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Biomedical subjects

R Beauchamp

Publications and source records attributed to R Beauchamp.

At least 19 recordsLinked to original sources
PubMed2006

AFM colloidal forces measured between microscopic probes and flat substrates in nanoparticle suspensions.

Colloidal forces between atomic force microscopy probes of 0.12 and 0.58 N/m spring constant and flat substrates in nanoparticle suspensions were measured. Silicon nitride tips and glass spheres with a diameter of 5 and 15 mum were used as the probes whereas mica and silicon wafer were used as substrates. Aqueous suspensions were made of 5-80 nm alumina and 10 nm silica particles. Oscillatory force profiles were obtained using atomic force microscope. This finding indicates that the nanoparticles remain to be stratified in the intervening liquid films between the probe and substrate during the force measurements. Such structural effects were manifested for systems featuring attractive and weak repulsive interactions of nanoparticles with the probe and substrate. Oscillation of the structural forces shows a periodicity close to the size of nanoparticles in the suspension. When the nanoparticles are oppositely charged to the probes, they tend to coat the probes and hinder probe-substrate contact.

Journal Article↗
PubMed2001

TGF-beta and colorectal carcinogenesis.

There is substantial evidence to support the contention that the Smad portion of the TGF-beta signal transduction pathway provides an important tumor-suppressor function. Mutational loss of function of Smad pathway members have been associated with the development of human cancers and appear to be causative in selected rodent carcinogenesis models. TGF-beta also has multiple other actions that appear to be independent of the growth-inhibitory/tumor suppressor effects. The predominant effect of TGF-beta appears to be dependent on the context of the responding cell. Once transformation has occurred, TGF-beta effects may be detrimental and may actually promote tumor cell survival, invasion, and metastasis. Recent work suggests that these effects may involve TGF-beta regulation of COX-2 and other pathways that may contribute to tumor cell aggressiveness. In gaining a better understanding of the mechanisms by which TGF-beta may promote tumor progression, it is likely that new therapeutic strategies may be developed that preserve tumor-suppressor function of TGF-beta while inhibiting the tumor-promoting effects.

Adenoma↗
PubMed2001

Determination of 2-butoxyethanol emissions from selected consumer products and its application in assessment of inhalation exposure associated with cleaning tasks.

Consumer products are important sources of human exposure to certain chemicals. Recent regulatory requirements for assessing human exposure to three glycol ethers, namely 2-methoxyethanol (ME), 2-ethoxyethanol (EE) and 2-butoxyethanol (BE), have prompted the investigation of these chemicals in consumer products and their emission characteristics. Thirteen products were selected for investigation based on their potential of containing the chemicals. Headspace results indicated that ME and EE were not present in any of the 13 selected products, while BE was detected in the headspace samples of seven products, of which five were household cleaning agents. Other related compounds such as 2-hexyloxyethanol (HE) and 2-(2-butoxyethoxy)ethanol (BEE) were also detected in the headspace samples of some products. BE emissions from five cleaning related products were measured using a field and laboratory emission cell (FLEC) with its subunit to provide emission data for inhalation exposure assessment purposes. These products had initial emission factors ranging from 145 to 938 mg m(-2) h(-1) under the experimental conditions. It was found that the emission factor of BE was inversely proportional to the dilution factor of the products. A good relationship was established between the emission factor of BE and its concentrations in water-based products. Based on product use scenarios developed by US EPA and an assumed "standard room," average daily inhalation exposure levels of a resident as a result of performing cleaning tasks were estimated to be 0.075 and 0.186 mg (kg b.w.)(-1) day(-1) for two all-purpose spray cleaners, and 0.004 and 0.006 mg (kg b.w.)(-1) day(-1) for two-spray glass cleaners, respectively.

Air Pollution, Indoor↗
PubMed1998

Analysis of molecular domains of epitope-tagged merlin isoforms in Cos-7 cells and primary rat Schwann cells.

The Neurofibromatosis 2 gene product, merlin, has striking similarity to ezrin, radixin, and moesin (ERM), members of the protein 4.1 family which have been demonstrated to connect proteins in the plasma membrane to the cytoskeletal components. The recent localization of merlin to the motile regions in cultured cells such as membrane ruffles further supports the notion that merlin represents a new class of tumor suppressors. Here we describe the localization of full-length and truncated polypeptides of merlin expressed as Flag-tagged proteins in transfected cells. Similar to endogenous merlin, the epitope-tagged full-length merlin localizes to the membrane ruffles in transfected Cos-7 cells and rat Schwann cells. In addition, the over-expressed merlin localizes to other actin-rich cortical structures, such as microvilli and filopodia. The amino-terminal half of merlin is seen dispersed throughout the cells and in membrane ruffles. Compared to the amino-terminal half of merlin, its carboxy-terminal half localizes more distinctly to membrane ruffles. The full-length and the carboxy-terminal portion of merlin co-localize with F-actin at the membrane ruffles. However, distinct from the ERM proteins, the carboxy-terminal-truncated merlin and F-actin do not co-localize with each other at the stress fibers. Our results suggest that both the amino- and the carboxy-terminal domains of merlin contribute to its membrane ruffle localization.

Animals↗
PubMed1997

A randomized clinical trial to compare selective posterior rhizotomy plus physiotherapy with physiotherapy alone in children with spastic diplegic cerebral palsy.

A randomized controlled single-blind trial was performed to compare lumbo-sacral selective posterior rhizotomy (SPR) followed by intensive physiotherapy, with intensive physiotherapy alone in improving motor function in children with spastic diplegic cerebral palsy. Fifteen patients were randomly assigned to each treatment modality. Patients in the SPR group had rhizotomy within 1 month, followed by intensive outpatient physiotherapy for 9 months. Patients assigned to physiotherapy alone had identical intensive physiotherapy. There was a statistically significant and clinically important difference in improvement in motor function in favor of the SPR group, with a mean increase in total Gross Motor Function Measure (GMFM) score of 11.3% at 9 months for the SPR group compared with 5.2% for the physiotherapy-only group (P = 0.007). Significant improvements in spasticity (P < 0.001) and range of movement (P < 0.001) were noted in the SPR group compared to the physiotherapy-only group. The results indicate that the improvement in motor function after SPR is more than can be explained by the associated intensive physiotherapy.

Cerebral Palsy↗
PubMed1997

Expression of NF2-encoded merlin and related ERM family proteins in the human central nervous system.

Germline mutations of the neurofibromatosis 2 (NF2) gene are associated with an increased incidence of gliomas and glial harmartomas, suggesting a role for the NF2-encoded protein, merlin, in glial growth control. Using monoclonal and polyclonal anti-merlin antibodies for Western blotting and immunohistochemistry, we evaluated the cellular pattern of merlin expression in the normal human central nervous system (CNS), reactive gliosis; and NF2-associated glial hamartomas. In the normal CNS, merlin is widely expressed in coarse cytoplasmic granules in both glia and neurons, with less pronounced expression in other cells. Merlin is also expressed in reactive astrocytes and in the astrocytes of NF2-associated glial hamartomas. In reactive astrocytes, however, merlin is also present at the cell membrane and in cellular processes, suggesting redistribution of the protein in activated cells. Merlin is structurally related to ezrin, radixin and moesin, which are also expressed in the CNS, as demonstrated by Western blotting. The pattern of merlin expression, however, is distinct from that of ezrin, which has been previously described, and that of moesin, in which immunohistochemistry with an anti-moesin antibody showed expression in endothelial cells, glia and neurons in a membranous or diffuse cytoplasmic pattern. These findings imply that merlin has widespread and specific functions in the human central nervous system.

Adult↗
PubMed1997

Universal absence of merlin, but not other ERM family members, in schwannomas.

NF2 (neurofibromatosis 2, encoding the merlin protein) gene mutations and chromosome 22q loss have been demonstrated in the majority of sporadic and NF2-associated schwannomas, but many schwannomas fail to demonstrate genetic evidence of biallelic NF2 gene inactivation. In addition, the role of the merlin-related ERM family members (ezrin, radixin, and moesin) remains unclear in these tumors. We therefore studied expression of NF2-encoded merlin as well as ezrin, radixin, and moesin in 22 vestibular and peripheral schwannomas that had been evaluated for NF2 mutations and chromosome 22q loss. Western blotting and immunohistochemistry with antibodies directed against the amino and carboxy termini of merlin demonstrated loss of merlin expression in all studied schwannomas, including 12 tumors lacking genetic evidence of biallelic NF2 gene inactivation. Western blotting with antibodies directed against ezrin, radixin, and moesin, however, showed expression of these proteins in all schwannomas. In addition, immunohistochemistry with an antibody to moesin revealed widespread expression in tumor and endothelial cells. These data indicate that the specific loss of merlin is universal to schwannomas and is not linked to loss of ezrin, radixin, or moesin expression.

Blood Proteins↗
PubMed1996

The merlin tumor suppressor localizes preferentially in membrane ruffles.

Merlin is a tumor suppressor whose inactivation underlies the familial schwannomas and meningiomas of neurofibromatosis 2 and their sporadic counterparts. It bears striking similarity to the ERM proteins, ezrin, radixin and moesin, members of the protein 4.1 superfamily that link proteins in the cytoskeleton and the plasma membrane. We have generated polyclonal and monoclonal antibodies that detect merlin as an approximately 66 kD protein in many different cell types. Using indirect immunofluorescence we have for the first time visualized endogenous merlin and localized it to the motile regions, such as leading or ruffling edges, in human fibroblast and meningioma cells. Merlin co-localizes with F-actin in these motile regions but is not associated with stress fibers. Merlin does not localize to the same structures as either ezrin or moesin in human meningioma cells, suggesting a function distinct from these ERMs. Thus, merlin is associated with motile regions of the cell and its participation in these structures may be intimately involved in control of proliferation in Schwann cells and meningeal cells.

Actins↗
PubMed1996

Ki-ras and p53 mutations in pancreatic ductal adenocarcinoma.

Pancreatic adenocarcinoma involves activation of the Ki-ras oncogene, inactivation of the p53 tumor suppressor gene, and dysregulation of growth factors and perhaps metastasis genes. Ki-ras oncogene point mutations are known to be involved in pancreatic oncogenesis. The p53 tumor suppressor gene product plays a critical role in cell cycle regulation and also functions as a nuclear transcription factor. Point mutations in the p53 gene have been observed in a variety of malignancies. We determined the frequency of p53 protein overexpression and p53 point mutations in the conserved and nonconserved domains in pancreatic cancers as well as the coincidence of Ki-ras mutation in pancreatic ductal adenocarcinoma. Genomic DNA was isolated from 20 frozen pancreatic adenocarcinomas (14 primary, six metastases) along with six specimens of control pancreatic tissue and screened by single-strand conformation polymorphism (SSCP) analysis followed by direct genomic sequencing of SSCP variants. SSCP analysis was accomplished by incorporating 32P-dCTP in 12 separate polymerase chain (PCR) amplifications covering the p53 coding exons 2-11. All mobility shifts on SSCP were subjected to direct genomic sequencing by the modified dideoxy method. Immunoperoxidase (IP) staining was also done with a p53 monoclonal antibody. Ki-ras codon 12 mutational analysis was accomplished by incorporating 32P-dCTP by polymerase chain reaction amplification utilizing mismatched primers, which create a BstN1 restriction endonuclease site spanning codon 12; the products were digested by BstN1. Polyacrylamide gel electrophoresis allowed distinction between wild-type and mutant Ki-ras. p53 mutations were found in 5 of 20 pancreatic cancers (three of 14 primary tumors, two of six metastatic tumors). Point mutations were observed in three of 14 primary tumors, and one of six metastases, while a 2-base pair duplication resulting in a premature stop codon in exon 5 was found in one metastatic tumor. Point mutations were noted in conserved domains (exons 4, 5, 8) and in the nonconserved domain (exon 10). IP staining revealed that eight of 14 of the primary tumors and two of six metastases exhibited moderate to strong nuclear staining (> 30%), while no nuclear staining was evident in the controls. Ki-ras codon 12 mutations were found in 14 of 20 (70%) pancreatic cancers (nine of 14 primary tumors, five of six metastatic tumors) and none of the six controls. Fifty percent of the primary pancreatic tumors demonstrated moderate to strong nuclear staining. Extensive genetic analysis demonstrated mutations in 30% of the pancreatic cancers. One cancer had a nonsense mutation not detected by IP. Seven of 19 (37%) pancreatic cancers exhibited both Ki-ras point mutation and p53 protein overexpression or mutation. Both genetic analysis and IP are required to characterize all p53 mutations in pancreatic cancer. Ki-ras codon 12 mutations and p53 protein overexpression are important steps in pancreatic oncogenesis.

Adenocarcinoma↗
PubMed1996

Ovarian, peritoneal, and endometrial serous carcinoma: clonal origin of multifocal disease.

The clonality of disseminated serous carcinoma involving the ovary, peritoneum, and, occasionally, the endometrium is controversial. Histopathologic examination alone cannot unequivocally distinguish between a monoclonal origin and a multicentric origin. Two patients with peritoneal serous carcinoma with minimal ovarian involvement (one with endometrial serous carcinoma), nine patients with stage III bilateral ovarian carcinoma, and one patient with stage III bilateral carcinosarcoma were studied for clonality. One patient with ovarian carcinoma that recurred after chemotherapy was also studied. Previous analyses of single frozen tumor specimens from these patients had identified different p53 gene mutations in each patient. To test the hypothesis that the disseminated cancers had a monoclonal origin, we assayed DNA from numerous foci from each patient to determine whether the known p53 mutation was present in each specimen. Identical mutations were detected in the tumor foci from each patient with peritoneal dissemination and minimal ovarian involvement, including one patient with an endometrial serous carcinoma as well. In all the patients with bilateral ovarian cancer, the genetic change in p53 was identical in both ovarian tumors. Genetic progression was observed in two patients, one of whom showed a loss of heterozygosity involving the p53 gene in a recurrent tumor. In the second patient, a p53 mutation not present in either ovarian tumor was detected in a metastatic tumor from the omentum. These results strongly suggest that disseminated serous carcinomas, whether primary in the ovary, endometrium, or peritoneum, are of monoclonal rather than multicentric origin; that bilateral stage III ovarian cancers are typically of monoclonal origin; and that additional genetic events involving p53 might occur during progression of these tumors.

Aged↗
PubMed1995

Neurofibromatosis 2 gene in human colorectal cancer.

Colon cancers commonly have allelic losses of chromosome 22q, which suggests the presence of a tumor suppressor gene on 22q. The candidate tumor suppressor gene on 22q is the neurofibromatosis 2 (NF2) gene. Using single strand conformation polymorphism (SSCP) analysis, we screened 24 pairs of colorectal cancer and adjacent normal mucosa, as well as 10 colon cancer cell lines from non-NF2 patients, for mutations in the coding sequence of the NF2 gene. Two SSCP variants, one in exon 14 and another one in exon 16, were detected in two of the sporadic colorectal cancers, but not in adjacent normal mucosa samples. Sequencing of these variants in one tumor detected an A-to-G transition in bp 1459 of the NF2 cDNA, resulting in the change of Ile to Val at codon 487 of merlin, the NF2 protein product. The other tumor showed a 2-bp (CT) deletion in the intronic sequence of the alternatively spliced exon 16. These results suggest that the NF2 gene is probably involved in some colorectal tumors, but is not the critical chromosome 22q tumor suppressor gene involved in colon tumorigenesis.

Base Sequence↗
PubMed1995

p53 gene analysis of ovarian borderline tumors and stage I carcinomas.

Mutations of the p53 gene are common in human ovarian carcinomas; however, their role in the early development of ovarian cancer is unclear. Twelve ovarian borderline tumors (BTs; eight of them p53 immunopositive) and 10 stage I carcinomas (four of them p53 immunopositive) were studied for genetic alterations in the p53 gene. The study was based on single-strand conformation polymorphism (SSCP) analysis and DNA sequencing of exons 2 through 11 of the p53 gene using DNA preparations from microdissected tumors. Mutations were found in 40% of the carcinomas (including a borderline component adjacent to carcinoma in one lesion) but in none of the pure BTs. These findings suggest that p53 mutations may not be commonly associated with the borderline phenotype of ovarian epithelial tumors but may occur during malignant transformation.

Adult↗
PubMed1993

p53 gene mutations and protein accumulation in human ovarian cancer.

Mutations of the p53 gene on chromosome 17p are a common genetic change in the malignant progression of many cancers. We have analyzed 38 malignant tumors of ovarian or peritoneal müllerian type for evidence of p53 variations at either the DNA or protein levels. Genetic studies were based on single-strand conformation polymorphism analysis and DNA sequencing of exons 2 through 11 of the p53 gene; mutations were detected in 79% of the tumors. These data show a statistically significant association between mutations at C.G pairs and a history of estrogen therapy. Two of 20 patients whose normal tissue could be studied carried germ-line mutations of p53. Immunohistochemical analysis of the p53 protein was carried out using monoclonal antibody PAb1801. Ninety-six percent of the missense mutations were associated with abnormal accumulation of p53 protein, but nonsense mutations, a splicing mutation, and most deletions did not result in p53 protein accumulation. A statistically significant association between p53 protein accumulation in poorly differentiated stage III serous carcinomas and small primary tumor size at diagnosis was found, perhaps suggesting that p53 protein accumulation accelerates the metastatic spread from a primary tumor. Overall, our findings indicate that alterations of p53 play a major role in ovarian cancer, including predisposition to the disease in some patients, and suggest a possible mechanism for somatic mutations leading to this cancer.

Amino Acid Sequence↗
PubMed1990

Correlation between integrated evoked EMG and respiratory function following atracurium administration in unanaesthetized humans.

In six healthy volunteers, integrated evoked electromyography (IEEMG) measured in response to ulnar nerve stimulation was correlated with respiratory function-tidal volume (VT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), maximum negative inspiratory pressure (NIP), hand grip (HG) and head-lift during steady-state infusion of subparalytic doses of atracurium. Studies were carried out at train-of-four T4/T1 = 0.2 and T4/T1 = 0.6. When T4/T1 = 0.2, all subjects had difficulty with swallowing and phonation, none could sustain any head-lift and HG was 26 per cent of control. However, VT was normal, FVC was 80 per cent, FEV1 was 82 per cent, and NIP was 50 per cent of control. AT T4/T1 = 0.6, all assessments of peripheral strength were normal, and all respiratory measurements were not significantly different from control, except for NIP which was 73 per cent of control (P less than 0.05). We conclude that an IEEMG of 0.6, recorded from the hypothenar muscles, in unanaesthetized subjects is consistent with near normal respiratory function.

Adult↗
PubMed1985

Ultraviolet photosensitivity in goldfish: an independent u.v. retinal mechanism.

Heart rate conditioned goldfish were sensitive to u.v. stimuli at wavelengths down to 340 nm. A u.v. peak had maximum sensitivity at about 380 nm and was depressed selectively by a u.v. adapting background. An opaque cone restricted light to the eye, reducing the probability of a dermal or pineal gland source of the response. Three experiments demonstrated a retinal origin for the u.v. peak. The conditioned response to u.v. stimuli was abolished following injection of Lidocaine into the eye. U.V. sensitivity remained when the cornea, iris and lens were extirpated. Finally, the u.v. peak showed an orderly change in sensitivity with alteration in adapting u.v. illumination.

Animals↗
PubMed1985

Ultrasound measures of vitreous chamber depth during ocular accommodation.

The vitreous chamber decreased in depth about 0.12 mm as accommodative demand increased from 0.2 to 7 D in nine accommodative steps. The depth decreases matched movement of the posterior lens surface toward the retina. Accommodation caused no significant increases in axial length compared to cyclopleged controls. These results do not favor the active role for the vitreous in accommodation proposed by Coleman in 1970. Computer analysis of A-scan interval counts demonstrated that multiple retinal complex peaks might erroneously point to vitreous or axial lengthening. About 30% of total lens thickening during accommodation was accounted for by posterior lens surface displacement.

Accommodation, Ocular↗