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C Hobbs

Publications and source records attributed to C Hobbs.

18 recordsLinked to original sources
PubMed1995

Functional characterization of novel IL-2 transcriptional inhibitors.

IL-2-mediated T cell proliferation is a critical early event in the inflammatory process. Formation of the NFAT-1 transcriptional complex on the IL-2 promoter is essential for IL-2 transcription. Using a cell line that is stably transfected with a trimer of the NFAT-1 regulatory element linked to a lac-Z reporter gene, we screened for inhibitors of NFAT-1-mediated beta-galactosidase activity. WIN 61058 and WIN 53071 were identified as microM inhibitors. These compounds also inhibited beta-galactosidase mRNA levels. Similar inhibition of NFAT-1-mediated gene expression was observed in a second cell line, which is stably transfected with NFAT-1 regulatory elements linked to the reporter gene for sCD8. At 10 microM, both compounds inhibited IL-2 mRNA and protein levels in the NFAT-1-linked lac-Z transfectants, and in human lymphocytes. Both compounds inhibited the mixed lymphocyte reaction, and this inhibition was reversed by exogenous IL-2. WIN 53071 inhibited IL-2 production induced in the calcium-dependent PMA and ionomycin pathway. Conversely, calcium-independent anti-CD28 Ab and PMA-induced IL-2 production was resistant. Both compounds altered the NFAT-1 transcriptional complex, causing its retarded mobility on gels. By these functional criteria, we believe we have identified two structurally distinct, novel inhibitors of NFAT-1-mediated transcription.

Base Sequence↗
PubMed1995

Selective binding of peripheral blood lymphocytes to the walls of cerebral vessels in frozen sections of human brain.

In order to identify the factors that control the binding of blood leucocytes to cerebral blood vessels we have modified and applied the frozen section assay of Stamper and Woodruff to the study of human brain. Cryostat sections of brain tissue obtained at post mortem were overlaid with blood lymphocytes and experimental conditions were defined which permitted optimum binding of the cells to transected blood vessel walls. The maximal binding of lymphocytes to cerebral vessels occurred when 6 x 10(6) lymphocytes were overlaid onto brain sections for 30 min at 7 degrees C with gentle agitation. Only a small proportion (0.01%) of the added lymphocytes bound to exposed cerebral vessels. However, lymphocytes were far more adherent than monocytes and polymorphonuclear cells (7-fold and 11-fold respectively: p < 0.001) and activation of lymphocytes with IL-2 enhanced their binding to blood vessel walls (mean 130% increase; p < 0.03). Further analysis revealed that CD4-positive T lymphocytes were the predominant cell population binding to the blood vessels. Antibody blocking studies showed that lymphocyte binding to cerebral blood vessels was inhibited by pretreating the lymphocytes with anti-CD11a, anti-CD18 or anti-CD49d (p < or = 0.02) and immunohistochemical studies revealed the presence of the counter-receptors ICAM-1 (CD54) and VCAM-1 (CD106) for these adhesion molecules in addition to the presence of E-selectin (CD62E) and P-selectin (CD62P) on the cerebral blood vessels. The establishment of a technique in situ which measures selective binding of CD4-positive peripheral lymphocytes to sections of cerebral blood vessels will assist in the molecular characterization of factors that control the interaction of leucocytes with the blood-brain barrier in health and disease.

Adult↗
PubMed1995

Penetration and damage of endothelial cells by Candida albicans.

The mechanisms of phagocytosis of Candida albicans by human vascular endothelial cells and subsequent endothelial cell injury were examined in vitro. Both live and killed C. albicans cells were phagocytized by endothelial cells. This organism specifically induced endothelial cell phagocytosis because neither Candida tropicalis nor Torulopsis glabrata was ingested. Endothelial cell microfilaments polymerized around C. albicans as the organisms were phagocytized. Cytochalasin D inhibited this polymerization of microfilaments around C. albicans and blocked phagocytosis. The blocking of actin depolymerization with phalloidin had no effect on microfilament condensation around the organism, indicating that the microfilaments surrounding C. albicans are formed from a pool of G-actin. Intact microtubules were also necessary for the phagocytosis of C. albicans, since the depolymerizing of endothelial cell microtubules with nocodazole prevented the condensation of actin filaments around the organisms and inhibited phagocytosis. In contrast, microtubule depolymerization was not required for microfilament function because the blocking of microtubule depolymerization with taxol had no effect on microfilament condensation around C. albicans. The phagocytosis of C. albicans was pivotal in the induction of endothelial cell damage, since the blocking of candidal internalization significantly reduced endothelial cell injury. Endothelial cells were not damaged by phagocytosis of dead organisms, indicating that injury was caused by a factor associated with viable organisms. Therefore, C. albicans is uniquely able to induce endothelial cell phagocytosis by comparison with non-albicans species of Candida. Furthermore, at least two components of the endothelial cytoskeleton, microfilaments and microtubules, are necessary for the phagocytosis of C. albicans.

Actin Cytoskeleton↗
PubMed1995

Expert witness.

Explore the source record for details and available documents.

Child↗
PubMed1994

Altered p53 expression and epidermal cell proliferation is seen in vulval lichen sclerosus.

Aberrant p53 immunoreactivity has been found in skin pre-malignancies and dysplasias such as Bowen's disease and actinic keratoses. Vulval lichen sclerosus (LS) has been reported to be pre-malignant, with an association of vulval carcinoma in 3% to 6% of patients. In contrast, non-genital LS appears to have no malignant potential. In this immunocytochemical study, we investigated p53 expression in 10 cases of histologically proven vulval LS and 9 cases of non-genital LS using the murine monoclonal antibody Do-1 raised against recombinant human p53 which reacts with both wild-type and mutant p53. None of the vulval specimens had epithelial dysplasia or malignancy. Normal vulval (7 cases) and non-genital skin (5 cases) were used as tissue controls, respectively. The cell proliferation index was also studied using the MIB 1 monoclonal antibody which detects the cell-cycle associated Ki-67 antigen. The technique of microwave irradiation for antigen unmasking was employed on formalin-fixed and paraffin-embedded tissues. There was a significant increase in p53 immunoreactivity in vulval LS (32.13 +/- 15.11 epidermal cells per 100 basal cells) compared to normal vulval skin (7.52 +/- 5.04 epidermal cells per 100 basal cells) (p < 0.001), whereas the MIB 1 labelling index was lower in vulval LS (39.45 +/- 15.88 epidermal cells per 100 basal cells) than in normal controls (86.26 +/- 32.31 epidermal cells per 100 basal cells) (0.001 < p < 0.01). In contrast, there was no significant difference in p53 immunoreactivity or MIB 1 labelling index between non-genital LS and normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The relevance of antibody concentration to the immunohistological quantification of cell proliferation-associated antigens.

A number of different factors can profoundly influence the quantification of immunostained cells. Given the characteristics of immunohistological detection systems with non-linearity of signal and antigen concentration, we investigated the relationship of signal (number of stained cells) to the dilution of antibody employed. Three antibodies were studied which have been advocated as being effective in fixed material as markers of cell proliferation: PC10 (anti-proliferating cell nuclear antigen (PCNA)), Ki-S1 and MIB1 (a novel anti-Ki-67). Serial sections of tonsil were immunostained with a range of antibody dilutions using a fixed detection system and the number of stained cells quantified. Similar experiments were performed on tumour xenografts with known growth fraction and, in vitro, on human diploid fibroblasts in logarithmic growth phase. With both PC10 and Ki-S1 the number of stained cells increased with decreasing antibody dilution with no plateau being identified. In contrast, MIB1 showed a clear plateau. Immunocytological data indicate that PCNA and Ki-S1 antigen are present at low (but detectable) levels in at least some non-cycling cells and thus an artificial 'cut-off' has to be employed in assessing the number of proliferating cells with these antibodies. The superiority of MIB1 probably reflects the rapidity of catabolism of the Ki-67 antigen at the end of M phase. Taken together, these data point to the importance of carefully considering fundamental immunochemical properties such as antibody concentration (as well as antibody affinity and sensitivity of detection system) when employing immunological markers of cell proliferation in quantitative procedures.

Animals↗
PubMed1993

p53 immunoreactivity in cutaneous PUVA tumors is similar to that in other non-melanoma skin neoplasms.

Expression of the p53 tumor suppressor gene product was determined in keratoses and skin cancers associated with psoralen photochemotherapy (PUVA). An immunocytochemical study was employed using CM-1 (polyclonal) and Do-1 (monoclonal) antibodies to human wild-type p53. Thirty-two cutaneous lesions and 20 perilesional PUVA-irradiated skin biopsies were examined from 7 patients, all of whom had received more than 200 PUVA treatments and/or a cumulative UVA dose of greater than 1000J/cm2 as treatment for widespread plaque psoriasis. p53 immunoreactivity was seen in 7 of 15 squamous cell carcinomas (46.7%), 5 of 8 dysplastic keratoses (62.5%) and in no basal cell carcinomas or benign keratoses. The overall prevalence of p53 immunoreactivity in 46.2% of malignant or dysplastic PUVA-associated skin tumors is similar to that previously found by our group in comparable skin tumors from the general population. Most patients with lesions showing positive p53 immunoreactivity had, however, been exposed to additional risk factors before receiving PUVA therapy. p53 gene sequencing of PUVA-associated non-melanoma skin cancer (NMSC) may clarify whether p53 mutation contributes to the development of these tumors and whether this relates to PUVA therapy or prior carcinogen exposure.

Adult↗
PubMed1992

Expression of mutant p53 gene in squamous carcinoma arising in patients with recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa, a rare genodermatosis, is characterized by increased skin fragility manifest as blistering and sometimes accompanied by scarring. The latter is particularly severe in the recessive dystrophic variant and may be complicated by the development of squamous carcinoma in up to 30% of patients. We have studied 23 such tumours in six patients with this variant, with an anti-serum to p53 protein. Twenty-six per cent of the squamous carcinomas labelled positively for mutant-type p53 protein. This low figure, however, reflects the large number of well-differentiated tumours in this series, where 14 out of 15 were negative. In the moderate to poorly differentiated examples the positivity rate was 63%. Of the three patients in the latter category, one has died from disseminated tumour and another has widespread metastases. The findings support the hypothesis that mutant p53 protein expression correlates with poorer tumour differentiation. They also suggest a possible correlation between p53 protein expression and tumour behaviour.

Carcinoma, Squamous Cell↗
PubMed1989

Menarcheal age in Ghanaian school girls.

In a cross-sectional retrospective study of 2087 Ghanaian school girls in various educational institutions in the Kumasi district, Ashanti region, Ghana, the mean menarcheal age was found to be 13.98 +/- 1.42 years. Differences in the menarcheal age of the girls was found to be significantly correlated to social class, parents ethnic origin, educational institution and home living area (P = 0.0001). The duration of the menarche and the interval between the menarche and the second period was found to be influenced by the age at menarche (P less than 0.01). Decline in menarcheal age in concurrence with world trends was observed. Further studies are necessary to identify the inherent and specific factors in the Ghanaian population which relate to and influence the age of menarche.

Adolescent↗
PubMed1989

The relation of the true conjugate to maternal height and obstetric performance in Ghanaians.

The true conjugate was determined intraoperatively with a caliper in 114 Ghanaian women and was correlated with their height, obstetric performance and fetal dimensions. Those patients undergoing cesarean section for cephalopelvic disproportion (Group Ia) were found to have a significantly shorter mean true conjugate (9.54 cm +/- 0.63 S.D.) and mean body height (152.68 cm +/- 5.46 S.D.) and a smaller true conjugate - fetal biparietal diameter difference (10.93 mm) than those who had no cephalopelvic disproportion (Group Ib) and whose mean measurements were 10.61 cm +/- 0.81 S.D., 157.20 cm +/- 5.69 S.D. and 21.50 mm, respectively (P = 0.0001). Recommendations for appropriate referral of rural clinic patients and for selection of patients for repeat cesarean sections are based on the above findings.

Birth Weight↗
PubMed1989

Cancer downwind from sour gas refineries: the perception and the reality of an epidemic.

A rural population in southwestern Alberta, Canada, living downwind from natural gas refineries, has expressed concerns about an excess of adverse health outcomes over the last 25 years. This has escalated to the point of causing a prominent sociopolitical controversy within the province. As part of a large field epidemiologic study undertaken during the summer of 1985 to investigate possible health effects, a residential cohort study was carried out to study cancer incidence. The cohort was defined as all those individuals who resided in the area in 1970. A total of 30,175 person-years of risk within Alberta were experienced by this cohort from 1970 to 1984. The incident cancers during this period were enumerated by computerized record linkage with the Alberta Cancer Registry. Age- and sex-standardized incidence ratios, based on expected rates from three prespecified demographically similar, nonmetropolitan Southern Alberta populations, were 1.05, 1.09, and 1.03, respectively, none of which was significantly different from unity. Although they do not address the issue of etiologic association, these data can provide considerable reassurance to a community that was convinced it had experienced an epidemic of cancer.

Acid Rain↗
PubMed1984

A structural basis for variegating position effects.

Variegating position effects in Drosophila result from chromosome rearrangements where normal genes, having been placed next to heterochromatin, are inactivated in some cells but not in others, thereby producing a variegated tissue. We have determined that the euchromatic breakpoints for three variegating white mutants are clustered and lie approximately 25 kb downstream of the white structural gene. In each case the white locus is adjoined in the heterochromatin to a mobile genetic element. Satellite sequences are not involved. We also demonstrate that revertants of the variegating mutant, wm4, are reinversions that leave the initial wm4-heterochromatic junction intact so that some heterochromatin-derived sequences remain joined to white at its new location. These results suggest a simple model for understanding the structure of heterochromatic domains and how variegating position effects may arise.

Animals↗
PubMedDate not supplied

A study of mortality near sour gas refineries in southwest Alberta: an epidemic unrevealed.

Concerns about excesses in a wide array of adverse health outcomes have been expressed for over 25 years by a rural population in southwestern Alberta, living downwind from natural gas refineries. Among these has been the perception that deaths have occurred more frequently than ought to have been expected. As part of a large field epidemiologic study undertaken during the summer of 1985 to investigate possible health effects in this area, a residential cohort study was carried out to study mortality. The cohort was defined as all those individuals who resided in the area in 1970. A total of 30,175 person-years of risk within Alberta were experienced by this cohort during 1970-84. The deaths during this period were enumerated by resident reports and by manual record linkage with the death records of the Alberta Bureau of Vital Statistics. Age- and sex-standardized mortality ratios, based on expected rates from 2 pre-specified demographically similar, non-metropolitan Southern Alberta populations, were 0.88 and 0.84 respectively, neither of which was significantly different from unity. These data cannot address the question of etiology but they can do much to allay the anxieties of a community convinced it had experienced an epidemic of death.

Adult↗