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Hepatocellular carcinoma (HCC) has one of the highest mortality rates worldwide. Abnormal glutamine metabolism (GM) has been reported to be involved in HCC progression. The current study sought to examine the predictive value of GM in HCC patient's prognosis and therapy response.The RNA-sequencing data and clinical information of HCC samples were obtained from The Cancer Genome Atlas (TCGA) database (N=377) and Gene Expression Omnibus (GEO) database (N=242). By analyzing a data set from TCGA, we showed that the GM landscape of HCC patients was developed based on the non-negative matrix factorization (NMF) algorithm. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analyses were used to construct a risk model. The accuracy of the model, which was based on the GM-related genes (GMRGs), was verified by Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curves. We also verified the reliability of the model based on GEO data. Finally, the immune infiltration analysis, pathway enrichment analysis, and treatment response prediction results were compared to each other in the 2 risk groups.In our study, the HCC samples were divided into 2 GM-related patterns; that is, C1 and C2. The multi-analysis revealed that the GM-related patterns were associated with the pathologic stage, T stages, N stages, histologic grade, and the tumor immune microenvironment (TIME). Next, the prognostic model containing 5 GMRGs (i.e., aldehyde dehydrogenase 5 family member A1In summary, we developed a GM-related 5-gene risk-score model, which may be a useful tool for predicting prognosis and guiding the treatment of HCC patients.

BackgroundGlutamine metabolism plays a key role in various biological processes of tumor. Glutaminase (GLS) is involved in Glutamine metabolism and plays a conserved regulatory role in the process. Nevertheless, there is no comprehensively analysis of GLS in pan-cancer.MaterialsComprehensive bioinformatics analysis was adopted to investigate the expression level, prognostic values, and association between expression of GLS and TME, immune cells' infiltration, immune checkpoint genes, TMB, MSI, drug sensitivity in pan-cancer. Bioinformatics tools including CCLE, immunophenoscore (IPS), Tumor Immune Dysfunction and Exclusion (TIDE), GSEA, and TIMER databases were used.ResultsDifferently expressed GLS between tumor and normal tissues were analyzed, and the clinical prognoses, MMR, MSI, and TMB in multiple types of cancer were associated with GLS expression. Furthermore, GLS closely correlated with tumor immunity and drug sensitivity, and found GLS were predicted to be involved in cancer metabolism and immunity pathways, through gene set enrichment analysis (GSEA).ConclusionThe GLS expression could be used as a prognostic biomarker for determining prognosis and provide further insights into anti-glutamine metabolism for cancer.

BACKGROUND The red blood cell distribution width (RDW) was reported to be related to the severity of liver diseases, but its clinical significance in patients with hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to explore the clinical significance of RDW in HCC patients. METHODS For the retrospective study, 422 HCC patients were enrolled in this study. Hematological parameters and liver biochemical indexes were analyzed. Child-Pugh grade and Barcelona Clinic Liver Cancer (BCLC) stages of the HCC patients were calculated. The diagnostic accuracy was evaluated according to the area under the receiver operating characteristic (ROC) curve. The medical records of HCC patients who were admitted to The Second Affiliated Hospital of Nanjing University of Chinese Medicine from January 2006 to August 2015 were retro-spectively reviewed. RESULTS Subgroup analysis showed that RDW level of HCC patients with tumor size more than 10 cm were higher than those of HCC patients with tumor size smaller than 3 cm, 3 - 5 cm, and 5 - 10 cm (14.77 ± 2.35%, 15.27 ± 2.65%, 15.32 ± 2.40% vs. 15.97 ± 2.39%, p < 0.001). RDW level significantly increased with worsening Child-Pugh grade and BCLC stages. In addition, RDW level were negatively correlated with red blood cell (RBC) counts, hematocrit (HCT), lymphocyte (LY) counts, hemoglobin (Hb), blood platelet (PLT) counts, and positively correlated with aspartate-aminotransferase (AST), and total bile acid (TBA). ROC curve analysis showed that RDW level was 14.15% was the optimal prognostic cutoff point to determine the survival rate of HCC patients. In the univariate analysis followed by multivariate analysis, RDW level below 14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor size were prognostic indicators for HCC patients. This indicated HCC patients with RDW level below 14.15% [hazard ratio of 0.530 (95% confidence interval, 0.395 - 0.710; p < 0.001)] had the lower mortality. CONCLUSIONS RDW level was positively associated with tumor size. The prognosis was better for HCC patients with RDW levels below14.15% together with better Child-Pugh grade, better BCLC stages, and smaller tumor lesions. It suggested RDW level might be an easily obtainable and inexpensive prognostic indicator for HCC patients.

Over-expression of the bromodomain and extraterminal (BET) family protein BRD4 is associated with hepatocellular carcinoma (HCC) progression. In the present study, we indentified a novel putative anti-BRD4 microRNA: microRNA-608 (“miR-608”). In HepG2 cells and primary human HCC cells, over-expression of miR-608, using a lentiviral construct, induced BRD4 downregulation and proliferation inhibition. Conversely, transfection of the miR-608 inhibitor increased BRD4 expression to promote HepG2 cell proliferation. Our results suggest that BRD4 is the primary target gene of miR-608 in HepG2 cells. shRNA-mediated knockdown or CRSIPR/Cas9-mediated knockout of BRD4 mimicked and overtook miR-608's actions in HepG2 cells. Furthermore, introduction of a 3′-untranslated region (3′-UTR) mutant BRD4 (UTR-A1718G) blocked miR-608-induced c-Myc downregulation and proliferation inhibition in HepG2 cells. In vivo, HepG2 xenograft tumor growth was significantly inhibited after expressing miR-608 or BRD4 CRSIPR/Cas9-KO construct. Importantly, BRD4 mRNA was upregulated in human HCC tissues, which was correlated with downregulation of miR-608. Together, we conclude that miR-608 inhibits HCC cell proliferation possibly via targeting BET family protein BRD4.

Patients with gallbladder carcinoma can present with a variety of paraneoplastic syndromes, including Cushing’s syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis and the sign of Leser-Trelat. Surgical resection of the primary tumor results in resolution of these paraneoplastic syndromes. We present a 67-year old female with facial and cervical erythema who was initially diagnosed with dermatomyositis. However, an abdominal computed tomography (CT) and positron emission tomography-CT scan was suspicious for gallbladder carcinoma with lymph node metastasis. After surgical resection, her dermatomyositis was resolved. This case demonstrates that dermatomyositis may be a manifestation of preexisting gallbladder carcinoma.

Phyllodes tumor of the breast is a rare disease constituting 0.3-0.9% of all breast neoplasms. Occurring mainly in females aged 35 to 55 yr, the disease is especially rare among adolescent females. There is no published literature about de novo phyllodes tumor after liver transplantation. Here we describe a case of de novo phyllodes tumors in an adolescent female after liver transplantation from a living donor for Wilson disease.

To probe into indication of living-related liver transplantation (LRLT) for Wilson's Disease.From January 2001 to February 2007, thirty-seven living-related liver transplants were performed. A retrospective analysis was carried on outcome of those patients. The indications for LRLT were acute hepatic failure in 3 patients and chronic advanced liver disease in 32 patients including 13 patients with Wilsonian neurological manifestations. Two patients presented with severe Wilsonian neurological manifestations even though their liver functions were stable. According to the scoring system for evaluation of the neurological impairment in Wilson disease based on neurological signs and functions (total score was 30), the pre-transplantation score of those patients with neurological manifestations was 15.9 +/- 4.3 (n = 15).Thirty-seven patients were followed up for 20 - 93 months. The survival rates of post-transplant patients and grafts at 1, 3, and 5 year were 91.9%, 83.8%, 75.7%, and 86.5%, 78.4%, 75.7%, respectively. Postoperative surgical complications occurred in 2 donors with bile leakage required drainage, in 2 recipients with hepatic thrombosis underwent retransplantation of cadaveric liver and in 1 recipient with hepatic stenosis required balloon dilatation. Neurological function was improved in all recipients and the score of posttransplantation at 6, 12, 18, 24, and 30 month was 17.5 +/- 3.7 (n = 13); 21.0 +/- 4.3 (n = 12); 23.9 +/- 3.9 (n = 10); 26.6 +/- 2.2 (n = 10) and 28.1 +/- 1.9 (n = 7) respectively.Patients with acute hepatic failure or patients with severe liver disease unresponsive to chelation treatment should be treated with LRLT. Early transplantation in patients with an unsatisfactory response medical treatment may prevent irreversible neurological deterioration even though their liver function is stable.

Living donor liver transplantation has been widely accepted as the treatment of choice for end-stage liver disease. Large amounts of nitric oxide generated by inducible nitric oxide synthase (iNOS) have been shown to play an important role in many inflammatory and immune reactions, but expression of iNOS in small-for-size liver transplantation is unknown. The aims of this study were to determine the time course of iNOS mRNA and protein as well as the redox state of liver biopsies in a rat model of small-for-size liver transplantation.Male Sprague-Dawley rats were divided into a control group, a warm ischemia-reperfusion (IR) group, and a small-for-size liver graft group. Real-time RT-PCR and Western blotting were used to characterize the time course of the expression of iNOS mRNA and protein, respectively. Malondialdehyde (MDA) and superoxide dismutase (SOD) were used as markers to characterize the redox state of liver tissues, and the time courses of MDA and SOD levels were also measured.The expression of iNOS mRNA and protein levels in the warm IR and small-for-size graft groups both significantly increased after reperfusion, and peaked at 3 hours. Moreover, the increase in MDA was accompanied by increased iNOS in the period of 1-24 hours after reperfusion. The MDA levels in the warm IR and small-for-size graft groups significantly increased after reperfusion, peaked at 3 hours, and decreased thereafter. The direction of change in SOD was opposite that of the change in MDA.The expression of iNOS mRNA and protein is activated after reperfusion both in hepatic warm IR injury and small-for-size liver graft. Furthermore, the results of this study suggest that iNOS contributes to the damage in warm IR injury and small-for-size grafts via free oxygen radicals.

Background To investigate hepatic regenerative response and associated mechanisms in different-size liver grafts in the rat. Methods Rat models of different-size-graft liver transplantation (whole, 50%-size, or 30%-size) were established, with a sham operation group serving as a control. Portal pressure, graft injury, interleukin 6 (IL-6), signal transducer and activator of transcription (Stat3), mitogen-activated protein kinase (MAPK), cyclin D1, and proliferating cell nuclear antigen (PCNA) were all assessed. Results The portal pressure was significantly higher and hepatic injury more severe in the smaller sized groups than in the whole graft group, especially in the 30%-size grafts. Hepatic IL-6 and tumor necrosis factor-α (TNF-α) levels in the two smaller sized groups were significantly higher than in the whole graft group, while IL-6 levels appeared to be negatively associated with graft sizes. Downstream markers of IL-6, Stat3 and MAPK phosphorylation, cyclin D1, and PCNA expression were also markedly increased in the small-sized grafts compared with the whole grafts, and appeared to positively correlate with early measurements of portal pressure and subsequent hepatic injury. Conclusion Vigorous hepatic regeneration in small-for-size liver grafts may be associated with highly activated IL-6/Stat3 and MAPK signaling, which may in turn correlate with graft size, portal pressure, and hepatic injury.

To evaluate the outcome of emergency adult right lobe living donor liver transplantation for fulminant hepatitis.Nine cases of adult right lobe living donor liver transplantation were performed from September 2002 to August 2005, the clinical and follow-up data was analyzed.According to Child Pugh Turcotte (CPT) classification, 9 patients were classified as grade C before transplant. The Model for End-Stage Liver Disease (MELD) scores of these patients were 26.7 +/- 8.8. The principal pre-transplant complications included hepatic encephalopathy (5 cases), electrolyte disturbance (3 cases), renal failure (2 cases), gastrointestinal bleeding (1 case). The operations in donors and recipients were all successful. The post-transplant complications induced pulmonary infection in 2 patients, acute renal failure in 3 and transplantation related encephalopathy in 1. There were no primary graft non-function and no blood vessel and bile tract complications occurred. One-year survival rate was 55.6%. No serious complication or death found in donors.Emergency adult to adult living donor liver transplantation is an effective treatment for fulminant hepatitis but the safety of the donors should be assessed strictly preoperation.

To investigate and evaluate different surgical methods applied in living-donor liver transplantation (LDLT).Fifty patients with end-stage liver disease received LDLT in our department between January 1995 and March 2006. The data were analyzed on a retrospective basis. The choice of different surgical methods, strategies applied to ensure the safety of donors and indications of LDLT in the series were reviewed.All donors recovered uneventfully. Among the 50 patients, 47 recipients presented with end-stage cirrhosis, 3 patients suffered from malignant tumor. To date, 6 recipients died after LDLT, among them, 3 recipients died of the operation and the other 3 recipients died of long-term complications. Resected donor livers included 9 cases of segments V, VI, VII and VIII (not including the middle hepatic veins) and 1 case of segments V, VI, VII and VIII (including the middle hepatic veins), 36 cases of segments II, III and IV (including the middle hepatic veins) and 4 cases of segments II, III, and part of IV (not including middle hepatic veins).LDLT helps tackle the problem of donor shortage in the world. The process is complicated, and it is very important to choose appropriate surgical methods for the improvement of surgical achievement and donor safety.

To summarize the experience in donor selection and surgical outcomes of living related liver transplantation (LRLT) for Wilson's disease (WD).Thirty-two WD patients, 29 children and 3 being over 14, underwent LRLT because of chronic advanced liver disease (29 cases) or fulminant hepatic failure (3 cases) among which 13 cases showed neurological dysfunction. The donors, including 7 fathers and 25 mothers, had their serum ceruloplasmin levels within normal limit or slightly lower and their 24-hour urine copper100 microg. The modes of operation included orthotopic partial liver transplantation (31 cases) and orthotopic accessory partial liver transplantation (1 case). The patients were followed p for 3-63 months postoperatively.Two patients die in the intraoperative period, and 2 died of bile leakage and severe rejection combined with infection. Twenty-eight patients survived, of which 2 had hepatic artery thrombosis and underwent retransplantation of cadaveric liver, one had anatomic stenosis 8 months after the original transplantation and underwent Roux-en-Y hepaticojejunostomy, 2 had chronic rejection 22 and 28 months after the LRLT respectively and were successfully rescued by switching their primary immunosuppressor from cyclosporine A to FK506. Eleven patients with neurological dysfunctions all showed long-term survival and their extrapyramidal signs and speech disorders, and dyskinesia all were alleviated.LRLT is the treatment of choice for WD patients with chronic advanced liver disease and fulminant hepatic failure. After LRLT the disorders of the nervous system are alleviated.

To investigate living donor liver transplantation for Wilson disease with neurologic features.From Jan 2001 to Mar 2003, fifteen cases of living donor liver transplantation were performed for Wilson Disease (WD), five of those were complicated with neurologic features. A retrospective analysis was given for cooper metabolism and neurologic features.All operation were living related liver transplantation and donors were mothers. Four left lobes with hepatic middle vein and one right lobe without hepatic middle vein were harvested from donors, and graft volume to recipient body weight ratio was 0.79 approximately 1.08. One patient occurred hepatic artery thrombosis and performed retransplantation later, the other recipients recovered satisfactorily. All patients showed Extrapyramidal sign and three patients companying with language handicap and dyskinesia alleviated postoperation follow-up between 2 and 16 months. All recipients are alive and remain well, and none have developed signs of recurrent WD.Living donor liver transplantation is effective treatment for WD complicated with nervous system symptom, ceruloplasmin is normal and Kayser-Fleischer ring and nervous system symptom are to various extents.

To investigate some principal surgical techniques of living donor liver transplantation (LDLT).Eleven patients of LDLT have been performed at our department from January 2001 to March 2002. The left lobe (segments II, III, IV, including the middle hepatic veins) was transplanted in 8 patients, the left lateral lobe (segments II, III) in one and the right lobe (segments V, VI, VII, VIII, not including the middle hepatic veins) in 2. The plane of liver resection was determined on the basis of donor liver volumetry using CT scan and the anatomic analysis of vascular structure of the hepatic vein, portal vein and hepatic artery using intraoperative ultrasound. The hepatic parenchyma was transected using ultrasound aspirator without blood vessel clamping or graft manipulation. The isolated graft was perfused in situ through the portal vein branch. The liver graft was transplanted into the recipients who underwent total hepatectomy with preservation of the inferior vena cava. The hepatic vein reconstruction was performed in end to end fashion or end to side to the vena cava after venoplasty. Arterial anastomoses were performed using microsurgical technique. Biliary reconstruction was made by using duct-to-duct anastomosis and placement of a T tube.All the 11 donors are uneventfully discharged after operation. In the 11 recipients, an 8-year-old girl needed retransplantation because of hepatic artery thrombosis, one case died of serious chronic rejection on the postoperative day 72. Ten recipients recovered and were discharged from hospital, whose liver function and cuprum oxidase had returned to normal.The procedure of LDLT is relatively safe for the donor. Reconstruction of vessels is a key step in the procedure. Comprehending anatomical variation of vessels pre- and intra-operatively and correct surgical management might reduce the incidence of complications.