Human embryonic stem cell-derived mesenchymal stromal cells suppress inflammation in mouse models of rheumatoid arthritis and lung fibrosis by regulating T-cell function.

BACKGROUND AIMS: Rheumatoid arthritis (RA) is characterized by an overactive immune system, with limited treatment options beyond immunosuppressive drugs or biological response modifiers. Human embryonic stem cell-derived mesenchymal stromal cells (hESC-MSCs) represent a novel alternative, possessing diverse immunomodulatory effects. In this study, we aimed to elucidate the therapeutic effects and underlying mechanisms of hESC-MSCs in treating RA. METHODS: MSC-like cells were differentiated from hESC (hESC-MSCs) and cultured in vitro. Cell proliferation was assessed using Cell Counting Kit-8 assay and Ki-67 staining. Flow cytometry was used to analyze cell surface markers, T-cell proliferation and immune cell infiltration. The collagen-induced arthritis (CIA) mouse model and bleomycin-induced model of lung fibrosis (BLE) were established and treated with hESC-MSCs intravenously for in vivo assessment. Pathological analyses, reverse transcription-quantitative polymerase chain reaction and Western blotting were conducted to evaluate the efficacy of hESC-MSCs treatment. RESULTS: Intravenous transplantation of hESC-MSCs effectively reduced inflammation in CIA mice in this study. Furthermore, hESC-MSC administration enhanced regulatory T cell infiltration and activation. Additional findings suggest that hESC-MSCs may reduce lung fibrosis in BLE mouse models, indicating their potential to mitigate complications associated with RA progression. In vitro experiments revealed a significant inhibition of T-cell activation and proliferation during co-culture with hESC-MSCs. In addition, hESC-MSCs demonstrated enhanced proliferative capacity compared with traditional primary MSCs. CONCLUSIONS: Transplantation of hESC-MSCs represents a promising therapeutic strategy for RA, potentially regulating T-cell proliferation and differentiation.

Novel, high accuracy models for hepatocellular carcinoma prediction based on longitudinal data and cell-free DNA signatures.

BACKGROUND & AIMS: Current hepatocellular carcinoma (HCC) risk scores do not reflect changes in HCC risk resulting from liver disease progression/regression over time. We aimed to develop and validate two novel prediction models using multivariate longitudinal data, with or without cell-free DNA (cfDNA) signatures. METHODS: A total of 13,728 patients from two nationwide multicenter prospective observational cohorts, the majority of whom had chronic hepatitis B, were enrolled. aMAP score, as one of the most promising HCC prediction models, was evaluated for each patient. Low-pass whole-genome sequencing was used to derive multi-modal cfDNA fragmentomics features. A longitudinal discriminant analysis algorithm was used to model longitudinal profiles of patient biomarkers and estimate the risk of HCC development. RESULTS: We developed and externally validated two novel HCC prediction models with a greater accuracy, termed aMAP-2 and aMAP-2 Plus scores. The aMAP-2 score, calculated with longitudinal data on the aMAP score and alpha-fetoprotein values during an up to 8-year follow-up, performed superbly in the training and external validation cohorts (AUC 0.83-0.84). The aMAP-2 score showed further improvement and accurately divided aMAP-defined high-risk patients into two groups with 5-year cumulative HCC incidences of 23.4% and 4.1%, respectively (p = 0.0065). The aMAP-2 Plus score, which incorporates cfDNA signatures (nucleosome, fragment and motif scores), optimized the prediction of HCC development, especially for patients with cirrhosis (AUC 0.85-0.89). Importantly, the stepwise approach (aMAP -> aMAP-2 -> aMAP-2 Plus) stratified patients with cirrhosis into two groups, comprising 90% and 10% of the cohort, with an annual HCC incidence of 0.8% and 12.5%, respectively (p <0.0001). CONCLUSIONS: aMAP-2 and aMAP-2 Plus scores are highly accurate in predicting HCC. The stepwise application of aMAP scores provides an improved enrichment strategy, identifying patients at a high risk of HCC, which could effectively guide individualized HCC surveillance. IMPACT AND IMPLICATIONS: In this multicenter nationwide cohort study, we developed and externally validated two novel hepatocellular carcinoma (HCC) risk prediction models (called aMAP-2 and aMAP-2 Plus scores), using longitudinal discriminant analysis algorithm and longitudinal data (i.e., aMAP and alpha-fetoprotein) with or without the addition of cell-free DNA signatures, based on 13,728 patients from 61 centers across mainland China. Our findings demonstrated that the performance of aMAP-2 and aMAP-2 Plus scores was markedly better than the original aMAP score, and any other existing HCC risk scores across all subsets, especially for patients with cirrhosis. More importantly, the stepwise application of aMAP scores (aMAP -> aMAP-2 -> aMAP-2 Plus) provides an improved enrichment strategy, identifying patients at high risk of HCC, which could effectively guide individualized HCC surveillance.

Simulation Guided Coaxial Electrospinning of Polyvinylidene Fluoride Hollow Fibers with Tailored Piezoelectric Performance.

Electrospun polyvinylidene fluoride (PVDF) piezoelectric fibers have high potential applicability in mechanical energy harvesting and self-powered sensing owing to their high electromechanical coupling capabilities. Strategies for tailoring fiber morphology have been the primary focus for realizing enhanced piezoelectric output. However, the relationship between piezoelectric performance and fiber structure remains unclear. This study fabricates PVDF hollow fibers through coaxial electrospinning, whose wall thickness can be tuned by changing the internal solution concentration. Simulation analysis demonstrates an increased effective deformation of the hollow fiber as enlarging inner diameter, resulting in enhanced piezoelectric output, which is in excellent agreement with the experimental results. This study is the first to unravel the influence mechanism of morphology regulation of a PVDF hollow fiber on its piezoelectric performance from both simulation and experimental aspects. The optimal PVDF hollow fiber piezoelectric energy harvester (PEH) delivers a piezoelectric output voltage of 32.6 V, ≈3 times that of the solid PVDF fiber PEH. Furthermore, the electrical output of hollow fiber PEH can be stably stored in secondary energy storage systems to power microelectronics. This study highlights an efficient approach for reconciling the simulation and tailoring the fiber PEH morphology for enhanced performances for future self-powered systems.

Development and validation a radiomics nomogram for predicting thymidylate synthase status in hepatocellular carcinoma based on Gd-DTPA contrast enhanced MRI.

OBJECTIVES: The purpose of this study was to develop and validate a radiomics nomogram for predicting thymidylate synthase (TYMS) status in hepatocellular carcinoma (HCC) by using Gd-DTPA contrast enhanced MRI. METHODS: We retrospectively enrolled 147 consecutive patients with surgically confirmed HCC and randomly allocated to training and validation set (7:3). The TYMS status was immunohistochemical determined and classified into low TYMS (positive cells ≤ 25%) and high TYMS (positive cells > 25%) groups. Radiomics features were extracted from the arterial phases and portal venous phase of Gd-DTPA contrast enhanced MRI. Least absolute shrinkage and selection operator (LASSO) were applied for generating the Rad score. Clinical data and MRI findings were assessed to build a clinical model. Rad score combined with clinical features was used to construct radiomics nomogram. RESULTS: A total of 2260 features were extracted and reduced to 7 features as the most important discriminators to build the Rad score. InAFP was identified as the only independent clinical factors for TYMS status. The radiomics nomogram showed good discrimination in training (AUC, 0.759; 95% CI 0.665-0.838) and validation set (AUC, 0.739; 95% CI 0.585-0.860), and showed better discrimination capability (P < 0.05) compared with clinical model in training (AUC, 0.656; 95% CI 0.555-0.746) and validation set (AUC, 0.622; 95% CI 0.463-0.764). CONCLUSIONS: The radiomics nomogram shows favorable predictive efficacy for TYMS status in HCC, which might be helpful for the personalized treatment of HCC.

Anatomic versus non-anatomic resection for early-stage intrahepatic cholangiocarcinoma: a propensity score matching and stabilized inverse probability of treatment weighting analysis.

BACKGROUND: Radical resection is still the most cost-effectiveness curative strategy for intrahepatic cholangiocarcinoma (ICC), but it remains controversial on the survival benefit of anatomic resection (AR). In this study, we sought to compare the oncologic outcomes between AR versus non-AR (NAR) as the primary treatment for early-stage ICC patients. METHODS: Data of ICC patients who underwent hepatectomy and staged at AJCC I were retrospectively collected from 12 hepatobiliary centers in China between Dec 2012 and Dec 2015. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) analysis were performed to minimize the effect of potential confounders, and the perioperative and long-term outcomes between AR and NAR groups were compared. RESULTS: Two hundred seventy-eight ICC patients staged at AJCC I were eligible for this study, including 126 patients receiving AR and 152 patients receiving NAR. Compared to the NAR group, the AR group experienced more intraoperative blood loss before and after PSM or stabilized IPTW (all P > 0.05); AR group also experienced more intraoperative transfusion after stabilized IPTW (P > 0.05). In terms of disease-free survival (DFS) and overall survival (OS), no significant differences were observed between the two groups before and after PSM or stabilized IPTW (all P > 0.05). Multivariable Cox regression analyses found that AR was not an independent prognostic factor for either DFS or OS (all P > 0.05). Further analysis also showed that the survival benefit of AR was not found in any subgroup stratified by Child-Pugh grade (A or B), cirrhosis (presence or absence), tumor diameter (≤ 5 cm or > 5 cm) and pathological type (mass-forming or non-mass-forming) with all P > 0.05. CONCLUSION: Surgical approach does not influence the prognosis of patients with stage I primary ICC, and NAR might be acceptable and oncological safety.

Retinoic acid receptor gamma is required for proliferation of pancreatic cancer cells.

Despite the expectation that retinoic acid receptor could be the potential therapeutic targets for pancreatic cancers, there has been the lack of information about the role and the impact of retinoic acid receptor gamma (RARγ, RARG) on pancreatic cancer, unlike other two RARs. Herein, we applied TCGA and GEO database to show that the expression and prognosis of RARG is closely related to pancreatic cancer, which demonstrates that RARG is commonly overexpressed in human pancreatic cancer and is an independent diagnostic marker predicting the poor prognosis of pancreatic cancer patients. In addition, we demonstrated that the reduction in the expression of RARG in human pancreatic cancer cells dramatically suppress their proliferation and tumor growth in vivo, partially attributable to the downregulation of tumor-supporting biological processes such as cell proliferation, antiapoptosis and metabolism and the decreased expression of various oncogenes like MYC and STAT3. Mechanistically, RARG binds on the promoters of MYC, STAT3, and SLC2A1 which is distinguished from well-known conventional Retinotic acid response elements (RAREs) and that the binding is likely to be responsible for the epigenetic activation in the level of chromatin, assessed by the measurement of deposition of the gene activation marker histone H3 K27 acetylation (H3K27ac) using ChIP-qPCR. In this study, we reveal that RARG plays important role in the tumorigenesis of pancreatic cancer and represents new therapeutic targets for human pancreatic cancer.

ALDH2 rs671 and MTHFR rs1801133 polymorphisms are risk factors for arteriosclerosis in multiple arteries.

BACKGROUND: Arteriosclerosis in multiple arteries has long been associated with heightened cardiovascular risk. Acetaldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR) play an important role in the pathogenesis of arteriosclerosis by participating in the oxidation and reduction reactions in vascular endothelial cells. The purpose was to investigate the relationship of ALDH2 and MTHFR gene polymorphisms with arteriosclerosis in multiple arteries. METHODS: 410 patients with arteriosclerosis in single artery and 472 patients with arteriosclerosis in multiple arteries were included. The relationship between ALDH2 rs671 and MTHFR rs1801133 polymorphisms and arteriosclerosis in single artery and arteriosclerosis in multiple arteries was analyzed. RESULTS: The proportion of ALDH2 rs671 A allele (35.6% vs. 30.9%, P = 0.038) and MTHFR rs1801133 T allele (32.6% vs. 27.1%, P = 0.012) in patients with arteriosclerosis in multiple arteries was significantly higher than that in arteriosclerosis in single artery, respectively. The proportion of history of alcohol consumption in patients with ALDH2 rs671 G/G genotype was higher than those in ALDH2 rs671 G/A genotype and A/A genotype (P < 0.001). The results of logistic regression analysis indicated that ALDH2 rs671 A/A genotype (A/A vs. G/G: OR 1.996, 95% CI: 1.258-3.166, P = 0.003) and MTHFR rs1801133 T/T genotype (T/T vs. C/C: OR 1.943, 95% CI: 1.179-3.203, P = 0.009) may be independent risk factors for arteriosclerosis in multiple arteries (adjusted for age, sex, smoking, drinking, hypertension, and diabetes). CONCLUSIONS: ALDH2 rs671 A/A and MTHFR rs1801133 T/T genotypes may be independent risk factors for arteriosclerosis in multiple arteries.

CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study.

BACKGROUND: Genetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population. METHODS: The study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed. RESULTS: The genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291-1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638-2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390-1.882, P < 0.001) may increase risk of hypertension. CONCLUSIONS: CYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.

Therapeutic Drug Monitoring-Guided Vancomycin Therapy of a Pediatric Patient after Liver Transplantation: a Case Report.

BACKGROUND: Vancomycin administration is challenging in critically ill patients because of pharmacokinetic changes and requires careful therapeutic drug monitoring (TDM) to guide the appropriate dosing for an effective serum concentration and to avoid toxicity. METHODS: We reported a one-year-old female pediatric patient with a body mass index of 15.4 had successful TDM-guided vancomycin therapy after a living donor liver transplantation for biliary atresia. RESULTS: The patient was admitted to the Intensive Care Unit for sepsis after her second liver transplantation. Even with the administration of the maximum approved vancomycin dosage (40 mg/kg/day), the serum trough levels were less than the recommended therapeutic level. After several adjustments based on TDM, a continuous pump infusion of up to 800 mg/day was needed to reach the desired serum trough concentration of > 10 µg/mL. Sepsis was controlled, and the patient was transferred from the Intensive Care Unit to the general ward and finally discharged home on a regular follow-up plan. CONCLUSIONS: TDM-guided vancomycin continuous infusion may be an effective therapeutic option for pediatric patients after liver transplantation.

The effect of adjuvant transarterial chemoembolization for hepatocellular carcinoma after liver resection based on risk stratification.

BACKGROUND: There is currently no standard adjuvant treatment proven to prevent hepatocellular carcinoma (HCC) recurrence. Recent studies suggest that postoperative adjuvant transarterial chemoembolization (PA-TACE) is beneficial for patients at high risk of tumor recurrence. However, it is difficult to select the patients. The present study aimed to develop an easy-to-use score to identify these patients. METHODS: A total of 4530 patients undergoing liver resection were recruited. Independent risk factors were identified by Cox regression model in the training cohort and the Primary liver cancer big data transarterial chemoembolization (PDTE) scoring system was established. RESULTS: The scoring system was composed of ten risk factors including alpha-fetoprotein (AFP), albumin-bilirubin (ALBI) grade, operative bleeding loss, resection margin, tumor capsular, satellite nodules, tumor size and number, and microvascular and macrovascular invasion. Using 5 points as risk stratification, the patients with PA-TACE had higher recurrence-free survival (RFS) compared with non-TACE in > 5 points group (P < 0.001), whereas PA-TACE patients had lower RFS compared with non-TACE in ≤ 5 points group (P = 0.013). In the training and validation cohorts, the C-indexes of PDTE scoring system were 0.714 [standard errors (SE) = 0.010] and 0.716 (SE = 0.018), respectively. CONCLUSIONS: The model is a simple tool to identify PA-TACE for HCC patients after liver resection with a favorable performance. Patients with > 5 points may benefit from PA-TACE.

Analysis of conditional survival in primary hepatocellular carcinoma after narrow-margin hepatectomy: a large-sample, dual-centre, retrospective study.

BACKGROUND: Overall survival (OS) reflects the constant hazard and survival probabilities calculated from the initial follow-up. Conditional survival (CS) dynamically estimates prognosis based on survival time after treatment. This study aimed to estimate CS in patients who had undergone narrow-margin hepatectomy for primary hepatocellular carcinoma. METHODS: The clinical data of 1010 eligible patients between 2012 and 2017 were retrospectively analysed. The equation CS1=OS(x+1)/OS(x) was used to calculate the probability of an additional 1-year survival in patients who had survived for x years. RESULTS: Tumour differentiation, microvascular invasion, and tumour emboli were independent risk factors for OS. Actuarial survival decreased from 91.53% at 1 year after hepatectomy to 48.92% at 4 years, whereas CS1 increased from 69.45% at 1 year to 94.62% at 4 years. The difference was more obvious in the tumour-emboli subgroup, with an OS of 26.38% at 5 years versus a CS1 of 88.91% at 4 years following narrow-margin hepatectomy (Δ62.53%). CONCLUSION: CS is potentially useful in providing a dynamic evaluation of survival, predicting prognosis more accurately than OS during follow-up, and formulating more appropriate treatment measures based on disease progression.

Electrohydrodynamic Pulling Consolidated High-Efficiency 3D Printing to Architect Unusual Self-Polarized ß-PVDF Arrays for Advanced Piezoelectric Sensing.

Piezoelectric pressure sensors are important for applications in robotics, artificial intelligence, communication devices, etc. The hyperboloid is theoretically predicted to be an unusual 3D structure that allows concerted piezoelectric enhancement owing to its synergistic effects of geometrical stress confinement and stress concentration, but has not been experimentally fulfilled due to a lack of efficient architecting techniques. In this work, a 3D hyperboloidal arrayed self-polarized PVDF piezoelectric energy harvester (PEH) is successfully fabricated by incorporating electrohydrodynamic (EHD) pulling technology into fused deposition modeling (FDM) 3D printing. This strategy not only simplifies the layer-by-layer constructing procedure for arrays, but simultaneously realizes a self-polarized and high ß-phase (92%) PVDF PEH in a single electric-pulling step, saving posttreatment such as poling and removing excessive additives. Such a PEH delivers a significantly enhanced piezoelectric potential which is around 8 times that of a 2D flat film sensor. Moreover, this PEH featuring excellent linearity within a wide pressure regime, enables the sensing of human activities in a relatively large force range, which is otherwise difficult for traditional film sensors to differentiate. This work demonstrates a potential roadmap to advanced piezoelectric sensors exploiting unusual 3D structures enabled by the unique EHD pulling coupled 3D printing technique.

Anomalous spontaneous emission dynamics at chiral exceptional points.

An open quantum system operated at the spectral singularities where dimensionality reduces, known as exceptional points (EPs), demonstrates distinguishing behavior from the Hermitian counterpart. Here, we present an analytical description of local density of states (LDOS) for microcavity featuring chiral EPs, and unveil the anomalous spontaneous emission dynamics from a quantum emitter (QE) due to the non-Lorentzian response of EPs. Specifically, we reveal that a squared Lorentzian term of LDOS contributed by chiral EPs can destructively interfere with the linear Lorentzian profile, resulting in the null Purcell enhancement to a QE with special transition frequency, which we call EP induced transparency. While for the case of constructive interference, the squared Lorentzian term can narrow the linewidth of Rabi splitting even below that of bare components, and thus significantly suppresses the decay of Rabi oscillation. Interestingly, we further find that an open microcavity with chiral EPs supports atom-photon bound states for population trapping and decay suppression in long-time dynamics. As applications, we demonstrate the advantages of microcavity operated at chiral EPs in achieving high-fidelity entanglement generation and high-efficiency single-photon generation. Our work unveils the exotic cavity quantum electrodynamics unique to chiral EPs, which opens the door for controlling light-matter interaction at the quantum level through non-Hermiticity, and holds great potential in building high-performance quantum-optics devices.

Fano effect induced giant and robust enhancement of photon correlations in cavity QED systems.

The Fano effect arising from the interference between two dissipation channels of the radiation continuum enables tuning of the photon statistics. Understanding the role of the Fano effect and exploiting it to achieve strong photon correlations are of both fundamental and applied significance. We present an analytical description of Fano-enhanced photon correlations based on cavity quantum electrodynamics to show that the Fano effect in atom-cavity systems can improve the degree of antibunching by over four orders of magnitude. The enhancement factors and the optimal conditions are explicitly given, and found to relate to the Fano parameter q. Remarkably, the Fano enhancement manifests robustness against the decoherence processes and can survive in the weak coupling regime. We expect our work to provide insight to tuning the photon statistics through the Fano effect, which offers a new, to the best of our knowledge, route to enhance the photon correlations, as well as the possibility of generating nonclassical light in a wider diversity of systems without the need of a strong light-matter interaction.

Pyroptosis related genes signature predicts prognosis and immune infiltration of tumor microenvironment in hepatocellular carcinoma.

Little is known on the relationship between the expression of pyroptosis related genes (PRGs) and prognosis of hepatocellular carcinoma (HCC). In this study, a specific PRGs prognostic model was developed with an aim to improve therapeutic efficiency among HCC patients. In total, 42 PRGs that were differentially expressed between HCC tissues and adjacent tissues and we exhibited the mutation frequency, classification, the location of copy number variation (CNV) alteration and the CNV variation frequency of PRGs. Two clusters were distinguished by the consensus clustering analysis based on the 42 differentially expressed genes (DEGs). There were significant differences in clinical features including T stage, grade, gender, and stage among different clusters. Kaplan-Meier curve analysis showed that cluster 1 had a better prognosis than cluster 2. The prognostic value of PRGs for survival was evaluated to construct a multigene signature using The Cancer Genome Atlas (TCGA) cohort. Based on the univariate analysis and multivariate analysis, a 10-gene signature was built and all HCC patients in the TCGA cohort were divided into low-risk group and high-risk group. HCC patients in the high-risk group showed significantly lower survival possibilities than those in the low-risk group (P < 0.001). Utilizing the median risk score from the TCGA cohort, HCC patients from International Cancer Genome Consortium (ICGC)-LIRI-JP cohort and Gene Expression Omnibus (GEO) cohort (GSE14520) were divided into two risk subgroups. The result showed that overall survival (OS) time was decreased in the high-risk group. Combined with the clinical characteristics, the risk score was an independent factor for predicting the OS of HCC patients. Then, ROC curve and survival analysis were performed to evaluate the prognostic prediction value of the model. Finally, we constructed a PRGs clinical characteristics nomogram to further predict HCC patient survival probability. There were significant differences in immune cell infiltration, GSEA enrichment pathway, IC50 of chemotherapeutics, PRGs mutation frequency between high-risk group and low-risk group. This work suggests PRGs signature played a crucial role in predicting the prognosis, infiltration of cancer microenvironment, and sensitivity of chemotherapeutic agents.

Cavity spectral-hole-burning to boost coherence in plasmon-emitter strong coupling systems.

Significant decoherence of the plasmon-emitter (i.e., plexcitonic) strong coupling systems hinders the progress towards their applications in quantum technology due to the unavoidable lossy nature of the plasmons. Inspired by the concept of spectral-hole-burning (SHB) for frequency-selective bleaching of the emitter ensemble, we propose 'cavity SHB' by introducing cavity modes with moderate quality factors to the plexcitonic system to boost its coherence. We show that the detuning of the introduced cavity mode with respect to the original plexcitonic system, which defines the location of the cavity SHB, is the most critical parameter. Simultaneously introducing two cavity modes of opposite detunings, the excited-state population of the emitter can be enhanced by 4.5 orders of magnitude within 300 fs, and the attenuation of the emitter's population can be slowed down by about 56 times. This theoretical proposal provides a new approach of cavity engineering to enhance the plasmon-emitter strong coupling systems' coherence, which is important for realistic hybrid-cavity design for applications in quantum technology.

Ulinastatin Improves Renal Microcirculation by Protecting Endothelial Cells and Inhibiting Autophagy in a Septic Rat Model.

INTRODUCTION: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. METHODS: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 h after the operation. Histological staining was used to evaluate kidney injury scores. Western blot was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors (interleukin-1ß, interleukin-6, and tumor necrosis factor-α) in kidney tissue, and enzyme-linked immunosorbent assay detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. RESULTS: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. CONCLUSION: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

Novel isatin-based hybrids as potential anti-rheumatoid arthritis drug candidates: Synthesis and biological evaluation.

Rheumatoid arthritis (RA) is an autoimmune disease accompanied with serious symptoms, such as joint destruction and chronic synovitis. Though many anti-RA drugs could improve the outcome of RA patients to a certain extent, about 40% inefficient rate, severe side effects, and high costs have become urgent problems. Therefore, exploring new alternative drugs for RA therapy is still an urgent need so far. Isatin is an important structural motif found in numerous biologically active compounds and therapeutic agents. Herein, we aim to synthesize several novel isatin analogues for RA therapy and further explore the mechanism of the most potential anti-RA drug candidate in suppressing the pathological progress of RA in vitro and in vivo. We found that the most therapeutic potential compound, a novel small molecule isatin-honokiol hybrid named CT5-2 inhibited the viability of RA-fibroblast-like synoviocytes (FLSs), an effector cell of synovial hyperplasia in the RA synovial tissue with IC50 ranging from 8.54 to 10.66 µM. In addition, CT5-2 reduced the DNA replication and triggered cell cycle arrest and apoptosis of RA-FLSs. Moreover, differential analyses of RNA-sequencing and the mechanistic studies demonstrated that CDCA7 is a key gene correlated with RA progression, and CT5-2 could inhibit the c-Myc/CDCA7/p65 pathway to regulate CDK1, Bcl-2, and vimentin in RA-FLSs. Furthermore, CT5-2 relieved collagen-induced arthritis (CIA) and reduced the level of CDCA7, CDK1, Bcl-2, and vimentin of synovial tissue in CIA mice. Taken together, the novel small molecule isatin-honokiol hybrid CT5-2 exhibits a potential anti-RA drug candidate that inhibits proliferation and triggers cell cycle arrest and apoptosis of RA-FLSs by regulating the c-Myc/CDCA7/p65 pathway. Our study lays a good foundation for further clinical research and structuralmodification of CT5-2.

Antiviral Therapy Improves Survival in Hepatocellular Carcinoma with Microvascular Invasion: A Propensity Score Analysis.

BACKGROUND AND AIMS: To investigate the effect of postoperative adjuvant antiviral therapy (AVT) on hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) with microvascular invasion (MVI) after R0 liver resection. METHODS: A total of 1008 patients with HBV-related HCC with MVI were recruited, which comprises 378 non-AVT groups and 630 AVT groups. Propensity score matching (PSM) was developed to reduce any bias in patient selection. Independent risk factors were identified by Cox regression analysis. RESULTS: After PSM, the 1-, 3-, and 5-year overall survival rates in the AVT group and non-AVT group were 89.2%, 62.4%, 42.1%, and 73.3%, 46.3%, 22.1%, (p < 0.01), respectively. The 1-, 3-, and 5-year recurrence-free survival rates in the AVT group and non-AVT group were 52.5%, 30.4%, 22.1%, and 46.3%, 26.8%, 13.2% (p = 0.02), respectively. Multivariate Cox analysis revealed that postoperative adjuvant AVT was the independent protective factor associated with mortality (HR = 0.55, 95%CI = 0.46-0.67, p < 0.01) and tumor recurrence (HR = 0.81, 95%CI = 0.69-0.96, p = 0.01). CONCLUSIONS: Among patients who underwent curative hepatectomy for HBV-related HCC with MVI, postoperative adjuvant AVT was the independent protective factor associated with mortality and tumor recurrence. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC with MVI, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

Splenic vein embolization as a feasible treatment for patients with hepatic encephalopathy related to large spontaneous splenorenal shunts.

INTRODUCTION AND OBJECTIVES: Although splenic vein embolization (SVE) has been performed for the management of patients with hepatic encephalopathy (HE) related to large spontaneous splenorenal shunts (SSRS) in recent years, its role remains poorly defined. In this study, we aimed to explore the safety and efficacy of SVE for HE patients with large SSRS. MATERIALS AND METHODS: Data from cirrhotic patients who were confirmed to have recurrent or persistent HE related to large SSRS and underwent SVE from January 2017 to April 2021 were retrospectively collected and analyzed at our center. The primary endpoints were the change of HE severity at 1 week after embolization and the recurrence of HE during the follow-up period. The secondary endpoints were procedure-related complications and changes in laboratory indicators and hepatic function (Child-Pugh score/grade and model for end-stage liver disease score). RESULTS: Of the eight cirrhotic patients included in the study, six were diagnosed with recurrent HE, and the others were diagnosed with persistent HE. Embolization success was achieved for all patients (100%), and no immediate procedure-related complications, de novo occurrence, or aggravation of symptoms related to portal hypertension were observed during the long-term follow-up. HE status was assessed at 1 week after embolization. The results demonstrated that the symptoms were mitigated in three patients and resolved completely in five patients. During the follow-up period, all patients were free of HE within 1 month after embolization, but one patient experienced the recurrence of HE within 6 months and another one experienced the recurrence of HE within 1 year. Compared with the preoperative parameters, the Child-Pugh score and grade were significantly improved at 1 week and 1 month after embolization (all P<0.05), and the serum ammonia level was significantly lower at 1 month after embolization (P<0.05). CONCLUSIONS: SVE could be considered as a feasible treatment for patients with HE related to large SSRS, but further validation is required.