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.

Tissue from the cutaneous metastases of bronchial carcinoid was examined. Fine argyrophil secretory granules were demonstrated in the cytoplasm of the abnormal cells which showed positive labelling with neuron-specific enolase. Ultrastructural studies revealed numerous electron-dense membrane bound neuro-secretory granules, 50-300 nm in diameter. Other characteristic features included inter-digitating pseudo pod-like processes (up to 2 mu in size) in the cytoplasmic membrane, perinuclear filaments, a well-defined Golgi zone and numerous large mitochondria.

Ultrastructural features of metastatic cutaneous carcinoid

Summary

Tissue from twenty-five patients with mycosis fungoides and three patients with poikiloderma atrophicans vasculare was examined ultrastructurally. Characteristic abnormal lymphoid cells were conspicuous in all biopsies comprising 30–60% of the cutaneous infiltrate. These cells possessed irregular nuclear outlines presenting a spectrum from mild indentation to grossly cerebriform shapes. The other prominent cell type was the histiocyte which occasionally appeared abnormal. Bizarre histiocytic cells resembling the interdigitating reticulum cell of lymph node T cell areas were also observed. In the epidermal infiltrate, abnormal lymphoid cells were seen singly infiltrating between keratinocytes and less frequently in groups, forming Pautrier microabscesses, or in close apposition to histiocytes. Langerhans cells appeared in normal numbers and were usually isolated but were occasionally seen in contact with lymphoid cells.

An ultrastructural study of the mononuclear cell infiltrate of mycosis fungoides and poikiloderma atrophicans vasculare.

HNK-1 antigen is not specific for natural killer cells.

SUMMARY

The presence of natural killer (NK) cells, as defined by reactivity with the monoclonal antibodies Leu 7, Leu 11 and Leu 19 was assessed in the inflammatory infiltrate around epidermal neoplasms and compared with findings in a range of inflammatory dermatoses. HNK-1+ (Leu 7) cells were present in a wide range of malignant, pre-malignant and inflammatory disorders. Cells positive for the more specific NK cell antigens CD16 (Leu 11)/ NKH-1 (Leu 19) had a distribution mainly restricted to cases of squamous cell carcinoma (five of nine) and keratoacanthoma (three of seven). The variability in distribution between the different antibodies suggests that the majority of cutaneous HNK-1+ cells are not NK cells, but represent cross-reacting T lymphocytes. The qualitatively distinct distribution of CD16+ and NKH-1+ cells around some cases of squamous cell carcinoma and keratoacanthoma is of interest but their absence from a number of such cases calls into question a specific effector role for natural killer cells in these squamoproliferative tumours.

Identification of CD16/NKH-1+ natural killer cells and their relevance to cutaneous tumour immunity

appeared, initially affecting the periorbital skin, but gradually extending to involve the forehead, cheeks, trunk, buttocks, upper thighs and vulva. Her main complaint was of vulval irritation. Examination. There are scattered, skin coloured papules on the face, lower back and buttocks (Fig. i). Vulval involvement consists of multiple papules becoming confluent and giving a cobblestone appearance. The fingers are shortened with thickened terminal phalanges and there is a simian crease. There is ocular hypertelorism, abnormal dentition with cramping ofthe lower teeth and a high arched palate. Histology. Biopsy of a lesion from the neck showed a syringoma. Comment. This case is difficult to classify but has several ofthe features of Cowden's disease, a rare disorder with autosomal dominant inheritance characterized by multiple facial papules (usually trichilemmomas) in association with mucosal papillomatosis (histologically fibromata). A wide variety of other abnormalities has also been described, the most important of which are palmo-plantar keratoses, keratoses involving the dorsa of hands and feet, a high arched palate and adenoid facies. The importance of this rare condition lies in its association with multisystem hamartomata and with internal malignancy (especially in females) particularly ofthe breast (36%) and thyroid (12\",,). Syringomata are, however, not a recognized feature of Cowden's disease.

60) Basal cell naevus syndrome (lacking basal cell carcinomata)

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