ObjectiveTumour pathology contains rich information, including tissue structure and cell morphology, that reflects disease progression and patient survival. However, phenotypic information is subtle ...and complex, making the discovery of prognostic indicators from pathological images challenging.DesignAn interpretable, weakly supervised deep learning framework incorporating prior knowledge was proposed to analyse hepatocellular carcinoma (HCC) and explore new prognostic phenotypes on pathological whole-slide images (WSIs) from the Zhongshan cohort of 1125 HCC patients (2451 WSIs) and TCGA cohort of 320 HCC patients (320 WSIs). A ‘tumour risk score (TRS)’ was established to evaluate patient outcomes, and then risk activation mapping (RAM) was applied to visualise the pathological phenotypes of TRS. The multi-omics data of The Cancer Genome Atlas(TCGA) HCC were used to assess the potential pathogenesis underlying TRS.ResultsSurvival analysis revealed that TRS was an independent prognosticator in both the Zhongshan cohort (p<0.0001) and TCGA cohort (p=0.0003). The predictive ability of TRS was superior to and independent of clinical staging systems, and TRS could evenly stratify patients into up to five groups with significantly different prognoses. Notably, sinusoidal capillarisation, prominent nucleoli and karyotheca, the nucleus/cytoplasm ratio and infiltrating inflammatory cells were identified as the main underlying features of TRS. The multi-omics data of TCGA HCC hint at the relevance of TRS to tumour immune infiltration and genetic alterations such as the FAT3 and RYR2 mutations.ConclusionOur deep learning framework is an effective and labour-saving method for decoding pathological images, providing a valuable means for HCC risk stratification and precise patient treatment.
Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in ...hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor‐educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro‐tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal‐regulated kinase 1/2, and v‐akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor‐derived CCR1+CD14+ monocytes expressed significantly higher levels of programmed cell death‐ligand 1, B7‐H3, and T‐cell immunoglobulin domain and mucin domain‐3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor‐infiltrating CCR1+CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro‐angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15‐CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor‐promoting inflammatory microenvironment was shaped by CCL15‐CCR1 axis in human HCC. Blockade of CCL15‐CCR1 axis in HCC could be an effective anticancer therapy.
It has been reported that tetraspanin CD151 acts as a promoter of metastasis in several tumors and plays an important role in c‐Met/hepatocyte growth factor signaling. However, the role of CD151 ...alone and coexpression of CD151/c‐Met in hepatocellular carcinoma (HCC) remains unclear. We found that expression of CD151 was positively related to metastatic potential of HCC cell lines, and modified cells with CD151high showed higher secretion of matrix metalloproteinase 9 and aggressiveness in vitro and higher metastatic ability in vivo. Furthermore, HCC patients with vascular invasion, large tumors, multiple tumors, high tumor‐node‐metastasis stage, and undifferentiated tumor were prone to have higher CD151 expression. The postoperative 3‐, 5‐, and 7‐year overall survival (OS) of patients in HCCs with CD151high were significantly lower than those in the CD151low group, and correspondingly cumulative recurrence rates in HCCs with CD151high were significantly higher than those in the CD151low group. Both CD151 and c‐Met were remarkably overexpressed in HCCs, compared with adjacent nontumorous and normal liver tissues. Pearson correlation analysis showed a slight correlation between CD151 and c‐Met in HCCs. Importantly, the 5‐ and 7‐year OS rates in CD151high/c‐Methigh patients were 50.5% and 37.8%, respectively, significantly lower than those of CD151low/c‐Metlow patients (63.9% and 54.6%, respectively). Five‐ and 7‐year cumulative recurrence rates in CD151high/c‐Methigh patients were 53.3% and 71.9%, respectively, markedly higher than those of CD151low/c‐Metlow patients (39.0% and 52.5%, respectively). Multivariate analysis revealed that CD151 and combination of CD151/c‐Met were independent prognostic indicators for OS and cumulative recurrence. Conclusion: CD151 is positively associated with invasiveness of HCC, and CD151 or combination of CD151/c‐Met is a novel marker in predicting the prognosis of HCC and a potential therapeutic target. (HEPATOLOGY 2008.)
Objectives To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA). Methods Design: a multicentre, ...open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. Intervention: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5 mg once a week, or TwHF 20 mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24. Results 174/207 (84.1%) patients completed 24 weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216). Conclusions TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA. Trial registration number NCT01613079.
MiR-34a, a direct target of p53, has been shown to target several molecules associated with the cell cycle and cell survival pathways, and its dysregulation is implicated in cancer drug resistance or ...sensitivity in several human cancers. However, the correlation between miR-34a expression and chemoresistance has not been explored in HCC. In this study, we confirmed that miR-34a was significantly down-regulated in HCC tissues and HCC cell lines by qRT-PCR. HCC tissues with lower miR-34a expression displayed higher expression of Bcl-2 protein than those with high expression of miR-34a; therefore, an inverse correlation is evident between the miR-34a level and Bcl-2 expression. Moreover, patients with lower miR-34a expression had significantly poorer overall survival. Bioinformatics and luciferase reporter assays revealed that miR-34a binds the 3'-UTR of the Bcl-2 mRNA and represses its translation. Western blotting analysis and qRT-PCR confirmed that Bcl-2 is inhibited by miR-34a overexpression. Functional analyses indicated that the restoration of miR-34a reduced cell viability, promoted cell apoptosis and potentiated sorafenib-induced apoptosis and toxicity in HCC cell lines by inhibiting Bcl-2 expression. This study is the first to demonstrate that miR-34a induces sensitivity to the anti-tumor effect of sorafenib in human HCC cells, suggesting a potential role of miR-34a in the treatment of HCC.
Hepatocellular carcinoma (HCC) has a complex and changeable tumor microenvironment. Despite emerging evidence focusing on autophagy process within immune cells, the function and regulatory mechanism ...of macrophage autophagy in tumor progression remains unclear. Our results of multiplex-immunohistochemistry and RNA-sequencing identified the reduced levels of autophagy in tumor macrophages in the HCC microenvironment, associated with a poor prognosis and increased microvascular metastasis in HCC patients. Specifically, HCC suppressed the macrophage autophagy initiation through the up-regulation of mTOR and ULK1 phosphorylation at Ser757. Knockdown of autophagy-related proteins to further inhibit autophagy significantly boosted the metastatic potential of HCC. Mechanistically, the accumulation of NLRP3 inflammasome mediated by autophagy inhibition promoted the cleavage, maturation, and release of IL-1β, which facilitated the HCC progression, eventually accelerating HCC metastasis via the epithelial-mesenchymal transition. Autophagy inhibition provoked macrophage self-recruitment through the CCL20-CCR6 signaling was also a crucial account of HCC progression. Recruited macrophages mediated the cascade amplification of IL-1β and CCL20 to form a novel pro-metastatic positive feedback loop through promoting HCC metastasis and increased macrophage recruitment, respectively. Notably, targeting IL-1β/IL-1 receptor signaling impaired lung metastasis induced by macrophage autophagy inhibition in a mice HCC lung metastasis model. In summary, this study highlighted that inhibition of tumor macrophage autophagy facilitated HCC progression by increasing IL-1β secretion via NLRP3 inflammasome accumulation and by macrophage self-recruitment through the CCL20 signaling pathway. Interruption of this metastasis-promoting loop by IL-1β blockade may provide a promising therapeutic strategy for HCC patients.
The double-helical gear system was widely used in ship transmission. In order to study the influence of backlash on the nonlinear frequency response characteristics of marine double-helical gear ...system, according to the structural characteristics of double-helical gear transmission, considering the time-varying meshing stiffness, backlash, damping, comprehensive transmission error, external load excitation, and other factors, a three-dimensional bending-torsional-axial-pendular coupling nonlinear dynamic modeling and dynamic differential equation of 24-DOF double-helical gear transmission system were established. The Runge–Kutta numerical method was used to analyze the influence of backlash, time-varying meshing stiffness, damping, error and external load excitation on the amplitude frequency characteristics. The results show that the backlash can cause the runout of the double-helical gear system, and the system has first harmonic and second harmonic response. With the increase of backlash, the amplitude of the system increases and the jumping phenomenon remains unchanged. The amplitude frequency response of the system is stimulated by time-varying meshing stiffness and comprehensive transmission error, and restrained by damping and external load excitation. The vibration displacement amplitude of the system increases with the increase of vibration displacement and has little effect on the state change of the system. The vibration test of double-helical gear is carried out. The frequency response components obtained by numerical simulation are basically consistent with the experimental results, which proves the correctness of the theoretical calculation. It provides a technical basis for the study of vibration and noise reduction performance of double-helical gear.
Hook F (
HF) is one of the most commonly used and effective traditional Chinese herbal medicines against rheumatoid arthritis (RA). Both Tripterygium Glycoside Tablets (TGT) and
Tablets (TWT) are the ...representative
HF-based agents enrolled into the 2019 edition of Medicine Catalog for National Basic Medical Insurance, Injury Insurance, and Maternity Insurance. However, individual differences in TGT/TWT response across patients usually exist in the process of treating RA, implying that the clinical application of the two agents may not be standardized leading to the ineffective treatment and the risk of side effects. Growing evidence show that the bioactive constituents of
HF may often have toxicity, the package insert of TGT and TWT may not be described in detail, and the therapeutic windows of the two agents are narrow. Thus, it is an urgent task to develop a standardized clinical practice guideline for TGT and TWT in the treatment of RA. In the current study, a group of clinical experts of traditional Chinese medicine and Western medicine in the research field of rheumatism diseases, pharmacists, and methodologists of evidence-based medicine were invited to select the clinical questions, to determine the levels of the evidence and the strength of the recommendations, and to develop the recommendations and good practice points. The guideline is formed based on the combination of clinical research evidence and expert experience (evidence-based, consensus, supplemented by experience). The clinical problems which are supported by clinical evidence may form recommendations, and the clinical problems without clinical evidence may form experts' suggestions. Both recommendations and experts' suggestions in this guideline summarized the clinical indications, usage, dosage, combined medication, and safety of TGT and TWT against RA systematically and comprehensively, which may offer a professional guidance in the context of the clinical application of the two
HF-based agents.
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