Biomedical subjects

James B Elder

Publications and source records attributed to James B Elder.

10 recordsLinked to original sources

PubMed2007

Primary colorectal tumors fail to express the proapoptotic mediator PTAG and its reexpression augments drug-induced apoptosis.

Genes implicated in tumor evolution and progression, including those in apoptotic pathways, are associated with methylation-associated gene silencing in different tumor types. By exploiting differential methylation we recently isolated a novel pituitary tumor derived apoptosis gene (PTAG) that augments drug-induced apoptosis. The importance of PTAG was determined in other tumor types, and these studies show that the majority of primary colorectal tumors fail to express the PTAG gene, indicating an important role for PTAG in colorectal tumorigenesis. The effects of expression of PTAG were examined through stable transfection of the colorectal cell lines HCT116 and SW480. Expression of PTAG, per se, had no discernible effects on cell viability or cell kinetics. In contrast to these findings, in cells subject to drug challenges that engaged either a death-receptor mediated or mitochondrial pathway, all of the experiments indicated a role for PTAG in the intrinsic pathway of apoptosis. Loss of PTAG therefore contributes to a blunted apoptotic response and is likely to predispose cells toward malignant transformation and resistance to chemotherapeutic interventions.

Adult↗

PubMed2006

Surgical interventions for primary central nervous system lymphoma.

Early diagnosis is central to proper management of primary central nervous system lymphomas (PCNSLs). Surgical intervention hinges on initial entertainment of a diagnosis of a PCNSL, based on acute neurological presentation and neuroimaging findings. Unless there is an urgent need for surgical decompression, a biopsy to obtain a diagnosis of PCNSL is the first step in surgical management. Repeated biopsy may be necessary in patients who have received preoperative steroid therapy. Patients with PCNSL may also present with leptomeningeal involvement, resulting in the need for an Ommaya reservoir for intrathecal chemotherapy. In cases in which hydrocephalus develops, placement of a ventriculoperitoneal shunt may be necessary. Two case studies are presented to highlight the role of surgical intervention in PCNSL.

Brain Neoplasms↗

PubMed2006

Polymorphisms in the glutathione S-transferase mu cluster are associated with tumour progression and patient outcome in colorectal cancer.

Glutathione S-transferase (GST) enzymes catalyse the detoxification of by-products of reactive oxygen species and are thus important in cellular defence mechanisms. The GSTs are polymorphic with allelic variants encoding isoforms with functional differences. GST polymorphism has been associated with susceptibility and clinical outcome in patients with cancer. In this retrospective cohort, we have investigated associations between common GSTM1, GSTM3 and GSTP1 polymorphisms with factors known to influence clinical out-come and patient survival in colorectal cancer. Significant linkage disequilibrium was demonstrated between GSTM1 and GSTM3 alleles (P< or =0.001). We identified no significant associations between the GSTP1(Ile105Val105) polymorphism and any clinical outcome parameters or patient survival. However significant associations were demonstrated with mu class GSTs. Those patients who were GSTM1 null presented less frequently with poorly-differentiated tumours (P=0.038). Furthermore, patients who were GSTM3 AA were less likely to present with advanced stage tumours (T-stage, P=0.036 and Dukes' classifications, P=0.012) or distant metastases (P=0.017) when examined alone. Upon further examination of the effect of linkage disequilibrium, we found that, in GSTM1 null individuals, GSTM3 AA (compared with other GSTM3 genotypes combined) had longer disease-free survival (HR=0.54, 95% CI 0.30-0.98, P=0.044). Thus, the GSTM3 AA genotype is associated with improved prognosis especially in those with GSTM1 null. Our findings suggest that the GST mu gene cluster mediates tumour characteristics and survival in patients with colorectal cancer.

Aged↗

PubMed2004

p16INK4a polymorphism: associations with tumour progression in patients with sporadic colorectal cancer.

Deregulated tumour expression of p16INK4a has previously been described in association with clinical progression in sporadic colorectal cancer patients (CRC). Furthermore, p16INK4a promoter hypermethylation leading to gene silencing has been shown to occur in advanced colorectal tumours and has been associated with patient survival. p16INK4a is polymorphic, with variant alleles being associated with tumour progression in melanoma. In this study we have examined p16INK4a polymorphism as a marker of tumour progression in sporadic CRC. Polymorphic sites G/A(442), C/G(500), and C/T(540), were studied, these alleles obeyed Hardy Weinberg equilibrium in a control group, but not in the CRC cases. G/A(442) and CG(500) alleles were in linkage disequilibrium in both cases and controls. In controls the C/T(540) alleles demonstrated no linkage with either other site, whilst an association was demonstrated between C/G(500) and C/T(540) alleles in the cases (p=0.011). Furthermore, the distribution of C/T(540) genotypes was different between the groups (p=0.002). Within the CRC cases, patients with the GG(442) genotype were more commonly associated with decreased tumour differentiation (p=0.018), advancing Dukes' stage (p=0.006) and T-stage (p=0.007) than patients with the GA(442) and AA(442) genotypes. Patients with the CC(500) genotype were more commonly associated with decreased tumour differentiation (p=0.012), advancing Dukes' stage (p=0.015), and N-stage (p=0.031). No associations between patient C/T(540) genotype and clinical prognostic parameters were found. An analysis of patient tumour expression with p16INK4a genotype revealed patients with the CC(500) genotype were more commonly associated with reduced tumour p16 expression (p=0.046). In summary our data indicate that p16INK4a polymorphism is associated with tumour progression in patients with sporadic CRC.

Colorectal Neoplasms↗

PubMed2003

Effect of dextran-induced changes in refractive index and aggregation on optical properties of whole blood.

The purpose of the present study is to investigate systematically the mechanisms of alterations in the optical properties of whole blood immersed in the biocompatible agent dextran, and to define the optimal concentration of dextrans required for blood optical clearing in order to enhance the capability of light penetration depth for optical imaging applications. In the experiments, dextrans with different molecular weights and various concentrations were employed and investigated by the use of the optical coherence tomography technique. Changes in light attenuation, refractive index and aggregation properties of blood immersed in dextrans were studied. It was concluded from the results that the mechanisms for blood optical clearing are characteristic of the types of dextrans employed, their concentrations and the application stages. Among the substances applied, Dx500 at a concentration at 0.5 g dl(-1) gives the best result in improving light penetration depth through the blood. The increase of light transmission at the beginning of the addition of dextrans is mainly attributed to refractive index matching between the scattering centres and the ground matter. Thereafter, the transmission change is probably due to a dextran-induced aggregation-disaggregation effect. Overall, light scattering in the blood could be effectively reduced by the application of dextrans. It represents a promising approach to increasing the imaging depth for in vivo optical imaging of biological tissue, for example optical coherence tomography.

Adult↗

PubMed2003

Theoretical model of optical coherence tomography for system optimization and characterization.

We present a detailed analytical model to describe optical coherence tomography (OCT) systems, which considers the propagation of the optical field within a scattering medium in the framework of the extended Huygens-Fresnel principle. The model includes use of the discrete-particle model and the fractal approach in treating biological tissue as being packed with scattering particles with a power-law distribution. In contrast to previous models, an imaginary lens proximal to the tissue surface is introduced that approximates the real focusing lens in the sample arm of the OCT system. This treatment avoids the consideration of backscattering light as traveling in the free space between the focusing lens and the tissue surface before mixing with the reference beam. Experiments on tissue phantoms were carried out to verify the validity of this model.

Computer Simulation↗

PubMed2002

Loss of heterozygosity on chromosome 10q is associated with earlier onset sporadic colorectal adenocarcinoma.

Recent studies have shown that loss of heterozygosity (LOH) on chromosome 10q is a frequent event in a number of tumour types including colorectal cancers. Because previous studies have used markers located mainly distally on chromosome 10, we have examined 114 sporadic colorectal adenocarcinomas for LOH using a panel of 9 highly polymorphic microsatellite markers spanning the long arm of chromosome 10. Using microdissected tumour material, LOH of one or more chromosome 10q markers was a frequent event (75 of 114; 66%). The highest frequency of loss (42 of 96; 44%) was observed at the marker D10S1790 located at 10q21.1. The mean age of presentation, of patients with LOH of D10S1790 was significantly (p = 0.0006) lower (67.1 years) compared to patients with retention of this marker (73.5 years). When we compared frequency of loss at this marker in patients presenting before 70 years of age (68%) to those above 70 years (23%) we observed a significant difference (p < 0.0001). Statistical analysis between loss, or instability at other markers and clinicopathological features did not show any significant associations. In addition LOH at D10S1790 was infrequent in adenomas (2 of 20; 10%) compared to adenocarcinomas (42 of 96; 44%) (p = 0.0047), suggesting that loss within this region is a late event in colorectal tumorigenesis. The association of loss at D10S1790 and an earlier age of presentation in adenocarcinomas suggests that this locus may harbor a tumour suppressor gene(s), which affects the rate of colorectal tumour progression. Identification of this region of genetic loss further refines our understanding of the paradigm in this tumour type of multiple-steps responsible for initiation and progression.

Adenocarcinoma↗

PubMed2002

Propylene glycol as a contrasting agent for optical coherence tomography to image gastrointestinal tissues.

BACKGROUND AND OBJECTIVE: Optical coherence tomography (OCT) is a recently developed imaging technique that has the potential to advance the early diagnosis of diseases in the human gastrointestinal (GI) tract. How ever, the high scattering nature of GI tissue limits its imaging depth and contrast. For more effective diagnosis using OCT, a concurrent improvement of imaging depth and contrast is, therefore, needed. In this work, we investigate the administration of chemical agents to the tissue as a means of improving the capability of OCT imaging of clinically relevant microstructures of the GI tract. STUDY DESIGN/MATERIALS AND METHODS: Normal human GI tissues, including stomach and oesophagus were obtained from patients in hospital, and were imaged with OCT within 0.5-2 hours of removal. Immediately after the first imaging of the specimens with OCT, about 0.5 ml of 80% propylene glycol solution was applied onto the tissue surface and the tissue allowed to absorb the chemical compounds for 20 minutes. Another image was then taken at the same position. The specimens were then embedded and stained in preparation for histologic evaluation. Co-registration of the images obtained using OCT before and after the topical application of the propylene glycol solution, and standard histopathologic processing provided basis for comparison. RESULTS: More detailed micro-structures, including the basal layer position and the cellular composition of the mucosal layer of GI tract tissues were observed after the topical application of propylene glycol solution, while these structures were not resolvable in the conventional OCT images. CONCLUSIONS: Propylene glycol could be used as a contrasting agent for OCT imaging of human GI tract tissues, allowing an increased capability of OCT for rapid clinical diagnosis in vivo.

Algorithms↗

PubMed2002

Changes in the immunologic phenotype of human malignant glioma cells after passaging in vitro.

Although immunotherapeutic strategies against glioblastomas have been promising both in vitro and in animal models, similar successes have not been realized in human clinical trials. One reason may be that immunotherapeutic strategies are based on prior studies that primarily have used human glioblastoma cell lines passaged in vitro, which may not accurately reflect the in vivo properties of glioblastoma cells. In this report, we used flow cytometry to quantify the expression of immunological cell surface molecules on human glioblastomas directly ex vivo (prior to any in vitro culturing) and after varying passages in vitro. Furthermore, we used ELISA to quantitate cytokine secretion after various passages in vitro. We demonstrate that in vitro culturing of established cell lines led to increases in the cell surface expression of MHC class I and ICAM-1 and secretion of IL-6 and TGF-beta(2). Furthermore, there were significant changes in the expression of MHC class I, MHC class II, B7-2, ICAM-1, and FasL when comparing ex vivo tumor cells to those after a single passage in vitro. After passaging once in vitro, there were also significant changes in the secretion of TGF-beta(2) and IL-10. This report indicates that in vitro culturing leads to significant changes in both cell surface molecules and secreted cytokines, which are known to affect the ability of immune cells to initiate an anti-tumor immune response. These changes in the immunological phenotype of glioblastomas after in vitro culturing may in part explain the limited success of immunotherapeutic strategies against glioblastomas in human clinical trials.

Antigens, CD↗

PubMed2002

Epidermal growth factor receptor and transformation.

The action of transforming growth factor peptides is mediated by distinct membrane receptors, which in turn activate a postreceptor signaling mechanism, eventually resulting in a mitogenic response. Such a signaling pathway may be modified by oncogene expression at the receptor or postreceptor levels, as well as by alterations in the levels of expression of the growth factor itself. One of the most extensively studied group of receptors is the type I epidermal growth factor receptor family. Activation of this receptor triggers the induction of receptor dimerization, which enables cross-phosphorylation to occur between two receptor molecules. This dimerization model provides a universal mechanism to activate the type I receptor family for growth factors and subsequent transformation.

Cell Transformation, Neoplastic↗