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Biomedical subjects

B E Johnson

Publications and source records attributed to B E Johnson.

At least 19 recordsLinked to original sources
PubMed1992

Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation.

Using immunoblotting techniques we studied the sera from small cell lung cancer and non-small cell lung cancer patients for antibodies directed against p53. We have also characterized the majority of these patients' tumors for p53 mutations. In the sera of 13% of the patients (4 of 40 small cell lung cancer and 2 of 6 non-small cell lung cancer) we found antibodies specific for the p53 tumor suppressor gene product. All of the antibody-positive patients tested had p53 missense mutations and expressed detectable p53 antigen in their tumor cell lines. No anti-p53 antibodies were detected in sera from patients whose tumor had p53 stop, splice/stop, splice, or frameshift mutations (n = 10). Thus, while we find that the ability of lung cancer patients to develop anti-p53 antibodies is correlated with the type of p53 mutation, many patients have tumors with missense p53 mutations and did not develop anti-p53 antibodies. The presence of p53 antibodies was not correlated to stage, prior treatment, sex, or survival. None of these lung cancer patient sera had measurable amounts of p53 antigen. By immunoblotting all six anti-p53 antisera we were able to detect a variety of mutant p53 proteins (including those from antibody-negative patients) and detected wild-type p53 protein. The development of anti-p53 antibodies represents an interesting model system for studying immune responses in cancer patients against mutant oncogene products.

Adenocarcinoma↗
PubMed1992

Antitumor activity of magainin analogues against human lung cancer cell lines.

Magainin 1 and magainin 2, originally isolated from African clawed frog Xenopus laevis skin, inhibit the growth of bacteria and fungi. Synthetic magainin A (MAG A) and magainin G (MAG G) are more potent against bacteria and protozoa. In order to determine the antitumor activity of these analogues, we have tested these two analogues against six small cell lung cancer (SCLC) cell lines NCI-H82, NCI-H526, NCI-H678, NCI-H735, NCI-H841, and NCI-H889, which were known to differ by more than 10-fold in their sensitivity to different chemotherapeutic agents, and four normal human fibroblast cell lines. Semiautomated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays of the six SCLC cell lines revealed average concentrations producing 50% inhibition (IC50) values of 2.6 microM (range, 0.49-9.30 microM) for cisplatin, 2.5 microM (range, 0.39-6.00 microM) for etoposide, and 138.8 nM (range, 55.0-450.0 nM) for doxorubicin. The average IC50 of MAG A was 8.64 microM (range, 6.23-11.7 microM) and that of MAG G was 8.82 microM (range, 4.44-12.5 microM) against the SCLC cell lines. Despite a 10-fold difference in sensitivity to standard chemotherapeutic agents, the IC50 of MAG A and MAG G differs by less than 3-fold. The average IC50 against four normal human fibroblast cell lines was 21.1 microM (range, 12.7-25.6 microM) for MAG A and 29.2 microM (range, 21.3-34.8 microM) for MAG G. Combined exposure to the IC50 concentration of MAG A or MAG G plus IC50 of etoposide or cisplatin decreased the percentage of surviving SCLC cells to 29.0% (range, 26.1-31.7%). MAG A or MAG G had an additive effect when used with standard chemotherapeutic agents. These data suggest that MAG A and MAG G have in vitro antitumor activity against SCLC cell lines.

Antimicrobial Cationic Peptides↗
PubMed1992

In vitro phototoxicity of nifedipine: sequential induction of toxic and non-toxic photoproducts with UVA radiation.

Anecdotal reports suggest that the dihydropyridine calcium antagonist, nifedipine (NIF), may be phototoxic in human skin. We have studied NIF phototoxicity in vitro using UVA fluorescent tubes (Sylvania PUVA). NIF was phototoxic to Candida albicans and induced photohaemolysis both with NIF present during irradiation and with pre-irradiated drug. In V79 hamster fibroblasts, NIF (10 micrograms ml-1) was phototoxic MTT assay) 24 h after irradiation (0-112 kJ m-2); at 7.5 kJ m-2, about 70% of cells were damaged whilst at 37.5 kJ m-2, only about 45% of cells were damaged. A similar pattern was seen with pre-irradiated NIF. Absorption spectroscopy showed that the NIF absorption maximum (Amax approximately 340 nm) blue-shifted to 314 nm at low UVA doses (7.5 kJ m-2 or less) and red-shifted to 345 nm at higher doses (isosbestic point, 325 nm). Thin layer chromatography of irradiated NIF showed a single photoproduct (PP1; Amax approximately 314 nm) formed at 7.5 kJ m-2 or less which disappeared at higher UVA doses to give further photoproducts. PP1 was highly dark toxic to V79 cells (50% damage at about 5 micrograms ml-1) but PP1 pre-irradiated with UVA was non-toxic. Preliminary gas chromatography-mass spectroscopy studies suggest that PP1 is the nitroso derivative of NIF. These results indicate that NIF phototoxicity in vitro is partially mediated by initial formation of a toxic photoproduct (PP1) but, paradoxically, subsequent UVA irradiation may reduce phototoxicity. The NIF concentrations required to induce in vitro phototoxicity are much greater than therapeutic plasma levels. Unless there is skin accumulation of NIF or PP1, our in vitro results suggest that NIF may not be an important skin-photosensitizing agent in vivo.

Animals↗
PubMed1992

Polymorphic sites within the MCC and APC loci reveal very frequent loss of heterozygosity in human small cell lung cancer.

Using single-strand conformation polymorphism we have found two polymorphic sites, AAC to AAT at codon 511 (exon 12) and GCT to GCG at codon 708 (exon 15), in the MCC gene. These sites and an RsaI polymorphic site in APC allowed us to study 23 human small cell lung cancer (SCLC) and 7 non-small cell lung cancer samples for allele loss. Of the 23 SCLC samples, 21 (91%) were informative for one or more of these markers, and we found allele loss in more than 80% (17 of 21). In non-small cell lung cancer samples, 5 of 7 (71%) were informative, and reduction or loss of one allele was found in 2 of 5 (40%). Seven cases were informative for both genes, loss of heterozygosity occurred for both genes in five, one retained heterozygosity for both, and one SCLC had loss of heterozygosity for APC but not for MCC. We conclude that loss of heterozygosity occurs frequently for MCC and APC in lung cancer of all histological types and is very frequent in SCLC. This suggests the presence of tumor suppressor gene(s) in the MCC/APC region of 5q21 involved in human lung cancer.

Base Sequence↗
PubMed1992

Estrogen and progesterone replacement therapy reduces glucocorticoid-induced bone loss.

This is a retrospective study of 15 postmenopausal or amenorrheic women aged 34-78 years who had taken prednisone for 6-108 months and were followed for 1 year while continuing to take doses of 5-15 mg/day. A total of 8 patients were treated with 0.6256 mg Premarin daily for 25 days and 5 mg/day of medroxyprogesterone on days 15-25 (ERT, group 2); 7 were followed without ERT (group 1). A group of 17 women, matched for age, were randomly selected from our computerized data base to serve as a control group (group 3), and 10 women of similar age who were taking ERT only (group 4) were selected to compare the response to ERT to that of group 2. Bone density (BD) was measured in the lumbar spine baseline and at 1 year using dual-photon or dual-energy x-ray absorptiometry. Spine density did not change significantly during the year of observation in group 1. Although BD decreased in 5 of 7 patients, the change was not significant (-0.034 +/- 0.018 g/cm2, p = 0.10). In group 2 BD increased significantly, with 7 of 8 patients showing an increase (0.037 +/- 0.011 g/cm2, p = 0.008). BD did not change significantly in the control group (0.013 +/- 0.008 g/cm2, p = 0.16). Loss of bone from the spine was significantly greater in group 1 than in controls (p = 0.02), but changes in group 2 were similar to those in the control group (p = 0.66).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1992

Force generation by orthodontic samarium-cobalt magnets.

The use of samarium-cobalt (Sm-Co) magnets for light force application is a relatively new concept in orthodontic tooth movement. This study reports on the forces generated by these magnets. Magnets were attached to aluminum rods mounted in a universal testing machine. The magnets were initially separated by 10 mm were moved toward each other at 2.5mm/min in repulsion or attraction, depending upon the magnetic pole orientation. The magnets were also positioned initially in contact and then moved apart at a rate of 2.5mm/min, again producing repulsion or attraction, depending upon the pole orientation. The Sm-Co magnets exhibit very large forces when in close approximation but forces decrease markedly at separations greater than 2mm. The force, P, generated between magnets is determined by their separation, d, and follows the relationship P = dn. At magnet separations of 0 to 2mm, the exponent n is equal to -0.4; at separations of 2mm to 7mm, exponent n equals -2.1 for both attraction and repulsion. Thus the classic Coulomb law of magnetic force was followed only at magnet separations of greater than 2mm. Force-separation behavior and the high cost of these magnets may not justify their routine clinical use.

Cobalt↗
PubMed1992

Paraneoplastic syndromes in lung cancer.

Paraneoplastic syndromes are caused by factors produced by cancer cells that often act at a site distant from both the primary site and its metastases. These syndromes are estimated to occur in only 7% to 15% of patients with cancer and are diagnoses of exclusion. If the definition of paraneoplastic syndrome is broadened to include indirect effects of the tumor such as cachexia or the anemia of chronic disease, the incidence is much higher. Lung cancer, particularly small cell lung cancer, is the most common malignancy causing paraneoplastic syndromes. This review focuses on recently published literature on paraneoplastic syndromes associated with lung cancer, including humoral hypercalcemia of malignancy, autoimmune paraneoplastic neurologic syndromes, neuromuscular disorders, and cancer cachexia. It includes advances in both molecular biology and immunology, and in clinical investigation.

Cachexia↗
PubMed1992

New diagnoses in a specialty clinic: opportunities for consultants.

The role consultants play in detecting disease coincidental to the reason for consultation is unclear. We sought to elucidate this function in the setting of a specialty clinic for osteoporosis. Making no specific attempt to screen for general conditions, we evaluated 760 women; any new diagnosis was found in the course of thoroughly examining the patient for osteoporosis. A total of 274 new diagnoses were counted, encompassing 68 conditions. There were 211 women (28%) in whom a new diagnosis was detected; a higher percentage of older women than younger women had a new diagnosis. A diagnosis severity grouping scheme was devised, groups C and D being those in which further evaluation was clearly indicated. The diagnoses in groups C and D accounted for 70% of all new diagnoses made, suggesting that trivial conditions were not overrepresented. The history and physical examination alone was responsible for 50% of the various conditions diagnosed and 64% of the total number of new diagnoses. The consultant has an excellent opportunity to detect disease while performing a specialty consultation.

Adult↗
PubMed1992

A comparison of the efficacy and relapse rates of narrowband UVB (TL-01) monotherapy vs. etretinate (re-TL-01) vs. etretinate-PUVA (re-PUVA) in the treatment of psoriasis patients.

Forty-five patients with extensive chronic plaque or guttate psoriasis were treated with either narrowband (TL-01) phototherapy, etretinate TL-01 combination therapy (re-TL-01) or etretinate and PUVA (re-PUVA) (15 patients in each group). Re-PUVA was the most effective therapy with 100% satisfactory clearance rate. TL-01 monotherapy had an 80% success rate; the relapse rate compared favourably with re-PUVA (50% in remission after 6 months). In the etretinate-TL-01 group, there was a 93% success rate and a one-third reduction in the total irradiation dose (8.0 J/cm2 vs. 12.7 J/cm2) but the relapse rate was higher, only 33% remaining in remission after 6 months.

Adult↗
PubMed1992

Effect of triiodothyronine on the expression of T cell markers and immune function in thyroidectomized White Leghorn chickens.

Hypothyroid K-strain chickens were produced by neonatal thyroidectomy and treatment with 6-propyl-2-thiouracil. Thyroidectomized birds were given 0, 1.5, 4.5, 15, or 45 micrograms/kg body wt of triiodothyronine (T3) by daily injection. At 5 weeks of age, thymocytes were prepared for flow cytometric analysis of CT-1a, CD3, CD4, and CD8 expression. Sham-operated birds had the smallest proportion of CT-1a+ cells and the brightest CT-1a+ cells. Unsupplemented thyroidectomized birds presented an inverse picture, while T3-treated thyroidectomized birds were intermediate. Fewer and less brightly labeled CD3+, CD4+, and CD8+ cells were associated with sham-operated birds or with higher levels of T3 replacement. Low levels (1.5 microgram/kg body wt) or no T3 treatment produced a greater proportion of positive, highly fluorescent cells. The ratios of CD4+ to CD8+ thymocytes were increased (P less than or equal to 0.05) by T3 supplementation. Functionally, thyroidectomy produced a decrease in mitogen-stimulated proliferation of peripheral blood lymphocytes. This effect was ameliorated by T3 supplementation. Further, thyroidectomy produced an elevation of plasma growth hormone concentrations. These results suggest that thyroid factors and alterations of thymic status significantly affect the generation of specific thymus-derived lymphocyte populations and their functional capabilities, perhaps due to changes in the thymic microenvironment. These alterations may have important consequences for the development of immunocompetence and disease resistance in chickens.

Animals↗
PubMed1992

Effect of thyroxine and chicken growth hormone on immune function in autoimmune thyroiditis (obese) strain chicks.

The effect of thyroxine (T4) and/or recombinant chicken growth hormone (rcGH) supplementation on immune function and on immune cell maturation was examined in Obese strain chickens. Day-old Obese strain chicks received the control treatments or were treated with either T4 (supplemented in the diet), T4-rcGH, or rcGH (by daily injection) in a full factorial design. At 4 weeks of age, the proliferative activity of peripheral blood T cells to either mitogenic or allogenic cell (mixed lymphocyte response) challenge was assessed. At the same time, peripheral blood lymphocytes and thymocytes were collected and prepared for flow cytometry analysis. Proliferative responses to both T cell mitogens and allogeneic splenocytes were significantly increased (P less than 0.05) by rcGH treatment, while the combined T4-rcGH treatment resulted in a significant increase in allogeneic and in concanavalin A responsiveness, but not in the response to phytohemagglutinin. All supplemented groups showed a significant decrease in the mean fluorescent intensity for CT-1a+ thymocytes, while thymocytes from birds receiving either T4 or rcGH alone had higher proportions of CD4+ and CD8+ cells. The monoclonal antibody staining of thymocytes from T4-rcGH-supplemented animals more closely resembled that of the unsupplemented controls. Among the peripheral blood lymphocytes, there were no changes in the numbers of CD4+, CD8+, or sIg+ cells as a result of treatment. The mean fluorescent intensity of sIg+ cells was significantly decreased, however, as a result of T4 supplementation when given either alone or in combination with rcGH. Finally, the mean fluorescent intensity ratios of CD4+ to CD8+ cells was significantly increased as a result of rcGH supplementation. These results strongly support a role for both the thyroid hormones and growth hormone in regulating and/or enhancing immune function, with changes in functional responses paralleled by concomitant changes in the T cell populations as expressed by shifts in T cell surface marker expression.

Animals↗
PubMed1992

myc family DNA amplification in tumors and tumor cell lines from patients with small-cell lung cancer.

The myc family DNA copy number of 291 specimens (183 tumors and 108 tumor cell lines) from patients with small-cell lung cancer has been reported in 15 different studies. Thirty-five of 108 (32%) cell lines from small-cell lung cancer patients have myc family DNA amplification (16 c-myc, 7 N-myc, and 12 L-myc). Thirty-seven of 183 (20%) tumors from patients with small-cell lung cancer have myc family DNA amplification (3 c-myc, 13 N-myc, and 18 L-myc). The myc family DNA copy number in tumors from patients with small-cell lung cancer is similar in the majority of sites from the same patient. The presence of myc family DNA amplification in the tumor cell line is also typically present in the tumor from the same patient. myc family DNA amplification is present in a minority of patients with small-cell lung cancer, and the data on its association with shorter survival of patients are meager at present. Future studies on the biology of the myc family in small-cell lung cancer may require use of newer technologies that can work with small tissue samples typically available at the start of therapy.

Carcinoma, Small Cell↗
PubMed1991

myc family DNA amplification in 107 tumors and tumor cell lines from patients with small cell lung cancer treated with different combination chemotherapy regimens.

We studied 107 specimens (38 tumors and 69 tumor cell lines) from 90 patients with small cell lung cancer to determine the characteristics and clinical situations of patients from whom tumor cell lines could be established and the myc family DNA copy number. The proportion of extensive stage small cell lung cancer patients from whom a tumor cell line could be established prior to the initiation of therapy increased during the 10 years of the study (P less than 0.001). Amplification of one of the myc family genes occurred in 3 of 40 (8%) of the untreated patient specimens compared to 19 of 67 (28%) of the treated patient specimens (P = 0.01). The myc family DNA amplification occurred in 17 of 54 (31%) of the specimens from patients treated with cyclophosphamide-based combinations and 2 of 13 (15%) of the specimens from patients treated with etoposide/cisplatin (P = 0.25). Both tumors and tumor cell lines were obtained from 17 patients with small cell lung cancer and the myc family DNA copy number was similar in 16 of the 17 patients. We conclude that: (a) myc family DNA amplification occurs more commonly in specimens from treated than untreated patients (b) there are no prominent differences in the frequency of amplification following treatment with different chemotherapy regimens; and (c) myc family DNA amplification is similar in tumors and tumor cell lines from the same patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Involvement of the RAF1 locus, at band 3p25, in the 3p deletion of small-cell lung cancer.

The ability to establish long-term cell lines of small-cell lung cancer (SCLC) has provided an in vitro model for the disease. We report on the characterization of 10 new human SCLC cell lines established from 34 cytopathologically positive specimens. Based on morphologic and biochemical characterization, growth properties, and expression of MYC and neuroendocrine properties, eight cell lines were categorized as "classic" and two cell lines as "variant". Cytogenetic examination revealed loss of all or part of 3p in all nine SCLC cell lines analyzed. The smallest deletion in common was found at 3p21-3p25. Restriction fragment length polymorphism (RFLP) analyses with probes for 3p were performed for correlation with karyotypic data and supported the cytogenetic findings. In 21 SCLC specimens (cell lines and tumor tissue) with normal DNA, used for comparison, we observed loss of heterozygosity at RAF1 (3p25) in ten of ten informative pairs by using two RFLPs from the RAF1 locus. In addition, loss of heterozygosity was noted in nine of 10 pairs examined with DNF15S2 (3p21) and four of four with D3S3 (3p14). Analysis of cell lines and tumor specimens that lacked paired normal tissue showed a homozygous pattern with the RAF1 probes in all 18 cases. Northern blots revealed significant expression of RAF1 in all cell lines tested. The transcript size was normal. The cytogenetic and RFLP data suggest that the RAF1 locus at 3p25 is involved in the chromosomal deletion of SCLC.

Blotting, Northern↗
PubMed1991

Paraneoplastic syndromes in thoracic malignancies.

Paraneoplastic syndromes are caused by factors produced by cancer cells that often act at a distance from both the primary site and its metastases. The most extensively characterized syndromes caused by cancer are those produced by polypeptide hormones, such as adrenocorticotropic hormone, and those produced by antibodies directed against tumor antigens that cross-react with neural tissue, such as in the Eaton-Lambert myasthenic syndrome. These syndromes develop in a minority of cancer patients, and are diagnoses of exclusion. Lung cancer, particularly small cell lung cancer, is the most common malignancy causing paraneoplastic syndromes. A large number of paraneoplastic syndromes have been described. This review focuses on the increased understanding of some of the well-documented syndromes that has occurred through recent advances principally in molecular biology and immunology.

Humans↗