The DEBR rat model for alopecia areata.
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Alopecia Areata↗
Biomedical subjects
B E Johnson
Publications and source records attributed to B E Johnson.
Phototumorigenicity of 6-methylangelicin derivatives.
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Animals↗
The DEBR rat: an animal model of human alopecia areata.
The Dundee experimental bald rat (DEBR) is reported as a model for human alopecia areata. Parallels with human alopecia areata were observed in relation to the gradual and patchy loss of hair and the penetration of both pelage and vibrissa follicles by mononuclear cells. In particular, the apparent disruption of the follicles within the precortical region of the epidermal component and consequent alterations of normal geometrical relationships between dermal and epidermal components relate directly to similar studies on human alopecia areata. In comparison with other previously described hypotrichotic rodent mutants, the DEBR rat exhibits a unique mechanism of hair loss which may provide important information regarding the pathomechanism of human alopecia areata.
Alopecia Areata↗
Differential effects of FK 506 and cyclosporine on hair regrowth in the DEBR model of alopecia areata.
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Alopecia Areata↗
Tanning with ultraviolet A sunbeds.
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Adult↗
Altered structure and expression of the human retinoblastoma susceptibility gene in small cell lung cancer.
Karyotypic and molecular genetic evidence has indicated that deletion or rearrangement of both chromosomes 3 and 13 may be important in the pathology of human small cell lung cancer (SCLC). The retinoblastoma susceptibility gene, RB, on chromosome 13 band q14, has previously been shown to be altered in SCLC [J. W. Harbour et al., Science (Wash. DC), 241: 353-357, 1988; J. Yokota et al., Oncogene, 3: 471-475, 1988]. Our studies of 26 SCLC tumor and normal DNA samples indicate that 6 of 6 patients whose normal cell DNA was heterozygous for an RB restriction fragment length polymorphism have lost one of the two alleles in their tumor DNA. Consistent with other studies, we find 2 of 26 tumors with homozygous deletions within the RB gene. Of 13 SCLC cell lines examined, only 3 expressed greater than trace amounts of RB mRNA. RB protein was detected in 2 of 14 SCLC cell lines examined, unlike the results of Yokota et al. (Oncogene, 3: 471-475, 1988) which showed no RB protein in any of the 9 cell lines they examined. Only unphosphorylated RB protein was detected in SCLC cell line H209, suggesting that the RB protein may be inactivated by a novel mechanism in this cell line. These data suggest that inactivation of the RB gene is a frequent if not universal event in SCLC.
Alleles↗
Characteristics of cell lines established from human gastric carcinoma.
We report the establishment and characterization of four continuous cell lines derived from human primary and metastatic gastric carcinomas, and we compare their properties with a panel of colorectal carcinoma cell lines previously established and reported by us. Our success rate in culturing gastric carcinomas was relatively low, especially from primary tumors, compared to colorectal carcinoma. These observations may reflect the relatively modest number of gastric carcinoma cell lines established (mainly from Japan), compared to the abundance of colorectal carcinoma lines established worldwide. All four gastric lines expressed the surface glycoproteins carcinoembryonic antigen and TAG-72 and three lines expressed CA 19-9. Two of the lines expressed aromatic amino acid decarboxylase but lacked other markers for neuroendocrine differentiation. All four lines were positive for vasoactive intestinal peptide receptors but lacked gastrin receptors. In addition, two lines expressed receptors for muscarinic/cholinergic receptors but not beta-adrenergic receptors. Cytogenetic evidence for gene amplification was present in the cell lines. All four lines contained varying numbers of double-minute chromosomes. One line, SNU-16, was amplified for the c-myc proto-oncogene and contained four homogeneously staining regions. While c-myc and c-erb-B-2 RNA were expressed by all lines, there was no evidence of amplification or overexpression of several other proto-oncogenes and growth factors. The multiple properties we have described in our gastric carcinoma cell lines are remarkably similar to those found in the panel of colorectal carcinoma cell lines. These properties include morphology, growth characteristics, expression of surface glycoproteins, partial expression of neuroendocrine cell markers, frequent chromosomal evidence of gene amplification, and occasional amplification of the c-myc proto-oncogene. Our four well characterized cell lines should provide useful additions to the modest number currently available for in vitro studies of gastric carcinoma.
Antigens, Neoplasm↗
Expression of the atrial natriuretic factor gene in small cell lung cancer tumors and tumor cell lines.
Hyponatremia in patients with small cell lung cancer can be caused by tumor production of arginine vasopressin (AVP) and result in the syndrome of inappropriate antidiuretic hormone. In evaluating the expression of AVP mRNA from tumor and tumor cell line specimens from five patients with small cell lung cancer and hyponatremia (presumed to have the syndrome of inappropriate antidiuretic hormone), we found that the tumors and tumor cell lines from two of these five patients expressed AVP mRNA. The RNA samples from the three patients with undetectable AVP mRNA expressed abundant atrial natriuretic factor (ANF) mRNA. Analysis of specimens from three patients with small cell lung cancer and normal serum sodium levels revealed no detectable AVP mRNA expression, and samples from only one of these three patients' specimens expressed detectable ANF mRNA. The AVP and ANF peptide levels in lysate preparations of the tumor cell lines from four of these patients were tested by radioimmunoassay and confirmed the gene expression data. These studies demonstrate ectopic production of ANF mRNA in small cell lung cancer specimens from patients with this cancer and the syndrome of inappropriate antidiuretic hormone. These findings will be of particular interest if future studies demonstrate that ectopic ANF production can cause sodium abnormalities in patients with small cell lung cancer.
Aged↗
Correlation of in vitro drug-sensitivity testing results with response to chemotherapy and survival in extensive-stage small cell lung cancer: a prospective clinical trial.
We devised a novel clinical protocol for extensive-stage small cell lung cancer (SCLC), selecting chemotherapy whenever possible on the basis of in vitro drug-sensitivity testing (DST) of individual patients' tumor specimens. Most of the specimens were obtained from metastatic sites during routine staging procedures. Increase of tumor cell number by culture in selective media usually was required before DST could be performed. We used the Weisenthal dye exclusion assay to place the seven drugs in rank order and to select the in vitro best regimen (IVBR), a three-drug combination of proved efficacy in SCLC. After initial staging and specimen acquisition, patients received etoposide and cisplatin (primary therapy) and were restaged after 12 weeks. Patients with partial or no responses and those relapsing after a complete response to primary therapy were switched to the IVBR if DST data were available. If DST data were unavailable, an empiric combination, vincristine-doxorubicin-cyclophosphamide, was administered as secondary therapy. Tumor-containing specimens were collected from 60 of the 80 patients (75%). One or more cell lines were established from 28 patients, and DST data were available from 26 patients (33% of total). Several parameters of in vitro drug sensitivity were significantly associated [two-sided P (P2) less than .05] with clinical response to primary therapy and also with response to the IVBR and were marginally associated with length of survival (.07 less than or equal to P2 less than or equal to .08). Sixteen patients (23%) received their IVBR as secondary therapy, and four of these (25%) attained a complete response, compared with three of 43 (7%) who received an empiric regimen (P2 = .16). We concluded that (a) selection of individualized chemotherapy is labor intensive but feasible in extensive-stage SCLC; (b) DST data are associated with clinical response to primary therapy and to secondary therapy with an IVBR; and (c) further observations will be required if we are to determine whether there is a modest therapeutic benefit to administering the IVBR as a secondary therapy.
Antineoplastic Combined Chemotherapy Protocols↗
The loss of antibiotic activity of ciprofloxacin by photodegradation.
Solutions of ciprofloxacin were irradiated with different wavebands of ultraviolet and visible radiation and the antibiotic activity of the drug was determined against Escherichia coli. A wavelength dependent loss of antibiotic activity was found with maximal effect around 320 nm; no effect occurred with visible irradiation. The degree of the decrease in activity with longer wavelength ultraviolet (UVA) radiation was sufficient to indicate that human exposure to sunlight through window glass (greater than 320 nm) or UVA from tanning sunbeds may result in a significant reduction in both cutaneous and circulating levels of ciprofloxacin.
Ciprofloxacin↗
Ciprofloxacin-induced photosensitivity: in vitro and in vivo studies.
Ciprofloxacin is one of the new series of broad-spectrum antibiotic quinolones, chemically related to nalidixic acid and which may, therefore, induce photosensitization of human skin. Three in vitro tests for phototoxicity: the destruction of histidine, killing of mouse peritoneal macrophages and inhibition of PHA-stimulated DNA synthesis in human lymphocytes have demonstrated this photosensitizing potential with UVA irradiation at an order of magnitude lower than that for nalidixic acid. The Candida albicans test and photohaemolysis were negative. Controlled irradiation monochromator phototesting of 12 subjects, before, during and after taking ciprofloxacin showed subclinical photosensitivity with significantly lowered minimal 24 h erythema doses at 335 +/- 30 nm, 365 +/- 30 nm and 400 +/- 30 nm but not at 305 +/- 5 nm or above 400 +/- 30 nm.
Adult↗
Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors.
To determine the subsequent evolution of neurologic, neuropsychologic, and intracranial anatomic findings in long-term survivors of small-cell cancer, we repeated an evaluation done 4 years previously in patients 6 to 13 years after treatment. Fifteen patients were reevaluated with a history and physical examination, mental status examination, neuropsychologic testing, computed cranial tomographic (CCT) scans, and magnetic resonance imaging (MRI). All but one was ambulatory and none were institutionalized. Thirteen of 15 had neurologic complaints, 10 of 15 had an abnormal neurologic examination, seven of 14 had an abnormal mental status examination, 12 of 14 had abnormal neuropsychologic testing, 12 of 15 had abnormal CCT scans, and seven of 15 had white-matter abnormalities on MRI scans. No dramatic decline in performance status, functional status, neurologic symptoms, or neurologic examination occurred in these patients with 4 years of additional follow-up. More patients showed a decline in mental status examinations and neuropsychologic testing than demonstrated improvement. Anatomic studies showed no dramatic changes in the CCT scans and MRI confirmed these findings. From these data we conclude that there is a slow decline in neuropsychologic function in some of the patients surviving more than 6 years from a diagnosis of small-cell lung cancer. The anatomic abnormalities documented by CCT scans and MRI are more frequent in patients with abnormal neuropsychologic function.
Antineoplastic Combined Chemotherapy Protocols↗
Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation.
We evaluated the 10- to 15-year outcome of 252 patients with small-cell lung cancer entered into therapeutic clinical trials with or without chest and cranial irradiation. Thirty-two patients (13%) survived free of cancer for 2 or more years. Twelve patients (5%) survived at least 10 years free of cancer, and 10 patients are currently alive and free of cancer beyond 10 years. Six of these 10 patients currently function at a level comparable with that before diagnosis. The other 22 patients who were cancer-free at 2 years have died. Nine patients died from recurrent small-cell lung cancer 2 to 6.2 years after initiation of chemotherapy. Five died from non-small-cell lung cancer, three died of other malignancies, and five died of causes other than cancer. A small fraction of patients with small-cell lung cancer are cured of their original malignancy, but these patients remain at high risk for second cancers and death from other causes.
Actuarial Analysis↗
Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years.
In a study of 411 patients with small-cell lung cancer (SCLC) entered on therapeutic clinical trials between 1973 and 1987, we analyzed whether changes in the prognostic importance of pretreatment factors had occurred during the 14-year time period. After adjusting for other prognostic factors, brain involvement was associated with shorter survival in patients treated before December 1979 (P = .024) but not in patients treated thereafter (P = .54). The patients diagnosed before 1979 had brain metastases documented by radionuclide scan while computed cranial tomography (CCT) was more commonly used after 1979. Patients who had brain metastases diagnosed by radionuclide scan lived a shorter period of time than patients who had the diagnosis made by the more sensitive CCT scan (P = .031). In contrast, Cox proportional hazards modeling showed that liver metastases in patients were associated with shorter survival in patients treated after 1979 (P = .0007) but not in patients treated before then (P = .30). A larger proportion of patients had a routine liver biopsy before 1979 than after 1979 when more patients had the liver staged with less sensitive imaging studies and biochemical parameters. Patients with SCLC whose cancer was confined to the thorax but had medical or anatomic contraindications to intensive chest radiotherapy had similar survival compared with patients with limited-stage SCLC who were treated with combination chemotherapy alone (P = .68). From these data we conclude: (1) the sensitivity of the staging procedures used can affect the impact on survival of cancer involvement of a given site; and (2) patients with cancer confined to their chest with medical or anatomic contraindications to chest radiotherapy do not have a shorter survival than patients with limited-stage disease treated with chemotherapy alone.
Adult↗
3-Methylcholanthrene-induced immunosuppression in mice to Trichinella spiralis antigens.
The immunosuppressive effects of in vivo (subcutaneous) exposure to 40 or 80 mg/kg 3-methylcholanthrene (MC) were examined in aryl hydrocarbon hydroxylase (AHH) responsive C57BL/6 (B6) and AHH non-responsive DBA/2 (D2) inbred strains of mice. Twenty-four hours after treatment with carcinogen or vehicle alone, animals were primed with crude L1 muscle larvae antigen from T. spiralis. Immune status was assessed in vitro after six days as antigen-specific lymphoproliferation. The proliferation of splenocytes from MC-treated D2 and B6 mice was significantly impaired compared to controls. To examine the cellular basis of the immunosuppression, primed splenocytes from control and MC-treated mice were separated into adherent and non-adherent fractions on Sephadex G-10 columns. When antigen-pulsed adherent cells from MC-treated B6 and D2 mice were recombined with control non-adherent cells from syngeneic and B6D2F1 mice, T-cell proliferation was significantly reduced. This suppression was not observed with the addition of increased numbers of adherent cells. Non-adherent cells from MC-treated mice showed a decreased capacity to respond to the presence of control antigen-pulsed adherent cells from appropriate mice. These results suggest that MC treatment has a similar suppressive effect on the immune responses of both B6 and D2 mice that involves the quality of accessory cell-T-cell interactions.
Animals↗
Drug and chemical photosensitivity.
Chemical (especially drug-induced) cutaneous photo-sensitization is an increasing problem in dermatology. Various molecular, biochemical, and pathophysiologic processes are involved in translation of ultraviolet (UV) or visible radiation energy into phototoxic and/or photoallergic reactions in the skin. Phototoxicity presents in four major reaction patterns, depending on the target for photosensitization. Photoallergy is now confirmed as an immune system cell mediated photosensitization. Drug-induced photosensitivity is not necessarily a good reason for stopping therapy. Sunlight avoidance, appropriate protection with clothing, sunscreens, and drug dose reduction may allow continuation of treatment. However, future drug registration procedures may require more detailed testing both in vitro and in vivo, and good clinical trials for which suitable protocols are becoming available.
Animals↗
Retention of chromosome 3 in extrapulmonary small cell cancer shown by molecular and cytogenetic studies.
In small cell lung carcinoma, one of the short arms of chromosome 3 is typically lost. To investigate chromosome 3 in extrapulmonary small cell carcinoma, we used DNA probes that detect restriction-fragment-length polymorphisms at loci on 3p. These probes were used to study DNA extracted from tumors and normal tissues and/or tumor cell lines from five patients with extrapulmonary small cell cancer. Tumor DNA from four of the five patients with extrapulmonary small cell cancer retained heterozygosity at loci on 3p. Cytogenetic studies of the tumor cell lines established from these four patients showed retention of both short arms of chromosome 3. We conclude that the loss of genetic material from 3p observed in small cell lung cancer is not typical in extrapulmonary small cell cancer.
Adult↗
MDR1 gene expression in lung cancer.
The MDR1 gene (also known as PGY1) is frequently overexpressed in multidrug-resistant cell lines. We investigated the role of MDR1 gene expression in lung cancer by performing RNA slot blot analysis in samples from a panel of 24 lung cancers, 10 corresponding nontumorous lung tissues, and 67 tumor cell lines of several histologic types. Almost all of the tumors, nontumorous lung tissues, and cell lines expressed low levels of MDR1 RNA. Relatively higher levels were found in only one type of lung cancer, a subgroup of non-small cell lung cancers expressing neuroendocrine markers. No evidence of MDR1 gene amplification or rearrangements was detected. We found no correlation between MDR1 gene expression in cell lines and (a) in vitro chemosensitivity of the cells, (b) prior therapy status of the patients, or (c) clinical response to therapy. We conclude that the clinical multidrug resistance of many lung cancers cannot be explained solely on the basis of expression of the MDR1 gene.
Drug Resistance↗