Development of a nomogram for predicting liver transplantation prognosis in hepatocellular carcinoma.

BACKGROUND: At present, liver transplantation (LT) is one of the best treatments for hepatocellular carcinoma (HCC). Accurately predicting the survival status after LT can significantly improve the survival rate after LT, and ensure the best way to make rational use of liver organs. AIM: To develop a model for predicting prognosis after LT in patients with HCC. METHODS: Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated. The expression levels of alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, Golgi protein 73, cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer. The best cutoff value of biomarkers was determined using the Youden index. Cox regression analysis was used to identify the independent risk factors. A forest model was constructed using the random forest method. We evaluated the accuracy of the nomogram using the area under the curve, using the calibration curve to assess consistency. A decision curve analysis (DCA) was used to evaluate the clinical utility of the nomograms. RESULTS: The total tumor diameter (TTD), vascular invasion (VI), AFP, and cytokeratin-18 epitopes M30 (CK18-M30) were identified as important risk factors for outcome after LT. The nomogram had a higher predictive accuracy than the Milan, University of California, San Francisco, and Hangzhou criteria. The calibration curve analyses indicated a good fit. The survival and recurrence-free survival (RFS) of high-risk groups were significantly lower than those of low- and middle-risk groups (P < 0.001). The DCA shows that the model has better clinical practicability. CONCLUSION: The study developed a predictive nomogram based on TTD, VI, AFP, and CK18-M30 that could accurately predict overall survival and RFS after LT. It can screen for patients with better postoperative prognosis, and improve long-term survival for LT patients.

Hourglass-like constriction of the anterior interosseous nerve in the left forearm: A case report.

BACKGROUND: Hourglass-like constriction neuropathy is a rare neurological disorder. The main clinical manifestation is peripheral nerve injury with no apparent cause, and the pathomorphological change is an unexplained narrowing of the diseased nerve. The diagnosis and treatment of the disease are challenging and there is no accepted diagnostic or therapeutic approach. CASE SUMMARY: This report describes a rare hourglass constriction of the anterior interosseous nerve in the left forearm in a 47-year-old healthy male who was treated surgically and gradually recovered function over a 6-mo follow-up period. CONCLUSION: Hourglass-like constriction neuropathy is a rare disorder. With the development of medical technology, more examinations are now available for diagnosis. This case aims to highlight the rare manifestations of Hourglass-like constriction neuropathy and provides a reference for enriching the clinical diagnosis and treatment experience.

Overexpression of Protein Phosphatase 2 Regulatory Subunit B"Alpha Promotes Glycolysis by Regulating Hexokinase 1 in Hepatocellular Carcinoma.

Objective: To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha ( PPP2R3A) and hexokinase 1 ( HK1) in glycolysis of hepatocellular carcinoma (HCC). Methods: In HepG2 and Huh7 cells, PPP2R3A expression was silenced by small interfering RNA (siRNA) and overexpression by plasmid transfection. The PPP2R3A-related genes were searched by RNA sequencing. Glycolysis levels were measured by glucose uptake and lactate production. QRT-PCR, ELISA, western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1. Cell proliferation, migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A. Results: RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1. PPP2R3A gene overexpression promotes, while gene silencing suppresses, the level of HK1 and glycolysis in HCC cells. In HCC tissue samples, PPP2R3A and HK1 were colocalized in the cytoplasm, and their expression showed a positive correlation. HK1 inhibition abrogated the promotion of glycolysis, proliferation, migration and invasion by PPP2R3A overexpression in liver cancer cells. Conclusion: Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC, which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.

Regulatory T Cells Promote Overexpression of Lgr5 on Gastric Cancer Cells via TGF-beta1 and Confer Poor Prognosis in Gastric Cancer.

Background: The leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) is considered a cancer stem cell marker, and is often overexpressed in tumors. The interaction between Lgr5 and the immune-related tumor microenvironment is not completely understood. The aim of this study was to examine the role of Lgr5 in the microenvironment of gastric cancer (GC), and to explore possible immunological mechanisms influencing Lgr5 expression that are governed by regulatory T cells. Methods: Lgr5 expression was examined in 180 GC tumors by immunohistochemistry, and in 80 pairs of GC tumors for analysis of Th1/Th2 cytokines by ELISA. In addition, SGC7901 cells were co-cultured with patient-derived Tregs, varying concentrations of TGF-ß1, TGF-ß1 neutralizing antibody, or TGF-ß receptor inhibitor SB431542, and Lgr5 and ß-catenin expression were examined by qRT-PCR and western blot. Results: In this study, an immunosuppressive microenvironment was associated with high Lgr5 expression in GC. Furthermore, Lgr5 expression was up-regulated in GC cells co-cultured with Tregs or treated with exogenous TGF-ß1. This up-regulation was partially inhibited by the TGF-ß1 neutralizing antibody, or TGF-ß1 receptor antagonist SB431542. ß-catenin was up-regulated with high Lgr5 expression induced by exogenous TGF-ß1, and this up-regulation was inhibited by SB431542. An increased number of Tregs and high Lgr5 expression in GC tissues were significantly associated with low overall survival. Conclusion: Tregs promoted increased Lgr5 expression in GC cells via TGF-ß1 and TGF-ß1 signaling pathway, which may involve activation of the Wnt signaling pathway. High Lgr5 expression via TGF-ß confer poor prognosis in gastric cancer.

Role of plasmacytoid dendritic cells and inducible costimulator-positive regulatory T cells in the immunosuppression microenvironment of gastric cancer.

Regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) play important roles in the immune escape of cancer. In this study, we investigated pDCs and pDC-induced inducible costimulator (ICOS)(+) Treg populations in peripheral blood from gastric cancer (GC) patients and healthy donors by flow cytometry. The distribution of these cells in carcinoma tissue, peritumor tissue, and normal gastric mucosa was detected by immunohistochemistry. Plasma and tissue concentration of the cytokines such as interleukin-10 and transforming growth factor-ß1 were also measured. We found that the numbers of pDCs, Tregs, and ICOS(+) Tregs in peripheral blood were increased in GC patients compared with healthy donors. In tissue, Tregs and ICOS(+) Tregs were found distributing mainly in carcinoma tissue, whereas pDCs were mainly found in peritumor tissue. Moreover, the Foxp3(+) ICOS(+) /Foxp3(+) cell ratio in carcinoma and peritumor tissue were higher than that in normal tissue. There were more ICOS(+) Tregs in tumor and peritumor tissue of late-stage GC patients. There was a positive correlation between pDCs and ICOS(+) Tregs in peripheral blood and peritumor tissue from GC patients. In conclusion, pDCs may play a potential role in recruiting ICOS(+) Tregs, and both participate in the immunosuppression microenvironment of GC.

Anti-tumor effects of Mfn2 in gastric cancer.

Mitofusin-2 (Mfn2) is a mitochondrial outer membrane protein involved in mitochondrial fusion. Its mutation can cause Charcot-Marie-Tooth disease. Recent studies of Mfn2 in cancer research have not included gastric cancer. We confirmed that Mfn2 expression was lower in tumor tissue than in normal gastric mucosal tissue and that it was negatively correlated with tumor size, indicating an anti-tumor role for Mfn2. In vitro experiments showed that Mfn2 overexpression suppressed gastric cancer cell proliferation and colony formation, weakened the invasion and migratory ability of cancer cells by downregulating MMP-2 and MMP-9, halted the cell cycle and induced apoptosis. Western blotting indicated the likely involvement of P21 and PI3K/Akt signaling. Therefore, Mfn2 is a potential anti-tumor gene and a potential therapeutic target for treating gastric cancer. The progress of gastric cancer may be delayed by controlling Mfn2 expression.

[Effect of swimming exercise on the expression of apelin and its receptor in pulmonary tissues of rats with hypoxic pulmonary hypertension].

OBJECTIVE: To study the effects of swimming exercise on the expression of apelin and its receptor (APJ) system in pulmonary tissues of rats with pulmonary hypertension induced by hypoxia. METHODS: Forty-five male SD rats were randomly divided into control group, hypoxia group (seven-week) and swimming group (four-week swimming group after three-week hypoxia). The animal model of hypoxic pulmonary hypertension was established by exposing the rats to isobaric hypoxic chamber (8 h/d, 6 d/w). The rats of swimming group swam 60 min/day, 7 d/week for 4 weeks after three-week hypoxia. The mean pulmonary arterial pressure (mPAP) and the mean carotid arterial pressure (mCAP) were measured by either right or left cardiac catheterization, and the weight ratio of right ventricule/left ventricle plus septum [RV/(LV + S)] were calculated. The Masson's trichrome stained lung specimens were used by light microscope to examine the vessel wall area/total area (WA/TA), vessel cavity area/total area (CA/TA) and media thickness of pulmonary arterioles (PAMT). Meanwhile, apelin/ APJ expressions were determined by Western blot and immunohistochemistry. RESULTS: (1) mPAP and RV/(LV + S) of hypoxia group were higher than those of control group by 73.6% and 31.2% (P < 0.01), and mPAP and RV/(LV + S) of swimming group were lower than those of hypoxia group by 21.1%and 8.9 % (P < 0.05), respectively. (2) Masson's trichrome staining revealed that WA/TA and PAMT of hypoxia group were higher than those of control group by 70.8% and 102%. However, WA/TA and PAMT of swimming group were lower than those of hypoxia group by 24.8% and 40.1% (all P < 0.01), respectively. CA/TA of hypoxia group was lower than that of control group by 15.1%, and CA/TA of swimming group was lower than that of hypoxia group by 10.3% (all P < 0.01). (3) Compared with control group, hypoxia group showed up-regulated apelin expression and down-regulated APJ expression in pulmonary tissues (all P < 0.01). Compared with hypoxia group, swimming group showed decreased apelin expression and elevated APJ expression in pulmonary tissues (all P < 0.01). (4) Apelin localized mainly in intracytoplasm of inflammatory cell and tunica adventitia of vessel, and APJ were in vascular intima and tunica externa and plasmalemma of inflammatory cell. CONCLUSION: The improving effect of swimming exercise on hypoxic pulmonary hypertension in rats could be mediated by regulating the pulmonary apelin/APJ system.

[Toll-like receptor 4 signal pathway may be involved in cerebral ischemic tolerance induced by hypoxic preconditioning: experiment with rats].

OBJECTIVE: To investigate the role of Toll-like receptor 4 (TLR4) inflammatory signal pathway in brain ischemic tolerance induced by hypoxia preconditioning (HP). METHODS: 160 Wistar rats were randomly divided into 4 groups: asphyxial cardiac arrest (ACA) group (n = 54, subjected to ACA for 4 min and then resuscitation), HP + ACA group [n = 44, subjected to apnea and ventilation (HP) for 1 min 4 times with an interval of 5 min between each 2 times, and then subjected to apnea for 4 min and resuscitation 24 h later), HP group (n = 42, subjected to HP 4 times only), and sham operation group (Group C, n = 20). The mortality within 24 h after resuscitation and circulatory functions were observed. Neurodeficit score (NDS) was recorded 24, 48, and 72 hours after successful resuscitation. Rats were killed 1, 3, 6, 12, 24, 48, and 72 h after preconditioning or operation to take out the left brain cortex. RT-PCR was used to detect the mRNA expression of TLR4. The levels of nuclear factor-kappaB (NFkappaB), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6 were detected by relevant kits. RESULTS: The mortality of the HP + ACA group was 5%, significantly lower than that of ACA group (30%, P < 0.01). The NDS levels at different time points of the HP group and Group C were all 100 +/- 0. The NDS levels of the HP + ACA group and ACA group at different time points were all significantly lower than those of the control group and HP group (all P < 0.01). The NDS levels at different time points of the ACA group were all significantly lower than those of the HP + ACA group (all P < 0.05). The NDS levels 72 h later of the HP + ACA and ACA groups were both significantly higher than those 24 h later of the corresponding groups (both P < 0.05). The TLR4 mRNA expression of the control group at any time points were all very weak, and the TLR4 mRNA expression level of the other groups increased since 1 h after hypoxia gradually and decreased 72 h later. The NFkappaB expression levels of the control group at any time points were all very weak, and the NFkappaB expression level of the other groups increased time-dependently since 1 h later, peaked 3 - 6 h later, and began to decrease 24 h later. There was a tendency of increase of NFkappaB expression level in the order of HP group < HP + ACA group < ACA group. The expression of TNF-alpha and IL-6 showed the same tendency as seen in the expression of TLR2 and NFkappaB. CONCLUSION: HP induces brain ischemic tolerance via a possible mechanism of activating TLR4 signal pathway and then inhibiting inflammatory response induced by ACA.