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Abstract We demonstrate that Debye shielding cannot be employed to constrain the cosmological abundance of magnetic monopoles, contrary to what is stated in the previous literature. Current model-independent bounds on the monopole abundance are then revisited for unit Dirac magnetic charge. We find that the Andromeda Parker bound can be employed to set an upper limit on the monopole flux at the level of F M ≲ 5.3 × 10−19cm−2s−1sr−1 for a monopole mass 1013 GeV/c 2 ≲ m ≲ 1016 GeV/c 2, which is more stringent than the MACRO direct search limit by two orders of magnitude. This translates into stringent constraints on the monopole density parameter Ω M at the level of 10−7˘10−4 depending on the mass. For larger monopole masses the scenarios in which magnetic monopoles account for all or the majority of dark matter are disfavored.

Abstract We aimed to build a deep learning-based pathomics model to predict the early recurrence of non-muscle-infiltrating bladder cancer (NMIBC) in this work. A total of 147 patients from Xuzhou Central Hospital were enrolled as the training cohort, and 63 patients from Suqian Affiliated Hospital of Xuzhou Medical University were enrolled as the test cohort. Based on two consecutive phases of patch level prediction and WSI-level predictione, we built a pathomics model, with the initial model developed in the training cohort and subjected to transfer learning, and then the test cohort was validated for generalization. The features extracted from the visualization model were used for model interpretation. After migration learning, the area under the receiver operating characteristic curve for the deep learning-based pathomics model in the test cohort was 0.860 (95% CI 0.752–0.969), with good agreement between the migration training cohort and the test cohort in predicting recurrence, and the predicted values matched well with the observed values, with p values of 0.667766 and 0.140233 for the Hosmer–Lemeshow test, respectively. The good clinical application was observed using a decision curve analysis method. We developed a deep learning-based pathomics model showed promising performance in predicting recurrence within one year in NMIBC patients. Including 10 state prediction NMIBC recurrence group pathology features be visualized, which may be used to facilitate personalized management of NMIBC patients to avoid ineffective or unnecessary treatment for the benefit of patients.

Abstract Objectives In this study, we aimed to validate the performance of the PAX1 and JAM3 methylation (PAX1 m /JAM3 m ) test as a triage tool for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3 +) in non-16/18 high-risk human papillomavirus-positive patients (non-16/18 hrHPV +). Methods The triage performance of liquid-based cytology (LBC) and the PAX1 m /JAM3 m test for detecting CIN3 + were compared. Results In total, 1851 participants had cervical histological outcomes and were included in the analysis. The sensitivity/specificity of the LBC test results with atypical squamous cells of undetermined significance or worse (LBC ≥ ASCUS) and the PAX1 m /JAM3 m test were 90.1%/26.7% and 84.8%/88.5%, respectively. PAX1 m /JAM3 m ( +) had the highest diagnostic AUC (0.866, 95% confidence interval (CI) 0.837–0.896) in the whole cohort. All cancers (n = 20) were detected by PAX1 m /JAM3 m (+). Compared with LBC ≥ ASCUS, PAX1 m /JAM3 m (+) reduced the number of patients who needed referral for colposcopy by 57.21% (74.66% vs. 17.45%). The odds ratios for detecting CIN3 + by LBC ≥ ASCUS and PAX1 m /JAM3 m (+) were 3.3 (95% CI 2.0–5.9) and 42.6 (27.1–69.6), respectively (p

Abstract In the third-generation (3G) gravitational-wave (GW) detector era, multi-messenger GW observation for binary neutron star (BNS) merger events can exert great impacts on exploring cosmic expansion history. In this work, we comprehensively explore the potential of 3G GW standard siren observations in cosmological parameter estimations by considering 3G GW detectors and the future short $$\gamma $$ γ -ray burst (GRB) detector THESEUS-like telescope joint observations. Based on a 10-year observation of different detection strategies, we predict that the numbers of detectable GW-GRB events are 334–674 with the redshifts $$z

Abstract Coiled-coil domain containing 88C (CCDC88C) is a component of non-canonical Wnt signaling, and its dysregulation causes colorectal cancer metastasis. Dysregulated expression of CCDC88C was observed in lymph node metastatic tumor tissues of breast cancer. However, the role of CCDC88C in breast cancer metastasis remains unclear. To address this, the stable BT549 and SKBR3 cell lines with CCDC88C overexpression or knockdown were developed. Loss/gain-of-function experiments suggested that CCDC88C drove breast cancer cell motility in vitro and lung and liver metastasis in vivo. We found that CCDC88C led to c-JUN-induced transcription activation. Overlapping genes were identified from the genes modulated by CCDC88C and c-JUN. CEMIP, one of these overlapping genes, has been confirmed to confer breast cancer metastasis. We found that CCDC88C regulated CEMIP mRNA levels via c-JUN and it exerted pro-metastatic capabilities in a CEMIP-dependent manner. Moreover, we identified the CCDC88C as a substrate of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6). GALNT6 was positively correlated with CCDC88C protein abundance in the normal breast and breast cancer tissues, indicating that GALNT6 might be associated with expression patterns of CCDC88C in breast cancer. Our data demonstrated that GALNT6 maintained CCDC88C stability by promoting its O-linked glycosylation, and the modification was critical for the pro-metastatic potential of CCDC88C. CCDC88C also could mediate the pro-metastatic potential of GALNT6 in breast cancer. Collectively, our findings uncover that CCDC88C may increase the risk of breast cancer metastasis and elucidate the underlying molecular mechanisms.

Background Microangiogenesis and lymphangiogenesis are essential for tumor growth in the tumor microenvironment, contributing to tumor invasion and metastasis. Limited literature exists on these processes in esophageal squamous cell carcinoma (ESCC). Therefore, the purpose of this study is to explore the impacts of microangiogenesis and lymphangiogenesis on the occurrence, progression, and prognosis assessment of ESCC. Methods Surgical specimens and paraffin-embedded human tissues were procured from ESCC patients, encompassing 100 ESCC tissues and 100 cancer-adjacent normal (CAN) tissues. CD34 and D2-40 were utilized as markers for microvessel endothelial cells and lymphatic vessel endothelial cells, respectively. Microvascular density (MVD) and lymphatic vessel density (LVD) were evaluated through immunohistochemical quantification. Results We found that tumor tissues in ESCC patients had significantly higher MVD and LVD than cancer-adjacent normal (CAN) tissues. High MVD and LVD were associated with lymph node metastasis and advanced tumor clinical stages. Additionally, both high MVD and high LVD were strongly linked to poorer prognosis among cancer patients. Furthermore, a positive correlation was found between high MVD and high LVD (p < 0.05). The presence of these markers individually indicated a worse prognosis, with their combined assessment showcasing enhanced prognostic value. Conclusions Overall, the increased MVD and LVD indicates higher invasion and metastasis of ESCC, closely correlating with unfavorablefor poor prognosis of ESCC patients.

Abstract A 6‐year‐old male golden retriever presented with swelling of the left upper eyelid of 2 months duration, which did not improve following a course of antibiotics. Routine serum biochemistry, complete blood count and diagnostic imaging identified no clinically significant abnormalities. The mass was surgically excised, and histopathologic examination was performed. Eosinophilic granulocytic sarcoma (GS) was diagnosed based on the results of histopathology and immunohistochemistry. This is the first report of GS affecting the eyelid of a dog.

To investigate the effect of adipose-derived stem cells (ASCs) transplantation on radiation-induced lung injury (RILI), Sprague-Dawley rats were divided into phosphate-buffered saline (PBS) group, ASCs group, Radiation + PBS group, and Radiation + ASCs group. Radiation + PBS and Radiation + ASCs groups received single dose of 30 Gy X-ray radiation to the right chest. The Radiation + PBS group received 1 mL PBS suspension and Radiation + ASCs group received 1 mL PBS suspension containing 1 × 107 CM-Dil-labeled ASCs. The right lung tissue was collected on Days 30, 90, and 180 after radiation. Hematoxylin–eosin and Masson staining were performed to observe the pathological changes and collagen fiber content in the lung tissue. Immunohistochemistry (IHC) and western blot (WB) were used to detect levels of fibrotic markers collagen I (Collal), fibronectin (FN), as well as transforming growth factor-β1 (TGF-β1), p-Smad 3, and Smad 3. Compared with the non-radiation groups, the radiation groups showed lymphocyte infiltration on Day 30 after irradiation and thickened incomplete alveolar walls, collagen deposition, and fibroplasia on Days 90 and 180. ASCs relieved these changes on Day 180 (Masson staining, P = 0.0022). Compared with Radiation + PBS group, on Day 180 after irradiation, the Radiation + ASCs group showed that ASCs could significantly decrease the expressions of fibrosis markers Collal (IHC: P = 0.0022; WB: P = 0.0087) and FN (IHC: P = 0.0152; WB: P = 0.026) and inhibit the expressions of TGF-β1 (IHC: P = 0.026; WB: P = 0.0152) and p-Smad 3 (IHC: P = 0.0043; WB: P = 0.0087) in radiation-induced injured lung tissue. These indicated that ASCs could relieve RILI by inhibiting TGF-β1/Smad 3 signaling pathway.

OBJECTIVES/GOALS: Clinical indicators predictive of venous thromboembolism (VTE) in trauma patients at multiple time points are not well outlined, particularly at time of discharge. We aimed to describe and predict inpatient and post-discharge risk factors of VTE after trauma using a multi-variate regression model and best of class machine learning (ML) models. METHODS/STUDY POPULATION: In a prospective, case-cohort study, all trauma patients (pts) who arrived as level 1 or 2 trauma activations, from June 2018 to February 2020 were considered for study inclusion. A subset of pts who developed incident, first time, VTE and those who did not develop VTE within 90 days of discharge were identified. VTE were confirmed either by imaging or at autopsy during inpatient stay or post-discharge. Outcomes were defined as the development of symptomatic VTE (DVT and/or PE) within 90 days of discharge.A multi-variate Cox regression model and a best in class of a set of 5 different ML models (support-vector machine, random-forest, naives Bayes, logistic regression, neural network]) were used to predict VTE using models applied a) at 24 hours of injury date or b) on day of patient discharge. RESULTS/ANTICIPATED RESULTS: Among 393 trauma pts (ISS=12.0, hospital LOS=4.0 days, age=48 years, 71% male, 96% with blunt mechanism, mortality 2.8%), 36 developed inpatient VTE and 36 developed VTE after discharge. In a weighted, multivariate Cox model, any type of surgery by day 1, increased age per 10 years, and BMI per 5 points were predictors of overall symptomatic VTE (C-stat 0.738). Prophylactic IVC filter placement (4.40), increased patient age per 10 years, and BMI per 5 points were predictors of post-discharge symptomatic VTE (C-stat= 0.698). A neural network ML model predicted VTE by day 1 with accuracy and AUC of 0.82 and 0.76, with performance exceeding those of a Cox model. A naīve Bayesian ML model predicted VTE at discharge, with accuracy and AUC of 0.81 and 0.77 at time of discharge, with performance exceeding those of a Cox model. DISCUSSION/SIGNIFICANCE: The rate of inpatient and post-discharge VTEs remain high. Limitations: single institution study, limited number of patients, internal validation only, with the use of limited number of ML models. We developed and internally validated a ML based tool.Future work will focus on external validation and expansion of ML techniques.

Abstract Traumatic brain injury (TBI) is a leading cause of injury-related disability and death around the world, but the clinical stratification, diagnosis, and treatment of complex TBI are limited. Due to their unique properties, extracellular vesicles (EVs) are emerging candidates for being biomarkers of traumatic brain injury as well as serving as potential therapeutic targets. However, the effects of different extracellular vesicle subtypes on the pathophysiology of traumatic brain injury are very different, or potentially even opposite. Before extracellular vesicles can be used as targets for TBI therapy, it is necessary to classify different extracellular vesicle subtypes according to their functions to clarify different strategies for EV-based TBI therapy. The purpose of this review is to discuss contradictory effects of different EV subtypes on TBI, and to propose treatment ideas based on different EV subtypes to maximize their benefits for the recovery of TBI patients. Video Abstract

The evolution of ablative Rayleigh–Taylor instability (ARTI) induced by single-mode stationary and time-varying perturbations in heat flux is studied numerically in two dimensions. Compared with the stationary case, time-varying heat-flux perturbation mitigates ARTI growth because of the enhanced thermal smoothing induced by the wave-like traveling heat flux. A resonance is found to form when the phase velocity of the heat-flux perturbation matches the average sound speed in the ablation region. In the resonant regime, the coherent density and temperature fluctuations enhance the electron thermal conduction in the ablation region and lead to larger ablation pressure and effective acceleration, which consequently yield higher linear growth rate and saturated bubble velocity. The enhanced effective acceleration offers increased implosion velocity but can also compromise the integrity of inertial confinement fusion shells by causing faster ARTI growth.

AbstractRheumatoid arthritis (RA) is a common type of chronic inflammatory disease. Elucidating the mechanism of fibroblast-like synovial (FLS) as a pathologic factor in RA may address the urgent medical requirement for the treatment of RA. Isorhynchophylline (IRN) is a tetracyclic hydroxyindole alkaloid isolated from uncinaria, which has multiple biological activities and affects the progression of osteoarthritis. However, the role of IRN in rheumatoid arthritis remains unclear. Herein, our study aimed to elucidate the potential effect of IRN on RA and reveal its mechanism. Human FLS cell line MH7A cells were stimulated with TNF-α for 24 h to construct a cell model. CCK-8, Edu, wound healing, as well as transwell assays were conducted to detect the effects of IRN on cell proliferation and motility. ELISA and Immunoblot assays were further performed to detect the production of pro-inflammatory factors and the expression levels of MMPs. Immunoblot and Immunostaining assays were conducted to uncover the mechanism. ELISA, H&E staining, and Immunoblot assays were used to confirm the effects of IRN on RA in a CIA rat model. We revealed that IRN restrained TNF-α-stimulated MH7A cell proliferation and motility. In addition, IRN blocked the production of pro-inflammatory factors and MMPs in TNF-α-stimulated-MH7A cells. We further found that IRN restrained FOXC1/β-catenin axis, and improved MH7A cell proliferation as well as migration via the FOXC1/β-catenin axis. IRN restores CIA by inhibiting pro-inflammatory cytokines in synovial tissues. In summary, IRN attenuates proliferation and migration of FLS in RA via the FOXC1 mediated β-catenin axis.

Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD patients. Here, we characterized the dynamics of myelin generation and loss in the APP/PS1 mouse model of AD. Unexpectedly, we observed a dramatic increase in the rate of new myelin formation in APP/PS1 mice, reminiscent of the robust oligodendroglial response to demyelination. Despite this increase, overall levels of myelination are decreased in the cortex and hippocampus of APP/PS1 mice and postmortem AD tissue. Genetically or pharmacologically enhancing myelin renewal, by oligodendroglial deletion of the muscarinic M1 receptor or systemic administration of the pro-myelinating drug clemastine, improved the performance of APP/PS1 mice in memory-related tasks and increased hippocampal sharp wave ripples. Taken together, these results demonstrate the potential of enhancing myelination as a therapeutic strategy to alleviate AD-related cognitive impairment.

Fast radio bursts (FRBs) have been found in great numbers, but the physical mechanism of these sources is still a mystery. The redshift evolutions of the FRB energy distribution function and the volumetric rate shed light on the origin of FRBs. However, such estimations rely on the dispersion measurement (DM)–redshift (z) relationship. A few FRBs that have been detected recently show large excess DMs beyond the expectation from the cosmological and Milky Way contributions, which indicates large spread of DMs from their host galaxies. In this work, we adopt two lognormal-distributed DMhost models and estimate the energy function using the non-repeating FRBs selected from the Canadian Hydrogen Intensity Mapping Experiment (CHIME)/FRB Catalog 1. By comparing the lognormal-distributed DMhost models to a constant DMhost model, the FRB energy function results are consistent within the measurement uncertainty. We also estimate the volumetric rate of the non-repeating FRBs in three different redshift bins. The volumetric rate shows that the trend is consistent with the stellar-mass density redshift evolution. Since the lognormal-distributed DMhost model increases the measurement errors, the inference of FRBs tracking the stellar-mass density is nonetheless undermined.

Ti–Al composite coating was prepared on the surface of a titanium alloy by the laser cladding technology and coaxial powder feeding under argon protection. The cladding material was AlSi10Mg aluminum alloy powder. The intermediate sample was thermally diffused at high temperature for 6 h and then placed in a certain intensity of the alternating electromagnetic field until completely cooled. The alloy substrate and coating solidified under the action of the alternating electromagnetic field, and the surface coating of a high strength titanium alloy was obtained. The morphology and microstructure of the composite coating were analyzed by SEM, XRD, and energy dispersive spectroscopy (EDS), and the hardness of the coating was measured. The results showed that the high temperature thermal diffusion promoted the interatomic diffusion; repaired some defects, such as cracks and pores; and eliminated the elemental metals that did not participate in the reaction, and the surface hardness of the coating joint reached the maximum. The electromagnetic stirring makes the titanium alloy coating and substrate bond well, the joint is relatively straight, the number of cracks and pores is obviously reduced, and the comprehensive performance of the coating is improved.

Abstract Introduction/aims To facilitate further investigation into the mechanisms of facial nerve regeneration, a simple and reliable model of facial nerve crush injury is essential. Nevertheless, the establishment of such models lacks standardization and repeatability, while the healing capacity of the nerve is often overlooked, potentially affecting future studies. Methods We made facial nerve trunk crush injury models with different pressing times and detected the changes from the distal nerves to the motoneurons via behavior analysis, electrophysiological test, and histomorphometry analysis. Results It revealed a particular capacity for self‐healing following facial nerve crush damage because there was almost no facial motoneuron apoptosis in the MC group during the observation period, and rats in MC group had total facial paralysis in behavioral tests following surgery and varying degrees of recovery 28 days postoperatively with no treatments. As the pressing time increased, the latency, wave amplitude, nerve fiber damage degree, nerve axon ratio, myelin thickness, electroneurograph (ENoG) value, ultrastructural damage, abnormal morphological changes, and the buccal muscle atrophy of each MC group gradually increased or got worse during the observation period. However, after 28 postoperative days, only the ENoG values of the M10min and M12min groups were beyond 90%, indicating no self‐healing. Discussion It suggests that a stable model of peripheral facial palsy may be created by applying a 12.5 cm mosquito clamped to the facial nerve trunk for at least 10 min, which laid the foundation for the subsequent research to objectively evaluate facial nerve regeneration.

Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding with spatial memory deficits. Inhibiting myelination by deletion of Olig2 in oligodendrocyte precursor cells impairs spatial memory in young mice, while enhancing myelination by deleting the muscarinic acetylcholine receptor 1 in oligodendrocyte precursor cells, or promoting oligodendroglial differentiation and myelination via clemastine treatment, rescues spatial memory decline during aging.

For the estimation problem of multiple adjacent targets, the traditional correlation function estimation method based on the matched filter (MF) is often limited by resolution, resulting in insufficient estimation accuracy. Subsequently, an exponential filter (EF) with high resolution was constructed by introducing a controllable exponent $p$ into the frequency response function of the matched filter. In this paper, we propose a sparse reconstruction and exponential filter-based estimation algorithm to estimate the time delays of multiple targets. This algorithm uses the exponential autocorrelation function (the output of the exponential filter) as a template and constructs a sparse overcomplete model of the time delays of the received signal in the exponential correlation domain. An interior-point method based on $l_{1}$ -norm regularization is then employed to solve the proposed overcomplete model. Notably, the proposed algorithm does not require prior knowledge of the target number. Theoretical analysis and Simulation results demonstrate that, the proposed algorithm can effectively reduce the coherence between adjacent targets and thus achieve high-accuracy time-delay estimation. When the input SNR is higher than −24 dB, it has a higher estimation accuracy for multi-target time delays (especially for adjacent targets) than the previous MF or EF based time-delay estimation algorithms. Particularly, at high signal-to-noise ratios, the estimation error of the proposed algorithm can approach the error bound of the time delays derived from the Cramér–Rao lower bound; when the input SNR is higher than −4 dB, it achieves completely accurate estimation.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a deadly gastrointestinal malignancy, and chemotherapy resistance is a key factor leading to its poor prognosis. M2 tumor-associated macrophages (M2-TAMs) may be an important cause of chemoresistance in ESCC, but its exact mechanism is still unclear. Methods In order to study the role of M2-TAMs in ESCC chemoresistance, CCK-8, clone formation assay, flow cytometric apoptosis assay, qRT-PCR, western blotting, and serum-free sphere formation assays were used. In vivo animal experiments and human ESCC tissues were used to confirm the findings. Results In vitro and in vivo animal experiments, M2-TAMs reduced the sensitivity of ESCC cells to cisplatin. Mechanistically, M2-TAMs highly secreted TGF-β1 which activated the TGFβR1-smad2/3 pathway to promote and maintain the stemness characteristic of ESCC cells, which could inhibit the sensitivity to cisplatin. Using TGFβ signaling inhibitor SB431542 or knockdown of TGFβR1 could reverse the cisplatin resistance of ESCC cells. In 92 cases of human ESCC tissues, individuals with a high density of M2-TAMs had considerably higher levels of TGF-β1. These patients also had worse prognoses and richer stemness markers. Conclusion TGF-β1 secreted from M2-TAMs promoted and maintained the stemness characteristic to induce cisplatin resistance in ESCC by activating the TGFβ1-Smad2/3 pathway.

Abstract Tibial dyschondroplasia (TD) with multiple incentives is a metabolic skeletal disease that occurs in fast-growing broilers. Perturbations in the gut microbiota (GM) have been shown to affect bone homoeostasis, but the mechanisms by which GM modulates bone metabolism in TD broilers remain unknown. Here, using a broiler model of TD, we noted elevated blood glucose (GLU) levels in TD broilers, accompanied by alterations in the pancreatic structure and secretory function and damaged intestinal barrier function. Importantly, faecal microbiota transplantation (FMT) of gut microbes from normal donors rehabilitated the GM and decreased the elevated GLU levels in TD broilers. A high GLU level is a predisposing factor to bone disease, suggesting that GM dysbiosis-mediated hyperglycaemia might be involved in bone regulation. 16S rRNA gene sequencing and short-chain fatty acid analysis revealed that the significantly increased level of the metabolite butyric acid derived from the genera Blautia and Coprococcus regulated GLU levels in TD broilers by binding to GPR109A in the pancreas. Tibial studies showed reduced expression of vascular regulatory factors (including PI3K, AKT and VEFGA) based on transcriptomics analysis and reduced vascular distribution, contributing to nonvascularization of cartilage in the proximal tibial growth plate of TD broilers with elevated GLU levels. Additionally, treatment with the total flavonoids from Rhizoma drynariae further validated the improvement in bone homoeostasis in TD broilers by regulating GLU levels through the regulation of GM to subsequently improve intestinal and pancreatic function. These findings clarify the critical role of GM-mediated changes in GLU levels via the gut–pancreas axis in bone homoeostasis in TD chickens.

Background: We investigated whether the degree of inflammation and fibrosis in para-carcinoma tissue can predict prognosis of patients with non-cirrhotic hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) after hepatectomy. We also explored the mechanisms through which inflammation and fibrosis might affect prognosis. Methods: Clinicopathological data were retrospectively analyzed from 293 patients with non-cirrhotic HBV-associated HCC who were treated at our institution by curative resection from 2012 to 2017. Based on the Scheuer score system, patients were classified into those showing mild or moderate-to-severe inflammation and fibrosis. Rates of overall and recurrence-free survival were compared between the groups using Kaplan–Meier curves, and survival predictors were identified using Cox regression. Using tumor and para-tumor tissues from independent samples of patients with non-cirrhotic HBV-associated HCC who were treated at our institution by curative resection from 2018 to 2019, we performed next-generation sequencing and time-of-flight cytometry (CyTOF) to examine the influence of inflammation and fibrosis on gene expression and immune cell infiltration. Results: In the analysis of the 293 patients, those with mild inflammation and fibrosis showed significantly better overall and recurrence-free survival than those with moderate-to-severe inflammation and fibrosis. Multivariate Cox regression confirmed that moderate-to-severe inflammation and fibrosis were independent risk factors for worse survival. RNA sequencing and CyTOF showed that more severe inflammation and fibrosis were associated with stronger invasion and migration by hepatocytes. In cancerous tissues, the biological processes of cell proliferation were upregulated, the signaling pathways promoting tumor growth were activated, the proportion of Th17 cells promoting tumor progression was increased, and CD8+ T cells expressed higher levels of PD-L1. In para-cancerous tissues, biological processes of immune response and cell chemotaxis were downregulated, and the proportion of tumor-killing immune cells was decreased. Conclusion: Worse inflammation and fibrosis in non-cirrhotic HBV-associated HCC is associated with worse prognosis, which may reflect more aggressive tumor behavior and an immunosuppressed, pro-metastatic tumor microenvironment.

Abstract Background The prognosis of hepatocellular carcinoma (HCC) varies considerably among patients with the same disease stage and characteristics, and only about two thirds show high levels of α-fetoprotein (AFP), a common prognostic indicator for HCC. Here, we assessed whether the combination of presurgical serum levels of AFP and carbohydrate antigen 19-9 (CA19-9) can predict the prognosis of HCC patients after hepatectomy. Methods The clinicopathological characteristics and post-hepatectomy outcomes of 711 HCC patients were retrospectively reviewed. The patients were classified into three groups based on whether their preoperative serum levels of both AFP and CA19-9 were higher than the respective cut-offs of 400 ng/ml and 37 U/ml [double positive (DP)], the level of only one marker was higher than the cut-off [single positive (SP)], or neither level was higher than the cut-off [negative (N)]. The overall survival (OS) and recurrence-free survival (RFS) rates were estimated using Kaplan–Meier curves. Univariate and multivariate survival analyses were performed to identify the clinicopathological factors significantly associated with HCC prognosis. Results The 1-year, 3-year, and 5-year RFS and OS rates in the N group were significantly higher than those in the SP group, while the DP group showed the lowest rates. Multivariate Cox regression analysis showed that large tumor size (> 5 cm), multiple tumors (≥ 2), incomplete tumor capsule, positive microvascular invasion, Barcelona Clinic Liver Cancer C stage, and CA19-9 level > 37 U/mL were independent risk factors for RFS and OS in HCC patients. Moreover, aspartate aminotransferase levels > 40 U/L proved to be an independent prognostic factor for OS. Conclusion The combination of serum AFP and CA19-9 levels may be a useful prognostic marker for HCC patients after hepatectomy.