Search

Serotonin exerts important functions in several liver pathophysiological processes. In this study, we investigated the role of serotonin in concanavalin A (Con A)-induced liver fibrosis (LF) in mice and the underlying mechanisms. To establish the mouse model of LF, mice of wild-type (WT) and tryptophan hydroxylase 1 (Tph1) knockout (serotonin depletion) received Con A for 8 successive weeks. Degree of fibrosis was assessed by Sirius red staining, as well as the measurements of alpha smooth muscle actin (α- SMA), hydroxyproline (Hyp) and type I collagen in liver tissues. To elucidate the potential mechanisms, we assessed the effect of serotonin depletion on inflammatory, oxidative stress as well as TGF-β1/Smads signaling pathway. We found that serotonin depletion significantly inhibited collagen deposition as evaluated by less collagenous fiber in Sirus Red staining and reduced contents of Hyp and type I collagen. In addition, the absence of serotonin significantly inhibited the release of several inflammatory cytokines, including interleukin-6 (IL-6), interferon-gamma (IFN-γ), tumor necrosis-alpha (TNF-α), and transforming growth factor β1 (TGF-β1). Oxidative stress was also largely mitigated in LF mice with serotonin deficiency as manifested by the decreases of oxidative stress markers (malonaldehyde (MDA) and myeloperoxidase (MPO)), as well as the increases of antioxidant stress indicators (glutathione (GSH), and GSH-px, catalase (CAT), superoxide dismutase (SOD)) in liver tissues. Moreover, the lack of serotonin may provide an antifibrotic role by inhibiting the intrahepatic expressions of TGF-β1, phosphorylated-smad2 (p-smad2), and phosphorylated-smad3 (p-smad3). These results indicated that, serotonin depletion attenuates Con A-induced LF through the regulation of inflammatory response, oxidative stress injury, and TGF-β1/Smads signaling pathway.

Hepatocellular carcinoma (HCC) constitutes a major global health threat due to the high incidence and mortality. Sorafenib is known as the first-line medication for advanced HCC; however, it only extends the limited benefit for HCC patients as the development of acquired resistance. Withaferin A exerts broad pharmaceutical applications in several cancers. However, its effects on HCC cell metastatic potential and sorafenib resistance remain elusive. Here, we corroborated that Withaferin A greatly restrained cell viability, invasion, vasculogenic mimicry (VM) formation, and VE-cadherin levels in HepG2 and SNU449 cells. Moreover, Withaferin A sensitized sorafenib (SR)-resistant HCC cells to sorafenib. In striking contrast to the parental cells, lower ferroptosis was observed in SR-resistant cells as the lower ROS, MDA, and higher intracellular GSH levels in SR-resistant cells. Of interest, Withaferin A enhanced ferroptosis in SR-resistant cells, which was reversed by ferroptosis antagonist liproxstation-1. Notably, Withaferin A elevated Keap1 expression to mitigate Nrf2 signaling activation-mediated epithelial to mesenchymal transition (EMT) and ferroptosis-related protein xCT expression. Importantly, blockage of the Keap1/Nrf2 signaling overturned Withaferin A-evoked ferroptosis and facilitated sorafenib resistance. In addition, knockdown of Keap1 antagonized the inhibitory efficacy of Withaferin A on HCC cell viability, invasion, and VM formation. Consequently, Withaferin A may attenuate the metastatic potential and sorafenib resistance by regulating Keap1/Nrf2-associated EMT and ferroptosis. Thus, Withaferin A may serve as a promising agent for HCC therapy, especially for advanced HCC.

Background Platelet-albumin-bilirubin (PALBI) has been demonstrated to be superior to conventional Child-Pugh (C-P) grade in evaluating liver function and prognosis of HCC patients. However, both thrombocytosis and thrombocytopenia are unfavorable for HCC survival. The aim of this study was to preliminarily investigate the prognostic value of PALBI in HCC patients with thrombocytopenia and excluding thrombocytopenia. Methods In this retrospective cohort study, we reviewed 465 cases of HCC patients who underwent radical surgery. PALBI grade was calculated based on preoperative serological examinations. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS), which were assessed by Kaplan-Meier method and Cox regression. The prognostic performances of PALBI and other models were estimated by using the concordance index (C-index). Results During a median follow-up time of 28 months, 31.6% (147/465) of patients died and 33.5% (156/465) experienced recurrence. Multivariate analyses revealed that both thrombocytosis and thrombocytopenia were independently associated with poor OS and RFS compared with normal platelet count (PLT) in HCC patients. Stratified analysis further revealed that PALBI was a significant predictor for HCC survival in patients excluding thrombocytopenia but not in patients with thrombocytopenia. In particular, in HCC patients excluding thrombocytopenia, the combination of tumor size with PALBI (C-index = 0.730, 95% CI: 0.674-0.786) may be superior to the classical Barcelona Clinic Liver Cancer (BCLC) and Cancer of Liver Italian Program (CLIP) staging systems in predicting survival. Conclusion In conclusion, PALBI grade, in particular the combination with tumor size, is an effective model for discriminating survival in HCC patients excluding thrombocytopenia but not in thrombocytopenic HCC patients.

Shuangchi Liu,1 Zhiduan Xu,1 Zhuling Fang,2 Dengyong Zhang,1 Zhongqiang Qin,1 Longfei Fan,1 Jiakang Duan,1 Hongxiang Yin,1 Yigang Zhang,1 Qing Pang,1,3 Yi Tan1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, Anhui, People’s Republic of China; 2Department of Medical Laboratory, Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China; 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of ChinaCorrespondence: Yi Tan; Qing PangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of ChinaEmail doctortanyi2007@126.com; portxiu2@126.comBackground: Advanced liver fibrosis can lead to cirrhosis, portal hypertension and liver failure. Besides, advanced liver fibrosis and cirrhosis are the major risk factors for hepatocellular carcinoma (HCC). Almost all patients with HCC also have liver cirrhosis. This study aims to predict the survival rate of hepatitis B-related hepatocellular carcinoma (HCC) by age, international standardized ratio, albumin and γ-glutamyl transpeptidase (AIAG), an indicator measuring the degree of cirrhosis.Methods: A total of 501 hepatitis B-related HCC patients experiencing radical surgery were analyzed, retrospectively. General data about demographics and labs were collected at the date of diagnosis to calculate AIAG [age, international standardized ratio (INR), albumin and gamma-glutamyl transferase (GGT)]. The Kaplan–Meier curves and Cox analysis were used to evaluate overall survival (OS) and recurrence-free survival (RFS). The C-index was calculated in R software (version 4.0.3) to evaluate the accuracy of the prognostic model.Results: During a median follow-up period of 30 months, 31.1% (156/501) of the patients died, and 34.3% (172/501) experienced the recurrence of HCC. Compared with patients with lower AIAG score, patients with higher AIAG score had higher Child-Pugh grade and were at higher Barcelona Clinic Liver Cancer (BCLC) stage (both P< 0.05). Multivariate analysis suggested that GGT, alpha fetoprotein (AFP), tumor size, BCLC stage and AIAG grade were independent predictors of OS and RFS. Furthermore, the combined use of tumor size, AFP and AIAG stage could predict survival significantly better (C-index=0.710, 95% CI: 0.669– 0.751) than BCLC stage.Conclusion: AIAG is significantly associated with survival of HCC patients, and provides additional prognostic information for patients with HCC. Our findings suggest that the combination of AIAG, tumor size and AFP stage has a better predictive value for the prognosis of patients with hepatitis B-related hepatocellular carcinoma. However, it is necessary for more external evidences to determine clinical utility.Keywords: AIAG, hepatocellular carcinoma, survival, prognosis

Posthepatectomy liver failure (PHLF) is a life-threatening complication after liver resection, resulting in an increased morbidity and mortality. Epidemiological evidence of the association between preoperative albumin-bilirubin (ALBI) score, a newly established model for assessing liver functional reserve, and the risk of PHLF and mortality remains controversial. A systematical search for relevant literature was performed in PubMed, Embase, and Web of Science databases from December 2014 to September 2020. Odds ratio (OR) value and 95% confidence interval (CI) were extracted or calculated to synthetically estimate the association of preoperative ALBI score with PHLF and mortality. Meta-analyses were performed using a random-effects model. Twelve studies with a total of 21,348 patients were included in this meta-analysis. It was indicated that, compared to patients with a lower preoperative ALBI grade, patients with a higher grade had a significantly elevated risk of PHLF (6 studies, 18,291 patients; OR = 2.48, 95%CI: 2.00–3.07) and mortality (4 studies15, 139 patients; OR = 2.35, 95% CI: 1.38–4.00). In addition, when it was expressed as a continuous variable, ALBI was also a significant predictor of PHLF (6 studies, 3,833 patients; OR = 3.16, 95% CI: 2.07–4.81, per 1-point increase in ALBI score). No significant publication biases were detected as suggested by funnel plots inspection and Begg’s tests. The current meta-analysis demonstrates that preoperative elevated ALBI is associated with higher risk of PHLF and mortality after hepatectomy.

Thermal demagnetization furnaces are widely used paleomagnetic facilities for progressive removal of naturally acquired magnetic remanence or the imparting of well controlled laboratory magnetization. An ideal thermal demagnetizer should maintain “zero” magnetic field in the sample chamber during thermal treatments. However, magnetic field noises, including the residual magnetic fields of the construction material and the induced fields caused by the alternating current (AC) in the heating element are always present, which often greatly contaminate the paleoamgnetic results at the elevated temperatures or for the magnetically weak samples. Here, we designed a new structure of heating wire named named straight core solenoid to develop a new demagnetization furnace with ultra-low magnetic field noise. Simulation and practical measurement show that the heating current magnetic field can be greatly reduced by using the new technology. Thermal demagnetization experiments demonstrate that the new demagnetizer can yield low noise results even for weakly magnetic samples.

Thermal demagnetization furnaces are routine facilities for paleomagnetic studies. The ideal thermal demagnetizer should maintain “zero” magnetic field during thermal treatments. However, magnetic field noises, including residual magnetic fields of material and induced fields caused by the heating current in the furnace are always present. The key to making high-performance demagnetization furnace is to reduce the magnetic field noises. By combining efficient demagnetization of shielding and a new structure of heating wire, we have developed a new demagnetization furnace with low magnetic field noises. Repeated progressive thermal demagnetization experiments using specimens that were previously completely thermal demagnetized above their Curie temperature were carry out to explore the effects of field within various types of furnace during demagnetization. These experiment confirm that magnetic field noises in the furnace can have an observable and detrimental impact on demagnetization behavior. Comparison between commercial furnaces and our new design show a notable reduction in the impacts of on thermal demagnetization behavior. The new heating element design and procedure for reducing magnetic field noises represent a significant improvement in the design of thermal demagnetizers and allows for extremely weak specimens to be successfully measured.

Additional file 1. Thermal demagnetization experiment of synthetic specimens.

The thick sequence of Cenozoic deposits in the Qaidam Basin of the NE Tibetan Plateau has great potential for understanding the tectonic and climatic evolution of the region. In this study, we performed detailed rock magnetic analyses of a well-dated (~20.7–11.2 Ma) Upper Cenozoic sedimentary sequence from the Huatugou (HTG) section in the NW Qaidam Basin. The magnetic susceptibility of the sequence is relatively low before 17.4 Ma, high during 17.4–14.5 Ma, and lower after 14.5 Ma again. This pattern is consistent with the occurrence of the Mid-Miocene Climatic Optimum (MMCO) during 17.4–14.5 Ma, with global climatic cooling thereafter. Measurements of multiple rock magnetic parameters indicate a peak in the concentration of fine-grained magnetic minerals during 17.4–14.5 Ma. This feature demonstrates that the enhancement of the magnetic susceptibility is due to the pedogenic production of superparamagnetic (SP) and single domain (SD) magnetite, suggesting the occurrence of relatively high effective precipitation and high temperature in the Qaidam Basin at this time. Comparing with regional and global climatic records, the warm and humid climatic conditions coincide with the MMCO, implying that global climate changes were responsible for the climatic evolution in the Qaidam Basin throughout the MMCO. However, after 14.5 Ma, the rapid uplift of the northern Tibetan Plateau caused it to reach a critical elevation which blocked the moisture supply to the Qaidam Basin and may also have contributed to the observed climatic changes.

A new measurement and analysis method was proposed to investigate the changes in elbow joint moments that occur with the use of a front-wheeled walker. A strain gauge-based walker instrumentation system was developed to monitor the hand loads during walker-assisted walking and integrated with an upper extremity biomechanical model. Preliminary system data were collected for 12 subjects following informed consent. Bilateral upper extremity kinematic data were acquired with a six-camera motion analysis system. Internal joint moments at the elbow were determined in the three clinical planes using the inverse dynamics method. Results showed that during a walker-assisted gait elbow joint moments mainly distributed in the walker stance period. There was a noted demand on the elbow extensor in the sagittal plane with the greatest record as 0.381 N·m/(kg·m). An interesting “bare phase” of mean elbow joint moments was also found in phase angle −240°–340° of gait cycle. Complete description of elbow joint moments of walker-assisted gait may provide insight into walker use parameters and rehabilitative strategies.

Thermal demagnetization furnaces are routine facilities that underpin countless paleomagnetic studies by allowing the progressive removal of naturally acquired magnetic remanence or the imparting o...