Cancer arises because of genetic changes in somatic cells, eventually giving rise to overt malignancy. Principle among genetic changes found in tumor cells are chromosomal translocations which give rise to fusion genes or enforced oncogene expression. These mutations are tumor-specific and result in production of tumor-specific mRNAs and proteins and are attractive targets for therapy. Also, in acute leukemias, many of these molecules are transcription regulators which involve cell-type-specific complexes, offering an alternative therapy via interfering with protein-protein interaction. We are studying these various features of tumor cells to evaluate new therapeutic methods. We describe a mouse model of de novo chromosomal translocations using the Cre-loxP system in which interchromosomal recombination occurs between the Mll and Af9 genes. We are also developing other in vivo methods designed, like the Cre-loxP system, to emulate the effects of these chromosomal abnormalities in human tumors. In addition, we describe new technologies to facilitate the intracellular targeting of fusion mRNAs and proteins resulting from such chromosomal translocations. These include a masked antisense RNA method with the ability to discriminate between closely related RNA targets and the selection and use of intracellular antibodies to bind to target proteins in vivo and cause cell death. These approaches should also be adaptable to targeting point mutations or to differentially expressed tumor-associated proteins. We hope to develop therapeutic approaches for use in cancer therapy after testing their efficacy in our mouse models of human cancer.

Animals↗

PubMedDate not supplied

Transcription enhancer identified near the human C mu immunoglobulin heavy chain gene is unavailable to the translocated c-myc gene in a Burkitt lymphoma.

In Burkitt lymphoma the c-myc gene, the cellular homologue of the viral oncogene v-myc, has been implicated in the aetiology of this human B-cell malignancy. Burkitt lymphoma cells possess specific chromosomal rearrangements involving the region proximal to the c-myc gene and one of the three human immunoglobulin loci. The nature of the effect exerted by the immunoglobulin loci on the translocated c-myc gene is controversial: whereas some reports have suggested c-myc transcription is elevated in Burkitt lymphoma cells, others have suggested the level of transcription is unaffected by the translation. Recently, transcription enhancer elements have been identified in the intron between the JH and C mu segments of the heavy-chain immunoglobulin gene in mice. If similar enhancers exist in humans they may lead to increased transcription of the translocated c-myc gene and thus contribute to oncogenesis in Burkitt lymphoma. We report here the identification of an enhancer element adjacent to the human C mu gene on normal chromosome 14, but this enhancer does not remain on the abnormal chromosome 14 to which the c-myc gene has been translocated in the Burkitt lymphoma cell line Raji. This element is, therefore, not available for control of the translocated c-myc gene in this case.

Base Sequence↗

PubMedDate not supplied

Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma.

Our previous studies of a translocated c-myc gene in the Raji Burkitt's lymphoma cell showed somatic mutations in exons 1 and 2. We have extended these observations to two other translocated c-myc genes and find a common occurrence of mutation in the noncoding exon 1. We also found that in Raji cells, unlike other Burkitt's lymphoma cell lines, the normal allele of the c-myc gene is transcribed as well as the translocated gene. These results support a model in which c-myc oncogene activation in Burkitt's lymphoma occurs by disruption of a normal transcriptional control mechanism in which the c-myc protein is itself involved.

Base Sequence↗

PubMedDate not supplied

Rearrangement of two distinct T-cell gamma-chain variable-region genes in human DNA.

Selective cloning procedures for T-cell-specific complementary DNAs have revealed the existence of a gene designated gamma as well as the main antigen receptor alpha- and beta-chain genes. The gamma-chain genes undergo rearrangement during T-cell differentiation but the patterns and complexity of such rearrangements differ markedly in mouse and human. In mouse, a panel of cytotoxic T-lymphocyte clones exhibit the same rearrangement pattern with a gamma-chain gene probe and a set of three gamma-chain variable (V) genes have been identified in the DNA. Clonal diversity in mouse seems to be confined to V-J (joining) regions. In contrast, human T-cell lines exhibit diverse rearrangements suggestive of a family of differing V gamma genes variously rearranging to the two gamma-chain constant (C) region genes. Here we report the cloning of two very different V gamma genes rearranged to J segments upstream of the two human C gamma genes. Both V gamma genes are rearranged productively but nucleotide sequence comparison shows that they possess very little homology with each other. This shows that human T-cell V gamma genes exist which differ significantly from each other at the nucleotide level and that such diverse genes can be usefully rearranged in different T cells.

Base Sequence↗

PubMedDate not supplied

An hypothesis paper on practice environment and the provision of health care: could hospital occupancy rates effect quality?

This paper will explore whether hospital occupancy influences quality of care. It discusses the 'systems' theory of error causation in the context of adverse medical outcomes. It then relates how high occupancy rates may cause problems in hospital systems. The evidence relating to quality of care and occupancy is reviewed. Finally, a new method of studying this relationship using time series analysis is proposed. We conclude that the relationship requires further exploration since revealing 'system' problems may compel clinicians to expose problems medical errors.

Bed Occupancy↗

PubMedDate not supplied

Immunoadsorption for coagulation factor inhibitors.

Inhibitors to coagulation factors are among the most difficult problems in the management of coagulation disorders. Most presently available therapy does not assure hemostasis. An extracorporeal immunoadsorption system, which selectively binds IgG, was used to lower inhibitor levels in eight patients on 10 occasions. In this system, separated plasma is delivered to two staphylococcal protein A-Sepharose columns, which are coupled to an elution monitor. Columns are eluted sequentially and regenerated to maximize IgG removal. Successful removal of the inhibitor was accomplished in all six hemophiliacs on seven occasions, as well as in a patient with acquired von Willebrand disease. All patients whose inhibitors were lowered to less than 10 Bethesda units achieved measurable factor levels when factor concentrate replacement was given. Immunoadsorption facilitates efficient removal of inhibitors, which allows factor replacement therapy.

Adult↗

PubMedDate not supplied

Effects of the removal of phenytoin, carbamazepine, and valproate on the electroencephalogram.

We report the EEG changes that occurred on discontinuance of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in patients with active epilepsy. Discontinuation of CBZ was associated with an increase in mean frequency of dominant rhythm and reduction in amount of slow activity. Patients who had a marked increase in seizures on discontinuation of an antiepileptic drug had a slower mean dominant rhythm at baseline than did patients who did not have an increase in seizures. Subsequent EEGs, during and at the end of drug reduction, showed an increase in bursts of interictal epileptiform activity (IEA) and in slow activity in patients who had a marked increase in seizures. The amount of slow activity and IEA did not alter in patients who did not have an increase in seizures. No patients developed photosensitivity.

Adolescent↗

PubMedDate not supplied

Day hospital and stroke patients.

Geriatric day hospitals are commonly used in the rehabilitation of stroke. However, there is little objective evidence about its effect for this condition. The potential advantages and disadvantages are finely balanced and further research, including cost-effectiveness analysis, is needed to define more clearly the role of this expensive facility.

Activities of Daily Living↗

PubMedDate not supplied

How support teams can develop research activity.

This report discusses an initiative whereby a research support team has been formed in order to encourage, support and develop research awareness and activity among nurses.

Humans↗

PubMedDate not supplied

Complement activation in the adult respiratory distress syndrome following cardiopulmonary bypass.

We investigated complement fractions in patients after extracorporeal circulation for coronary bypass operations or cardiac valve replacement, and in two cases developing an adult respiratory distress syndrome (ARDS) after this type of intervention. The patients presenting an ARDS had significantly increased levels of C3d (p less than 0.001), the small molecular breakdown product of C3, associated with decreased levels of total classic haemolytic activity (p less than 0.05) and of the complement component C1q (p less than 0.001) when compared to a group of 10 patients who had uneventful evolution after bypass. However, all patients undergoing cardiopulmonary bypass had significantly increased levels of C3d (p less than 0.005 or less) associated with significant decrease of various complement components within 24 h after bypass, when compared to a control group of 5 patients investigated after aorto-iliac bypass graft surgery. We conclude that significant complement activation can persist in patients 24 h after bypass and--at higher levels--be a pathogenic and biological marker of ARDS after extracorporeal circulation.

Adult↗

PubMedDate not supplied

[Prevention of stress ulcers in intensive care. Cimetidine and alkalines as prophylaxis of digestive hemorrhage].

Explore the source record for details and available documents.

Adult↗

PubMedDate not supplied

The value of serum magnesium estimations in the diagnosis of acute perioperative myocardial infarction after coronary artery surgery.

Serum magnesium levels fall significantly after acute myocardial infarction. Even greater decreases have been found in all patients undergoing aorto-coronary bypass surgery. This is probably related to the use of cardiopulmonary bypass. No significant difference in serum magnesium levels was found between those patients who had a well documented peri-operative infarct and those who had an uncomplicated course. Thus determination of serum magnesium levels if of no use in the diagnosis of peri-operative myocardial infarction.

Coronary Artery Bypass↗