Biomedical subjects

Bruce G Robinson

Publications and source records attributed to Bruce G Robinson.

40 records · Page 3Linked to original sources

PubMed2002

Bioactivity of PTH/PTHrP analogs lacking the 1-14 N-terminal domain.

The N-terminal regions of 1-34 parathyroid hormone (PTH) and 1-34 parathyroid hormone related protein (PTHrP) are thought to be required for full agonist activity of these molecules and for signal transduction by cyclic AMP (cAMP). The C-terminal regions are thought to be involved in receptor binding and protein kinase C activation. In this study, two analogs of PTH/PTHrP lacking the segment 1-14 exhibited agonist activity in opossum kidney (OK) 3B2 cells. Analogs cPTHrP(15-34) and ANA NPY(13-36), an analog of neuropeptide Y, which both have amphipathic alpha helices, inhibited phosphate uptake and stimulated cAMP production in a dose-dependent manner, with half maximal activity in the microM range, compared to the nM range for hPTHrP(1-34) and hPTH(1-34). They also exhibited proportionately lower receptor binding affinities. cAMP production by these analogs was suppressed by the antagonist hPTHrP(7-34). Inhibition of phosphate uptake in response to the analogs was partially suppressed by H-89, but not by bisindolylmaleimide. The analogs also inhibited phosphate uptake and stimulated cAMP in parent OK cells and stimulated cAMP production in UMR-106 cells. These studies present the novel finding that in these cell types, a C-terminal region encompassing PTH/PTHrP(24-31), with the alpha-helical structure maintained, is sufficient for full activity at reduced potency.

Amino Acid Sequence↗

PubMed2002

Independent genetic events associated with the development of multiple parathyroid tumors in patients with primary hyperparathyroidism.

Multiple parathyroid tumors, as opposed to hyperplasia, have been reported in a subset of patients with sporadic primary hyperparathyroidism (PHPT). It is not clear whether these multiple tumors are representative of a neoplastic process or whether they merely represent hyperplasia that has affected the parathyroid glands differentially and resulted in asynchronous growth. The molecular genetic techniques of comparative genomic hybridization (CGH), loss of heterozygosity (LOH), and MEN1 mutation analysis were performed on a series of five patients with multiglandular PHPT, each of which had two parathyroid tumors removed. Analysis of these multiple parathyroid tumors from patients with PHPT revealed that independent genetic events were associated with the development of a subset of these tumors. The DNA sequence copy number changes, identified by CGH analyses, either involved different chromosomal regions in the paired glands of a patient (two patients), or those regions implicated in one gland were not changed in a second gland from the same patient (two patients). Each of the three patients exhibiting LOH demonstrated different changes between the paired glands. Where LOH was detected in one gland from a patient, the other gland from the same patient either exhibited no allelic loss or the loss detected was in another region. Each of the three tumors exhibiting LOH at 11q13 was found to contain a somatic MEN1 mutation in the remaining allele, however these mutations were not present in the germline or in the paired gland from the same patient. Although it is possible that a separate series of genetic changes has arisen randomly in two separate glands within the same individual, it seems more likely that the development of these multiple tumors has arisen because of the involvement of other unknown factors. These factors may be genetic [such as the involvement of one or more germline mutations in an unknown low-penetrance gene(s), germline mosaicism or alterations in calcium-sensing receptor gene(s)], epigenetic, physiological, or environmental.

Cell Transformation, Neoplastic↗

PubMed2002

Minimally invasive parathyroidectomy using the 'focused' lateral approach. I. Results of the first 100 consecutive cases.

BACKGROUND: A feasibility study of 'focused' minimally invasive parathyroidectomy (MIP) using a lateral approach was commenced in 1999. The aim of the present paper was to evaluate the effectiveness and safety of this procedure in the first 100 consecutive patients. METHODS: This was a prospective, non-randomized case-control study. One hundred consecutive patients with primary hyperparathyroidism (mean age 63.1 years; 74 females, 26 males) who fulfilled the inclusion criteria underwent focused MIP between May 1999 and December 2000. The results for the first and last 50 consecutive patients were compared to see whether they were reflective of a learning curve. The role of intraoperative quick parathyroid hormone (QPTH) estimation was also evaluated. RESULTS: Focused MIP was successfully completed in 93 of 100 patients, with seven conversions. Three (3.2%) of the 93 patients had persistent hyperparathyroidism. Quick PTH was measured in 81 patients and the results were true positive (for cure) in 72 patients, false negative in six patients, true negative in two patients and false positive in one patient. Transient recurrent laryngeal nerve paresis occurred in one patient. During the same time period, open parathyroidectomy was performed in 242 patients. The results were not different between the first and later 50 patients undergoing MIP, nor were the outcomes significantly different from patients undergoing open parathyroidectomy. CONCLUSIONS: Focused MIP is a safe and effective operative approach for appropriately selected patients. Failed procedures were invariably related to shortcomings of the localization studies. Measurement of QPTH, although accurate, is unreliable in the presence of multigland disease.

Adenoma↗

PubMed2002

Comparative genomic hybridization analysis of adrenocortical tumors.

Comparative genomic hybridization (CGH) is a molecular cytogenetic technique that allows the entire genome of a tumor to be surveyed for gains and losses of DNA copy sequences. A limited number of studies reporting the use of this technique in adult adrenocortical tumors have yielded conflicting results. In this study we performed CGH analysis on 13 malignant, 18 benign, and 1 tumor of indeterminate malignant potential with the aim of identifying genetic loci consistently implicated in the development and progression of adrenocortical tumors. Tissue samples from 32 patients with histologically proven adrenocortical tumors were available for CGH analysis. CGH changes were seen in all cancers, 11 of 18 (61%) adenomas, and the 1 tumor of indeterminate malignant potential. Of the adrenal cancers, the most common gains were seen on chromosomes 5 (46%), 12 (38%), 19 (31%), and 4 (31%). Losses were most frequently seen at 1p (62%), 17p (54%), 22 (38%), 2q (31%), and 11q (31%). Of the benign adenomas, the most common change was gain of 4q (22%). Mann-Whitney analysis showed a highly significant difference between the cancer group (mean changes, 7.6) and the adenoma group (mean changes, 1.1) for the number of observed CGH changes (P < 0.01). Logistic regression analysis showed that the number of CGH changes was highly predictive of tumor type (P < 0.01). This study has identified several chromosomal loci implicated in adrenocortical tumorigenesis. Activation of a protooncogene(s) on chromosome 4 may be an early event, with progression from adenoma to carcinoma involving activation of oncogenes on chromosomes 5 and 12 and inactivation of tumor suppressor genes on chromosome arms 1p and 17p.

Adenoma↗