Summary Monocyte-macrophage series have an important role in host surveillance against cancer. The cytotoxic/cytostatic activity of macrophages is, to a great extent, attributed to the up-regulation of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). Here, in 28 patients with primary lung cancer and 20 control subjects, we measured the concentration of exhaled NO and nitrite in epithelial lining fluid (ELF) using a chemiluminescence NO analyser, and studied NOS expression in alveolar macrophages (AM) and lung tissues by flow cytometry; immunohistochemical analysis was also undertaken. The mean fluorescence intensity (Fl) of iNOS expression in AM was significantly increased in patients with lung cancer (tumour side 263.5 ± 15.2 Fl, normal side 232.4 ± 18.6 Fl; n = 28) compared with that in control subjects (27.3 ± 3.2 Fl; n = 20, P< 0.001). The level of exhaled NO from cancer patients (16.9 ± 0.9 p.p.b.; n = 28) was significantly higher than that in the control group (6.0 ± 0.5 p.p.b.; n = 20, P < 0.001). The level of nitrite was also significantly higher in ELF from cancer patients (tumour side 271.1 ± 28.9 nm and normal side 257.4 ± 19.6 nm vs control subjects 32.9 + 4.1 nM; P< 0.001). The intensity of iNOS expression in AM was correlated with the level of exhaled NO (rS = 0.73, n = 76, P < 0.001) and the nitrite released in ELF (r, = 0.56, n = 76, P < 0.001). The nitrite generation of cultured AM from patients with lung cancer was significantly enhanced compared with that of control subjects after culture for 24 h (tumour side 5.75 ± 0.69 and normal side 5.68 ± 0.58 gM per 106 cells vs control group 38.3 + 3.6 nm per 106 cells; P< 0.001). The distribution of iNOS was identified in AM, tumour-associated macrophages, endothelium, chondrocytes, airway epithelium of both lungs and malignant cells (adenocarcinoma and alveolar cell carcinoma) of cancer patients. cNOS was labelled in alveolar macrophages, endothelial cells and nerve elements from lung tissue. Our results indicate that, in patients with primary lung cancer, the production of NO from alveolar macrophages was increased as a result of the up-regulation of iNOS activity. The increased NO production was not specific to the tumour side and might be attributed to the tumour-associated non-specific immunological and inflammatory processes of the host.Keywords: lung cancer; alveolar macrophage; nitric oxide; nitric oxide synthase; nitrite; cytotoxicity The host defence mechanism is important in the development and growth of tumours. The incidence of malignancy is reported to be increased in subjects with compromised immunity (Penn, 1986). The complex defence and immunological mechanisms against cancer contain several types of cells, including macrophages (Fidler et al, 1988) and mediators, such as nitric oxide (NO) (Farias-Eisner et al, 1996).Macrophages have a role in host surveillance against cancer (Hibbs et al, 1978). Macrophages can be activated both in vivo and in vitro to kill tumour cells. The oncolytic activity of macrophag...
Thymosin ␣ 1 (T␣) is an immune modifier that has been shown in a pilot study to be effective for chronic hepatitis B; this requires confirmation. Ninety-eight patients with clinicopathologically proven chronic hepatitis B were randomly allocated to 3 groups: 1) group A received a 26-week course of T␣ with a 1.6-mg subcutaneous injection two times a week (T 6 group); 2) group B received the same regimen as group A, but T␣ therapy extended for 52 weeks (T 12 group); and 3) group C served as a control group and was followed up for 18 months without specific treatment (T 0 group). The three groups were comparable in clinicohistological features at entry. The complete virological response rate (clearance of serum hepatitis B virus [HBV] DNA and hepatitis B e antigen [HBeAg]) was higher in group A (40.6%) and group B (26.5%) than in group C (9.4%) (group A vs. group C: P ؍ .004; group B vs. group C: P ؍ .068) when assessed 18 months after entry, although complete response rates among these three groups were similar when first assessed at the end of therapy. There was a trend for complete virological response to increase or accumulate gradually after the end of T␣ therapy. None of the responders lost hepatitis B surface antigen. Blinded histological assessment showed a significant improvement in treated patients, particularly in lobular necroinflammation and scores excluding fibrosis. No significant side effects were observed. These results suggest that a 26-week course of T␣ therapy is effective and safe in patients with chronic hepatitis B. (HEPATOLOGY 1998;27:1383-1387.)Chronic hepatitis B virus (HBV) infection is a serious problem because of its worldwide distribution and possible adverse sequalae, such as cirrhosis and hepatocellular carcinoma. [1][2][3][4][5] The ultimate goals of therapy for chronic hepatitis B are to prevent progression to cirrhosis and to prevent development of hepatocellular carcinoma. Over the past 20 years, many antiviral or immunomodulatory agents, or both, have been used in patients with chronic HBV infection. 6,7 Among them, interferon alfa (IFN-␣) has been shown to be effective, because 30% to 40% of adult white patients with elevated alanine transaminase (ALT) levels lost hepatitis B e antigen (HBeAg) and HBV DNA when treated with IFN-␣ at a dose of 5 MU daily or 10 MU three times a week for 16 weeks. 8,9 However, the response rate is far from satisfactory, particularly in Asian patients, although corticosteroid priming may enhance the efficacy of interferon therapy. [10][11][12] Thymosin ␣ 1 (T␣) is an immune modifier that has been shown to trigger maturational events in lymphocytes, to augment T-cell function, and to promote reconstitution of immune defects. 13 A small pilot study conducted by Mutchnick et al. 14 showed an 80% complete response associated with clinical, immunological, and histological improvement in patients with chronic hepatitis B. However, a multicenter American study involving 97 patients only showed a marginally significant benefit. 15 Thus, the efficacy of ...
We examined the full-length hepatitis B virus (HBV) envelope (surface antigen or HBV small surface antigen [HBsAg]) sequences of 12 different liver samples from 10 different hepatoma-containing chronic carriers. Surprisingly, novel and frequent mutations occurred predominantly at amino acids 40 and 47 of HBsAg, in addition to within a known protective B-cell epitope (so-called group a determinant of HBsAg 124-148). Approximately 58% of chronic carriers contain mutations at the group a determinant. The mutation frequency at the hotspot codons 40 and 47 is approximately 83%, 1 order of magnitude higher than at the known polymorphic sites of subtype-specific determinants at codons 122 and 160, which is approximately 4%. This new mutational domain is found to coincide with a major histocompatibility complex class I-restricted T-cell epitope. The potential biological significance of this novel mutation in the immunopathogenesis of HBV chronic carriers is discussed.
Although most colorectal cancer develops based on the adenoma–adenocarcinoma sequence, morphologically, colorectal cancer is not a homogeneous disease entity. Generally, there are two distinct morphological types: polypoid and ulcerative colorectal tumours. Previous studies have demonstrated that K-ras codon 12 mutations are preferentially associated with polypoid growth of colorectal cancer; however, little is known about the molecular mechanism that determines ulcerative growth of colorectal cancer. β-catenin complex plays a critical role both in tumorigenesis and morphogenesis. We examined the differential expression of β-catenin and its related factors among different types of colorectal cancer in order to determine any relationship with gross tumour morphology. Immunohistochemical staining of β-catenin, E-cadherin and MMP-7 was performed on 51 tumours, including 26 polypoid tumours and 25 ulcerative tumours. Protein truncation tests and single-strand conformational polymorphism for mutation of the adenomatous polyposis coli tumour suppressor gene, as well as single-strand conformational polymorphism for the mutation of β-catenin exon 3 were also done. Nuclear expression of β-catenin was observed in 18 out of 25 (72%) cases of ulcerative colorectal cancer and seven out of 26 (26.9%) cases of polypoid colorectal cancer. A significant relationship of nuclear β-catenin expression with ulcerative colorectal cancer was found (P<0.001). However, this finding was independent of adenomatous polyposis coli tumour suppressor gene mutation and E-cadherin expression. Together with previous data, we propose that different combinations of genetic alterations may underlie different morphological types of colorectal cancer. These findings should be taken into consideration whenever developing a new genetic diagnosis or therapy for colorectal cancer.British Journal of Cancer (2002) 86, 1124–1129. DOI: 10.1038/sj/bjc/6600214 www.bjcancer.com© 2002 Cancer Research UK
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