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Biomedical subjects

B Cole

Publications and source records attributed to B Cole.

At least 55 records · Page 3Linked to original sources
PubMed1997

Concurrent paclitaxel, carboplatin, and radiotherapy in advanced head and neck cancers: a phase II study--preliminary results.

Radiotherapy or surgery alone for advanced head and neck cancer generally yields poor results. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin have both shown excellent radiosensitization through two discrete mechanisms, namely, blocking the cell cycle in the G2/M phase and inhibiting DNA repair. In an effort to improve locoregional control and survival, a prospective phase II study was initiated using paclitaxel 60 mg/ml and carboplatin (area under the concentration-time curve of 1), each given as a single dose weekly with concurrent conventional fractionated external beam radiotherapy. Patients were stratified into two groups: operable and inoperable/unresectable. The operable and inoperable groups received 5 weeks (45 Gy) and 8 weeks (72 Gy) of chemoradiotherapy, respectively. Patients in the operable group were evaluated with repeat biopsies from the primary site after 5 weeks. Those with a positive biopsy underwent surgery; those with a negative biopsy received 3 additional weeks of chemoradiotherapy. Thirty-four patients were entered in the operable group (28 men and six women; 40 to 71 years of age; 12 stage III and 22 stage IV). Of 26 evaluable patients, 19 (73%) had a complete clinical response (95% confidence interval [CI], 52% to 88%) and six (23%) had a partial response (95% CI, 9% to 44%), for a total clinical response rate of 96% (95% CI, 80% to 100%). A pathologic complete response at the primary site (two had an unknown primary site) occurred in 17 of 24 (71%) patients (95% CI, 49% to 87%). Of 20 patients with N1-3 nodes who underwent neck dissection, 17 (85%) had pathologically negative lymph nodes. Seven patients with residual tumor at the primary site were resected (oral cavity, three; maxilla, one; base of tongue, one; and larynx, two). Grades 3 and 4 mucositis were seen in 19 (73%) patients; mucositis was the most common and significant morbidity. Accrual for the inoperable group continues. Concomitant paclitaxel, carboplatin, and external beam radiotherapy yielded excellent clinical responses, but produced significant grade 3/4 toxicity. In the operable group, the majority of responders had a complete pathologic response. These preliminary findings will be assessed in terms of response duration, organ preservation, and long-term survival.

Adult↗
PubMed1996

p53 mutations do not predict response to paclitaxel/radiation for nonsmall cell lung carcinoma.

BACKGROUND: Mutations in the tumor suppressor gene p53 have been associated with resistance to ionizing radiation and chemotherapy. Paclitaxel and concurrent radiation (paclitaxel/RT) achieve high response rates with locally advanced nonsmall cell lung carcinoma (NSCLC). In vitro data and animal studies suggest that paclitaxel may have a unique ability to activate tumor cell apoptosis in the absence of wild-type p53 function. The authors sought to determine whether p53 mutations affect response to paclitaxel/RT in patients with locally advanced NSCLC. METHODS: Thirty patients with Stage IIIA or IIIB NSCLC who participated in Brown University Oncology Group protocols utilizing paclitaxel/RT had tumor tissue that was adequate for analysis. Mutations were detected in tumor tissue by single-strand conformation polymorphism analysis of exons 5 through 8 of the p53 gene, and confirmed by direct sequencing. RESULTS: Mutations in p53 were found in 12 of 30 patients (40%). The response rates (complete plus partial) of 75% for patients with tumors with p53 mutations, and 83% for patients with wild-type p53, did not differ significantly (P = 0.70). CONCLUSIONS: p53 mutations do not predict response of patients with NSCLC to paclitaxel/RT. This finding is in striking contrast to results with other chemotherapeutic agents and ionizing radiation. These clinical data support in vitro data and animal studies regarding the unique mechanism of the action of paclitaxel. Further investigation is needed to determine the mechanism of lung tumor cell death after paclitaxel/RT. These results suggest that paclitaxel/RT may be an active regimen for patients with other locally advanced neoplasms with high rates of p53 gene mutations.

Aged↗
PubMed1996

DSP-4 treatment influences olfactory preferences of developing rats.

Control cagemates of rats treated with the norepinephrine (NE) neurotoxin DSP-4, showed normal olfactory learning as infants, but abnormal aversion to home-cage odors as juveniles. Neither age nor social housing conditions influenced the odor preferences of DSP-4-treated rats: they showed tolerance or attraction to familiar odors at both developmental stages. Controls, but not DSP-4-treated juveniles, housed in mixed treatment groups, showed elevated concentrations of a serotonin metabolite and reduced NE concentrations in the hippocampus, suggesting that this social situation was particularly stressful for the controls. DSP-4-treated juveniles, but not infants, produced odors that were discriminable from controls'. Thus, conflicting olfactory signals in the home-cages of mixed juvenile groups may have led to the development of stress in controls. NE depletion appeared to lessen social stress effects in their DSP-4-treated cagemates. These findings support other data suggesting that NE modulates the biobehavioral effects of the social environment.

Adrenergic Agents↗
PubMed1996

Phase II study of 5-fluoruracil leucovorin and azidothymidine in patients with metastatic colorectal cancer.

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy with 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (AZT), a thymidine nucleoside analog. By itself, AZT has limited antineoplastic efficacy. However, experimental studies indicate that 5-FU enhances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into nucleic acids. A phase I study defined the maximum tolerated dose of AZT as 7 g/m2 with hypotension during the infusion being the dose-limiting toxicity. A phase II study was performed with oral leucovorin (100 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bolus 5-FU (400 mg/m2) followed 1 h later by a 2-h infusion of AZT (7 g/m2). Treatment was given weekly for 4 weeks followed by a 1-week break, which constituted a cycle of therapy. Responses were evaluated after every two cycles. Patients continued on therapy as long as they tolerated treatment and did not have progressive disease. Of 15 evaluable patients who had received no chemotherapy there was 1 complete response and 4 partial responses (a 33% response rate), whereas only 1 of 6 patients who had received prior adjuvant chemotherapy had a partial response (17%). An additional 10 patients had stable disease lasting 2-14 months. Therapy was well tolerated with the only one instance each of grade 3 nausea and vomiting, diarrhea, anemia, and hypotension. Approximately 50% of treatments were accompanied by mild hypotension, which was easily corrected by increasing the rate of normal saline infusion. There was no difficulty administering this regimen in the outpatient setting. While the overall response rate (29%) is comparable to that seen with combinations of 5-FU and leucovorin alone, in most reported series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively little 5-FU toxicity, increasing the dose of 5-FU in this regimen would appear to be feasible and might result in a higher response rate.

Adenocarcinoma↗
PubMed1996

Living-unrelated renal transplantation provides comparable results to living-related renal transplantation: a 12-year single-center experience.

BACKGROUND: The increasing success of renal transplantation is paralleled by the increased size of the waiting list. Efforts to increase the donor pool have included the use of living-unrelated kidney donors (LURDs). METHODS: During a 12-year period our center performed 309 transplantation from living donors; 279 patients received living-related donor (LRD) transplants, and 30 patients received LURD transplants. During the same period 543 patients received cadaveric renal donor transplants. A total of 86.7% of LURD transplants were spousal transplants. A total of 29% of the patients who received LRDs were human leukocyte antigen-identical with their donors and 53% were haploidentical, versus 0 human leukocyte antigen-identical or haploidentical in the LURD group. RESULTS: Twenty-seven (90%) Of 30 LURD recipients are alive, as are 240 (86%) of 279 LRD recipients. Mean current creatinine is 1.6 mg/dl for the LURD group and 1.7 mg/dl for the LRD group Kaplan-Meier 1- and 5-year graft survival was 94.9% and 82.9% for the LRD group, 93.1% and 85.9% for the LURD group (p = not significant), and 84.6% and 70.7% for the cadaveric renal donor group (p < 0.05). CONCLUSIONS: LURD patient and graft survival is comparable to LRD transplants despite inferior human leukocyte antigen matching. LURD transplant survival is superior to that of cadaveric renal donor transplants. LURDs are an excellent but underused source of organs for renal transplant recipients.

Adult↗
PubMed1995

Mutational analysis of two DR alpha residues involved in dimers of HLA-DR molecules.

Crystallographic analysis of HLA-DR1 molecules reveals a "dimer of dimers" with two reciprocal salt bridges between Glu 88 and Lys 111 of the two DR alpha chains. To determine whether these amino acids are critical for Ag presentation, we generated a panel of human B cell transfectants expressing DR alpha chains with mutations at residues 88, 111, or both. The mutant DR alpha chains, paired with endogenous DR3 beta chain, form cell surface dimers that retain epitopes recognized by a panel of anti-DR3 Abs. Replacement of Glu 88 with Ala (88A) selectively eliminates the ability to activate an alloreactive (anti-DR3) T cell clone. Mutant DR molecules with Lys substituted for Glu 88 (88K) fail to activate an alloreactive, an Ag-specific, and a peptide-specific T cell line. The DR alpha 88 mutants bind an exogenously supplied DR3-specific peptide and the mutant DR molecules migrate as dimers on SDS-PAGE, implying that their defective Ag presentation is not due to an inability to bind antigenic peptides. In contrast, substitution of Lys 111 with either Ala (111A) or Glu (111E) does not abrogate Ag presentation. Further, the defect introduced by Glu 88 to Lys mutation (88K) is not overcome by compensatory Lys to Glu mutation at position 111 (111E). Taken together, these results indicate an important functional or structural role for position 88 of the DR alpha chain, but argue against a requirement for interaction between DR alpha 88 and 111 during Ag-specific T cell stimulation.

Antigen Presentation↗
PubMed1995

Replacement of N-glycosylation sites on the MHC class II E alpha chain. Effect on thymic selection and peripheral T cell activation.

MHC class II molecules play a central role in thymic selection of developing T cells, Ag presentation to immunocompetent CD4+ T cells, and T cell activation by superantigens. We have established transgenic A.CA mice expressing either the wild-type E alpha d molecule (E alpha/E beta), or an E alpha d molecule altered at an N-glycosylation site on the E alpha chain (residue 78, 78E alpha/E beta or residue 118, 118E alpha/E beta) to identify a possible role for carbohydrates in thymic selection and peripheral T cell activation. Striking differences were found among these transgenic mice. Although V beta 10+ T cells were selected positively in all three transgenic strains, positive selection of V beta 7+ T cells was impaired in 118E alpha/E beta transgenic mice. Spleen cells from both strains with mutant E alpha chains showed selective defects in presentation of peptides to particular T cell hybridomas. In contrast, neither mutation affected presentation of the superantigen Mycoplasma arthriditis mitogen. These results demonstrate that alterations in the glycosylation of class II E alpha chains might affect both central and peripheral T cell regulation.

Amino Acid Sequence↗
PubMed1994

Age and sex modulate effects of stress on the immune system: a multivariate analysis.

Multivariate analyses indicate that both age and sex can modulate examination stress effects on immune factors. Stress lowered eosinophil counts in females but raised them in males. Age modulated stress effects on CD4 and CD8 cells, hemoglobin, and erythrocytes. CD4 decreased more in older subjects; CD8 increased in older and decreased in younger subjects; hemoglobin decreased in younger but not older subjects; erythrocytes increased in older and decreased in younger subjects. Initial age and/or sex differences in levels of neutrophils and lymphocytes were not statistically altered by stress. Stress effects not modulated by age or sex increased serum IgA and IgM, CD19, and stimulated phagocytic activity but decreased serum IgG, CD3, basophils, and unstimulated phagocytic activity. The immunological effects of stress are multiple and are influenced by variations in age and sex of the person.

Adult↗
PubMed1989

Neonatal 6-hydroxydopa, but not DSP-4, elevates brainstem monoamines and impairs inhibitory avoidance learning in developing rats.

The involvement of brain monoamines in learning and memory in developing rats was studied by comparing the effects of 3 different noradrenergic neurotoxin treatments. Two experimental groups of male Sprague-Dawley rat pups were injected systemically with 50 micrograms/g of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) either on the day of birth or on postnatal days 17-18. Rats in the third experimental group were injected systemically with 60 micrograms/g of 6-hydroxydopa (6-OHDOPA) on postnatal days 0 and 2. Control littermates received vehicle. The animals were trained on an inhibitory avoidance task on postnatal days 27-29 and tested for retention 24 h later. The drug treatments produced comparable depletion of norepinephrine in the hippocampus and frontal cortex. 6-OHDOPA, but neither DSP-4 treatment, significantly elevated brainstem concentrations of norepinephrine and serotonin. In addition, 6-OHDOPA, but not DSP-4, significantly impaired retention of the inhibitory avoidance task. The impairment did not reflect insensitivity to the footshock used in training: both neonatal drug treatments tended to lower, not raise, footshock thresholds, as measured by a flinch test. High affinity choline uptake was not affected by either neonatal drug treatment in any of the brain areas examined. Thus, the 6-OHDOPA-induced behavioral deficit did not involve altered acetylcholine function. The results implicate brainstem monoamines in the modulation of learning and memory during development.

Animals↗
PubMed1989

Regulation of cell proliferation by beta-adrenergic receptors in a human lung adenocarcinoma cell line.

We have recently reported that the tobacco-related nitrosamines N-nitrosodiethylamine (DEN) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) stimulate cell proliferation in cell lines derived from human neuroendocrine carcinoma and adenocarcinoma (comprised of Clara cells) of the lung. In the neuroendocrine cell line, this effect was inhibited by antagonists of nicotinic cholinergic receptors which regulate the secretion of peptide hormones and cell proliferation of pulmonary neuroendocrine cells. No such inhibition was observed in the adenocarcinoma line. Clara cells reportedly do not have acetylcholine receptors and secretion of this cell type is regulated by beta-adrenergic receptors instead. In this experiment, we test the hypothesis that the latter types of receptors are involved in the regulation of cell growth of normal and nitrosamine-stimulated adenocarcinoma cells with features of Clara cells. Our data demonstrate a pronounced stimulation of cell growth by the beta-adrenergic agonist isoproterenol, DEN and NNK, as well as a dose-dependent inhibition of such growth-stimulating effects by the beta-adrenergic antagonist propranolol. These findings suggest an important role of beta-adrenergic receptors in the regulation of cell proliferation in lung tumors comprised of this cell type.

Adenocarcinoma↗