PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1.

BACKGROUND: Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis. METHODS: HBV-positive human liver cancer tissues were checked for PTEN expression. Transgenic HBV, Alb-Cre and Ptenfl/fl mice were inter-crossed to generate WT, HBV, Pten-/- and HBV; Pten-/- mice. Immunoblotting, histological analysis and qRT-PCR were used to study these livers. Gp73-/- mice were then mated with HBV; Pten-/- mice to illustrate the role of hepatic tumor biomarker golgi membrane protein 73 (GP73)/ golgi membrane protein 1 (GOLM1) in hepatic oncogenesis. RESULTS: Pten deletion and HBV transgene synergistically aggravated liver injury, inflammation, fibrosis and development of mixed hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). GP73 was augmented in HBV; Pten-/- livers. Knockout of GP73 blunted the synergistic effect of deficient Pten and transgenic HBV on liver injury, inflammation, fibrosis and cancer development. CONCLUSIONS: This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.

Construction of a miR-15a-based risk prediction model for vascular calcification detection in patients undergoing hemodialysis.

Vascular calcification (VC) is highly prevalent in patients undergoing hemodialysis, and is a significant contributor to the mortality rate. Therefore, biomarkers that can accurately predict the onset of VC are urgently required. Our study aimed to investigate serum miR-15a levels in relation to VC and to develop a predictive model for VC in patients undergoing hemodialysis at the Beijing Friendship Hospital hemodialysis center between 1 January 2019 and 31 December 2020. The patients were categorized into two groups: VC and non-VC. Logistic regression (LR) models were used to examine the risk factors associated with VC. Additionally, we developed an miR-15a-based nomogram based on the results of the multivariate LR analysis. A total of 138 patients under hemodialysis were investigated (age: 58.41 ± 13.22 years; 54 males). VC occurred in 79 (57.2%) patients. Multivariate LR analysis indicated that serum miR-15a, age, and WBC count were independent risk factors for VC. A miR-15a-based nomogram was developed by incorporating the following five predictors: age, dialysis vintage, predialysis nitrogen, WBC count, and miR-15a. The receiver operating characteristic (ROC) curve had an area under the curve of 0.921, diagnostic threshold of 0.396, sensitivity of 0.722, and specificity of 0.932, indicating that this model had good discrimination. This study concluded that serum miR-15a levels, age, and white blood cell (WBC) count are independent risk factors for VC. A nomogram constructed by integrating these risk factors can be used to predict the risk of VC in patients undergoing hemodialysis.

Effects of aerobic exercise or Tai Chi Chuan interventions on problematic mobile phone use and the potential role of intestinal flora: A multi-arm randomized controlled trial.

BACKGROUND: Problematic use of mobile phones (PMPU) has been described as a serious public health issue. METHODS: This study was a parallel three-arm randomized controlled trial and has completed registration (ClinicalTrials.gov Identifier: NCT05843591). Ninety college students with PMPU were randomly assigned to the aerobic exercise group (AE group, n = 30), the Tai Chi Chuan group (TCC group, n = 30), or the wait-list control group (WLC group, n = 30). At the end of the intervention, stool samples from the study participants were collected for biological analysis based on 16 S rDNA amplicon sequencing technology. The primary outcome was addiction symptoms assessed by the Smartphone Addiction Scale-Short Version (SAS-SV). The secondary outcomes are emotional symptoms, physical symptoms, and flora species. RESULTS: Compared with the WLC group, the AE and TCC groups showed reductions in PMPU levels, physical and mental fatigue, but there was no difference between the two groups. Moreover, the effect of increasing self-esteem embodied in the TCC group was not present in the AE group. Compared to the WLC group, the relative abundance of Bacteroidaceae and Bacteroides were lower in the AE group, while the relative abundance of Erysipelotrichaceae and Alistipes were lower in the TCC group. And the relative abundance of Bacteroidaceae, Bacteroides, and Alistipes were significantly and negatively correlated with the decline in PMPU scores. CONCLUSION: AE or TCC is an effective, safe and efficient intervention for college students with PMPU, providing some physiological and psychological benefits and having some impact on their intestinal flora.

The Role of microRNA-23a-3p in the Progression of Human Aging Process by Targeting FOXO3a.

Aging results in deterioration of body functions and, ultimately, death. miRNAs contribute to the regulation of aging. The aim of this study was to explore the contribution of miRNAs to aging and senescence-related changes in gene expression. The expression changes of miRNAs in the blood of people and animal samples collected from different age subjects were examined using Affymetrix miRNA 4.0 microarray and qRT-PCR. MTT assay and flow cytometry were used to examine the effect of miR-23a on cell functions in WI-38 cells. The expression levels of 48 miRNAs, including miR-23a, miR-21, and miR-100, in the blood samples were higher in the middle-aged group than in the young or elderly group. Animal studies further suggested that the expression of miR-23a increased with age. In addition, upregulation of miR-23a dramatically suppressed the cell proliferation and arrested the WI-38 cell cycle in vitro. FOXO3a has been identified as a target gene of miR-23a. MiR-23a downregulated the expression of FOXO3a in WI-38 cells. MiRNAs have different expression levels in different age groups. miR-23a could suppress cell proliferation and arrest the cell cycle in WI-38 cells, which elucidated the mechanism through which miR-23a exerts pivotal role in WI-38 cells by targeting FOXO3a.

Prediction of Clinical Precision Chemotherapy by Patient-Derived 3D Bioprinting Models of Colorectal Cancer and Its Liver Metastases.

Methods accurately predicting the responses of colorectal cancer (CRC) and colorectal cancer liver metastasis (CRLM) to personalized chemotherapy remain limited due to tumor heterogeneity. This study introduces an innovative patient-derived CRC and CRLM tumor model for preclinical investigation, utilizing 3d-bioprinting (3DP) technology. Efficient construction of homogeneous in vitro 3D models of CRC/CRLM is achieved through the application of patient-derived primary tumor cells and 3D bioprinting with bioink. Genomic and histological analyses affirm that the CRC/CRLM 3DP tumor models effectively retain parental tumor biomarkers and mutation profiles. In vitro tests evaluating chemotherapeutic drug sensitivities reveal substantial tumor heterogeneity in chemotherapy responses within the 3DP CRC/CRLM models. Furthermore, a robust correlation is evident between the drug response in the CRLM 3DP model and the clinical outcomes of neoadjuvant chemotherapy. These findings imply a significant potential for the application of patient-derived 3DP cancer models in precision chemotherapy prediction and preclinical research for CRC/CRLM.

Portal Vein Pressure Estimation and Portal Hypertension Discrimination Based on Subharmonic Scattering of Ultrasound Contrast Agent Microbubbles.

OBJECTIVE: The acquisition of real-time portal vein pressure (PVP) is important for portal hypertension (PH) discrimination to monitor disease progress and select treatment options. To date, the PVP evaluation approaches are either invasive or noninvasive but with less stability and sensitivity. METHODS: We customized an open ultrasound scanner to explore in vitro and in vivo the ultrasound contrast agent SonoVue microbubbles' subharmonic characteristics with acoustic pressure and local ambient pressure, and obtained promising results of PVP measurements in canine models with induced PH by ligation or embolization of portal vein. RESULTS: In in vitro experiments, the highest correlations between the subharmonic amplitude of SonoVue microbubbles and ambient pressure were observed at acoustic pressures of 523 kPa and 563 kPa (r = -0.993, -0.993, P<0.05, respectively). The correlation coefficients between absolute subharmonic amplitudes and PVP (10.7-35.4 mmHg) were the highest among existing studies using microbubbles as pressure sensors (r values ranged from -0.819 to -0.918). The PH (>16 mmHg) diagnostic capacity also achieved a high level (563 kPa, sensitivity = 93.3%, specificity = 91.7%, accuracy = 92.6%). CONCLUSION: This study proposes a promising measurement for PVP with the highest accuracy, sensitivity, and specificity in an in vivo model compared to existing studies. Future investigations are planned to assess the feasibility of this technique in clinical practice. SIGNIFICANCE: This is the first study that comprehensively investigates the role of the subharmonic scattering signals from SonoVue microbubbles in evaluating PVP in vivo. It represents a promising alternative to invasive measurements for portal pressure.

Frailty and Adverse Outcomes After SARS-CoV-2 Infection in Elderly Patients on Maintenance Hemodialysis: A Cohort Study.

Purpose: Frailty is an important geriatric syndrome associated with aging and adverse events, especially in patients with severe infection. To help guide prognosis for elderly patients undergoing maintenance hemodialysis (MHD) who experience acute infection, this study investigated whether baseline (pre-infection) frailty may be associated with adverse outcomes in elderly patients undergoing MHD who suffer SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. Patients and Methods: Patients (aged ≥60 y) receiving MHD had been assessed for overall frailty and the 5 frailty components based on the Fried Frailty Phenotype scale within 3 months prior to SARS-CoV-2 infection. Results: There were 59 and 98 patients in the frail and non-frail groups, respectively. Three months after SARS-CoV-2 infection, 21 (13.4%) and 45 (28.7%) patients had died or were in hospital. The multivariate COX proportional risk model suggested that the all-cause mortality rate in patients judged overall frail or with low activity was significantly higher compared with that of the non-frail (P = 0.049; 0.003). The multivariate logistic regression analysis showed that hospitalization 3 months after SARS-CoV-2 infection was associated with both overall frailty and low activity (OR 2.276, 95% CI: 1.034-5.010, P = 0.041; OR 2.809, 95% CI: 1.311-6.020, P = 0.008, respectively). Conclusion: Overall frailty and specifically low activity were significantly associated with all-cause mortality and hospitalization in this elderly MHD population after SARS-CoV-2 infection. Early assessment of frailty and effective interventions are recommended to improve the prognosis of patients receiving MHD who are at higher risk of acute infection.

Pre-Exposure Prophylaxis Care Continuum for HIV Risk Populations: An Umbrella Review of Systematic Reviews and Meta-Analyses.

Pre-exposure prophylaxis (PrEP) is an effective biomedical strategy for HIV prevention. This umbrella review is aimed at providing a comprehensive summary of the current status of each stage of the PrEP care cascade. A systematic literature search was conducted in PubMed, Embase, and Cochrane. Additionally, a Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) tool and Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist were used to evaluate their methodological and reporting quality, respectively. A total of 30 systematic reviews met the inclusion criteria. According to the results of methodological quality assessment, 3 reviews were rated as low, while 27 as critically low. Furthermore, the results of the reporting quality evaluation revealed a mean score of 23.03 for the included reviews. Across all the reviews, awareness of PrEP was generally moderate in all populations, and the acceptability was even higher compared with awareness. Unfortunately, the PrEP uptake among different groups was even less optimal, although the adherence was almost above moderate, and several barriers that hindered the utilization of PrEP were identified, and the most common are as follows: cost, stigma, lack of knowledge, mistrust, low risk perception, and more. Although PrEP has proven to be an effective prevention method to date, the promotion of PrEP failed to achieve the anticipated outcome. To reinforce the generalization of and use of PrEP, and effectively control HIV transmission, it is urgent to identify the underlying causes of low uptake rates so that efficient interventions can be implemented.

Promoter characterization of a citrus linalool synthase gene mediating interspecific variation in resistance to a bacterial pathogen.

BACKGROUND: Terpenoids play essential roles in plant defense against biotic stresses. In Citrus species, the monoterpene linalool mediates resistance against citrus canker disease caused by the gram-negative bacteria Xanthomonas citri subsp. citri (Xcc). Previous work had associated linalool contents with resistance; here we characterize transcriptional responses of linalool synthase genes. RESULTS: Leaf linalool contents are highly variable among different Citrus species. "Dongfang" tangerine (Citrus reticulata), a species with high linalool levels was more resistant to Xcc than "Shatian" pummelo (C. grandis) which accumulates only small amounts of linalool. The coding sequences of the major leaf-expressed linalool synthase gene (STS4) are highly conserved, while transcript levels differ between the two Citrus species. To understand this apparent differential transcription, we isolated the promoters of STS4 from the two species, fused them to a GUS reporter and expressed them in Arabidopsis. This reporter system revealed that the two promoters have different constitutive activities, mainly in trichomes. Interestingly, both linalool contents and STS4 transcript levels are insensitive to Xcc infestation in citrus plants, but in these transgenic Arabidopsis plants, the promoters are activated by challenge of a bacterial pathogen Pseudomonas syringae, as well as wounding and external jasmonic acid treatment. CONCLUSIONS: Our study reveals variation in linalool and resistance to Xcc in citrus plants, which may be mediated by different promoter activities of a terpene synthase gene in different Citrus species.

Microwave-assisted depolymerization of chitin and chitosan extracted from crayfish shells waste: A sustainable approach based on graphene oxide catalysis.

This study targeted the sustainable utilization of chitin and chitosan from crayfish shell waste, and further depolymerization of the recovered products in one step through synergy between microwaves and graphene oxide, aiming for the monosaccharides, 5-hydroxymethylfurfural and other high-value products. The results indicated that graphene oxide was more effective than graphene in enhancing the microwave absorption properties of the system, which is contrary to the parameters of their dielectric properties. The heating rate was increased by 0.37 K/s and 0.26 K/s when graphene oxide was introduced into the chitin and chitosan depolymerization systems, respectively, at a microwave power of 5 W/g. The mechanism underlying the impact of graphene oxide on chitin and chitosan under a microwave field was proposed by analyzing the variations in the depolymerization products of chitin and chitosan systems under different reaction conditions, including holding time, catalyst content, solvent content, and reaction temperature. Furthermore, the recovered graphene oxide exhibited delamination upon redispersion in water, which was not observed in the initial samples. The infrared spectra and scanning electron microscopy results suggest that the catalytic reaction is associated with oxygen-containing functional groups. This study demonstrated the synergistic effect of microwaves and graphene oxide on the depolymerization of chitin and chitosan, and the ability to achieve rapid one-step depolymerization in an acid/alkali-free solvent, which provides a green and promising development for the degradation of carbohydrate macromolecules in crustacean solid waste.

Intratumoural microbiome can predict the prognosis of hepatocellular carcinoma after surgery.

BACKGROUND: The dismal prognosis of hepatocellular carcinoma (HCC) is closely associated with characteristics of the tumour microenvironment (TME). Recent studies have confirmed the presence and potential influence of the microbiome in TME on cancer progression. Elucidating the relationship between microbes in the TME and cancer could provide valuable insights into novel diagnostic markers and therapeutic strategies for HCC and thus warrants a closer investigation of the role of intratumoural microbiome in the HCC TME. METHODS: We determined the presence of intratumoural microbiome using fluorescence in situ hybridisation, and explored the microbial community profiles in the HCC TME in paired tumour and adjacent normal tissues using 16S rDNA sequencing. Microbial signatures were characterised in the paired group, and their correlation with clinical characteristics was further investigated. We clustered the microbial signatures of tumour tissues by hepatotypes, and further analysis was performed to elucidate the independent prognostic value of the hepatotypes. RESULTS: This study revealed that microbial profiles and community networks differed notably between tumours and adjacent normal tissues. Proteobacteria and Actinobacteria were the most abundant phyla in the HCC TME. The TME microbial profiles also revealed heterogeneities between individuals and between multiple tumour lesions. Clustering of the microbial profiles into two hepatotypes revealed different microbial network patterns. Additionally, the hepatotypes were revealed to be independent prognostic factors in patients with resected HCC. CONCLUSIONS: Our study illuminates the microbial profiles in the TME of HCC and presents the hepatotype as a potential independent biomarker for the prognostic prediction of HCC after surgery.

Polar Solomon rings in ferroelectric nanocrystals.

Solomon rings, upholding the symbol of wisdom with profound historical roots, were widely used as decorations in ancient architecture and clothing. However, it was only recently discovered that such topological structures can be formed by self-organization in biological/chemical molecules, liquid crystals, etc. Here, we report the observation of polar Solomon rings in a ferroelectric nanocrystal, which consist of two intertwined vortices and are mathematically equivalent to a [Formula: see text] link in topology. By combining piezoresponse force microscopy observations and phase-field simulations, we demonstrate the reversible switching between polar Solomon rings and vertex textures by an electric field. The two types of topological polar textures exhibit distinct absorption of terahertz infrared waves, which can be exploited in infrared displays with a nanoscale resolution. Our study establishes, both experimentally and computationally, the existence and electrical manipulation of polar Solomon rings, a new form of topological polar structures that may provide a simple way for fast, robust, and high-resolution optoelectronic devices.

3D bioprinted liver tissue and disease models: Current advances and future perspectives.

Three-dimensional (3D) bioprinting is a promising technology for fabricating complex tissue constructs with biomimetic biological functions and stable mechanical properties. In this review, the characteristics of different bioprinting technologies and materials are compared, and development in strategies for bioprinting normal and diseased hepatic tissue are summarized. In particular, features of bioprinting and other bio-fabrication strategies, such as organoids and spheroids are compared to demonstrate the strengths and weaknesses of 3D printing technology. Directions and suggestions, such as vascularization and primary human hepatocyte culture, are provided for the future development of 3D bioprinting.

Study on drug screening multicellular model for colorectal cancer constructed by three-dimensional bioprinting technology.

The existing in vitro models for antitumor drug screening have significant limitations. Many compounds that inhibit two-dimensional (2D) cultured cells do not exhibit the same pharmacological effects in vivo, thereby wasting human and material resources and time during drug development. Therefore, it is crucial to develop new models. Three-dimensional (3D) bioprinting technology has greater advantages in constructing human tissues than sandwich culture and organoid construction. We used 3D bioprinting technology to construct a 3D multicellular model of SW480 cells, tumor-associated macrophages, and endothelial cells. The biological activities of the model were evaluated by immunofluorescence, hematoxylin and eosin staining of frozen pathological sections, and transcriptome sequencing. Compared with 3D bioprinted single-cell model (3D printing-S), 3D bioprinted multicellular models (3D printing-M) showed significantly improved expression of tumor-related genes, including hub genes IL1B, FCGR2A, FCGR3A, CYBB, SPI1, CCL2, ITGAM, and ITGB2. Antitumor drug screening experiment showed that the IC50 values of 5-FU, oxaliplatin, and irinotecan in 3D printing-S group/2D culture group were 31.13 µM/12.79 µM, 26.79 µM/0.80 µM, and 16.73 µM/10.45 µM, respectively. Compared with the 3D printing-S group, 3D printing-M group was significantly more resistant to chemotherapy.

Personalized treatment for hepatocellular carcinoma in the era of targeted medicine and bioengineering.

Hepatocellular carcinoma (HCC) is a major global health burden, causing approximately 8.3 million deaths each year, and it is the third leading cause of cancer-related death worldwide, with a relative 5-year survival rate of around 18%. Due to the advanced stage of diagnosis in most patients, systemic treatment based on targeted therapy has become the only feasible option. Genomic studies have established a profile of molecular alterations in hepatocellular carcinoma with potentially actionable mutations, but these mutations have yet to be translated into clinical practice. The first targeted drug approved for systemic treatment of patients with advanced hepatocellular carcinoma was Sorafenib, which was a milestone. Subsequent clinical trials have identified multiple tyrosine kinase inhibitors, such as Lenvatinib, Cabozantinib, and Regorafenib, for the treatment of hepatocellular carcinoma, with survival benefits for the patient. Ongoing systemic therapy studies and trials include various immune-based combination therapies, with some early results showing promise and potential for new therapy plans. Systemic therapy for hepatocellular carcinoma is complicated by the significant heterogeneity of the disease and its propensity for developing drug resistance. Therefore, it is essential to choose a better, individualized treatment plan to benefit patients. Preclinical models capable of preserving in vivo tumor characteristics are urgently needed to circumvent heterogeneity and overcome drug resistance. In this review, we summarize current approaches to targeted therapy for HCC patients and the establishment of several patient-derived preclinical models of hepatocellular carcinoma. We also discuss the challenges and opportunities of targeted therapy for hepatocellular carcinoma and how to achieve personalized treatment with the continuous development of targeted therapies and bioengineering technologies.

Longitudinal association between problematic smartphone use and sleep disorder among Chinese college students during the COVID-19 pandemic.

BACKGROUND: Problematic smartphone use (PSU) and sleep disorders (SD) are common public health problems among college students. While previous cross-sectional studies have found a relationship between PSU and SD, the causal direction of this relationship remains unclear. This study aims to examine the longitudinal changes of PSU and SD during the COVID-19 pandemic, determine the causal relationship between them, and identify confounding factors that affect this association. METHODS: The study sample consisted of 1186 Chinese college students (47.7% male) with a mean age of 18.08 years. Participants completed the Smartphone Addiction Scale - Short Version (SAS-SV) and the Pittsburgh Sleep Quality Index (PSQI) at both baseline and follow-up surveys, conducted one year apart. The cross-lagged panel model (CLPM) was used to examine the causal relationship between PSU and SD, stratified by gender and duration of daily physical activity. The fixed effect panel regression was used to confirm the findings of CLPM. RESULTS: The results of the CLPM analysis showed a significant bidirectional relationship between PSU and SD for the overall sample, which was consistent with the fixed effects model findings. However, subgroup analyses revealed that the bidirectional association disappeared among males or those who engaged in daily physical activity for more than 1 h. CONCLUSIONS: Our study shows a significant bidirectional association between PSU and SD, with variations across gender and daily physical activity levels. Encouraging physical activity may serve as a potential intervention to disrupt the bidirectional association between PSU and SD, which has important implications for public health strategies aimed at reducing the negative consequences of PSU and SD.