The p53 tumor suppressor gene has come to the forefront of cancer research because it is commonly mutated in human cancer and the spectrum of p53 mutations in these cancers is providing clues to the etiology and molecular pathogenesis of neoplasia (1â€”3). Detection of p53 abnormalities may have diagnostic, prognostic, and therapeutic implications (4). The 15-year history of p53 investigations is a paradigm in cancer research, illustrating the convergence of previously parallel lines of basic, clinical, and epidemiological investigation and the rapid trans fer of research findings from the laboratory to the clinic. p53 is clearly a component in biochemical pathways central to human carcinogen esis; p53 protein alterations due to missense mutations and loss of p53 protein by nonsense or frameshift mutations provide a selective ad vantage for clonal expansion of preneoplastic and neoplastic cells (5). The potential for a missense mutation to cause loss of tumor suppres sor function and gain of oncogenic activity, i.e., to transform cells by two mechanisms, is one explanation for the commonality of p53 mutations in human cancer. Recent studies investigating the mecha nisms underlying the biological activity of p53 indicate that the protein is involved in gene transcription, DNA synthesis and repair, genomic plasticity, and programmed cell death (1â€”6).These complex biochemical processes are performed by multicomponent protein ma chines; therefore, it is not surprising that the p53 protein forms complexes with other cellular proteins (Fig. 1) and that some viral oncoproteins alter the functions of these machines by binding to p53 and perturbing its interaction with other cellular protein components. In this Perspective, we will focus on the origin of p.53 mutations, the mutational spectrum of p.53 in human cancers, and the hypotheses generated by the analysis of p53 mutations in premalignant and malignant cells. The interpretation ofp53 mutations in human cancers is based on observations of the patterns of DNA damage induced by chemical and physical mutagens in model systems. In this Introduc tion, we will review these data, which provide the background for many of the inferences drawn from p53 mutational analysis.

https://cancerres.aacrjournals.org/content/canres/54/18/4855.full.pdf

Mutations in the p53 Tumor Suppressor Gene: Clues to Cancer Etiology and Molecular Pathogenesis

http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.

Connexin 26 mutations in hereditary non-syndromic sensorineural deafness

Although a bewildering array of cell surface carbohydrate structures have been described, the physiological relevance of any of these complex molecules has often eluded biologists. A family of cell surface glycoproteins, the "selectins," has a characteristic ability to use some of these carbohydrate structures in adhesive mechanisms that help localize leukocytes to regions of inflammation. This article will review the biology of these carbohydrate-binding adhesive proteins and discuss the potential for developing anti-inflammatory antagonists that could inhibit binding events that are selectin-mediated.

https://science.sciencemag.org/content/sci/258/5084/964.full.pdf

Selectins: interpreters of cell-specific carbohydrate information during inflammation.

Molecular mechanisms regulating hair follicle development.

Introduction In sensitized individuals, a reaction to allergen can exhibit a succession of phases. Thus, in skin a biphasic reaction frequently follows an intradermal injection of allergen [1]. An analogous phenomenon is observed in the airways of certain asthmatics who respond to antigen inhalation with both acute and more sustained phases of airway obstruction [2]. As both early and late responses to allergen inhalation can be abolished by administration of disodium cromoglycate (DSCG) [2], it has been assumed that mast cell activation provides a basis for both phases of the reaction [3]. More recently, it has been observed that biphasic reactions result from injection of Paf-acether into human skin [4, 5[. Paf-acether is 1-o-alkyl-2-acetyl-snglyceryl-3-phosphorylcholine, an ether-linked phospholipid which is released during IgE-mediated responses from cells other than the mast cell, and has properties appropriate to a mediator of asthma and inflammation [6]. Preliminary observations have shown that the late-onset response to Paf-acether is inhibited by DSCG in certain individuals, indicating an alternative to mast cell degranulation for production of late-onset responses to allergen and thus providing a novel mechanism for DSCG efficacy in asthma lTJ. The present study has compared biphasic inflammatory responses induced by Paf-acether with responses to histamine and to the histamine liberator, codeine phosphate, and has assessed the sensitivity of these responses to DSCG.

Actions of disodium cromoglycate (DSCG) on human skin responses to histamine, codeine and Paf-acether

Summary

An immunohistochemical study of basal cell carcinomas of varying histological type, using a panel of antibodies to constituents of the epidermal basement membrane, showed marked deficiencies in the expression of the antigens identified by the antibodies LH7.2.GB3 and G71. There was no correlation between loss of immunoreactivity to these antibodies and the histological features of the tumour.

The epidermal basement membrane in basal cell carcinoma: an immunohistochemical study.

Cyclosporin A has been demonstrated to be an effective alternative to conventional immunosuppressive agents, such as azathioprine and prednisolone, in promoting successful organ transplantation. Although the association between immunosuppression and the development of skin malignancy has been well documented, the cutaneous carcinogenic potential of cyclosporin remains uncertain. This report concerns two recipients of renal allografts, in whom conversion from azathioprine and prednisolone to cyclosporin A was followed by the development of a variety of hyperplastic, dysplastic and malignant cutaneous lesions. These ranged from a keratoacanthoma with small foci of dysplasia and viral wartsshowing marked dysplastic changes, to carcinoma in situ and frank invasive anaplastic squamous cell carcinoma. Furthermore, in both cases the distribution of these proliferative lesions was confined to sun-exposed regions of the body. Although both subjects were immunosuppressed for 8 and 12 years respectively prior to the change in their therapy, the temporal relationship between conversion and the appearance of dysplastic and malignant lesions provides strong circumstantial evidence for incriminating cyclosporin A particularly in their genesis. In addition, their localizaton to sun-exposed areas suggests that ultraviolet light plays a role in their pathogenesis and highlights the need for sun avoidance in transplanted patients.

Cyclosporin A and cutaneous malignancy

It is recognized that cells of melanocytic naevi may resemble neuroid structures and the term neurotization has been used to describe this phenomenon. This may result in difficulty in the histological differentiation between naevi and neurofibromas. We report the case of a patient with a giant bathing trunk naevus which has undergone marked neurotization and in whom there had been diagnostic difficulty.

A case of giant bathing trunk naevus with neurofibroma-like change

Flegel's disease, not Kyrle's disease.

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