3 research outputs found
The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response
No full textA positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans
No full textSeborrheic keratoses (SKs) are common, benign epithelial tumors of the skin that do not, or very rarely, progress into malignancy, for reasons that are not understood. We investigated this by gene expression profiling of human SKs and cutaneous squamous cell carcinomas (SCCs) and found that several genes previously connected with keratinocyte tumor development were similarly modulated in SKs and SCCs, whereas the expression of others differed by only a few fold. In contrast, the tyrosine kinase receptor FGF receptor-3 (FGFR3) and the transcription factor forkhead box N1 (FOXN1) were highly expressed in SKs, and close to undetectable in SCCs. We also showed that increased FGFR3 activity was sufficient to induce FOXN1 expression, counteract the inhibitory effect of EGFR signaling on FOXN1 expression and differentiation, and induce differentiation in a FOXN1-dependent manner. Knockdown of FOXN1 expression in primary human keratinocytes cooperated with oncogenic RAS in the induction of SCC-like tumors, whereas increased FOXN1 expression triggered the SCC cells to shift to a benign SK-like tumor phenotype, which included increased FGFR3 expression. Thus, we have uncovered a positive regulatory loop between FGFR3 and FOXN1 that underlies a benign versus malignant skin tumor phenotype
The diocese of Coventry and Lichfield, 1603-1642
No full textThis thesis investigates religious life among the clergy and laity in the diocese of
Lichfield, 1603-1642, including the role of Puritans, Catholics and Church
Papists. Nicholas Tyacke has maintained that the implementation of Laudianism
in Charles I's reign proved contentious, an interpretation criticised by some
historians who aver that the Church continued to maintain a 'middle way'. This
study finds that the evidence from the diocese largely supports Tyacke's
interpretation.
Proto-Laudian reforms were implemented in the see some years before the
Laudian ascendancy through the episcopates of Neile and Overall. Every bishop
in the period who undertook a programme of reform met local hostility and
indifference, and sometimes the opposition of his ecclesiastical and lay superiors.
Every religious group underwent change and development. Puritans and
Catholics pursued strategies for survival, supported by their respective religious
networks. Official opposition often had the effect of strengthening their resolve
and confirming them in their beliefs. Local conformists' commitment to the
established Church deepened during this period. They respected the Church's role
as the official purveyor of religion, morality and the ecclesiastical rites of passage,
without evidencing much theological understanding.
In the 1630s Bishop Wright oversaw the Laudian programme of
sacramental, sacerdotal and liturgical reform, but his lack of organisation, zeal and
commitment frustrated Charles, Laud and some local diocesan officials. The
changes met resistance, which gathered strength with the collapse of the Personal
Rule and manifested itself either in a desire to return to the pre-Laudian Church,
or in its root and branch reform. The strength of an individual's anti-Catholicism
indicated which religious solution s/he supported. When war came, for the most
part Puritans predictably supported Parliament, but a number of moderate Puritans
supported the King. Even among the 'godly' fraternity allegiance could
sometimes be determined by a variety of considerations
