5-脂氧合酶促癌机制研究进展

5-脂氧合酶蛋白是花生四烯酸代谢途径中的一种关键酶,在恶性肿瘤的发生、发展过程中起了重要作用．抑制5-脂氧合酶及其产物的表达有可能预防和逆转恶性肿瘤的发生,本文结合国内外文献,就5-脂氧合酶分子生物学特征及促癌机制的研究进展作一综述．     

Structural and functional differentiation of sinusoidal endothelial cells during liver organogenesis in humans

During fetal life, human liver sinusoids, which differentiate between 4 and 12 weeks of gestation from capillaries of the septum transversum, must support an important hematopoietic function and acquire the structural and functional characteristics of adult sinusoids. To gain insight into their differentiation process, we studied the expression of (1) markers of continuous endothelia, absent from adult sinusoidal endothelial cells (PECAM-1, CD34, and 1F10); (2) functional markers of adult sinusoidal endothelial calls (CD4, 1CAM-1, CD32, and CD14); and (3) extracellular matrix components (laminin, tenascin, fibronectin, and thrombospondin) in 37 fetuses of different gestational ages. We identified two successive differentiation events. (1) An early structural differentiation, occurring from 5 to 12 weeks of gestation, was characterized by the loss of continuous endothelial cell markers and a reduction in the perisinusoidal amount of laminin and in the deposition of tenascin, fibronectin, and thrombospondin; at the end of this process, fetal liver sinusoids present structural characteristics comparable to those of the sinuses in adult hematopoietic bone marrow. (2) A later functional differentiation was characterized by the acquisition of the markers of adult sinusoidal endothelial cells, initiating at 10 weeks of gestation and completed by 20 weeks of gestation; this process likely contributes to adapt liver sinusoids to the specific functions of the adult hepatic tissue.     

Lymphokine abnormalities in aplastic anemia: implications for the mechanism of action of antithymocyte globulin

Anti-thymocyte globulin (ATG) provides effective therapy for many patients with aplastic anemia, and its mechanism of action has been presumed to be secondary to lymphocytotoxicity. However, our studies of lymphocyte function in aplastic anemia show marked abnormalities of lymphokine production, which ATG may modulate. In 12 of 17 patients with aplastic anemia, interleukin 2 (IL2) production was markedly elevated in vitro (P less than .01 by paired statistical analysis). Expression of the IL2 receptor, or Tac antigen, on peripheral lymphocytes assessed by flow microfluorometry was also increased above the normal range in 11 of 15 cases. Studies of ATG suggested that it might act to stimulate lymphocyte function. In vitro, ATG is a mitogen, as measured by incorporation of 3H-thymidine into blood mononuclear cells; the response of cells to ATG from patients with aplastic anemia was exaggerated in comparison with normals. Cell proliferation was accompanied by production of IL2 to levels that were, in some cases, similar to those obtained with lectin stimulation. Finally, supernatants from lymphocytes cultured in the presence of ATG were able to replace adherent cells in providing growth factors for the support of nonadherent cells in methylcellulose hematopoietic colony assays. These results provide a mechanism for an "immunostimulatory" action of ATG in effecting hematopoietic response in some patients with aplastic anemia.     

Comparison Between Living Donor Liver Transplantation Recipients Who Met the Milan and UCSF Criteria After Successful Downstaging Therapies

Background and Aims

Various downstaging therapies were introduced to liver recipients who could not meet the relative criteria for liver transplantation, and many endpoints were reported. The most common criteria used were the Milan criteria and the University of California, San Francisco (UCSF) criteria. However, no comparison was made between them, and we attempted to find possible differences between the living donor liver transplantation (LDLT) patients who met the Milan criteria and those who met the UCSF criteria after accepting preoperative downstaging therapies.

Materials and Methods

We performed a retrospective study of all 72 patients at our center from January 2003 to March 2009 who were diagnosed with advanced hepatocellular carcinoma but accepted various downstaging therapies. Some patients met the Milan criteria (group 1), and some met the UCSF criteria (group 2) but not the Milan criteria. We collected the data from the two groups and then compared the preoperative demographic data, downstaging therapies, intraoperative data from LDLT, and the recovery and complications after LDLT. Survival rates were compared using Kaplan?CMeier analysis.

Results

Only 44 patients (61.1?%) met the criteria for liver transplantation, 21 cases met the Milan criteria (group 1), and 23 cases met the UCSF criteria (group 2) but not the Milan criteria. All of the 44 patients accepted right lobe living liver donor liver transplantation in our center. The difference in the baseline characteristics between the two groups did not reach statistical significance. The mean number of downstaging treatments per patient was 1.81?±?0.35 in group 1 and 1.83?±?0.41 in group 2 (P?=?0.928). Most of the patients received only one downstaging treatment, and transcatheter arterial chemoembolization (TACE) was the most common downstaging therapy. Four patients suffered complications after downstaging therapies: intra-abdominal hemorrhage after right hepatectomy, upper gastrointestinal hemorrhage after TACE, biliary fistula after resection, and hand?Cfoot syndrome after taking sorafenib. All complications after LDLT, classified according to the Clavien?CDindo system, were compared within the two groups, and the calculated score of the complications in group 1 was 1.48?±?1.63, which was greater than that of group 2 (1.39?±?1.64), but this difference did not reach statistical significance (P?=?0.865). The 1-, 3-, and 5-year survival rates were 90.4, 76.2, and 71.4?% in group 1 and 91.3, 73.9, and 69.6?% in group 2, respectively (P?>?0.05). Seven patients (three in group 1 and four in group 2) had tumor recurrence after a median follow-up period of 72?months. The pathology findings were not different between the two groups.

Conclusion

Recipients who meet the Milan or UCSF criteria after accepting successful preoperative downstaging therapy in LDLT can achieve the same result.     

Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro

Smad7 is a principal inhibitor of the TGFβ–Smad signalling pathway. We have investigated the functional significance of Smad7 in hepatocellular carcinoma (HCC). Smad7 knockout (KO) and wild‐type (WT) mice were injected with diethylnitrosamine (DEN) to induce HCC. The effects of Smad7 on cellular features were examined in HCC cells, using a Smad7 over‐expression or deletion approach. Signalling pathway components modulated by Smad7 in HCC were evaluated using luciferase reporter assay and co‐immunoprecipitation. Smad7 was down‐regulated in human HCCs compared with the adjacent normal tissues (p < 0.001). Smad7 KO mice were more susceptible to DEN‐induced HCC than WT mice (78% versus 22%, p < 0.05). HCCs from KO mice displayed a greater proliferation activity (p < 0.05) and a reduced apoptotic index compared with WT littermates (p < 0.05). Deletion of Smad7 promoted cell proliferation in primary cultured HCC cells. In addition, over‐expression of Smad7 in HCC cell lines markedly suppressed cell growth (p < 0.0001) and colony formation (p < 0.01). Cell cycle analysis revealed an increase in the G₁ phase and a reduction in the S‐phase populations, accompanied by up‐regulation of p27^Kip1 and down‐regulation of cyclin D1. Smad7 increased cell apoptosis (p < 0.01) by mediating an intrinsic [caspase‐9, caspase‐3 and poly(ADP‐ribose) polymerase] apoptotic pathway. Moreover, Smad7 inhibited NF‐κB signalling by interacting with TAB2, an upstream activator of NF‐κB, and inhibited TGFβ signalling by suppressing phosphorylation of Smad3. In conclusion, loss of Smad7 enhances susceptibility to HCC. Smad7 suppresses HCC cell growth by inhibiting proliferation and G₁–S phase transition and inducing apoptosis through attenuation of NF‐κB and TGFβ signalling. Smad7 acts as a potential tumour suppressor in liver. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

沉香呋喃类立体异构体的气相色谱及气-质联用分析研究

采用GC及GC—MS方法,对沉香呋喃类中的三对差向异构体进行了成功的分离鉴定,确定了每对异构体的比例,建立了倍半萜类异构体的分析方法,从而有效地指导了合成反应,加快了合成的进度,为产物合成提供了可靠的依据。     

Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10) [see comments]

In a multicenter pilot study, 32 patients showing steroid-resistant acute graft-versus-host disease (GVHD) were treated by in vivo administration of anti-interleukin-2 (IL-2) receptor monoclonal antibody (MoAb B-B10). Twenty-three patients received marrow from HLA- matched related donors, four from matched unrelated donors and five from partially matched related donors. The overall grade of GVHD was II in 16 patients, III in two, and IV in five. Five milligrams of B-B10 MoAb was infused in bolus daily for 10 days and then every second day for a further 10 days in an attempt to reduce GVHD recurrence. No clinical side effects were noted during the B-B10 treatment period. A complete response (CR) acute GVHD was achieved in 21 patients (65.6%). Six patients (18.7%) showed partial improvement (PR) and 5 patients (15.6%) no response (NR). A significant factor associated with GVHD response was the delay between the onset of the GVHD and the first day of B-B10 infusion. The earlier B-B10 was introduced, the greater the probability of CR (P = .03). There was no correlation between the serum B-B10 level and GVHD response (P = .69). There was, however, a significant correlation between the clinical response and the B-B10 kinetics as a function of time: serum B-B10 levels attained a plateau level more rapidly in the CR group than in the PR/NR group. Among the 26 complete and partial evaluable responders, GVHD recurred in 10 cases (38.4%). Host anti-B-B10 MoAb immune response occurred in only one (7.1%) of the 14 patients analyzed. Fourteen of the 32 patients (43.7%) are currently alive between 2 and 14 months after GVHD treatment with B- B10 was completed.