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11.
12.
Evidence from both experimental carcinogenesis and studies in human cirrhotic liver suggest that defective repair of the
promutagenic DNA base lesion, O
6-methylguanine, is a factor in the multistep process of hepatocellular carcinogenesis. Ubiquitous environmental alkylating
agents such as N-nitroso compounds can produce O
6-methylguanine in cellular DNA. Unrepaired, O
6-methylguanine can lead to the formation of G ? A transition mutations, a known mechanism of human oncogene activation and
tumour suppressor gene inactivation. Combined treatment of rodents with an agent producing O
6-methylguanine in DNA, and an agent promoting cell proliferation, leads to development of hepatic nodules and hepatocellular
carcinoma (HCC), cell division, hence DNA replication, being required for the propagation of tumorigenic mutation(s) in hepatocyte
DNA. The paramount importance of O
6-methylguanine in hepatocellular carcinogenesis is indicated by the observation that transgenic mice engineered to have increased
hepatic levels of repair enzyme O
6-methylguanine-DNA methyltransferase (MGMT) are significantly less prone to hepatocellular carcinogenesis following alkylating
agent treatment. Cirrhosis is a universal risk factor for development of human HCC, and a condition that is characterized
by increased hepatocyte proliferation as a result of tissue regeneration. Levels of the human repairing enzyme for O
6-methylguanine were found to be significantly lower in cirrhotic liver than in normal tissue. In accord with findings from
animal models, this suggested a mechanism in which persistence of O
6-methylguanine due to defective DNA repair by MGMT, together with increased hepatocyte proliferation, might lead to specific
gene mutation(s) and hepatocellular carcinogenesis. Screening for the presence and persistence of O
6-methylguanine in human DNA presently involves formidable technical difficulty. Indications are that such limitations might
be overcome by the use of an ultrasensitive method such as immuno-polymerase chain reaction (PCR). This approach should allow
parallel measurement of DNA adduct and repair enzyme in routine liver biopsy samples. It might also enable investigation of
O
6-methylguanine in human genes specifically associated with hepatocellular carcinogenesis. Given the wide variation in human
MGMT levels observed between individuals, tissues, and cells, this technology should be adapted to permit the ultrasensitive
localisation and measurement of adducts and repairing enzyme in liver biopsy tissue sections. Ability to ultrasensitively
measure O
6-methylguanine, and its repair enzyme, should prove valuable in the risk assessment of cirrhotic patients for developing hepatocellular
carcinoma.
Received for publication on July 6, 1998; accepted on Aug. 12, 1998 相似文献
13.
14.
Involvement of JC virus-infected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy 总被引:18,自引:0,他引:18
15.
Mao WC Bardwell WA Major JM Dimsdale JE 《International journal of behavioral medicine》2003,10(4):331-342
Previous studies of coping, hostility, and depressive symptoms have highlighted the significant relations between all possible
pairs of these 3 variables. To more completely explore the nature of depressive symptoms, we link them all together in this
study by testing a coping→hostility→depressive symptoms path model.
One hundred forty participants completed psychological questionnaires measuring coping strategies, hostility, and depressive
symptoms. While controlling age and social class as covariates, SPSS stepwise regression analyses were used to examine relations
among these 3 constructs.
Results suggest that coping has a direct relation with depressive symptoms as well as an indirect relation mediated by hostility.
Passive coping may lead to increased hostility, resulting in depressive symptoms. Active coping may have the opposite effect.
These findings suggest that the inclusion of measures of both coping strategies and hostility yields a more thorough understanding
of concomitants of depressive symptoms. From a clinical perspective, knowing what coping strategies a person uses and how
much anger they experience and express may be useful in guiding the management of depressive symptoms. 相似文献
16.
Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy 总被引:2,自引:0,他引:2
Pan TC; Zhang RZ; Pericak-Vance MA; Tandan R; Fries T; Stajich JM; Viles K; Vance JM; Chu ML; Speer MC 《Human molecular genetics》1998,7(5):807-812
The Bethlem myopathy is a rare autosomal dominant proximal myopathy
characterized by early childhood onset and joint contractures. Evidence for
linkage and genetic heterogeneity has been established, with the majority
of families linked to 21q22.3 and one large family linked to 2q37,
implicating the three type VI collagen subunit genes, COL6A1 (chromosome
21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes.
Mutations of the invariant glycine residues in the triple-helical
domain-coding region of COL6A1 and COL6A2 have been reported previously in
the chromosome 21-linked families. We report here the identification of a
G-->A mutation in the N-terminal globular domain-coding region of COL6A3
in a large American pedigree (19 affected, 12 unaffected), leading to the
substitution of glycine by glutamic acid in the N2 motif, which is
homologous to the type A domains of the von Willebrand factor. This
mutation segregated to all affected family members, to no unaffected family
members, and was not identified in 338 unrelated Caucasian control
chromosomes. Thus mutations in either the triple-helical domain or the
globular domain of type VI collagen appear to cause Bethlem myopathy.
相似文献
17.
Linear regression of eye velocity on eye position and head velocity suggests a common oculomotor neural integrator 总被引:3,自引:0,他引:3
Goldman MS Kaneko CR Major G Aksay E Tank DW Seung HS 《Journal of neurophysiology》2002,88(2):659-665
The oculomotor system produces eye-position signals during fixations and head movements by integrating velocity-coded saccadic and vestibular inputs. A previous analysis of nucleus prepositus hypoglossi (nph) lesions in monkeys found that the integration time constant for maintaining fixations decreased, while that for the vestibulo-ocular reflex (VOR) did not. On this basis, it was concluded that saccadic inputs are integrated by the nph, but that the vestibular inputs are integrated elsewhere. We re-analyze the data from which this conclusion was drawn by performing a linear regression of eye velocity on eye position and head velocity to derive the time constant and velocity bias of an imperfect oculomotor neural integrator. The velocity-position regression procedure reveals that the integration time constants for both VOR and saccades decrease in tandem with consecutive nph lesions, consistent with the hypothesis of a single common integrator. The previous evaluation of the integrator time constant relied upon fitting methods that are prone to error in the presence of velocity bias and saccades. The algorithm used to evaluate imperfect fixations in the dark did not account for the nonzero null position of the eyes associated with velocity bias. The phase-shift analysis used in evaluating the response to sinusoidal vestibular input neglects the effect of saccadic resets of eye position on intersaccadic eye velocity, resulting in gross underestimates of the imperfections in integration during VOR. The linear regression method presented here is valid for both fixation and low head velocity VOR data and is easy to implement. 相似文献
18.
19.
Recognition of peptidyl epitopes by polymorphic epithelial mucin (PEM)-specific monoclonal antibodies. 总被引:1,自引:0,他引:1
A S Dion N I Smorodinsky C J Williams D H Wreschner P P Major I Keydar 《Hybridoma》1991,10(5):595-610
Peptidyl epitope recognition by several murine monoclonal antibodies (MAbs E29, H23, HMFG-1, HMFG-2, MA5, MA6 and MA9) which react with the polymorphic epithelial mucins [PEM; epithelial membrane antigen (EMA)] was studied by using ten synthetic peptides representative of the 20 residue tandem repeat as test antigens. Antibody binding to 6-10 residue overlaps and to peptides having a common carboxy-terminus and staggered amino-termini (8-31 residues) was assessed by solid phase and competition ELISA techniques. From these analyses, all MAbs except MA9 were found to react predominantly with the carboxy-terminal half of the repeat motif. Polyclonal antibody responses in mice immunized with intact EMA/PEM-containing preparations also displayed significant reactivities against synthetic repeat peptide antigens and, conversely, synthetic peptides as carrier-conjugated immunogens induced antibodies recognizing intact antigens. These results are discussed vis-à-vis peptide conformation, the potential effects of O-glycosylation on secondary structure, and the possible effects of these parameters on immunogenicity and antigenicity. 相似文献
20.
Szládek G Juhász A Kardos G Szoke K Major T Sziklai I Tar I Márton I Kónya J Gergely L Szarka K 《Journal of clinical pathology》2005,58(4):402-405
BACKGROUND: The aetiology and factors leading to the progression of laryngeal cancer are still unclear. Although human papillomavirus (HPV) has been suggested to play a role, reports concerning the effect of HPV infection on tumour development are controversial. Recently, transfusion transmitted virus (TTV) was suggested to play a role in certain infections as a causative or coinfecting agent. AIMS: To investigate whether the development and progression of laryngeal squamous cell carcinoma is associated with coinfection with TTV and HPV. METHODS: The prevalence of TTV and HPV was investigated using the polymerase chain reaction in tissue samples from 40 healthy individuals, 10 patients with recurrent papillomatosis, five patients with papillomatosis with malignant transformation, and 25 patients with laryngeal carcinoma. The obtained prevalence data were compared and analysed statistically. RESULTS: In the 11 patients with carcinoma who had metastasis or relapse there was a high rate of coinfection with genogroup 1 TTV and HPV (eight of 11), whereas in the 14 without tumour progression no coinfection was found. Coinfection was associated with significantly lower tumour free survival in patients with carcinoma (p < 0.001). Furthermore, four of five patients who had papillomatosis with malignant transformation were coinfected with genogroup 1 TTV and HPV. CONCLUSIONS: Although the nature of cooperation between HPV and TTV needs to be investigated further, coinfection with genogroup 1 TTV and HPV appears to be associated with poor clinical outcome in laryngeal cancer. 相似文献