Optimizing hepatocellular carcinoma disease staging systems by incorporating tumor micronecrosis: A multi-institutional retrospective study.

Tumor micronecrosis is a pathological feature that reflects malignant biological behavior in hepatocellular carcinoma (HCC). However, whether micronecrosis can optimize HCC staging systems remains unilluminated. A total of 1632 HCC patients who underwent curative hepatectomy in four institutions from January 2014 to December 2021 were enrolled in this study. Independent prognostic factors were identified, and optimized staging models were established using a training cohort (n = 934). The performance of optimized staging models was validated using an external cohort consisting of cases from three other institutions (n = 232). In addition, patients from our prospectively collected database (n = 379) tested the application effectiveness of the models. Harrel's c-statistics and the corrected Akaike information criterion (AICc) were used to assess the performance of staging models. In most of Barcelona Clinic Liver Cancer (BCLC) and tumor (T) stages, HCC patients with tumor micronecrosis showed poorer prognosis than those without. Tumor micronecrosis, microvascular invasion, multiple tumors and tumor size >2 cm were independent prognostic-related factors. The BCLC and T staging models incorporating tumor micronecrosis showed better performance than the original systems (c-statistic, 0.712 and 0.711 vs. 0.664 and 0.679; AICc, 2314.8 and 2322.3 vs. 2338.2 and 2338.1; respectively). Furthermore, the external validation cohort confirmed that the optimized staging models had improved efficiency compared with the original ones. Moreover, the prospective cohort demonstrated the applicability of the optimized staging systems. Tumor micronecrosis plays a stage-ascending role in HCC patients. The BCLC and T staging systems incorporating tumor micronecrosis can improve the prognosis stratification efficiency of patients.

Development and Validation of Novel Models Including Tumor Micronecrosis for Predicting the Postoperative Survival of Patients with Hepatocellular Carcinoma.

Background: The heterogeneity of hepatocellular carcinoma (HCC) leads to the unsatisfying predictive performance of current staging systems. HCC patients with pathological tumor micronecrosis have an immunosuppressive microenvironment. We aimed to develop novel prognostic models by integrating micronecrosis to predict the survival of HCC patients after hepatectomy more precisely. Methods: We enrolled 765 HCC patients receiving curative hepatic resection. They were randomly divided into a training cohort (n= 536) and a validation cohort (n = 229). We developed two prognostic models for postoperative recurrence-free survival (RFS) and overall survival (OS) based on independent factors identified through multivariate Cox regression analyses. The predictive performance was assessed using the Harrell concordance index (C-index) and the time-dependent area under the receiver operating characteristic curve, compared with six conventional staging systems. Results: The RFS and OS nomograms were developed based on tumor micronecrosis, tumor size, albumin-bilirubin grade, tumor number and prothrombin time. The C-indexes for the RFS nomogram and OS nomogram were respectively 0.66 (95% CI, 0.62-0.69) and 0.74 (95% CI, 0.69-0.79) in the training cohort, which was significantly better than those of the six common staging systems (0.52-0.61 for RFS and 0.53-0.63 for OS). The results were further confirmed in the validation group, with the C-indexes being 0.66 and 0.77 for the RFS and OS nomograms, respectively. Conclusion: The two nomograms could more accurately predict RFS and OS in HCC patients receiving curative hepatic resection, thereby aiding in formulating personalized postoperative follow-up plans.

Tumor micronecrosis predicts poor prognosis of patients with hepatocellular carcinoma after liver transplantation.

BACKGROUND: Tumor micronecrosis is a histopathological feature predicting poor prognosis in patients with hepatocellular carcinoma (HCC) who underwent liver resection. However, the role of tumor micronecrosis in liver transplantation remains unclear. METHODS: We retrospectively reviewed patients with HCC who underwent liver transplantation between January 2015 and December 2021 at our center. We then classified them into micronecrosis(-) and micronecrosis(+) groups and compared their recurrence-free survival (RFS) and overall survival (OS). We identified independent prognostic factors using Cox regression analysis and calculated the area under the receiver operating characteristic curve (AUC) to evaluate the predictive value of RFS for patients with HCC after liver transplantation. RESULTS: A total of 370 cases with evaluable histological sections were included. Patients of the micronecrosis(+) group had a significantly shorter RFS than those of the micronecrosis(-) group (P = 0.037). Shorter RFS and OS were observed in micronecrosis(+) patients without bridging treatments before liver transplantation (P = 0.002 and P = 0.007), while no differences were detected in those with preoperative antitumor therapies that could cause iatrogenic tumor necrosis. Tumor micronecrosis improved the AUC of Milan criteria (0.77-0.79), the model for end-stage liver disease score (0.70-0.76), and serum alpha-fetoprotein (0.63-0.71) for the prediction of prognosis after liver transplantation. CONCLUSION: Patients with HCC with tumor micronecrosis suffer from a worse prognosis than those without this feature. Tumor micronecrosis can help predict RFS after liver transplantation. Therefore, patients with HCC with tumor micronecrosis should be treated with adjuvant therapy and closely followed after liver transplantation. CLINICAL TRIALS REGISTRATION: Not Applicable.

Histological tumor micronecrosis in resected specimens after R0 hepatectomy for hepatocellular carcinomas is a factor in determining adjuvant TACE: A retrospective propensity score-matched study.

BACKGROUND: Tumor micronecrosis is a less investigated pathological feature of hepatocellular carcinoma (HCC). This study was aimed at evaluating the value of micronecrosis for guiding adjuvant transcatheter arterial chemoembolization (TACE) in HCC management. METHODS: We retrospectively reviewed the data of patients with HCC who underwent curative liver resection in our center from 2014 to 2018. The patients were divided into micronecrosis (+) and micronecrosis (-) groups. In each group, overall survival (OS) and disease-free survival (DFS) were compared between patients who underwent adjuvant TACE and those who did not. Propensity score matching (PSM) was conducted at a ratio of 1:1 to control selection bias. Univariate and multivariate analyses were performed to determine independent prognostic factors. Mass cytometry was applied to compare the immunological status of HCCs between the two groups. RESULTS: A total of 897 patients were included, with 417 and 480 patients in the micronecrosis (+) and micronecrosis (-) groups, respectively. No significant difference was detected in baseline parameters after PSM. In the micronecrosis (+) group, patients who underwent adjuvant TACE had significant longer OS than did those who did not (P = 0.004). However, patients in the micronecrosis (-) group did not benefit from adjuvant TACE. Although adjuvant TACE prolonged the DFS of patients with severe micronecrosis (P = 0.034), it may adversely affect the DFS of patients without micronecrosis (P = 0.131). Multivariate analysis showed that TACE was an independent prognostic factor for patients with micronecrosis but not for those without micronecrosis. The abundance of exhausted and regulatory T cells was significantly higher in patients with micronecrosis. CONCLUSIONS: For HCC patients with micronecrosis, adjuvant TACE after curative resection could improve the prognosis, while its survival benefits were limited in HCC patients without micronecrosis. TACE should be selectively performed in patients with micronecrosis, especially those with an Nscore = 2. The immunosuppressive status of HCC patients with micronecrosis may explain the effectiveness of adjuvant TACE in such scinario.

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

Method of Tumor Pathological Micronecrosis Quantification Via Deep Learning From Label Fuzzy Proportions.

The presence of necrosis is associated with tumor progression and patient outcomes in many cancers, but existing analyses rarely adopt quantitative methods because the manual quantification of histopathological features is too expensive. We aim to accurately identify necrotic regions on hematoxylin and eosin (HE)-stained slides and to calculate the ratio of necrosis with minimal annotations on the images. An adaptive method named Learning from Label Fuzzy Proportions (LLFP) was introduced to histopathological image analysis. Two datasets of liver cancer HE slides were collected to verify the feasibility of the method by training on the internal set using cross validation and performing validation on the external set, along with ensemble learning to improve performance. The models from cross validation performed relatively stably in identifying necrosis, with a Concordance Index of the Slide Necrosis Score (CISNS) of 0.9165±0.0089 in the internal test set. The integration model improved the CISNS to 0.9341 and achieved a CISNS of 0.8278 on the external set. There were significant differences in survival (p = 0.0060) between the three groups divided according to the calculated necrosis ratio. The proposed method can build an integration model good at distinguishing necrosis and capable of clinical assistance as an automatic tool to stratify patients with different risks or as a cluster tool for the quantification of histopathological features. We presented a method effective for identifying histopathological features and suggested that the extent of necrosis, especially micronecrosis, in liver cancer is related to patient outcomes.

Cubic nano-silver-decorated manganese dioxide micromotors: enhanced propulsion and antibacterial performance.

The increasing threat of antibiotic-resistant bacterial strains represents the current antibacterial dilemma and requires novel bactericidal treatment to circumvent this problem. In this work, an efficient strategy for killing bacteria using PEDOT/MnO2@Ag micromotors is reported based on the intense motion-induced convection and excellent sterilization ability of silver (Ag) ions. A distinctive inner surface structure with cubic Ag nanoparticle growth and dispersion in the MnO2 layer was constructed by simple cathodic co-electrodeposition. Due to the synergistic catalytic reaction of both MnO2 and Ag, the micromotors can rapidly swim in very low concentrations of hydrogen peroxide (H2O2). The antibacterial efficiency of the micromotors was evaluated with the Escherichia coli (E. coli) model. The continuous movement of micromotors, corresponding to violent mass transfer, along with the on-the-fly release of silver ions, greatly enhanced bacteria killing efficacy, with about 14% increase in bacterial death in 0.2% H2O2 solution as compared to no motors. Such proposed micromotors could be ideal candidates for combating antibiotic-resistant bacteria in the fields of biomedical and environmental applications.

Ultrafast Growth and Locomotion of Dandelion-Like Microswarms with Tubular Micromotors.

Dynamic assembly and cooperation represent future frontiers for next generations of advanced micro/nano robots, but the required local interaction and communication cannot be directly translated from macroscale robots through the minimization because of tremendous technological challenges. Here, an ultrafast growth and locomotion methodology is presented for dandelion-like microswarms assembled from catalytic tubular micromotors. With ultrasound oscillation of self-generated bubbles, such microswarms could overcome the tremendous and chaotic drag force from extensive and disordered bubble generation in single units. Tubular MnO2 micromotor individuals headed by self-generated oxygen bubbles are ultrasonically driven to swim rapidly in surfactant-free H2 O2 solutions. A large bubble core fused from multiple microbubbles is excited to oscillate and the resultant local intensified acoustic field attracts the individual micromotors to school around it, leading to a simultaneous growth of dandelion-like microswarms. The bubble-carried micromotor groups driven by ultrasound could swarm at a zigzag pattern with an average speed of up to 50 mm s-1 , which is validated in low H2 O2 concentrations. Additionally, such superfast locomotion could be ultrasonically modulated on demand. The ultrafast microswarm growth and locomotion strategy offers a new paradigm for constructing distinct dynamic assemblies and rapid transmission of artificial microrobots, paving the way to a myriad of promising applications.

Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas.

OBJECTIVE: Hepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice. DESIGN: We harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings. RESULTS: Tumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis. CONCLUSION: There is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.

Fish-Scale-Like Intercalated Metal Oxide-Based Micromotors as Efficient Water Remediation Agents.

With compelling virtues of a large specific surface area, abundant active sites, and fast interfacial transport, nanomaterials have been demonstrated to be indispensable tools for water remediation applications. Accordingly, micro/nanomotors made by nanomaterials would also benefit from these properties. Though tuning the surface architecture on demand becomes a hot topic in the field of nanomaterials, there are still limited reports on the design of active surface architectures in chemically driven tubular micro/nanomachines. Here, a unique architecture composed of a fish-scale-like intercalated (FSI) surface structure and an active layer with 5 nm nanoparticles is constructed, which composes of Fe2O3 and ramsdellite MnO2, Mn2O3, in the tubular micromotor using a versatile electrodeposition protocol. Tailoring the electrodeposition parameters enables us to modulate the active MnO2 surface structure on demand, giving rise to a pronounced propulsion performance and catalytic activity. Upon exposure to the azo-dye waste solution, the degradation efficacy greatly raises by around 22.5% with FSI micromotor treatment when compared to the normal compact motors, owing to the synergistic effect between the Fe-related Fenton reaction and a large catalytic area offered by the hierarchically rough inner surface. Such unique micromachines with a large active surface area have great potential for environmental and biomedical applications.

Metal-Based Transient Micromotors: From Principle to Environmental and Biomedical Applications.

Inspired by transient devices, transient self-destroying micromotors that are propelled by metal-water/acid reactions and autonomously disappear after completing their tasks have emerged as promising tools for diverse applications. Such transient machines require careful selection of the metal matrix and well-designed architectures for effective propulsion and customized functionality. In particular, recent advances in transient micromotors based on the active metals Zn, Fe, and Mg are introduced here. First, the fundamental design principles of transient micromotors are discussed. Then, their recent progress in environmental and biomedical applications is highlighted.

Electrochemical Deposition Tailors the Catalytic Performance of MnO2 -Based Micromotors.

Artificial micro/nanomotors that could perform diverse tasks autonomously at the micro/nanoscale have been emerging as promising tools in many practical applications. Electrochemical synthesis is one of the dominating methods to fabricate these micro/nanodevices with diverse geometries and material components. By changing the conditions of electrochemical deposition, the surface morphology, crystal structure, and hence the resultant performance of deposited material could be tailored. In the current work, a feasible fabrication strategy is presented in terms of three unique electrodeposition types (i.e., potentiodynamic, potentiostatic (PS), and galvanostatic) to synthesize different MnO2 -based micromotors. Distinct propulsion behavior as well as the catalytic degradation of azo-dye organic waste (with methylene blue as the representative), between three kinds of MnO2 -based micromotors is clearly displayed, owing to the distinctive chemical composition and morphology designs. The activated R-MnO2 -based micromotors in PS mode exhibit fast motion speed (up to 12 body length per second), leading to the highest degradation efficiency. Such propulsion performance is comparable with the microrockets made by noble metals such as Pt and Ag. The new protocol will have a profound impact on the design of synthetic micro/nanomotors and hold a considerable promise for their diverse applications.

Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (TH 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORγ.

RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators.