Search PubMed⌕ Search

Biomedical subjects

R Cox

Publications and source records attributed to R Cox.

At least 109 records · Page 6Linked to original sources
PubMed1994

Molecular mechanisms of radiation oncogenesis.

Resolving the molecular mechanisms of radiation oncogenesis represents an important but daunting challenge in radiation research. This brief review outlines the principal oncogenic mechanisms that need to be considered in the context of radiation effects on the genome, how these might relate to specific gene and chromosomal changes relevant to neoplasia and the possible implications of such knowledge for the modelling of cancer risk. The long-term application of this mechanistic knowledge to the determination of tumour causality and for the assessment of individual cancer risk is also briefly discussed.

Humans↗
PubMed1994

Human cancer predisposition and the implications for radiological protection.

It is well established from clinical, epidemiological and laboratory studies that specific human germ line mutation can predispose to spontaneously arising cancer. Some of the responsible genes have been characterized at the molecular level and evidence is rapidly accumulating on mechanistic aspects of the problem. A major outstanding issue is the extent to which genetically determined cancer predisposition in man interacts with exposures to environmental genotoxic agents such as ionizing radiation. This brief review considers the current position regarding the different forms and frequencies of cancer-predisposing mutations in the human population and provides an interim view of the possible implications for protection of man from ionizing radiation.

DNA Damage↗
PubMed1993

Telomere-like DNA polymorphisms associated with genetic predisposition to acute myeloid leukemia in irradiated CBA mice.

There is evidence that interstitial telomere (TTAGGG)n-like sequences at chromosome 2 fragile sites play an important role in the somatic events that characterize the earliest phases of radiation-induced acute myeloid leukemia in the CBA/H mouse. Here we show that the highly inbred CBA/H colony unexpectedly contains four genotypic variants for telomere-like sequence arrays and that almost all induced myeloid leukemias derive from one of the variant subpopulations that constitutes approximately 20% of the colony. Preliminary evidence on the irregular inheritance patterns for these variant sequences is discussed together with the proposal that one form of these telomere sequence arrays either represents or is closely linked to a locus that influences chromosome 2 breakage patterns in hemopoietic cells following irradiation and, through this, susceptibility to induced myeloid leukemia.

Acute Disease↗
PubMed1993

The role of DNA repeats and associated secondary structures in genomic instability and neoplasia.

Tumour-associated genetic changes frequently involve DNA translocation or deletion. Many of these events will have arisen from initial genomic damage, induced by either the activity of endogenous metabolic processes or from exposure to environmental genotoxic agents. Although initial genomic damage will have been widely distributed, tumorigenic events are confined to certain DNA target sites. Furthermore, within these target sites there appear to be regions of preferential DNA rearrangement, and examination of these sites implies that the location and extent of such rearrangement may be influenced by DNA primary and secondary structure rather than simply by the point of damage. We selectively review evidence relating to DNA structures that may predispose certain regions of the genome to damage-induced rearrangement, and discuss the possible role of interstitial, inverted telomere-like sequence arrays in promoting chromosomal events of a type known to be associated with some human and animal tumours.

Animals↗
PubMed1993

Murine radiation myeloid leukaemogenesis: relationship between interstitial telomere-like sequences and chromosome 2 fragile sites.

While the specific nature of chromosomal fragile sites and their relationship to human leukaemogenesis remain obscure, there is evidence that chromosomal fragility may, in some circumstances, be associated with telomere-like repeat sequences and that chromosome 2 fragility in the mouse is involved in the initiation of myeloid leukaemia by ionising radiation. Here we describe the molecular cloning and characterisation of two murine telomere-like sequences, one having an inverted repeat structure and the other a simple tandem repeat organisation. The inverted telomere repeat clone generates an in situ chromosome 2 hybridisation pattern very similar to the distribution of the radiation-sensitive fragile sites previously found to be associated with leukaemogenic initiation. Furthermore, statistical comparison of the distributions of radiation induced breakpoints and sites of inverted telomere repeat hybridization indicates concordance at all chromosome 2 sites excluding the terminal regions. These data are discussed with respect to mechanisms of radiation-induced, site-specific chromosome 2 rearrangement and their implications for leukaemogenic initiation.

Acute Disease↗
PubMed1993

Weiss Lecture. Effects of radiations of different qualities on cells: molecular mechanisms of damage and repair.

Studies of ionizing radiations of different quality are discussed with particular emphasis on damage to DNA of mammalian cells. Three related themes are followed. Firstly, inactivation and mutation experiments with ultrasoft X-rays and slow heavy ions, coupled with theoretical analyses of the structures of the radiation tracks, have emphasized the biological importance of localized track features over nanometre dimensions. This led to the suggestion that the critical physical features of the tracks are the stochastic clusterings of ionizations, directly in or very near to DNA, resulting in clustered initial molecular damage including various combinations of breaks, base damages, cross-links, etc. in the DNA. The quantitative hypotheses imply that final cellular effects from high-LET radiations are dominated by their more severe, and therefore less repairable, clustered damage, and that these are qualitatively different from the dominant low-LET damage. Second, relative effectiveness of different types of radiation led to questions on the mechanisms of induction of chromosome exchanges. The high efficiency of ultrasoft X-rays, despite their very short track lengths, suggested that single sites of DNA damage may lead to exchanges by a molecular process involving interaction with undamaged DNA. Also it is shown that a single site-specific DNA break, introduced by restriction enzymes, sometimes leads to a large deletion when misrepaired by cell extracts. These deletions occur between short DNA repeats, and are therefore a form of 'illegitimate' recombination, but clearly do not involve the interaction of two damage sites. Third, it was shown that cells from patients with the radiosensitive disorder ataxia-telangiectasia (AT) lack a post-irradiation recovery process. The sensitivity of AT cells to high LET radiations was found to be reduced relative to that for normal cells, reinforcing the concept that high LET damage is less easy to repair. AT patients are prone to lymphoreticular cancers, and their cells show characteristic chromosomal rearrangements, which may be associated with misrepair at specific genomic sequences. Similarly, studies of radiation-induced leukaemia in the mouse have implicated rearrangement at specific interstitial chromosome sites, which are rich in telomere-like repeat sequences.

Animals↗
PubMed1992

Reliability problems associated with the modified Schöber technique for true lumbar flexion measurement.

The modified Schöber technique, a method for assessing lumbar spine flexion, was subjected to an analysis of reliability. Fifty normal subjects (21 men, 29 women) were evaluated for lumbar flexion mobility using a blind inter-rater "worst case" protocol. Simultaneously, other sources of error affecting test reliability, such as presence of dimples of Venus, relationship of skin distraction to movement of underlying structures, and upper level of Schöber skin landmarks were also considered. Analysis suggested that systematic error can be introduced that adversely affects inter-rater reliability (r = 0.71). Moreover, skin landmarks are inconsistently present, being completely absent in 26% of cases. Skin tends to distract even over completely immobile bony structures (eg, the sacrum), whereas, on average, only 3.5 of the 6 spinal segments (T12-S1) are included in the Schöber technique for purported measurement of "lumbar spine flexion." The utility of this method is questioned on both scientific and clinical grounds.

Adult↗
PubMed1992

Permeation of divalent cations through the Ca2+ channel of rabbit portal vein myocytes.

The divalent selectivity of the Ca2+ channel in the rabbit portal vein myocyte was examined by the whole cell clamp method. A concentration-dependent selectivity of divalent ion permeation was found such that when Ca2+ was replaced by Ba2+ or Sr2+, the order of maximum current was Ca2+ = Ba2+ greater than Sr2+ at 2 mM and Ba2+ greater than Sr2+ greater than or equal to Ca2+ at 5-10 mM. The possibility of block of the Ca2+ channel by micromolar concentrations of "contaminant" Ca2+ as a determinant of change in the order of selectivity of divalents was examined. Ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (500 microM) significantly increased maximum Ba2+ current (IBa) or ISr in solution containing 5 mM Ba2+ or Sr2+. Furthermore, at 5 mM extracellular Ba2+ concentration, addition of 10, 20, 50, and 100 microM Ca2+ caused a 6, 14, 22, and 33% decrease in IBa, respectively. These results suggest that the portal vein Ca2+ channel has three orders of magnitude higher selectivity for Ca2+ over Ba2+ and Sr2+ such that micromolar Ca2+ may block permeation of other divalents through the channel.

Animals↗
PubMed1992

Pediatric cardiology: auscultation from 280 miles away.

New long-distance audio/video and data communications links among health-care facilities promise to reduce rural patients' travel time and waiting time for subspecialty consultations. To offer a satisfactory alternative to face-to-face examination, the long-distance system must meet the subspecialty's minimum criteria. For pediatric cardiology in particular, the system has to permit satisfactory cardiac auscultation. A preliminary test of remote auscultation that uses an electronic stethoscope involved two pediatric cardiologists, one listening hands-on with an acoustic stethoscope, the other listening independently at long distance with the electronic instrument. Taking the acoustic findings as the reference standard, the electronic stethoscope did not miss the one case of heart disease, correctly recommended echocardiogram follow-up in the two cases requiring it, and agreed on 80% of the murmurs' qualitative specifics. The patients' parents also indicated that the system was highly acceptable. We are following up these results with a full-scale study of the effectiveness and parental acceptance of remote auscultation.

Cardiology↗
PubMed1991

Rapid and quantitative separation of nicotinamide and its N1-methylated metabolite by Dowex AG50-X4 chromatography.

The use of column chromatography with Dowex AG50-X4 resin has allowed the quantitative separation of nicotinamide from its primary metabolite, N1-methylnicotinamide. Although the sensitivity is similar to earlier high-performance liquid chromatographic methods, this procedure allows multiple assays to be carried out simultaneously in a matter of minutes. This method should be useful to study nicotinamide methyltransferase activity in either whole cells or extracts, and is particularly well suited to screen column fractions for enzyme purification purposes.

Anion Exchange Resins↗
PubMed1991

A novel and rapid method for isolating sequences adjacent to rare cutting sites and their use in physical mapping.

We describe a simple PCR based technique which can be used to isolate sequences adjacent to rare cutter sites and can subsequently be employed for the construction of long range physical maps. The method involves the ligation of an adaptor to rare cutter sequences and its use as a target for forward priming in PCR. Primers to Alu repeat elements initiate synthesis of the reverse strand. Using this technique any rare cutter site which has a repeat element within amplification range can be cloned. We have isolated six unique sequences around NotI sites from an irradiation reduced hybrid containing a fragment of human chromosome 22 and are using these for physical mapping around the Ewing's sarcoma translocation breakpoint on chromosome 22.

Base Sequence↗