A framework for longitudinal latent factor modelling of treatment response in clinical trials with applications to Psoriatic Arthritis and Rheumatoid Arthritis.

OBJECTIVE: Clinical trials involve the collection of a wealth of data, comprising multiple diverse measurements performed at baseline and follow-up visits over the course of a trial. The most common primary analysis is restricted to a single, potentially composite endpoint at one time point. While such an analytical focus promotes simple and replicable conclusions, it does not necessarily fully capture the multi-faceted effects of a drug in a complex disease setting. Therefore, to complement existing approaches, we set out here to design a longitudinal multivariate analytical framework that accepts as input an entire clinical trial database, comprising all measurements, patients, and time points across multiple trials. METHODS: Our framework composes probabilistic principal component analysis with a longitudinal linear mixed effects model, thereby enabling clinical interpretation of multivariate results, while handling data missing at random, and incorporating covariates and covariance structure in a computationally efficient and principled way. RESULTS: We illustrate our approach by applying it to four phase III clinical trials of secukinumab in Psoriatic Arthritis (PsA) and Rheumatoid Arthritis (RA). We identify three clinically plausible latent factors that collectively explain 74.5% of empirical variation in the longitudinal patient database. We estimate longitudinal trajectories of these factors, thereby enabling joint characterisation of disease progression and drug effect. We perform benchmarking experiments demonstrating our method's competitive performance at estimating average treatment effects compared to existing statistical and machine learning methods, and showing that our modular approach leads to relatively computationally efficient model fitting. CONCLUSION: Our multivariate longitudinal framework has the potential to illuminate the properties of existing composite endpoint methods, and to enable the development of novel clinical endpoints that provide enhanced and complementary perspectives on treatment response.

Predictive value of angiopoietin-like protein 8 in metabolic dysfunction-associated fatty liver disease and its progression: A case-control study.

BACKGROUND: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population. Liver fibrosis represents a crucial stage in the development of MAFLD, with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma. Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers. However, imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints. Consequently, it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis. AIM: To investigate the predictive value of angiopoietin-like protein 8 (ANGPTL8) in MAFLD and its progression. METHODS: We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department, Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology, during September 2021-July 2022. Using abdominal ultrasonography and MAFLD diagnostic criteria, among the 160 patients, 80 patients (50%) were diagnosed with MAFLD. The MAFLD group was divided into the liver fibrosis group (n = 23) and non-liver fibrosis group (n = 57) by using a cut-off fibrosis-4 index ≥ 1.45. Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression. Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression. RESULTS: Compared with non-MAFLD patients, MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose (TyG) index (both P < 0.05). Serum ANGPTL8 (r = 0.576, P < 0.001) and TyG index (r = 0.473, P < 0.001) were positively correlated with MAFLD. Serum ANGPTL8 was a risk factor for MAFLD [odds ratio (OR): 1.123, 95% confidence interval (CI): 1.066-1.184, P < 0.001). Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD [area under the curve (AUC): 0.832 and 0.886, respectively; both P < 0.05]. Compared with MAFLD patients without fibrosis, those with fibrosis had higher serum ANGPTL8 and TyG index (both P < 0.05), and both parameters were positively correlated with MAFLD-associated fibrosis. Elevated serum ANGPTL8 (OR: 1.093, 95%CI: 1.044-1.144, P < 0.001) and TyG index (OR: 2.383, 95%CI: 1.199-4.736, P < 0.013) were risk factors for MAFLD-associated fibrosis. Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD-associated fibrosis (AUC: 0.812 and 0.835, respectively; both P < 0.05). CONCLUSION: The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD. They can serve as predictors for the risk of MAFLD and liver fibrosis, with the ANGPTL8 + TyG index potentially exhibiting even higher predictive value.

Mitochondria-Targeted Prodrug Nanoassemblies for Efficient Ferroptosis-Based Therapy via Devastating Ferroptosis Defense Systems.

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency of tumorous ferroptosis was seriously restricted by intracellular ferroptosis defense systems, the glutathione peroxidase 4 (GPX4) system, and the ubiquinol (CoQH2) system. Inspired by the crucial role of mitochondria in the ferroptosis process, we reported a prodrug nanoassembly capable of unleashing potent mitochondrial lipid peroxidation and ferroptotic cell death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) was combined with triphenylphosphonium moiety through a disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within a single-molecular framework. After being trapped in cancer cells, the acidic condition provoked the structural disassembly of QSSP to liberate free prodrug molecules. The mitochondrial membrane-potential-driven accumulation of the lipophilic cation prodrug was delivered explicitly into the mitochondria. Afterward, the thiol-disulfide exchange would occur accompanied by downregulation of reduced glutathione levels, thus resulting in mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, the released QA from the hydrolysis reaction of the adjacent ester bond could further devastate mitochondrial defense and evoke robust ferroptosis via the DHODH-CoQH2 system. This subcellular targeted nanoassembly provides a reference for designing ferroptosis-based strategy for efficient cancer therapy through interfering antiferroptosis systems.

Quantitative evaluation of disc degeneration using dual-energy CT: advantages of R-VH, D-VH values and the IVNCa + CT model.

OBJECTIVE: To evaluate the correlation between dual-energy CT (DECT) virtual calcium free (VNCA), CT attenuation, the ratio and difference of VNCA to CT attenuation, and Pfirrmann grading of lumbar disc degeneration. METHODS: A retrospective analysis on 135 intervertebral discs from 30 patients who underwent DECT and MR. Discs was graded using the Pfirrmann system. ROIs on the sagittal plane assessed HU value, VNCA value, Rho value, Z value, R-VH value, and D-VH value. Correlation, grade differences, and multivariate regression models were assessed. Diagnostic performance and cut-off values were determined using AUC. RESULTS: VNCA (r = 0.589, P < 0.001), R-VH (r = 0.622, P < 0.001), and D-VH (r = 0.613, P < 0.001) moderately correlated with Pfirrmann grading. HU (r = 0.388, P < 0.001), Rho (r = 0.142, P = 0.102), and Z (r = -0.125, P = 0.153) showed a weak correlation. R-VH, D-VH, and VNCA had significantly higher correlation than HU. Statistically significant differences were observed in P values of VNCA, HU, R-VH, and D-VH in relative groups (P < 0.05), but not in Rho and Z values (P > 0.05). R-VH and D-VH had significant differences between Pfirrmann grades 1 and 2, and grades 2 and 3 (early stage) (P < 0.05). AUC readings of R-VH and D-VH (≥2, ≥3, ≥4) were higher. The multivariate model IVNCa + CT had the highest AUC. CONCLUSION: The new quantitative indices R-VH value and D-VH value of DECT have advantages over VNCA value and HU value in evaluating early-stage disc degeneration (≥2 grades, ≥3 grades). The multivariate model IVNCa + CT has the best AUC values for evaluating disc degeneration at all stages.

A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy.

Both chemodynamic therapy and photodynamic therapy, based on the production of reactive oxygen (ROS), have excellent potential in cancer therapy. However, the abnormal redox homeostasis in tumor cells, especially the overexpressed glutathione (GSH) could scavenge ROS and reduce the anti-tumor efficiency. Therefore, it is essential to develop a simple and effective tumor-specific drug delivery system for modulating the tumor microenvironment (TME) and achieving synergistic therapy at the tumor site. In this study, self-assembled nanoparticles (named CDZP NPs) were developed using copper ion (Cu2+), doxorubicin (Dox), zinc phthalocyanine (ZnPc) and a trace amount of poly(2-(di-methylamino)ethylmethacrylate)-poly[(R)-3-hydroxybutyrate]-poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA-PHB-PDMAEMA) through chelation, π-π stacking and hydrophobic interaction. These triple factor-responsive (pH, laser and GSH) nanoparticles demonstrated unique advantages through the synergistic effect. Highly controllable drug release ensured its effectiveness at the tumor site, Dox-induced chemotherapy and ZnPc-mediated fluorescence (FL) imaging exhibited the distribution of nanoparticles. Meanwhile, Cu2+-mediated GSH-consumption not only reduced the intracellular ROS elimination but also produced Cu+ to catalyze hydrogen peroxide (H2O2) and generated hydroxyl radicals (˙OH), thereby enhancing the chemodynamic and photodynamic therapy. Herein, this study provides a green and relatively simple method for preparing multifunctional nanoparticles that can effectively modulate the TME and improve synergetic cancer therapy.

Characterising the distribution of mangroves along the southern coast of Vietnam using multi-spectral indices and a deep learning model.

Mangroves are an ecologically and economically valuable ecosystem that provides a range of ecological services, including habitat for a diverse range of plant and animal species, protection of coastlines from erosion and storms, carbon sequestration, and improvement of water quality. Despite their significant ecological role, in many areas, including in Vietnam, large scale losses have occurred, although restoration efforts have been underway. Understanding the scale of the loss and the efficacy of restoration requires high resolution temporal monitoring of mangrove cover on large scales. We have produced a time series of 10-m-resolution mangrove cover maps using the Multispectral Instrument on the Sentinel 2 satellites and with this tool measured the changes in mangrove distribution on the Vietnamese Southern Coast (VSC). We extracted the annual mangrove cover ranging from 2016 to 2023 using a deep learning model with a U-Net architecture based on 17 spectral indices. Additionally, a comparison of misclassification by the model with global products was conducted, indicating that the U-Net architecture demonstrated superior performance when compared to experiments including multispectral bands of Sentinel-2 and time-series of Sentinel-1 data, as shown by the highest performing spectral indices. The generated performance metrics, including overall accuracy, precision, recall, and F1-score were above 90 % for entire years. Water indices were investigated as the most important variables for mangrove extraction. Our study revealed some misclassifications by global products such as World Cover and Global Mangrove Watch and highlighted the significance of our study for local analysis. While we did observe a loss of 34,778 ha (42.2 %) of mangrove area in the region, 47,688 ha (57.8 %) of new mangrove area appeared, resulting in a net gain of 12,910 ha (15.65 %) over the eight-year period of the study. The majority of new mangrove areas were concentrated in Ca Mau peninsulas and within estuaries undergoing recovery programs and natural recovery processes. Mangrove loss occurred in regions where industrial development, wind farm projects, reclaimed land, and shrimp pond expansion is occurring. Our study provides a theoretical framework as well as up-to-date data for mapping and monitoring mangrove cover change that can be readily applied at other sites.

Inflammatory cytokines mediating the effect of oral lichen planus on oral cavity cancer risk: a univariable and multivariable mendelian randomization study.

BACKGROUND: While observational studies and experimental data suggest a link between oral lichen planus (OLP) and oral cavity cancer (OCC), the causal relationship and the role of inflammatory cytokines remain unclear. METHODS: This study employed a univariable and multivariable Mendelian Randomization (MR) analysis to investigate the causal relationship between OLP and the risk of OCC. Additionally, the potential role of inflammatory cytokines in modulating this association was explored. Instrumental variables were derived from genetic variants associated with OLP (n = 377,277) identified in Finngen R9 datasets, with 41 inflammatory cytokines as potential mediators, and OCC (n = 4,151) as the outcome variable. Analytical methods including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, and MR-PRESSO were utilized to assess the causal links among OLP, inflammatory cytokines, and OCC risk. Multivariable MR (MVMR) was then applied to quantify the mediating effects of these cytokines in the relationship between OLP and increased OCC risk. RESULTS: MR analysis provided strong evidence of a causal relationship between OLP (OR = 1.417, 95% CI = 1.167-1.721, p < 0.001) and the risk of OCC. Furthermore, two inflammatory cytokines significantly influenced by OLP, IL-13 (OR = 1.088, 95% CI: 1.007-1.175, P = 0.032) and IL-9 (OR = 1.085, 95% CI: 1.005-1.171, P = 0.037), were identified. Subsequent analysis revealed a significant causal association only between IL-13 (OR = 1.408, 95% CI: 1.147-1.727, P = 0.001) and higher OCC risk, establishing it as a potential mediator. Further, MVMR analysis indicated that IL-13 (OR = 1.437, 95% CI = 1.139-1.815, P = 0.002) mediated the relationship between OLP and OCC, accounting for 8.13% of the mediation. CONCLUSION: This study not only elucidates the potential causal relationship between OLP and the risk of OCC but also highlights the pivotal mediating role of IL-13 in this association.

CXCL9 mediating the effect of thyroid disorders on oral and oropharyngeal cancer risk: A mediation Mendelian randomization study.

INTRODUCTION: The established association between thyroid disorders (TD) and its two main subtypes-hyperthyroidism and hypothyroidism-and the incidence of oral and oropharyngeal cancer (OCPC) has been substantiated. However, the direct causal relationship and potential intermediary mechanisms linking these conditions have not been clearly defined in prior studies. MATERIAL & METHODS: This study employed univariate Mendelian randomization (MR) analysis to explore those relationship. Instrumental variables from genome-wide association study (GWAS) datasets for TD (n = 218,792), hyperthyroidism (n = 460,499), hypothyroidism (n = 213,990), and OCPC (n = 12,619), along with 41 intermediary inflammatory cytokines (n = 8293), were analyzed. Inverse variance weighting (IVW) method assessed the causal relationships, while summary MR analysis with pQTL datasets from decode and 91 inflammatory cytokines explored the cytokines' roles as biomarkers and therapeutic targets for OCPC. Multivariable MR (MVMR) analysis quantified the mediation effect of these cytokines in the TD-OCPC relationship. RESULTS: UVMR analysis provided strong evidence for a causal relationship between TD (OR = 1.376, 95 % CI = 1.142-1.656, p = 0.001), hyperthyroidism (OR = 1.319, 95 % CI=1.129-1.541, p = 0.001), hypothyroidism (OR = 1.224, 95 % CI = 1.071-1.400, p = 0.003), and the risk of OCPC. CXCL9 was identified as a significant intermediary in mediating the risk of OCPC from TD and its two subtypes (OR = 1.218, 95 % CI = 1.016-1.461, P = 0.033), suggesting its potential as a predictive biomarker for OCPC. MVMR analysis further revealed that CXCL9 mediated 7.94 %, 14.4 %, and 18 % of the effects of TD, hyperthyroidism, and hypothyroidism on OCPC risk, respectively. DISCUSSION: This study not only elucidated the potential causal relationships between TD including its two subtypes and OCPC risk, but also highlighted CXCL9 as a pivotal mediator in this association.

Silkworm pupae protein co-degradation by magnetic nanoparticles immobilized proteinase K and Mucor circinelloides aspartic protease for further utilization of sericulture by-products.

Silkworm pupae, by-product of sericulture industry, is massively discarded. The degradation rate of silkworm pupae protein is critical to further employment, which reduces the impact of waste on the environment. Herein, magnetic Janus mesoporous silica nanoparticles immobilized proteinase K mutant T206M and Mucor circinelloides aspartic protease were employed in the co-degradation. The thermostability of T206M improved by enhancing structural rigidity (t1/2 by 30 min and T50 by 5 °C), prompting the degradation efficiency. At 65 °C and pH 7, degradation rate reached the highest of 61.7%, which improved by 26% compared with single free protease degradation. Besides, the immobilized protease is easy to separate and reuse, which maintains 50% activity after 10 recycles. Therefore, immobilized protease co-degradation was first applied to the development and utilization of silkworm pupae resulting in the release of promising antioxidant properties and reduces the environmental impact by utilizing a natural and renewable resource.

Toxic effects of microplastics and nitrite exposure on intestinal histology, digestion, immunity, and microbial community of shrimp Litopenaeus vannamei.

Nitrite and microplastics (MPs) are environmental pollutants that threaten intestinal integrity and affect immune function of shrimp. In this study, the shrimp Litopenaeus vannamei were exposed to the individual and combined stress of nitrite and microplastics for 14 days, and the changes of intestinal histology and physiological functions were investigated. After single and combined stress, affectations occurred in intestinal tissue; the antioxidant enzyme activities (MDA, H2O2, CAT increased) and gene expression levels (CAT, SOD, GPx, HSP70 up-regulated) changed. The expression levels of detoxification genes (CYP450, UGT down-regulated, GST up-regulated), apoptosis genes (CASP-3 up-regulated) and endoplasmic reticulum stress genes (Bip, GRP94 down-regulated) changed. Furthermore, the stress also increased intestinal microbial diversity, causing bacterial composition variation, especially beneficial bacteria and pathogenic bacteria. These results suggested that nitrite and microplastics stress had adverse effects on the intestinal health of L. vannamei by affecting intestinal tissue morphology, immune response and microbial community.

shinyTempSignal: an R shiny application for exploring temporal and other phylogenetic signals.

The molecular clock model is fundamental for inferring species divergence times from molecular sequences. However, its direct application may introduce significant biases due to sequencing errors, recombination events, and inaccurately labeled sampling times. Improving accuracy necessitates rigorous quality control measures to identify and remove potentially erroneous sequences. Furthermore, while not all branches of a phylogenetic tree may exhibit a clear temporal signal, specific branches may still adhere to the assumptions, with varying evolutionary rates. Supporting a relaxed molecular clock model better aligns with the complexities of evolution. The root-to-tip regression method has been widely used to analyze the temporal signal in phylogenetic studies and can be generalized for detecting other phylogenetic signals. Despite its utility, there remains a lack of corresponding software implementations for broader applications. To address this gap, we present shinyTempSignal, an interactive web application implemented with the shiny framework, available as an R package and publicly accessible at https://github.com/YuLab-SMU/shinyTempSignal. This tool facilitates the analysis of temporal and other phylogenetic signals under both strict and relaxed models. By extending the root-to-tip regression method to diverse signals, shinyTempSignal helps in the detection of evolving features or traits, thereby laying the foundation for deeper insights and subsequent analyses.

A Sn-Based Hybrid Ferroelastic Semiconductor with High-Temperature Dielectric Switching.

Organic-inorganic halide hybrids have been extensively developed and used in optoelectronic devices because of their superior performance such as ease of assembly, flexible structural tunability, and excellent optoelectronic properties. Ferroelastic strain might be used to modulate and control photoelectric properties such as photovoltaic voltage, while organic-inorganic hybrid ferroelastic semiconductors remain relatively unexplored. Herein, we successfully design a new Sn-base, lead-free hybrid ferroelastic semiconductor, [TPMA]2[SnCl6] (TPMA = benzyl trimethylammonium). It undergoes a high-temperature -3mF-1-type ferroelastic phase transition at 408 K, and intriguingly, its ferroelastic domains can be simultaneously switched under the stimulation of external heat and stress. The ferroelastic phase transition might be derived from the order-disorder transition of organic cations during heating and cooling. Moreover, [TPMA]2[SnCl6] also demonstrates a high-temperature dielectric switching property around 408 K, which has good stability and reproducibility. With those benefits, [TPMA]2[SnCl6] shows great potential in applications such as energy storage devices, optoelectronic devices, shape memory, intelligent switches, and so on.

Hemodynamic assessment for intracranial atherosclerosis from angiographic images: a clinical validation study.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) is one of the leading causes of ischemic stroke. Conventional anatomical analysis by CT angiography, MRI, or digital subtraction angiography can provide valuable information on the anatomical changes of stenosis; however, they are not sufficient to accurately evaluate the hemodynamic severity of ICAS. The goal of this study was to assess the diagnostic performance of the pressure ratio across intracranial stenoses (termed as fractional flow (FF)) derived from cerebral angiography for the diagnosis of hemodynamically significant ICAS defined by pressure wire-derived FF. METHODS: This retrospective study represents a feasible and reliable method for calculating the FF from cerebral angiography (AccuFFicas). Patients (n=121) who had undergone wire-based measurement of FF and cerebral angiography were recruited. The accuracy of the computed pressure ratio was evaluated using wire-based FF as the reference standard. RESULTS: The mean value of wire-based FF was 0.78±0.19, while the computed AccuFFicas had an average value of 0.79±0.18. Good correlation (Pearson's correlation coefficient r=0.92, P<0.001) between AccuFFicas and FF was observed. Bland-Altman analysis showed that the mean difference between AccuFFicas and FF was -0.01±0.07, indicating good agreement. The area under the curve (AUC) of AccuFFicas in predicting FF≤0.70, FF≤0.75, and FF≤0.80 was 0.984, 0.986, and 0.962, respectively. CONCLUSION: Angiography-based FF computed from cerebral angiographic images could be an effective computational tool for evaluating the hemodynamic significance of ICAS.

Provider communication contributes to colorectal cancer screening intention through improving screening outcome expectancies and perceived behavioral control.

Colorectal cancer (CRC) screening continues to be underutilized in the US despite the availability of multiple effective, guideline-recommended screening options. Provider recommendation has been consistently shown to improve screening completion. Yet, available literature provides little information as to how specific information providers communicate influence patient decision-making about CRC screening. We tested the pathways through which information communicated by providers about the "Why" and "How" of CRC screening using the mt-sDNA test contributes to intention to complete the test. Data came from a behavioral theory-informed survey that we developed to identify psychosocial factors associated with mt-sDNA screening. RTI International administered the survey between 03/2022-06/2022 to a sample of US adults ages 45-75 who received a valid order for mt-sDNA screening with a shipping date between 5/2021-9/2021. Participants completed an electronic or paper survey. We tested the proposed relationships using structural equation modeling and tested indirect effects using Monte Carlo method. A total of 2,973 participants completed the survey (response rate: 21.7%) and 81.6% (n = 2,427) reported have had a conversation with their health care provider about mt-sDNA screening before the test was ordered. We found that "Why" information from providers was positively associated with perceived effectiveness of mt-sDNA screening, while "How" information was positively associated with perceived ease of use. "Why" information contributed to screening intention through perceived effectiveness while "How" information contributed to screening intention through perceived ease of use. These findings emphasize the critical role of provider communication in shaping patient decision-making regarding CRC screening. CRC screening interventions could consider implementing provider-patient communication strategies focusing on improving patient understanding of the rationale for CRC screening and the effectiveness of available screening options as well as addressing barriers and enhancing patients' self-efficacy in completing their preferred screening option.

DSPE-PEG2000-methotrexate nanoparticles encapsulating phenobarbital sodium kill cancer cells by inducing pyroptosis.

Cancer is a life-threatening disease worldwide. Nanomedicine and nanodelivery systems are recently developed scientific field that employs specific materials in the nanoscale range to deliver drugs. Lipid-based nanoparticles are an ideal delivery system since they exhibit many advantages, including high bioavailability, self-assembly, formulation simplicity, and the ability to exhibit a plethora of physicochemical properties. Herein, we report that phenobarbital sodium can kill cancer cells by using the DSPE-PEG2000-methotrexate nanoparticle delivery system, which can target folate receptors that are usually overexpressed on a variety of cancer cells. The released phenobarbital then executes cancer cells by inducing pyroptosis. Results from our animal model further indicate that the nanomedicine of nanoparticle-encapsulated phenobarbital sodium is a promising anticancer therapy.

Development and validation of a prognostic score to identify the optimal candidate for preemptive TIPS in patients with cirrhosis and acute variceal bleeding.

BACKGROUND AND AIM: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining "high-risk" have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. APPROACH AND RESULTS: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). CONCLUSIONS: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.

Spinal interleukin-16 mediates inflammatory pain via promoting glial activation.

Proinflammatory cytokines are crucial contributors to neuroinflammation in the development of chronic pain. Here, we identified il16, which encodes interleukin-16 (IL-16), as a differentially expressed gene in spinal dorsal horn of a complete Freund's Adjuvant (CFA) inflammatory pain model in mice by RNA sequencing. We further investigated whether and how IL-16 regulates pain transmission in the spinal cord and contributes to the development of inflammatory pain hypersensitivity. RNA sequencing and bioinformatics analysis revealed elevated IL-16 transcript levels in the spinal dorsal horn after CFA injection. This increase was further confirmed by qPCR, immunofluorescence, and western blotting. Knockdown of IL-16 by intrathecal injection of IL-16 siRNA not only attenuated CFA-induced mechanical and thermal pain hypersensitivity, but also inhibited enhanced c-fos expression and glial activation in the spinal dorsal horn in male mice injected with CFA. Moreover, exogenous IL-16 induced nociceptive responses and increased c-fos expression and glial activation in spinal dorsal horn. This effect was largely impaired when CD4, the binding receptor for IL-16, was inhibited. In addition, CD4 expression was upregulated in the spinal dorsal horn after CFA injection and CD4 was present in microglia and in contact with astrocytes and activated spinal neurons. Taken together, these results suggest that enhanced IL-16-CD4 signaling triggers pain and activates microglia and astrocytes in the spinal dorsal horn, thus contributing to inflammatory pain. IL-16 may serve as a promising target for the treatment of inflammatory pain.

CD95 promotes stemness of colorectal cancer cells by lncRNA MALAT1.

Colorectal cancer (CRC) is the second most fatal cancer. Many studies have shown that cancer stemness contributes to resistance to conventional chemotherapy and poor prognosis. However, the mechanisms involved in maintaining cancer stemness in CRC are still obscure and few clinical drugs were used to target cancer stemness. Previous studies had reported CD95 increases the stemness of cancer cells with long-term stimulation of exogenous agonist CD95 ligand (CD95L). However, the expression of CD95L is relative low in certain human tumor tissues. In this study, we found that CD95 was highly expressed in CRC cells, and in vitro it promoted the tumorsphere formation, chemotherapy resistance and in vivo tumor growth without stimulation of exogenous CD95L. Mechanistically, the bulk and single-cell RNA-sequencing results suggested that CD95 promotes stemness of CRC cells through upregulation of long non-coding RNAs metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1). MALAT1 knockdown inhibited CD95-induced tumorsphere formation and chemotherapy resistance. In summary, our findings reveal that CD95 has the capability to modulate cancer stemness via the action of the lncRNA MALAT1. Targeting CD95 may be a promising strategy to inhibit cancer stemness in CRC.

Interleukin-8 predicts short-term mortality in acute-on-chronic liver failure patients with hepatitis B-related-related cirrhosis background.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a distinctive and severe syndrome, marked by an excessive systemic inflammatory response. In vivo, interleukin 8 (IL-8) is an essential pro-inflammatory cytokine. We aimed to investigate the value of serum IL-8 levels in predicting mortality in ACLF patients in the background of hepatitis B virus-related cirrhosis. METHODS: In this study, we conducted a retrospective analysis of the clinical baseline characteristics of 276 patients with ACLF in the context of HBV-related cirrhosis. Logistic regression analysis was employed to identify independent risk factors for short-, intermediate-, and long-term mortality. Using these independent risk factors, we developed a nomogram model, which was subsequently validated. To assess the clinical usefulness of the nomogram model, we performed decision curve analysis (DCA). RESULTS: Out of the 276 patients with ACLF, 98 (35.5%), 113 (40.9%), and 128 (46.4%) died within 28, 90, and 180 days, respectively. Serum IL-8 levels were only an independent predictor of 28-day mortality and could simply classify ACLF patients. Conversely, mean arterial pressure (MAP), HBV-DNA, and COSHACLF IIs were independent predictors of mortality across all three observation periods. We constructed a nomogram based on IL-8 that was able to visualise and predict 28-day mortality with a C-index of 0.901 (95% CI: 0.862-0.940). Our calibration curves, Predicted Probability of Death & Actual Survival Status plot, and Confusion Matrix demonstrated the nomogram model's strong predictive power. DCA indicated the nomogram's promising clinical utility in predicting 28-day mortality in ACLF patients. CONCLUSION: Serum IL-8 levels predict short-term mortality in ACLF patients in the background of HBV-associated cirrhosis, and the developed Nomogram model has strong predictive power and good clinical utility.

Systemic inflammatory response is a pathophysiological feature of patients with acute-on-chronic liver failure, and the serum level of interleukin-8 can predict the short-term prognosis of patients.

Spinal apolipoprotein E is involved in inflammatory pain via regulating lipid metabolism and glial activation in the spinal dorsal horn.

INTRODUCTION: Inflammation and nerve injury promote astrocyte activation, which regulates the development and resolution of pain, in the spinal dorsal horn. APOE regulates lipid metabolism and is predominantly expressed in the astrocytes. However, the effect of astrocytic APOE and lipid metabolism on spinal cellular function is unclear. This study aimed to investigate the effect of spinal Apoe on spinal cellular functions using the complete Freund's adjuvant (CFA)-induced inflammatory pain mouse model. METHODS: After intraplantar injection of CFA, we assessed pain behaviors in C57BL6 and Apoe knockout (Apoe-/-) mice using von Frey and Hargreaves' tests and analyzed dorsal horn samples (L4-5) using western blotting, immunofluorescence, quantitative real-time polymerase chain reaction, and RNA sequencing. RESULTS: The Apoe levels were markedly upregulated at 2 h and on days 1 and 3 post-CFA treatment. Apoe was exclusively expressed in the astrocytes. Apoe-/- mice exhibited decreased pain on day 1, but not at 2 h, post-CFA treatment. Apoe-/- mice also showed decreased spinal neuron excitability and paw edema on day 1 post-CFA treatment. Global transcriptomic analysis of the dorsal horn on day 1 post-CFA treatment revealed that the differentially expressed mRNAs in Apoe-/- mice were associated with lipid metabolism and the immune system. Astrocyte activation was impaired in Apoe-/- mice on day 1 post-CFA treatment. The intrathecal injection of Apoe antisense oligonucleotide mitigated CFA-induced pain hypersensitivity. CONCLUSIONS: Apoe deficiency altered lipid metabolism in astrocytes, exerting regulatory effects on immune response, astrocyte activation, and neuronal activity and consequently disrupting the maintenance of inflammatory pain after peripheral inflammation. Targeting APOE is a potential anti-nociception and anti-inflammatory strategy.