ABSTRACT
BACKGROUND/AIMS: At present, there are relatively few reports on the treatment consisting of transarterial chemoembolization (TACE) combined with lenvatinib, and there is no unified conclusion on the curative effect. The objective of this research was to assess the efficacy and safety of combining TACE with lenvatinib for the treatment of unresectable hepatocellular carcinoma (uHCC). MATERIALS AND METHODS: This study was a retrospective analysis of the patient's medical records. In this study, 249 patients (uHCC) in our hospital from 2020 to 2021 were divided into 2 groups, including the TACE-alone group (198 patients received TACE alone) and the TACE-LEN group (51 patients were treated with TACE combined with lenvatinib). According to the propensity score matching method, there were TACE-LEN group (51 patients) and TACE-alone group (51 patients). With the help of surgical experts, the overall survival (OS), progression-free survival (PFS), and tumor response (according to mRECIST) of the 2 groups were sorted and recorded, and then analyzed. Survival curves were established, the prognostic factors of OS and PFS were analyzed by univariate and multivariate analyses, and the independent prognostic factors were recorded. The adverse reactions of patients after treatment were recorded. RESULTS: The 1-year and 2-year OS rates were 50.98% and 19.48% for the TACE-LEN group, 27.45% and 8.55% for the TACE-alone group (P = .042), respectively. The PFS of patients in the TACE-LEN group was also longer (1-year PFS rate: 25.49% vs. 11.76%, 2-year PFS rate: 19.17% vs. 5.88%; P = .0069). The disease control rate (68.63% vs. 49.10%, P = .044) of the TACE-LEN group was significantly higher. In the subgroup analysis, the OS of the TACE-LEN group was better than TACE-alone group in patients with Barcelona Clinic Liver Cancer stage C (1-year OS rate: 44.44% vs. 17.14%, 2-year OS rate: 8.67% vs. 0%; P = .009). Factor analysis concluded that serum alkaline phosphatase and treatment protocol (TACE-LEN vs. TACE) were independent influencing factors of OS. The most common treatment-related AEs included decreased albumin (n = 28, 54.9%), hypertension (n = 23, 45.1%), elevated aspartate transaminase (n = 21, 41.2%) and elevated total bilirubin (n = 18, 35.2%) in TACE-LEN group. CONCLUSION: Compared with TACE monotherapy, TACE combined with lenvatinib effectively prolonged the OS time with a controllable safety profile for patients with uHCC.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Phenylurea Compounds , Quinolines , Humans , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/therapy , Liver Neoplasms/drug therapy , Chemoembolization, Therapeutic/methods , Retrospective Studies , Female , Male , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/therapeutic use , Middle Aged , Quinolines/administration & dosage , Quinolines/therapeutic use , Aged , Antineoplastic Agents/administration & dosage , Treatment Outcome , Combined Modality Therapy , Propensity ScoreABSTRACT
BACKGROUND CONTEXT: Prior studies have hypothesized that degenerative cervical spondylolisthesis (DCS) may be influenced by loss of stability due to disc, facet joint or cervical alignment. Meanwhile, it is commonly believed that the facet joints and paraspinal muscles participate in maintaining cervical spine stability. However, the impact of paraspinal muscle morphology and detailed facet joint features on DCS requires further investigation. PURPOSE: To compare facet joint characteristics, disc degeneration and muscle morphology between patients with DCS and those without DCS. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Consecutive surgical patients with degenerative cervical spondylosis from June 2016 to August 2023 were recruited. OUTCOME MEASURES: DCS was assessed on X-ray based on the translation distance. Cervical facet joint degeneration (CFD), the facet joint angle on the axial plane (FA-A) and the facet joint angle on the sagittal plane (FA-S), and facet joint tropism (FT) were measured on computerized tomography (CT). Paraspinal muscle degeneration was assessed on magnetic resonance imaging (MRI) including by the adjusted cross-sectional area (aCSA), the functional aCSA, the fat infiltration ratio (FI%). The Pfirrmann grade of the cervical disc was also evaluated. METHODS: Demographic and clinical data were compared in matched and unmatched cohorts. Disc degeneration, muscle degeneration and facet joint characteristics, including FA, FT and CFD, were compared between patients with and without DCS. Furthermore, the degree of CFD was compared with that of adjacent segments in both groups. Additionally, logistic regression was performed to determine independent risk factors for DCS. Finally, the receiver operating characteristic (ROC) curve, area under the curve (AUC) and cutoff value for the risk factors were calculated. RESULTS: A total of 431 surgical patients were propensity score matched for age, sex and BMI, and 146 patients were included in the final analysis, with 73 patients in the DCS group and 73 patients in the non-DCS group. DCS patients exhibited more severe CFD at C4/5 (segment with spondylolisthesis). Additionally, DCS was generally associated with more severe CFD, a more horizontal FA-S, more FT and worse paraspinal muscle health but similar disc degeneration. In addition, anterior spondylolisthesis was related to more severe CFD and decreased functional aCSA of the flexors and extensors. Finally, more severe CFD, a more horizontal FA-S and a higher FI% on deep extensor were revealed to be risk factors for DCS, with cutoff values of 1.5, 44.5Ì, and 37.1%, respectively. CONCLUSIONS: This study demonstrated that CFD, the FA and FT and parasipnal muscle degeneration were associated with DCS. And may provide novel insight into the pathogenesis and nature history of DCS and suggest the evolution of degeneration in the cervical spine.
ABSTRACT
Facial infiltrating lipomatosis (FIL) is a congenital disorder. The pathogenesis of FIL is associated with PIK3CA mutations, but the underlying mechanisms remain undetermined. We found that the adipose tissue in FIL demonstrated adipocytes hypertrophy and increased lipid accumulation. All adipose-derived mesenchymal stem cells from FIL (FIL-ADSCs) harbored PIK3CA mutations. Moreover, FIL-ADSCs exhibited a greater capacity for adipogenesis. Knockdown of PIK3CA resulted in a reduction in the adipogenic potential of FIL-ADSCs. Furthermore, WX390, a dual-target PI3K/mTOR inhibitor, was found to impede PIK3CA-mediated adipogenesis both in vivo and in vitro. RNA sequencing (RNA-seq) revealed that the expression of transient receptor potential vanilloid subtype 1 (TRPV1) was upregulated after PI3K pathway inhibition, and overexpression or activation of TRPV1 both inhibited adipogenesis. Our study showed that PIK3CA mutations promoted adipogenesis in FIL-ADSCs and this effect was achieved by suppressing TPRV1. Pathogenesis experiments suggested that WX390 may serve as an agent for the treatment of FIL.
ABSTRACT
Copper-mediated cell death presents distinct pathways from established apoptosis processes, suggesting alternative therapeutic approaches for colon cancer. Our research aims to develop a predictive framework utilizing long-noncoding RNAs (lncRNAs) related to cuproptosis to predict colon cancer outcomes while examining immune interactions and intercellular signaling. We obtained colon cancer-related human mRNA expression profiles and clinical information from the Cancer Genome Atlas repository. To isolate lncRNAs involved in cuproptosis, we applied Cox proportional hazards modeling alongside the least absolute shrinkage and selection operator technique. We elucidated the underlying mechanisms by examining the tumor mutational burden, the extent of immune cell penetration, and intercellular communication dynamics. Based on the model, drugs were predicted and validated with cytological experiments. A 13 lncRNA-cuproptosis-associated risk model was constructed. Two colon cancer cell lines were used to validate the predicted representative mRNAs with high correlation coefficients with copper-induced cell death. Survival enhancement in the low-risk cohort was evidenced by the trends in Kaplan-Meier survival estimates. Analysis of immune cell infiltration suggested that survival was induced by the increased infiltration of naïve CD4+ T cells and a reduction of M2 macrophages within the low-risk faction. Decreased infiltration of naïve B cells, resting NK cells, and M0 macrophages was significantly associated with better overall survival. Combined single-cell analysis suggested that CCL5-ACKR1, CCL2-ACKR1, and CCL5-CCR1 pathways play key roles in mediating intercellular dialogues among immune constituents within the neoplastic microhabitat. We identified three drugs with a high sensitivity in the high-risk group. In summary, this discovery establishes the possibility of using 13 cuproptosis-associated lncRNAs as a risk model to assess the prognosis, unravel the immune mechanisms and cell communication, and improve treatment options, which may provide a new idea for treating colon cancer.
ABSTRACT
OBJECTIVE: Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome. DESIGN: We recruited 358 patients with unruptured IA (UIA) and 161 with ruptured IA (RIA) from two distinct geographical regions for conducting an integrated analysis of plasma metabolomics and faecal metagenomics. Machine learning algorithms were employed to develop a classifier model, subsequently validated in an independent cohort. Mouse models of IA were established to verify the potential role of the specific metabolite identified. RESULTS: Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. A model harnessing gut-microbiome-derived tryptophan metabolites demonstrated remarkable efficacy in distinguishing RIA from UIA patients in the validation cohort (AUC=0.97). Gut microbiota depletion by antibiotics decreased plasma IS concentration, reduced IA formation and rupture in mice, and downregulated matrix metalloproteinase-9 expression in aneurysmal walls with elastin degradation reduction. Supplement of IS reversed the effect of gut microbiota depletion. CONCLUSION: Our investigation highlights the potential of gut-microbiome-derived tryptophan metabolites as biomarkers for distinguishing RIA from UIA patients. The findings suggest a novel pathogenic role for gut-microbiome-derived IS in elastin degradation in the IA wall leading to the rupture of IA.
ABSTRACT
Tumor-associated macrophages (TAMs) are one of the most plentiful immune compositions in the tumor microenvironment, which are further divided into anti-tumor M1 subtype and pro-tumor M2 subtype. Recent findings found that TAMs play a vital function in the regulation and progression of tumorigenesis. Moreover, TAMs promote tumor vascularization, and support the survival of tumor cells, causing an impact on tumor growth and patient prognosis. Numerous studies show that reducing the density of TAMs, or modulating the polarization of TAMs, can inhibit tumor growth, indicating that TAMs are a promising target for tumor immunotherapy. Recently, clinical trials have found that treatments targeting TAMs have achieved encouraging results, and the U.S. Food and Drug Administration has approved a number of drugs for use in cancer treatment. In this review, we summarize the origin, polarization, and function of TAMs, and emphasize the therapeutic strategies targeting TAMs in cancer treatment in clinical studies and scientific research, which demonstrate a broad prospect of TAMs-targeted therapies in tumor immunotherapy.
ABSTRACT
BACKGROUND: Krüppel-like factor 15 (KLF15) has been reported to be involved in ischemia injury of multiple types of diseases. Nevertheless, the roles and underlying mechanisms of KLF15 in preeclampsia (PE) are still unclear. METHODS: In this study, the expression of KLF15 in placenta tissues and hypoxia/reoxygenation (H/R)-induced HTR8/SVneo cells was evaluated by GSE66273 database, qRT-PCR and western blot assay. CCK-8 assay was employed to detect cell proliferation. Wound healing assay and transwell assay were used to detect cell migration and invasion. Cell oxidative stress was measured by DCFH-DA staining and kits. Cell apoptosis was evaluated by TUNEL assay and western blot assay. The JASPAR database was used to analyze the binding site of KLF15 and insulin-like growth factor-1 receptor (IGF1R) promoter region. The luciferase reporter assay was used to detect IGF1R promoter activity and ChIP assay was used to verify the combination of KLF15 and IGF1R promoter. Moreover, western blot was employed to measure the expressions of PI3K/Akt-related proteins. RESULTS: The data showed that the expression of KLF15 was significantly downregulated in GSE66273 database, tissues and HTR8/SVneo cells. KLF15 overexpression increased H/R-induced HTR8/SVneo cell proliferation, invasion and migration, and inhibited oxidative stress and cell apoptosis. In addition, IGF1R was highly expressed in H/R-induced HTR8/SVneo cells after KLF15 overexpression, and the binding of KLF15 and IGF1R promoter was verified. Silencing of IGF1R reversed the effects of KLF15 overexpression on H/R-induced HTR8/SVneo cell proliferation, migration, invasion, oxidative stress and cell apoptosis. Moreover, KLF15 overexpression and IGF1R silencing regulated the expressions of PI3K/Akt-related proteins in H/R-induced HTR8/SVneo cells. CONCLUSION: In conclusion, KLF15 overexpression promoted the proliferation and metastasis, and suppressed oxidative stress and cell apoptosis of H/R-induced HTR8/SVneo cells through mediating the PI3K/Akt pathway, which may provide a promising target for the treatment of preeclampsia.
ABSTRACT
Background: Vasopressors remain an important strategy for managing spinal anesthesia-induced hypotension in women with preeclampsia. The aim of this study was to investigate the ED90s and efficacy ratio of phenylephrine and norepinephrine in managing spinal anesthesia-induced hypotension in women with preeclampsia during cesarean delivery. Methods: 60 women with preeclampsia, who underwent cesarean delivery, were randomly assigned to receive either a continuous intravenous infusion of phenylephrine or norepinephrine following spinal anesthesia. The initial dosage of phenylephrine or norepinephrine for the first women was 0.5 or 0.05 µg/kg/min, respectively, and subsequent infusion dosages were adjusted based on their efficacy in preventing spinal anesthesia-induced hypotension (defined as a systolic blood pressure less than 80% of the baseline level). The incremental or decremental doses of phenylephrine or norepinephrine were set at 0.1 or 0.01 µg/kg/min. The primary outcomes were the ED90s and efficacy ratio of phenylephrine and norepinephrine infusions for preventing spinal anesthesia-induced hypotension prior to delivery. Results: The results obtained from isotonic regression analysis revealed that the ED90 values of the phenylephrine and norepinephrine group for preventing spinal anesthesia-induced hypotension were 0.597 (95% CI: 0.582-0.628) and 0.054 (95% CI: 0.053-0.056) µg/kg/min, respectively, with an efficacy ratio of 11.1:1. The results of Probit regression analysis revealed that the ED90 values were determined to be 0.665 (95% CI: 0.576-1.226) and 0.055 (95% CI: 0.047-0.109) µg/kg/min, respectively, with an efficacy ratio of 12.1:1. Conclusion: The administration of 0.6 µg/kg/min phenylephrine and 0.05 µg/kg/min norepinephrine has been found to effectively manage a 90% incidence of spinal anesthesia-induced hypotension in women with preeclampsia.
Subject(s)
Anesthesia, Spinal , Cesarean Section , Hypotension , Norepinephrine , Phenylephrine , Pre-Eclampsia , Humans , Female , Pregnancy , Phenylephrine/administration & dosage , Pre-Eclampsia/drug therapy , Anesthesia, Spinal/adverse effects , Hypotension/prevention & control , Hypotension/chemically induced , Norepinephrine/administration & dosage , Adult , Infusions, Intravenous , Dose-Response Relationship, Drug , Vasoconstrictor Agents/administration & dosage , Blood Pressure/drug effects , Young AdultABSTRACT
SIGNIFICANCE: Characterisation of tobacco product emissions is an important step in assessing their impact on public health. Accurate and repeatable emissions data require that a leak-tight seal be made between the smoking or vaping machine and the mouth-end of the tobacco product being tested. This requirement is challenging because of the variety of tobacco product mouth-end geometries being puffed on by consumers today. We developed and tested a prototype universal smoking machine adaptor (USMA) that interfaces with existing machines and reliably seals with a variety of tobacco product masses and geometries. METHODS: Emissions were machine-generated using the USMA and other available adaptors for a variety of electronic cigarettes (n=7 brands), cigars (n=4), cigarillos (n=2), a heated tobacco product, and a reference cigarette (1R6F), and mainstream total particulate matter (TPM) and nicotine were quantified. Data variability (precision, n≥10 replicates/brand) for all products and error (accuracy) from certified values (1R6F) were compared across adaptors. RESULTS: TPM and nicotine emissions generated using the USMA were accurate, precise and agreed with certified values for the 1R6F reference cigarette. Replicate data indicate that USMA repeatability across all tobacco products tested generally meets or exceeds that from the comparison adaptors and extant data. CONCLUSION: The USMA seals well with a variety of combustible tobacco products, e-cigarettes with differing geometries and plastic-tipped cigarillos. Variability for all measures was similar or smaller for the USMA compared with other adaptors.
ABSTRACT
SIGNIFICANCE: Historically, tobacco product emissions testing using smoking machines has largely focused on combustible products, such as cigarettes and cigars. However, the popularity of newer products, such as electronic cigarettes (e-cigarettes), has complicated emissions testing because the products' mouth-end geometries do not readily seal with existing smoking and vaping machines. The demand for emissions data on popularly used products has led to inefficient and non-standardised solutions, such as laboratories making their geometry-specific custom adaptors and/or employing flexible tubing, for each unique mouth-end geometry tested. A user-friendly, validated, universal smoking machine adaptor (USMA) is needed for testing the variety of tobacco products reflecting consumer use, including e-cigarettes, heated tobacco products, cigarettes, plastic-tipped cigarillos and cigars. METHODS: A prototype USMA that is compatible with existing smoking/vaping machines was designed and fabricated. The quality of the seal between the USMA and different tobacco products, including e-cigarettes, cigars and cigarillos, was evaluated by examining the leak rate. RESULTS: Unlike commercial, product-specific adaptors, the USMA seals well with a wide range of tobacco product mouth-end geometries and masses. This includes e-cigarettes with non-cylindrical mouth ends and cigarillos with cuboid-like plastic tips. USMA leak rates were lower than or equivalent to commercial, product-specific adaptors. CONCLUSION: This report provides initial evidence that the USMA seals reliably with a variety of tobacco product mouth-end geometries and can be used with existing linear smoking/vaping machines to potentially improve the precision, repeatability and reproducibility of machine smoke yield data. Accurate and reproducible emissions testing is critical for regulating tobacco products.
ABSTRACT
AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.
Subject(s)
Chlorogenic Acid , Diabetic Nephropathies , Fibrosis , Kidney , Lipid Metabolism , Receptor, Notch1 , STAT3 Transcription Factor , Signal Transduction , STAT3 Transcription Factor/metabolism , Receptor, Notch1/metabolism , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Animals , Signal Transduction/drug effects , Fibrosis/drug therapy , Chlorogenic Acid/pharmacology , Chlorogenic Acid/therapeutic use , Humans , Mice , Male , Kidney/pathology , Kidney/drug effects , Kidney/metabolism , Lipid Metabolism/drug effects , Molecular Docking Simulation , Mice, Inbred C57BL , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Cell LineABSTRACT
Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child-Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.
ABSTRACT
Early detection of rice blast disease is pivotal to ensure rice yield. We collected in situ images of rice blast and constructed a rice blast dataset based on variations in lesion shape, size, and color. Given that rice blast lesions are small and typically exhibit round, oval, and fusiform shapes, we proposed a small object detection model named GCPDFFNet (global context-based parallel differentiation feature fusion network) for rice blast recognition. The GCPDFFNet model has three global context feature extraction modules and two parallel differentiation feature fusion modules. The global context modules are employed to focus on the lesion areas; the parallel differentiation feature fusion modules are used to enhance the recognition effect of small-sized lesions. In addition, we proposed the SCYLLA normalized Wasserstein distance loss function, specifically designed to accelerate model convergence and improve the detection accuracy of rice blast disease. Comparative experiments were conducted on the rice blast dataset to evaluate the performance of the model. The proposed GCPDFFNet model outperformed the baseline network CenterNet, with a significant increase in mean average precision from 83.6 to 95.4% on the rice blast test set while maintaining a satisfactory frames per second drop from 147.9 to 122.1. Our results suggest that the GCPDFFNet model can accurately detect in situ rice blast disease while ensuring the inference speed meets the real-time requirements.
Subject(s)
Oryza , Plant Diseases , Image Processing, Computer-Assisted/methods , AlgorithmsABSTRACT
PURPOSE: Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. METHODS AND MATERIALS: Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. RESULTS: A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]). CONCLUSION: Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.
Subject(s)
Algorithms , Anthracyclines , Breast Neoplasms , Neoadjuvant Therapy , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Female , Anthracyclines/therapeutic use , Anthracyclines/administration & dosage , Neoadjuvant Therapy/methods , Middle Aged , China/epidemiology , Adult , Homologous Recombination , Mutation , Aged , DNA Copy Number Variations , BRCA1 Protein/geneticsABSTRACT
OBJECTIVE: This study focused on the metabolic characteristics of tongue coating in patients with intra-oral halitosis (IOH) to investigate potential diagnostic biomarkers for IOH. METHODS: Oral healthy participants were enrolled in this study. Halitosis was evaluated with an organoleptic assessment, a Halimeter®, and an OralChroma™. Tongue coating samples were collected from 18 halitosis patients and 18 healthy controls. Liquid chromatography-mass spectrometry was conducted to reveal the IOH-related metabolic variations in tongue coating. RESULTS: A total of 2214 metabolites were obtained. Most metabolites were shared between the two groups. A total of 274 upregulated metabolites, such as paramethasone acetate and indole-3-acetic acid, and 43 downregulated metabolites, including deoxyadenosine and valyl-arginine, were detected in the halitosis group. Functional analysis indicated that several metabolic pathways, including arginine biosynthesis, arginine and proline metabolism, histidine metabolism, and lysine degradation were significantly enriched in the IOH group. The least absolute shrinkage and selection operator logistic regression analysis revealed that paramethasone acetate, {1-[2-(4-carbamimidoyl-benzoylamino)-propionyl]-piperidin-4-yloxy}-acetic acid, indole-3-acetic acid, and valyl-arginine were remarkably associated with IOH. CONCLUSIONS: This study revealed the metabolites present in tongue coating and identified effective biomarkers, providing essential insights into the prediction, pathogenesis, and diagnosis of IOH.
ABSTRACT
The aim of the study is to create and validate a model of the relationship between specialization in leisure activities, the individual's adaptation to the environment and the heart flow experience. In order to clarify the role of the individual's adaptation to the environment in the relationship between specialization in leisure activities and the heart flow experience. The study utilized purposive sampling, cluster sampling, and random sampling. Using questionnaires and interviews to survey 525 cycling enthusiasts. Descriptive analysis, model construction and testing of the constructed path relationships were conducted using SPSS 20.0 and Amos 20.0. The results indicate that the model of the relationship between recovery specialization, individual-environment fit and heart flow experience has a good overall fit. The model shows good reliability and validity. Cyclists' recreational specialization has a statistically significant effect on individual-environment fit (ß = 0.38, P < 0.001). The fit between individual and environment has a statistically significant influence on the heart flow experience (ß = 0.39, P < 0.001). The fit between individual and environment serves as a mediating variable between recreational specialization and the heart flow experience, with the path showing statistical significance (ß = 0.15, P < 0.001). Recreational specialization has a statistically significant effect on the heart flow experience (ß = 0.30, P < 0.001). And the overall path of the effects of recreational specialization of cyclists on the fit between individual and environment is (ß = 0.45, P < 0.001), with the path showing statistical significance. Conclusion: The stronger the recreational specialization of cyclists and the greater the fit between individual and environment, the stronger their heart flow experience. The fit between individual and environment plays a partially mediating role.
ABSTRACT
BACKGROUND: Previous research has demonstrated that neuroinflammation is a key element in the progress of epilepsy. Nevertheless, it is currently unidentified which inflammatory factors and proteins increase or decrease the risk of epilepsy. METHODS: We adopted Mendelian randomization techniques to explore the causal relationship between circulating inflammatory factors and proteins and various epilepsy. Our principal approach was inverse variance weighting, supplemented by several sensitivity analyses to guarantee the robustness of our findings. RESULTS: Studies have identified associations between epilepsy and specific inflammatory factors and proteins: three inflammatory factors and six proteins are linked to epilepsy in general; one inflammatory factor and four proteins are associated with focal epilepsy with no documented lesions; two inflammatory factors and three proteins are related to focal epilepsy, excluding cases with hippocampal sclerosis; two inflammatory factors and two proteins are connected to juvenile myoclonic epilepsy; two inflammatory factors and five proteins are linked to juvenile absence epilepsy; four inflammatory proteins are associated with childhood absence epilepsy; two inflammatory factors are related to focal epilepsy overall; two inflammatory factors and two proteins are connected to generalized epilepsy; and two inflammatory proteins are linked to generalized epilepsy with tonic-clonic seizures. Additionally, six inflammatory factors may play a downstream role in focal epilepsy. CONCLUSION: Our study uncovers various inflammatory factors and proteins that influence the risk of epilepsy, offering instructive insights to the diagnosis and therapy of the condition.
Subject(s)
Cytokines , Epilepsy , Mendelian Randomization Analysis , Humans , Epilepsy/blood , Epilepsy/genetics , Cytokines/blood , Inflammation/bloodABSTRACT
ABSTRACT: Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.
Subject(s)
Aorta , Aortic Diseases , Atherosclerosis , Disease Models, Animal , Mice, Inbred C57BL , Mice, Knockout, ApoE , Plaque, Atherosclerotic , Proprotein Convertase 9 , Receptors, LDL , Sapogenins , Animals , Atherosclerosis/metabolism , Atherosclerosis/pathology , Atherosclerosis/drug therapy , Atherosclerosis/prevention & control , Atherosclerosis/genetics , Sapogenins/pharmacology , Proprotein Convertase 9/metabolism , Proprotein Convertase 9/genetics , Receptors, LDL/genetics , Receptors, LDL/metabolism , Humans , Male , Aortic Diseases/pathology , Aortic Diseases/prevention & control , Aortic Diseases/metabolism , Aortic Diseases/genetics , Aortic Diseases/drug therapy , Aorta/drug effects , Aorta/metabolism , Aorta/pathology , Proteolysis/drug effects , Hep G2 Cells , PCSK9 Inhibitors , Signal Transduction/drug effects , Sterol Regulatory Element Binding Protein 2/metabolism , Sterol Regulatory Element Binding Protein 2/genetics , Mice , Diet, High-Fat , Apolipoproteins EABSTRACT
Herpes simplex virus-1 (HSV-1) infection can cause various diseases and the current therapeutics have limited efficacy. Small interfering RNA (siRNA) therapeutics are a promising approach against infectious diseases by targeting the viral mRNAs directly. Recently, we employed a novel tRNA scaffold to produce recombinant siRNA agents with few natural posttranscriptional modifications. In this study, we aimed to develop a specific prodrug against HSV-1 infection based on siRNA therapeutics by bioengineering technology. We screened and found that UL8 of the HSV-1 genome was an ideal antiviral target based on RNAi. Next, we used a novel bio-engineering approach to manufacture recombinant UL8-siRNA (r/si-UL8) in Escherichia coli with high purity and activity. The r/si-UL8 was selectively processed to mature si-UL8 and significantly reduced the number of infectious virions in human cells. r/si-UL8 delivered by flexible nano-liposomes significantly decreased the viral load in the skin and improved the survival rate in the preventive mouse zosteriform model. Furthermore, r/si-UL8 also effectively inhibited HSV-1 infection in a 3D human epidermal skin model. Taken together, our results highlight that the novel siRNA bioengineering technology is a unique addition to the conventional approach for siRNA therapeutics and r/si-UL8 may be a promising prodrug for curing HSV-1 infection.