Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects.

PURPOSE: Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects. METHODS: A single oral dose of 600 mg (150 µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification. RESULTS: After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study. CONCLUSION: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.

Enhancing photodynamic immunotherapy by reprograming the immunosuppressive tumor microenvironment with hypoxia relief.

Tumor hypoxia impairs the generation of reactive oxygen species and the induction of immunogenic cell death (ICD) for photodynamic therapy (PDT), thus impeding its efficacy and the subsequent immunotherapy. In addition, hypoxia plays a critical role in forming immunosuppressive tumor microenvironments (TME) by regulating the infiltration of immunosuppressive tumor-associated macrophages (TAMs) and the expression of programmed death ligand 1 (PD-L1). To simultaneously tackle these issues, a MnO2-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. The MnO2-catalyzed oxygen supply bolsters the efficacy of PDT and PTX-mediated chemotherapy, collectively amplifying the induction of ICD and the expansion of tumor-specific cytotoxic T lymphocytes (CTLs). More importantly, hypoxia releif reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint blockade (ICB) by NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.

Observation of an isothermal glass transition in metallic glasses.

Glass transition, commonly manifested upon cooling a liquid, is continuous and cooling rate dependent. For decades, the thermodynamic basis in liquid-glass transition has been at the center of debate. Here, long-time isothermal annealing was conducted via molecular dynamics simulations for metallic glasses to explore the connection of physical aging in supercooled liquid and glassy states. An anomalous two-step aging is observed in various metallic glasses, exhibiting features of supercooled liquid dynamics in the first step and glassy dynamics in the second step, respectively. Furthermore, the transition potential energy is independent of initial states, proving that it is intrinsic for a metallic glass at a given temperature. We propose that the observed dynamic transition from supercooled liquid dynamics to glassy dynamics could be glass transition manifested isothermally. On this basis, glass transition is no longer cooling rate dependent, but is shown as a clear phase boundary in the temperature-energy phase diagram. Hence, a modified out-of-equilibrium phase diagram is proposed, providing new insights into the nature of glass transition.

Prognostic significance of liver stiffness in patients with primary biliary cholangitis: validation of Baveno VII criteria.

BACKGROUND: The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated. AIMS: To clarify the prognostic role of LSM and to validate the "novel concepts" proposed by the Baveno VII Working Group. METHODS: An analysis of the prognostic significance of LSM was performed involving 672 patients. RESULTS: LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes, p < 0.001, both). A rule of 5 kPa for LSM (10-15-20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (p < 0.05, all), which can be defined as a decrease in LSM of > - 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (p < 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa. CONCLUSIONS: LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.

Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid / El fenofibrato normaliza la fosfatasa alcalina y mejora los resultados a largo plazo en pacientes con colangitis biliar primaria avanzada refractaria al ácido ursodesoxicólico

Background: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. Aims: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. Methods: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan–Meier plots with inverse probability of treatment weighting (IPTW). Results: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07–0.75, P=0.015; and HR: 11.66, 95% CI: 5.02–27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. (AU)

Antecedentes: Aunque los pacientes con enfermedad hepática avanzada se han incluido en los estudios que evalúan los fibratos para el tratamiento de la colangitis biliar primaria, la frecuencia de las respuestas bioquímicas y los efectos adversos para este grupo de pacientes no se informó por separado y de forma exhaustiva. Objetivos: Evaluar la eficacia y la seguridad del tratamiento adicional con fenofibrato en pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico. Métodos: Se analizaron los pacientes de forma retrospectiva para determinar los efectos terapéuticos clínicos del ácido ursodesoxicólico con terapia adicional de fenofibrato frente a la monoterapia continuada con ácido ursodesoxicólico. La supervivencia sin trasplante de hígado y las tasas de normalización de la fosfatasa alcalina se estimaron mediante análisis de regresión de Cox y gráficos de Kaplan-Meier con ponderación de la probabilidad inversa del tratamiento. Resultados: Se incluyeron un total de 118 pacientes: 54 recibieron ácido ursodesoxicólico solo y 64 recibieron ácido ursodesoxicólico en combinación con el tratamiento con fenofibrato. En los grupos de fenofibrato y ácido ursodesoxicólico, 37 y 11% de los pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico, respectivamente, lograron la normalización de la fosfatasa alcalina (p=0,001). El tratamiento adicional con fenofibrato mejoró tanto la supervivencia libre de trasplante de hígado como la tasa de normalización de la fosfatasa alcalina tras la ponderación de la probabilidad inversa del tratamiento (cociente de riesgos: 0,23, intervalo de confianza del 95% [IC 95%]: 0,07-0,75, p=0,015; y cociente de riesgos: 11,66, IC 95%: 5,02–27,06, p=0,001, respectivamente). (AU)

Recent Advances of Tumor Microenvironment-Responsive Nanomedicines-Energized Combined Phototherapy of Cancers.

Photodynamic therapy (PDT) has emerged as a powerful tumor treatment tool due to its advantages including minimal invasiveness, high selectivity and thus dampened side effects. On the other side, the efficacy of PDT is severely frustrated by the limited oxygen level in tumors, thus promoting its combination with other therapies, particularly photothermal therapy (PTT) for bolstered tumor treatment outcomes. Meanwhile, nanomedicines that could respond to various stimuli in the tumor microenvironment (TME) provide tremendous benefits for combined phototherapy with efficient hypoxia relief, tailorable drug release and activation, improved cellular uptake and intratumoral penetration of nanocarriers, etc. In this review, we will introduce the merits of combining PTT with PDT, summarize the recent important progress of combined phototherapies and their combinations with the dominant tumor treatment regimen, chemotherapy based on smart nanomedicines sensitive to various TME stimuli with a focus on their sophisticated designs, and discuss the challenges and future developments of nanomedicine-mediated combined phototherapies.

Controllable hypoxia-activated chemotherapy as a dual enhancer for synergistic cancer photodynamic immunotherapy.

The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.

Steerable Microneedles Enabling Deep Delivery of Photosensitizers and CRISPR/Cas9 Systems for Effective Combination Cancer Therapy.

Although gene therapy has shown prospects in treating triple-negative breast cancer, it is insufficient to treat such a malignant tumor. Herein, nanoparticles (NPs)-embedded dissolving microneedles (IR780-PL/pFBXO44@MNs) with steerable and flectional property were developed to achieve the codelivery of FBXO44-targeted CRISPR/Cas9 plasmids (pFBXO44) and hydrophobic photosensitizers. For improved NP penetration in tumor tissue, collagenase@MNs were preapplied to degrade the tumor matrix. Under light irradiation, IR780 exhibited remarkable phototherapy, while the escape efficiency of NPs from lysosomes was improved. pFBXO44 was subsequently released in tumor cell cytoplasm via reducing the disulfide bonds of NPs, which could specifically knock out the FBXO44 gene to inhibit the migration and invasion of tumor cells. As a result, tumor cells were eradicated, and lung metastasis was effectively suppressed. This micelle-incorporated microneedle platform broadens the potential of combining gene editing and photo synergistic cancer therapy.

Iron deposition in ovarian endometriosis evaluated by magnetic resonance imaging R2* correlates with ovarian function.

RESEARCH QUESTION: Does iron overload in patients with endometriosis affect ovarian function? Can a method be developed to visually reflect this? DESIGN: Magnetic resonance imaging (MRI) R2* was used to evaluate the correlation between iron deposition of ovarian and anti-Müllerian hormone (AMH) in patients with endometriosis. All patients underwent T2* MRI scanning. Serum AMH levels were measured preoperatively. The area of focal iron deposition, iron content of the cystic fluid and AMH levels between the endometriosis and control groups were compared using non-parametric tests. The effects of iron overload on AMH secretion in mouse ovarian granulosa cells were investigated by adding different concentrations of ferric citrate to the medium. RESULTS: A significant difference was found between endometriosis and control groups in area of iron deposition (P < 0.0001), cystic fluid iron content (P < 0.0001), R2* of lesions (P < 0.0001) and R2* of the cystic fluid (P < 0.0001). Negative correlations were found between serum AMH levels and R2* of cystic lesions in patients with endometriosis aged 18-35 years (rs = -0.6484, P < 0.0001), and between serum AMH levels and R2* of cystic fluid (rs = -0.5074, P = 0.0050). Transcription level (P < 0.0005) and secretion level (P < 0.005) of AMH significantly decreased with the increase in iron exposure. CONCLUSION: Iron deposits can impair ovarian function, which is reflected in MRI R2*. Serum AMH levels and R2* of cystic lesions or fluid in patients aged 18-35 years had a negative correlation with endometriosis. R2* can be used to reflect the changes of ovarian function caused by iron deposition.

Quantum Instruction Set Design for Performance.

A quantum instruction set is where quantum hardware and software meet. We develop characterization and compilation techniques for non-Clifford gates to accurately evaluate its designs. Applying these techniques to our fluxonium processor, we show that replacing the iSWAP gate by its square root SQiSW leads to a significant performance boost at almost no cost. More precisely, on SQiSW we measure a gate fidelity of up to 99.72% and averaging at 99.31%, and realize Haar random two-qubit gates with an average fidelity of 96.38%. This is an average error reduction of 41% for the former and a 50% reduction for the latter compared to using iSWAP on the same processor.

Reactive oxygen species-powered cancer immunotherapy: Current status and challenges.

Reactive oxygen species (ROS) are crucial signaling molecules that can arouse immune system. In recent decades, ROS has emerged as a unique therapeutic strategy for malignant tumors as (i) it can not only directly reduce tumor burden but also trigger immune responses by inducing immunogenic cell death (ICD); and (ii) it can be facilely generated and modulated by radiotherapy, photodynamic therapy, sonodynamic therapy and chemodynamic therapy. The anti-tumor immune responses are, however, mostly downplayed by the immunosuppressive signals and dysfunction of effector immune cells within the tumor microenvironment (TME). The past years have seen fierce developments of various strategies to power ROS-based cancer immunotherapy by e.g. combining with immune checkpoints inhibitors, tumor vaccines, and/or immunoadjuvants, which have shown to potently inhibit primary tumors, metastatic tumors, and tumor relapse with limited immune-related adverse events (irAEs). In this review, we introduce the concept of ROS-powered cancer immunotherapy, highlight the innovative strategies to boost ROS-based cancer immunotherapy, and discuss the challenges in terms of clinical translation and future perspectives.

Distinct relaxation mechanism at room temperature in metallic glass.

How glasses relax at room temperature is still a great challenge for both experimental and simulation studies due to the extremely long relaxation time-scale. Here, by employing a modified molecular dynamics simulation technique, we extend the quantitative measurement of relaxation process of metallic glasses to room temperature. Both energy relaxation and dynamics, at low temperatures, follow a stretched exponential decay with a characteristic stretching exponent ß = 3/7, which is distinct from that of supercooled liquid. Such aging dynamics originates from the release of energy, an intrinsic nature of out-of-equilibrium system, and manifests itself as the elimination of defects through localized atomic strains. This finding is also supported by long-time stress-relaxation experiments of various metallic glasses, confirming its validity and universality. Here, we show that the distinct relaxation mechanism can be regarded as a direct indicator of glass transition from a dynamic perspective.

Recent applications of phase-change materials in tumor therapy and theranostics.

Phase-change materials (PCMs) are a type of special material which can store and release a large amount of thermal energy without any significant temperature change. They are emerging in recent years as a promising functional material in tumor therapy and theranostics due to their accurate responses to the temperature variations, biocompatibility and low toxicity. In this review, we will introduce the main types of PCMs and their desirable physiochemical properties for biomedical applications, and highlight the recent progress of PCM's applications in the modulated release of antitumor drugs, with special attentions paid to various ways to initiate temperature-dependent phase change, the concomitant thermal therapy and its combination with or activation of other therapies, particularly unconventional therapies. We will also summarize PCM's recent applications in tumor theranostics, where both drugs and imaging probes are delivered by PCMs for controlled drug release and imaging-guided therapy. Finally, the future perspectives and potential limitations of harnessing PCMs in tumor therapy will be discussed.

Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid.

BACKGROUND: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. AIMS: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. METHODS: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan-Meier plots with inverse probability of treatment weighting (IPTW). RESULTS: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.75, P=0.015; and HR: 11.66, 95% CI: 5.02-27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. During the follow-up period, serum levels of ALP and aminotransferase decreased significantly, while total bilirubin, albumin, platelet, serum creatinine, and estimated glomerular filtration rate remained stable in fenofibrate-treated participants. No fenofibrate-related significant adverse events were observed in our cohort. CONCLUSIONS: Additional fenofibrate therapy significantly improved LT-free survival and ALP normalization in patients with advanced and UDCA-refractory PBC. Furthermore, adding-on fenofibrate therapy appeared to be safe and well tolerated in this population.

Mechanistic insights of different release behaviors dominated by drug physicochemical properties in polyisobutylene pressure sensitive adhesive.

The purpose of this study was to investigate the effect of the physicochemical parameters of drugs on their own release behaviors in polyisobutylene pressure sensitive adhesive (PIB PSA), which provided a theoretical guidance for the application of PIB in transdermal drug delivery system (TDDS). Seven drugs with different physicochemical parameters including clonidine (CLO), flurbiprofen (FLU), diclofenac (DIC), ibuprofen (IBU), zolmitriptan (ZOL), lidocaine (LID), tulobuterol (TUL) and the mixed adhesive (7:3, w/w) of Oppanol® B 15 N (M.W. = 108,000 Da) and Oppanol® N 50 (M.W. = 565,000 Da) were selected for in vitro drug release and skin permeation studies. Regression analysis was used to study the relationship between physicochemical parameters and release behaviors. The release behaviors of drugs were a negative correlation with polarizability and dipole moment per molecular volume (µ/V), which represented van der Waals and dipole-dipole interaction, respectively. Fourier transform infrared spectroscopy (FT-IR), modulated temperature differential scanning calorimetry (MDSC) and molecular dynamics simulation were used to provide molecular details of the interaction between the drug and PIB. The free volume and molecular mobility of PIB were characterized using mechanical property tests, rheology study, MDSC and molecular dynamics simulation. Based on the above results, drugs with high polarizability and µ/V had stronger van der Waals and dipole-dipole interaction with PIB, reducing the free volume and molecular mobility of PIB, so that the drug struggled to release from PIB. In addition, the diffusion activation energy of the drug was calculated by using the variable temperature release study to characterize the ease of drug release from the kinetic aspect. And the trends of in vitro drug release and skin penetration profiles were basically similar. Thus, it was thought that the physicochemical parameters of the drug played a vital role in the drug release behavior of PIB PSAs and would affect the skin penetration process, which provided a reference for the design and application of patches based on PIB PSAs in TDDS.

Photoclick and Release: Co-activation of Carbon Monoxide and a Fluorescent Self-reporter, COS or Sulfonamide with Fast Kinetics.

Bioorthogonal prodrugs with both fast reaction kinetics and multiple outputs are highly desirable but are only found sporadically. Herein, we report a novel photoclick-and-release strategy for the co-activation of carbon monoxide and a self-reporter, carbonyl sulfide, or sulfonamide with fast reaction kinetics (k: 1.4-22.6 M-1 s-1 ). Such a photoclick-and-release strategy was successfully applied in live cells to deliver carbon monoxide and a fluorescent self-reporter, both of which exhibited pronounced antiproliferative activity against 4T1 cancer cells. It is conceivable that this photoclick-and-release strategy could find applications in other fields, in which a controlled bond cleavage is preferred.

A multi-scale, multi-region and attention mechanism-based deep learning framework for prediction of grading in hepatocellular carcinoma.

BACKGROUND: Histopathological grading is a significant risk factor for postsurgical recurrence in hepatocellular carcinoma (HCC). Preoperative knowledge of histopathological grading could provide instructive guidance for individualized treatment decision-making in HCC management. PURPOSE: This study aims to develop and validate a newly proposed deep learning model to predict histopathological grading in HCC with improved accuracy. METHODS: In this dual-centre study, we retrospectively enrolled 384 HCC patients with complete clinical, pathological and radiological data. Aiming to synthesize radiological information derived from both tumour parenchyma and peritumoral microenvironment regions, a modelling strategy based on a multi-scale and multi-region dense connected convolutional neural network (MSMR-DenseCNNs) was proposed to predict histopathological grading using preoperative contrast enhanced computed tomography (CT) images. Multi-scale inputs were defined as three-scale enlargement of an original minimum bounding box in width and height by given pixels, which correspondingly contained more peritumoral analysis areas with the enlargement. Multi-region inputs were defined as three regions of interest (ROIs) including a squared ROI, a precisely delineated tumour ROI, and a peritumoral tissue ROI. The DenseCNN structure was designed to consist of a shallow feature extraction layer, dense block module, and transition and attention module. The proposed MSMR-DenseCNN was pretrained by the ImageNet dataset to capture basic graphic characteristics from the images and was retrained by the collected retrospective CT images. The predictive ability of the MSMR-DenseCNN models on triphasic images was compared with a conventional radiomics model, radiological model and clinical model. RESULTS: MSMR-DenseCNN applied to the delayed phase (DP) achieved the highest area under the curve (AUC) of 0.867 in the validation cohort for grading prediction, outperforming those on the arterial phase (AP) and portal venous phase (PVP). Fusion of the results on triphasic images did not increase the predictive ability, which underscored the role of DP for grading prediction. Compared with a single-scale and single-region network, the DP-phase based MSMR-DenseCNN model remarkably raised sensitivity from 67.4% to 75.5% with comparable specificity of 78.6%. MSMR-DenseCNN on DP defeated conventional radiomics, radiological and clinical models, where the AUCs were correspondingly 0.765, 0.695 and 0.612 in the validation cohort. CONCLUSIONS: The MSMR-DenseCNN modelling strategy increased the accuracy for preoperative prediction of grading in HCC, and enlightens similar radiological analysis pipelines in a variety of clinical scenarios in HCC management.

Enhanced Fuzzy Fault Estimation of Discrete-Time Nonlinear Systems via a New Real-Time Gain-Scheduling Mechanism.

The problem of enhancing the robust performance of nonlinear fault estimation (FE) is addressed by proposing a novel real-time gain-scheduling mechanism for discrete-time Takagi-Sugeno fuzzy systems. The real-time status of the operating point for the considered nonlinear plant is characterized by using these available normalized fuzzy weighting functions at both the current and the past instants of time. To achieve this, the developed fuzzy real-time gain-scheduling mechanism produces different switching modes by introducing key tunable parameters. Thus, a pair of exclusive FE gain matrices is designed for each switching mode on the strength of time-varying balanced matrices developed in this study, respectively. Since the implementation of more FE gain matrices can be scheduled according to the real-time status of the operating point at each sampling instant, the robust performance of nonlinear FE will be enhanced over the previous methods to a great extent. Finally, considerable numerical comparisons are implemented in order to illustrate that the proposed method is much superior to those existing ones reported in the literature.

Distributed Fault-Tolerant Bipartite Output Synchronization of Discrete-Time Linear Multiagent Systems.

This article studies the distributed fault-tolerant bipartite output synchronization problem of discrete-time linear multiagent systems (MASs) with process faults under a general directed signed graph. The reference signal is generated by an autonomous exosystem, which can also be seen as a leader. All followers are divided into two subgroups with antagonistic interactions, and the followers in each subgroup are cooperative. We aim to solve the bipartite fault-tolerant control (FTC) problem via the output regulation theory such that bipartite output synchronization can be achieved in the presence of process faults, that is, the outputs of followers with different subgroups can approach the output of exosystem with the same magnitude and the opposite sign regardless of process faults. To estimate the states and the faults of each follower, a simultaneous state and fault estimator based on the neighboring signed output estimation error and the standard discrete-time algebraic Riccati equation (ARE) is designed. Besides, a new exosystem observer with two classes of convergence conditions relying on the respective solutions of standard and modified AREs is provided. All eigenvalues of the exosystem matrix can lie completely outside the unit circle. Based on these estimations, we present a distributed fault-tolerant output feedback controller, which can overcome the no-loops constraint. Finally, simulation results are given to demonstrate the analytic results.

Distributed robust group output synchronization control for heterogeneous uncertain linear multi-agent systems.

This paper investigates the distributed robust group output synchronization problem of heterogeneous uncertain linear leader-follower multi-agent systems (MASs), whose followers have nonidentical and parameter uncertain dynamics. To achieve cooperative tracking with multiple targets, a new group synchronization framework based upon the output regulation technique is established. In the underlying directed communication topology, all nonidentical followers are divided into several subgroups. Meanwhile, each subgroup has its output tracking objective generated by an autonomous exosystem which is seen as the leader of each subgroup. Since not all followers can access their exosystems directly, the distributed exosystem observer based on the algebraic Riccati inequality (ARI) is designed to obtain the information of exosystems. Moreover, to compensate for parameter uncertainties for different group topologies, the p-copy internal model is synthesized into distributed control laws, i.e., dynamic state feedback control protocol under an acyclic directed graph and dynamic output feedback control protocol under a general directed graph. It is shown that group synchronization can be respectively achieved with these controllers under acyclic and general partitions regardless of parameter uncertainties. Finally, some examples are provided to verify the validity of the analytic results.