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The southeastern China coast is a region of special interest in the study of past and present relative sea-level change, given its distal location from giant ice sheets (far-field regions). During the past decades, a large number of biological, geological, and archaeological sea-level indicators have been retrieved from the Fujian coastal region which allows for recalibration and recalculation of sea-level index points (SLIPs). This study constructs a database of Holocene relative sea-level (RSL) observations for the Fujian coast, southeastern China. The database contains 59 quality-controlled SLIPs which show that RSL for the Fujian coast did not exceed present (0 m) during the Holocene, except potentially during 7.5–5.5 cal. kyr BP and 1.8–0.7 cal. kyr BP. Rates of RSL change were highest during the early Holocene and have decreased over time, due to the diminishing response of the Earth's mantle to glacial isostatic adjustment (GIA) and reduction of meltwater input. A series of sea-level oscillations were recorded in our SLIPs-based reconstructions which might correspond to global climate warming or cooling events. We assessed the spatial variability of RSL histories and compared these with the ICE-6G_C and ANU-ICE GIA model predictions. Substantial misfits between GIA predictions and regional RSL reconstructions were recognized: (1) the deceleration of the early-Holocene sea-level rise ended about one millennia earlier in the ICE-6G_C model than in the SLIPs-based reconstructions; (2) GIA model predictions show a mid-Holocene sea-level highstand of 1–3 m which is absent from our SLIPs-based reconstructions; and (3) all GIA model predicted a gradual RSL fall to 0 m since the middle Holocene, while our reconstruction displays significant RSL oscillations. It is presently unknown whether these misfits are caused by uncertainties in regional tectonic movement estimation or parameters used in the GIA models. Future applications of spatiotemporal statistical techniques are required to better quantify the gradient of the isostatic contribution and to provide improved context for the assessment of the ongoing acceleration of sea-level rise. Ministry of Education (MOE) National Research Foundation (NRF) Submitted/Accepted version This work was financially supported by the National Natural Science Foundation of China (Grant No. 42076207 to Fengling Yu); the Funda- mental Research Funds for the Central Universities of Xiamen University (Grant No. 20720190096 to Fengling Yu); the China Postdoctoral Sci- ence Foundation (Grant No. 2021M691862 to Nannan Li); the Singapore Ministry of Education Academic Research Fund MOE2019-T3-1-004 and MOE-T2EP50120-0007, the National Research Foundation Singapore, and the Singapore Ministry of Education, under the Research Centers of Excellence initiative (to Tanghua Li).

Yicheng Li,1,2,* Wentao Xu,1,* Pu Chen,1,* Minjun Liao,1,3 Wanying Qin,1 Weijia Liao,1 Zhaoquan Huang1,4 1Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, People’s Republic of China; 2Second Clinical Medical College, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 3Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 4Department of Pathology, Guilin Medical University, Guilin 541001, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijia LiaoLaboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, People’s Republic of ChinaEmail liaoweijia288@163.comZhaoquan HuangDepartment of Pathology, Guilin Medical University, Guilin 541001, Guangxi, People’s Republic of ChinaEmail 191990449@qq.comBackground: The purpose of this retrospective study was to investigate the relationship between serum iron levels and the prognosis and risk of recurrence in patients with hepatocellular carcinoma (HCC).Methods: A total of 253 HCC patients who underwent radical resection were involved in this study.Results: According to the receiver operating characteristic (ROC) curve, the optimal cut-off value for preoperative serum iron in the assessment of HCC postoperative prognosis was 94 ug/dL. The overall survival (OS) of patients in the high iron group was significantly better than that in the low iron group (p < 0.001). The recurrence rate of patients in the low iron group was higher than that in the high iron group (p = 0.011). Correlation analysis showed that preoperative serum iron level was correlated with tumor size >5 cm (χ2 = 11.590, p < 0.001), recurrence (χ2 = 5.714, p = 0.017) and microvascular invasion (χ2 = 5.087, p = 0.024). In addition, univariate analysis showed that OS and disease-free survival (DFS) of HCC patients with high iron level were better than those with low iron level. Furthermore, multivariate COX proportional hazards regression analysis showed that serum iron ≤94 μg/dL, tumor size >5 cm, and microvascular invasion were independent predictors for shorter OS and DFS in HCC patients after operation, while recurrence was for shorter OS.Conclusion: Patients with low preoperative serum iron level had worse postoperative survival and higher recurrence rate in HCC. Preoperative serum iron is an independent predictor of HCC patients. For HCC patients with low iron levels, prognosis of patients may be improved if appropriate iron is supplemented.Keywords: HCC, serum iron, prognosis, recurrence, survival rate

Yicheng Li,1– 3,* Zhengli Li,2,* Kangjian Deng,2,* Minjun Liao,2,4 Shengguang Yuan,1,2 Zhaoquan Huang2,5 1Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, Guangxi, People’s Republic of China; 2Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, People’s Republic of China; 3Second Clinical Medical College, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 4Science Experiment Center, Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 5Department of Pathology, Guilin Medical University, Guilin 541001, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhaoquan Huang; Shengguang YuanLaboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, People’s Republic of ChinaEmail 477922581@qq.com; yuanshengguang6@163.comPurpose: Preoperative fibrinogen levels are associated with the development, recurrence and metastasis of malignant tumors. This study was designed to investigate the clinical value of preoperative fibrinogen/lymphocyte count ratio (FLR) index in hepatocellular carcinoma (HCC).Patients and Methods: The clinical data of 479 patients with HCC who underwent radical resection were retrospectively analyzed. The correlation between FLR and clinicopathological features was analyzed by chi-square test or non-parametric test. The overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan–Meier method.Results: The optimal cut-off value of FLR was determined as 1.6 according to the receiver operating characteristic curve (ROC) analysis, in order to predict prognosis for HCC patients after radical resection. It was further found that FLR level was correlated with tumor size, TNM stage, microvascular invasion and prognosis. Multivariate Cox regression analyses found that FLR was an independent predictor for postoperative OS (overall survival) (p = 0.002) and PFS (progression-free survival) (p = 0.001) in patients with HCC; and the 1-, 3- and 5-year OS and PFS of HCC patients in the FLR ≤ 1.6 level group were significantly higher than those in the FLR > 1.6 level group.Conclusion: Preoperative FLR level is a novel and effective predictor of prognosis in patients with HCC, and elevated FLR level is associated with poor prognosis in patients with HCC.Keywords: hepatocellular carcinoma, FLR, prognosis, recurrence

Aim Vasa vasorum neovascularization is a key feature of atherosclerosis (AS) and is strongly associated with inflammatory infiltration, lipid deposition, intraplaque hemorrhage, and hemosiderin deposit. Here we investigate the effects of Endostar, a strong anti-angiogenic drug, on vasa vasorum neovascularization in the experimental porcine model of early AS. Methods Eighteen adult male Ba-Ma mini pigs were randomized into three groups, with six animals in each group. The pigs in the normal (N) group were fed a normal diet for 18 weeks, without balloon injury surgery. The animals in the atherosclerotic (AS) control and AS＋Endostar groups were fed a hypercholesterolemic diet for 12 weeks after balloon injury surgery; they received either saline or Endostar for an additional six weeks, while continuing the hypercholesterolemic diet. The atherosclerotic abdominal aorta and levels of serum lipids, TNF-alpha, IL-6, and hs-CRP were analyzed at 18 weeks. Results The AS group had a significantly higher body weight and serum lipid concentration levels than the N group (p ＜ 0.05), confirming the success of the hypercholesterolemic diet. However, no statistical differences were noted between the AS and AS＋Endostar groups. Histopathology results revealed that vasa vasorum density and intima-media thickness (IMT) had also increased in the AS group compared with those in the N group (p ＜ 0.05). The Endostar treatment significantly alleviated AS with decreased vasa vasorum density and IMT (AS vs. AS＋Endostar, p ＜ 0.05). Western blot analysis indicated that the expression of VEGF, β-catenin, and TNF-alpha in the atherosclerotic abdominal aorta was considerably reduced by the Endostar treatment. In addition, immunohistochemistry results showed that the angiogenesis markers VEGF and β-catenin were predominately localized in endothelial cells of the adventitial vasa vasorum. The levels of the serum inflammatory markers TNF-alpha, hs-CRP, and IL-6 were markedly higher in the AS group than in the N group (p ＜ 0.05) but showed no marked difference during the Endostar treatment, suggesting that the local inhibition of angiogenesis was not accompanied by a change in serum inflammatory markers and that the inhibitive effect of Endostar on local TNF-alpha expression could be because of the prevention of vasa vasorum neovascularization. Conclusions Our results demonstrated that the Endostar treatment inhibited vasa vasorum neovascularization and AS progression in the experimental porcine model of early AS, supporting the role of vasa vasorum neovascularization in the development of AS and the therapeutic potential of anti-angiogenesis intervention in AS.

Objective: Atherosclerotic plaques and neovascularization play an important role in the course of coronary atherosclerosis. This study evaluated the effect of recombinant endostatin on experimental atherosclerotic plaques and neovascularization in rabbits. Methods: Eighteen healthy male rabbits were divided into three groups: control group, atherosclerotic model group, and recombinant endostatin treated group. The atherosclerotic model was established via a high-cholesterol diet after balloon catheter injury. The subject weights, serum total cholesterol, creatine kinase-myocardial band fraction (CKMB), and matrix metalloproteinase-2 (MMP-2) were measured. Six weeks after treatment, the aortic roots were taken for pathological assay. The thickness ratio of the intima to media was measured by hematoxylin and eosin (HE) staining, and the number of neovessels was measured by immunohistochemistry via monoclonal antibody CD31 staining. Results: The weight, plasma total cholesterol, and CKMB were not significantly different between the atherosclerotic model group and the recombinant endostatin treated group, but much higher than those of the control group (P0.05) in the recombinant endostatin treated group, compared to the atherosclerotic model group. Conclusions: Recombinant endostatin is able to inhibit the growth of neovascularization in the atherosclerotic plaque and the development of plaque.

Endostar, a novel modified recombinant human endostatin, is now widely studied for the treatment of diseases that are characterized or caused by pathological angiogenesis. However, its molecular mechanism remains unclear. In this study, we investigated the effects of Endostar on the Wnt/β-catenin signaling pathway, which has emerged as an important aspect of angiogenesis. We showed that Endostar significantly inhibited the proliferation, migration, invasion, and capillary-like tube formation of human umbilical vascular endothelial cells in a dose-dependent manner. Using a luciferase reporter assay, we also demonstrated that Endostar suppressed β-catenin-dependent T cell factor transcriptional activity in increasing doses. Moreover, we found that Endostar treatment also restricted the stabilized mutant β-catenin-mediated increase in transcriptional activity, suggesting that Endostar exerts its inhibitory influence on Wnt/β-catenin signaling by targeting β-catenin or its downstream molecules. Western blot and immunofluorescence results revealed that Endostar significantly decreased nuclear and total β-catenin levels. Finally, we discovered that Endostar down-regulated cyclin D1 and VEGF, two proteins that are known as the downstream targets of Wnt/β-catenin signaling and that also play important roles in angiogenesis. Our findings suggested that Endostar inhibits angiogenesis and that the downregulation of the Wnt/β-catenin signaling pathway may be involved in the inhibition of angiogenesis by Endostar. These results support the use of Endostar in further clinical applications.