Mapping Six New Susceptibility to Colon Cancer ( Scc ) Loci Using a Mouse Interspecific Backcross

Colorectal cancer (CRC) has a complex etiology resulting from the combination of multiple genetic and environmental factors, each with small effects. Interactions among susceptibility modifier loci make many of the loci difficult to detect in human genome-wide association studies. Previous analyses in mice have used classical inbred strains, which share large portions of their genomes due to common ancestry. Herein, we used an interspecific backcross between the Mus musculus strain A/J and the Mus spretus strain SPRET/EiJ to map 6 additional CRC modifier loci (Scc16-21) and 2 suggestive loci. Three loci modify the location of tumors along the proximal-distal axis of the colon. Six CRC modifiers previously mapped in intraspecific crosses were also replicated. This work confirms genetic models suggesting that CRC is caused by many small effect alleles and brings the catalog of reported CRC modifier loci to 23 spread across 13 chromosomes. Furthermore, this work provides the foundation for large population-level epistatic interaction tests to identify combinations of low effect alleles that may have large effects on CRC susceptibility

Miscellaneous Problems

Contains reports on five research projects

Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma

Treatment of metastatic renal cell carcinoma (mRCC) with agents that block signaling through vascular endothelial growth factor receptor 2 (VEGFR2) induces disease regression or stabilization in some patients; however, these responses tend to be short-lived. Therefore, development of combination therapies that can extend the efficacy of VEGFR antagonists in mRCC remains a priority. We studied murine xenograft models of RCC that become refractory to treatment with the VEGFR tyrosine kinase inhibitor (TKI) sunitinib. Dalantercept is a novel antagonist of Activin receptor-like kinase 1 (ALK1)/Bone morphogenetic protein (BMP) 9 signaling. Dalantercept inhibited growth in the murine A498 xenograft model which correlated with hyperdilation of the tumor vasculature and an increase in tumor hypoxia. When combined with sunitinib, dalantercept induced tumor necrosis and prevented tumor regrowth and revascularization typically seen with sunitinib monotherapy in two RCC models. Combination therapy led to significant downregulation of angiogenic genes as well as downregulation of endothelial specific gene expression particularly of the Notch signaling pathway. We demonstrate that simultaneous targeting of molecules that control distinct phases of angiogenesis, such as ALK1 and VEGFR, is a valid strategy for treatment of mRCC. At the molecular level, combination therapy leads to downregulation of Notch signaling

The attitudes, beliefs and behaviours of GPs regarding exercise for chronic knee pain: a systematic review

<p>Abstract</p> <p>Background</p> <p>Joint pain, specifically chronic knee pain (CKP), is a frequent cause of chronic pain and limitation of function and mobility among older adults. Multiple evidence-based guidelines recommend exercise as a first-line treatment for all patients with CKP or knee osteoarthritis (KOA), yet healthcare practitioners' attitudes and beliefs may limit their implementation. This systematic review aims to identify the attitudes, beliefs and behaviours of General Practitioners (GPs) regarding the use of exercise for CKP/KOA.</p> <p>Methods</p> <p>We searched four electronic databases between inception and January 2008, using subject headings to identify studies examining the attitudes, beliefs or behaviours of GPs regarding the use of exercise for the treatment of CKP/KOA in adults aged over 45 years in primary care. Studies referring to patellofemoral pain syndrome or CKP secondary to other causes or that occurring in a prosthetic joint were excluded. Once inclusion and exclusion criteria were applied, study data were extracted and summarised. Study quality was independently reviewed using two assessment tools.</p> <p>Results</p> <p>From 2135 potentially relevant articles, 20 were suitable for inclusion. A variety of study methodologies and approaches to measuring attitudes beliefs and behaviours were used among the studies. Quality assessment revealed good reporting of study objective, type, outcome factors and, generally, the sampling frame. However, criticisms included use of small sample sizes, low response rates and under-reporting of non-responder factors. Although 99% of GPs agreed that exercise should be used for CKP/KOA and reported ever providing advice or referring to a physiotherapist, up to 29% believed that rest was the optimum management approach. The frequency of actual provision of exercise advice or physiotherapy referral was lower. Estimates of provision of exercise advice and physiotherapy referral were generally higher for vignette-based studies (exercise advice 9%-89%; physiotherapy referral 44%-77%) than reviews of actual practice (exercise advice 5%-52%; physiotherapy referral 13-63%). <it>A</it><it>dvice to exercise </it>and exercise <it>prescription </it>were not clearly differentiated.</p> <p>Conclusions</p> <p>Attitudes and beliefs of GPs towards exercise for CKP/KOA vary widely and exercise appears to be underused in the management of CKP/KOA. Limitations of the evidence base include the paucity of studies directly examining attitudes of GPs, poor methodological quality, limited generalisability of results and ambiguity concerning GPs' expected roles. Further investigation is required of the roles of GPs in using exercise as first-line management of CKP/KOA.</p

Organic residues in archaeology - the highs and lows of recent research

YesThe analysis of organic residues from archaeological materials has become increasingly important to our understanding of ancient diet, trade and technology. Residues from diverse contexts have been retrieved and analysed from the remains of food, medicine and cosmetics to hafting material on stone arrowheads, pitch and tar from shipwrecks, and ancient manure from soils. Research has brought many advances in our understanding of archaeological, organic residues over the past two decades. Some have enabled very specific and detailed interpretations of materials preserved in the archaeological record. However there are still areas where we know very little, like the mechanisms at work during the formation and preservation of residues, and areas where each advance produces more questions rather than answers, as in the identification of degraded fats. This chapter will discuss some of the significant achievements in the field over the past decade and the ongoing challenges for research in this area.Full text was made available in the Repository on 15th Oct 2015, at the end of the publisher's embargo period

Epiregulin Is Not Essential for Development of Intestinal Tumors but Is Required for Protection from Intestinal Damage

Epiregulin, an epidermal growth factor family member, acts as a local signal mediator and shows dual biological activity, stimulating the proliferation of fibroblasts, hepatocytes, smooth muscle cells, and keratinocytes while inhibiting the growth of several tumor-derived epithelial cell lines. The epiregulin gene (Ereg) is located on mouse chromosome 5 adjacent to three other epidermal growth factor family members, epigen, amphiregulin, and betacellulin. Gene targeting was used to insert a lacZ reporter into the mouse Ereg locus and to ablate its function. Although epiregulin is broadly expressed and regulated both spatially and temporally, Ereg null mice show no overt developmental defects, reproductive abnormalities, or altered liver regeneration. Additionally, in contrast to previous hypotheses, Ereg deficiency does not alter intestinal cancer susceptibility, as assayed in the Apc(Min) model, despite showing robust expression in developing tumors. However, Ereg null mice are highly susceptible to cancer-predisposing intestinal damage caused by oral administration of dextran sulfate sodium