ABSTRACT
Hepatitis B virus (HBV) chronically infects approximately 300 million people worldwide, and permanently repressing transcription of covalently closed circular DNA (cccDNA), the episomal viral DNA reservoir, is an attractive approach toward curing HBV. However, the mechanism underlying cccDNA transcription is only partially understood. In this study, by illuminating cccDNA of wild-type HBV (HBV-WT) and transcriptionally inactive HBV that bears a deficient HBV X gene (HBV-ΔX), we found that the HBV-ΔX cccDNA more frequently colocalizes with promyelocytic leukemia (PML) bodies than that of HBV-WT cccDNA. A small interfering RNA (siRNA) screen targeting 91 PML body-related proteins identified SMC5-SMC6 localization factor 2 (SLF2) as a host restriction factor of cccDNA transcription, and subsequent studies showed that SLF2 mediates HBV cccDNA entrapment in PML bodies by interacting with the SMC5/6 complex. We further showed that the region of SLF2 comprising residues 590 to 710 interacts with and recruits the SMC5/6 complex to PML bodies, and the C-terminal domain of SLF2 containing this region is necessary for repression of cccDNA transcription. Our findings shed new light on cellular mechanisms that inhibit HBV infection and lend further support for targeting the HBx pathway to repress HBV activity. IMPORTANCE Chronic HBV infection remains a major public health problem worldwide. Current antiviral treatments rarely cure the infection, as they cannot clear the viral reservoir, cccDNA, in the nucleus. Therefore, permanently silencing HBV cccDNA transcription represents a promising approach for a cure of HBV infection. Our study provides new insights into the cellular mechanisms that restrict HBV infection, revealing the role of SLF2 in directing HBV cccDNA to PML bodies for transcriptional repression. These findings have important implications for the development of antiviral therapies against HBV.
Subject(s)
Hepatitis B , Leukemia , Humans , Hepatitis B virus/genetics , Hepatitis B virus/metabolism , DNA, Circular/genetics , DNA, Circular/metabolism , Antiviral Agents/pharmacology , DNA, Viral/genetics , DNA, Viral/metabolism , Promyelocytic Leukemia Protein/genetics , Promyelocytic Leukemia Protein/metabolism , Virus Replication/genetics , Chromosomal Proteins, Non-Histone/metabolism , Cell Cycle Proteins/metabolismABSTRACT
Dental caries, as a biofilm-related disease, is closely linked to dysbiosis in microbial ecology within dental biofilms. Beyond its impact on oral health, bacteria within the oral cavity pose systemic health risks by potentially entering the bloodstream, thereby increasing susceptibility to bacterial endocarditis, among other related diseases. Streptococcus mutans, a principal cariogenic bacterium, possesses virulence factors crucial to the pathogenesis of dental caries. Its ability to adhere to tooth surfaces, produce glucans for biofilm formation, and metabolize sugars into lactic acid contributes to enamel demineralization and the initiation of carious lesions. Its aciduricity and ability to produce bacteriocins enable a competitive advantage, allowing it to thrive in acidic environments and dominate in changing oral microenvironments. In contrast, commensal streptococci, such as Streptococcus sanguinis, Streptococcus gordonii, and Streptococcus salivarius, act as primary colonizers and compete with S. mutans for adherence sites and nutrients during biofilm formation. This competition involves the production of alkali, peroxides, and antibacterial substances, thereby inhibiting S. mutans growth and maintaining microbial balance. This dynamic interaction influences the balance of oral microbiota, with disruptions leading to shifts in microbial composition that are marked by rapid increases in S. mutans abundance, contributing to the onset of dental caries. Thus, understanding the dynamic interactions between commensal and pathogenic bacteria in oral microecology is important for developing effective strategies to promote oral health and prevent dental caries. This review highlights the roles and competitive interactions of commensal bacteria and S. mutans in oral microecology, emphasizing the importance of maintaining oral microbial balance for health, and discusses the pathological implications of perturbations in this balance.
ABSTRACT
Cytochrome P450 3A4 (CYP3A4) is involved in first-pass metabolism in the small intestine and is heavily implicated in oral drug bioavailability and pharmacokinetics. We previously reported that vitamin D3 (VD3), a known CYP enzyme inducer, induces functional maturation of iPSC-derived enterocyte-like cells (iPSC-ent). Here, we identified a Notch activator and CYP modulator valproic acid (VPA), as a promotor for the maturation of iPSC-ent. We performed bulk RNA sequencing to investigate the changes in gene expression during the differentiation and maturation periods of these cells. VPA potentiated gene expression of key enterocyte markers ALPI, FABP2, and transporters such as SULT1B1. RNA-sequencing analysis further elucidated several function-related pathways involved in fatty acid metabolism, significantly upregulated by VPA when combined with VD3. Particularly, VPA treatment in tandem with VD3 significantly upregulated key regulators of enterohepatic circulation, such as FGF19, apical bile acid transporter SLCO1A2 and basolateral bile acid transporters SLC51A and SLC51B. To sum up, we could ascertain the genetic profile of our iPSC-ent cells to be specialized toward fatty acid absorption and metabolism instead of transporting other nutrients, such as amino acids, with the addition of VD3 and VPA in tandem. Together, these results suggest the possible application of VPA-treated iPSC-ent for modelling enterohepatic circulation.
Subject(s)
Induced Pluripotent Stem Cells , Valproic Acid , Humans , Valproic Acid/pharmacology , Valproic Acid/metabolism , Cholecalciferol/pharmacology , Cholecalciferol/metabolism , Induced Pluripotent Stem Cells/metabolism , Enterocytes/metabolism , Cells, CulturedABSTRACT
BACKGROUND: Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system, and childhood AML accounts for about 20% of pediatric leukemia. ANP32B, an important nuclear protein associated with proliferation, has been found to regulate hematopoiesis and CML leukemogenesis by inhibiting p53 activity. However, recent study suggests that ANP32B exerts a suppressive effect on B-cell acute lymphoblastic leukemia (ALL) in mice by activating PU.1. Nevertheless, the precise underlying mechanism of ANP32B in AML remains elusive. RESULTS: Super enhancer related gene ANP32B was significantly upregulated in AML patients. The expression of ANP32B exhibited a negative correlation with overall survival. Knocking down ANP32B suppressed the proliferation of AML cell lines MV4-11 and Kasumi-1, along with downregulation of C-MYC expression. Additionally, it led to a significant decrease in H3K27ac levels in AML cell lines. In vivo experiments further demonstrated that ANP32B knockdown effectively inhibited tumor growth. CONCLUSIONS: ANP32B plays a significant role in promoting tumor proliferation in AML. The downregulation of ANP32B induces cell cycle arrest and promotes apoptosis in AML cell lines. Mechanistic analysis suggests that ANP32B may epigenetically regulate the expression of MYC through histone H3K27 acetylation. ANP32B could serve as a prognostic biomarker and potential therapeutic target for AML patients.
ABSTRACT
Interest in macropinocytosis has risen in recent years owing to its function in tumorigenesis, immune reaction, and viral infection. Cancer cells utilize macropinocytosis to acquire nutrients to support their uncontrolled proliferation and energy consumption. Macropinocytosis, a highly dynamic endocytic and vesicular process, is regulated by a series of cellular signaling pathways. The activation of small GTPases in conjunction with phosphoinositide signaling pivotally regulates the process of macropinocytosis. In this review, we summarize important findings about the regulation of macropinocytosis and provide information to increase our understanding of the regulatory mechanism underlying it.
Subject(s)
Pinocytosis , Signal Transduction , Humans , Animals , Phosphatidylinositols/metabolism , Neoplasms/metabolism , Neoplasms/pathologyABSTRACT
The metabolites in the plasma serve as potential biomarkers of disease. We previously established an early-onset diabetes mouse model, Ins2+/Q104del Kuma mice, under a severe immune-deficient (Rag-2/Jak3 double-deficient in BALB/c) background. Here, we revealed the differences in plasma amino acid profiles between Kuma and the wild-type mice. We observed an early reduction in glucogenic and ketogenic amino acids, a late increase in branched-chain amino acids (BCAAs) and succinyl CoA-related amino acids, and a trend of increasing ketogenic amino acids in Kuma mice than in the wild-type mice. Kuma mice exhibited hyperglucagonemia at high blood glucose, leading to perturbations in plasma amino acid profiles. The reversal of blood glucose by islet transplantation normalized the increases of the BCAAs and several aspects of the altered metabolic profiles in Kuma mice. Our results indicate that the Kuma mice are a unique animal model to study the link between plasma amino acid profile and the progression of diabetes for monitoring the therapeutic effects.
Subject(s)
Diabetes Mellitus, Type 2 , Hyperglycemia , Mice , Animals , Blood Glucose/metabolism , Insulin/metabolism , Diabetes Mellitus, Type 2/metabolism , Amino Acids , Amino Acids, Branched-Chain/metabolismABSTRACT
A diabetic foot ulcer is a common high-risk complication in diabetic patients, but there is still no universal dressing for clinical treatment. In this study, a novel dual-functional sulfated galactofucan polysaccharide/poly(vinyl alcohol) hydrogel (DPH20) is developed during freeze-thaw cycles. Experimental results indicated that DPH20 had a high specific surface area, a dense porous structure, and a good swelling property, which could effectively adsorb the exudates and keep the wound moist. Furthermore, DPH20 exhibited remarkably recruited macrophage capability and accelerated the inflammation stage by improving the expression of the mRNA of CCL2, CCR2, and CCL22 in macrophages. DPH20 could promote cell migration and growth factor release to accelerate tube formation under hyperglycemic conditions in cell models of L929s and HUEVCs, respectively. Significantly, DPH20 accelerates the reconstruction of the full-thickness skin wound by accelerating the recruitment of macrophages, promoting angiogenesis, and releasing the growth factor in the diabetic mouse model. Collectively, DPH20 is a promising multifunctional dressing to reshape the damaged tissue environment and accelerate wound healing. This study provides an efficient strategy to repair and regenerate diabetic skin ulcers.
Subject(s)
Diabetes Mellitus , Hydrogels , Mice , Animals , Humans , Hydrogels/pharmacology , Hydrogels/chemistry , Wound Healing , Polyvinyl Alcohol/pharmacology , Polyvinyl Alcohol/chemistry , Macrophages , Intercellular Signaling Peptides and ProteinsABSTRACT
Lycopene is a promising biological functional component with various biological activities and excellent pharmacological activities. However, its low water solubility and stability lead to low oral bioavailability, which limits its edible and medicinal research. Then, it is necessary to explore effective methods to protect lycopene from destruction and further exploit its potential benefits. The absorption of lycopene in vivo is affected by solubility, stability, isomer type, emulsifying ability, difficulty in forming micelles in vivo, and interaction with food components. Emulsions, pickering emulsions, micelles, liposomes, bigels, beasds, solid dispersions, microcapsules, nanoparticles, electrospinning and other drug delivery systems can be used as good strategies to improve the stability and bioavailability of lycopene. In this paper, the absorption process of lycopene in vivo and the factors affecting its bioavailability were discussed, and the preparation strategies for improving the stability, bioavailability, and health benefits of lycopene were reviewed, to provide some clues and references for the full utilization of lycopene in the field of health. However, there are still various unresolved mysteries regarding the metabolism of lycopene. The safety and in vivo studies of various preparations should be further explored, and the above technologies also face the challenge of industrial production.
ABSTRACT
With the recent endorsement of PrEP by the Chinese government, research is urgently needed to better understand factors impacting PrEP uptake among gay, bisexual, and other men who have sex with men (GBMSM) in China. This study examined willingness to use PrEP for HIV prevention among GBMSM in China through structural equation modeling. We examined the relationship among PrEP-related attitudes, subjective norms, PrEP-related knowledge and beliefs about medicines and willingness to use PrEP. The analysis showed a good fit between the data and both the measurement model (RMSEA = 0.060) and structural model (RMSEA = 0.054). Knowledge, attitudes, and subjective norms were significantly related to intention to use PrEP, whereas the effect of general beliefs about medicines was insignificant. These effect mechanisms point to the importance of designing interventions to support PrEP uptake that target knowledge, enhance positive attitudes about PrEP within social networks, and build positive social norms around PrEP among sexually active GBMSM.
Subject(s)
HIV Infections , Pre-Exposure Prophylaxis , Sexual and Gender Minorities , Male , Humans , Homosexuality, Male , Latent Class Analysis , HIV Infections/prevention & control , ChinaABSTRACT
BACKGROUND: This study aimed to determine whether postnatal treatment with recombinant human IGF-1 (rhIGF-1)/binding peptide 3 (BP3) ameliorates lung injury and prevents pulmonary hypertension (PH) in bronchopulmonary dysplasia (BPD) models. METHODS: We used two models of BPD in this study: one model that was associated with chorioamnionitis (CA), stimulated by intra-amniotic fluid and exposure to lipopolysaccharide (LPS), whereas the other was exposed to postnatal hyperoxia. Newborn rats were treated with rhIGF-1/BP3 (0.2 mg/Kg/d) or saline via intraperitoneal injection. The study endpoints included the wet/dry weight (W/D) ratio of lung tissues, radial alveolar counts (RACs), vessel density, right ventricular hypertrophy (RVH), lung resistance, and lung compliance. Hematoxylin and eosin (H&E) and Masson staining were used to evaluate the degree of lung injury and pulmonary fibrosis. IGF-1 and eNOS expression were detected using western blotting or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The levels of SP-C, E-cadherin, N-cadherin, FSP1, and Vimentin in the lung tissues were detected by immunofluorescence. RESULTS: LPS and hyperoxia treatment increased lung injury and pulmonary fibrosis, enhanced RVH and total respiratory resistance, and decreased RAC, pulmonary vascular density and pulmonary compliance in young mice (all p < 0.01). Simultaneously, LPS and hyperoxia induced an increase in epithelial-mesenchymal transition (EMT) in airway epithelial cells. However, rhIGF-1/BP3 treatment reduced lung injury and pulmonary fibrosis, decreased RVH and total respiratory resistance, and enhanced RAC, pulmonary vascular density and pulmonary compliance, as well as inhibited EMT in airway epithelial cells in LPS and hyperoxia treated mice. CONCLUSION: Postnatal rhIGF-1/BP3 treatment relieved the effects of LPS or hyperoxia on lung injury and prevented RVH, providing a promising strategy for the treatment of BPD.
Subject(s)
Bronchopulmonary Dysplasia , Hyperoxia , Hypertension, Pulmonary , Lung Injury , Pulmonary Fibrosis , Infant, Newborn , Pregnancy , Female , Rats , Animals , Humans , Mice , Bronchopulmonary Dysplasia/metabolism , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/prevention & control , Hypertension, Pulmonary/metabolism , Lung Injury/metabolism , Hyperoxia/metabolism , Lipopolysaccharides/pharmacology , Pulmonary Fibrosis/pathology , Animals, Newborn , Insulin-Like Growth Factor I/metabolism , Rats, Sprague-Dawley , Lung/pathology , Hypertrophy, Right Ventricular/etiology , Hypertrophy, Right Ventricular/prevention & control , Hypertrophy, Right Ventricular/metabolism , Disease Models, AnimalABSTRACT
The anthocyanin biosynthetic pathway is the main pathway regulating floral coloration in Iris germanica, a well-known ornamental plant. We investigated the transcriptome profiles and targeted metabolites to elucidate the relationship between genes and metabolites in anthocyanin biosynthesis in the bitone flower cultivar 'Clarence', which has a deep blue outer perianth and nearly white inner perianth. In this study, delphinidin-, pelargonidin-, and cyanidin-based anthocyanins were detected in the flowers. The content of delphinidin-based anthocyanins increased with the development of the flower. At full bloom (stage 3), delphinidin-based anthocyanins accounted for most of the total anthocyanin metabolites, whereas the content of pelargonidin- and cyanidin-based anthocyanins was relatively low. Based on functional annotations, a number of novel genes in the anthocyanin pathway were identified, which included early biosynthetic genes IgCHS, IgCHI, and IgF3H and late biosynthetic genes Ig F3'5'H, IgANS, and IgDFR. The expression of key structural genes encoding enzymes, such as IgF3H, Ig F3'5'H, IgANS, and IgDFR, was significantly upregulated in the outer perianth compared to the inner perianth. In addition, most structural genes exhibited their highest expression at the half-color stage rather than at the full-bloom stage, which indicates that these genes function ahead of anthocyanins synthesis. Moreover, transcription factors (TFs) of plant R2R3-myeloblastosis (R2R3-MYB) related to the regulation of anthocyanin biosynthesis were identified. Among 56 R2R3-MYB genes, 2 members belonged to subgroup 4, with them regulating the expression of late biosynthetic genes in the anthocyanin biosynthetic pathway, and 4 members belonged to subgroup 7, with them regulating the expression of early biosynthetic genes in the anthocyanin biosynthetic pathway. Quantitative real-time PCR (qRT-PCR) analysis was used to validate the data of RNA sequencing (RNA-Seq). The relative expression profiles of most candidate genes were consistent with the FPKM of RNA-seq. This study identified the key structural genes encoding enzymes and TFs that affect anthocyanin biosynthesis, which provides a basis and reference for the regulation of plant anthocyanin biosynthesis in I. germanica.
Subject(s)
Iris Plant , Transcriptome , Anthocyanins , Iris Plant/genetics , Iris Plant/metabolism , Plant Proteins/metabolism , Transcription Factors/metabolism , Flowers/metabolism , Gene Expression Regulation, PlantABSTRACT
The light-sensitive capacity of fish larvae is determined by the structure of the retina and the opsins expressed in the retinal and nonretinal photoreceptors. In this study, the retinal structure and expression of opsin genes during the early developmental stage of Takifugu rubripes larvae were investigated. Histological examination showed that at 1 days after hatching (dah), seven layers were observed in the retina of T. rubripes larva, including the pigment epithelial layer [retinal pigment epithelium layer (RPE)], photoreceptor layer (PRos/is), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL) and ganglion cell layer (GCL). At 2 dah, optic fibre layer (OFL) can be observed, and all eight layers were visible in the retina. By measuring the thickness of each layer, opposing developmental trends were found in the thickness of ONL, OPL, INL, IPL, GCL and OFL. The nuclear density of ONL, INL and GCL and the ratios of ONL/INL, ONL/GCL and INL/GCL were also measured and the ratio of ONL/GCL ranged from 1.9 at 2 dah to 3.4 at 8 dah and no significant difference was observed between the different developmental stages (P > 0.05). No significant difference was observed for the INL/GCL ratio between the different developmental stages, which ranged from 1.2 at 2 dah to 2.0 at 18 dah (P > 0.05). The results of quantitative real-time polymerase chain reaction (PCR) showed that the expression of RH1, LWS, RH2-1, RH2-2, SWS2, rod opsin, opsin3 and opsin5 could be detected from 1 dah. These results suggest that the well-developed retina and early expression of the opsins of T. rubripes during the period of transition from endogenous to mixed feeding might be critical for vision-based survival skills during the early life stages after hatching.
Subject(s)
Opsins , Takifugu , Animals , Rod Opsins , Retina , EpitheliumABSTRACT
BACKGROUND: White tea has become more and more popular with consumers due to its health benefits and unique flavor. However, the key aroma-active compounds of white tea during the aging process are still unclear. Thus, the key aroma-active compounds of white tea during the aging process were investigated using gas chromatography-time-of-flight-mass spectrometry (GC-TOF-MS) and gas chromatography-olfactometry (GC-O) combined with sensory-directed flavor analysis. RESULTS: A total of 127 volatile compounds were identified from white tea samples with different aging years by GC-TOF-MS. Fifty-eight aroma-active compounds were then determined by GC-O, and 19 of them were further selected as the key aroma-active compounds based on modified frequency (MF) and odor activity value (OAV). CONCLUSION: Aroma recombination and omission testing confirmed that 1-octen-3-ol, linalool, phenethyl alcohol, geraniol, (E)-ß-ionone, α-ionone, hexanal, phenylacetaldehyde, nonanal, (E, Z)-(2,6)-nonadienal, safranal, γ-nonalactone and 2-amylfuran were the common key aroma-active compounds to all samples. Cedrol, linalool oxide II and methyl salicylate were confirmed peculiar in new white tea, while ß-damascenone and jasmone were peculiar in aged white tea. This work will offer support for further studies on the material basis of flavor formation of white tea. © 2023 Society of Chemical Industry.
Subject(s)
Odorants , Volatile Organic Compounds , Olfactometry/methods , Odorants/analysis , Gas Chromatography-Mass Spectrometry/methods , Volatile Organic Compounds/chemistry , Tea/chemistryABSTRACT
BACKGROUND: A profound understanding of the various frontal tissues' morphology and their relationship with forehead lines can efficiently guide clinical treatment. OBJECTIVES: The authors explored the relationship between frontal anatomy and frontal lines. METHODS: We measured the thickness and shape of tissues in different regions of the forehead of 241 Asians. Then, we analyzed the relationship between the types of frontalis muscle and frontal lines, as well as the relationship between the frontal anatomical structures and the production of frontal lines. RESULTS: We classified the types of frontalis muscle into 3 categories comprising 10 subtypes. The skin (0.78 mm vs 0.90 mm, P < .05), superficial subcutaneous tissue (0.66 mm vs 0.75 mm, P < .05), and frontalis muscle thickness (0.29 mm vs 0.37 mm, P < .05) of people with obvious dynamic forehead lines were significantly thicker than those of people without significant dynamic forehead lines. However, no significant difference in the deep subcutaneous tissue thickness was found between people with and without static forehead lines (1.36 mm vs 1.34 mm, P < .05). CONCLUSIONS: This study shows the relationship between the frontal structure and frontal lines. Therefore, these results can provide references for treating frontal lines, to a certain extent.
Subject(s)
Forehead , Skin , Humans , Forehead/diagnostic imaging , Forehead/anatomy & histology , Ultrasonography , Skin/diagnostic imaging , Subcutaneous Tissue/diagnostic imagingABSTRACT
This study aimed to investigate the effects of Erxian Decoction(EXD)-containing serum on the proliferation and osteogenic differentiation of MC3T3-E1 cells under oxidative stress through BK channels. The oxidative stress model was induced in MC3T3-E1 cells by H_2O_2, and 3 mmol·L~(-1) tetraethylammonium(TEA) chloride was used to block the BK channels in MC3T3-E1 cells. MC3T3-E1 cells were divided into a control group, a model group, an EXD group, a TEA group, and a TEA+EXD group. After MC3T3-E1 cells were treated with corresponding drugs for 2 days, 700 µmol·L~(-1) H_2O_2 was added for treatment for another 2 hours. CCK-8 assay was used to detect cell proliferation activity. The alkaline phosphatase(ALP) assay kit was used to detect the ALP activity of cells. Western blot and real-time fluorescence-based quantitative PCR(RT-qPCR) were used to detect protein and mRNA expression, respectively. Alizarin red staining was used to detect the mineralization area of osteoblasts. The results showed that compared with the control group, the model group showed significantly blunted cell proliferation activity and ALP activity, reduced expression of BK channel α subunit(BKα), collagen â (COL1), bone morphogenetic protein 2(BMP2), osteoprotegerin(OPG), and phosphorylated Akt, decreased mRNA expression levels of Runt-related transcription factor 2(RUNX2), BMP2, and OPG, and declining area of calcium nodules. EXD-containing serum could significantly potentiate the cell proliferation activity and ALP activity, up-regulate the protein expression of BKα, COL1, BMP2, OPG, and phosphorylated Akt, and forkhead box protein O1(FoxO1), promote the mRNA expression of RUNX2, BMP2, and OPG, and enlarge the area of calcium nodules. However, BK channel blockage by TEA reversed the effects of EXD-containing serum in promoting the protein expression of BKα, COL1, BMP2, OPG, and phosphorylated Akt and FoxO1, increasing the mRNA expression of RUNX2, BMP2, and OPG, and enlarging the area of calcium nodules. EXD-containing serum could improve the proliferation activity, osteogenic differentiation, and mineralization ability of MC3T3-E1 cells under oxidative stress, which might be related to the regulation of BK channels and downstream Akt/FoxO1 signaling pathway.
Subject(s)
Cell Differentiation , Core Binding Factor Alpha 1 Subunit , Large-Conductance Calcium-Activated Potassium Channels , Osteogenesis , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Core Binding Factor Alpha 1 Subunit/genetics , Core Binding Factor Alpha 1 Subunit/metabolism , Core Binding Factor Alpha 1 Subunit/pharmacology , Large-Conductance Calcium-Activated Potassium Channels/genetics , Large-Conductance Calcium-Activated Potassium Channels/metabolism , Osteogenesis/drug effects , RNA, Messenger/genetics , Drugs, Chinese Herbal/pharmacology , Gene Expression/drug effects , Animals , Mice , Cell LineABSTRACT
BACKGROUND The Integrated Liver Inflammatory Score (ILIS), which includes 5 serum indicators (albumin, bilirubin, neutrophil count, alpha-fetoprotein [AFP], and alkaline phosphatase [ALP]), is a novel inflammation-based predictive model associated with poor survival in hepatocellular carcinoma (HCC) patients. Our study aimed to assess the prognostic value of ILIS in HCC patients undergoing radical hepatectomy and establish a nomogram and artificial neural network based on their ILIS scores. MATERIAL AND METHODS This multicenter retrospective study included patients from 2 institutions from 2007 to 2017. Independent risk factors associated with Recurrence-free survival (RFS) and overall survival (OS) were identified through univariate and multifactor analysis in the training and validation groups, respectively. Afterward, column line graphs and artificial neural networks (ANN) were constructed and validated using the validation group. RESULTS A total of 432 patients were included in this study (275 in the training group and 157 in the validation group). In both cohorts, ILIS was correlated with pathological features such as tumor size, degree of differentiation, Child-Pugh class classification, and BCLC staging. Moreover, ILIS was identified as an independent risk factor for OS. ILIS-based nomograms and artificial neural networks also showed the prognostic value of ILIS. CONCLUSIONS Preoperative ILIS is an independent and effective predictor of prognosis in HCC patients treated with radical hepatectomy, as shown by the fact that higher ILIS are associated with worse patient prognosis. We have also established nomograms and ANNs that predict HCC prognosis with high accuracy.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis , Liver Neoplasms , Carcinoma, Hepatocellular/pathology , Hepatectomy/methods , Humans , Liver Neoplasms/pathology , Prognosis , Retrospective StudiesABSTRACT
This study examined the social context and lived experience of HIV risk management among sexual minority men in China. An interpretative phenomenological analysis of 25 in-depth interviews with participants in five Chinese cities was undertaken. Findings show how men managed HIV risk in the context of high risk perception and anxiety, and strong perceived social discrimination and marginalisation. Men's choice of risk management strategies was influenced by their often-negative perceptions of gay community, social norms around condom use, and prior lived experience. Results underscore the importance of considering these contexts when planning pre-exposure prophylaxis (PrEP) implementation in China and highlight the need for strategies to address potential PrEP-related stigma among sexual minority men.
Subject(s)
HIV Infections , Pre-Exposure Prophylaxis , Sexual and Gender Minorities , China , HIV Infections/drug therapy , HIV Infections/prevention & control , Homosexuality, Male , Humans , Male , Pre-Exposure Prophylaxis/methods , Risk Management , Sexual BehaviorABSTRACT
Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for refractory depression, however, therapeutic outcomes vary. Mounting evidence suggests that clinical response relates to functional connectivity with the subgenual cingulate cortex (SGC) at the precise DLPFC stimulation site. Critically, SGC-related network architecture shows considerable interindividual variation across the spatial extent of the DLPFC, indicating that connectivity-based target personalization could potentially be necessary to improve treatment outcomes. However, to date accurate personalization has not appeared feasible, with recent work indicating that the intraindividual reproducibility of optimal targets is limited to 3.5 cm. Here we developed reliable and accurate methodologies to compute individualized connectivity-guided stimulation targets. In resting-state functional MRI scans acquired across 1,000 healthy adults, we demonstrate that, using this approach, personalized targets can be reliably and robustly pinpointed, with a median accuracy of ~2 mm between scans repeated across separate days. These targets remained highly stable, even after 1 year, with a median intraindividual distance between coordinates of only 2.7 mm. Interindividual spatial variation in personalized targets exceeded intraindividual variation by a factor of up to 6.85, suggesting that personalized targets did not trivially converge to a group-average site. Moreover, personalized targets were heritable, suggesting that connectivity-guided rTMS personalization is stable over time and under genetic control. This computational framework provides capacity for personalized connectivity-guided TMS targets to be robustly computed with high precision and has the flexibly to advance research in other basic research and clinical applications.
Subject(s)
Connectome/standards , Depressive Disorder, Treatment-Resistant/therapy , Dorsolateral Prefrontal Cortex , Transcranial Magnetic Stimulation/standards , Adult , Connectome/methods , Depressive Disorder, Treatment-Resistant/diagnostic imaging , Dorsolateral Prefrontal Cortex/diagnostic imaging , Feasibility Studies , Female , Humans , Magnetic Resonance Imaging , Male , Reproducibility of Results , Transcranial Magnetic Stimulation/methods , Young AdultABSTRACT
Training lay health workers is a critical intervention strategy to support HIV pre-exposure prophylaxis (PrEP) implementation. However, few evaluations of such trainings have been published. We conducted multi-time-point surveys to evaluate the effect of a training intervention on knowledge, PrEP stigma, and implementation behavior among lay HIV workers in China. Results indicated high acceptability and appropriateness of the training. PrEP knowledge score increased by 65% from pre- to post-training, and remained high one-month post-training. We observed a significant decrease in PrEP stigma and a positive influence on determinants of implementation behaviors. All lay HIV workers surveyed one-month after the training reported having disseminated PrEP information in social networks; 43% reported integrating PrEP education into routine work. The training is an effective strategy to build lay HIV workers' capacity in PrEP implementation. Longer-term post-training follow up would be ideal to further assess actual PrEP uptake and sustained effects on PrEP implementation.
Subject(s)
Anti-HIV Agents , HIV Infections , Pre-Exposure Prophylaxis , Anti-HIV Agents/therapeutic use , Diffusion of Innovation , HIV Infections/drug therapy , HIV Infections/prevention & control , Humans , Patient Acceptance of Health Care , Social StigmaABSTRACT
BACKGROUND/AIMS: Early integration of behavioral and social sciences research into clinical trials can improve trial conduct and facilitate future implementation of biomedical interventions. We sought to examine participants' experiences in clinical trials with broadly neutralizing antibodies and describe the development of educational materials for use in future broadly neutralizing antibody research. METHODS: We conducted semi-structured interviews with trial participants in phase 1 trials evaluating safety and efficacy of broadly neutralizing antibodies for HIV prevention and treatment and key informants (i.e. trial staff involved in broadly neutralizing antibody research). Semi-structured interviews were transcribed and analyzed thematically. Based on findings from the interviews, we developed educational materials addressing concerns and misconceptions identified among trial participants with input from community and research stakeholders. Educational materials were used in subsequent clinical trials with broadly neutralizing antibodies. We evaluated trial staff's experiences with newly developed educational materials in follow-up key informant interviews. RESULTS: Although most participants were concerned about long-term harms related to the investigational product upon enrollment, absence of severe side effects in the trial led to an underestimation of risks related to the study during trial participation. Participants showed a poor understanding of what broadly neutralizing antibodies are and the differences between broadly neutralizing antibodies and other HIV prevention and treatment products, such as antiretrovirals. Many trial participants overestimated the possible public health impact of the broadly neutralizing antibody trials in which they were enrolled, associating broadly neutralizing antibody research with the development of vaccine or cure for HIV in the near future. Based on these concerns and misconceptions among trial participants, we developed a frequently asked questions document and adapted an existing educational video about broadly neutralizing antibodies. In follow-up interviews, key informants reported that materials helped address trial participants' concerns and questions related to the trial. Key informants reported using the educational materials not only during informed consent but also throughout trial participation, which contributed to making informed consent an "ongoing" process. CONCLUSION: Integration of behavioral research into clinical trials with broadly neutralizing antibodies is key to identify and address key concerns among trial participants. Behavioral and social sciences research promotes communication between trial participants and biomedical researchers, facilitates engagement of participants and trial staff, and strengthens trial conduct. Development of educational materials collaboratively by behavioral and clinical scientists, trial staff, and community stakeholders is feasible and may help to address trial participants' concerns and misconceptions. Future research should evaluate the impact of educational materials in recruitment and retention of trial participants.