[Effects of evodiamine on carbon tetrachloride-induced liver fibrosis mice based on modulating gut microbiota].

Objective: To access the effects of evodiamine on carbon tetrachloride (CCl(4)) -induced liver fibrosis mice and study the mechanism based on modulating gut microbiota. Methods: From August 2019, 30 SPF male C57BL/6 mice were randomly divided into normal, model and evodiamine groups. Mice in control group received intraperitoneal injection of olive oil (2 ml/kg, twice per week) for 6 weeks. Mice in model and evodiamine groups received intraperitoneal injection of 20% CCl(4) (2 ml/kg, twice per week) for 6 weeks to induce liver fibrosis mice. Then, mice in evodiamine group received orally of evodiamine (18 mg/kg) for 4 weeks. The levels of serum alanine aminotransferase (ALT) , aspartate aminotransferase (AST) , albumin (ALB) and total protein (TP) were detected. The pathological changes of liver tissue were observed. The effects of evodiamine on the abundance and diversity of intestinal microflora in liver fibrosis mice were determined. The mRNA and protein expression levels of inflammatory factors[interleukin-6 (IL-6) , interleukin-1ß (IL-1ß) , and tumor necrosis factor α (TNF-α) ] in liver tissue were measured. Results: Compared with the normal group, the body weight, serum ALB and TP levels of the model group were decreased, the liver index, ALT and AST levels were increased, and the intestinal flora Shannon and Simpson indexes were decreased (P<0.01) . Compared with the normal group, the abundance of Lactobacillus, Akkermansia and Bacteroides in the feces of the model group decreased, while the abundance of Enterococcus and Lachnoclostridium increased (P<0.01) . Compared with the normal group, the mRNA and protein expressions levels of IL-6, IL-1ß, and TNF-α in the liver tissue of the model group were significantly increased (P<0.01) . Compared with the model group, evodiamine could reduce liver index and serum ALT and AST levels, increase ALB and TP levels (P<0.05) , improve inflammatory cell infiltration and fibrosis degree in liver tissue, and up regulate intestinal flora Shannon and Simpson indexes in liver fibrosis mice (P<0.05) . Compared with the model group, evodiamine could increase the abundance of Lactobacillus, Akkermansia, Bacteroides, and reduce the abundance of Enterococcus and Lachnoclostridiun (P<0.05) . Compared with the model group, evodiamine could reduce the mRNA and protein levels of IL-6, IL-1ß and TNF-α in liver tissue of liver fibrosis mice (P<0.05) . Conclusion: Evodiamine can ameliorate CCl(4)-induced liver fibrosis through modulating gut microbiota and inhibiting the inflammatory response in liver.

Health-Related Quality of Life and Psychological Distress in Patients With Early-Stage Hepatocellular Carcinoma After Hepatic Resection or Transplantation.

BACKGROUND: The aim of our study was to compare the post-operative health-related quality of life in patients with small hepatocellular carcinoma (HCC; within the Milan criteria) after liver resection or liver transplantation. METHODS: From August 2000 to December 2010, 207 patients were diagnosed with early HCC within the Milan criteria. We divided these patients into 2 groups according to their curative schedule: the liver transplantation group (n = 95) and the liver resection group (n = 110). We compared the baseline characteristics of these 2 groups of patients, after which we focused on comparing the post-operative health-related quality of life (HRQOL) and psychological outcome in these 2 groups. RESULTS: The demographics of the patients in the 2 groups were similar, and there were no significant differences except for higher family income in the transplantation group (P = .002).With long-term follow-up, there were no significant differences in the 8 domains of the HRQOL and the 9 domains of the psychological outcome measure between the 2 groups. Both the transplantation and resection groups exhibited good outcomes in both HRQOL and psychological outcome measures. CONCLUSIONS: Several years after operation, early-stage HCC patients who underwent liver transplantation or resection had similar long-term HRQOL and psychological outcomes.

Response to transarterial chemoembolization as a selection criterion for resection of hepatocellular carcinomas.

BACKGROUND: Liver resection for intermediate (Barcelona Clinic Liver Cancer (BCLC) stage B) hepatocellular carcinoma (HCC) remains controversial. This study attempted to demonstrate the effectiveness of preresection transarterial chemoembolization (TACE) as a selection criterion for BCLC-B HCC. METHODS: The study included patients with BCLC-B HCC who underwent liver resection after TACE. The tumour response to TACE was evaluated according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST). Patients with a complete or partial response comprised the responder group, whereas those with stable or progressive disease were classified as non-responders. RESULTS: A total of 242 patients were included. After between one and eight sessions of TACE, 141 patients were included in the responder group: 37 patients (15·3 per cent) who achieved a complete response and 104 who had a partial response. The cumulative 1-, 3- and 5-year overall survival rates were 97·2, 88·7 and 75·2 per cent respectively in the responder group, compared with 90·1, 67·3 and 53·5 per cent among 101 non-responders (P < 0·001). Tumour-free survival rates were also better among responders than non-responders (P < 0·001). In multivariable analysis, independent predictors of overall and tumour-free survival were response to TACE and microvascular invasion (all P < 0·001). CONCLUSION: mRECIST may represent selection criterion for intermediate HCC for surgical treatment.

Association between positive murine double minute 2 expression and clinicopathological characteristics of esophageal squamous cell carcinoma: a meta-analysis.

The correlations of murine double minute 2 (MDM2) T309G and esophageal cancer were elucidated because the association between MDM2 expression states and clinicopathological parameters of esophageal squamous cell carcinoma (ESCC) is controversial. We conducted a meta-analysis on studies screened from PubMed, Web of Science, Embase, the Cochrane Library, and the Chinese Biomedical Literature Databases that were published before October 2014. All studies describing the association between MDM2 and ESCC were traced. Meta-analysis was performed using the STATA software (Stata Corp., College Station, TX, USA). A total of 9 studies with 707 cases and 324 controls were included. MDM2 expression was higher in ESCC than in normal esophageal epithelium (odds ratio [OR] 10.38, 95% confidence interval [CI] 6.42-16.78, P < 0.001). High MDM2 expression was associated with early primary tumor stage (T1/T2 vs. T3/T4, OR 0.59, 95% CI 0.38-0.92, P = 0.018) and increased risk of regional lymph node metastasis (N0 vs. N1, OR 1.66, 95% CI 1.03-2.67, P = 0.039). However, no relationship was observed between MDM2 expression and the risk of distant metastasis (OR = 2.09, 95% CI 1.00-4.36, P = 0.050), and MDM2 was not significantly correlated with TP53 expression (OR 1.22, 95% CI 0.53-2.77, P = 0.643). Our analysis suggests that MDM2 acts as a potent marker of early primary tumor stage but higher risk of regional lymph node metastasis in ESCC. However, because of the limited number of studies included, the result should be further clarified by well-designed prospective studies.

Hepatocellular Carcinoma Patients May Benefit From Postoperative Huaier Aqueous Extract After Liver Transplantation.

BACKGROUND: Liver transplantation has been the first choice for most early- or intermediate-stage hepatocellular carcinoma (HCC) cases. However, postoperative anti-HCC therapies remain controversial. In this study, we aimed to evaluate the safety and efficacy of Huaier aqueous extract (Jinke), when used as an adjuvant postoperative anti-HCC therapy. METHODS: We retrospectively collected the clinical and follow-up data of HCC patients who underwent liver transplantation at our center. We divided them into 2 groups: a control liver transplantation group and a Huaier treatment group. The baseline characteristics, tumor characteristics, intraoperative data, postoperative recovery, long-term overall survival rate, and tumor-free survival rate were compared between the 2 groups. RESULTS: Fifty-three patients were included in our study, including 28 patients who underwent postoperative Huaier therapy and 25 patients who underwent liver transplantation without postoperative Huaier therapy. The baseline and tumor characteristics were similar between the 2 groups. None of the patients in the Huaier group experienced any severe adverse events. The long-term predictive overall survival was similar between the 2 groups (P = .202). However, the Huaier group had a higher predictive tumor-free survival rate than the control group (P = .029). And the 10- and 30-month predictive tumor recurrence rates were 17.9% and 35.7% in the Huaier group, which were significantly lower than those in the control group (60% and 64%; P < .05). CONCLUSIONS: HCC patients may benefit from Huaier therapy after liver transplantation, but a longer follow-up time and larger cohort study may be necessary to be sure.

Radiofrequency ablation versus surgical resection for small unifocal hepatocellular carcinomas.

We aimed to compare the effectiveness and safety of hepatic resection and radiofrequency ablation (RFA) for small hepatocellular carcinomas (HCCs) less than 5 cm in diameter. A total of 289 patients were diagnosed with a small HCC (a single tumor no larger than 5 cm). Among these patients, 133 underwent hepatic resection, and 156 received RFA. Demographic data, intraoperative data, post-operative recovery data, and the baseline characteristics of the 2 groups of patients were compared. The incidence of post-operative complications; 1-, 3-, and 5-year survival rates; and tumor recurrence were determined. No statistically significant differences in the baseline characteristics were noted between the 2 groups. By contrast, operation time (P = 0.003), intraoperative blood loss (P = 0.000), and the length of post-operative hospital stay (P = 0.000) were significantly lower in the RFA group compared with the surgical resection group. The 2 groups displayed similar post-operative complication rates (12% or 16/133 in the liver resection group vs. 8.3% or 13/156 in the RFA group, P = 0.395). The 1-, 3-, and 5-year overall survival rates of the patients in the liver resection group were 88.7%, 78.2%, and 66.2%, respectively, whereas the rates in the RFA group were 90.4%, 76.3%, and 66.0%, respectively (P = 0.722). The 1-, 3-, and 5-year tumor-free survival rates of patients in the resection group were 87.2%, 69.9%, and 58.6%, respectively, whereas the rates in the RFA group were 85.9%, 66.0%, and 54.5%, respectively (P = 0.327). In addition, among HCC patients receiving RFA, patients with tumors no greater than 3 cm in diameter exhibited no significant differences regarding overall survival and tumor-free survival rates compared with patients with tumors 3 to 5 cm in diameter (all P > 0.05). RFA is an effective and safe treatment option for small HCCs and may be a preferred choice for HCC patients with small lesions.

Immediate radical therapy or conservative treatments when meeting the Milan criteria for advanced HCC patients after successful TACE.

BACKGROUND AND AIMS: Many advanced hepatocellular carcinoma (HCC) cases can be successfully downstaged into the Milan criteria; however, immediate radical therapy cannot be applied to all such patients for various reasons. Of the patients who are not eligible for immediate radical therapy, some accept repeated downstaging therapies and some undergo persistent observation. The aim of the present study was to compare long-term survival between these two groups of patients. PATIENTS AND METHODS: Between August 2003 and October 2008, 156 HCC patients successfully received downstaging therapy resulting in compliance with the Milan criteria. Of those, 98 cases accepted radical therapies, including liver transplantation (LT), resection, or radiofrequency ablation (RFA) (group 1), and 58 cases underwent repeated transcatheter arterial chemoembolization (TACE) or persistent observation (group 2). The baseline characteristics, demographic data, downstaging protocol, and information on long-term outcomes were collected and compared. RESULTS: No significant differences were observed in the patient demographic data, downstaging protocols, or tumor characteristics between the two groups. The 1-, 3-, and 5-year overall survival rates were 92.9, 82.7, and 78.6 %, respectively, in group 1, whereas these rates were 82.8, 65.5, and 48.3 %, respectively, in group 2 (P = 0.046). Among the 58 patients in group 2, the 1-, 3-, and 5-year overall survival rates were 92.3, 65.4, and 46.2 %, respectively, in the repeated TACE group, and 81.3, 65.6, and 50 %, respectively, in the persistent observation group (P = 0.783). CONCLUSION: Immediate radical therapy should be the first choice for advanced HCC patients who undergo successful TACE, and repeated TACE is unnecessary.

Intraoperative "no go" donor hepatectomy in living donor liver transplantation.

BACKGROUND AND OBJECTIVE: Although there are many reports on donor safety, there are few concerning aborted donations. We sought to analyze the "no go" donor hepatectomies in our liver transplantation center over 10 years' experience. METHODS: Among 290 living donors brought to the operating room for liver graft harvest from March 2002 to April 2012, we examined the reasons to abandon the procedure, comparing their data with those of successful donors. RESULTS: The donor operation was aborted in 5 cases various for reasons. The main reason for the abandonment of the operation process was poor liver quality: in single cases there was: poor liver quality due to a massive cirrhotic nodule observed by laparoscopy; serious steatosis of the liver, indicated by an intraoperative biopsy; and an unsuitable biliary anatomy, including 4 branches with 2 small ones. In another case, a biliary duct variation in the intraoperative cholangiogram showed a narrow crotch of the left and right ducts. In the 5th case, the donor would have been left with only a small remaining left lobe (<30%) if the right lobe had been harvested. All 5 donors proceeded to accept a right lobe hepatectomy. Comparison with the 285 successful donors showed no significant differences in preoperative demographic data. All 5 donors recovered without complication and were in good condition over long-term follow-up. CONCLUSIONS: A low rate of "no go" donor hepatectomy can be achieved. There was no short- or long-term harm to the living donor owing to abandonment of the procedure.

Recombinant disintegrin domain of ADAM15 inhibits the proliferation and migration of Bel-7402 cells.

ADAM15 (A Disintegrin And Metalloproteinase 15), a transmembrane protein containing seven domains, interacts with some integrins via its disintegrin domain and overexpresses in many solid tumors. In this study, the effect of the recombinant human disintegrin domain (rhddADAM15) on the proliferation and migration of Bel-7402 cells was evaluated in vitro and in vivo in zebrafish xenografts. rhddADAM15 (4 µM) severely inhibited the proliferation and migration of Bel-7402 cells, inducing a partial G2/S arrest and morphological nucleus changes of apoptosis. Moreover, the activity of caspases 8, 9 and 3 in Bel-7402 cells was increased. In addition, the zebrafish was used as a model for apoptosis-induction and tumor-xenograft. rhddADAM15 (1 pM) inhibited the growth and metastasis of Bel-7402 cell xenografts in zebrafish and a lower concentration (0.1 pM) induced severe apoptosis in the somatic cells of zebrafish. In conclusion, our data identified rhddADAM15 as a potent inhibitor of tumor growth and metastasis, making it a promising tool for use in anticancer treatment.

Prediction factors of postoperative hyperbilirubinemia in living right lobe donor: a single-center analysis of 210 cases.

BACKGROUND: Hyperbilirubinemia in living liver donor is very common, but the causes are still unclear. AIMS: We sought to clarify the risk factors and predictors of nonobstructive hyperbilirubinemia among living donors. METHODS: We divided 210 consecutive right liver lobe donors into two groups according to the peak total bilirubin postoperatively. We collected data on preoperative, intraoperative, and postoperative biochemical measurements retrospectively, performing multivariate logistic regression analysis adjusting for potential confounders of the risk of hyperbilirubinemia. RESULTS: There were significant differences between the two groups in donor age, body mass index, operative time, blood loss, macrovescicular steatosis, allogeneic blood transfusion rate, intensive care unit stay, hospital stay and Clavien score after donation (P < .05). Age, graft/donor weight, operative time, and blood loss were significantly associated with the risk of hyperbilirubinemia upon logistic regression analysis. CONCLUSION: Hyperbilirubinemia, one type of hepatic dysfunction after a living donor procedure, was associated with multiple independent risk factors.

Pigmented renal clear cell carcinoma with melanocytic differentiation.

Renal cell carcinoma (RCC) is the most common malignant tumor of the adult kidney, and its incidence has been steadily rising. RCC consists of several subtypes, each of which has its own clinical features, and cytogenetic and molecular characteristics. Recognizing histologic patterns of RCC is important not only for correct diagnosis, but also for providing insight into the biological behavior of the tumor and subsequent appropriate medical care for the patient. Pigments other than hemosiderin has been observed in RCC, but none of them have been proved to be melanin. Melanotic tumors, either primary or metastatic, are rare in the kidney. We present an unusual case of melanin-pigmented clear cell RCC with melanocytic differentiation, an unusual variant that may lead to errors in diagnosis and treatment.

Biological effects of cementum and bone extracts on human periodontal fibroblasts.

BACKGROUND: Non-collagenous proteins of mineralized tissues play important roles in bone induction during mineralization and in regulating the activity of many types of mesenchymal cells. This study was conducted to determine the effects of acetic acid extracts of bone and cementum on alkaline phosphatase (ALPase) activity and in vitro mineralization of cultured human periodontal fibroblasts (hPF). METHODS: Alveolar bone and cementum obtained from clinically healthy subjects were extracted by a solution containing 0.5 M acetic acid and enzyme inhibitors. Osteoblastic phenotypes of hPF were assayed by ALPase activity, gene expression of bone marker proteins, and the ability to produce in vitro mineralization in culture media containing 50 microg/ml ascorbic acid, 10 mM sodium beta-glycerophosphate, and 10(-7) M dexamethasone. The effects of cementum and bone extracts on the expression of osteoblastic phenotypes in hPF were also determined. RESULTS: Many protein components, varying in molecular weight from 10 to 14 to 120 kDa, were detectable in 10% SDS-PAGE of both cementum and alveolar bone extracts. The hPF cells were found to exhibit a moderate ALPase activity when compared with rat osteosarcoma (ROS) 17/2.8 cells under the same experimental conditions. Gene expression for ALPase, osteocalcin bone sialoprotein, osteopontin, and BMP-7 at mRNA message was detected by RT-PCR in hPF and ROS 17/2.8 cells. The confluent hPF and ROS 17/2.8 cells showed evidence of calcium deposition in the extracellular milieu at 30 and 15 to 30 days' cultures, respectively, under a mineralization medium. The hPF appeared to form mineralized foci with morphological characteristics different from the mineralized nodules produced by ROS 17/2.8 cells. The addition of low concentrations (5 microg/ml) of either cementum or bone extract produced an increase in the size and number of mineralization spots, as well as greater ALPase activity in both hPF and ROS 17/2.8 cultures during the observation periods. CONCLUSIONS: These results suggest that hPF possess certain mineralizing phenotypes, and that acetic acid extracts of bone and cementum contain components capable of stimulating osteogenic differentiation of hPF.

Microcystic adnexal carcinoma associated with primary immunodeficiency, recurrent diffuse herpes simplex virus infection, and cutaneous T-cell lymphoma.

Cutaneous microcystic adnexal carcinoma (MAC) is a rare and poorly understood tumor that predominantly occurs in the head and neck. MAC usually affects people in their fourth and fifth decades. Some patients have had a history of radiation. We present a case of MAC occurring in the left antecubital fossa of an 18-year-old white woman with an unusual immunodeficiency syndrome. The patient also developed a squamous cell carcinoma, a cutaneous T-cell malignancy, and a perigastric leiomyoma. A congenital infection of herpes simplex virus (HSV) persisted throughout her life. The association of HSV infection with MAC and squamous cell carcinoma and that of peripheral T-cell lymphoma with Epstein-Barr virus is discussed in relation to her immunodeficiency.

Insights into autoregulation from the crystal structure of twitchin kinase.

Many protein kinases are self-regulated by an intrasteric mechanism where part of the enzyme's structure directly inhibits the active site. This inhibitory structure is called a pseudosubstrate and specific regulators are required to remove it from the active site to allow substrates access. Removal of the pseudosubstrate sequence from members of the myosin light-chain kinase subfamily, including twitchin kinase, activates them but it is not known whether the pseudosubstrate sequence binds to the active site. Native twitchin is a 753K protein (6,839 residues) located in muscle A-bands of the nematode Caenorhabditis elegans and because of its size has not been easy to study. We have determined the crystal structure, refined to 2.8 A resolution, of a recombinant fragment (residues 5,890 to 6,262) of twitchin kinase that contains the catalytic core and a 60 residue carboxy-terminal tail. The C-terminal tail extends through the active site, wedged between the small and large lobes of the structure and making extensive contacts with the catalytic core which accounts for autoinhibition and provides direct support for the intrasteric mechanism of protein kinase regulation.