An integrated machine learning model enhances delayed graft function prediction in pediatric renal transplantation from deceased donors.

BACKGROUND: Kidney transplantation is the optimal renal replacement therapy for children with end-stage renal disease; however, delayed graft function (DGF), a common post-operative complication, may negatively impact the long-term outcomes of both the graft and the pediatric recipient. However, there is limited research on DGF in pediatric kidney transplant recipients. This study aims to develop a predictive model for the risk of DGF occurrence after pediatric kidney transplantation by integrating donor and recipient characteristics and utilizing machine learning algorithms, ultimately providing guidance for clinical decision-making. METHODS: This single-center retrospective cohort study includes all recipients under 18 years of age who underwent single-donor kidney transplantation at our hospital between 2016 and 2023, along with their corresponding donors. Demographic, clinical, and laboratory examination data were collected from both donors and recipients. Univariate logistic regression models and differential analysis were employed to identify features associated with DGF. Subsequently, a risk score for predicting DGF occurrence (DGF-RS) was constructed based on machine learning combinations. Model performance was evaluated using the receiver operating characteristic curves, decision curve analysis (DCA), and other methods. RESULTS: The study included a total of 140 pediatric kidney transplant recipients, among whom 37 (26.4%) developed DGF. Univariate analysis revealed that high-density lipoprotein cholesterol (HDLC), donor after circulatory death (DCD), warm ischemia time (WIT), cold ischemia time (CIT), gender match, and donor creatinine were significantly associated with DGF (P < 0.05). Based on these six features, the random forest model (mtry = 5, 75%p) exhibited the best predictive performance among 97 machine learning models, with the area under the curve values reaching 0.983, 1, and 0.905 for the entire cohort, training set, and validation set, respectively. This model significantly outperformed single indicators. The DCA curve confirmed the clinical utility of this model. CONCLUSIONS: In this study, we developed a machine learning-based predictive model for DGF following pediatric kidney transplantation, termed DGF-RS, which integrates both donor and recipient characteristics. The model demonstrated excellent predictive accuracy and provides essential guidance for clinical decision-making. These findings contribute to our understanding of the pathogenesis of DGF.

Efficacy and safety of compound porcine cerebroside and ganglioside injection (CPCGI) versus piracetam on cognition and functional outcomes for adults with traumatic brain injury: A study protocol for randomized controlled trial.

Background: Traumatic brain injury (TBI) is a common neurosurgical disease in emergency rooms with poor prognosis, imposing severe burdens on patients and their families. Evidence indicates that piracetam and compound porcine cerebroside and ganglioside injection (CPCGI) can improve cognitive levels in TBI patients to enhance functional prognosis, but there is still a research gap regarding the efficacy of CPCGI. This study aims to determine the effectiveness and safety of CPCGI in improving cognitive and functional outcomes in TBI patients. Methods: This study is a multicenter, randomized, parallel-group, double-blind trial aiming to recruit 900 adult patients with mild to moderate TBI. After providing informed consent, 600 patients will be randomly assigned to the CPCGI group (20 ml/d, for 14 days), and 300 patients will be randomized to the piracetam group as a control (20 ml/d, for 14 days), followed up for 3 months after treatment. The primary outcome is the change in the Montreal Cognitive Assessment (MoCA) score from baseline after 3 months. The main secondary outcome measures include Mini-Mental State Examination (MMSE) scores, Glasgow Outcome Scale-Extended (GOS-E), and the Barthel Index at 1 and 3 months. Discussion: This multi-center clinical trial aims to provide high-quality evidence on the efficacy and safety of CPCGI in improving cognitive and functional outcomes in mild to moderate TBI patients. Trial registration: ChiCTR2000040466, date of registration: November 28, 2020.

Inhibition of CTLA-4 accelerates atherosclerosis in hyperlipidemic mice by modulating the Th1/Th2 balance via the NF-κB signaling pathway.

Objective: Though an increased risk of atherosclerosis is associated with anti-CTLA-4 antibody therapy, the underlying mechanisms remain unclear. Methods: C57BL/6 mice were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody twice a week for 4 weeks, after being injected with AAV8-PCSK9 and fed a Paigen diet (PD). The proportion of aortic plaque and lipid accumulation were assessed using Oil Red O staining, while the morphology of atherosclerotic lesions was analyzed with hematoxylin and eosin staining. Collagen content was evaluated through Picrosirius Red (PSR) staining, while inflammatory cell infiltration was examined with immunofluorescence staining. CD4+ T cells secreting IFN-γ and IL-4, which represent Th1 and Th2 cells respectively, were detected by flow cytometry and real-time PCR. Protein levels of p-IκBα, IκBα, p-p65, and p65 were determined by Western blot. Results: Inhibiting CTLA-4 exacerbated PD-induced plaque progression and promoted CD4+ T cell infiltration in the aortic root. The anti-CTLA-4 antibody promoted CD4+ T cell differentiation toward the Th1 type, as indicated by an increase in the Th1/Th2 ratio. Compared to the anti-IgG group, treatment with anti-CTLA-4 antibody significantly elevated the protein levels of p-IκBα and p-p65, as well as the mRNA levels of TNF-α, IL-6, ICAM-1, and VCAM-1. Inhibiting the NF-κB signaling pathway attenuated the overall pathological phenotype induced by the anti-CTLA-4 antibody treatment. Conclusion: Anti-CTLA-4 treatment promotes the progression of atherosclerosis by activating NF-κB signaling and modulating the Th1/Th2 balance. Our results provide a rationale for preventing and/or treating atherosclerosis accelerated by anti-CTLA-4 antibody therapy in cancer patients.

Identification of Psychological Symptom Clusters and Their Influencing Factors in Women Undergoing Assisted Reproductive Technology in China: a Cross-Sectional Study.

Background: There are multiple psychological symptoms in women undergoing assisted reproductive technology, which seriously affect health-related quality of life and even cause patients to stop treatment. Aim: This study aimed to identify psychological symptom clusters and their influencing factors in women undergoing assisted reproductive technology. Methods: A cross-sectional survey was conducted from June to November 2023 at the reproductive centers of Nanjing Women and Children's Healthcare Hospital. Data on demographic and clinical characteristics and Symptom Checklist-90 were collected. Exploratory factor analysis was performed to identify psychological symptom clusters. Univariate logistic regression analysis and multivariate logistic regression analysis were performed to explore influencing factors. Results: A total of 213 patients were recruited. The study found that the included participants scored higher on all SCL scales than the general Chinese females. The three most common were trouble remembering things (81.7%), feeling easily annoyed or irritated (81.2%), and feeling low in energy or slowed down (70.9%). Six symptom clusters were identified: paranoid ideation, depression, obsessive-compulsive disorder, interpersonal sensitivity, somatization, and sleep disorders. Multivariate logistic regression analysis showed that duration of infertility treatment (>12 months) was identified as a risk factor for sleep disorder cluster (OR=2.833, 95% CI:1.355~5.922), adverse pregnancy history was identified as a risk factor for paranoid ideation cluster (OR=2.961,95% CI:1.406~6.253), depression cluster (OR=2.404,95% CI:1.240~4.660), and obsessive-compulsive cluster (OR=1.810, 95% CI:1.016~3.233), financial burden during treatment was identified as risk factors for all symptom clusters[(OR=5.869, 95% CI:1.717~20.057),(OR=6.490,95% CI:2.210~19.063),(OR=3.034,95% CI:1.560~5.898),(OR=7.078,95% CI:2.420~20.698),(OR=4.532,95% CI:1.845~10.397),(OR=2.151,95% CI:1.129~4.098)]. Conclusion: Women undergoing ART experience various psychological symptoms that are interrelated and exist in the form of symptom clusters. More attention should be paid to the psychological status of patients with longer duration of infertility treatment, adverse pregnancy history, and financial burden during treatment. This study guides the development of targeted and effective psychological interventions to facilitate symptom management in women undergoing ART.

An Immersive and Interactive VR Dataset to Elicit Emotions.

Images and videos are widely used to elicit emotions; however, their visual appeal differs from real-world experiences. With virtual reality becoming more realistic, immersive, and interactive, we envision virtual environments to elicit emotions effectively, rapidly, and with high ecological validity. This work presents the first interactive virtual reality dataset to elicit emotions. We created five interactive virtual environments based on corresponding validated 360° videos and validated their effectiveness with 160 participants. Our results show that our virtual environments successfully elicit targeted emotions. Compared with the existing methods using images or videos, our dataset allows virtual reality researchers and practitioners to integrate their designs effectively with emotion elicitation settings in an immersive and interactive way.

Coadministration of Quercetin and Indocyanine Green via PEGylated Phospholipid Micelles for Augmented Chem-Photothermal Combination Tumor Therapy.

A significant impediment persists in developing multicomponent nanomedicines designed to dismantle the heat shock protein (HSP)-based protective mechanism of malignant tumors during photothermal therapy. Herein, well-defined PEGylated phospholipid micelles were utilized to coencapsulate quercetin (QUE, a natural anticancer agent and potent HSP inhibitor) and indocyanine green (ICG, a photothermal agent) with the aim of achieving synchronized and synergistic drug effects. The subsequent investigations validated that the tailored micellar system effectively enhanced QUE's water solubility and augmented its cellular internalization efficiency. Intriguingly, the compositional PEGylated phospholipids induced extraordinary endoplasmic reticulum stress, thereby sensitizing the tumor cells to QUE. Furthermore, QUE played a crucial role in inhibiting the stress-induced overexpression of HSP70, thereby augmenting the photothermal efficacy of ICG. In systemic applications, the proposed nanotherapeutics exhibited preferential accumulation within tumors and exerted notable tumoricidal effects against 4T1 xenograft tumors under 808 nm near-infrared irradiation, facilitated by prominent near-infrared fluorescence imaging-guided chemo-photothermal therapy. Therefore, our strategy for fabricating multicomponent nanomedicines emerges as a coordinated platform for optimizing antitumor therapeutic efficacy and offers valuable insights for diverse therapeutic modalities.

CircCOCH plays a critical role in Hepatocellular carcinoma through modulating miR-450a and activating PI3K/mTOR pathway.

Hepatocellular carcinoma (HCC) is a primary liver cancer with high pathogenicity and extremely poor prognosis. The role of circular RNAs (circRNAs) in HCC carcinogenesis and progression remains to be determined. Based on the analysis of HCC-related databases, as well as the expression analysis and identification of 25 HCC patient tissues and HCC cell lines, we found that the hsa_circ_0031431 (circCOCH) is significantly highly expressed in HCC tissues and cell lines. High circCOCH expression is associated with enhanced tumor proliferation and metastasis, and knocking down circCOCH can inhibit the growth of HCC in vivo and in vitro. Mechanistic studies show that circCOCH upregulates the expression of epidermal growth factor receptor (EGFR) through sponge miR-450a, thereby activating the Phosphoinositide 3-kinases (PI3Ks) cell pathway to promote HCC proliferation and metastasis. Futhermore, we found that IGF2BP3 mediates the biogenesis of circCOCH. The present study provides innovative insights into the role of circRNAs in the etiology of HCC carcinogenesis and might serve as a new promising therapeutic target for HCC.

Blocking CTLA-4 promotes pressure overload-induced heart failure via activating Th17 cells.

Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.

Ulinastatin shortens the length of ICU stay in critical patients with organ failure: A 7-year real-world study.

BACKGROUND: Ulinastatin has been applied in a series of diseases associated with inflammation but its clinical effects remain somewhat elusive. OBJECTIVE: We aimed to investigate the potential effects of ulinastatin on organ failure patients admitted to the intensive care unit (ICU). METHODS: This is a single-center retrospective study on organ failure patients from 2013 to 2019. Patients were divided into two groups according to using ulinastatin or not during hospitalization. Propensity score matching was applied to reduce bias. The outcomes of interest were 28-day all-cause mortality, length of ICU stay, and mechanical ventilation duration. RESULTS: Of the 841 patients who fulfilled the entry criteria, 247 received ulinastatin. A propensity-matched cohort of 608 patients was created. No significant differences in 28-day mortality between the two groups. Sequential organ failure assessment (SOFA) was identified as the independent risk factor associated with mortality. In the subgroup with SOFA ≤ 10, patients received ulinastatin experienced significantly shorter time in ICU (10.0 d [interquartile range, IQR: 7.0∼20.0] vs 15.0 d [IQR: 7.0∼25.0]; p = .004) and on mechanical ventilation (222 h [IQR:114∼349] vs 251 h [IQR: 123∼499]; P = .01), but the 28-day mortality revealed no obvious difference (10.5% vs 9.4%; p = .74). CONCLUSION: Ulinastatin was beneficial in treating patients in ICU with organ failure, mainly by reducing the length of ICU stay and duration of mechanical ventilation.

Linguistic and cultural validation of symptom questionnaire for visual dysfunctions (SQVD) for psychometric analysis in the Chinese context.

The Spanish scale symptom questionnaire for visual dysfunctions (SQVD) was sinicized and tested for reliability and validity in the Chinese context, employing both classical measurement theory and item response theory. A meticulous translation was conducted using the modified Brislin translation model, with input from experts for cross-cultural debugging and in-depth review. Following a pre-survey study, the Chinese version of the SQVD was finalized. A convenience sampling method was used to select 270 patients from the target group and 252 valid questionnaires were successfully collected. The Rasch model was employed to assess response category functionality, fit statistics, unidimensionality, person and item reliability, separation, targeting, and differential item functioning. Classical test theory was applied to evaluate internal consistency and retest reliability, supplemented by correlation analysis. Job characteristic curves were also plotted to assess diagnostic accuracy. The Chinese SQVD conformed to a unidimensional structure with excellent reliability and validity. Person and item reliabilities were 0.85 and 0.99, respectively, indicating, high stability. Person and item separation indices were 2.37 and 11.54, respectively, signifying strong differentiation ability. Retest reliability was 0.917, further emphasizing the stability of the scale. The area under the receiver operating characteristic curve was 0.908 (95% CI: 0.854, 0.962), with a cutoff value of 7.5 and Youden index of 0.733, highlighting the scale's high diagnostic accuracy. The translated and culturally adapted Chinese SQVD demonstrated excellent psychometric properties. With streamlined items, short assessment time, and high efficiency, the scale is a stable and reliable clinical tool for detecting a variety of conditions related to refractive, regulatory, and binocular vision dysfunction.

Activating α7nAChR suppresses systemic inflammation by mitigating neuroinflammation of the medullary visceral zone in sepsis in a rat model.

Our previous studies have shown that activating α7nAChRs suppresses systemic inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP) in early sepsis. Now that the medullary visceral zone (MVZ) is the center of CAP and responsible for regulating systemic inflammation, what changes will occur in MVZ's pathology and function in sepsis, especially when interfering with α7nAChRs? Does activation of MVZ's α7nAChRs contribute to the inhibition of systemic inflammation? To clarify these issues, we explored the systemic inflammation and immunity state by detecting serum levels of TNF-α, IL-6, HMGB1, sCD14, and CD4+CD25+Treg and TH17 lymphocytes percentage, meanwhile, we analyzed the apoptosis of cholinergic and catecholaminergic neurons and the expressions of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT) in MVZ in sepsis and the interfering effects on α7nAChRs. In this study, we found that in sepsis, serum TNF-α, IL-6, HMGB1, sCD14, CD4+CD25+Treg, and TH17 lymphocytes significantly increased and the ratio of Treg/TH17 significantly decreased, cholinergic and catecholaminergic neurons underwent apoptosis with low expressions of TH and CHAT in MVZ; activation of α7nAChRs not only significantly decreased the levels of septic serum TNF-α, IL-6, HMGB1, sCD14, and TH17 lymphocytes (P ＜ 0.05), but also significantly reduced cholinergic and catecholaminergic neurons' apoptosis, and promoted expressions of TH/CHAT. Our study reveals that sepsis undermines MVZ through neuroinflammation which contributes to the uncontrolled systemic inflammation. Activating central α7nAChRs is not only helpful to restore MVZ's structure and function but also beneficial to subside the inflammatory storm in sepsis. Even if MVZ is damaged in sepsis, cholinergic neurons in MVZ still regulate the systemic inflammation stably.

Hla protein expression and artesunate prevented mice from further damage caused by Staphylococcus aureus pneumonia.

The laboratory standard MRSA strain WHO-2 and clinical isolate S1 were used to establish a pneumonia infection model. The results showed that methicillin increased the expression of Hla and PVL protein at subminimum inhibitory concentration, while artesunate decreased the secretion of Hla and PVL protein. Artesunate alone reduced hemolysin expression and reversed methicillin-induced increases in Hla and PVL proteins. In addition, the study found that the combination of artesunate and methicillin had the best therapeutic effect, with survival rates of 70 % and 40 % at seven days, respectively (corresponding to the WHO-2 and S1 strains). The combination treatment was able to reduce cell mortality, showing a 65 % and 46 % reduction in cell mortality, respectively. The study also found that the combination therapy decreased the expression of alpha-hemolysin and pantone valentin leukin in the culture medium and significantly reduced the activation of NF-kB. This is caused by a significant decrease in the expression of inflammatory factors.

A dual-prodrug nanogel combining Vorinostat and Pyropheophorbide a for a high efficient photochemotherapy.

The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy.

The Discovery of GIT1/ß-Pix Inhibitors: Virtual Screening and Biological Evaluation of New Small-molecule Compounds with Anti-invasion Effect in Gastrointestinal Neoplasms.

Background and Objective: GIT1 (G-protein-coupled receptor kinase interacting protein-1) has been found to be highly related with cancer cell invasion and metastasis in many cancer types. ß-Pix (p21-activated kinase-interacting exchange factor) is one of the proteins that interact with GIT1. Targeting GIT1/ß-Pix complex might be a potential therapeutic strategy for interfering cancer metastasis. However, at present, no well-recognized small-molecule inhibitor targeting GIT1/ß-Pix is available. Thus, we aim to discover novel GIT1/ß-Pix inhibitors with simple scaffold, high activity and low toxicity to develop new therapeutic strategies to restrain cancer metastasis. Methods: GIT1/ß-Pix inhibitors were identified from ChemBridge by virtual screening. Briefly, the modeling of GIT1 was performed and the establishment of GIT1/ß-Pix binding pocket enabled the virtual screening to identify the inhibitor. In addition, direct binding of the candidate molecules to GIT1 was detected by biolayer interferometry (BLI) to discover the hit compound. Furthermore, the inhibitory effect on invasion of stomach and colon cancer cells in vitro was carried out by the transwell assay and detection of epithelial-mesenchymal transition (EMT)-related proteins. Finally, the binding mode of hit compound to GIT1 was estimated by molecular dynamics simulation to analyze the key amino residues to guide further optimization. Results: We selected the top 50 compounds from the ChemBridge library by virtual screening. Then, by skeleton similarity analysis nine compounds were selected for further study. Furthermore, the direct interaction of nine compounds to GIT1 was detected by BLI to obtain the best affinitive compound. Finally, 17302836 was successfully identified (KD = 84.1±2.0 µM). In vitro tests on 17302836 showed significant anti-invasion effect on gastric cancer and colorectal cancer. Conclusion: We discovered a new GIT1/ß-Pix inhibitor (17302836) against gastrointestinal cancer invasion and metastasis. This study provides a promising candidate for developing new GIT1/ß-Pix inhibitors for tumor treatment.

Effect of l-oxiracetam and oxiracetam on memory and cognitive impairment in mild-to-moderate traumatic brain injury patients: Study protocol for a randomized controlled trial.

Objectives: Patients with traumatic brain injury (TBI) often suffer memory and cognitive impairments, and oxiracetam-like drugs are considered to have a positive impact on these symptoms potentially. However, the efficacy and safety of l-oxiracetam and oxiracetam in TBI patients have not been sufficiently investigated. Methods: The study adopts a multicenter, randomized, double-blind, parallel-group, phase 3 clinical trial design in 74 centers across 51 hospitals in China. A total of 590 TBI patients meeting criteria will be randomly allocated into three groups in a 2:2:1 ratio: l-oxiracetam group, oxiracetam group, and placebo group. The treatment period is 14 days, with a follow-up period of 90 days. The primary outcome measure is the change in the Loewenstein Occupational Therapy Cognitive Assessment score at 90 days after treatment. Secondary outcomes include changes in other cognitive assessments, neurological function, activities of daily living, and safety assessments. Discussion: There is no robust evidence to suggest that l-oxiracetam and oxiracetam can enhance memory and cognitive function in patients with mild to moderate TBI. This study has the potential to answer this crucial clinical question. Trial registration: chinadrugtrials.org.cn, identifier CTR20192539; ClinicalTrials.gov, identifier NCT04205565.

Utilizing a suture-constrained covered stent for shunt reduction to treat transjugular intrahepatic portosystemic shunt-related refractory hepatic encephalopathy: a retrospective study.

PURPOSE: Refractory hepatic encephalopathy (RHE) can occur as a consequence of excessive shunting following the creation of a transjugular intrahepatic portosystemic shunt (TIPS). We describe a technique that utilizes a suture-constrained covered stent for shunt reduction to treat TIPS-related RHE. MATERIALS AND METHODS: Between January 2017 and September 2023, 25 patients with TIPS-related RHE who underwent shunt reduction utilizing a suture-constrained covered stent were reviewed. The procedure involved reducing the diameter of a polytetrafluoroethylene-covered stent from 8 to 5 mm with a non-absorbable suture and inserting it into the existing TIPS stent to reduce shunt flow. RESULTS: Twelve of the 25 patients were evaluated. Shunt reduction was technically successful in all patients and no immediate complications related to the procedures were observed. Varying degrees of improvement in HE symptoms were observed after shunt reduction, with a mean increase in portosystemic gradient of 5 mmHg compared to pre-procedure, and complete disappearance of symptoms was observed in seven (58.3%) individuals. After a median follow-up of 8.3 months, HE recurred in 4 patients (33.3%) and TIPS indication recurred in 2 patients (16.7%) in the form of ascites and variceal bleeding, respectively. One patient (8.3%) developed shunt dysfunction detected by Doppler ultrasound and was accompanied by the presence of hepatic hydrothorax and ascites. At the end of the study, 5 patients (41.7%) were alive, 5 (41.7%) succumbed to liver failure, and 2 (16.7%) succumbed to pneumonia. CONCLUSIONS: Constraining the stent diameter with a suture is feasible, and using this suture-constrained covered stent for shunt reduction can effectively improve TIPS-related RHE. Further investigations are warranted to precisely delineate the impact of the increased portosystemic gradient and to optimize patient survival.

Crafting Docetaxel-Loaded Albumin Nanoparticles Through a Novel Thermal-Driven Self-Assembly/Microfluidic Combination Technology: Formulation, Process Optimization, Stability, and Bioavailability.

Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges. Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated. Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX. Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.

FTO is Associated with Patient Prognosis and Immune Infiltrates in Gastric Cancer and Regulates TGF-ß Expression.

AIMS: This study aimed to examine the associations of FTO expression with prognosis, tumor microenvironment (TME), immune cell infiltration, immune checkpoint genes, and relevant signaling pathways in GC. Furthermore, the relationship between FTO and TGF-ß was studied in GC. METHODS: The mRNA expression and clinical survival data of GC samples were obtained from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD). TIMER2, TNM plot, and GEPIA database were used to analyze FTO expression. The associations of FTO with prognosis and clinicopathologic features were assessed using the Kaplan-Meier plotter and UALCAN database, respectively. The R software was employed to analyze its related signaling pathways and the associations with TME, immune cell infiltration, and immune checkpoint genes. GEPIA and ENCORI were used to examine the association of FTO with TGF-ß expression. The SRAMP website was utilized to predict m6A modification of TGF-ß. IHC, Western blot, and qPCR were used to analyze the expression levels of FTO and TGF-ß in clinical gastric cancer tissue samples or gastric cancer cell lines. In addition, a m6A RNA methylation assay kit was used to determine m6A levels in gastric cancer cells. RESULTS: FTO mRNA and protein levels were significantly elevated in GC compared to normal gastric tissues. Kaplan-Meier survival analysis suggested that upregulated FTO was associated with a worse prognosis in GC. Upregulated FTO was markedly correlated with differentiation degree, lymph node metastasis, and clinical TNM stage. GO and KEGG pathway analyses revealed that FTO-associated molecules were enriched in neuroactive ligand-receptor interaction, calcium signaling, PI3k-Akt signaling, cAMP signaling pathways, and TGF-ß signaling pathways, among others. The TME score was remarkably higher in the high-FTO group than in the low-FTO group. Furthermore, FTO expression had positive correlations with different types of immune cells and immune checkpoint genes. Moreover, FTO may regulate TGF-ß in an m6A RNA modification manner in GC. CONCLUSION: FTO may become an independent predictive prognostic biomarker correlating with TME, immune cell infiltration, and immune checkpoint genes in gastric cancer and might influence GC progression by regulating TGF-ß expression.

Obeticholic acid attenuates the intestinal barrier disruption in a rat model of short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS. METHODS AND RESULTS: Through testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors. CONCLUSIONS: OCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation.