Biological functions of CDK5 and potential CDK5 targeted clinical treatments.

Cyclin dependent kinases are proline-directed serine/threonine protein kinases that are traditionally activated upon association with a regulatory subunit. For most CDKs, activation by a cyclin occurs through association and phosphorylation of the CDK\u27s T-loop. CDK5 is unusual because it is not typically activated upon binding with a cyclin and does not require T-loop phosphorylation for activation, even though it has high amino acid sequence homology with other CDKs. While it was previously thought that CDK5 only interacted with p35 or p39 and their cleaved counterparts, Recent evidence suggests that CDK5 can interact with certain cylins, amongst other proteins, which modulate CDK5 activity levels. This review discusses recent findings of molecular interactions that regulate CDK5 activity and CDK5 associated pathways that are implicated in various diseases. Also covered herein is the growing body of evidence for CDK5 in contributing to the onset and progression of tumorigenesis

Geoffrey Hill: poetry, criticism and philosophy

This thesis examines the role played by philosophy in the poetry and criticism of Geoffrey Hill. Despite countless references to philosophy throughout Hill’s critical authorship, there exists no study of any length on this vital aspect of his thought. Through close readings of his poetry, criticism, and archival material, I attempt to demonstrate that philosophy has played a more crucial role in Hill’s work than has hitherto been assumed. Hill’s sceptical attitude to philosophy is intimately connected with his understanding of poetry as a sensate form of cognition. My thesis examines the ways Hill’s poetry and criticism responds to the challenges imposed upon this scepticism by a tradition of philosophy that emphasises the importance of the aesthetic to its analyses of modernity’s contradictions. I argue that a tradition of Anglophone Idealist thinkers, from S.T. Coleridge, via T.H. Green and F.H. Bradley, to Gillian Rose, is of sustained relevance to Hill’s work, shaping the way he thinks about politics, ethics and literature. In particular, German Idealism’s attempts to negotiate universality and particularity via an emphasis on the aesthetic bases of critical thought lay the groundwork for an understanding of poetry as a mode of cognition. Reading Hill’s poetry from For the Unfallen to Oraclau/Oracles, I try to show the ways in which problems traditionally conceived of as philosophical can be cognised in prosody and syntax. In part a vindication of Hill’s elevation of poetry over philosophy, these readings also show the degree to which Hill’s ‘craft of vision’ is indebted to conceptual and aesthetic models supplied by philosophy

A Branch of Magic, or the Possibility of Myth in Esther Kinsky’s Am Fluß

This article demonstrates how literary walks can evoke myth in a meaningful way for contemporary life. In particular, through a close reading of Esther Kinsky’s Am Fluß [River], I argue that the landscape experienced on foot can articulate and give access to the transcendent component of myth. I begin with a survey of how magic and transcendent experience is configured in related literary forms (namely new nature writing, the post-secular, new materialism, and the literature of re-enchantment) but remains bound by material reality. I then define the meaning and function of myth in relation to contemporary literature. These general observations lay the ground for a reading of Kinsky’s novel which focuses on the mythical symbolism of the protagonist’s solitary walks in the edgelands around London’s River Lea (among other locations). Although Am Fluß ostensibly resists both categories of “myth” and “psychogeography,” it walks the city, symbolically using myth in a way which works against dominant (nationalist and capitalist) structures of power. I finally consider the relationship between the novel and the potential for the purifying or expiatory powers of walking and walking literature. Like myth, Am Fluß brings an ineffable situation within the bounds of thought and comprehension, exemplifying a productive relationship with the environment

A study into the effectiveness of cognitive behavioural therapy for sufferers of chronic tension type headache

The aim of this research was to examine the effectiveness of Cognitive Behavioural Therapy on patients with Chronic Tension Type Headache referred from an acute medical setting. This study also aimed to examine the impact of therapy on other areas known to be implicated in the maintenance of chronic pain conditions. Results have shown that Cognitive Behavioural Therapy is useful in reducing a number of aspects of chronic tension type headache. Additional changes in more general psychological measures over time suggest that Cognitive Behavioural Therapy also successfully addresses issues that may mediate the experience of chronic pain

Stromal cyclin D1 promotes heterotypic immune signaling and breast cancer growth

The cyclin D1 gene encodes the regulatory subunit of a holoenzyme that drives cell autonomous cell cycle progression and proliferation. Herein we show cyclin D1 abundance is increased >30-fold in the stromal fibroblasts of patients with invasive breast cancer, associated with poor outcome. Cyclin D1 transformed hTERT human fibroblast to a cancer-associated fibroblast phenotype. Stromal fibroblast expression of cyclin D1 (cyclin D1Stroma) in vivo, enhanced breast epithelial cancer tumor growth, restrained apoptosis, and increased autophagy. Cyclin D1Stroma had profound effects on the breast tumor microenvironment increasing the recruitment of F4/80+ and CD11b+ macrophages and increasing angiogenesis. Cyclin D1Stroma induced secretion of factors that promoted expansion of stem cells (breast stem-like cells, embryonic stem cells and bone marrow derived stem cells). Cyclin D1Stroma resulted in increased secretion of proinflammatory cytokines (CCL2, CCL7, CCL11, CXCL1, CXCL5, CXCL9, CXCL12), CSF (CSF1, GM-CSF1) and osteopontin (OPN) (30-fold). OPN was induced by cyclin D1 in fibroblasts, breast epithelial cells and in the murine transgenic mammary gland and OPN was sufficient to induce stem cell expansion. These results demonstrate that cyclin D1Stroma drives tumor microenvironment heterocellular signaling, promoting several key hallmarks of cancer

Cyclin d1 induces chromosomal instability.

We developed mouse model systems to investigate the potential for cyclin D1 to induce CIN in vivo. In a mammary gland specific Tet-inducible model the acute expression profile regulated by cyclin D1 after 7 days was enriched in genes that rank highly with CIN. We also used a mammary gland targeted model (MMTV) to continuously express cyclin D1. The mice started to develop mammary gland tumors at 400 days and the tumor-free incidence was 40% in MMTV-cyclin D1. The gene expression profile of the tumors showed enrichment for the CIN signature. We next compared cyclin D1 expression and the highest ranking CIN genes to a breast cancer expression database and discovered that expression of genes promoting CIN are highly enriched in luminal subtype and that high cyclin D1 and CIN expression correlate specifically in the luminal B subtype. There is increasing interest in employing drugs in the clinic that exploit CIN in tumors. The high CIN expression index in luminal B breast cancer provides a basis for using Cdk and CIN inhibitors as a targeted therapeutic approach

DACH1 suppresses breast cancer as a negative regulator of CD44.

Dachshund homolog 1 (DACH1), a key cell fate determination factor, contributes to tumorigenesis, invasion, metastasis of human breast neoplasm. However, the exact molecular mechanisms for the anti-tumor roles of DACH1 in breast carcinoma are still lack of extensive understanding. Herein, we utilized immunohistochemistry (IHC) staining and public microarray data analysis showing that DACH1 was higher in normal breast, low-grade and luminal-type cancer in comparison with breast carcinoma, high-grade and basal-like tumors respectively. Additionally, both correlation analysis of public databases of human breast carcinoma and IHC analysis of mice xenograft tumors demonstrated that DACH1 inversely related to cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) inducers and basal-enriched molecules, while cluster of differentiation 44 (CD44) behaved in an opposite manner. Furthermore, mice transplanted tumor model indicated that breast cancer cells Met-1 with up-regulation of DACH1 were endowed with remarkably reduced potential of tumorigenesis. Importantly, meta-analysis of 19 Gene Expression Omnibus (GEO) databases of breast cancer implicated that patients with higher DACH1 expression had prolonged time to death, recurrence and metastasis, while CD44 was a promising biomarker predicting worse overall survival (OS) and metastasis-free survival (MFS). Collectively, our study indicated that CD44 might be a novel target of DACH1 in breast carcinoma