Kruppel-Like Factor 4 Regulates Granule Cell Pax6 Expression and Cell Proliferation in Early Cerebellar Development.

Kruppel-like factor 4 (Klf4) is a transcription factor that regulates many important cellular processes in stem cell biology, cancer, and development. We used histological and molecular methods to study the expression of Klf4 in embryonic development of the normal and Klf4 knockout cerebellum. We find that Klf4 is expressed strongly in early granule cell progenitor development but tails-off considerably by the end of embryonic development. Klf4 is also co-expressed with Pax6 in these cells. In the Klf4-null mouse, which is perinatal lethal, Klf4 positively regulates Pax6 expression and regulates the proliferation of neuronal progenitors in the rhombic lip, external granular layer and the neuroepithelium. This paper is the first to describe a role for Klf4 in the cerebellum and provides insight into this gene's function in neuronal development.

CAGE-defined promoter regions of the genes implicated in Rett Syndrome.

BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes. RESULTS: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum. CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome.

Management of periocular basal cell carcinoma by Mohs micrographic surgery.

BACKGROUND/AIMS: To determine the success of Mohs micrographic surgery (MMS) for periocular basal cell carcinoma (BCC) at a tertiary referral centre in the UK. DESIGN: A retrospective interventional case series covering 5 years of practice. METHODS: Review of medical records of 104 consecutive patients who underwent MMS for confirmed periocular BCC. The main outcome measure was biopsy-proven recurrence of BCC at the same anatomical location after MMS. Secondary outcome measures included tumour site, histological subtype and length of follow-up. RESULTS: 104 patients underwent MMS for periocular BCC from January 2003 to July 2008. 63 (62%) of the surgeries were for primary BCC and 25 procedures (25%) were for recurrent or residual BCC. 64% of tumours were nodular BCC. The mean follow-up was 28 months (range 1-85 months). Six recurrences were identified in total. The recurrence rate following MMS for primary BCC was 1.6% (1 patient) compared to 20% (5 patients) in the patient group treated for residual or recurrent tumours. The mean time to recurrence was 39 months (range 16-71 months). CONCLUSIONS: MMS for primary BCC has a very high success rate but the recurrence rate increases significantly in cases of recurrent or residual tumours.

Terahertz pulsed spectroscopy of human Basal cell carcinoma.

Good contrast is seen between normal tissue and regions of tumor in terahertz pulsed imaging of basal cell carcinoma (BCC). To date, the source of contrast at terahertz frequencies is not well understood. In this paper we present results of a spectroscopy study comparing the terahertz properties (absorption coefficient and refractive index) of excised normal human skin and BCC. Both the absorption coefficient and refractive index were higher for skin that contained BCC. The difference was statistically significant over the range 0.2 to 2.0 THz (6.6 cm(-1) to 66.6 cm(-1)) for absorption coefficient and 0.25 to 0.90 THz (8.3 cm(-1) to 30 cm(-1)) for refractive index. The maximum difference for absorption was at 0.5 THz(16.7 cm(-1)). These changes are consistent with higher water content. These results account for the contrast seen in terahertz images of BCC and explain why parameters relating to the reflected terahertz pulse provide information about the lateral spread of the tumor. Knowing the properties of the tissue over the terahertz frequency range will enable the use of mathematical models to improve understanding of the terahertz response of normal and diseased tissue.

Simulating the response of terahertz radiation to basal cell carcinoma using ex vivo spectroscopy measurements.

Studies of basal cell carcinoma using terahertz pulsed imaging have revealed a significant difference between regions of tumor and healthy tissue. These differences are manifested in the reflected pulse due to what is thought to be changes in refractive index and absorption. We present measurements of the refractive index and absorption coefficient of excised normal tissue and basal cell carcinoma using terahertz (THz) transmission spectroscopy. We extract Debye parameters from these data and enter them into a finite difference time domain simulation to predict the shape of the waveforms reflected off the normal tissue and basal cell carcinoma and compare them with published in vivo data. Simulating the interaction of terahertz radiation with normal and cancerous tissue is a key step toward understanding the origin of contrast in terahertz images of skin cancer.

The relationship between constitutive pigmentation and sensitivity to ultraviolet radiation induced erythema is dose-dependent.

The relationship between skin colour and experimental exposure to ultraviolet radiation (UVR) B, with response measured as erythema was studied. Two reflectance methods were used to measure skin colour--tristimulus colorimetry using a Minolta instrument (summarized as the alpha characteristic angle) and the melanin index based on the Diastron reflectance instrument. As expected both measures are highly correlated (0.91). A dose-dependent relationship between skin colour measured as the alpha characteristic angle and UVR was established, with the gradient increasing from 0.99 at 119 mJ to 2.7 at 300 mJ, with the relevant standard errors being 0.39 and 0.47, respectively. Similarly, for the melanin index (where the scale goes in the opposite direction) the gradient differs between -0.49 for 119 mJ and -0.91 for 300 mJ, with the standard errors being 0.14 and 0.17 respectively. The proportion of variation explained is also greater at higher UVR challenge doses. Studies relating UVR sensitivity and pigmentation need to take account of the dose of UVR administered.

Time course of ultraviolet B-induced erythema in people with red hair harbouring homozygous melanocortin 1 receptor mutations.

It has previously been reported that the time course of erythema may be delayed in those with sun-sensitive skin types and those with skin cancer. One molecular explanation for this putative phenotype would be that it is caused by mutations of the melanocortin 1 receptor (MC1R). In the present study of 20 persons, 10 of whom were MC1R homozygous, we measured erythema over a 21-day period in response to a range of ultraviolet B doses using methods that improved on previous studies. We could detect no consistent differences in ultraviolet radiation-induced erythema between the groups studied. The pharmacological mechanisms underpinning such prolonged inflammatory responses merit further investigation.

Mapping of nasopharyngeal carcinoma tumor-suppressive activity to a 1.8-megabase region of chromosome band 11q13.

Nasopharyngeal carcinoma (NPC) is a malignancy that is particularly prevalent among populations from Southern China and Southeast Asian countries. Evidence for a genetic contribution to the disease has been documented, although the genetic basis for NPC development is not yet fully understood. Previous functional evidence of tumor-suppressive activity on chromosome band 11q13 in NPC was obtained using a microcell-mediated chromosome-transfer approach with HONE1 NPC cells. In the present study, this region was subjected to a detailed investigation of microcell hybrids and their tumor segregants using microsatellite analysis to narrow down the region of tumor-suppressive activity. Fluorescence in situ hybridization was also performed with BAC and cosmid probes to confirm the microsatellite data. The critical region responsible for tumor suppression was narrowed down to a 1.8-Mb interval, which does not tolerate an additional normal allele by chromosome transfer. One or two alleles from either endogenous or exogenous chromosomes at 11q13 were consistently eliminated during tumor growth. Results of this study suggest that a candidate tumor-suppressor gene, not the MEN1 gene, maps between D11S4907 and GSTP1 in NPC.

Red hair--a desirable mutation?

Red hair is one of the most striking variants of human hair coloration and has historically been of profound social importance. Red hair in man is due to certain loss of function mutations of one of the peptide products of the pro-opiomelanocortin (POMC) gene, the melanocortin-1 receptor (MC1R, MIM 155555). Such functional mutations enable the melanocyte to produce red-yellow pheomelanin in preference to the default, black-brown eumelanin. This paper reviews the path of discovery of the MC1R in control of animal coat colour, the subsequent role of MC1R in human physiology and possibly wider role of MC1R in human skin carcinogenesis and human development through history.