Glutathione S-transferases M1, T1, and P1 and breast cancer: a pooled analysis.

The glutathione S-transferase (GST) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the genes GSTM1 and GSTT1 and a base transition polymorphism at codon 105 (Ile-->Val) in GSTP1 were investigated in relation to breast cancer risk. Tobacco smoking and reproductive factors were examined as potential effect modifiers. Individual data from seven case-control studies were pooled within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens. To measure the effect of GSTs on breast cancer risk, odds ratios and 95% confidence intervals were computed adjusting for study center and age. The modifying effect was investigated by stratification on variables of smoking habits and reproductive history. A total of 2,048 cases with breast cancer and 1,969 controls were analyzed. The relative odds ratio (95% confidence interval) of breast cancer was 0.98 (0.86-1.12) with the GSTM1 null, 1.11 (0.87-1.41) with the GSTT1 null, 1.01 (0.79-1.28) with GSTP1 heterozygous mutants, and 0.93 (0.62-1.38) with GSTP1 homozygous mutants. Stratification by smoking or reproductive factors did not reveal a modifying effect of these variables, nor was there any association between GSTM1 and age at diagnosis of breast cancer. This is the largest study investigating susceptibility to breast cancer due to polymorphisms in the GST genes. The results conclusively show that single gene GST polymorphisms do not confer a substantial risk of breast cancer to its carriers. Furthermore, GSTs did not interact with smoking or reproductive history to modify cancer risk.     

Single Immunization of Newborn Mice with Heterologous Type-II Collagen Induces Arthritic Disease

Collagen-induced arthritis (CIA) is a widely accepted model of autoimmune disease with significant similarities to rheumatoid arthritis in humans. CIA is provoked in susceptible strains upon immunization of adult mice with native type-II collagen in complete Freund's adjuvant (CFA). Neonatal exposure to antigen is supposed to result in T cell clone deletion and induction of tolerance. Here we report that the neonatal injection of bovine type-II collagen (bCII) to ICR (CD-2) mice triggers the development of autoimmune chronic joint inflammation. Compared with standard CIA significant joint swelling was not observed and anti-collagen antibodies were not detected if the second challenge with the antigen was not supplied. Histopathologic examination of the joints showed cell infiltration, synovial hyperplasia and at the later period bone destruction. Mice immunized as neonates expressed Ag-specific proliferative response and delayed type hypersensitivity (DTH) reaction to bCII.     

BUB1 infrequently mutated in human breast carcinomas

The BUB1 gene is a key player in the mitotic spindle checkpoint machinery that monitors proper segregation of sister chromatides during mitosis. It has been suggested that mutations in BUB1 may disrupt the spindle checkpoint and thereby cause chromosomal instability, which is a hallmark of solid tumors including those from the breast. From a series of breast carcinomas we selected 20 cases with genomic instability, as scored by Comparative Genome Hybridization (CGH), and without somatic TP53 (p53) mutations, and sequenced the entire coding region of the BUB1 gene. Two different constitutional sequence variants were found; a base substitution in exon 5, c.481G>A (CAG>CAA, a synonymous change encoding Gln144) in two samples, and a base substitution 8 bp upstream of exon 10, c.1007-8T>C in two other samples. No somatic mutations were detected. These results indicate that genomic instability scored as copy number alterations by CGH in TP53 wild type breast carcinomas is not caused by somatic mutations in the BUB1 gene.     

Visual Event-Related Potentials in Cirrhotic Patients without Overt Encephalopathy

Ambulant patients with cirrhosis and no clinical evidence of encephalopathy were screened for impaired brain function by neuroelectrophysiological testing dependent on cognitive function. Infrequent large checkerboard visual stimuli were randomly interleaved with frequent small ones to elicit P300 event-related potentials (ERPs). Three ERP components, N200, P3a and P3b, were derived from the electroencephalogram (EEG) by computer averaging. The use of 10% contrast and a minimum of four precisely placed scalp electrodes were found to be necessary for optimal separation of ERPs from sensory evoked potentials. Visual ERPs, onset/offset and pattern-reversal visual evoked potentials (VEPs), the spontaneous EEG and the time taken to complete a standard number connection test (NCT) were obtained from 20 normal adult subjects and 19 age-matched patients with histologically-confirmed cirrhosis and no clinical evidence of encephalopathy. The latencies and amplitudes of evoked potentials and the alpha rhythm of the EEG were determined. In 6 of the 19 patients the latencies of P3a and/or P3b exceeded the corresponding mean for controls+2 standard deviations of that mean. In 4 other patients the NCT was prolonged. In all of the patients the N200, VEPs and alpha rhythm of the EEG were normal. In conclusion: (i) Optimal isolation of ERPs is critically dependent on stimulus contrast and electrode placement; (ii) ERPs appear to be more sensitive than primary sensory evoked potentials or the EEG in detecting impaired brain neuroelectrophysiological function; and (iii) Cirrhotic patients without overt encephalopathy in whom P3a and/or P3b latencies are prolonged may have subclinical hepatic encephalopathy.     

The role of CYP2E1 and 2B1 in metabolic activation of benzene derivatives

CYP2B1 and 2E1 oxidized toluene, aniline and monochlorobenzene (MCB) to water-soluble metabolites and to products covalently binding to microsomal proteins from male Wistar rats at high efficiency. Oxidation of benzene to covalently binding metabolites was catalysed by CYP2B1 and 2E1 more effectively than the formation of water-soluble metabolites, especially at low benzene levels. Thus, the formation of covalently binding products was inversely related but formation of soluble metabolites was proportional to benzene concentration. 1,4-Benzoquinone was responsible for the majority of covalent binding to microsomal proteins, being suppressed by ascorbate; 1,4-semiquinone was not important, since α-tocopherol did not inhibit the covalent binding and ESR showed its rapid decay, if NADPH was available. Specific antibodies and inhibitors confirmed the role of CYP2B1 and 2E1 induction. Covalent binding of benzene to DNA was largely due to benzene oxide; ∼50% was due to N-7 guanine adduct. CYP2E1 oxidizing benzene via phenol to 1,4-hydroquinone appeared to mediate its further oxidation to 1,4-benzoquinone, which also occurred spontaneously, but was reversed in a reducing environment of microsomes with NADPH. Production of OH radicals in microsomes with NADPH was greatly stimulated by HQ and less by BQ, especially in CYP2E1 induced microsomes, although the quinones themselves failed to produce OH radicals. The quinones could act by stimulation of the CYP futile cycle. Therefore, CYP2B1 and 2E1 in rats appeared essential for metabolic activation of benzene derivatives to potentially genotoxic products; BQ dominated the covalent binding of benzene to proteins, whereas DNA adducts were largely due to benzene oxide. Received: 12 March 1996/Accepted: 5 July 1996     

Limb apraxia in corticobasal syndrome

Corticobasal syndrome (CBS) is a progressive neurodegenerative disorder with asymmetric presentation and course characterized by degeneration of basal ganglia and cortical structures. Limb apraxia is a commonly observed deficit in CBS. Few studies have examined comprehensively the nature of deficits in limb apraxia. The goal of our study was to investigate the severity of deficits in various conceptual and gesture production task modalities. CBS patients were divided in two groups based on the side of brain that was initially affected by the disease. Ten patients with right hemisphere presentation (RHP) and seven with left hemisphere presentation (LHP) were included. The results showed that while selective conceptual tasks deficits were present in both groups, the overall picture suggests preserved conceptual representations of tools and actions in CBS patients with either LHP or RHP. Both groups were impaired relative to controls on gesture production tasks. Performance on transitive gestures was more severely affected in both groups than intransitive gestures. Imitation was more severely affected than pantomime, suggesting deficits in visuomotor transformations. The addition of verbal cuing during concurrent imitation affected only the LHP patients, rendering them more impaired relative to controls in their imitation with verbal cuing as opposed to their imitation only performance. Imitation of non-representational gestures was least accurate and intransitive gestures were most accurate. Patients were more severely impaired relative to controls when holding the object and when they were shown pictures of tools to pantomime.     

Brain injury in a forensic psychiatry population

OBJECTIVES: The prevalence and profile of adults with a history of traumatic brain injury (TBI) has not been studied in large North American forensic mental health populations. This study investigated how adults with a documented history of TBI differed with the non-TBI forensic population with respect to demographics, psychiatric diagnoses and history of offences. METHOD: A retrospective chart review of all consecutive admissions to a forensic psychiatry programme in Toronto, Canada was conducted. Information on history of TBI, psychiatric diagnoses, living environments and types of criminal offences were obtained from medical records. RESULTS: History of TBI was ascertained in 23% of 394 eligible patient records. Compared to those without a documented history of TBI, persons with this history were less likely to be diagnosed with schizophrenia but more likely to have alcohol/substance abuse disorder. There were also differences observed with respect to offence profiles. CONCLUSIONS: This study provides evidence to support routine screening for a history of TBI in forensic psychiatry.     

Detection of Chlamydia trachomatis,Ureaplasma urealyticum and Mycoplasma hominis in infertile Bulgarian men with multiplex real‐time polymerase chain reaction

The effect of Chlamydia trachomatis, Ureaplasma urealyticum and Mycoplasma hominis over the sperm quality is still unclear. The aim of this study was to determine their prevalence in infertile Bulgarian men. A total of 281 men were examined by applying mRT‐PCR. The registered prevalence was as follows: C. trachomatis – 13.9%, U. urealyticum – 19.2%, M. hominis – 9.9%. Co‐infection was established in eight swabs. This first in Bulgaria to study for detection of chlamydia and mycoplasmas in infertile men by mRT‐PCR demonstrates higher prevalence of the tested microorganisms in the infertile group toward the control one.     

Somatic EP300-G211S mutations are associated with overall somatic mutational patterns and breast cancer specific survival in triple-negative breast cancer

Purpose

We have compared the mutational profiles of human breast cancer tumor samples belonging to all major subgroups with special emphasis on triple-negative breast cancer (TNBC). Our major goal was to identify specific mutations that could be potentially used for clinical decision making in TNBC patients.

Patients and methods

Primary tumor specimens from 149 Norwegian breast cancer patients were available. We analyzed the tissue samples for somatic mutations in 44 relevant breast cancer genes by targeted next-generation sequencing. As a second confirmatory technique, we performed pyrosequencing on selected samples.

Results

We observed a distinct subgroup of TNBC patients, characterized by an almost completely lack of pathogenic somatic mutations. A point mutation in the adenoviral E1A binding protein p300 (EP300-G211S) was significantly correlated to this TNBC subgroup. The EP300-G211S mutation was exclusively found in the TNBC patients and its presence reduced the chance for other pathological somatic mutations in typical breast cancer genes investigated in our gene panel by 94.9% (P?<?0.005). Interestingly, the EP300-G211S mutation also predicted a lower risk for relapses and decreased breast cancer-specific mortality during long-term follow-up of the patients.

Conclusion

Next-generation sequencing revealed specific mutations in EP300 to be associated with the mutational patterns in typical breast cancer genes and long-term outcome of triple-negative breast cancer patients.