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AIMS: This study aims to develop and validate an optimal model for predicting worsening heart failure (WHF). Multiple machine learning (ML) algorithms were compared, and the results were interpreted using SHapley Additive exPlanations (SHAP). A clinical risk calculation tool was subsequently developed based on these findings. METHODS AND RESULTS: This nested case-control study included 200 patients with chronic heart failure (CHF) from the China-Japan Friendship Hospital (September 2019 to December 2022). Sixty-five variables were collected, including basic information, physical and chemical examinations, and quality of life assessments. WHF occurrence within a 3-month follow-up was the outcome event. Variables were screened using LASSO regression, univariate analysis, and comparison of key variables in multiple ML models. Eighty per cent of the data was used for training and 20% for testing. The best models were identified by integrating nine ML algorithms and interpreted using SHAP, and to develop a final risk calculation tool. Among participants, 68 (34.0%) were female, with a mean age (standard deviation, SD) of 68.57 (12.80) years. During the follow-up, 60 participants (30%) developed WHF. N-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine (Cr), uric acid (UA), haemoglobin (Hb), and emotional area score on the Minnesota Heart Failure Quality of Life Questionnaire were critical predictors of WHF occurrence. The random forest (RF) model was the best model to predict WHF with an area under the curve (AUC) (95% confidence interval, CI) of 0.842 (0.675-1.000), accuracy of 0.775, sensitivity of 0.900, specificity of 0.833, negative predictive value of 0.800, and positive predictive value of 0.600 for the test set. SHAP analysis highlighted NT-proBNP, UA, and Cr as significant predictors. An online risk predictor based on the RF model was developed for personalized WHF risk assessment. CONCLUSIONS: This study identifies NT-proBNP, Cr, UA, Hb, and emotional area scores as crucial predictors of WHF in CHF patients. Among the nine ML algorithms assessed, the RF model showed the highest predictive accuracy. SHAP analysis further emphasized NT-proBNP, UA, and Cr as the most significant predictors. An online risk prediction tool based on the RF model was subsequently developed to enhance early and personalized WHF risk assessment in clinical settings.

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Patient-derived organoids (PDOs) have been proposed as a novel in vitro tumor model that can be applied to tumor research and drug screening. However, current tumor organoid models lack components of the tumor microenvironment, particularly tumor-associated macrophages(TAMs).We collected peripheral blood and tumor samples from 6 patients with extrahepatic cholangiocarcinoma(eCCA). Monocytes were induced into TAMs by cytokine and conditioned medium, and then co-cultured with tumor organoids. Our comprehensive analysis and comparison of histopathology and genomics results confirmed that this co-culture model can better capture intra- and inter-tumor heterogeneity retain the specific mutations of the original tumor. Drug sensitivity data in vitro revealed that gemcitabine and cisplatin are effective drugs for cholangiocarcinoma, but TAMs in the tumor microenvironment promote organoids growth and chemotherapy resistance. In conclusion, our organoid model of cholangiocarcinoma co-cultured with TAMs can not only shorten the model construction cycle, but also preserve the heterogeneity of original tumors to improve the accuracy of drug screening, and can also be applied to the researches of TAMs and tumors.

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Porcine reproductive and respiratory syndrome (PRRS) caused by porcine reproductive and respiratory syndrome virus (PRRSV) causes considerable economic losses to the global swine industry every year and seriously hinders the healthy development of this industry. Although tremendous efforts have been made over the past 30 years toward the development of prevention and control strategies against PRRSV infection, to date, treatments with proven efficacy have yet to be available due to our incomplete understanding of the molecular basis and complexity of the infection machinery. This review systematically discusses recent advances in the research and development of anti-PRRSV therapies targeting different stages of the viral life cycle. Furthermore, this review puts forward novel intervention targets and research approaches based on our in-depth exploration of virus-host interactions and the latest biological technologies, which have the potential to complement or transform current anti-PRRSV strategies and become breakthrough points for the control of PRRS in the future.

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Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.

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OBJECTIVE: To develop preoperative nomograms using risk factors based on clinicopathological and MRI for predicting the risk of positive surgical margin (PSM) after radical prostatectomy (RP). PATIENTS AND METHODS: This study retrospectively enrolled patients who underwent prostate MRI before RP at our center between January 2015 and November 2022. Preoperative clinicopathological factors and MRI-based features were recorded for analysis. The presence of PSM (overall PSM [oPSM]) at pathology and the multifocality of PSM (mPSM) were evaluated. LASSO regression was employed for variable selection. For the final model construction, logistic regression was applied combined with the bootstrap method for internal verification. The risk probability of individual patients was visualized using a nomogram. RESULTS: In all, 259 patients were included in this study, and 76 (29.3%) patients had PSM, including 40 patients with mPSM. Final multivariate logistic regression revealed that the independent risk factors for oPSM were tumor diameter, frank extraprostatic extension, and annual surgery volume (all p < 0.05), and the nomogram for oPSM reached an area under the curve (AUC) of 0.717 in development and 0.716 in internal verification. The independent risk factors for mPSM included the percentage of positive cores, tumor diameter, apex depth, and annual surgery volume (all p < 0.05), and the AUC of the nomogram for mPSM was 0.790 in both development and internal verification. The calibration curve analysis showed that these nomograms were well-calibrated for both oPSM and mPSM. CONCLUSIONS: The proposed nomograms showed good performance and were feasible in predicting oPSM and mPSM, which might facilitate more individualized management of prostate cancer patients who are candidates for surgery.

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Imagen por Resonancia Magnética , Márgenes de Escisión , Nomogramas , Prostatectomía , Neoplasias de la Próstata , Humanos , Masculino , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Imagen por Resonancia Magnética/métodos , Factores de Riesgo

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The indirect exchange interaction between local magnetic moments via surface electrons has been long predicted to bolster the surface ferromagnetism in magnetic topological insulators (MTIs), which facilitates the quantum anomalous Hall effect. This unconventional effect is critical to determining the operating temperatures of future topotronic devices. However, the experimental confirmation of this mechanism remains elusive, especially in intrinsic MTIs. Here, we combine time-resolved photoemission spectroscopy with time-resolved magneto-optical Kerr effect measurements to elucidate the unique electromagnetism at the surface of an intrinsic MTI MnBi2Te4. Theoretical modeling based on 2D Ruderman-Kittel-Kasuya-Yosida interactions captures the initial quenching of a surface-rooted exchange gap within a factor of two but overestimates the bulk demagnetization by one order of magnitude. This mechanism directly explains the sizable gap in the quasi-2D electronic state and the nonzero residual magnetization in even-layer MnBi2Te4. Furthermore, it leads to efficient light-induced demagnetization comparable to state-of-the-art magnetophotonic crystals, promising an effective manipulation of magnetism and topological orders for future topotronics.

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Achilles tendinopathy is a common musculoskeletal condition characterized by pain, lower muscle strength, gait abnormality, and reduced quality of life. There are two categories of Achilles tendinopathy: insertional Achilles tendinopathy and mid-portion Achilles tendinopathy. Currently, mechanical loading programs are considered the standard of care for the population with Achilles tendinopathy. Extracorporeal shockwave therapy (ESWT) is considered a secondary conservative treatment for tendinopathy as it is effective and safe. It can be used either as a monotherapy or as part of a multimodal treatment plan. ESWT has been extensively studied in orthopedics, where it was shown to intensify fracture healing and successfully treat overuse conditions of tendons and fascia. It is believed that shockwaves have both mechanical and cellular effects that ultimately result in the repair of damaged tendinous tissue and improved function of the Achilles tendon. However, there is a lack of consistency in the literature surrounding the effectiveness, especially the protocols. Therefore, we enrolled 36 patients with a diagnosis of Achilles tendinopathy, using radial ESWT (0.48 mJ/mm2, 2,000 shockwaves, 10 Hz, 1.6 bars, 2 sessions once a week). Freedom from pain was experienced by 16.7% of these participants, and there was a significant decrease in pain in all of them.

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Tendón Calcáneo , Tratamiento con Ondas de Choque Extracorpóreas , Tendinopatía , Tendinopatía/terapia , Tratamiento con Ondas de Choque Extracorpóreas/métodos , Humanos , Adulto , Masculino , Femenino , Persona de Mediana Edad

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The development of traditional Chinese medicine(TCM) preparations as an incubator for new drugs in medical institutions has flourished, while an evaluation index system remains to be established for comprehensively assessing the development value of these prescriptions. This study established an item pool through literature research, employed the Delphi method to determine the content of evaluation indexes, and adopted the superiority chart to determine the weight of each index. Two-level evaluation index system for the development value of TCM preparations in medical institutions was established, which included 7 first-level items and 36 se-cond-level items, demonstrating scientific validity. The first-level items(weight) were inheritance(10.61%), effectiveness(23.22%), safety(22.71%), innovation(13.21%), economy(10.00%), suitability(8.57%), and accessibility(11.68%). The top three second-level items in terms of weight distribution were adverse reaction monitoring(6.73%), evidence of therapeutic effect(5.71%), and clinical response rate(4.75%). The bottom three second-level items were production advantages(0.86%), medicinal dosage(0.48%), and medicinal smell or taste(0.18%). The content validity of the established system was assessed, which revealed that the index system was reliable, with the overall and average content validity indexes of 0.47 and 0.90, respectively. Furthermore, the established evaluation index system was used to evaluate six TCM preparations in a city-level hospital of TCM in Sichuan Province, which demonstrated that the system had operability. The results indicate that the evaluation index system is scientific, reliable, and operable, providing a reference for developers to selectively develop TCM preparations in medical institutions. In practical application, the system can be adjusted regarding the index weights according to actual conditions.

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Medicamentos Herbarios Chinos , Medicina Tradicional China , Medicina Tradicional China/normas , Medicamentos Herbarios Chinos/normas , Medicamentos Herbarios Chinos/análisis , Medicamentos Herbarios Chinos/química , Humanos

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The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has surged due to changes in economic and lifestyle patterns, leading to significant health challenges. Previous reports have studied the establishment of animal and cellular models for MASLD, highlighting differences between them. In this study, a cellular model was created by inducing fat accumulation in MASLD. HepG2 cells were stimulated with the unsaturated fatty acid oleic acid at various concentrations (0.125 mM, 0.25 mM, 0.5 mM, 1 mM) to emulate MASLD. The model's efficacy was assessed using cell counting kit-8 assays, Oil Red O staining, and lipid content analysis. This study aimed to create a simple-to-operate cellular model for MASLD cells. Results from the cell counting kit-8 assays showed that the survival of HepG2 cells was dependent on the concentration of oleic acid, with a GI50 of 1.875 mM. Cell viability in the 0.5 mM and 1 mM groups were significantly lower than those in the control group (P < 0.05). Furthermore, Oil Red O staining and lipid content analysis examined fat deposition at varying oleic acid concentrations (0.125 mM, 0.25 mM, 0.5 mM, 1 mM) on HepG2 cells. The lipid content of the 0.25 mM, 0.5 mM, and 1 mM groups was significantly higher than that of the control group (P < 0.05). Additionally, triglyceride levels in the OA groups were significantly higher than those in the control group (P < 0.05).

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Hígado Graso , Ácido Oléico , Humanos , Células Hep G2 , Ácido Oléico/farmacología , Hígado Graso/metabolismo , Hígado Graso/patología , Compuestos Azo , Metabolismo de los Lípidos/fisiología , Modelos Biológicos

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Spin-polarized light-emitting diodes (spin-LEDs) convert the electronic spin information to photon circular polarization, offering potential applications including spin amplification, optical communications, and advanced imaging. The conventional control of the emitted light's circular polarization requires a change in the external magnetic field, limiting the operation conditions of spin-LEDs. Here, we demonstrate an atomically thin spin-LED device based on a heterostructure of a monolayer WSe2 and a few-layer antiferromagnetic CrI3, separated by a thin hBN tunneling barrier. The CrI3 and hBN layers polarize the spin of the injected carriers into the WSe2. With the valley optical selection rule in the monolayer WSe2, the electroluminescence exhibits a high degree of circular polarization that follows the CrI3 magnetic states. Importantly, we show an efficient electrical tuning, including a sign reversal, of the electroluminescent circular polarization by applying an electrostatic field due to the electrical tunability of the few-layer CrI3 magnetization. Our results establish a platform to achieve on-demand operation of nanoscale spin-LED and electrical control of helicity for device applications.

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BACKGROUND: This meta-analysis seeks to assess the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. METHODS: Databases from PubMed, Embase, and the Cochrane Library were all thoroughly searched for pertinent research. Outcomes include complete response (CR), partial response (PR), stable disease (SD), disease progression (PD), overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and adverse events (AEs) were retrieved for further analysis. RESULTS: Ten trials with 721 patients were included in this meta-analysis. The pooled results for patients with cervical cancer receiving pembrolizumab were as follows: CR (0.06, 95%CI: 0.02-0.10), PR (0.15, 95%CI: 0.08-0.22), SD (0.16, 95%CI: 0.13-0.20), PD (0.50, 95%CI: 0.25-0.75), ORR (0.26, 95%CI: 0.11-0.41) and DCR (0.42, 95%CI: 0.13-0.71), respectively. Regarding survival analysis, the pooled mPFS and mOS were 3.81 and 10.15 months. Subgroup analysis showed that pembrolizumab in combination was more beneficial in CR (0.16 vs. 0.03, p = 0.012), PR (0.24 vs. 0.08, p = 0.032), SD (0.11 vs. 0.19, p = 0.043), ORR (0.42 vs. 0.11, p = 0.014), and mPFS (5.54 months vs. 2.27 months, p < 0.001) than as single agent. The three most common AEs were diarrhoea (0.25), anaemia (0.25), and nausea (0.21), and the incidence of grade 3-5 AEs was significantly lower, rarely surpassing 0.10. CONCLUSIONS: For patients with advanced or recurrent cervical cancer, this systematic review and meta-analysis demonstrated that pembrolizumab had a favourable efficacy and tolerability. Future research will primarily focus on optimising customised regiments that optimally integrate pembrolizumab into new therapies and combination strategies. Designed to maximise patient benefit and efficiently control adverse effects while maintaining a high standard of living.

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This study demonstrated the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. The study found that an upfront combination of chemotherapy and pembrolizumab immunotherapy appears to be a compelling strategy for these patients. More large-scale and multicentre randomised controlled trials will be required in the future to validate the precise benefits of pembrolizumab in new therapies and combination strategies for the treatment of cervical cancer.

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Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Recurrencia Local de Neoplasia , Neoplasias del Cuello Uterino , Humanos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/mortalidad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Femenino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Resultado del Tratamiento , Supervivencia sin Progresión , Persona de Mediana Edad

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In recent years, heavy metal pollution has become a global environmental problem and poses a great threat to the health of people and ecosystems. Therefore, strategies for the effective remediation of Cd from contaminated soil are urgently needed. In this study, ryegrass was utilized as a remediation plant, and its remediation potential was enhanced through the application of Citric Acid (CA) in conjunction with Bacillus megaterium (B. megaterium). The P3 treatment (CA + Bacillus megaterium) exhibited a significantly higher efficiency in promoting cadmium extraction by ryegrass, resulting in a 1.79-fold increase in shoot cadmium accumulation compared to the control group (CK) with no Bacillus megaterium or CA. Moreover, the P3 treatment led to an increased abundance of Actinobacteriota, Acidobacteriota, and Patescibacteria in the rhizosphere. The concentration of amino derivatives (such as betaine, sulfolithocholylglycine, N-alpha-acetyl-lysine, glycocholic acid, arginyl-threonine) showed significant upregulation following the P3 treatment. In summary, this study proposes a viable approach for phytoremediation of soil contaminated with cadmium by harnessing the mobilizing abilities of soil bacteria.

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Our aim was to gain a comprehensive understanding of the mechanisms involved in phytoremediation. These findings contribute to the existing knowledge by providing insights into the mechanism of phytoremediation in Cd-contaminated soil. They are expected to serve as a theoretical foundation for further elucidation of the phytoremediation mechanisms employed in Cd-contaminated soil.

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OBJECTIVES: Pseudohypoparathyroidism (PHP) comprises a cluster of heterogeneous diseases characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone (PTH) resistance. PHP type 1B (PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16. STX16 exon 2-6 deletion is commonly observed in autosomal dominant (AD)-PHP1B, while sporadic PHP1B commonly results from methylation abnormalities of maternal differentially methylated regions and remains unclear at the molecular level. CASE PRESENTATION: A 39-year-old male patient with PHP1B, who had his first seizure at 15 years of age, presented to our hospital. The methylation-specific multiplex ligation-dependent probe amplification results showed a half-reduced copy number of STX16 exon 5-7 and loss of methylation at GNAS exon A/B. His mother also had a half-reduced copy number of STX16 exon 5-7 but with normal methylation of GNAS. His father has a normal copy number of STX16 and normal methylation of GNAS. CONCLUSIONS: For the recognition and early diagnosis of this kind of disease, here we report the clinical symptoms, auxiliary examinations, genetic testing characteristics, and treatment of the patient.

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Exones , Seudohipoparatiroidismo , Sintaxina 16 , Humanos , Masculino , Seudohipoparatiroidismo/genética , Seudohipoparatiroidismo/complicaciones , Adulto , Sintaxina 16/genética , Exones/genética , Eliminación de Secuencia , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Pronóstico , Cromograninas/genética

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Rhei Radix et Rhizoma and Magnoliae Officinalis Cortex have been used together to treat constipation in the clinical practices for more than 2000 years. Nonetheless, their compatibility mechanism is still unclear. In this study, the amelioration of Rhei Radix et Rhizoma combined with Magnoliae Officinalis Cortex on constipation was systematically and comprehensively evaluated. The results showed that their compatibility could markedly shorten gastrointestinal transport time, increase fecal water content and frequency of defecation, improve gastrointestinal hormone disorders and protect colon tissue of constipation rats compared with the single drug. Furthermore, according to 16S rRNA sequencing in conjunction with UPLC-Q-TOF/MS, the combination of two herbal medications could greatly raise the number of salutary bacteria (Lachnospiraceae, Romboutsia and Subdoligranulum) while decreasing the abundance of pathogenic bacteria (Erysipelatoclostridiaceae). And two herb drugs could markedly improve the disorder of fecal metabolic profiles. A total of 7 different metabolites associated with constipation were remarkably shifted by the compatibility of two herbs, which were mainly related to arachidonic acid metabolism, alpha-linolenic acid metabolism, unsaturated fatty acid biosynthesis and other metabolic ways. Thus, the regulation of intestinal microbiome and its metabolism could be a potential target for Rhei Radix et Rhizoma and Magnoliae Officinalis Cortex herb pair to treat constipation. Furthermore, the multi-omics approach utilized in this study, which integrated the microbiome and metabolome, had potential for investigating the mechanism of traditional Chinese medicines.

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Estreñimiento , Medicamentos Herbarios Chinos , Heces , Microbioma Gastrointestinal , Magnolia , Ratas Sprague-Dawley , Rheum , Ratas , Animales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Magnolia/química , Microbioma Gastrointestinal/efectos de los fármacos , Estreñimiento/tratamiento farmacológico , Estreñimiento/metabolismo , Masculino , Rheum/química , Heces/microbiología , Heces/química , Cromatografía Líquida de Alta Presión , Metabolómica , Rizoma/química , Metaboloma/efectos de los fármacos , Multiómica

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Purpose: Long noncoding RNAs (lncRNAs) might be closely associated with hepatocellular carcinoma (HCC) progression and could serve as diagnostic and prognostic markers. This study aimed to investigate lncRNA-based diagnostic biomarkers for hepatitis B virus (HBV)-associated HCC. Materials and Methods: High-throughput transcriptome sequencing was conducted on the liver tissues of 15 patients with HBV-associated liver diseases (5 with chronic hepatitis B [CHB], 5 with liver cirrhosis [LC], and 5 with HCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze lncRNA expressions. Potential diagnostic performance for HBV-associated HCC screening was evaluated. Results: Through trend analysis and functional analysis, we found that 8 lncRNAs were gradually upregulated and 1 lncRNA was progressively downregulated by regulation of target mRNAs and downstream HCC-associated signaling pathways. The validation of dysregulated lncRNAs in peripheral blood mononuclear cells (PBMCs) and HCC tissues by qRT-PCR revealed that ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were significantly increased in HCC compared with CHB and cirrhosis. Moreover, differentially expressed lncRNAs were aberrantly elevated in Huh7, Hep3B, HepG2, and HepG2.215 cells compared with LX2 cells. Furthermore, ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were identified as novel biomarkers for HBV-associated HCC. For distinguishing HCC from CHB, ADAMTSL4-AS1, AC067931, and SOCS2-AS1 combined with alpha-fetoprotein (AFP) had an area under the curve (AUC) of 0.945 (sensitivity, 83.9%; specificity, 89.8%). Similarly, for distinguishing HCC from LC, this combination had an AUC of 0.871 (sensitivity, 91.1%; specificity, 68.2%). Furthermore, this combination showed the highest diagnostic ability to distinguish HCC from CHB and LC (AUC, 0.905; sensitivity, 91.1%; specificity, 75.3%). In particular, this combination identified AFP-negative (AFP < 20 ng/mL) (AUC = 0.814), small (AUC = 0.909), and early stage (AUC = 0.863) tumors. Conclusion: ADAMTSL4-AS1, SOCS2-AS1, and AC067931 combined with AFP in PBMCs may serve as a noninvasive diagnostic biomarker for HBV-associated HCC, especially AFP-negative, small, and early stage HCC.

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The discipline development is the pillar for the development of traditional Chinese medicine( TCM). The academic progress in TCM is the commanding height of the discipline development of TCM. To lead and promote the development and academic progress of TCM, the China Association of Chinese Medicine has summarized the Top Ten Academic Achievements in Traditional Chinese Medicine during 2020-2022, the Major Scientific Problems, Engineering Technical Problems, and Industrial Technical Problems in Traditional Chinese Medicine during 2019-2023, and the Remarkable Research Achievements of Traditional Chinese Medicine during 2012-2022. Based on the above research reports and the research achievements awarded the national science and technology prizes in TCM in the last 20 years and according to the current situation and layout of TCM discipline development, this paper reviews the major research achievements of TCM in the last two decades and the latest research progress in TCM during 2020-2023. The major scientific, engineering technical, and industrial technical problems in TCM are analyzed and the emerging trends of TCM are prospected in accordance with the development laws and characteristics of TCM. This review provides new ideas and reference for the high-quality development of TCM in the new era.

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Medicina Tradicional China , Medicina Tradicional China/tendencias , China , Humanos , Medicamentos Herbarios Chinos

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INTRODUCTION: To investigate the role of a novel type of protein kinase C delta (PKCδ) in the neuroinflammation of Alzheimer's disease (AD). METHODS: We analyzed PKCδ and inflammatory cytokines levels in cerebrospinal fluid (CSF) of AD and normal controls, as well as their correlations. The cellular expression pattern of PKCδ and the effects of PKCδ modulation on microglia-mediated neuroinflammation were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, RNA sequencing (RNA-seq), and immunofluorescence staining. RESULTS: PKCδ levels were increased dramatically in the CSF of AD patients and positively correlated with cytokines. PKCδ is expressed mainly in microglia in the brain. Amyloid beta (Aß) stimulation increased PKCδ expression and secretion, which led to upregulation of the nuclear factor kappa B (NF-κB) pathway and overproduction of proinflammatory cytokines. Downregulation or inhibition of PKCδ attenuated Aß-induced microglial responses and improved cognitive function in an AD mouse model. DISCUSSION: Our study identifies PKCδ as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD. HIGHLIGHTS: Protein kinase C delta (PKCδ) levels increase in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), and positively correlate with elevated inflammatory cytokines in human subjects. PKCδ is expressed mainly in microglia in vivo, whereas amyloid beta (Aß) stimulation increases PKCδ expression and secretion, causing upregulation of the nuclear factor kappa B (NF-κB) pathway and production of inflammatory cytokines. Downregulation or inhibition of PKCδ attenuates Aß-enhanced NF-κB signaling and cytokine production in microglia and improves cognitive function in AD mice. PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD.

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Enfermedad de Alzheimer , Biomarcadores , Citocinas , Microglía , Enfermedades Neuroinflamatorias , Proteína Quinasa C-delta , Proteína Quinasa C-delta/metabolismo , Microglía/metabolismo , Animales , Ratones , Humanos , Biomarcadores/líquido cefalorraquídeo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Masculino , Citocinas/metabolismo , Citocinas/líquido cefalorraquídeo , Modelos Animales de Enfermedad , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Femenino , Anciano , Ratones Transgénicos , FN-kappa B/metabolismo

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PURPOSE: To evaluate the performance of multi-pool Chemical exchange saturation transfer (CEST) MRI in prediction of glioma grade, isocitrate dehydrogenase (IDH) mutation, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss and Ki-67 labeling index (LI), based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5). METHODS: 95 patients with adult-type diffuse gliomas were analyzed. The amide, direct water saturation (DS), nuclear Overhauser enhancement (NOE), semi-solid magnetization transfer (MT) and amine signals were derived using Lorentzian fitting, and asymmetry-based amide proton transfer-weighted (APTwasym) signal was calculated. The mean value of tumor region was measured and intergroup differences were estimated using student-t test. The receiver operating curve (ROC) and area under the curve (AUC) analysis were used to evaluate the diagnostic performance of signals and their combinations. Spearman correlation analysis was performed to evaluate tumor proliferation. RESULTS: The amide and DS signals were significantly higher in high-grade gliomas compared to low-grade gliomas, as well as in IDH-wildtype gliomas compared to IDH-mutant gliomas (all p < 0.001). The DS, MT and amine signals showed significantly differences between ATRX loss and retention in grade 2/3 IDH-mutant gliomas (all p < 0.05). The combination of signals showed the highest AUC in prediction of grade (0.857), IDH mutation (0.814) and ATRX loss (0.769). Additionally, the amide and DS signals were positively correlated with Ki-67 LI (both p < 0.001). CONCLUSION: Multi-pool CEST MRI demonstrated good potential to predict glioma grade, IDH mutation, ATRX loss and Ki-67 LI.

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Neoplasias Encefálicas , Glioma , Isocitrato Deshidrogenasa , Imagen por Resonancia Magnética , Mutación , Clasificación del Tumor , Humanos , Glioma/genética , Glioma/diagnóstico por imagen , Glioma/metabolismo , Glioma/patología , Glioma/clasificación , Masculino , Femenino , Persona de Mediana Edad , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Imagen por Resonancia Magnética/métodos , Isocitrato Deshidrogenasa/genética , Anciano , Adulto Joven , Proliferación Celular , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Antígeno Ki-67/metabolismo

RESUMEN

BACKGROUND: Deuterium metabolic imaging (DMI) has emerged as a promising non-invasive technique for studying metabolism in vivo. This review aims to summarize the current developments and discuss the futures in DMI technique in vivo. METHODS: A systematic literature review was conducted based on the PRISMA 2020 statement by two authors. Specific technical details and potential applications of DMI in vivo were summarized, including strategies of deuterated metabolites detection, deuterium-labeled tracers and corresponding metabolic pathways in vivo, potential clinical applications, routes of tracer administration, quantitative evaluations of metabolisms, and spatial resolution. RESULTS: Of the 2,248 articles initially retrieved, 34 were finally included, highlighting 2 strategies for detecting deuterated metabolites: direct and indirect DMI. Various deuterated tracers (e.g., [6,6'-2H2]glucose, [2,2,2'-2H3]acetate) were utilized in DMI to detect and quantify different metabolic pathways such as glycolysis, tricarboxylic acid cycle, and fatty acid oxidation. The quantifications (e.g., lactate level, lactate/glutamine and glutamate ratio) hold promise for diagnosing malignancies and assessing early anti-tumor treatment responses. Tracers can be administered orally, intravenously, or intraperitoneally, either through bolus administration or continuous infusion. For metabolic quantification, both serial time point methods (including kinetic analysis and calculation of area under the curves) and single time point quantifications are viable. However, insufficient spatial resolution remains a major challenge in DMI (e.g., 3.3-mL spatial resolution with 10-min acquisition at 3 T). CONCLUSIONS: Enhancing spatial resolution can facilitate the clinical translation of DMI. Furthermore, optimizing tracer synthesis, administration protocols, and quantification methodologies will further enhance their clinical applicability. RELEVANCE STATEMENT: Deuterium metabolic imaging, a promising non-invasive technique, is systematically discussed in this review for its current progression, limitations, and future directions in studying in vivo energetic metabolism, displaying a relevant clinical potential. KEY POINTS: • Deuterium metabolic imaging (DMI) shows promise for studying in vivo energetic metabolism. • This review explores DMI's current state, limits, and future research directions comprehensively. • The clinical translation of DMI is mainly impeded by limitations in spatial resolution.

Asunto(s)

Deuterio , Humanos , Animales

RESUMEN

Many cancers display whole chromosome instability (W-CIN) and structural chromosomal instability (S-CIN), referring to increased rates of acquiring numerically and structurally abnormal chromosome changes. This protocol provides detailed steps to analyze the W-CIN and S-CIN across cancer types, intending to leverage large-scale bulk sequencing and SNP array data complemented with the computational models to gain a better understanding of W-CIN and S-CIN.

Asunto(s)

Inestabilidad Cromosómica , Neoplasias , Polimorfismo de Nucleótido Simple , Humanos , Neoplasias/genética , Aberraciones Cromosómicas , Biología Computacional/métodos