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Biomedical subjects

M J Black

Publications and source records attributed to M J Black.

At least 19 recordsLinked to original sources
PubMed2001

Action of low calcemic 1alpha,25-dihydroxyvitamin D3 analogue EB1089 in head and neck squamous cell carcinoma.

BACKGROUND: 1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and its analogues inhibit growth of various types of cancer cells. Although the therapeutic potential of 1,25(OH)(2)D(3) is limited by its tendency to induce hypercalcemia, analogues such as EB1089 are potent inhibitors of cell growth and exhibit reduced calcemic effects. We analyzed the antiproliferative and calcemic effects of EB1089 in tissue culture and animal models of head and neck squamous cell carcinoma (SCC) to investigate its potential as a chemotherapeutic/chemopreventive agent. METHODS: The effects of 1,25(OH)(2)D(3) and EB1089 on cell growth and expression of p21(WAF1/CIP1) and p27(KIP1), which encode cyclin-dependent kinase inhibitors, and a novel target, gadd45alpha, a growth-arrest and DNA-damage gene, were monitored in cultured murine AT-84 SCC cells. The effects of these agents on AT-84 cell growth in vitro and on growth of AT-84 tumors in syngeneic C3H mice were monitored; treatment started at the time of tumor implantation (early tumor model) or after 12 days (late tumor model). Weight and serum calcium levels were also monitored in these animals. All P values were two-sided. RESULTS: Both 1,25(OH)(2)D(3) and EB1089 arrested proliferation of AT-84 cells in G(0)/G(1) phase, inhibited p21(WAF1/CIP1) expression, and induced expression of p27(KIP1) protein. 1,25(OH)(2)D(3) also enhanced the expression of gadd45alpha, apparently by a p53-independent mechanism. There was a statistically significant decrease in tumor growth for 1,25(OH)(2)D(3)-treated mice (P<.001 for early tumor model) and EB1089-treated mice (P<.001 and P =.001 for early and late tumor models, respectively). Unlike 1,25(OH)(2)D(3), EB1089 did not induce cachexia or hypercalcemia. The effects of 1,25(OH)(2)D(3) and EB1089 on expression of p21(WAF1/CIP1) and GADD45alpha were similar in tumors and in vitro. CONCLUSIONS: EB1089 completely inhibited growth of AT-84 SCC cells at nanomolar concentrations, reduced tumor growth, and did not have calcemic effects. Our results support continued investigation of EB1089 as a chemopreventive/chemotherapeutic agent for head and neck SCC.

Animals↗
PubMed2001

Effect of angiotensin-converting enzyme inhibition on renal filtration surface area in hypertensive rats.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor treatment leads to protective effects on the cellular structure of the glomerulus and the kidney. The aim of this study was to determine whether ACE inhibition increases renal filtration surface area in the spontaneously hypertensive rat (SHR). METHODS: SHR were treated with the ACE inhibitor perindopril at a high dose (3 mg/kg/day) or a low dose (0.1 mg/kg/day) during the period of hypertension development, from 7 to 14 weeks of age. Some animals were treated concomitantly with the bradykinin B2 receptor antagonist, S16118. Tail-cuff systolic blood pressure and body weights were measured twice weekly. At termination of treatment, glomerular number and volume, length, and surface area of glomerular capillaries and renal filtration surface area were estimated using unbiased stereological techniques. RESULTS: There were significant dose-related reductions in blood pressure with high- and low-dose perindopril treatment. Neither low- nor high-dose perindopril treatment had any effect on glomerular number or size or glomerular capillary length and surface area. Hence, there was no significant difference in total renal filtration surface area between any of the experimental groups (8721 +/- 610 mm2 in untreated SHR and 7879 +/- 338 mm2 and 8767 +/- 437 mm2 in the low and high dose perindopril-treated groups, respectively). Coadministration of the bradykinin antagonist did not affect any of the glomerular parameters. CONCLUSIONS: ACE inhibition during the period of hypertension development does not lead to an enhanced glomerular capillary growth or increases in total renal filtration surface area in this model.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Skin metastases in squamous cell carcinoma of the head and neck.

UNLABELLED: Distant metastases in squamous cell carcinoma of the head and neck (SCCHN) are most often to the lung, liver, and bone. SCCHN rarely metastasizes to skin sites. OBJECTIVE: To ascertain the significance of skin metastases (SM) on the prognosis of patients with SCCHN. METHODS: A retrospective review of all patients between 1987 and 1999 with SCCHN was conducted. Patients in whom SM developed were identified. Data pertaining to demographics, primary tumor staging, SM development, and outcome were investigated. RESULTS: In 798 consecutive patients diagnosed with SCCHN between 1987 and 2000, 19 developed SM. The average time of onset of the SM was 17.65 months. The average survival time was 7.2 months after the development of SM. The overall survival time of patients who developed SM from the initial presentation of the primary tumor was 24.85 months. The 1-year survival rate from the time of development of SM was 0%. CONCLUSIONS: Metastasis to skin sites is an uncommon feature of SCCHN. SM may represent the first clinical evidence of impending loco-regional recurrence or distant metastasis. The development of SM is an ominous sign associated with an extremely poor prognosis, similar to the development of distant metastasis at more typical sites. Both the development of SM and survival of patients developing SM are independent of primary tumor stage. Current treatment options of SM are limited in their efficacy.

Carcinoma, Squamous Cell↗
PubMed2001

Effect of angiotensin-converting enzyme inhibition on myocardial vascularization in the adolescent and adult spontaneously hypertensive rat.

OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibition treatment enhances myocardial vascularization in adolescent and adult spontaneously hypertensive rats (SHRs). METHODS: Male SHRs were treated from 7 to 14 or from 16 to 24 weeks of age with the ACE inhibitor, perindopril, in either a low dose (0.1 mg/kg per day) or a high dose (1 mg/kg per day). Some rats were concomitantly treated with a bradykinin antagonist. At termination of treatment, the left ventricular wall was extensively sampled and the surface area density and length density of myocardial blood vessels stereologically determined. RESULTS: High-dose perindopril treatment prevented the development of hypertension and left ventricular hypertrophy in adolescent SHRs and markedly reduced blood pressure and left ventricular size in adult SHRs. SHRs treated with the low dose of perindopril remained hypertensive, although there were significant reductions in blood pressure and left ventricular growth. High-dose perindopril treatment in adolescent SHRs led to a significant increase in the surface area density of blood vessels in the left ventricle after 4 weeks of treatment and an increase in both the surface area density and length density of blood vessels after 7 weeks of treatment Co-administration with the bradykinin antagonist did not reverse these effects. In contrast, ACE inhibitor treatment had no effect on myocardial vascularization in adult rats with established hypertension. CONCLUSION: ACE inhibitor treatment enhances vascularization in the adolescent heart through reductions in myocardial mass, but not capillary growth. ACE inhibition in the adult heart with established hypertension reduces left ventricular hypertrophy, but does not enhance myocardial capillarization.

Aging↗
PubMed2001

Regulation of gene Expression by 1alpha,25-dihydroxyvitamin D3 and Its analog EB1089 under growth-inhibitory conditions in squamous carcinoma Cells.

Analogs of 1alpha,25-dihydroxyvitamin D(3) (1alpha, 25(OH)2D3) inhibit growth in vitro and in vivo of cells derived from a variety of tumors. Here, we examined the effects of 1alpha,25(OH)2D3 and its analog EB1089 on proliferation and target gene regulation of human head and neck squamous cell carcinoma (SCC) lines SCC4, SCC9, SCC15, and SCC25. A range of sensitivities to 1alpha,25(OH)2D3 and EB1089 was observed, from complete G0/G1 arrest of SCC25 cells to only 50% inhibition of SCC9 cell growth. All lines expressed similar levels of vitamin D3 receptor (VDR) mRNA and protein, and no significant variation was observed in 1alpha,25(OH)2D3-dependent induction of the endogenous 24-hydroxylase gene, or of a transiently transfected 1alpha,25(OH)2D3-sensitive reporter gene. The antiproliferative effects of 1alpha,25(OH)2D3 and EB1089 in SCC25 cells were analyzed by screening more than 4,500 genes on two cDNA microarrays, yielding 38 up-regulated targets, including adhesion molecules, growth factors, kinases, and transcription factors. Genes encoding factors implicated in cell cycle regulation were induced, including the growth arrest and DNA damage gene, gadd45alpha, and the serum- and glucocorticoid-inducible kinase gene, sgk. Induction of GADD45alpha protein in EB1089-treated cells was confirmed by Western blotting. Moreover, while expression of proliferating cell nuclear antigen (PCNA) was reduced in EB1089-treated cells, coimmunoprecipitation studies revealed increased association between GADD45alpha and PCNA in treated cells, consistent with the capacity of GADD45alpha to stimulate DNA repair. While 1alpha,25(OH)2D3 and EB1089 modestly induced transcripts encoding the cyclin-dependent kinase inhibitor p21(waf1/cip1), no changes in protein levels were observed, indicating that p21(waf1/cip1) induction does not contribute to the antiproliferative effects of 1alpha,25(OH)2D3 and EB1089 in SCC cells. Finally, in partially resistant SCC9 cells, there was extensive loss of target gene regulation (10 of 10 genes tested), indicating that resistance arises from widespread loss of 1alpha,25(OH)2D3-dependent gene regulation in the presence of normal levels of functional VDRs.

Blotting, Northern↗
PubMed2001

An aggressive approach to the surgical management of suspicious thyroid nodules.

Thyroid cancer accounted for about 2.5% of all new cancers among Canadian females in the year 2000. The surgical management of well-differentiated thyroid cancer remains controversial. We reviewed 100 consecutive cases of total thyroidectomy for thyroid masses suspicious for malignancy done between 1998 and 1999. When feasible, a capsular dissection was performed using only the bipolar cautery for hemostasis. The accuracy of preoperative diagnosis and complications of surgery are evaluated. We suggest that total thyroidectomy can be performed, without excessive morbidity. If performed for all suspicious thyroid nodules, it will eliminate the need for completion thyroidectomies and high ablative does of 131I.

Adenocarcinoma, Follicular↗
PubMed2000

Is Fos protein expressed by dying striatal neurons after immature hypoxic-ischemic brain injury?

The transient induction of mRNA for the immediate-early gene c-fos has been reported following hypoxic-ischemic brain injury in the immature brain. However, no studies have examined the temporal expression of Fos protein, which is the functionally relevant product of c-fos gene expression. Increased expression of Fos protein has been linked to cell death. We therefore examined whether Fos protein is expressed by dying neurons after immature hypoxic-ischemic brain injury. A well characterized immature rat model of hypoxic-ischemic injury at postnatal day (PN) 7 was used. Three hypoxic-ischemic and three normoxic control pups were studied per time point (i.e., 0, 2, 12, 24, 48, and 72 h posttreatment). Expression of Fos within striatal and other neurons was detected immunocytochemically. Fos protein was expressed within dying striatal neurons at 0-12 h after hypoxia-ischemia. However, detection was only seen in 2 of 17 hypoxic-ischemic pups. These 2 pups had >/=80% of their striatal neurons dying within their right, hypoxic-ischemic-exposed hemisphere. Fos protein expression after severe injury may, therefore, be a response to extraordinary or extreme stress. The absence of Fos protein expression in the majority of hypoxic-ischemic pups, which all exhibited striatal neuronal death, suggests that Fos expression is not necessary for cell death to occur. Therapies directed against Fos protein expression may therefore have limited usefulness in immature hypoxic-ischemic brain injury.

Animals↗
PubMed2000

Evaluation of microparticle enzyme immunoassay against HPLC-mass spectrometry for the determination of whole-blood tacrolimus in heart- and lung-transplant recipients.

OBJECTIVES: Tacrolimus is an immunosuppressant drug with a narrow therapeutic window and thus requires therapeutic drug monitoring. This study evaluates the suitability of the second-generation microparticle enzyme immunoassay (MEIA II) against a specific method, high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS), for the measurement of tacrolimus in both heart- and lung-transplant groups. A secondary objective was to investigate the effect of tacrolimus concentration on MEIA II measurement. METHODS: The HPLC-MS assay was conducted as per our reported method and MEIA II performed according to manufacturer's instructions. Quality-control samples at 5, 11, and 22 microg/L were run in each batch to ensure assay integrity in both methods. Multiple trough samples from 18 heart patients (n = 126) and 17 lung patients (n = 203) were analyzed. RESULTS: The inter-batch imprecision and analytical recovery over the quality-control range by HPLC-MS (n = 12) was <6% and 98.2% to 104%, respectively, and by MEIA II (n = 16) <15% and 92.0% to 99.1%, respectively. The mean overestimation by MEIA II between the two methods for heart- and lung-transplant patient samples was found to be 9.9% (range: -37.4-45.4%) and 13.2% (range: -29.2-64.3%), respectively. Stratification of these data based on the tacrolimus concentration determined by MEIA II, yielded no statistically significant differences in bias between concentration subgroups within the clinically relevant range (p > 0.4). However, a statistically significant difference was detected between the highest concentration subgroup (>20.0 microg/L) and lower concentration subgroups in both transplant populations (p < 0.05). CONCLUSIONS: This study suggests that where HPLC-MS is not available, MEIA II may be suitable for the therapeutic drug monitoring of tacrolimus in heart- and lung-transplant recipients. However, the clinical importance of the observed mean bias, considering the wide range in overestimation in heart- and lung-transplant patient samples, is yet to be determined.

Adolescent↗
PubMed2000

No association between P53 codon 72 polymorphism and risk of squamous cell carcinoma of the head and neck.

An initial report suggested that patients homozygous for the arginine allele at codon 72 of P53 were at increased risk for human papillomavirus (HPV)-related cervical cancer, but other groups have not confirmed this finding. Since approximately 18-36% of head and neck cancers are HPV-related, we examined the genotypic frequencies at that locus in 163 cases with squamous cell carcinoma of the head and neck (SCCHN) and 163 ethnically matched controls. We found no significant excess of arginine homozygotes in cases compared to controls (P= 0.50). No significant differences in allele frequencies were observed when the data were stratified by tobacco exposure or by cancer site. These findings suggest a limited role, if any, for this P53 polymorphism in SCCHN.

Base Sequence↗
PubMed2000

Squamous cell carcinoma of the nasal vestibule.

Squamous cell carcinoma of the nasal vestibule is a rare disease. Most advocate radiotherapy as a primary treatment for early tumours, with surgery reserved for salvage. For advanced disease, combined therapy with surgery and postoperative radiotherapy is generally recommended. Fourteen patients with squamous cell carcinoma of the nasal vestibule were reviewed. A classification of early versus late lesions was used. We achieved a 78% local regional control rate (minimum follow-up 3 years) in patients with early disease, with either radiotherapy or surgery as a primary modality of treatment. All patients with late disease recurred, requiring further surgical and/or radiation treatment. Only 20% of these patients were disease free at 2 years. Recurrent disease in either group, whether local or regional, carried a grave prognosis, with a 25% disease-free survival at 3 years.

Adult↗
PubMed1999

Human papillomavirus and prognoses of patients with cancers of the upper aerodigestive tract.

BACKGROUND: Some studies have shown that human papillomavirus (HPV) infection may play not only an etiologic role in anogenital cancers but also a role in the clinical outcome. The objective of the current study was to determine whether detection of HPV DNA in primary squamous cell carcinomas of the upper aerodigestive tract (UADT) is a prognostic factor in patients with the disease. METHODS: The authors analyzed archival specimens of UADT tumors from 101 randomly selected patients with evaluable samples for HPV DNA detection. HPV testing was performed using a general primer-mediated polymerase chain reaction. RESULTS: The overall detection rate was 16.8% (17 of 101 specimens). HPV DNA was detected at higher rates in specimens from younger patients and in well-differentiated tumors. Pharyngeal tumors were more likely to be HPV positive (30.0%) than buccal (10.3%) or laryngeal tumors (15.4%), but the differences were not significant. The detection rate was similar for T1-T2 tumors (17.4%) and T3-T4 tumors (15.6%). However, tumors without lymph node metastasis were more likely to be HPV positive (21.4%) than tumors with lymph node involvement (6.5%). Kaplan-Meier and Cox regression survival analyses did not show any difference in overall or disease free survival according to HPV detection. CONCLUSIONS: Although the HPV DNA detection rate was slightly higher in local than in regionally spread tumors, our results support the hypothesis that it is very unlikely that HPV detection plays any role in the prognoses of patients with UADT squamous cell carcinoma.

Aged↗
PubMed1999

Fibromatosis.

Fibromatosis represents a diverse group of fibroproliferative tumours. Their behaviour and pathological qualities are situated in an intermediate position between benign and malignant disease. The following represents the pathological and radiological presentation of a 29-year-old female with fibromatosis.

Adult↗
PubMed1999

Occult cervical metastases: immunoperoxidase analysis of the pathologically negative neck.

OBJECTIVES: The purpose of this study is to better estimate the true incidence of occult regional metastases associated with stage I and II squamous cell carcinoma of the oral cavity. The clinical and prognostic significance of micrometastatic disease discovered by cytokeratin immunoperoxidase reactivity in the previously pathologically N0 neck is also evaluated. METHODS: Forty patients treated between 1985 and 1996 with T1 or T2 squamous cell carcinoma of the lip and oral cavity were studied. All had primary surgical treatment including functional neck dissection. No metastases were demonstrated on hematoxylin and eosin microscopy. All specimens were reexamined with immunoperoxidase staining for cytokeratin. RESULTS: Five percent of patients had micrometastatic disease. Retrospective analysis of patients with a minimum follow-up of 2 years has failed to show a statistically significant association between a positive cytokeratin analysis and poor locoregional control or overall survival. CONCLUSIONS: Results suggest that the true incidence of occult metastases with carcinoma of the oral cavity is significantly higher than previously documented. However, the prognostic significance of these findings remains unclear.

Adult↗