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1.
J Phys Chem Lett ; 15(36): 9301-9310, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39235319

RESUMEN

The development of monolithic integrated energy-efficient complementary circuits is crucial for the large-scale application of wide bandgap semiconductor-based high-frequency and high-power field-effect transistors (FETs). However, the inferior performance of p-channel FETs attributed to low hole density and mobility presents a substantial challenge. Diamond is a promising candidate due to its excellent comprehensive electrical properties and high thermal conductivity. Here, we report the fabrication of normally off diamond FETs based on a low work function metal gate and (110) hydrogen-terminated diamond with high hole density. The use of high-quality SiO2 layer ensures the complete depletion of the channel by the gate and offers high gating efficiency. Therefore, the developed devices demonstrate exceptional reproducibility of normally off characteristics with centrally distributed threshold voltages (-0.37 ± 0.3 V) and realize large current and voltage handling capabilities and low static standby power consumption in a synergic manner with record-high on/off ratio exceeding 1010, high current density (∼200 µA·µm-1), ultralow off-state current (∼fA·µm-1), and high breakdown voltage (-676 V). Additionally, the thermal desorption of negatively charged acceptors has been proven to significantly reduce carrier scattering. This work offers superior performance p-channel FETs for implementing energy-efficient complementary circuits, laying the groundwork for accelerated development in wide bandgap semiconductor power electronics.

2.
Eur J Med Chem ; 277: 116769, 2024 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-39163778

RESUMEN

Phosphodiesterases (PDEs) constitute a family of enzymes that play a pivotal role in the regulation of intracellular levels of cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Dysregulation of PDE activity has been implicated in diverse pathological conditions encompassing cardiovascular disorders, pulmonary diseases, and neurological disorders. Small-molecule inhibitors targeting PDEs have emerged as promising therapeutic agents for the treatment of these ailments, some of which have been approved for their clinical use. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation PDE inhibitors. The objective of this review is to provide an overview of the synthesis and clinical application of representative approved small-molecule PDE inhibitors, with the aim of offering guidance for further advancements in the development of novel PDE inhibitors.


Asunto(s)
Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Bibliotecas de Moléculas Pequeñas , Animales , Humanos , Estructura Molecular , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-Actividad , AMP Cíclico/química , AMP Cíclico/metabolismo , AMP Cíclico/farmacología
3.
Eur J Med Chem ; 277: 116762, 2024 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-39151275

RESUMEN

In 2023, the European Medicines Agency (EMA) granted approval to 77 new molecular entities (NMEs), consisting of 45 new chemical entities (NCEs) and 32 new biological entities (NBEs). These pharmacological agents encompass a broad spectrum of therapeutic domains, including oncology, cardiology, dermatology, diagnostic medicine, endocrinology, gastroenterology and hepatology, metabolic disorders, and neurology. Among the 77 approved pharmaceuticals, three received accelerated review status, and 17 (22 %) were granted orphan drug designation for the treatment of rare diseases. This review provides an overview of the clinical applications and synthetic routes of 42 newly approved NCEs by the EMA in 2023. The objective is to offer a comprehensive understanding of the synthetic approaches used in the development of these drug molecules, thereby inspiring the creation of novel, efficient, and applicable synthetic methodologies.


Asunto(s)
Aprobación de Drogas , Humanos , Europa (Continente) , Estructura Molecular
4.
Plant Cell Physiol ; 2024 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-39096526

RESUMEN

Low temperature significantly inhibits the plant growth in wheat (Triticum aestivum L.), prompting the exploration of effective strategies to mitigate low temperature stress. Several priming methods enhance low temperature stress tolerant, however, the role of ozone priming remains unclear in wheat. Here we found ozone priming alleviated low temperature stress in wheat. Transcriptome analysis showed that ozone priming positively modulated 'photosynthesis-antenna proteins' pathway in wheat under low temperature. Which was confirmed by the results of the ozone-primed plants had higher trapped energy flux and electron transport flux per reaction, and less damage to chloroplasts than non-primed plants under low temperature. Ozone priming also mitigated the overstimulation of glutathione metabolism and induced the accumulation of total ascorbic acid and glutathione, maintained redox homeostasis in wheat under low temperature. Moreover, gene expressions and enzyme activities in glycolysis pathways were upregulated in ozone priming comparing with non-priming after the low temperature stress. Furthermore, exogenous antibiotics significantly increased low temperature tolerance, which further proved that the inhibition of ribosome biogenesis by ozone priming was involved in low temperature tolerance in wheat. In conclusion, ozone priming enhanced wheat low temperature tolerance through promoting light-harvesting capacity, redox homeostasis, and carbohydrate metabolism, as well as inhibiting ribosome biogenesis.

5.
Bioorg Chem ; 151: 107653, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39024803

RESUMEN

This comprehensive review undertakes a meticulous scrutiny of the synthesis and clinical applications pertaining to small-molecule tyrosine kinase inhibitors (TKIs) directed towards the human epidermal growth factor receptor 2 (HER2), a pivotal protagonist in the pathogenesis of cancer. Focused on compounds like lapatinib, neratinib, and tucatinib, the review delves into the intricate synthesis strategies, emphasizing the challenges associated with their structural complexity. The clinical utilization of HER2 TKIs underscores noteworthy strides in the therapeutic landscape for HER2-positive breast and gastric malignancies. Lapatinib, a dual HER2/ epidermal growth factor receptor (EGFR) inhibitor, has demonstrated efficacy in combination therapies, addressing the need for overcoming resistance mechanisms. Neratinib, an irreversible HER2 inhibitor, presents a promising avenue for patients with refractory tumors. Tucatinib, strategically engineered to traverse the blood-brain barrier, epitomizes a groundbreaking advancement in the management of metastatic HER2-positive breast cancer manifesting cerebral involvement. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation HER2 TKIs. This comprehensive review serves as a valuable resource for pharmaceutical scientists, offering insights into the synthetic intricacies and clinical impact of small-molecule TKIs targeting HER2.


Asunto(s)
Antineoplásicos , Inhibidores de Proteínas Quinasas , Receptor ErbB-2 , Humanos , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Estructura Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología
6.
FASEB J ; 38(13): e23756, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38949649

RESUMEN

Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as "airway remodeling", are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-ß1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-ß1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-ß1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-ß1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-ß1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma , Factores de Transcripción Forkhead , Glucólisis , Sirtuina 2 , Asma/metabolismo , Asma/patología , Animales , Sirtuina 2/metabolismo , Sirtuina 2/genética , Ratones , Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Humanos , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Transición Epitelial-Mesenquimal , Ratones Endogámicos BALB C , Femenino , Factor de Crecimiento Transformador beta1/metabolismo , Pulmón/metabolismo , Pulmón/patología , Línea Celular
7.
Eur J Med Chem ; 276: 116722, 2024 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-39079309

RESUMEN

Fluorine possesses distinctive chemical characteristics, such as its strong electron-withdrawing ability and small atomic size, which render it an invaluable asset in the design and optimization of pharmaceuticals. The utilization of fluorine-enriched medications for combating cancer has emerged as a prominent approach in medicinal chemistry and drug discovery, offering improved clinical outcomes and enhanced pharmacological properties. This comprehensive review explores the synthetic approaches and clinical applications of approved 22 representative fluorinated anti-cancer drugs from 2019 to present, shedding light on their historical development, brand names, drug target activity, mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity. Additionally, the review provides an extensive analysis of the representative synthetic techniques employed. Overall, this review emphasizes the significance of incorporating fluorine chemistry into anti-cancer drug research while highlighting promising future prospects for exploring compounds enriched with fluorine in the battle against cancer.


Asunto(s)
Antineoplásicos , Flúor , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Flúor/química , Neoplasias/tratamiento farmacológico , Animales , Estructura Molecular
8.
Small ; : e2403490, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39031997

RESUMEN

The miniaturization, integration, and increased power of electronic devices have exacerbated serious heat dissipation issues. Thermally conductive adhesives, which effectively transfer heat and firmly bond components, are critical for addressing these challenges. This paper innovatively proposed a composite comprising inorganic phosphate/alumina as a matrix and diamond as filler. The composite achieved an isotropic thermal conductivity (TC) of up to 18.96 W m-1 K-1, significantly surpassing existing reports while maintaining electrical insulation. First-principles calculations and experimental tests confirmed that the high TC of phosphate and excellent interface contact ensured efficient heat transfer. To optimize bonding performance, a modified-diamond/Al(H2PO4)3@epoxy hybrid composite is subsequently developed using an organic modification method. The unique hybrid structure, combining inorganic thermal pathways and an organic adhesive network, enabled the hybrid composite to simultaneously possess a high TC (3.23 W m-1 K-1) and strong adhesion (14.35 MPa). Compared to previous reports, the comprehensive performance of this hybrid thermally conductive adhesive is exceptionally remarkable. The superior heat dissipation capability of the hybrid thermal adhesive is demonstrated in chip cooling scenarios. This organic/inorganic hybrid approach offered a new direction for obtaining advanced thermal interface materials, demonstrating significant application potential in chip soldering, packaging, and heat dissipation.

10.
J Neural Eng ; 21(3)2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38861996

RESUMEN

Objective.Distributed hypothalamic-midbrain neural circuits help orchestrate complex behavioral responses during social interactions. Given rapid advances in optical imaging, it is a fundamental question how population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. This paper aims to investigate the correspondence between MFP data and social behaviors.Approach:We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include a continuous-state linear dynamical system and a discrete-state hidden semi-Markov model. We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively.Main results:Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states, and produce interpretable latent states. Our approach is also validated in computer simulations in the presence of known ground truth.Significance:Overall, these analysis approaches provide a state-space framework to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks.


Asunto(s)
Fotometría , Conducta Social , Animales , Ratones , Fotometría/métodos , Masculino , Femenino , Ratones Endogámicos C57BL , Red Nerviosa/fisiología , Simulación por Computador , Conducta Sexual Animal/fisiología , Agresión/fisiología , Modelos Neurológicos
11.
Neuroendocrinology ; 114(8): 733-748, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38710164

RESUMEN

INTRODUCTION: Well-calibrated models for personalized prognostication of patients with gastrointestinal neuroendocrine neoplasms (GINENs) are limited. This study aimed to develop and validate a machine-learning model to predict the survival of patients with GINENs. METHODS: Oblique random survival forest (ORSF) model, Cox proportional hazard risk model, Cox model with least absolute shrinkage and selection operator penalization, CoxBoost, Survival Gradient Boosting Machine, Extreme Gradient Boosting survival regression, DeepHit, DeepSurv, DNNSurv, logistic-hazard model, and PC-hazard model were compared. We further tuned hyperparameters and selected variables for the best-performing ORSF. Then, the final ORSF model was validated. RESULTS: A total of 43,444 patients with GINENs were included. The median (interquartile range) survival time was 53 (19-102) months. The ORSF model performed best, in which age, histology, M stage, tumor size, primary tumor site, sex, tumor number, surgery, lymph nodes removed, N stage, race, and grade were ranked as important variables. However, chemotherapy and radiotherapy were not necessary for the ORSF model. The ORSF model had an overall C index of 0.86 (95% confidence interval, 0.85-0.87). The area under the receiver operation curves at 1, 3, 5, and 10 years were 0.91, 0.89, 0.87, and 0.80, respectively. The decision curve analysis showed superior clinical usefulness of the ORSF model than the American Joint Committee on Cancer Stage. A nomogram and an online tool were given. CONCLUSION: The machine learning ORSF model could precisely predict the survival of patients with GINENs, with the ability to identify patients at high risk for death and probably guide clinical practice.


Asunto(s)
Neoplasias Gastrointestinales , Aprendizaje Automático , Tumores Neuroendocrinos , Humanos , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/terapia , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/patología , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Gastrointestinales/mortalidad , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/terapia , Anciano , Pronóstico , Adulto , Modelos de Riesgos Proporcionales , Nomogramas
12.
Eur J Nutr ; 63(5): 1945-1959, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38753171

RESUMEN

BACKGROUND: Postmenopausal osteoporosis (PMO) is a chronic condition characterized by decreased bone strength. This study aims to investigate the effects and mechanisms of the combination of Butyricicoccus pullicaecorum (Bp) and 3-hydroxyanthranilic acid (3-HAA) on PMO. METHODS: The effects of Bp and 3-HAA on PMO were evaluated in ovariectomized (OVX) rats by assessing stereological parameters, femur microstructure, and autophagy levels. The T helper (Th) 17/Regulatory T (Treg) cells of rats were detected using flow cytometric analysis. Furthermore, the impact of Bp and 3-HAA on the gut microbiota of rats was assessed using 16S rRNA gene sequencing. The correlation between the gut microbiota of rats and Th17/Treg immune factors, as well as femoral stereo parameters, was separately assessed using Spearman rank correlation analysis. RESULTS: Bp and 3-HAA treatments protected OVX rats by promoting osteogenesis and inhibiting autophagy. Compared to the Sham group, OVX rats showed an increase in Th17 cells and a decrease in Treg cells. Bp and 3-HAA reversed these changes. Enterorhabdus and Pseudomonas were significantly enriched in OVX rats. Bp and 3-HAA regulated the gut microbiota of OVX rats, enriching pathways related to nutrient metabolism and immune function. There was a correlation between the gut microbiota and the Th17/Treg, as well as femoral stereo parameters. The concurrent administration of Bp and 3-HAA medication facilitated the enrichment of gut microbiota associated with the improvement of PMO. CONCLUSION: The combination therapy of Bp and 3-HAA can prevent PMO by modulating the gut microbiota and restoring Th17/Treg immune homeostasis.


Asunto(s)
Microbioma Gastrointestinal , Osteoporosis Posmenopáusica , Linfocitos T Reguladores , Células Th17 , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Femenino , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Ratas , Osteoporosis Posmenopáusica/prevención & control , Ratas Sprague-Dawley , ortoaminobenzoatos/farmacología , Probióticos/farmacología , Probióticos/administración & dosificación , Humanos , Ovariectomía/métodos , Clostridiales , Modelos Animales de Enfermedad
13.
Front Pediatr ; 12: 1370224, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38725990

RESUMEN

Background: Little is known about the safety of mite extract product Novo-Helisen Depot (NHD) as subcutaneous immunotherapy (SCIT) in the children with mite allergy especially immediate/late local reaction (LRs). Methods: We conducted a retrospective study analyzing the adverse events of the children undergoing subcutaneous immunotherapy with NHD. Adverse events included local and systemic adverse reactions (SRs) at the very early and late stage. The correlation of the basic characteristics, laboratory analysis results, LRs and SRs were analyzed. Results: Two hundred and eighty-seven patients received at least 15 months of subcutaneous immunotherapy with NHD were included in the analysis. Skin-prick testing (SPT) results of D. pteronyssinus was associated with an increased risk of immediate LRs in build-up phase (OR = 1.53, 95% CI: 1.02, 2.37) and delayed LRs in maintenance phase (OR = 1.58, 95% CI: 1.05, 2.46), while SPT results of D. farinae was associated with an increased risk of SRs (OR = 3.22, 95% CI: 1.17, 10.00) and severe SRs (OR = 7.68, 95% CI: 1.13, 109.50). Serum IgE level of D. pteronyssinus was associated with an increased risk of SRs (OR = 1.01, 95% CI: 1.00, 1.03). Patients with both asthma and allergic rhinitis was associated with an increased risk of SR, and severe SRs (P < 0.05). Conclusion: NHD as SCIT is safe. The children with higher SPT level with D. farinae or D. pteronyssinus, higher serum IgE level of D. pteronyssinus, children with both asthma and allergic rhinitis, and the children with treatment interruption had higher risk of adverse events.

14.
Ann Intensive Care ; 14(1): 68, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38668955

RESUMEN

BACKGROUND: It remains unclear whether conservative oxygen therapy (COT) or liberal oxygen therapy (LOT) is more beneficial to the clinical outcomes of intensive care unit (ICU) patients. We systematically reviewed the efficacy and safety of conservative versus liberal oxygen therapy for ICU patients. METHODS: We systematically searched PubMed, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, MedRxiv, and BioRxiv for reports on randomized controlled trials (RCTs) that compared the effects of COT versus LOT on the clinical outcomes of ICU patients published in English before April 2024. The primary outcome was the mortality rate, secondary outcomes included ICU and hospital length of stay, days free from mechanical ventilation support (MVF), vasopressor-free time (VFT), and adverse events. RESULTS: In all, 13 RCTs involving 10,632 patients were included in analyses. Meta-analysis showed COT did not reduce mortality at 30-day (risk ratio [RR] = 1.01, 95% confidence interval [CI] 0.94 to 1.09, I2 = 42%, P = 0.78), 90-day (RR = 1.01, 95% CI 0.95 to 1.08, I2 = 9%, P = 0.69), or longest follow-up (RR = 1.00, 95% CI 0.95 to 1.06, I2 = 22%, P = 0.95) compared to LOT in ICU patients. In subgroup analyses, no significant difference was observed between the two groups in terms of the different ICU, baseline P/F, and actual PaO2. In addition, COT did not affect ICU length of stay, hospital length of stay, or VFT, it only affected MVF days. CONCLUSIONS: COT did not reduce all-cause mortality in ICU patients. Further RCTs are urgently needed to confirm the impact of COT strategy on specific populations.

16.
Int J Anal Chem ; 2024: 6139928, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38481558

RESUMEN

The combined prescriptions of nirmatrelvir/ritonavir and other drugs are limited due to potential drug-drug interactions, so therapeutic drug monitoring (TDM) becomes particularly important. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for determination of the nirmatrelvir/ritonavir in plasma of patients with COVID-19, providing technical and theoretical support for the TDM. Plasma samples were processed by protein precipitation using acetonitrile, and analytes were separated on an Agilent Poroshell 120 SB-C18 (2.1 × 75 mm, 2.7 µm) column at 35°C. Acetonitrile and 0.1% formic acid in water (52 : 48) were utilized as the mobile phases at a flow rate of 0.3 mL/min. In the multiple reaction monitoring (MRM) mode, nirmatrelvir and ritonavir were monitored using precursor/product ions: m/z 500.2/110.1 and 721.3/296.1, respectively, with selinexor as the internal standard. The linear range of both analytes was 2.0 ng/mL to 5000 ng/mL with good inter- and intraday precision and accuracy, and the recovery was 92.0%-107% for nirmatrelvir and 85.7%-106% for ritonavir. Finally, this method was successfully applied to monitor the exposure levels of nirmatrelvir/ritonavir in plasma samples from hemodialysis patients.

17.
Cancer Lett ; 588: 216655, 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38460724

RESUMEN

Cancer remains a major burden globally and the critical role of early diagnosis is self-evident. Although various miRNA-based signatures have been developed in past decades, clinical utilization is limited due to a lack of precise cutoff value. Here, we innovatively developed a signature based on pairwise expression of miRNAs (miRPs) for pan-cancer diagnosis using machine learning approach. We analyzed miRNA spectrum of 15832 patients, who were divided into training, validation, test, and external test sets, with 13 different cancers from 10 cohorts. Five different machine-learning (ML) algorithms (XGBoost, SVM, RandomForest, LASSO, and Logistic) were adopted for signature construction. The best ML algorithm and the optimal number of miRPs included were identified using area under the curve (AUC) and youden index in validation set. The AUC of the best model was compared to previously published 25 signatures. Overall, Random Forest approach including 31 miRPs (31-miRP) was developed, proving highly efficient in cancer diagnosis across different datasets and cancer types (AUC range: 0.980-1.000). Regarding diagnosis of cancers at early stage, 31-miRP also exhibited high capacities, with AUC ranging from 0.961 to 0.998. Moreover, 31-miRP exhibited advantages in differentiating cancers from normal tissues (AUC range: 0.976-0.998) as well as differentiating cancers from corresponding benign lesions. Encouragingly, comparing to previously published 25 different signatures, 31-miRP also demonstrated clear advantages. In conclusion, 31-miRP acts as a powerful model for cancer diagnosis, characterized by high specificity and sensitivity as well as a clear cutoff value, thereby holding potential as a reliable tool for cancer diagnosis at early stage.


Asunto(s)
MicroARN Circulante , MicroARNs , Neoplasias , Humanos , MicroARN Circulante/genética , Neoplasias/diagnóstico , Neoplasias/genética , MicroARNs/genética , MicroARNs/metabolismo , Algoritmos , Diagnóstico Precoz
18.
Sci Rep ; 14(1): 2845, 2024 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-38310124

RESUMEN

Phenotype-guided gene prioritizers have proved a highly efficient approach to identifying causal genes for Mendelian diseases. In our previous study, we preliminarily evaluated the performance of ten prioritizers. However, all the selected software was run based on default settings and singleton mode. With a large-scale family dataset from Deciphering Developmental Disorders (DDD) project (N = 305) and an in-house trio cohort (N = 152), the four optimal performers in our prior study including Exomiser, PhenIX, AMELIE, and LIRCIAL were further assessed through parameter optimization and/or the utilization of trio mode. The in-depth assessment revealed high diagnostic yields of the four prioritizers with refined preferences, each alone or together: (1) 83.3-91.8% of the causal genes were presented among the first ten candidates in the final ranking lists of the four tools; (2) Over 97.7% of the causal genes were successfully captured within the top 50 by either of the four software. Exomiser did best in directly hitting the target (ranking the causal gene at the very top) while LIRICAL displayed a predominant overall detection capability. Besides, cases affected by low-penetrance and high-frequency pathogenic variants were found misjudged during the automated prioritization process. The discovery of the limitations shed light on the specific directions of future enhancement for causal-gene ranking tools.


Asunto(s)
Programas Informáticos , Humanos , Fenotipo
19.
Indian J Orthop ; 58(2): 151-161, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38312904

RESUMEN

Aims: This study aimed to establish a nomogram model for predicting the probability of postoperative deep vein thrombosis (DVT) risk in patients with hip fractures. Methods: 504 patients were randomly assigned to the training set and validation set, and then divided into a DVT group and a non-DVT group. The study analysed the risk factors for DVT using univariate and multivariate analyses. Based on these parameters, a nomogram model was constructed and validated. The predicting performance of nomogram was evaluated by discrimination, calibration, and clinical usefulness. Results: The predictors contained in the nomogram model included age, surgical approach, 1-day postoperative D-dimer value and admission ultrasound diagnosis of the lower limb vein. Furthermore, the area under the ROC curve (AUC) for the specific DVT risk-stratification nomogram model (0.815; 95% CI 0.746-0.884) was significantly higher than the current model (Caprini) (0.659; 95% CI 0.572-0.746, P < 0.05). According to the calibration plots, the prediction and actual observation were in good agreement. In the range of threshold probabilities of 0.2-0.8, the predictive performance of the model on DVT risk could be maximized. Conclusions: The current predictive model could serve as a reliable tool to quantify the possibility of postoperative DVT in hip fractures patients.

20.
Heliyon ; 10(3): e24507, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38314308

RESUMEN

Background: Tuberculosis continues to be a significant public health concern in China, particularly among the elderly population. This study aimed to assess the risk factors of tuberculosis among elderly individuals in China through a cohort study, focusing on this high-risk population. Methods: The population-based census was strategically designed to cover diverse regions and demographics across the city. The survey captured demographic and lifestyle information, as well as a clinical examination. Participants were prospectively followed up over a specified duration to monitor the incidence of tuberculosis cases. Results: After a follow-up period of more than 7 years, 246 individuals developed tuberculosis, resulting in an incidence rate of 92.21 per 100,000 person-years (95 % CI 81.2-104.3). In multivariate analysis, the following factors were found to have significant associations with active tuberculosis. Increasing age correlated with a higher risk of active tuberculosis (AHR = 1.03 per 1-year increase in age, 95%CI: 1.01, 1.04, P < 0.001). Males continued to have a higher risk compared to females (HR = 2.73, 95%CI: 2.08, 3.58, P < 0.001). Individuals with a normal Body Mass Index (BMI) faced nearly three times higher risk compared to their obese counterparts (HR = 2.87, 95 % CI: 1.51, 5.46, P = 0.001). Conversely, those with an underweight BMI had a ten-fold higher risk compared to the obese group (HR = 9.89, 95 % CI: 4.92, 19.85, P < 0.001). Elderly individuals who quit smoking had a 1.35-fold increased risk compared to non-smokers (HR = 1.35, 95%CI: 1.12, 1.64, P < 0.001). Conclusions: Tuberculosis incidence among the elderly population in China remained alarmingly high. This finding emphasizes the urgent need for implementing proactive case detection measures specifically tailored to address the specific needs of this vulnerable demographic, particularly in individuals who are male, have a history of former or current smoking, and have a low BMI. Moreover, we must not underestimate the influence of former smoking on tuberculosis risk.

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