N the inorphologic identification of chromosomes, the location of the I centromere is the most useful landmark, and one which is characterized by great constancy. It would seem that not much could be added to the definitions by E. B. WILSON (1928) of the locations on the chromosome of the centrornere or, in the terminology of that time, the spindle attachment: “Attachment of the chromosome to the spindle is commonly limited to a small area, and is of two general types, namely: (1) terminnl or telomitic and (2) non-ferminal or atelomitic, being in the former case at one end, and in the latter at some other point or points. Non-terminal attachment may be at the middle point (median) or at an intermediate point (submedian, sub-terminal). All gradations exist between these various cases;” (I.c., p. 130-131). In the acconipanying picture (l.c., Fig. 56, p. 132), here reprinted as Fig. l., the four locations of median, submedian, subterminal and terminal are represented, and, in addition, “lateral”, which corresponds to the modern term “diffuse centromere”. Nevertheless, at the present time, with the immense increase in research activity in mammalian cytology, the terminology of the centromeric position has become burdened by much obscurity and confusion. One cause of confusion is that different authors, and even the same author on different occasions, have used the terms median, submedian etc. with great amplitude, and it is often difficult to know in a specific case what each term signifies. Another cause of confusion is that a set of terms for chromosomes with specific centromeric positions, such as metacentric, acrocentric, telocentric, have come into wide usage without being clearly defined in relation to the positional terms median, submedian, subterminal and terminal. During the spring of 1963 the present writers exchanged epistolary

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1601-5223.1964.tb01953.x

Nomenclature for centromeric position on chromosomes

Roles moleculaires des proteines de choc thermique dans le fonctionnement des organismes a des temperatures normales et suite a des chocs thermiques; differents genes impliques

The heat-shock proteins

Multiple genetic changes occur during the evolution of normal cells into cancer cells. This evolution is facilitated in cancer cells by loss of fidelity in the processes that replicate, repair, and segregate the genome. Recent advances in our understanding of the cell cycle reveal how fidelity is normally achieved by the coordinated activity of cyclin-dependent kinases, checkpoint controls, and repair pathways and how this fidelity can be abrogated by specific genetic changes. These insights suggest molecular mechanisms for cellular transformation and may help to identify potential targets for improved cancer therapies.

https://science.sciencemag.org/content/sci/266/5192/1821.full.pdf

Cell cycle control and cancer

Sex Chromosomes and Sex-Linked Genes

There is increasing evidence that the pathogenesis of cancer proceeds by sequential steps from normal cells to premalignant foci to localized tumors to invasive tumors and to metastatic lesions. The concept of stages of tumor progression was initially analyzed by Foulds (1), and a model for tumor progression based on genetic instability and clonal selection has been pro posed by Nowell (2). Individual steps in tumor progression have been operationally delineated in mouse skin by the responses of cells to different chemicals (3). A progression of phenotypic changes has been described in human tumors, the anatomical localization of which has made it feasible to obtain serial biopsies (2, 4). Sequential somatic chromosomal abnormalities have been reported in human cancers including malignant mel anoma (5), colon cancer (6), gliomas (7), adenocarcinoma of the esophagus (8), and small cell carcinomas of the lung (9). In addition, a multiplicity of different mutations has been carefully documented in human breast cancer (10). The dilemma is that there are too many mutations in human tumors. In this perspective, I will consider the relationships between mutation rates and cancer. At least two mutations are required to account for the chromosomal changes observed in certain human inherited diseases (11). An analysis of the literature indicates that the spontaneous mutation rate in cells is of sufficient magnitude to account for a two mutation hypothesis for the initiation of cancer. However, a larger number of mu tations are observed in many human tumors. The spontaneous mutation rate in somatic cells is not sufficient to account for these multiple mutations. If the multiple mutations in tumors are causally associated with and not just an accompaniment of cancer, then I argue that an early step in tumor progression is one that induces a mutator phenotype. An increased mutation rate in tumors could be the basis for the multiple mutations that characterize many cancers.

https://cancerres.aacrjournals.org/content/canres/51/12/3075.full.pdf

Mutator Phenotype May Be Required for Multistage Carcinogenesis

Identification of a polypeptide associated with the malignant phenotype in acute leukemia.

The cytotoxic action of physical and chemical agents on 10 skin fibroblast strains in culture derived from individuals with Cockayne's syndrome was measured in terms of colony-forming ability. As compared to fibroblasts from normal donors, all Cockayne cell strains tested exhibited a significantly increased sensitivity to UV light and a normal sensitivity to X-rays. Cells from two sets of parents of unrelated Cockayne children showed an intermediate level of UV sensitivity. There was no effect of 0.5 mM caffeine on UV survival in normal and two Cockayne strains tested, indicating that postreplicational repair in Cockayne cells as measured by caffeine sensitivity was probably normal. Sensitivity of normal and Cockayne cells to the chemical carcinogens and mutagens 4NQO, N-AcO-AAF, ICR-170 and EMS was also compared. An increased sensitivity of Cockayne cells to 4NQO of N-AcO-AAF, but not to ICR-170 or EMS, was observed. However, unlike the intermediate UV sensitivity, the cell strains from two parents of Cockayne patients showed the same sensitivity to N-AcO-AAF or 4NQO as fibroblasts from normal individulas. Quantitation of damage to the DNA after 20 J · m−2 UV irradiation indicates normal levels of [3H]thymidine incorporation in the Cockayne cells, in contrast to UV-irradiated xeroderma pigmentosum cells (XP 12BE) in which there was a very low level of repair synthesis. Moreover, we have shown previoulsy that excision of UV-induced pyrimidine dimers in 2 of the 10 Cockayne cell strains was normal.

/pdf/effects-of-dna-damaging-agents-on-cultured-fibroblasts-2nqmgtnww1.pdf

Effects of DNA damaging agents on cultured fibroblasts derived from patients with Cockayne syndrome.

Inhibition of repair of UV-damaged DNA by caffeine and mutation induction in Chinese hamster cells.

12-0-Tetradecanoyl-phorbol-13-acetate (TPA) and phorbol were tested in Chinese hamster cells for their effects on mutagenesis (resistance to 6-thioguanine and to ouabain), DNA repair, and survival after ultraviolet (UV) irradiation. Recovery of 6-thioguanine- and ouabain-resistant colonies was significantly increased by TPA treatment and, to a lesser extent, by phorbol in UV-irradiated cells. Moreover, maximum enhancement of recoverable UV-induced 6-thioguanine- and ouabain-resistant mutants occurred when TPA was present after the mutation "expression" time and after the completion of DNA repair. This eenhancement effect, while persisting up to 18 days in the 6-thioguanine mutation system, was maximal when TPA was applied about 2 days after UV irradiation for the ouabain resistance mutation system. No significant decrease in cell survival was noted after post-UV treatment with TPA or phorbol, under conditions where there was a slight but nonspecific inhibition of unscheduled DNA repair synthesis. These results do not support the hypothesis that the tumor-promoting activity of TPA is due to its ability to inhibit "error-free" excision repair. The results are, however, consistent with a "two-stage" hypothesis of carcinogenesis which includes mutational and epigenetic mechanisms to explain the initiation and promotion phases.

https://cancerres.aacrjournals.org/content/canres/37/1/188.full.pdf

Effect of phorbol myristate acetate on the recovery of spontaneous and ultraviolet light-induced 6-thioguanine and ouabain-resistant Chinese hamster cells.

https://www.pnas.org/content/pnas/47/4/571.full.pdf

Ernest H. Y. Chu

Papers

Identification of a polypeptide associated with the malignant phenotype in acute leukemia.

Effects of DNA damaging agents on cultured fibroblasts derived from patients with Cockayne syndrome.

Inhibition of repair of UV-damaged DNA by caffeine and mutation induction in Chinese hamster cells.

Effect of phorbol myristate acetate on the recovery of spontaneous and ultraviolet light-induced 6-thioguanine and ouabain-resistant Chinese hamster cells.

An xxy male in the mouse.