Telomerase activation cooperates with inactivation of p16 in early head and neck tumorigenesis

Alteration of the p16/pRb pathway may cooperate with telomerase activation during cellular immortalization and tumour progression. We studied p16 expression status by immunohistochemistry and telomerase activity using the TRAP assay in 21 premalignant lesions of the head and neck epithelium as well as 27 squamous-cell carcinomas. We also examined expression of other components of the pathway (cyclin D1 and pRb) as well as presence of human papillomavirus genomes which can target these molecules. 4 of 9 mild dysplastic lesions (44%), 8 of 12 moderate/severe dysplastic lesions (67%), and 25 of 27 squamous-cell carcinomas (92%) demonstrated high telomerase activity (P = 0.009). There was a parallel increase with severity of lesions for the trend in proportions of cases demonstrating p16 inactivation or cyclin D1 overexpression (P = 0.02 and P = 0.01, respectively). For Ki67, a marker of cell proliferation, this trend was not significant (P = 0.08). Human papillomavirus infection was only found in 4 cases among the 48 samples tested (8.3%). In conclusion, progression of disease is accompanied by a parallel and continuous increase in telomerase activity and alterations in cell cycle regulators (p16, cyclin D1), as proposed by in vitro models. © 2001 Cancer Research Campaign http://www.bjcancer.co

Next-Generation Sequencing Reveals High Concordance of Recurrent Somatic Alterations Between Primary Tumor and Metastases From Patients With Non-Small-Cell Lung Cancer

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Deficiency in Nucleotide Excision Repair Family Gene Activity, Especially ERCC3, Is Associated with Non-Pigmented Hair Fiber Growth

We conducted a microarray study to discover gene expression patterns associated with a lack of melanogenesis in non-pigmented hair follicles (HF) by microarray. Pigmented and non-pigmented HFs were collected and micro-dissected into the hair bulb (HB) and the upper hair sheaths (HS) including the bulge region. In comparison to pigmented HS and HBs, nucleotide excision repair (NER) family genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, XPA, NTPBP, HCNP, DDB2 and POLH exhibited statistically significantly lower expression in non- pigmented HS and HBs. Quantitative PCR verified microarray data and identified ERCC3 as highly differentially expressed. Immunohistochemistry confirmed ERCC3 expression in HF melanocytes. A reduction in ERCC3 by siRNA interference in human melanocytes in vitro reduced their tyrosinase production ability. Our results suggest that loss of NER gene function is associated with a loss of melanin production capacity. This may be due to reduced gene transcription and/or reduced DNA repair in melanocytes which may eventually lead to cell death. These results provide novel information with regard to melanogenesis and its regulation

Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers

Molecular segmentation of breast cancer allows identification of small groups of patients who present high sensitivity to targeted agents. A patient, with chemo- and trastuzumab-resistant HER2-overexpressing breast cancer, who presented concomitant acute promyelocytic leukemia, showed a response in her breast lesions to retinoic acid, arsenic, and aracytin. We therefore investigated whether RARA gene amplification could be associated with sensitivity to retinoic acid derivatives in breast cancers.|Array comparative genomic hybridization and gene expression arrays were used to characterize RARA amplifications and expression in 103 breast cancer samples. In vitro activity of ATRA was characterized in T47D, SKBR3, and BT474 cell lines.|Retinoic acid receptor alpha was gained or amplified in 27% of HER2-positive and 13% of HER2-negative breast cancer samples. Retinoic acid receptor alpha can be coamplified with HER2. Retinoic acid receptor alpha copy number changes could be correlated with messenger RNA expression. All-trans-retinoic acid reduced cell viability of RARA-amplified, but not RARA-normal, cell lines through apoptosis. Gene expression arrays showed that ATRA-induced apoptosis in RARA-amplified cell lines was related to an increase in CASP1 and IRF1.|The results of this study suggest that breast cancers exhibiting RARA amplifications could be sensitive to retinoic acid. A phase II trial will evaluate this hypothesis in the clinical setting

The Aging Hair Pigmentary Unit

NoAs a highly visual and social species we communicate significantly via our physical appearance. Thus, it is unsurprising that the phenotypic aspects (including color) of our skin and hair feature prominently in such communication. Perhaps, one of the more potent reminders of aging is the change in pigmentation from birth to puberty and through to young adulthood, middle age, and beyond. Indeed, the hair bulb melanocyte may be viewed as an exquisitely sensitive aging sensor. In this context, we can appreciate that the loss of pigmentation from the hair tends to be earlier and much more striking than the age-associated pigmentation changes that we see in the epidermis. This phenotypic difference between the hair follicle and the epidermis-melanocyte subpopulations is of considerable interest, not least as both subpopulations originate from the same embyrologic neural crest and that the melanoctye stem cells in the adult hair follicle can occupy vacant niches in the epidermis. A major source of the differential aging of melanocytes in the hair bulb vs. the epidermis is likely due to the former¿s stringent coupling to the hair growth cycle when compared with the latter¿s continuous and UV-sensitive melanogenesis. Also likely to be involved is the maintenance of permissive microenvironments in these different skin compartments including their differing redox environments and variable connectivity with neuroendocrine axis. Over the last few years, we and others have striven to develop advanced cell culture methodologies for isolated hair follicle melanocytes and for intact anagen hair follicle organ culture, which may provide research tools to elucidate the regulatory mechanisms of hair follicle pigmentation. Others have assessed the robustness of the hair follicle-melanocyte stem compartment with age and other functional stressors. In the long term, it may be feasible to develop strategies to modulate some of these aging-associated changes in the hair follicle that impinge particularly of the melanocyte populations

Next-Generation Sequencing Reveals High Concordance of Recurrent Somatic Alterations Between Primary Tumor and Metastases From Patients With Non–Small-Cell Lung Cancer

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