Respiratory muscle weakness in Addison's disease.
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Addison Disease↗
Biomedical subjects
J Wass
Publications and source records attributed to J Wass.
Establishment and characterization of a new human bladder cancer cell line showing features of squamous and glandular differentiation.
Tumour-cell heterogeneity has been studied in a continuous cell line, UCRU-BL-17CL, established from a xenografted human primary bladder carcinoma. The cell line, grown in vitro for more than 30 generations, reflects the pathology of both the xenograft from which it was derived and the original human tumour. It comprises mainly adenocarcinoma cells which secrete mucin in vitro, as well as squamous and transitional carcinoma cells. Features of both adenocarcinomatous and squamous differentiation have been observed within the same cell. The line expresses ABH blood group isoantigens, binds to peanut lectin and reacts with monoclonal antibodies (MAbs) raised against keratin and against normal and malignant epithelial cells. It also reacts with MAbs against ras p21 proteins and the epidermal growth factor receptor (EGFR). It shows high levels of lactic acid dehydrogenase isozyme 5, consistent with a high-grade tumour, forms colonies in methylcellulose and is tumorigenic in nude mice. The karyotype (human) shows many marker chromosomes, consistent with expression of EGF receptors and ras p21 proteins, and an 11:13 translocation. DNA content, as studied by flow cytometry, reveals a shift from tetraploid to near triploid. This line may provide a useful model for studies of the histogenesis of bladder cancer and the relationship between transitional-cell carcinoma and the other histological subtypes of this disease.
Aged↗
Features of squamous and adenocarcinoma in the same cell in a xenografted human transitional cell carcinoma: evidence of a common histogenesis?
Ultrastructural features of squamous differentiation have been found in adenocarcinomatous cells in a xenografted line (UCRU-BL-17) established in nude mice from a primary human bladder transitional cell carcinoma (grade III, stage T4) with a tetraploid DNA component. The line has been characterized by light and electron microscopy, flow cytometry and immunocytochemistry. The initial xenograft showed predominantly adenocarcinomatous differentiation with mucin secretion, whilst the subsequent passages also contained cells showing squamous differentiation. A xenograft subline established from a cell culture of the initial xenograft shows the emergence of a population of cells with near triploid DNA, which are less differentiated, grow more quickly, show decreased expression of carcinoembryonic antigen, and a change in the distribution of staining with peanut lectin from cell surface to cytoplasm. These lines offer an unusual opportunity to study the histogenetic relationships between the histological subtypes of bladder cancer.
Adenocarcinoma↗
Cyclosporin for central nervous system sarcoidosis.
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Adult↗
Human bladder cancer grown as xenografts and in tissue culture as models of the biology and treatment of invasive bladder cancer.
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Animals↗
Flow cytometric and karyotypic analysis of a primary small cell carcinoma of the prostate: a xenografted cell line.
A human small cell undifferentiated carcinoma of the prostate, xenografted in nude mice, was analyzed both cytogenetically and by DNA flow cytometry. The DNA content of the line indicated its stability on serial passage, and was consistent with the cytogenetic findings. The banded karyotype was hypodiploid with nonrandom losses of chromosomes #6, #7, #10, and #13. Structural rearrangements involved chromosomes #1 and #2, and there were three unidentified markers. The findings were compared with those described in other types of prostatic carcinoma.
Animals↗
Fine needle aspiration sampling of bone marrow for DNA flow cytometric analysis.
Fine needle aspiration (FNA) was used to obtain bone marrow samples from 57 patients with a variety of hematologic disorders, and from three normal subjects. We confirm that the technique is well tolerated and show that reliable cytokinetic and cell differential data can be obtained provided marrow fragments are isolated for analysis. This requires aspiration of a larger volume of marrow than originally described but this can still be achieved with minimal discomfort to the patient. The technique thus provides a means by which marrow samples could be obtained at frequent intervals in the monitoring of chemotherapy.
Biopsy, Needle↗
Significance of secondary cytogenetic changes in patients with Ph-positive chronic granulocytic leukemia in the acute phase.
The karyotypic abnormalities in 29 patients in the acute phase of Ph-positive chronic granulocytic leukemia are described. Of 18 Giemsa banded samples, 11 showed one or more of the typical additional abnormalities found in the acute phase, namely +Ph, +8, or i(17q). Survival data from these patients was combined with three published series providing 135 patients and the effect of one, two, or three of these abnormalities tested. The prognosis was significantly worse in patients with two or more additional abnormalities, compared with those with one or none. Analysis of the subset of patients with only one additional abnormality [+Ph or +8 or i(17q)] suggested a worse prognosis in those with +8 than in those with +Ph or i(17q), although the differences were not significant. There also was a trend for patients in whom all metaphases showed abnormalities in addition to the Ph chromosome to have a worse prognosis than those in whom some or all metaphases contained the Ph only. However, this trend just failed to reach a 5% level of significance.
Adult↗
A preliminary report on the suitability of sheep epidermal squamous cell carcinoma as a solid tumor model in the evaluation of intra-arterial methotrexate administration.
A preliminary study was undertaken to assess the sensitivity of sheep epidermal squamous cell carcinoma, in the head and neck region, to intra-arterial (IA) methotrexate (MTX) infusion. There was an objective tumor response (40-56% regression) in all three IA-infused sheep, whereas tumor progression was observed in all three animals treated intravenously (IV). Regional and systemic side effects were negligible in all cases. Technically, IA drug infusion in the sheep was an improvement on previous small animal models, with no problems related to arterial catheter insertion, blockage, or dislodgement, and tolerable infusion times being of markedly longer duration. The histological differentiation of moderately differentiated stage II lesions improved during therapy irrespective of clinical response, whilst the histology of well-differentiated stage III and IV tumors remained unchanged. Tumor cell cycle stage and ploidy characteristics, as determined by flow cytometric DNA analysis, were little affected by either mode of drug administration. It is concluded that sheep epidermal carcinoma is responsive to IA MTX, and that this animal model is the most appropriate yet utilised to study the comparative effects of IA and IV chemotherapy in the head and neck region.
Animals↗
Ploidy and proliferative characteristics of sheep epidermal squamous cell carcinoma determined by flow cytometric DNA analysis.
Multiple biopsies from each of 22 primary sheep epidermal squamous cell carcinomas were analysed by flow cytometry to determine the G0/G1 modal DNA content ("ploidy") and cell cycle characteristics within each tumour. Ten of 12 tumours where aneuploidy was present demonstrated uniform intra-tumour aneuploid populations regardless of the site of biopsy. Increasing tumour volume (from stage I/II to stage III/IV lesions) was associated with increased histological variability and ultimate heterogeneity of G0/G1 DNA content, whilst the mean numbers of S phase cells decreased. These features were consistent with the effects of variable tissue hypoxia seen with changes in effective vascularity in developing tumours. Decreasing histological differentiation was associated with an increase in numbers of cells synthesising DNA within 44 biopsies with measurable S phase, and, in stage I/II biopsies, correlated with an increased incidence of aneuploidy.
Animals↗
Effects of ultraviolet radiation and immunosuppressive therapy on mouse epidermal cell kinetics.
The effects of immunosuppressive drugs on epidermal cell mitotic activity and the proliferative response of epidermis following ultraviolet radiation (UVR) were tested. Hairless (Skh-hr 1) mice were treated with immunosuppressive drugs at equivalent clinical doses with or without concomitant UVR (290-400 nm). Epidermal parameters measured were mitotic index (Im), rate of entry into mitosis (Fm), flash labelling index (FLI), rate of entry into DNA synthesis (Fs) and DNA content (flow cytometric analysis). In non-irradiated skin, prednisolone therapy depressed both mitotic activity and DNA synthesis; azathioprine and cyclosporin A had no effect; cyclophosphamide therapy increased the Fm and FLI values. Following repeated doses of UVR, there were enhanced mitotic activity and DNA synthesis in epidermis. Prednisolone therapy moderately depressed both proliferative responses; cyclophosphamide enhanced mitotic activity; azathioprine and cyclosporin A had no effect on these responses. The significance of these findings in relation to potential for increased susceptibility of skin to UV-induced carcinogenesis is discussed.
Animals↗
Bladder cancer xenografts: a model of tumor cell heterogeneity.
Twenty bladder biopsies from patients with primary transitional cell carcinoma were inoculated into nude mice. To date, eleven of these have grown as primary implants and three serially transplantable xenograft lines (UCRU-BL-12, UCRU-BL-13, UCRU-BL-14) have been established. The histological and ultrastructural features of human transitional cell carcinoma have been maintained in each line. Despite a relatively uniform histological appearance, several indices of occult tumor heterogeneity have been revealed. Immunocytochemical staining was negative for beta-subunit human chorionic gonadotrophin but positive for carcinoembryonic antigen only in areas of squamous differentiation. All three tumors bound peanut lectin. Flow cytometric DNA analysis of UCRU-BL-13 showed multiple aneuploid peaks, separate populations being demonstrated in different xenografts of the same generation. However, the morphologies of these tumors remained identical. On initial implantation UCRU-BL-12 and UCRU-BL-14 were near diploid but aneuploid populations became apparent with increasing passage number. Each xenograft line caused cachexia in the host mice. Treatment with the cisplatin analogue, isopropyl platinum, ameliorated the cachexia displayed by mice carrying UCRU-BL-14 but did not cause tumor regression. UCRU-BL-12, when tested with cisplatin, isopropyl platinum, and carboplatin, showed equivalent growth retardation with each drug. These xenografted human bladder cancers may be useful models for the study of heterogeneity of the tumor populations in bladder cancer and for the evaluation of new approaches to treatment.
Adult↗
Fragment filtration: a method for the accurate determination of flow cytometric kinetic data from bone marrow aspirates.
The extent to which bone marrow obtained by conventional aspiration is contaminated by peripheral blood has been confirmed and quantitated. In marrow aspirates from normal subjects the median percentage of nucleated cells that had originated from the peripheral blood was 32% (range 2.5%-64%), in patients with acute leukemia 23% (range 0.5%-96.5%), in patients with chronic leukemia 59% (range 17%-76%), and in patients with lymphoma 31% (range 0.5%-74%). Flow cytometric (FCM) DNA analysis of conventional marrow aspirates from a range of subjects significantly underestimated the proportions of S-phase cells present, when compared with results from trephines obtained at the same time. Having shown, using 51Cr-labeled red cells in mice, that circulating red cells do not reenter the marrow parenchyma, a mathematical correction for contaminating blood similar to that described by Holdrinet et al. was devised. This correction improved the S-phase cell estimate from aspirated marrows, and the corrected values were not significantly different from values from paired trephine samples. A previously described technique for collecting fragments by filtration of aspirated marrow has been adapted for FCM analysis as a more direct way of overcoming problems due to blood contamination. This method was shown to yield estimates of S-phase cells not significantly different from those in paired marrow trephines and offers an alternative to routine trephine biopsies for FCM analysis of marrow cell kinetics.
Animals↗
Malignant melanoma: analysis by DNA flow cytometry.
The DNA content of 14 primary and 111 secondary melanomas was determined by flow cytometry. Aneuploidy was detected in 67% of samples. The frequency with which aneuploid cells were found was similar in primary and metastatic melanomas and, in the metastatic group, for melanotic and amelanotic tumours. Aneuploid diversity was marked with a wide variation in DNA content between tumours. Serial biopsies were performed in 14 patients, and in 10 there was discordance in DNA profiles between first and subsequent biopsies. Tumour biopsies taken from different sites at the same time also showed discordance in 3 of 5 cases. These features highlight the degree of cellular heterogeneity in malignant melanoma.
Aneuploidy↗
Treatment of prolactinomas with megavoltage radiotherapy.
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Humans↗
Cavitary histoplasmosis occurring during two large urban outbreaks. Analysis of clinical, epidemiologic, roentgenographic, and laboratory features.
We have compared risk factors for cavitary histoplasmosis in 62 patients with that manifestation of the infection and in 679 patients with other forms of histoplasmosis, and we have evaluated the clinical and laboratory findings in 45 patients with cavitary histoplasmosis who were cared for at the Indiana University Medical Center hospitals during two large histoplasmosis outbreaks. Chronic obstructive lung disease and old age were the strongest risk factors for cavitary histoplasmosis but male sex, white race and immunosuppression were also important in certain patient groups. Fever, sweats, weight loss, productive cough, anemia, lymphopenia, and alkaline phosphatase elevation were common findings. The patients were occasionally incorrectly treated for presumed class 3 tuberculosis. Cultures were positive in 58% of patients, with sputum samples providing the highest yield (61%). Histoplasmal serologic tests provided useful clues to the diagnosis, positive in over 90% of cases. About one-third of patients recovered spontaneously while another 35% improved following treatment. About 4% developed chronic untreated cavitary histoplasmosis characterized by clinical and roentgenographic exacerbations and remissions. Of the deaths in four patients with untreated disease, one was caused by disseminated histoplasmosis while three died of other causes. Ketoconazole appeared effective in three of seven patients while its effect in three additional patients was uncertain. Toxicity precluded completion of ketoconazole therapy in one patient. Only amphotericin B has been proven to be effective therapy for cavitary histoplasmosis.
Adolescent↗
Inhibition of interleukin 2 production by factors released from tumor cells.
In previous studies, cultured melanoma cells were shown to have a suppressive influence on the induction of cytotoxic T cells. Our investigation of the mechanism of these effects revealed that supernatants from certain cultures of melanoma cells contained inhibitory activity against the production of interleukin 2 (IL 2) from phytohemagglutinin (PHA)-stimulated cultures of lymphocytes. These supernatants did not inhibit interleukin 1 production, and also did not inhibit the mitogenic activity of performed IL 2 on IL 2-dependent target cells. Production of the inhibitory activity could be reduced by inhibitors of protein synthesis, but this activity was not inhibited by digestion with the proteolytic enzymes trypsin or pronase. Gel filtration analysis of tumor supernatants revealed that the majority of the inhibitory activity was detected in fractions of approximately 44 and 7 Kd. The addition of supernatants with inhibitory activity to PHA-stimulated cultures of lymphocytes was associated with reduced transition of cells from G1 to S phase of cell division, which could be reversed by the addition of IL 2. Preliminary studies suggest that the release of the factor(s) from melanoma cells may be related to rapid progression of tumor growth in patients, and therefore may be of prognostic significance in tumor host relationships.
Cell Cycle↗
Cell cycle homogeneity in bone marrow samples from different sites: flow cytometric evaluation of multiple samples from sheep.
The distributions of cells in each of the phases of the cell cycle, determined by flow cytometry (FCM), were compared in multiple marrow trephine biopsy samples from 3 sites (both iliac bones and sternum) in 5 sheep. Within any one animal no significant differences could be found between the proportions of cells in the G0/G1, S or G2 + M phases of the cycle from different sites. Differences between animals were detected and these were consistent for any of the sites sampled. We conclude that the proliferative characteristics of marrow cells as determined by FCM in any one animal at one time are comparable at anatomically distinct marrow sites, and that a sample from one site is representative of the whole.
Animals↗