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1.
Front Immunol ; 15: 1362642, 2024.
Article in English | MEDLINE | ID: mdl-38745649

ABSTRACT

Hyperuricaemia (HUA) is a metabolic disorder characterised by high blood uric acid (UA) levels; moreover, HUA severity is closely related to the gut microbiota. HUA is also a risk factor for renal damage, diabetes, hypertension, and dyslipidaemia; however, current treatments are associated with detrimental side effects. Alternatively, Fangyukangsuan granules are a natural product with UA-reducing properties. To examine their efficacy in HUA, the binding of small molecules in Fangyukangsuan granules to xanthine oxidase (XOD), a key factor in UA metabolism, was investigated via molecular simulation, and the effects of oral Fangyukangsuan granule administration on serum biochemical indices and intestinal microorganisms in HUA-model rats were examined. Overall, 24 small molecules in Fangyukangsuan granules could bind to XOD. Serum UA, creatinine, blood urea nitrogen, and XOD levels were decreased in rats treated with Fangyukangsuan granules compared to those in untreated HUA-model rats. Moreover, Fangyukangsuan granules restored the intestinal microbial structure in HUA-model rats. Functional analysis of the gut microbiota revealed decreased amino acid biosynthesis and increased fermentation of pyruvate into short-chain fatty acids in Fangyukangsuan granule-treated rats. Together, these findings demonstrate that Fangyukangsuan granules have anti-hyperuricaemic and regulatory effects on the gut microbiota and may be a therapeutic candidate for HUA.


Subject(s)
Disease Models, Animal , Drugs, Chinese Herbal , Gastrointestinal Microbiome , Hyperuricemia , Uric Acid , Animals , Hyperuricemia/drug therapy , Hyperuricemia/metabolism , Gastrointestinal Microbiome/drug effects , Rats , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Male , Uric Acid/blood , Xanthine Oxidase/metabolism , Rats, Sprague-Dawley
2.
Org Lett ; 26(18): 3923-3928, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38662964

ABSTRACT

A novel visible-light-induced radical cascade bromocyclization of N-arylacrylamides has been accomplished. This reaction overcomes the overbromination at the benzene rings suffered in traditional electrophilic reactions, thus enabling the first highly chemoselective synthesis of valuable 3-bromomethyloxindoles. The combination of pyridine and anhydrous medium is identified as the key factor for the high chemoselectivity in the current photoreaction system, which might work by suppressing the in situ generation of low-concentration Br2 from N-bromosuccinimide. Moreover, the mild reaction conditions ensure the generation of a wide range of the new desired products with excellent functional group tolerance.

3.
Expert Rev Hematol ; 17(4-5): 173-180, 2024.
Article in English | MEDLINE | ID: mdl-38616308

ABSTRACT

BACKGROUND: Studies on dasatinib-based low-intensity induction regimens and post-remission strategies are limited in China. Therefore, we conducted a single-center phase 2 trial in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) to establish the efficacy and safety of this treatment approach. RESEARCH DESIGN AND METHODS: Patients received one month of dasatinib plus low-intensity chemotherapy and two months of dasatinib monotherapy for induction, followed by a single course of high-dose methotrexate for consolidation. Subsequently, they underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or tyrosine kinase inhibitor (TKI)-based treatment for maintenance therapy between October 2015 and August 2022. RESULTS: Twenty-two patients were enrolled. Median age was 45 years (range, 20-71). The rates of major and complete molecular responses in the third month were 18.2% and 40.9% respectively. With a median follow-up of 15 months (range, 5-89), the estimated 3-year disease-free survival (DFS) and overall survival (OS) were 52.4% and 73.2%, respectively. The TKI-based cohort had a significantly poorer DFS (p = 0.014) and OS (p = 0.008) than the allo-HSCT cohort. CONCLUSIONS: Our results suggest that dasatinib-based low-intensity chemotherapy is safe and effective as an induction strategy in the Chinese population. Allo-HSCT plays a crucial role in the long-term outcomes of patients with Ph+ ALL. CLINICAL TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov as NCT02690922.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Dasatinib , Hematopoietic Stem Cell Transplantation , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Dasatinib/therapeutic use , Dasatinib/administration & dosage , Adult , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Female , Male , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Young Adult , Treatment Outcome , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Methotrexate/therapeutic use , Methotrexate/administration & dosage
4.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 55(2): 455-460, 2024 Mar 20.
Article in Chinese | MEDLINE | ID: mdl-38645853

ABSTRACT

Objective: To construct a deep learning-based target detection method to help radiologists perform rapid diagnosis of lesions in the CT images of patients with novel coronavirus pneumonia (NCP) by restoring detailed information and mining local information. Methods: We present a deep learning approach that integrates detail upsampling and attention guidance. A linear upsampling algorithm based on bicubic interpolation algorithm was adopted to improve the restoration of detailed information within feature maps during the upsampling phase. Additionally, a visual attention mechanism based on vertical and horizontal spatial dimensions embedded in the feature extraction module to enhance the capability of the object detection algorithm to represent key information related to NCP lesions. Results: Experimental results on the NCP dataset showed that the detection method based on the detail upsampling algorithm improved the recall rate by 1.07% compared with the baseline model, with the AP50 reaching 85.14%. After embedding the attention mechanism in the feature extraction module, 86.13% AP50, 73.92% recall, and 90.37% accuracy were achieved, which were better than those of the popular object detection models. Conclusion: The feature information mining of CT images based on deep learning can further improve the lesion detection ability. The proposed approach helps radiologists rapidly identify NCP lesions on CT images and provides an important clinical basis for early intervention and high-intensity monitoring of NCP patients.


Subject(s)
Algorithms , COVID-19 , Deep Learning , Pneumonia, Viral , SARS-CoV-2 , Tomography, X-Ray Computed , Humans , COVID-19/diagnostic imaging , Tomography, X-Ray Computed/methods , Pneumonia, Viral/diagnostic imaging , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/diagnosis , Pandemics , Betacoronavirus
5.
Clin Cardiol ; 47(3): e24217, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38439605

ABSTRACT

BACKGROUND: Radiofrequency ablation has been applied for the treatment of hypertrophic obstructive cardiomyopathy (HOCM). The two known procedures are percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) and endocardial radiofrequency septal ablation (ERSA). METHODS: This study presents a retrospective analysis of the PIMSRA and ERSA procedures in patients with drug-refractory HOCM. A total of 28 patients participated in the study, with 12 receiving PIMSRA and 16 receiving ERSA. The objective of our study was to compare the short-term effects of these two radiofrequency ablation procedures. RESULTS: At the 30-day follow-up, the PIMSRA group demonstrated a greater reduction in left ventricular outflow tract peak gradient at rest compared to the ERSA group (22.25 [16.72] mmHg versus 47.75 [21.94] mmHg) (p < .01). The values for the PIMSRA group decreased from 99.33 (32.00) mmHg to 22.25 (16.72) mmHg (p < .01), while the ERSA group decreased from 97.75 (30.24) mmHg to 47.75 (21.94) mmHg (p < .01). Only the PIMSRA group exhibited a decrease in mitral regurgitation (MR). The area of MR decreased from 10.13 (4.12) mm2 to 3.65 (2.80) mm2 in the PIMSRA group (p < .01). Additionally, the PIMSRA group experienced reductions in left atrial diameter (LAD) and left ventricular ejection fraction (LVEF)%. The values for LAD changed from 43.58 (7.53) mm to 37.08 (6.92) mm (p = .03), and the values for LVEF% decreased from 65.75 (6.12) pg/mL to 60.83 (4.06) pg/mL (p = .03). CONCLUSION: In terms of the two types of radiofrequency ablation methods used in HOCM, it has been observed that PIMSRA demonstrates a more favorable early treatment effect compared to ERSA.


Subject(s)
Atrial Appendage , Cardiomyopathy, Hypertrophic , Mitral Valve Insufficiency , Radiofrequency Ablation , Humans , Retrospective Studies , Stroke Volume , Ventricular Function, Left , Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/surgery
6.
Brain Behav ; 14(3): e3469, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38494708

ABSTRACT

AIMS: Huntington's disease (HD) is a progressive neurodegenerative disorder with heterogeneous clinical manifestations. Identifying distinct clinical clusters and their relevant biomarkers could elucidate the underlying disease pathophysiology. METHODS: Following the Enroll-HD program initiated in 2018.09, we have recruited 104 HD patients (including 21 premanifest) and 31 health controls at Beijing Tiantan Hospital. Principal components analysis and k-means cluster analysis were performed to determine HD clusters. Chi-square test, one-way ANOVA, and covariance were used to identify features among these clusters. Furthermore, plasma cytokines levels and brain structural imaging were used as biomarkers to delineate the clinical features of each cluster. RESULTS: Three clusters were identified. Cluster 1 demonstrated the most severe motor and nonmotor symptoms except for chorea, the lowest whole brain volume, the plasma levels of IL-2 were higher and significantly associated with cluster 1. Cluster 2 was characterized with the most severe chorea and the largest pallidum volume. Cluster 3 had the most benign motor symptoms but moderate psychiatric problems. CONCLUSION: We have identified three HD clusters via clinical manifestations with distinct biomarkers. Our data shed light on better understanding about the pathophysiology of HD.


Subject(s)
Chorea , Huntington Disease , Humans , Huntington Disease/diagnostic imaging , Magnetic Resonance Imaging , Neuroimaging , Biomarkers
7.
Rev Sci Instrum ; 95(2)2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38345452

ABSTRACT

Numerous scientific satellites require micronewton thrusters for compensating environmental disturbances. The mass flow control proportional valve plays a crucial role in precisely regulating the thrust. To meet the high resolution and wide range requirements of the thrusters, this paper introduces a novel proportional valve with two sets of independently controllable piezoelectric stack. One set of the piezo-stack is used to compensate the stroke loss of the valve core, mainly caused by the deformation of the valve seat. The valve sealing mechanism is carefully analyzed to reduce the stroke loss. Another set of the stack works as the primary actuator, enabling the high mass flow control resolution. Two sets of independently controlled piezoelectric stacks not only expand the range and improve the range ratio but also provide redundancy and enhance reliability. This means that the actuator can still operate at lower ranges even if one piezo-stack is damaged. The piezo-actuators are assembled using U-shaped connectors, creating a compact and space-efficient overall design. Experimental tests have been conducted to verify the performance of the valve, which demonstrated a mass flow range of 0-675 µg/s with a resolution better than 0.1 µg/s and a flow noise below 0.1 µg/s/Hz1/2 at 0.1 mHz-1 Hz.

8.
Zhongguo Zhong Yao Za Zhi ; 49(1): 162-174, 2024 Jan.
Article in Chinese | MEDLINE | ID: mdl-38403349

ABSTRACT

This study aims to investigate whether tetramethylpyrazine(TMP) can stimulate angiogenesis in cerebral microvascular endothelial cells and alleviate cerebral ischemic stroke(CIS) and to explore the underlying mechanisms. In the animal study, adult Sprague-Dawley rats(n=15) were assigned into sham surgery(sham), middle cerebral artery occlusion/reperfusion(MCAO/R), and MCAO/R+TMP(intraperitoneal injection of 20 mg·kg~(-1)) groups. The neurological function was evaluated by the Z-Longa method. The cerebral infarction volume was detected by TTC staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the expression of vascular endothelial growth factor(VEGF), angiopoietin(Ang), and platelet-derived growth factor(PDGF). Immunofluorescence staining was employed to detect Ki67 and the expression of vascular endothelial growth factor A(VEGFA) and slient information regulator 1(SIRT1). Western blot was employed to determine the expression levels of VEGFA, SIRT1, angiopoietin-2(Ang-2), and platelet-derived growth factor B(PDGFB). In the cell study, mouse brain-derived endothelial cells(Bend.3) were cultured, and the optimal concentration of TMP was determined. Then, VEGF, Ang, and PDGF were detected by ELISA after the addition of cabozantinib. Western blot was employed to measure the expression of VEGFA, Ang-2, and PDGFB. Immunofluorescence staining was used to detect CD31, CD34, and Ki67, and the proliferation, migration, and tube formation ability of Bend.3 cells were observed in vitro. Western blot and immunofluorescence staining were performed to measure the expression of SIRT1 and VEGFA after addition of the SIRT1-specific inhibitor selisistat(EX-527). The results showed that compared with the sham group, the MCAO/R group had severe neurological function damage, increased infarction volume, up-regulated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, and PDGFB, and down-regulated expression of Ki67 and SIRT1(P<0.01). Compared with the MCAO/R group, the MCAO/R+TMP group presented alleviated neurological function damage, reduced infarction volume, and activated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, Ki67, and SIRT1(P<0.01). The cell experiments showed that compared with the normal group, Bend.3 cells were activated by oxygen glucose deprivation/reoxygenation(OGD/R) treatment(P<0.05, P<0.01). Compared with the OGD/R group, the OGD/R+TMP group upregulated the expression levels of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, SIRT1, Ki67, CD31, and CD34, enhanced the angiogenic ability of Bend.3 cells without being inhibited by BMS or EX-527(P<0.05, P<0.01, P<0.001). The results suggest that TMP can activate the SIRT1/VEGFA signaling pathway to stimulate angiogenesis and alleviate CIS injury.


Subject(s)
Brain Ischemia , Ischemic Stroke , Pyrazines , Stroke , Rats , Animals , Mice , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Endothelial Cells/metabolism , Brain Ischemia/drug therapy , Brain Ischemia/genetics , Brain Ischemia/metabolism , Rats, Sprague-Dawley , Proto-Oncogene Proteins c-sis , Sirtuin 1/genetics , Sirtuin 1/metabolism , Angiogenesis , Ki-67 Antigen/metabolism , Stroke/drug therapy , Stroke/genetics , Signal Transduction , Infarction, Middle Cerebral Artery
9.
Front Oncol ; 14: 1349315, 2024.
Article in English | MEDLINE | ID: mdl-38371618

ABSTRACT

Aiming at the problems of small sample size and large feature dimension in the identification of ipsilateral supraclavicular lymph node metastasis status in breast cancer using ultrasound radiomics, an optimized feature combination search algorithm is proposed to construct linear classification models with high interpretability. The genetic algorithm (GA) is used to search for feature combinations within the feature subspace using least absolute shrinkage and selection operator (LASSO) regression. The search is optimized by applying a high penalty to the L1 norm of LASSO to retain excellent features in the crossover operation of the GA. The experimental results show that the linear model constructed using this method outperforms those using the conventional LASSO regression and standard GA. Therefore, this method can be used to build linear models with higher classification performance and more robustness.

10.
Environ Sci Pollut Res Int ; 31(2): 2836-2850, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38063969

ABSTRACT

Carbon reduction has become a major challenge for China's economy in its transition toward sustainability. The government has been monitoring the behavior of enterprises through regulations to protect the environment, while green finance has rapidly developed in recent years as a new tool to reduce carbon emissions. Despite these measures, few studies have explored the interaction between these two drivers of carbon reduction. Therefore, this study aimed to examine the impact of green finance and environmental regulations on carbon emissions. To determine whether their coordination can lead to greater carbon reduction, the spatial spillover effect of this impact was also investigated. The results show that green finance can reduce carbon emissions and that the interaction of green finance with environmental regulations plays a significant positive role in reducing carbon emissions. Finally, this study concludes that the carbon reduction effects of green finance and environmental regulations have positive spillover effects on adjacent areas.


Subject(s)
Carbon , Government , China , Economic Development
11.
Cancer Immunol Immunother ; 72(12): 4441-4456, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37919522

ABSTRACT

BACKGROUND: Hypercholesterolemia is one of the risk factors for colorectal cancer (CRC). Cholesterol can participate in the regulation of human T cell function and affect the occurrence and development of CRC. OBJECTIVE: To elucidate the pathogenesis of CRC immune escape mediated by CD8+ T cell exhaustion induced by cholesterol. METHODS: CRC samples (n = 217) and healthy individuals (n = 98) were recruited to analyze the relationship between peripheral blood cholesterol levels and the clinical features of CRC. An animal model of CRC with hypercholesterolemia was established. Intraperitoneal intervention with endoplasmic reticulum stress (ERS) inhibitors in hypercholesterolemic CRC mice was performed. CD69, PD1, TIM-3, and CTLA-4 on CD8+ T cells of spleens from C57BL/6 J mice were detected by flow cytometry. CD8+ T cells were cocultured with MC38 cells (mouse colon cancer cell line). The proliferation, apoptosis, migration and invasive ability of MC38 cells were detected by CCK-8 assay, Annexin-V APC/7-AAD double staining, scratch assay and transwell assay, respectively. Transmission electron microscopy was used to observe the ER structure of CD8+ T cells. Western blotting was used to detect the expression of ERS and mitophagy-related proteins. Mitochondrial function and energy metabolism were measured. Immunoprecipitation was used to detect the interaction of endoplasmic reticulum-mitochondria contact site (ERMC) proteins. Immunofluorescence colocalization was used to detect the expression and intracellular localization of ERMC-related molecules. RESULTS: Peripheral blood cholesterol-related indices, including Tc, low density lipoproteins (LDL) and Apo(a), were all increased, and high density lipoprotein (HDL) was decreased in CRCs. The proliferation, migration and invasion abilities of MC38 cells were enhanced, and the proportion of tumor cell apoptosis was decreased in the high cholesterol group. The expression of IL-2 and TNF-α was decreased, while IFN-γ was increased in the high cholesterol group. It indicated high cholesterol could induce exhaustion of CD8+ T cells, leading to CRC immune escape. Hypercholesterolemia damaged the ER structure of CD8+ T cells and increased the expression of ER stress molecules (CHOP and GRP78), lead to CD8+ T cell exhaustion. The expression of mitophagy-related proteins (BNIP3, PINK and Parkin) in exhausted CD8+ T cells increased at high cholesterol levels, causing mitochondrial energy disturbance. High cholesterol enhanced the colocalization of Fis1/Bap31, MFN2/cox4/HSP90B1, VAPB/PTPIP51, VDAC1/IPR3/GRP75 in ERMCs, indicated that high cholesterol promoted the intermolecular interaction between ER and mitochondrial membranes in CD8+ T cells. CONCLUSION: High cholesterol regulated the ERS-ERMC-mitophagy axis to induce the exhaustion of CD8+ T cells in CRC.


Subject(s)
Colorectal Neoplasms , Hypercholesterolemia , Humans , Animals , Mice , Mitochondria Associated Membranes , CD8-Positive T-Lymphocytes/metabolism , Hypercholesterolemia/metabolism , T-Cell Exhaustion , Mice, Inbred C57BL , Cholesterol , Mitochondria/metabolism , Colorectal Neoplasms/pathology , Endoplasmic Reticulum Stress , Apoptosis , Protein Tyrosine Phosphatases/metabolism
12.
J Biol Chem ; 299(11): 105329, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37805139

ABSTRACT

Prion diseases are a group of transmissible neurodegenerative diseases primarily caused by the conformational conversion of prion protein (PrP) from α-helix-dominant cellular prion protein (PrPC) to ß-sheet-rich pathological aggregated form of PrPSc in many mammalian species. Dogs exhibit resistance to prion diseases, but the mechanism behind the phenomenon remains poorly understood. Compared with human PrP and mouse PrP, dog PrP has two unique amino acid residues, Arg177 and Asp159. Because PrPC contains a low-complexity and intrinsically disordered region in its N-terminal domain, it undergoes liquid-liquid phase separation (LLPS) in vitro and forms protein condensates. However, little is known about whether these two unique residues modulate the formation of PrPC condensates. Here, using confocal microscopy, fluorescence recovery after photobleaching assays, thioflavin T binding assays, and transmission electron microscopy, we report that Arg177 and Asp159 from the dog PrP slow the LLPS of full-length human PrPC, shifting the equilibrium phase boundary to higher protein concentrations and inhibit amyloid formation of the human protein. In sharp contrast, His177 and Asn159 from the human PrP enhance the LLPS of full-length dog PrPC, shifting the equilibrium phase boundary to lower protein concentrations, and promote fibril formation of the canid protein. Collectively, these results demonstrate how LLPS and amyloid formation of PrP are inhibited by a single residue Arg177 or Asp159 associated with prion disease resistance, and how LLPS and fibril formation of PrP are promoted by a single residue His177 or Asn159. Therefore, Arg177/His177 and Asp159/Asn159 are key residues in modulating PrPC liquid-phase condensation.


Subject(s)
Prion Diseases , Prions , Mice , Dogs , Humans , Animals , Prion Proteins/metabolism , Prions/metabolism , Amyloid/chemistry , Amyloidogenic Proteins , Mammals/metabolism
13.
Int Immunopharmacol ; 124(Pt A): 110791, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37619413

ABSTRACT

Multiple sclerosis (MS) is a central nervous system (CNS) disease with complicated etiology. Multifocal demyelination and invasion of inflammatory cells are its primary pathological features. Fasudil has been confirmed to improve experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, Fasudil is accompanied by several shortcomings in the clinical practice. Hydroxyfasudil is a metabolite of Fasudil in the body with better pharmaceutical properties. Therefore, we attempted to study the influence of Hydroxyfasudil upon EAE mice. The results demonstrated that Hydroxyfasudil relieved the symptoms of EAE and the associated pathological damage, reduced the adhesion molecules and chemokines, decreased the invasion of peripheral immune cells. Simultaneously, Hydroxyfasudil modified the rebalance of peripheral T cells. Moreover, Hydroxyfasudil shifted the M1 phenotype to M2 polarization, inhibited inflammatory signaling cascades as well as inflammatory factors, and promoted anti-inflammatory factors in the CNS. In the end, mice in the Hydroxyfasudil group expressed more tight junction proteins, indirectly indicating that the blood-brain barrier (BBB) was protected. Our results indicate that Hydroxyfasudil may be a prospective treatment for MS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Mice , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/therapeutic use , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Mice, Inbred C57BL
14.
Methods ; 218: 176-188, 2023 10.
Article in English | MEDLINE | ID: mdl-37586602

ABSTRACT

Drug-target interaction (DTI) prediction serves as the foundation of new drug findings and drug repositioning. For drugs/targets, the sequence data contains the biological structural information, while the heterogeneous network contains the biochemical functional information. These two types of information describe different aspects of drugs and targets. Due to the complexity of DTI machinery, it is necessary to learn the representation from multiple perspectives. We hereby try to design a way to leverage information from multi-source data to the maximum extent and find a strategy to fuse them. To address the above challenges, we propose a model, named MOVE (short for integrating multi-source information for predicting DTI via cross-view contrastive learning), for learning comprehensive representations of each drug and target from multi-source data. MOVE extracts information from the sequence view and the network view, then utilizes a fusion module with auxiliary contrastive learning to facilitate the fusion of representations. Experimental results on the benchmark dataset demonstrate that MOVE is effective in DTI prediction.


Subject(s)
Drug Development , Drug Repositioning , Computer Simulation , Drug Development/methods
15.
Front Oncol ; 13: 1195837, 2023.
Article in English | MEDLINE | ID: mdl-37496667

ABSTRACT

Synchronous multiple gastric carcinoma (SMGC) is a rare condition characterized by the simultaneous occurrence of two or more primary malignant tumors in the stomach, each with its own distinct pathological morphology. SMGC differs from gastric metastases, which originate from primary gastric or non-gastric tumors. At present, the incidence of SMGC is low in China, with no established guidelines for standard treatment. Here, we report a rare case of advanced SMGC that achieved long-lasting clinical benefits through a treatment strategy informed by next-generation sequencing (NGS). Dynamically monitoring of the tumor and/or circulating cell-free DNA guided the patient's treatment sequentially. The patient received anti-HER2 therapy, followed by immunotherapy, pembrolizumab in combination with trastuzumab and chemotherapy, and ultimately underwent successful total gastrectomy. This case highlights a novel approach of utilizing liquid biopsy-based NGS to gain insights into disease progression and molecular response to NGS-guided treatment in SMGC patients.

16.
Mol Ther Methods Clin Dev ; 29: 426-436, 2023 Jun 08.
Article in English | MEDLINE | ID: mdl-37273900

ABSTRACT

Transient transfection of mammalian cells using plasmid DNA is a standard method to produce adeno-associated virus (AAV) vectors allowing for flexible and scalable manufacture. Typically, three plasmids are used to encode the necessary components to facilitate vector production; however, a dual-plasmid system, termed pDG, was introduced over 2 decades ago demonstrating two components could be combined resulting in comparable productivity to triple transfection. We have developed a novel dual-plasmid system, pOXB, with an alternative arrangement of sequences that results in significantly increased AAV vector productivity and percentage of full capsids packaged in comparison to the pDG dual design and triple transfection. Here, we demonstrate the reproducibility of these findings across seven recombinant AAV genomes and multiple capsid serotypes as well as the scalability of the pOXB dual-plasmid transfection at 50-L bioreactor scale. Purified drug substance showed a consistent product quality profile in line with triple-transfected vectors, except for a substantial improvement in intact genomes packaged using the pOXB dual- transfection system. Furthermore, pOXB dual- and triple-transfection-based vectors performed consistently in vivo. The pOXB dual plasmid represents an innovation in AAV manufacturing resulting in significant process gains while maintaining the flexibility of a transient transfection platform.

17.
BMC Neurol ; 23(1): 240, 2023 Jun 21.
Article in English | MEDLINE | ID: mdl-37344817

ABSTRACT

BACKGROUND: Sandhoff disease (SD) is a rare neurological disease with high clinical heterogeneity. SD in juvenile form is much rarer and it is often misdiagnosed in clinics. Therein, it is necessary to provide more cases and review the literature on juvenile onset SD. CASE PRESENTATION: A 14 years-old boy with eight years of walking difficulties, and was ever misdiagnosed as spinocerebellar ataxia. We found this patient after genetic testing carried rs201580118 and a novel gross deletion in HEXB (g.74012742_74052694del). Through review the literature, we found that was the first gross deletion identified at the 3'end of HEXB, associated with juvenile onset SD from China. CONCLUSION: This case expanded our knowledge about the genotype and phenotype correlations in SD. Comprehensive genetic testing is important for the diagnosis of unexplained ataxia.


Subject(s)
Sandhoff Disease , Humans , Sandhoff Disease/diagnosis , Sandhoff Disease/genetics , beta-Hexosaminidase beta Chain/genetics , Genetic Testing , Genotype , Phenotype , Mutation
18.
Clin. transl. oncol. (Print) ; 25(6): 1661-1672, jun. 2023. ilus, graf
Article in English | IBECS | ID: ibc-221198

ABSTRACT

Background Lymph node metastasis is the main metastatic mode of CRC. Lymph node metastasis affects patient prognosis. Objective To screen differential intestinal bacteria for CRC lymph node metastasis and construct a prediction model. Methods First, fecal samples of 119 CRC patients with lymph node metastasis and 110 CRC patients without lymph node metastasis were included for the detection of intestinal bacterial 16S rRNA. Then, bioinformatics analysis of the sequencing data was performed. Community structure and composition analysis, difference analysis, and intragroup and intergroup correlation analysis were conducted between the two groups. Finally, six machine learning models were used to construct a prediction model for CRC lymph node metastasis. Results The community richness and the community diversity at the genus level of the two groups were basically consistent. A total of 12 differential bacteria (Agathobacter, Catenibacterium, norank_f__Oscillospiraceae, Lachnospiraceae_FCS020_group, Lachnospiraceae_UCG-004, etc.) were screened at the genus level. Differential bacteria, such as Agathobacter, Catenibacterium, norank_f__Oscillospiraceae, and Lachnospiraceae_FCS020_group, were more associated with no lymph node metastasis in CRC. In the discovery set, the RF model had the highest prediction accuracy (AUC = 1.00, 98.89% correct, specificity = 55.21%, sensitivity = 55.95%). In the test set, SVM model had the highest prediction accuracy (AUC = 0.73, 72.92% correct, specificity = 69.23%, sensitivity = 88.89%). Lachnospiraceae_FCS020_group was the most important variable in the RF model. Lachnospiraceae_UCG − 004 was the most important variable in the SVM model. Conclusion CRC lymph node metastasis is closely related to intestinal bacteria. The prediction model based on intestinal bacteria can provide a new evaluation method for CRC lymph node metastasis (AU)


Subject(s)
Humans , Colorectal Neoplasms/pathology , Lymphatic Metastasis , RNA, Ribosomal, 16S/metabolism , Gastrointestinal Microbiome , Lymph Nodes/pathology , Prognosis
19.
Front Neurosci ; 17: 1180679, 2023.
Article in English | MEDLINE | ID: mdl-37255750

ABSTRACT

Background: Hippocampal sclerosis (HS) is the most common pathological type of temporal lobe epilepsy (TLE) and one of the important surgical markers. Currently, HS is mainly diagnosed manually by radiologists based on visual inspection of MRI, which greatly relies on MRI quality and physician experience. In clinical practice, non-thin MRI scans are often used due to the time and efficiency needed for the acquisition. However, these scans can be difficult for junior physicians to interpret accurately. Thus, the rapid and accurate diagnosis of HS using real-world MRI images in clinical settings is a challenging task. Objective: Our aim was to explore the feasibility of using computer vision methods to diagnose HS on real-world clinical MRI images and to provide a reference for future clinical applications of artificial intelligence methods to aid in detecting HS. Methods: We proposed a deep learning algorithm called "HS-Net" to discriminate HS using real-world clinical MRI images. First, we delineated and segmented a region of interest (ROI) around the hippocampus. Then, we utilized the fractional differential (FD) method to enhance the textures of the ROIs. Finally, we used a small-sample image classification method based on transfer learning to fine-tune the feature extraction part of a pretrained model and added two fully connected layers and an output layer. In the study, 96 TLE patients with HS confirmed by postoperative pathology and 89 healthy controls were retrospectively enrolled. All subjects were cross-validated, and models were evaluated for performance, robustness, and clinical utility. Results: The HS-Net model achieved an area under the curve (AUC) of 0.894, an accuracy of 82.88%, an F1-score of 84.08% in the test cohort based on real, routine, clinical T2-weighted fluid attenuated inversion recovery (FLAIR) sequence MRI images. Additionally, the AUC, accuracy and F1 scores of our model all increased by around 3 percentage points when the inputs were augmented with the ROIs of the textures enhanced using the FD method. Conclusions: Our computational model has the potential to be used for the diagnosis of HS in real clinical MRI images, which could assist physicians, particularly junior physicians, in improving the accuracy of discrimination.

20.
Ying Yong Sheng Tai Xue Bao ; 34(5): 1272-1280, 2023 May.
Article in English | MEDLINE | ID: mdl-37236944

ABSTRACT

Datura stramonium, as a major invasive plant in Liaoning Province, is difficult to be removed after its successful invasion, and is a great threat to ecological environment and biodiversity. To evaluate the habitat suitabi-lity of D. stramonium, we collected its geographic distribution data in Liaoning Province through field investigation and database query, and using the Biomod2 combination model, and investigated its potential and suitable distribution areas and main influencing environmental variables at present and under future climate change scenarios, respectively. The results showed that the combined model which composed of GLM (generalized linear model), GBM (generalized boosting regression model), RF (random forest model), and MaxEnt (maximum entropy model) had a good performance. By classifying the habitat suitability of D. stramonium into four categories: high-, medium-, low- and un-suitable habitats, we found that the high-suitable habitats were generally distributed in the northwest and south of Liaoning Province, with an area of about 3.81×104 km2, accounting for 25.8% of the total area. The medium-suitable habitats were mostly distributed in the northwest and central parts of Liaoning Province, with an area of about 4.19×104 km2, accounting for 28.3% of the total area. Slope and clay content of topsoil (0-30 cm) were the two main variables explaining the habitat suitability of D. stramonium, and the total suitability of D. stramonium first increased and then decreased with the increasing slope and clay content of topsoil in this region. Under future climate change scenarios, the total suitability of D. stramonium showed an expanding trend, and its suitability would be obviously increased in Jinzhou, Panjin, Huludao, and Dandong.


Subject(s)
Datura stramonium , Introduced Species , Clay , Ecosystem , Biodiversity , Climate Change
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