Tobacco and the risk of acute leukaemia in adults

Self-reported smoking histories were collected during face-to-face interviews with 807 patients with acute leukaemia and 1593 age- and sex-matched controls. Individuals who had smoked regularly at some time during their lives were more likely to develop acute leukaemia than those who had never smoked (odds ratio (OR) = 1.2, 95% confidence interval (CI) 1.0-1.4). The association was strongest for current smokers, defined here as smoking 2 years before diagnosis (OR = 1.4, 95% CI 1.1-1.7). With respect to the numbers of years smoked, risk estimates were raised in all groups except those who had smoked for fewer than 10 years. Similarly, the odds ratio decreased as the number of years 'stopped smoking' increased, falling to one amongst those who had given up smoking for more than 10 years. No significant linear trends were found, however, with either the numbers of years smoked or the numbers of years stopped smoking, and no significant differences were found between AML and ALL.     

Breast tumour cell-induced down-regulation of type I collagen mRNA in fibroblasts

This study investigated the modulation of type I collagen gene expression in normal fibroblasts by breast tumour cells. Northern analysis of total RNA extracted from stages I, II and III breast tumour tissue revealed that collagen mRNA levels were elevated in stage I tumours compared to the adjacent normal breast tissues, whereas they were decreased in stages II and III breast tumours. This aberrant collagen gene expression was confirmed by non-radioactive RNA:RNA in situ hybridization analysis of 30 breast carcinomas which localized the production of type I collagen mRNA to the stromal fibroblasts within the vicinity of the tumour cells. In order to determine whether the tumour cells were directly responsible for this altered collagen production by the adjacent fibroblasts, breast tumour cell lines were co-cultured with normal fibroblasts for in vitro assessment of collagen and steady-state collagen RNA levels. Co-culture of tumour cells and normal fibroblasts in the same dish resulted in down-regulation of collagen mRNA and protein. Treatment of the fibroblasts with tumour-cell conditioned medium also resulted in decreased collagen protein levels but the mRNA levels, however, remained unaltered. These results suggested that the tumour cells either secrete a labile 'factor', or express a cell surface protein requiring direct contact with the fibroblasts, resulting in down-regulation of collagen gene expression. Modulation of the ECM is a common characteristic of invading tumour cells and usually involves increased production of collagenases by the tumour cells or stromal fibroblasts. This study showed that tumour cells were also able to modulate collagen mRNA production by stromal fibroblasts, which may facilitate tumour cell invasion and metastasis.     

Ethical ramifications of alternative means of recruiting research participants from cancer registries.

BACKGROUND: The protection of confidentiality and the extent to which voluntary and meaningful informed consent can be obtained from potential participants are critical when recruiting patients for clinical research from cancer registries. In the current study the authors describe the influence of two methods of recruitment from a cancer registry (direct contact by research staff and contact by research staff after physicians alert potential participants) on these issues. METHODS: Enrollment rates were tabulated using each recruitment method and complaints received from potential participants regarding recruitment were reviewed. RESULTS: Of 416 women approached to participate, the first 351 women were recruited by way of direct contact by research staff and the remaining 65 women were recruited by research staff after their physician had sent them an alert letter. There was no difference in the enrollment rate using the two methods. One potential participant believed that her confidentiality had been violated and another hung up the telephone when contacted directly; two potential subjects reported feeling pressure to participate because their physician sent them a letter. CONCLUSIONS: Although concerns regarding violating confidentiality clearly are justified when recruiting research participants from cancer registries, patients also may feel pressure to participate if physician notification is part of the process. It is incumbent on investigators and institutional review boards charged with overseeing this research that they respect confidentiality and avoid pressuring persons to participate in research. It also is critical that persons whose medical information will be entered into cancer registries be informed about this process as well as how the registry will be used for research.     

Mapping of novel regions of DNA gain and loss by comparative genomic hybridization in esophageal carcinoma in the Black and Colored populations of South Africa

Esophageal cancer (EC) is the leading cause of cancer death in the Black male population in South Africa. Although several oncogenes and tumor suppressor genes have previously been found altered in this cancer, many novel genes remain to be identified. To identify the chromosomal location of these unknown genes, we have analyzed DNA of 29 South African EC patients by comparative genomic hybridization. Frequent loss occurred at chromosome 1p (52%), 4p (52%), 18q (48%), 19p (52%), 19q (55%), and 22q (41%). The most common gains were detected at 1q (41%), 2q (52%), 3q (72%), 5p (31%), 7p (48%), 7q (45%), 8q (55%), and Xq (69%). High level amplification was detected at 2q24-33, 6p21.1-q14, 7p12-q21, 7q11.2-31, 8q22-24, 8q13-qter, 13q21-34, and at 13q32-34. The present comparative genomic hybridization study opens the way for additional targeted studies on these particular chromosomal regions to identify the specific genes involved in the higher susceptibility to specific subtypes of esophageal carcinoma in different geographical regions. The loss of 8p (28%) and Xp (17%) in tumors of male individuals may provide clues to the basis of the sex-biased frequency of occurrence of EC favoring men.     

Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions

Inheritance of germ-line mutant alleles of BRCA1 and BRCA2 confers a markedly increased risk of breast cancer and we have previously reported a higher incidence of p53 mutations in these tumours than in grade matched sporadic tumours. We have now characterized these p53 mutants. The results of these studies identify a novel class of p53 mutants previously undescribed in human cancer yet with multiple occurrences in BRCA-associated tumours which retain a profile of p53-dependent activities in terms of transactivation, growth suppression and apoptosis induction which is close or equal to wild-type. However, these mutants fail to suppress transformation and exhibit gain of function transforming activity in rat embryo fibroblasts. These mutants therefore fall into a novel category of p53 mutants which dissociate transformation suppression from other wild-type functions. The rarity of these mutants in human cancer and their multiple occurrence in BRCA-associated breast tumours suggests that these novel p53 mutants are selected during malignant progression in the unique genetic background of BRCA1- and BRCA2-associated tumours.     

Diagnostic and therapeutic efficacy of cervical conization.

Cervical conization was perfromed on 756 patients at the University of Kentucky Medical Center from July 1, 1964, to January 1, 1973. Sixty-six patients were pregnant at the time of conization. Eighty-six per cent of patients with cytologic findings of carcinoma in situ had histologic verification of carcinoma in situ or severe dysplasia, and there was absolute correlation between cytology and histology in 75 per cent of patients will occult invasive cancer. Cervical biopsies without colposcopic direction predicted either severe dysplasia or carcinoma in situ in 77 per cent of cases but were accurate in only seven of 24 patients with occult invasive cancer. Carcinoma in situ was present in 30 per cent of hysterectomy specimens following conization but recurred in only seven per cent of patients followed without hysterectomy. Recurrent carcinoma in situ following hysterectomy was more common in patients with residual intraepithelial cancer in the uterus but was independent of the size of the vaginal cuff removed. Major postconization complications requiring hospitalization occurred in 3.4 per cent of nonpregnant patients and in 7.5 per cent of pregnant patients.     

Structural variants of a human 5-HT1a receptor intracellular loop 3 peptide

To better understand cytoplasmic loop 3/G protein coupling, variations in a bioactive synthetic peptide probe (P1) were constructed according to the published sequences of the human 5HT1a receptor. These probes were tested in a model system of human 5HT1a receptor stably expressed in Chinese hamster ovary cells. In agonist inhibition studies, peptides with amino acid substitutions of residues 6-9 from the amino terminus of loop 3 were less active than P1. Truncated peptide P4, conserving the residue 6-9 region, was also less active than P1. Truncates P5 and P6, deleting the residue 6-9 region, were inactive. When cAMP levels were measured, both substituted peptides were more active than P1 in this negatively coupled system. In contrast, the truncated peptides were without activity in the cAMP assays. Thus, P1 and its derivatives (P2-P6) constitute a small group of peptides with differential uncoupling (agonist inhibition) and signal transduction (cAMP) activities in this G-protein-linked system. It is proposed that these peptides will be useful in future studies detailing the molecular determinants at the receptor/G protein interface.     

Effects of noradrenaline depletion in the brain on response to novelty in isolation-reared rats

RATIONALE: Social isolation from weaning in the rat produces a variety of neurochemical and behavioural effects in the adult that in part parallel changes seen in human schizophrenia. OBJECTIVES: The study investigated the effects of central noradrenaline (NA) depletion by the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the behaviour of isolation-reared rats. METHODS: Male Lister hooded rats were reared singly or in groups after weaning. During week 2, the rats were tested in photocell activity cages and were then injected with DSP-4 (25 mg/kg, IP). During week 4, rats were tested in the open field under the following conditions: open field alone, with two novel stimuli (T1), and with a familiar and a novel object (T2), and in the activity cages. RESULTS: DSP-4 significantly reduced cortical and hippocampal NA levels with no effect on the hypothalamus. Isolation-reared rats exhibited locomotor hyperactivity and reduced habituation to the testing arena, although their exploration of the novel objects in T1 was not significantly different from group-reared rats. DSP-4 treatment in group-reared rats increased inner zone activity in the open field but did not significantly affect the exploration of novel objects. DSP-4 treatment in isolates reduced exploration of objects at T2 while increasing exploration of the general environment. CONCLUSIONS: Isolation rearing influences the behavioural effects of central NA depletion. The results suggest isolation-induced changes in the central noradrenergic system in the isolated rat, supporting the view that early environmental factors can have long-term effects on central noradrenergic function as well as other neurotransmitter systems.