It is suggested that the cytoplasmic overexpression of EGFr plays a significant role in the progression of pancreatic ductal adenocarcinoma, especially in the invasion and acquisition of aggressive clinical behavior. Both membrane and cytoplasmic expression of HER-2 showed no significant correlation between tumor differentiation and poor survival.
Chronic viral hepatitis patients, especially hepatitis C patients, often fall victim to liver cirrhosis and subsequent hepatocellular carcinoma (HCC). 1 It is now believed that the HCV infection in hepatocytes itself is not cytopathic whereas the cellular immune response to infected hepatocytes may indeed cause hepatocyte injury. 1 It has been suggested that nonspecific NK cell activation 1,2 and viral antigen-specific activation of either CD4 ϩ T cells or cytotoxic CD8 ϩ T cells may be responsible for hepatocyte injury. 1,3-6 Consistent with this hypothesis, it has also been reported that liver lymphocytes expressed T helper 1 cytokine, IFN-␥, and IL-2 messenger RNA, and the serum levels of these cytokines were elevated in the patients with HCV. 7,8 On the other hand, livers from mice and humans have recently been reported to contain not only a large population of NK cells but also of T cells with NK cell markers. 9-13 Namely, mouse NK1.1 antigen ϩ T (NKT) cells and human CD56 ϩ T cells are abundant in the livers. NKT cells in mice were activated by IL-12 and inhibited tumor metastases in the liver of mice 10,11,14-16 (for a review, see Seki et al.,16 ). Human peripheral blood CD56 ϩ T cells were also activated in vitro by IL-12 and thus acquired an antitumor cytotoxicity against NK-resistant tumors. 13 Furthermore, strongly activated mouse liver NKT cells destroyed the syngeneic hepatocytes. 17 Therefore, the possibility has been raised that human CD56 ϩ T cells may also play an important role in both hepatocyte injury in chronic viral hepatitis and antitumor immunity in the liver. In the present study, we show that human liver MNC activated by anti-CD3 Ab or a combination of IL-2 and IL-12 (or IL-2 alone) both produced IFN-␥ and killed tumors more effectively than did PBMC. Furthermore, human liver CD56 ϩ T cells and CD56 ϩ NK cells gradually decreased in parallel with the progress of the hepatitis C and diminished in livers with cirrhosis. These liver MNC from cirrhotic livers could not effectively produce IFN-␥ and could not effectively kill not only K562 cells and Raji cells but also a human HCC cell line, HuH-7 cells, thus suggesting that the decrease in CD56 ϩ T cells and NK cells may be one of the mechanisms explaining why HCC frequently originates from cirrhotic livers. PATIENTS AND METHODSPatients and Liver Specimens. Liver specimens were obtained during surgery from the patients listed in Table 1 after obtaining their informed consent. Liver specimens obtained from the anti-HCV Aband HBs antigen (Ag)-negative patients with cancers other than HCC and were regarded as the HCV (Ϫ) liver specimens. Other liver specimens were from anti-HCV Ab-positive patients with chronic hepatitis C or with liver cirrhosis. Peripheral blood samples were also obtained during surgery. All liver specimens were obtained from areas other than tumor nodules.Reagents. Anti-CD3 Ab (UCHT1, mouse IgG1) were purchased from PharMingen (San Diego, CA). Recombinant human IL-2 and IL-12 were purchased from PEPRO TECH EC (London, UK). ...
The addition of spinal block to sevoflurane general anesthesia accompanying surgery attenuates the suppression of tumoricidal function of liver mononuclear cells, presumably by preserving the T helper 1/T helper 2 (Th1/Th2) balance, and thereby reduces the promotion of tumor metastasis.
Highly activated neutrophils play a critical role in mediating organ injury in sepsis by releasing neutrophil elastase (NE). Toll-like receptors (TLRs) play an important role in the host defense against invading microbes, and their signaling pathway is critical to the activation of the proinflammatory response. However, the relationship between TLR expression and the host defense mechanism during sepsis has not been fully elucidated. In this paper, we investigated the relationships among chemokine (MIP-2), TLR-4, and NE expression in human sepsis and murine peritonitis (CLP). TLR-4 expression on monocytes/macrophages was examined in patients with sepsis and in murine peritonitis and was markedly increased in both populations. LPS-induced MIP-2 production by bronchoalveolar cells and liver mononuclear cells in mice with peritonitis was also significantly increased compared with sham-operated mice. Pretreatment of the macrophage cell line, RAW 264.7 cells, with a NE inhibitor before their exposure to LPS resulted in a significant dose-dependent decrease in MIP-2 production, which was comparable to that seen following pretreatment with TLR-4 antibody. Furthermore, NE and LPS both up-regulated TLR-4 expression on human peripheral blood monocytes. Thus, chemokine-induced recruitment of neutrophils in sepsis may result in further increased chemokine production and increased expression of TLR-4. Neutrophil-derived NE may be associated with increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback loop for the inflammatory response among the different cell populations.
These results showed that the number of peripheral blood CD16+ CD14+ monocytes and monocytic TLR-4 expression were markedly increased, and the production of pro-inflammatory cytokines in response to LPS significantly reduced in patients with sepsis. PMX-F treatment was found to be effective in reducing the number of CD16+ CD14+ monocytes and in decreasing the monocytic expression of TLR-4 in patients with septic shock.
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