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Biomedical subjects

G Goodwin

Publications and source records attributed to G Goodwin.

52 records · Page 3Linked to original sources
PubMed1991

Induction of differentiation of avian erythroblastosis virus-transformed erythroblasts by the protein kinase inhibitor H7: analysis of the transcription factor EF1.

The protein kinase inhibitor H7 [1-5(isoquinolinesulfonyl-2-methylpiperazine)] together with a temperature shift to 42 degrees C was found to reproducibly and efficiently induce differentiation of avian erythroblasts transformed with the avian erythroblastosis virus containing v-erbA and a temperature-sensitive v-erbB oncogene. Although a temperature shift to 42 degrees C without H7 results in some elevation of globin transcripts, much higher levels of transcripts accrue when cells are incubated at 42 degrees C with H7; under such conditions, 50-70% of the cells become benzidine positive. In order to investigate the mechanism by which the differentiation occurs, we have characterized and analyzed the levels of the erythroid transcription factor EF1, originally described as a factor binding to the beta H-globin promoter. Protein sequencing of EF1 shows that it is identical to the factor Eryf1. Using a peptide antibody and DNA-binding assays, we demonstrate that EF1 is present at high levels in the nucleus of undifferentiated HD3 cells, and, although there may be a small change when the cells are shifted to 42 degrees C, incubation of the cells with H7 at 42 degrees C does not result in a further elevation commensurate with the high levels of globin transcripts. It is concluded that v-erbA and v-erbB do not repress differentiation by limiting the levels of EF1.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

A novel T-cell protein which recognizes a palindromic sequence in the negative regulatory element of the human immunodeficiency virus long terminal repeat.

Two major protein-binding sites within the negative regulatory element of the human immunodeficiency virus type 1 long terminal repeat have been identified. One (site B) contained a palindromic sequence with homology to steroid/thyroid hormone response elements but was distinct from previously described binding sites of this class. A novel T-cell protein recognized the palindromic sequence within site B and also bound estrogen- or thyroid hormone-response elements with lower affinity. A 7-base-pair mutation in the site B palindrome, which destroyed protein binding, resulted in increased expression from the human immunodeficiency virus type 1 long terminal repeat in T cells.

Base Sequence↗
PubMed1989

GATAAG; a cis-control region binding an erythroid-specific nuclear factor with a role in globin and non-globin gene expression.

An erythroid-specific nuclear protein factor binds to a sequence motif (GATAAG) which is present in the promoter region of the mouse alpha and beta major globin genes, and in the erythroid-specific promoter of the human porphobilinogen deaminase (PBG-D) gene. The protein activity is conserved across species, being found in mouse erythroleukaemia (MEL) cells, chicken erythrocytes, the human erythroid K562 and KMOE cell lines, but not in a variety of non-erythroid mouse tissues or in HeLa cells. Functional analysis of this element in the alpha globin gene promoter by stable transfection experiments show that the GATAAG motif resides in a 68 bp sequence which has a stimulatory effect on transcription in mouse erythroleukaemia but not fibroblast cells. The GATAAG motif is conserved in the promoters and 3' enhancers of a variety of globin and non-globin genes implying that it is a cis-element involved in the tissue-specific up-regulation of several genes that are co-expressed during erythroid cell differentiation.

Animals↗
PubMed1989

Practical evaluation of trauma deaths.

The TRISS method of auditing trauma deaths necessitates audit of patients with minor injuries who die of their underlying medical problems. Using an anatomic definition of injury as a criterion for audit, as suggested by Wesson et al. at the Hospital for Sick Children in Toronto, excludes patients with minor injuries but necessitates audit of patients who expired due to systems problems rather than in-hospital patient care. We propose combining the TRISS and Toronto methods in order to identify the deaths truly appropriate for detailed review of hospital care. Fifty-four trauma deaths over a 22-month period were audited and categorized as frankly preventable, potentially salvageable, or nonpreventable. Considering only in-hospital care, the deaths designated as potentially salvageable by audit were likely to be identified by both TRISS and Toronto, while deaths targeted by only one system were more likely to be nonpreventable by audit. The predictive value of this combination of methods (84.6%) was better than Toronto (52.4%) or TRISS (54.5%) using audit results as the standard for comparison. This simple computerized method may serve as a practical and inexpensive method of targeting deaths for in-depth review.

Adolescent↗
PubMed1985

The risk of child abuse among mothers who attempt suicide.

The association between parental attempted suicide and child abuse was investigated in 114 mothers with children aged five years and under, referred to a general hospital following suicide attempts. The risk was greatly increased in the attempted suicide mothers, compared with both similar mothers at risk for depression and general population control mothers; well-documented risk of child abuse was identified in 29.8% of those who attempted suicide. No major differences were found between the attempted suicide mothers whose children were at risk and those whose children were not at risk. During the general hospital assessment of mothers with young children who attempt suicide, careful enquiry concerning the relationship with the children is essential.

Adult↗
PubMed1983

Analysis of cell surface proteins delineates a differentiation pathway linking endocrine and nonendocrine human lung cancers.

We have previously determined that the cell surface protein phenotype distinguishes human small cell lung carcinoma (SCC), a neoplasm with endocrine properties, from non-SCC in culture. We now demonstrate that cloned cell cultures of human large cell undifferentiated lung carcinoma, established directly from a patient with mixed SCC and non-SCC, simultaneously express surface proteins characteristic of SCC and non-SCC lung cancer cells. Hence, SCC and a form of large cell carcinoma appear linked through a continuum of differentiation events that: (i) may explain clinically important transitions that occur between the major types of human lung cancer and (ii) provide evidence for a common cellular origin of endocrine and nonendocrine cells in the bronchial mucosa.

Amine Oxidase (Copper-Containing)↗
PubMed1982

Relationships between neuroendocrine differentiation and sensitivity to gamma-radiation in culture line OH-1 of human small cell lung carcinoma.

After 16 months, an established line of human small cell lung cancer (OH-1) underwent a subtle morphological change which was associated with a virtually complete loss of neuroendocrine differentiation as judged by electron microscopy studies and a 12-fold loss in L-dopa decarboxylase activity. In nude (athymic) mouse heterotransplants, the histology of the early-passage cells (oat or lymphocyte-like) differed only slightly from the late-passage cells (intermediate or polygonal type); cytology studies showed no diagnostic differences between the passages. However, the early-passage endocrine-like cells showed up to 100-fold less cell survival after irradiation than the late-passage cells. Thus, subtle changes in the morphology of OH-1 cells are accompanied by a profound loss of neuroendocrine differentiation and the emergence of radiation resistance. These changes could have important parallelisms for behavior of small-cell lung carcinoma in humans. The cell culture model described may be useful in investigating the interrelationships occurring between endocrine and nonendocrine cells in the spectrum of human lung cancer. The findings emphasize that neuroendocrine-related ultrastructure and biochemistry may help define important cell populations in lung cancer with respect to therapeutic sensitivity.

APUD Cells↗
PubMed1981

Polyamines are necessary for the survival of human small-cell lung carcinoma in culture.

Many human small-cell lung carcinoma culture lines grow as multicellular aggregate spheroids, for which high L-dopa decarboxylase activity is a marker. During the initial cell aggregation and the exponential growth phase, there is a marked increase in ornithine decarboxylase activity and an accumulation of polyamines. alpha-Difluoromethylornithine, a specific enzyme-activated, irreversible ornithine decarboxylase inhibitor, blocks the increase in ornithine decarboxylase activity and in polyamines and inhibits human small-cell lung carcinoma cell growth. After the onset of a decreased proliferation rate, the multicellular spheroid aggregates become poorly formed, cell loss ensues, and there is a decrease in L-dopa decarboxylase activity. These findings support the hypothesis that ornithine decarboxylase and the polyamines play an essential role not only in the proliferative phase but also in the viability of human small-cell lung carcinoma cells in culture. The results suggest that alpha-difluoromethylornithine, a virtually nontoxic compound, may be potentially useful in the therapy of this human tumor.

Carcinoma, Small Cell↗
PubMed1981

Endocrine-related biochemistry in the spectrum of human lung carcinoma.

The association of hormonal syndrome and APUD (amine precursor uptake, decarboxylase) features with small cell carcinoma of the lung (SCC) has suggested that SCC has a separate cell origin from other major forms of lung cancer. Recently, however, both SCC and non-SCC lung cancers have been found to contain small polypeptide hormones and APUD enzymes. The present study quantitates, in 50 samples of human lung cancer tissue, relationships among the 4 major types of lung cancer and endocrine-related properties. Among 4 parameters measured (dopa decarboxylase, histaminase, beta-endorphin, and calcitonin), no single marker clearly separated SCC from non-SCC lung cancer. The high activity of dopa decarboxylase (the "D" in "APUD") best separated SCC from non-SCC, but significant overlap existed even for this critical APUD property. In fact, 2 adenocarcinomas had among the highest concentrations of dopa decarboxylase, histaminase, and calcitonin of any tumor tissue studied. The simultaneous appearance of high levels of 2 or more markers favored SCC. This was quantitated by deriving an index unit based upon the product of the values for the 4 markers in each lesion. This index separated all SCC from all non-SCC lung carcinomas, with the exception of the above 2 adenocarcinomas. Endocrine-related properties thus occur throughout the spectrum of human lung cancer. Biochemical differences between the major histopathological types are quantitative rather than qualitative and probably reflect the fact that the major forms of lung cancer represent a continuum of differentiation within a common cell lineage which includes both SCC and non-SCC lung tumors.

APUD Cells↗
PubMed1980

Activities of L-dopa decarboxylase and diamine oxidase (histaminase) in human lung cancers and decarboxylase as a marker for small (oat) cell cancer in cell culture.

The neuroendocrine [amine precursor uptake (decarboxylase)] properties of small (oat) cell lung cancer (SCC) have suggested that this neoplasm may have a separate histogensis from the other major types of human lung tumors. We now report that a key element of this concept, L-dopa decarboxylase activity, is present in surgical and autopsy tissues from all forms of lung cancer. Values are highest in SCC lesions; however, lung adenocarcinoma tissues can have considerable activity, and values overlap those for SCC and fall between values for SCC and large cell and squamous cell carcinoma. The distribution of diamine oxidase activity is identical except that even more overlap occurs between the major tumor types. These data may provide further evidence that SCC and other human lung cancers could share a common origin in the bronchial mucosa. In cell cuture, the distribution of the two enzyme activities is different. The average L-dopa decarboxylase activity is much higher (seven separate culture lines) than in the in vivo specimens, and it completely separates these cell lines from non-SCC lung tumors (four lines). Diamine oxidase is generally low in both SCC cells and non-SCC cells in culture and does not separate the various cell types. L-Dopa decarboxylase activity thus does appear to be a valuabe marker for separating SCC cells from other lung cancer cells in vitro.

Adenocarcinoma↗
PubMedDate not supplied

Controlled trial of lamotrigine (Lamictal) for refractory partial seizures.

The antiepileptic effect of lamotrigine (LTG) was assessed in a double-blind, placebo-controlled crossover trial in 24 adult patients with refractory partial seizures. LTG or placebo was added to existing antiepileptic drugs (AEDs). The dose of LTG varied from 75 to 400 mg daily. Three patients did not complete the trial. One was withdrawn from the trial with ataxia, tiredness, dyspnea, and diplopia while receiving LTG and died 18 days later of invasive carcinoma involving the liver. A second patient was withdrawn during baseline for contravening admission criteria, and a third received LTG in error during both treatment periods. Twenty-one patients (12 men and 9 women) completed the trial. An analysis of seizure counts in the 12-week treatment period with LTG showed a statistically significant reduction in seizures as compared with placebo for total seizures (p less than 0.002), partial seizures (p less than 0.002), and secondarily generalized seizures (p less than 0.05). The analysis of total seizure days showed a significant reduction during LTG treatment (p less than 0.002). There were no statistically significant changes in plasma concentrations of phenytoin (PHT), carbamazepine (CBZ), primidone (PRM), or phenobarbital (PB) between the two treatment periods. The most common adverse events reported during the trial were diplopia, drowsiness, tiredness, ataxia, and headache, but although these were more frequent during LTG treatment, the differences from placebo were not statistically significant. No hematological or biochemical changes were noted.

Adolescent↗