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BACKGROUND: Nasopharyngeal carcinoma (NPC) is diagnosed relatively late and has a poor prognosis, requiring early detection to reduce the disease burden. This diagnostic test accuracy meta-analysis evaluated the serological diagnostic value of nine EBV-related IgA antibody panels (EBNA1-IgA, VCA-IgA, EA-IgA, Zta-IgA, EBNA1-IgA + VCA-IgA, VCA-IgA + EA-IgA, VCA-IgA + Rta-IgG, EBNA1-IgA + VCA-IgA + Zta-IgA and VCA-IgA + EA-IgA + Rta-IgG), aiming to identify suitable serological detection biomarkers for NPC screening. METHODS: PubMed, Embase, China National Knowledge Infrastructure and Chinese BioMedical Literature Database were searched from January 1st, 2000 to September 30th, 2023, with keywords nasopharyngeal carcinoma, IgA, screening, early detection, early diagnosis, sensitivity and specificity. Articles on the diagnostic value of serum EBV-related IgA antibody panels for NPC were included. Study selection, data extraction, and quality assessment were performed independently by two researchers, and a third researcher was consulted in the case of disagreement. Bivariate models were used for statistical analysis. The quality of included studies was evaluated through Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). RESULTS: A total of 70 articles were included, involving 11 863 NPC cases and 34 995 controls. Among the nine EBV-related IgA antibody panels, EBNA1-IgA + VCA-IgA [0.928 (0.898, 0.950)], VCA-IgA + Rta-IgG [0.925 (0.890, 0.949)], EBNA1-IgA + VCA-IgA + Zta-IgA [0.962 (0.909, 0.985)] and VCA-IgA + EA-IgA + Rta-IgG [0.945 (0.918, 0.964)] demonstrated higher pooled sensitivity (95%CI). In terms of diagnostic odds ratio (DOR) (95%CI), EBNA1-IgA + VCA-IgA [107.647 (61.173, 189.430)], VCA-IgA + Rta-IgG [105.988 (60.118, 186.857)] and EBNA1-IgA + VCA-IgA + Zta-IgA [344.450 (136.351, 870.153)] showed superior performance. Additionally, the SROC curves for EBNA1-IgA + VCA-IgA and VCA-IgA + Rta-IgG were more favorable. However, publication bias was detected for VCA-IgA (P = 0.005) and EBNA1-IgA + VCA-IgA (P = 0.042). CONCLUSIONS: In general, parallel detection of serum EBNA1-IgA, VCA-IgA and Zta-IgA antibodies using ELISA demonstrates better pooled sensitivity and DOR among the studied panels. In the cases where fewer indicators are used, serum VCA-IgA and EBNA1-IgA/Rta-IgG antibody panel exhibits a comparable performance. TRIAL REGISTRATION: The International Prospective Register of Systematic Reviews registration number: CRD42023426984, registered on May 28, 2023.
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Anticuerpos Antivirales , Infecciones por Virus de Epstein-Barr , Inmunoglobulina A , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/inmunología , Detección Precoz del Cáncer/métodos , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/sangre , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/inmunología , Carcinoma Nasofaríngeo/virología , Carcinoma Nasofaríngeo/sangre , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/inmunología , Neoplasias Nasofaríngeas/sangre , Neoplasias Nasofaríngeas/virología , Sensibilidad y Especificidad , Pruebas Serológicas/métodosRESUMEN
Purpose: To explore the relationship between Red cell distribution width/albumin ratio (RAR) and vascular complications, including atherosclerosis of the lower limbs, diabetic nephropathy(DN), and diabetic retinopathy(DR), in patients with type 2 diabetes mellitus(T2DM). Patients and Methods: The study included 427 patients with type 2 diabetes mellitus who were hospitalized in the Department of Endocrinology of the First Affiliated Hospital of Jinan University (Guangzhou, China) between April 1, 2022 and May 31, 2023. Baseline characteristics were displayed according to the quartiles of the RAR. Logistic regression analysis and receiver operating characteristic curves (ROC) were used to analyze the data. Results: After adjusting for confounders, a higher RAR quartile(the fourth quartile) was associated with an increased risk of atherosclerosis of the lower limbs(OR: 2.973, 95% CI 1.281-6.906, p = 0.011), and diabetic nephropathy(OR: 2.876, 95% CI 1.315-6.287, p = 0.008) compared to the lowest RAR quartile. The patients were further divided into two groups according to urinary albumin to creatinine ratio (UACR≥30mg/g and UACR < 30mg/g) and Glomerular Filtration Rate (eGFR<60 mL·min⻹ (1.73 m²) ⻹ and eGFR≥60 mL·min⻹ (1.73 m²) ⻹). Similar results were observed. However, We found that RAR quartile did not significantly increase the likelihood of developing diabetic retinopathy(OR: 1.183, 95% CI 0.633-2.211, p = 0.598). Conclusion: The RAR ratio is associated with an increased risk of atherosclerosis of the lower limbs and diabetic nephropathy in patients with T2DM. The RAR ratio may be an important clinical marker of vascular complications in T2DM.
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In this paper, triphenylamine served as the structural core and was bonded to aromatic groups having various substituents [-OH, -OMe, or -N(Et)2] by a =N-N= chain and then connected with aromatic groups having various substituents [-OH, -OMe, or -N(Et)2]. The geometric and electronic properties of these probes were examined. It was found that the presence of electron donors enhanced the selectivity and emission quantum yield (QY). When exposed to Cu2+, the fluorescence intensity decreased. The optimal probe (T5) showed a significant decrease in emission QY from 17.1 to 0.5% and recovered to 16.8% after exposure to CO for 342 s. The sensing mechanism was revealed to be static quenching, forming a nonfluorescent adduct between probe and Cu2+. After reacting with CO, Cu2+ was reduced to Cu+, and the probe emission was recovered. The bioimaging performance of the optimal probe was assessed as well.
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Hepatitis B virus (HBV) infection is a significant global health concern due to elevated immunosuppressive viral antigen levels, the host immune system's inability to manage HBV, and the liver's immunosuppressive conditions. While immunotherapies utilizing broadly reactive HBV neutralizing antibodies present potential due to their antiviral capabilities and Fc-dependent vaccinal effects, they necessitate prolonged and frequent dosing to achieve optimal therapeutic outcomes. Toll-like receptor 7/8 (TLR7/8) agonists have been demonstrated promise for the cure of chronic hepatitis B, but their systemic use often leads to intense side effects. In this study, we introduced immune-stimulating antibody conjugates which consist of TLR7/8 agonists 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-imidazo[4,5-c]quinolin-4-amine (IMDQ) linked to an anti-hepatitis B surface antigen (HBsAg) antibody 129G1, and designated as 129G1-IMDQ. Our preliminary study highlights that 129G1-IMDQ can prompt robust and sustained anti-HBsAg specific reactions with short-term administration. This underscores the conjugate's potential as an effective strategy for HBsAg clearance and seroconversion, offering a fresh perspective for a practical therapeutic approach in the functional cure of CHB. Highlights: HBV-neutralizing antibody 129G1 was linked with a TLR7/8 agonist small molecule compound IMDQ.Treatment with 129G1-IMDQ has shown significant promise in lowering HBsAg levels in AAV/HBV mice.129G1-IMDQ were eliciting a strong and lasting anti-HBsAg immune response after short-term treatment in AAV/HBV mice.
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The behavior of the potassium alumanyl, [{SiNDipp}AlK]2 ({SiNDipp} = {CH2SiMe2N(Dipp)}2; Dipp = 2,6-i-Pr2C6H3), toward organic nitriles has been investigated. In common with earlier studies of the reactivity of charge neutral Al(I) species with multiply bonded small molecules, it is suggested that the initial step in all the reactions involves [2 + 1] cycloaddition and the generation of an [η2-C=N-Al] alumina azacyclopropane unit. In the cases of o- and m-tolyl-substituted aryl nitriles, this species is too kinetically labile to allow its isolation and undergoes C-C coupling via immediate Al-C/C≡N insertion to yield the alumina diazabutadiene derivatives. In contrast, the increased steric profile of alkyl nitriles imposes a marked influence on the nature of the products formed. Consistent with the proposed sequential pathway, reaction of [{SiNDipp}AlK]2 with t-BuCN provides an isolable alumina cyclopropane species that is kinetically resistant to onward reaction with a further nitrile equivalent. While reduction in the alkyl nitrile steric demands by use of i-PrCN again facilitates C-C bond formation, the crowding of the Al center by the resultant alumina-diazabutadienediide moiety appears to be beyond the limit of kinetic viability, resulting in an unusual 2-fold C-H to N-H isomerization from one of the C-iso-propyl substituents and the isolation of a 1-alumina-2,5-diazabutadiene structure.
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Aim: This study investigated the role of lncRNA LINC01232 in ferroptosis of colorectal cancer (CRC).Materials & methods: Real time quantitative polymerase chain reaction or western blot experiments were performed to examine relevant mRNAs and proteins expression. The kit assays evaluated malondialdehyde, iron, Fe2+ and glutathione levels. ROS levels were verified by flow cytometry. Chromatin immunoprecipitation and RNA immunoprecipitation analysis monitored the correlation among LINC01232, H3K27ac, p300 and ARNTL2.Results: LINC01232 or ARNTL2 knockdown facilitated erastin-induced ferroptosis. The interaction between LINC01232 and p300 resulted in the enhancement of H3K27ac levels at ARNTL2 promoter to promote ARNTL2 transcriptional activity. ARNTL2 overexpression reversed the promoting effect of LINC01232 knockdown on ferroptosis.Conclusion: LINC01232 inhibited the ferroptosis in CRC by epigenetically upregulating the transcriptional activity of ARNTL2.
Colorectal cancer (CRC) is a malignant disease of the digestive tract that occurs worldwide, which has high morbidity and mortality but has not effective targeted therapy. Ferroptosis has emerged as a new target for treating CRC since its proposed in 2012. Long noncoding RNAs are noncoding RNAs with a length greater than 200 nucleotides and their role in ferroptosis of cancer cells has attracted more and more attention in recent years. Herein, our study explored the effect of long noncoding RNA LINC01232 on CRC progression. This research exhibited the relationship between LINC01232 and the ferroptosis at the occurrence and development of CRC, which is expected to provide a potential therapeutic target for the treatment of CRC.
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OBJECTIVES: To investigate how maternal MTR gene polymorphisms and their interactions with periconceptional folic acid supplementation are associated with the incidence of ventricular septal defects (VSD) in offspring. METHODS: A case-control study was conducted, recruiting 426 mothers of infants with VSD under one year old and 740 mothers of age-matched healthy infants. A questionnaire survey collected data on maternal exposures, and blood samples were analyzed for genetic polymorphisms. Multivariable logistic regression analysis and inverse probability of treatment weighting were used to analyze the associations between genetic loci and VSD. Crossover analysis and logistic regression were utilized to examine the additive and multiplicative interactions between the loci and folic acid intake. RESULTS: The CT and TT genotypes of the maternal MTR gene at rs6668344 increased the susceptibility of offspring to VSD (P<0.05). The GC and CC genotypes at rs3768139, AG and GG at rs1050993, AT and TT at rs4659743, GG at rs3768142, and GT and TT at rs3820571 were associated with a decreased risk of VSD (P<0.05). The variations at rs6668344 demonstrated an antagonistic multiplicative interaction with folic acid supplementation in relation to VSD (P<0.05). CONCLUSIONS: Maternal MTR gene polymorphisms significantly correlate with the incidence of VSD in offspring. Mothers with variations at rs6668344 can decrease the susceptibility to VSD in their offspring by supplementing with folic acid during the periconceptional period, suggesting the importance of periconceptional folic acid supplementation in genetically at-risk populations to prevent VSD in offspring.
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5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa , Suplementos Dietéticos , Ácido Fólico , Defectos del Tabique Interventricular , Humanos , Ácido Fólico/administración & dosificación , Femenino , Defectos del Tabique Interventricular/genética , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Estudios de Casos y Controles , Lactante , Adulto , Embarazo , Polimorfismo Genético , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Currently, surgical resection remains the primary approach for treating oral squamous cell carcinoma (OSCC), with limited options for effective drug therapy. Cardamonin, a principal compound derived from Myristica fragrans of the Zingiberaceae family, has garnered attention for its potential to suppress the onset and progression of various malignancies encompassing breast cancer, hepatocellular carcinoma, and ovarian cancers. Nevertheless, the involvement of cardamonin in the treatment of OSCC and its underlying mechanisms are yet to be elucidated. This research explored the possible target of cardamonin in treating OSCC via network pharmacological analysis. Subsequently, this research investigated the impact of cardamonin on OSCC cells via in vitro experiments, revealing its capacity to impede the migration, proliferation, and invasion of OSCC cells. Additionally, western blotting analysis demonstrated that cardamonin facilitates apoptosis by regulating the PI3K/AKT pathway. The findings suggest that MMP9 and the PI3K/AKT signaling pathway may serve as the target and pathway of cardamonin in treating OSCC. To summarize, the research findings suggest that cardamonin may facilitate apoptosis in OSCC cells by inhibition of PI3K/AKT pathway activation. These outcomes offer a theoretical basis for the utilization of cardamonin as a natural drug for treating OSCC.
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Apoptosis , Carcinoma de Células Escamosas , Movimiento Celular , Proliferación Celular , Chalconas , Neoplasias de la Boca , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Chalconas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Metaloproteinasa 9 de la Matriz/metabolismoRESUMEN
Photodetectors and gas sensors are vital in modern technology, spanning from environmental monitoring to biomedical diagnostics. This paper explores the UV detection and gas sensing properties of a zinc oxide (ZnO) nanorod array (ZNA) grown on silver nanowire mesh (AgNM) using a hydrothermal method. We examined the impact of different zinc acetate precursor concentrations on their properties. Results show the AgNM forms a network with high transparency (79%) and low sheet resistance (7.23 Ω/â¡). A sol-gel ZnO thin film was coated on this mesh, providing a seed layer with a hexagonal wurtzite structure. Increasing the precursor concentration alters the diameter, length, and area density of ZNAs, affecting their performance. The ZNA-AgNM-based photodetector shows enhanced dark current and photocurrent with increasing precursor concentration, achieving a maximum photoresponsivity of 114 A/W at 374 nm and a detectivity of 6.37 × 1014 Jones at 0.05 M zinc acetate. For gas sensing, the resistance of ZNA-AgNM-based sensors decreases with temperature, with the best hydrogen response (2.71) at 300 °C and 0.04 M precursor concentration. These findings highlight the potential of ZNA-AgNM for high-performance UV photodetectors and hydrogen gas sensors, offering an alternative way for the development of future sensing devices with enhanced performance and functionality.
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The locked segment is critical for determining the stability of locked segment-type landslides. Research indicates that the volume expansion point marks the transition from the secondary creep stage to the tertiary creep stage in a landslide's evolution, and also separates the stable crack growth stage from the unstable crack growth stage in the locked segment. Identifying the volume expansion point is essential for early warning and predicting locked segment-type landslides. A series of instruments (resistance strain gauges, acoustic emission system, piezoelectric acceleration sensors, etc.) were used to conduct physical model tests of the landslide with retaining-wall-like locked segment under external load on the landslide's trailing edge. The evolution process of this landslide was analyzed through changes in slope shape and stress response characteristics. The experimental results reveal the failure mechanism of the landslide with retaining-wall-like locked segment: the upper part of the landslide thrusts and slides, the middle part squeezes and uplifts, the retaining-wall-like locked segment produces a locking effect, and compression-shear fracture of the retaining-wall-like locked segment leads to landslide failure. Based on the deformation and acoustic emission characteristics of the locked segment, a method for identifying the volume expansion point was established. This point was used as the onset of acceleration point in the inverse velocity method to predict the failure time of the locked segment-type landslides, incorporating the three-stage creep model and Fukumoto's theory.
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BACKGROUND: Surgical treatment for a benign or low-grade malignant tumor in the pancreatic head remains a challenge at present. As an organ-sparing procedure, enucleation is ideal. However, it is still controversial whether laparoscopic enucleation (LapEN) can be safely performed for a pancreatic head tumor, especially a deeply embedded one. METHODS: The cases who underwent LapEN of a pancreatic tumor from January 2014 to September 2022 in our hospital were collected and analyzed. RESULTS: A total of 151 cases were collected. The incidence of pancreatic fistula (PF, grade B) was 21.9 %. No patient developed PF (grade C) or died. Compared with enucleating a tumor in the distal pancreas (N = 98), enucleating a tumor in the pancreatic head (N = 53) showed a longer operation time and a higher incidence of conversion. The cases with a tumor in the pancreatic head were then divided into the group with a deeply embedded tumor (N = 32) and the group with a superficial tumor (N = 21). The embedded group had a smaller tumor size and a higher proportion of insulinoma. There were no statistical differences in the parameters of operation time, blood loss and incidence of complications between the two groups. The outcomes of enucleating a tumor deeply embedded in the proximal and distal pancreas were further analyzed, which indicated no statistical differences in clinical parameters between the two groups. CONCLUSION: LapEN of a tumor in the pancreatic head is feasible and safe, even for a deeply embedded tumor.
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Semi-supervised learning (SSL) has achieved significant success due to its capacity to alleviate annotation dependencies. Most existing SSL methods utilize pseudo-labeling to propagate useful supervised information for training unlabeled data. However, these methods ignore learning temporal representations, making it challenging to obtain a well-separable feature space for modeling explicit class boundaries. In this work, we propose a semi-supervised Time Series classification framework via Bidirectional Consistency with Temporal-aware (TS-BCT), which regularizes the feature space distribution by learning temporal representations through pseudo-label-guided contrastive learning. Specifically, TS-BCT utilizes time-specific augmentation to transform the entire raw time series into two distinct views, avoiding sampling bias. The pseudo-labels for each view, generated through confidence estimation in the feature space, are then employed to propagate class-related information into unlabeled samples. Subsequently, we introduce a temporal-aware contrastive learning module that learns discriminative temporal-invariant representations. Finally, we design a bidirectional consistency strategy by incorporating pseudo-labels from two distinct views into temporal-aware contrastive learning to construct a class-related contrastive pattern. This strategy enables the model to learn well-separated feature spaces, making class boundaries more discriminative. Extensive experimental results on real-world datasets demonstrate the effectiveness of TS-BCT compared to baselines.
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BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by the presence of hyperphosphorylated and misfolded tau aggregates in neurons and glia. Recent studies have illuminated the prion-like cell-to-cell propagation of tau via exosomes. Recognizing the potential significance of excretion through urine as a crucial pathway for eliminating pathological tau from the central nervous system, this study aimed to investigate whether exosomes derived from the urine of PSP-Richardson's syndrome (PSP-RS) patients can elicit tau pathology and PSP-like symptoms in mice. METHODS: Urinary exosomes obtained from PSP-RS patients and normal controls (NCs) were stereotactically injected into the bilateral globus pallidus of mouse brains. Behavioral analyses were conducted every 3 months post-injection. After 6 months, mice were sacrificed for pathological evaluation. RESULTS: Elevated levels of phosphorylated tau and neural cell markers were observed in urinary exosomes from PSP-RS patients compared to NCs. At the 6-month mark post-injection, tau inclusions were evident in the brains of mice receiving urinary exosomes from PSP-RS patients, with widespread distribution in both injection sites and distant brain regions (cortex, hippocampus, and substantia nigra). Tau pathology manifested in neurons and astrocytes. Moreover, mice injected with urinary exosomes from PSP-RS patients exhibited impaired motor coordination and balance, mirroring PSP motor symptoms. CONCLUSION: Our findings indicate that urinary exosomes from PSP-RS patients can induce tau pathology and trigger PSP-like motor symptoms in mice. This leads to the hypothesis that exosomes may play a role in the pathogenesis of PSP.
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Exosomas , Parálisis Supranuclear Progresiva , Proteínas tau , Animales , Parálisis Supranuclear Progresiva/metabolismo , Parálisis Supranuclear Progresiva/patología , Parálisis Supranuclear Progresiva/orina , Exosomas/metabolismo , Proteínas tau/metabolismo , Proteínas tau/orina , Ratones , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Encéfalo/metabolismo , Encéfalo/patología , Tauopatías/metabolismo , Tauopatías/patología , Neuronas/metabolismo , Neuronas/patología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Astrocitos/metabolismo , FosforilaciónRESUMEN
Salivary glands are the principal organs responsible for secreting saliva in the oral cavity. Tumors, trauma, inflammation, and other factors can cause functional or structural damage to the glands, leading to reduced saliva secretion. In this study, we innovatively prepared a acinar-mimetic silk fibroin-collagen-astragalus polysaccharide (SCA) scaffold using low-temperature three-dimensional (3D) printing and freeze-drying techniques. We evaluated the material properties and cell compatibility of the scaffold in vitro and implanted it into the damaged parotid glands (PG) of rats to assess its efficacy in tissue reconstruction and functional repair. The results demonstrated that the SCA scaffold featured a porous structure resembling natural acini, providing an environment conducive to cell growth and orderly aggregation. It exhibited excellent porosity, water absorption, mechanical properties, and biocompatibility, fulfilling the requirements for tissue engineering scaffolds. In vitro, the scaffold facilitated adhesion, proliferation, orderly polarization, and spherical aggregation of PG cells. In vivo, the SCA scaffold effectively recruited GECs locally, forming gland-like acinar structures that matured gradually, promoting the regeneration of damaged PGs. The SCA scaffold developed in this study supports tissue reconstruction and functional repair of damaged PGs, making it a promising implant material for salivary gland regeneration.
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Colágeno , Fibroínas , Glándula Parótida , Polisacáridos , Impresión Tridimensional , Ingeniería de Tejidos , Andamios del Tejido , Fibroínas/química , Fibroínas/farmacología , Andamios del Tejido/química , Animales , Glándula Parótida/química , Ratas , Colágeno/química , Ingeniería de Tejidos/métodos , Polisacáridos/química , Polisacáridos/farmacología , Porosidad , Regeneración/efectos de los fármacos , Ratas Sprague-Dawley , Células Acinares/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Proliferación Celular/efectos de los fármacos , MasculinoRESUMEN
This study introduces a novel self-supervised learning method for single-frame subtraction and vessel segmentation in coronary angiography, addressing the scarcity of annotated medical samples in AI applications. We pretrain a U-Net model on a large dataset of unannotated coronary angiograms using an image-to-image translation framework, then fine-tune it on a limited set of manually annotated samples. The pretrained model excels at comprehensive single-frame subtraction, outperforming existing DSA methods. Fine-tuning with just 40 samples yields a Dice coefficient of 0.828 for vessel segmentation. On the public XCAD dataset, our model sets a new state-of-the-art benchmark with a Dice coefficient of 0.755, surpassing both unsupervised and supervised learning approaches. This method achieves robust single-frame subtraction and demonstrates that combining pretraining with minimal fine-tuning enables accurate coronary vessel segmentation with limited manual annotations. We successfully apply this approach to assist physicians in visualizing potential vascular stenosis sites during coronary angiography. Code, dataset, and a live demo will be available available at: https://github.com/newfyu/DeepSA .
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Angiografía Coronaria , Vasos Coronarios , Angiografía Coronaria/métodos , Humanos , Vasos Coronarios/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Algoritmos , Angiografía de Substracción Digital/métodosRESUMEN
Arsenic trioxide (ATO) has exhibited remarkable efficacy in treating acute promyelocytic leukemia (APL), primarily through promoting the degradation of the PML-RARα fusion protein. However, ATO alone fails to confer any survival benefit to non-APL acute myeloid leukemia (AML) patients and exhibits limited efficacy when used in combination with other agents. Here, we explored the general toxicity mechanisms of ATO in APL and potential drugs that could be combined with ATO to exhibit synergistic lethal effects on other AML. We demonstrated that PML-RARα degradation and ROS upregulation were insufficient to cause APL cell death. Based on the protein synthesis of different AML cells and their sensitivity to ATO, we established a correlation between ATO-induced cell death and protein synthesis. Our findings indicated that ATO induced cell death by damaging nascent polypeptides and causing ribosome stalling, accompanied by the activation of the ZAKα-JNK pathway. Furthermore, ATO-induced stress activated the GCN2-ATF4 pathway, and ribosome-associated quality control cleared damaged proteins with the assistance of p97. Importantly, our data revealed that inhibiting p97 enhanced the effectiveness of ATO in killing AML cells. These explorations paved the way for identifying optimal synthetic lethal drugs to enhance ATO treatment on non-APL AML.
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Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E-degraders are developed by linking two previously reported E-binding small molecules, GNF-2, and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E-degrader with ABL inhibitory activity while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof of concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class of direct-acting antiviral drugs.
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Human organic anion transporting polypeptide 1B3 (OATP1B3) and 1B1 are two liver-specific and highly homologous uptake transporters, whose structures consist of 12 transmembrane domains. The present study showed that OATP1B3 is more heavily N-glycosylated than OATP1B1 in extracellular loop 2 (EL2) and EL5. OATP1B3 has six N-glycosylation sites, namely N134, N145, N151, N445, N503, and N516, which is twice of that of OATP1B1. Single removal of individual N-glycans seems to have minimal influence on the surface expression and function of OATP1B3. However, simultaneous removal of all N-glycans will lead to OATP1B3's large retention in the endoplasmic reticulum and cellular degradation and thus significantly disrupts its surface expression. While N-glycosylation plays a crucial role in the surface expression of OATP1B3, it also has some effect on the transport function of OATP1B3 per se, which is not due to a decrease of substrate binding affinity but due to a reduced transporter's turnover number. Taken together, N-glycosylation is essential for normal surface expression and function of OATP1B3. Its disruption by some liver diseases such as NASH might alter the pharmacokinetic/pharmacodynamic properties of OATP1B3's substrate drugs.
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Transportador 1 de Anión Orgánico Específico del Hígado , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Glicosilación , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genética , Células HEK293RESUMEN
BACKGROUND: Evidence exists that maternal antenatal depression may have adverse impacts on perinatal outcomes. However, the results of those studies are inconsistent and mainly focus on maternal depressive symptoms in the second or third trimester. METHODS: This prospective cohort study used a sub-sample of participants from the Sino-Canadian Healthy Life Trajectories Initiative trial. The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for depressive symptoms in the first, second, and third trimesters, respectively. Infant growth indicator measurements were conducted in the first year of life. Logistic regression, Spearman correlation analyses and Generalized estimation equation (GEE) models were used to test the hypotheses. RESULTS: 2053 participants were recruited in this study, 326 of whom had at least one EPDS score ≥ 10 during pregnancy. A higher EPDS score in the first (aOR=1.053, 95â¯% CI: 1.004-1.103) or in the second trimester (aOR=1.060, 95â¯% CI: 1.007-1.115) was associated with greater risk of macrosomia. A higher EPDS score in the third trimester was associated with higher risks of preterm birth (aOR=1.079, 95â¯% CI: 1.006-1.157) and the infant being small for gestational age (aOR=1.097, 95â¯% CI: 1.015-1.185). GEE models showed that a greater EPDS score in the third trimester was associated with higher infant subscapular skinfold thickness (adjusted ß=0.026, 95â¯% CI: 0.003-0.050). CONCLUSION: Maternal depressive symptoms in different trimesters were differentially associated with infant weight and growth parameters at birth and postnatally. The present study further highlights the importance of depression screening in all trimesters of pregnancy, including the first trimester.
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Depresión , Complicaciones del Embarazo , Humanos , Femenino , Embarazo , China/epidemiología , Adulto , Estudios Prospectivos , Complicaciones del Embarazo/epidemiología , Recién Nacido , Depresión/epidemiología , Trimestres del Embarazo , Nacimiento Prematuro/epidemiología , Resultado del Embarazo/epidemiología , Macrosomía Fetal/epidemiología , Lactante , Recién Nacido Pequeño para la Edad GestacionalRESUMEN
Purpose To determine whether the unsupervised domain adaptation (UDA) method with generated images improves the performance of a supervised learning (SL) model for prostate cancer (PCa) detection using multisite biparametric (bp) MRI datasets. Materials and Methods This retrospective study included data from 5150 patients (14 191 samples) collected across nine different imaging centers. A novel UDA method using a unified generative model was developed for PCa detection using multisite bpMRI datasets. This method translates diffusion-weighted imaging (DWI) acquisitions, including apparent diffusion coefficient (ADC) and individual diffusion-weighted (DW) images acquired using various b values, to align with the style of images acquired using b values recommended by Prostate Imaging Reporting and Data System (PI-RADS) guidelines. The generated ADC and DW images replace the original images for PCa detection. An independent set of 1692 test cases (2393 samples) was used for evaluation. The area under the receiver operating characteristic curve (AUC) was used as the primary metric, and statistical analysis was performed via bootstrapping. Results For all test cases, the AUC values for baseline SL and UDA methods were 0.73 and 0.79 (P < .001), respectively, for PCa lesions with PI-RADS score of 3 or greater and 0.77 and 0.80 (P < .001) for lesions with PI-RADS scores of 4 or greater. In the 361 test cases under the most unfavorable image acquisition setting, the AUC values for baseline SL and UDA were 0.49 and 0.76 (P < .001) for lesions with PI-RADS scores of 3 or greater and 0.50 and 0.77 (P < .001) for lesions with PI-RADS scores of 4 or greater. Conclusion UDA with generated images improved the performance of SL methods in PCa lesion detection across multisite datasets with various b values, especially for images acquired with significant deviations from the PI-RADS-recommended DWI protocol (eg, with an extremely high b value). Keywords: Prostate Cancer Detection, Multisite, Unsupervised Domain Adaptation, Diffusion-weighted Imaging, b Value Supplemental material is available for this article. © RSNA, 2024.