell (RGC) restoration. In this study, we introduce a promising avenue for providing directional guidance to regenerated cells in the retina. First, we developed a technique for construction of gradient interfaces based on functionalized conductive polymers, which could be applied with various functionalized ehthylenedioxythiophene (EDOT) monomers. Using a tree-shaped channel encapsulated with a thin PDMS and a specially designed electrochemical chamber, gradient flow generation could be converted into a functionalized-PEDOT gradient film by cyclic voltammetry. The characteristics of the successfully fabricated gradient flow and surface were analyzed using fluorescent labels, time of flight secondary ion mass spectrometry (TOF-SIMS), and X-ray photoelectron spectroscopy (XPS). Remarkably, hiPSC-RGCs seeded on PEDOT exhibited improvements in neurite outgrowth, axon guidance and neuronal electrophysiology measurements. These results suggest that our novel gradient PEDOT may be used with hiPSC-based technologies as a potential biomedical engineering scaffold for functional restoration of RGCs in retinal degenerative diseases and optic neuropathies.
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Células-Tronco Pluripotentes Induzidas , Polímeros , Células Ganglionares da Retina , Humanos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Polímeros/química , Orientação de Axônios , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Propriedades de Superfície , Condutividade Elétrica , Fatores de Crescimento Neural/metabolismo , Axônios/metabolismo , Axônios/fisiologiaRESUMO
BACKGROUND: Limited research has explored the impact of cardiovascular disease (CVD) on healthy life expectancy (HLE) especially in resource-limited areas. This study aimed to investigate the association between CVD and HLE in Chinese rural population. METHODS: This study included 11,994 participants aged 45 years and older from the baseline and follow-up surveys of the Henan rural cohort study. Healthy status was measured via a Visual Analogue Scale. The multistate Markov model was applied to estimate the association between CVD and transitions in health, unhealthiness and death. Gender-specific total life expectancy, HLE and unhealthy life expectancy were calculated by the multistate life table method. RESULTS: During a mean follow-up time of 3.85 (3.84-3.86) years, there were 588 deaths recorded. For individuals with CVD, the risk of switching from health to unhealthiness status was increased by 71% [hazard ratio (HR) = 1.71, 95% CI: 1.42-2.07], the chance of recovery was reduced by 30% (HR = 0.70, 95% CI: 0.60-0.82). Men aged 45 years without CVD could gain an extra 7.08 (4.15-10.01) years of HLE and lose 4.00 (1.60-6.40) years of unhealthy life expectancy compared to their peers with CVD, respectively. The corresponding estimates among women were 8.62 (5.55-11.68) years and 5.82 (2.59-9.04) years, respectively. CONCLUSIONS: This study indicated that CVD was significantly associated with poorer health status and lower HLE among Chinese rural population. It is an important public health policy to adopt targeted measures to reduce the CVD burden and enhance the quality of life and HLE in resource-limited areas.
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Triphenyl phosphate (TPHP) and tris(1.3-dichloroisopropyl) phosphate (TDCIPP) are emerging contaminants that pervade diverse ecosystems and impair the thyroid and neural signaling pathways. The intricate interactions between thyroid and neurodevelopmental effects mediated by TPHP and TDCIPP remain elusive. This study integrates in vivo, in vitro, and in silico approaches to elucidate these mechanisms in Cyprinus carpio at varying temperatures. It showed that TPHP and TDCIPP hindered fish growth, particularly at low temperatures, by interfering with thyroid hormone synthesis and transport processes. Both compounds have been identified as environmental hormones that mimic thyroid hormone activity and potentially inhibit acetylcholinesterase, leading to neurodevelopmental disorders characterized by brain tissue damage and disrupted cholinergic synapses, such as axon guidance and regeneration. Notably, the bioaccumulation of TPHP was 881.54 % higher than that of TDCIPP, exhibiting temperature-dependent variations with higher levels of TDCIPP at low temperatures (20.50 % and 250.84 % above optimum and high temperatures, respectively), suggesting that temperature could exacerbate the toxicity effects of OPEs. This study sheds new light on the mechanisms underlying thyroid endocrine disruption and neurodevelopmental toxicity in C. carpio. More importantly, these findings indicate that temperature affects the environmental fate and effects of TPHP and TDCIPP, which could provide an important basis for ecological environmental zoning control of emerging contaminants in the future.
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BACKGROUND: During the COVID-19 pandemic, there has been an increasing trend in healthcare-associated infections (HAIs) caused by carbapenem-resistant Acinetobacter baumannii (CRAB), posting a global public health concern. The heightened sensitivity of whole-genome sequencing (WGS) renders it an optimal and potent tool for monitoring outbreaks and tracing the transmission routes of nosocomial pathogens. METHOD: We collected CRAB isolates from March 1, 2023, to April 6, 2023 in Chang Gung Memorial Hospital Lin Kou branch, a tertiary medical center in northern Taiwan. Any two or more isolates with the same identifiable capsular K-locus (KL) types were selected, and analyzed via WGS to identify putative transmission clusters, combined with epidemiologic and retrospective analysis on medical records to confirm risk factors and hidden transmission chains. RESULT: A total of 48 non-redundant CRAB isolates were collected, belonging to ST2 of Pasteur MLST scheme and identifiable KL types of KL2, KL3, KL9, KL10, KL22, KL52. Excluding the KL types that was only found in 1 case, KL2 (n = 9, 22.5 %), KL3 (n = 24, 60 %), KL9 (n = 3, 7.5 %), and KL10 (n = 4, 10 %) were selected for further WGS analysis. Four distinct transmission clusters comprised of 2, 3, 10, and 23 cases were identified on a basis of phylogenetic status. 12 probable transmission chains were revealed, and 2 hidden transmission routes can be speculated. CONCLUSION: This study referred to some hidden transmission chains that may be missed from traditional surveillance measures. Despite its low prevalence and high cost currently, implementing WGS could be a efficient, prompt, and unequivocal option for future MDRO infection control.
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BACKGROUND: Pediatric CKD is associated with a high risk of cardiovascular disease (CVD). Early detection of subclinical CVD in childhood CKD can be achieved through various cardiovascular (CV) assessments, including carotid intima-media thickness (cIMT), ambulatory blood pressure monitoring (ABPM), and arterial stiffness indices. Lactoferrin (LF), a key functional glycoprotein found in breast milk, has been linked to several diseases and has potential as a biomarker. METHODS: In our study of 102 children with CKD stages G1-G4, we explored the relationship between LF and CV risk markers. RESULTS: We found that LF concentration was not related to the severity or underlying causes of childhood CKD, but was positively correlated with overweight/obesity. Lower LF levels were correlated with increased cIMT and elevated arterial stiffness indices. Notably, abnormalities in ABPM profiles were observed in up to 60% of the children with CKD, with low LF levels linked to nighttime hypertension, nocturnal non-dipping, and ABPM abnormalities. CONCLUSIONS: In conclusion, LF shows promise as a biomarker for detecting subclinical CVD in children with CKD. Its potential utility in early detection could be instrumental in guiding timely interventions and improving long-term CV outcomes, although further research is needed to clarify the underlying mechanisms.
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Phycoerythrin (PE) is a naturally occurring plant protein of algal origin. The colour, bioactivity and stability of PE are inextricably linked to its structure. PE has powerful antioxidant properties that effectively prevent oxidative stress and cellular damage, for which the chromophore structure plays a key role. However, the relationship between the chromophore and thermal stability is unclear in PE. The environmental factors affecting the thermal stability of PE are mainly light, high temperature and extreme pH. PE stability can be enhanced through various techniques, including the incorporation of additives, cross-linking processes, and the formation of complexes. Improving the stability of PE is of significant importance for its applications within the food industry. This paper outlines the structural characteristics of PE, discusses the relationship between its structure and antioxidant activity, and focuses on the application of PE in the food industry, as well as the factors affecting its stability and strategies for its improvement.
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INTRODUCTION: EGFR tyrosine kinase inhibitors (TKIs) are the standard therapy for non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations in the first-line setting. Despite initial efficacy, resistance to EGFR-TKIs often develops, and platinum-based chemotherapy is the predominant subsequent treatment. For this study, we aimed to identify prognostic factors for overall survival (OS) and progression-free survival (PFS) among advanced EGFR-mutant NSCLC patients receiving platinum-pemetrexed after progression on EGFR-TKIs. Our analysis specifically focuses on 1st-line treatments limited to 1st- or 2nd-generation EGFR-TKIs, while not restricting later-line treatments involving osimertinib prior to chemotherapy. MATERIALS AND METHODS: From 2012 to 2017, 363 patients who received first-line treatment with first- or second-generation EGFR-TKIs, including gefitinib, erlotinib, and afatinib were enrolled. Some patients received different EGFR-TKIs, including osimertinib, as later-line treatment before platinum-pemetrexed. RESULTS: Median OS from the initiation of platinum-pemetrexed was 22.0 months and median PFS with platinum-pemetrexed was 6.2 months. In the multivariate Cox model, we identified three independent prognostic factors for better OS: postoperative recurrence (HR: 0.34, p = 0.004), first-line EGFR-TKI PFS ≥12 months (HR: 0.54, p = 0.002), and osimertinib treatment after platinum-pemetrexed (HR: 0.56, p = 0.005) while BMI <18.5 indicated poor prognosis (HR:1.76, p = 0.049). No statistically significant independent prognostic factors for PFS were found. Receiving osimertinib before platinum-pemetrexed treatment did not impact PFS with platinum-pemetrexed treatment (HR: 1.11, p = 0.64). CONCLUSION: Postoperative recurrence, first-line EGFR-TKI PFS ≥12 months and osimertinib treatment after platinum-pemetrexed predicted better OS, while BMI <18.5 predicted worse OS. Osimertinib treatment before platinum-pemetrexed treatment did not affect the efficacy of platinum-pemetrexed.
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Objective: To examine the precise function of influenza A virus target genes (IATGs) in malignancy. Methods: Using multi-omics data from the TCGA and TCPA datasets, 33 tumor types were evaluated for IATGs. IATG expression in cancer cells was analyzed using transcriptome analysis. Copy number variation (CNV) was assessed using GISTICS 2.0. Spearman's analysis was used to correlate mRNA expression with methylation levels. GSEA was used for the enrichment analysis. Pearson's correlation analysis was used to examine the association between IATG mRNA expression and IC50. The ImmuCellAI algorithm was used to calculate the infiltration scores of 24 immune cell types. Results: In 13 solid tumors, IATG mRNA levels were atypically expressed. Except for UCS, UVM, KICH, PCPG, THCA, CHOL, LAMI, and MESO, most cancers contained somatic IATG mutations. The main types of CNVs in IATGs are heterozygous amplifications and deletions. In most tumors, IATG mRNA expression is adversely associated with methylation. RT-PCR demonstrated that EGFR, ANXA5, CACNA1C, CD209, UVRAG were upregulated and CLEC4M was downregulated in KIRC cell lines, consistent with the TCGA and GTEx data. Conclusion: Genomic changes and clinical characteristics of IATGs were identified, which may offer fresh perspectives linking the influenza A virus to cancer.
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Genômica , Vírus da Influenza A , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/virologia , Vírus da Influenza A/genética , Variações do Número de Cópias de DNA , MultiômicaRESUMO
Spin-crossover (SCO) ferroelectrics with dual-function switches have attracted great attention for significant magnetoelectric application prospects. However, the multiferroic crystals with SCO features have rarely been reported. Herein, a molecular multiferroic Fe(II) crystalline complex [FeII(C8-F-pbh)2] (1-F, C8-F-pbh = (1Z,N'E)-3-F-4-(octyloxy)-N'-(pyridin-2-ylmethylene)-benzo-hydrazonate) showing the coexistence of ferroelectricity, ferroelasticity, and SCO behavior is presented for the first time. By H/F substitution, the low phase transition temperature (270 K) of the non-fluorinated parent compound is significantly increased to 318 K in 1-F, which exhibits a spatial symmetry breaking 222F2 type ferroelectric phase transition with clear room-temperature ferroelectricity. Besides, 1-F also displays a spin transition between high- and low-spin states, accompanied by the d-orbital breaking within the t2g 4eg 2 and t2g 6eg° configuration change of octahedrally coordinated FeII center. Moreover, the 222F2 type ferroelectric phase transition is also a ferroelastic one, verified by the ferroelectric domains reversal and the evolution of ferroelastic domains. To the knowledge, 1-F is the first multiferroic SCO molecular crystal. This unprecedented finding sheds light on the exploration of molecular multistability materials for future smart devices.
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Lactoferrin, a glycoprotein derived from breastmilk, is recognized for its health benefits in infants and children; however, its protective effects when administered during gestation and lactation against offspring hypertension remain unclear. This study aimed to investigate whether maternal lactoferrin supplementation could prevent hypertension in offspring born to mothers with chronic kidney disease (CKD), with a focus on nitric oxide (NO), renin-angiotensin system (RAS) regulation, and alterations in gut microbiota and short-chain fatty acids (SCFAs). Prior to pregnancy, female rats were subjected to a 0.5% adenine diet for 3 weeks to induce CKD. During pregnancy and lactation, pregnant rats received one of four diets: normal chow, 0.5% adenine diet, 10% lactoferrin diet, or adenine diet supplemented with lactoferrin. Male offspring were euthanized at 12 weeks of age (n = 8 per group). Supplementation with lactoferrin during gestation and lactation prevented hypertension in adult offspring induced by a maternal adenine diet. The maternal adenine diet caused a decrease in the index of NO availability, which was restored by 67% with maternal LF supplementation. Additionally, LF was related to the regulation of the RAS, as evidenced by a reduced renal expression of renin and the angiotensin II type 1 receptor. Combined maternal adenine and LF diets altered beta diversity, shifted the offspring's gut microbiota, decreased propionate levels, and reduced the renal expression of SCFA receptors. The beneficial effects of lactoferrin are likely mediated through enhanced NO availability, rebalancing the RAS, and alterations in gut microbiota composition and SCFAs. Our findings suggest that maternal lactoferrin supplementation improves hypertension in offspring in a model of adenine-induced CKD, bringing us closer to potentially translating lactoferrin supplementation clinically for children born to mothers with CKD.
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Adenina , Suplementos Nutricionais , Microbioma Gastrointestinal , Hipertensão , Lactação , Lactoferrina , Fenômenos Fisiológicos da Nutrição Materna , Sistema Renina-Angiotensina , Animais , Lactoferrina/administração & dosagem , Lactoferrina/farmacologia , Feminino , Gravidez , Masculino , Hipertensão/prevenção & controle , Hipertensão/induzido quimicamente , Hipertensão/etiologia , Ratos , Sistema Renina-Angiotensina/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Óxido Nítrico/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/induzido quimicamente , Ácidos Graxos Voláteis/metabolismo , Ratos Sprague-Dawley , DietaRESUMO
OBJECTIVE: Pituitary neuroendocrine tumours (PitNETs) are the second most common type of intracranial tumour. Several studies have explored the prognostic factors for PitNETs. However, prognostic factors for postoperative PitNET recurrence remain not fully understood. This study aimed to explore potential prognostic factors for PitNET recurrence, such as surrounding tissue invasion and the extent of surgical resection in patients with postoperative PitNETs. METHODS: We included 106 patients who underwent PitNET surgery between 2013 and 2018, dividing them into two groups: those with recurrence and those without recurrence. Tumours were classified based on demographics, neuroradiological, and immunohistological characteristics. Univariate and multivariate analyses were used to determine factors predicting recurrence. Kaplan-Meier plots and log-rank tests were used to analyse each independent factor based on the cumulative 5-year recurrence rate. RESULTS: During the 5-year follow-up period, 29.2% of the patients (n = 31) had disease recurrence. Univariate analysis showed that predictors of recurrence included cavernous and sphenoid sinus invasions, optic chiasm compression, larger tumour volume, giant adenoma >4 cm, and gross total resection (GTR). Multivariate analysis showed that lactotroph tumour type, sphenoid sinus invasion, and GTR were independent predictors. Kaplan-Meier analysis revealed significant differences in the 5-year recurrence rate among the three independent predictors, with significantly lower recurrence rate in patients with lactotroph tumours and GTR, and a significantly higher recurrence risk in patients with sphenoid sinus invasion. CONCLUSIONS: Lactotroph tumour type, sphenoid sinus invasion, and GTR are independent predictors of postoperative PitNET recurrence. This study provides insights into the factors affecting postoperative PitNET recurrence.
PitNETs are the second most common intracranial tumour typePrognostic factors for postoperative PitNET recurrence remain not fully understoodWe explored potential prognostic factors in patients with postoperative PitNETsProlactin secretion and GTR failure were independent recurrence predictorsProliferative factors did not correlate with recurrence.
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Ferroelectrics as emerging and attractive catalysts have shown tremendous potential for applications including wastewater treatment, hydrogen production, nitrogen fixation, and organic synthesis, etc. In this study, we demonstrate that molecular ferroelectric crystal TMCM-CdCl3 (TMCM = trimethylchloromethylammonium) with multiaxial ferroelectricity and superior piezoelectricity has an effective catalytic activity on the direct construction of the pharmacologically important substituted quinoline derivatives via one-pot [3 + 2 + 1] annulation of anilines and terminal alkynes by using N,N-dimethylformamide (DMF) as the carbon source. The recrystallized TMCM-CdCl3 crystals from DMF remain well ferroelectricity and piezoelectricity. Upon ultrasonic condition, periodic changes in polarization contribute to the release of free charges from the surface of the ferroelectric domains in nano size, which then quickly interacts with the substrates in the solution to trigger the pivotal redox process. Our work advances the molecular ferroelectric crystal as a catalytic route to organic synthesis, not only providing valuable direction for molecular ferroelectrics but also further enriching the executable range of ferroelectric catalysis.
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Background: The ligamentum flavum (LF) degeneration is a critical factor in spinal stenosis, leading to nerve compression and pain. Even with new treatment options becoming available, it is vital to have a better understanding of LF degeneration to ensure the effectiveness of these treatments. Objective: This study aimed to provide insight into LF degeneration by examining the connections between various aspects of LF degeneration, including histology, microstructure, chemical composition, and biomechanics. Method: We analyzed 30 LF samples from 27 patients with lumbar vertebrae, employing magnetic resonance imaging (MRI) to link lumbar disc degeneration grades with fibrosis levels in the tissue. X-ray diffraction (XRD) analysis assessed microstructural alterations in the LF matrix component due to degeneration progression. Instrumented nanoindentation combined with Raman spectroscopy explored the spatial microbiomechanical and biochemical characteristics of the LF's ventral and dorsal regions. Results: Our outcomes revealed a clear association between the severity of LF fibrosis grades and increasing LF thickness. XRD analysis showed a rise in crystalline components and hydroxyapatite molecules with progressing degeneration. Raman spectroscopy detected changes in the ratio of phosphate, proteoglycan, and proline/hydroxyproline over the amide I band, indicating alterations in the extracellular matrix composition. Biomechanical testing demonstrated that LF tissue becomes stiffer and less extensible with increasing fibrosis. Discussion: Notably, the micro-spatial assessment revealed the dorsal side of the LF experiencing more significant mechanical stress, alongside more pronounced biochemical and biomechanical changes compared to the ventral side. Degeneration of the LF involves complex processes that affect tissue histology, chemical composition, and biomechanics. It is crucial to fully understand these changes to develop new and effective treatments for spinal stenosis. These findings can improve diagnostic accuracy, identify potential biomarkers and treatment targets, guide personalized treatment strategies, advance tissue engineering approaches, help make informed clinical decisions, and educate patients about LF degeneration.
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Introduction: Early lung cancer detection programs improve surgical resection rates and survival but may skew toward more indolent cancers. Methods: Hypothesizing that differences in stage-stratified survival indicate differences in biological aggressiveness and possible length-time and overdiagnosis bias, we assessed a cohort who had curative-intent resection, categorized by diagnostic pathways: screening, incidental pulmonary nodule program, and non-program based. Survival was analyzed using Kaplan-Meier plots, log-rank tests, and Cox regression, comparing aggregate and stage-stratified survival across cohorts with Tukey's method for multiple testing. Results: Of 1588 patients, 111 patients (7%), 357 patients (22.5%), and 1120 patients (70.5%) were diagnosed through screening, pulmonary nodule, and non-program-based pathways; 0% versus 9% versus 6% were older than 80 years (p = 0.0048); 17%, 23%, and 24% had a Charlson Comorbidity score greater than or equal to 2 (p = 0.0143); 7%, 6%, and 9% had lepidic adenocarcinoma; 26%, 31%, and 34% had poorly or undifferentiated tumors (p = 0.1544); and 93%, 87%, and 77% had clinical stage I (p < 0.0001).Aggregate 5-year survival was 87%, 72%, and 65% (p = 0.0009), including 95%, 74%, and 74% for pathologic stage I. Adjusted pairwise comparisons showed similar survival in screening and nodule program cohorts (p = 0.9905). Nevertheless, differences were significant between screening and non-program-based cohorts (p = 0.0007, adjusted hazard ratio 0.33 [95% confidence interval: 0.18-0.6]) and between nodule and nonprogram cohorts (adjusted hazard ratio 0.77 [95% confidence interval: 0.61-0.99]). Stage I comparisons yielded p = 0.2256, 0.1131, and 0.911. In respective pathways, 0%, 2%, and 2% of patients with stage I disease who were older than 80 years had a Charlson score greater than or equal to 2 (p = 0.3849). Conclusions: Neither length-time nor overdiagnosis bias was evident in NSCLC diagnosed through screening or incidental pulmonary nodule programs.
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Background: Tunneling technique has shown preliminary promise in lung segmentectomy which requires the use of staplers in specific procedures. However, the obstacle when staples pass is the most obvious factor hindering the implementation and development of this technique. This study investigated whether the obstacle of the technology could be addressed by using an innovative self-designed stapler tractor and analyzed the combined and respective advantages of them. Methods: The clinical data of patients with lung nodules located near anatomical sites with potential tunnel creation treated by segmentectomy were analyzed in this retrospective case-control study. The data were divided into four groups according to four distinct surgical strategies: In Group A, the tunneling technique was performed with a stapler tractor; in Group B, the tunneling technique was performed without a stapler tractor; in Group C, didn't perform the tunneling technique but using stapler tractor in a normal approach; and in Group D, neither performed the technique nor used the stapler tractor. The general linear data, operation times, intraoperative adverse events, postoperative recovery and complications were compared. Results: Compared with other groups, Group A exhibited the best surgical outcomes in comprehensive aspects. Separately, the tunnel groups (Group A&B) had better outcomes in the macro implementation of operation, including resection margin, the number of sampled intrapulmonary lymph nodes and resected subsegments, while the staple tractor groups (Group A&C) performed better on details of the procedure, including operation time, conversion to thoracotomy, and intraoperative bleeding (p < 0.05). Both of them were beneficial for shorter hospital stay, and the tunnel group was more advantageous. Conclusion: The tunneling technique is an advanced and beneficial surgical strategy for performing precise resection of lung segments while a stapler tractor can promote and facilitate it as a supplementary instrument. They show more combined benefits in effectively minimizing the occurrence of erroneous injuries and enhancing the operational efficacy.
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Introduction: Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that affects brain parenchyma, eyes, cerebrospinal fluid, and spinal cord. Diagnosing PCNSL can be challenging because imaging studies often show similar patterns as other brain tumors, and stereotactic brain lesion biopsy conformation is invasive and not always possible. This study aimed to validate a previous proteomic profiling (PMID: 32610669) of cerebrospinal fluid (CSF) and develop a CSF-based proteomic panel for accurate PCNSL diagnosis and differentiation. Methods: CSF samples were collected from patients of 30 PCNSL, 30 other brain tumors, and 31 tumor-free/benign controls. Liquid chromatography tandem-mass spectrometry targeted proteomics analysis was used to establish CSF-based proteomic panels. Results: Final proteomic panels were selected and optimized to diagnose PCNSL from tumor-free controls or other brain tumor lesions with an area under the curve (AUC) of 0.873 (95%CI: 0.723-0.948) and 0.937 (95%CI: 0.807- 0.985), respectively. Pathways analysis showed diagnosis panel features were significantly enriched in pathways related to extracellular matrices-receptor interaction, focal adhesion, and PI3K-Akt signaling, while prion disease, mineral absorption and HIF-1 signaling were significantly enriched with differentiation panel features. Discussion: This study suggests an accurate clinical test panel for PCNSL diagnosis and differentiation with CSF-based proteomic signatures, which may help overcome the challenges of current diagnostic methods and improve patient outcomes.
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Biomarcadores Tumorais , Neoplasias Encefálicas , Proteômica , Humanos , Proteômica/métodos , Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Diagnóstico Diferencial , Adulto , Linfoma não Hodgkin/líquido cefalorraquidiano , Linfoma não Hodgkin/diagnósticoRESUMO
Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4ß2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.
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Epilepsia Generalizada , Humanos , Feminino , Masculino , Epilepsia Generalizada/patologia , Epilepsia Generalizada/fisiopatologia , Adulto , Adulto Jovem , Imageamento por Ressonância Magnética , Tálamo/patologia , Tálamo/diagnóstico por imagem , Tálamo/metabolismo , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Adolescente , Putamen/patologia , Putamen/diagnóstico por imagem , Putamen/metabolismo , Estudos de Casos e Controles , Hipocampo/patologiaRESUMO
BACKGROUND: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive. METHODS: Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations. RESULTS: Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. IFIH1 is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients. CONCLUSIONS: IFIH1 variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of IFIH1 variants.
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Epilepsia Generalizada , Sequenciamento do Exoma , Estudos de Associação Genética , Helicase IFIH1 Induzida por Interferon , Mutação de Sentido Incorreto , Convulsões Febris , Humanos , Convulsões Febris/genética , Epilepsia Generalizada/genética , Masculino , Feminino , Helicase IFIH1 Induzida por Interferon/genética , Mutação de Sentido Incorreto/genética , Pré-Escolar , Lactente , Criança , Predisposição Genética para Doença , Adulto , FenótipoRESUMO
Emerging evidence has underscored the complex link between gut microbiota and chemotherapy efficacy; however, establishing causality remains elusive due to confounding factors. This study, leveraging bidirectional two-sample Mendelian randomization (MR) analyses, explores the casual relationship between gut microbiota and chemotherapy efficacy. Utilizing genome-wide association study (GWAS) data from the MiBioGen consortium for gut microbiota and IEU Open GWAS for chemotherapy efficacy, we employed genetic variants as instrumental variables (IVs). The inverse variance weighted (IVW) method, weighted median estimator (WME), and MR-Egger regression method were applied, with sensitivity analyses ensuring robustness. Furthermore, we conducted reverse MR analyses between chemotherapy efficacy and identified significant gut microbial taxa. The results indicated that genus Butyricicoccus (OR = 3.7908, 95% CI: 1.4464-9.9350, P = 0.01), Dorea (OR = 3.3295, 95% CI: 1.2794-8.6643, P = 0.01), Hungatella (OR = 2.6284, 95% CI: 1.0548-6.5498, P = 0.04), and Turicibacter (OR = 2.5694, 95% CI: 1.0392-6.3526, P = 0.04) were positively associated with chemotherapy efficacy using the IVW method. Conversely, family Porphyromonadaceae (OR = 0.2283, 95% CI: 0.0699-0.7461, P = 0.01) and genus Eggerthella (OR = 0.4953, 95% CI: 0.2443-1.0043, P = 0.05) exhibited negative associations. WME demonstrated consistent results with IVW method only for genus Eggerthella (OR = 0.3343, 95% CI: 0.1298-0.8610, P = 0.02). No significant heterogeneity or horizontal pleiotropy was observed. Reverse MR analyses revealed no significant causal effect of chemotherapy on identified gut microbiota. This study sheds light on the intricate relationship between gut microbiota, with a particular emphasis on the genus Eggerthella, and chemotherapy efficacy, offering valuable insights for refining cancer treatment strategies.IMPORTANCEGlobal advancements in cancer treatment, particularly in chemotherapy, have notably decreased mortality rates in recent years. However, the correlation between gut microbiota and chemotherapy efficacy remains elusive. Our study, emphasizing the role of genus Eggerthella, represented a crucial advance in elucidating this intricate interplay. The identified associations offer potential therapeutic targets, contributing to global efforts for enhanced treatment precision and improved patient outcomes. Furthermore, our findings hold promise for personalized therapeutic interventions, shaping improved strategies in the ever-evolving landscape of cancer treatment.