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Biomedical subjects

T Alper

Publications and source records attributed to T Alper.

At least 19 recordsLinked to original sources
PubMed1992

The infectivity of spongiform encephalopathies: does a modified membrane hypothesis account for lack of immune response?

Scrapie, the prototype of a group of diseases which have the unique property of being both hereditary and infectious, is also exceptional in that it fails to evoke an immune response. Purification of crude scrapie preparations revealed a strong association of infectivity with a membrane protein ('PrPsc'); but a protein with the same amino acid sequence ('PrPc') was subsequently also found in normal mammalian nervous tissue. It is postulated by some investigators that 'PrPsc' is itself the infectious agent, or the most important part thereof, but in papers making that proposal immunological aspects have not been addressed. Experimental evidence supporting the hypothesis of a membrane fragment as agent has likewise lately not been taken into account. A modified form of the membrane hypothesis could account for immunological as well as genetic aspects of these diseases.

Animals↗
PubMed1989

The role of repair in radiobiology.

Apart from cancer and mutation induction, radiobiological effects on mammals are mostly attributable to cell 'death', defined as loss of proliferative capacity. Survival curves relate retention of that capacity to radiation dose, and often manifest a quasi-threshold ('shoulder'). The shoulder is attributable to an initial mechanism of repair ('Q-repair') which is gradually depleted as dose increases. Another form of repair, which is not depleted ('P-repair'), increases the dose required to deliver an average of one lethal event per cell (dose 'D0'). Neither form of repair can unambiguously be linked with repair of defects in isolated DNA. An important initial lesion may well be disruption of the complex structural relationship between the DNA, nuclear membrane and associated proteins. One form of P-repair may be restoration of that structural relationship.

Animals↗
PubMed1987

The cell as single-hit detector.

The common manifestation of shoulders to survival curves, particularly for mammalian cells, has diverted attention from the importance of single-hit action as a radiobiological mechanism. Exponential survival is diagnostic for that mode of action. Of various interpretations of shouldered curves, the one best fitted by experimental facts is that single energy deposits can indeed be lethal; but many cells have capacity for a specific type of repair that is depleted, in a dose-dependent manner, until it ceases to function. The curve then assumes its exponential 'tail'. Genomic DNA seems an obvious target for the scoring of lethal hits. But a body of evidence indicates the presence in the cell of a second, chemically different, target, one in which oxygen interacts at the sites of energy deposits to fix damage, so causing radiosensitization. The nuclear membrane is a likely candidate. In cells proficient at repairing DNA, and irradiated with oxygen present, only a minority of lethal events are attributable to energy deposited in DNA. The hypothesis that hits are scored by .OH, based to a large extent on the phenomenon of chemical protection, is not justified by all the facts and is in conflict with some experimental observations. On the other hand, e-aq may well be damaging to DNA unless oxygen is present to act as scavenger.

Animals↗
PubMed1986

High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation.

When mammalian cells are irradiated in vitro, the component cells of a normal-appearing survivor colony or clone are commonly thought to have proliferative capacity equivalent to that of the unirradiated cells. We have found, however, that cells appearing in survivor colonies may carry heritable lethal defects which come to light, perhaps only after numerous successful divisions, in the form of plating efficiencies that are reduced below those of unirradiated cells in a dose-dependent manner. We regard these heritable defects as signs of the induction of lethal mutations, which, like non-lethal mutations, may require many generations before they are expressed. This effect has been noted in two very dissimilar mammalian cell lines, one a primary culture from adult tissue, the other an immortal cell line. We suggest that induction of lethal mutations may occur also in somatic cells in vivo; this would account for the well-known observation that previously irradiated but apparently healed tissue is subsequently proved to be extraordinarily sensitive to subsequent exposure to irradiation or cytotoxic drugs. The results of our experiments in vitro suggest that current methods of estimating mutation or transformation yields may yield underestimates. If lethal mutations are induced also in vivo, interpretations of the results of fractionation experiments on normal tissues may have to be reconsidered.

Animals↗
PubMed1984

Constants of the Alper and Howard-Flanders oxygen equation for damage to bacterial membrane, deduced from observations on the radiation-induced penicillin-sensitive lesion.

Energy deposited in the bacterial envelope of E. coli B/r induces lesions which are lethally attacked by penicillin in concentration insufficient to affect unirradiated bacteria. The critical lesions are probably in the membrane moiety. Bacteria were irradiated in the presence of 100 per cent oxygen, oxygen-free nitrogen and mixtures of 1.01, 0.59, 0.3, 0.1 and 0.06 per cent oxygen in nitrogen. Changes in sensitivity with pO2 conformed with the Alper and Howard-Flanders equation, for bacteria treated after irradiation by penicillin as well as for the untreated ones. The values of m were respectively 4.8 and 3.3; the values of K were identical, within experimental error, i.e. 4.4 mmHg. Sensitivity to induction of the penicillin-sensitive lesion was calculated from the difference in the reciprocals of D0 values proper to untreated and treated bacteria, for every gas used. The value of m could not be directly calculated because the effect of penicillin on anoxically irradiated bacteria was not detectable. For that reason, a transformation of the oxygen equation was used which allowed estimates to be made of both m and K, provided the results conformed with the equation. Within experimental error they did so conform. The calculated values of m and K for induction of the penicillin-sensitive lesion were respectively 8 and 5.9 mmHg, but it is shown that the oxygen enhancement ratio was probably underestimated and the K value overestimated. On the assumptions that these values of m and K are specific for radiation damage to bacterial membrane, and that radiation-induced killing is attributable to lethal lesions in the membrane as well as the DNA, the results demonstrate that any interaction of oxygen with sites of energy deposition in the DNA must play a very much smaller role in radiosensitization than does interaction with sites of energy deposition in the membrane.

Cell Membrane↗
PubMed1984

Adding two components of radiosensitization by oxygen.

It has been shown, or inferred, in various contexts that radiosensitization of cells by oxygen is the sum of two (or more) components. If the component sensitivities conform with the Alper and Howard-Flanders equation their sum cannot also conform, but, in practice, even the most meticulous experimental techniques will fail to reveal lack of conformity unless one of the component K values is at least nine times the other. Thus, despite the many results that have demonstrated conformity with the equation, the existence of at least two components may well be a general phenomenon. The killing of cells by radiation is attributable to a summation of lesions in different structures; different K values for the contributing components are therefore to be expected, since neither oxygen nor its competitors are likely to be present in uniform concentration in all elements of the cell nucleus. Provided the components have intrinsic values of o.e.r. greater than one, their addition results in sensitivity that increases monotonically with PO2, approaching asymptotically to the overall o.e.r. which is a weighted average of the component o.e.r.s. In a curve plotted with PO2 on a linear scale a point of inflection can occur only if one component o.e.r. has a value less than one (i.e. oxygen is protective for that component), and then only if relationships between the other parameters satisfy certain conditions. In cases in which points of inflection in the sensitivity curve has been observed these are unlikely to be accounted for by the addition of two components. The analysis of the consequences of adding two components of oxygen sensitization could apply also to chemical sensitization of hypoxic cells.

Cell Survival↗
PubMed1984

Implications of repair models for LET effects and other radiobiological phenomena.

Repair models account for shoulders to survival curves by the postulate of a mode of repair which is depleted ("saturated") as dose increases, and which should therefore be distinguished, conceptually and linguistically, from what is commonly known as "repair of potentially lethal damage". Acceptance of repair models entails new interpretations of some radiobiological phenomena. "Recovery" of cells between dose fractions would be attributable to reconstitution or resynthesis of the putative agent of repair, so elucidation of the mechanism of such "recovery" requires a different approach from any that have been used in attempts to discover the nature of "sub-lethal lesions" or the mechanism of their repair--attempts that have not been attended by success. Even mammalian cells can yield exponential survival curves; but this fact has been ignored in some proposals for mechanisms of radiation-induced cell killing, and in "theories of RBE" based on multi-sublethal lesion models for shouldered survival curves. According to repair models, however, cells in general are basically single-hit detectors. Comparisons between the responses of repair-proficient cells and their deficient mutants to change in radiation quality support the hypothesis that increases in RBE are attributable to reduced capacity for some mode(s) of repair as LET increases; but there is evidence that some capacity remains, even at very high values of LET.

Animals↗
PubMed1978

The scrapie agent: evidence against its dependence for replication on intrinsic nucleic acid.

Exposure of the scrapie agent to u.v. light at various wavelengths has shown that light of 237 nm is 4 to 5 times as effective in inactivating it as 'germicidal' wavelengths (250 to 270 nm); whereas with systems that depend on RNA or DNA for function, inactivation is most effective by wavelengths in the germicidal range and there is a minimum of response in the wavelength region round 240 nm. The action spectrum for the scrapie agent is reminiscent of the absorption spectrum for purified bacterial endotoxin, identified as a lipopolysaccharide complex. Dilute aqueous suspensions of scrapie agent were exposed to ionizing radiations in the presence or absence of oxygen. In dilute suspensions of test systems depending on the integrity of nucleic acid or protein, oxygen is almost invariably protective, but it was extremely sensitizing for inactivation of the scrapie agent, to an extent approached only in the case of membranous systems like lysosomes. Results of these two methods argue against dependence of the scrapie agent on an intrinsic nucleic acid moiety for ability to replicate. They suggest that a lipid fraction is an important component and to that extent provide additional support for the 'membrane hypothesis'.

Animals↗
PubMed1977

The role of membrane damage in radiation-induced cell death.

Radiation-induced cell death is probably mediated primarily through deposition of energy, in single events, in a few vital macromolecules, or targets, the integrity of which is indispensable for proliferation. The genome is customarily regarded as the main target, but several lines of evidence support the inference that there are important consequences of events in nuclear membranes in eukaryotes, and plasma membrane in bacteria. The identification of a target depends to some extent on parallelism between modifications of biological damage to putative targets and to the cell as a whole. An important modifying procedure is removal of oxygen from the irradiated system. The presence of oxygen almost always sensitizes cells, but when model systems with biological function are irradiated extra-cellularly a high degree of sensitization by oxygen has been observed only with those in which membrane function is important. This makes sense because the lipid content of membranes renders them readily peroxidizable. When the quality of the radiation is changed, its effectiveness changes in opposite directions for subcellular model targets and for cells. This could be accounted for if interactions between lesions in membranes and in attached DNA play a substantial role in cellular radiation effects.

Animals↗
PubMed1975

A marked dependence of the comparative effectiveness of neutrons on tumour line, and its implications for clinical trials.

The responses of five transplantable rat tumour lines to neutron and X irradiation have been compared by a method in which radiation-induced delay in tumour growth is used as a measure of effect. All the tumours were sarcomas and were irradiated at the same size, after growth in the same site, and under standard conditions. This group of similar tumours exhibited a large range in values of RBE in a dose range within which fractions of hypoxic cells did not detectably influence the result of X irradiation. Of the five tumour lines used, there were two pairs the members of which had a common origin and were histologically similar; the greatest differences in RBE values were between members of the pairs. These results suggest that the therapeutic use of high LET radiation cannot be expected uniformly to achieve local control better than conventional treatment of tumours at a given site, or even of a given histological type. Research is needed into methods that will have predictive value for the relative success of neutron therapy.

Animals↗