Biddle A.,Queen Mary, University of London |
Biddle A.,Blizard Institute of Cell and Molecular Science |
Mackenzie I.C.,Queen Mary, University of London
Cancer and Metastasis Reviews | Year: 2012
The majority of deaths from carcinoma are caused by secondary growths that result from tumour invasion and metastasis. The importance of epithelial-to-mesenchymal transition (EMT) as a driver of invasion and metastasis is increasingly recognised, and recent evidence has highlighted a link between EMT and the cancer stem cells that initiate and maintain tumours and have also been implicated in invasion and metastasis. Here, we review cancer stem cells and their link with EMT, and explore the importance of this link in metastasis and therapeutic resistance of tumours. We also discuss new evidence from our laboratory demonstrating that cancer stem cells display a remarkable phenotypic plasticity that enables them to switch between an epithelial phenotype that drives tumour growth and an EMT phenotype that drives metastasis. As successful therapies must eradicate cancer stem cells in all their guises, the identification of sub-types of cancer stem cells that display therapeutic resistance and phenotypic plasticity has important implications for the future design of therapeutic strategies. The ability to assay the responses of different cancer stem cell phenotypes in vitro holds promise for the rapid development of a new generation of targeted therapies that fulfil this objective. © 2012 Springer Science+Business Media, LLC.
MacGregor E.A.,Blizard Institute of Cell and Molecular Science
Maturitas | Year: 2012
Migraine is affected by fluctuating estrogen levels so it is not surprising that the perimenopause is a time of peak rate of change of migraine prevalence in women. Evidence supports estrogen 'withdrawal' as one of the important triggers of menstrual attacks of migraine without aura, while high levels are associated with migraine aura. This mini review addresses the issues of diagnosing migraine, treating the symptoms of migraine, and controlling co-morbid migraine and hot flushes with hormonal and non-hormonal options. Maintaining a stable estrogen environment is the most effective treatment for vasomotor symptoms and can also benefit estrogen-withdrawal migraine. Using only the lowest doses necessary to control symptoms minimizes the risk of unwanted side effects. Non-hormonal options for both conditions are limited but there is evidence of efficacy for fluoxetine and venflaxine, with less evidence for gabapentin. © 2011 Elsevier Ireland Ltd. All rights reserved.
Hunt D.,University of Edinburgh |
Giovannoni G.,Blizard Institute of Cell and Molecular Science
Practical Neurology | Year: 2012
Natalizumab reduces relapse frequency, delays onset of disease progression and improves disease outcomes in relapsing-remitting multiple sclerosis (MS) and is a cost-effective treatment for rapidly evolving severe relapsing-remitting MS. However, it is associated with the development of progressive multifocal leucoencephalopathy (PML), a serious opportunistic brain infection caused by a neurotropic strain of the JC virus (JCV). Until May 2011, 83 300 patients had received natalizumab for MS. One hundred and twenty-four patients had developed PML, of whom 23 (19%) died. In order to maximise the benefi t-risk ratio of natalizumab for MS patients it is important to develop a strategy for risk profi ling and monitoring for PML. Central to this is an understanding of the biology of the JCV and the emerging clinical picture of natalizumab-associated PML. This paper reviews the evidence for managing the risk of PML in natalizumab-treated patients and the authors propose an algorithm for risk profi ling and risk management. Key features of this algorithm include risk stratifi cation based on emerging risk factors, heightened clinical vigilance for the clinical features of natalizumab-associated PML and considerations for temporary and permanent cessation of natalizumab dosing.
MacDonald T.T.,Blizard Institute of Cell and Molecular Science |
Monteleone I.,University of Rome Tor Vergata |
Fantini M.C.,University of Rome Tor Vergata |
Monteleone G.,University of Rome Tor Vergata
Gastroenterology | Year: 2011
The gastrointestinal tract is the largest immune interface with the environment. Exposure to large numbers of dietary and microbial antigens requires complex and highly regulated immune responses by different mucosal cell types, which result in the induction and maintenance of intestinal homeostasis. Defects in this equilibrium can disrupt the homeostatic mechanisms and lead to chronic intestinal inflammation. We review the cell populations and mechanisms involved in the control of intestinal homeostasis and inflammation, focusing on inflammatory bowel diseases. We describe some aspects of gut immunity that could alter the delicate balance between inflammatory and tolerogenic responses and result in chronic gastrointestinal tract inflammation in patients. © 2011 AGA Institute.
MacGregor E.A.,St. Bartholomew's Hospital |
MacGregor E.A.,Blizard Institute of Cell and Molecular Science
Neurologic Clinics | Year: 2012
Primary headaches are most common in women during their reproductive years and are affected by the hormonal fluctuations during pregnancy. Most headaches follow a benign course during pregnancy, although migraine is associated with increased risk of hypertensive disorders of pregnancy and stroke. Management of primary headaches during pregnancy is essentially similar to management in the nonpregnant state, with a few exceptions. This article reviews the epidemiology, prognosis, and management of primary headaches during pregnancy and lactation, and considers secondary headaches that are important to exclude. © 2012 Elsevier Inc.
Hypponen E.,University College London |
Boucher B.J.,Blizard Institute of Cell and Molecular Science
British Journal of Nutrition | Year: 2010
Prevalence of hypovitaminosis D in Western populations is high; pregnant women are identified as a high-risk group, especially if dark skinned. Consequences of severe clinical vitamin D deficiency in pregnancy can be life threatening to the newborn, while lesser degrees of hypovitaminosis D may have important long-term implications for offspring health. Past experiences with routine provision of 10g/d (400IU/d) to all pregnant mothers suggest that this dose is sufficient to prevent overt neonatal complications of vitamin D deficiency. Recent data suggest that supplementation with dosages above 10g/d may be required for optimal health in the mother and child; however, further research is required for the assessment of the benefits and safety of supplementation with higher dosages. Lack of unified advice on vitamin D supplementation of pregnant mothers in the UK hinders the implementation of primary prevention strategies and is likely to leave some deficient mothers without supplementation. © 2010 The Authors.
Hawkes C.H.,Blizard Institute of Cell and Molecular Science
Multiple Sclerosis and Related Disorders | Year: 2013
This review addresses several areas of contention related to the genetic theory for multiple sclerosis (MS). It is argued (a) that the concept of MS as a 'complex disease' has little value, (b) just because a disorder is found in multiple families, it is not necessarily genetically based, (c) although twin studies are claimed to show that MS is '30% genetically based' this concept derives from widely varying data, (d) although genome-wide association studies (GWAS) suggest the presence of several MS related genes this has yet to be proven, (e) monozygotic twins discordant for MS should have a different genetic sequence if the disorder has a genetic basis but data so far suggest this may not be correct and (f) epigenetics or epistasis are contentious topics and may not provide the answer. It is concluded that the role of genetics in MS etiology may be overstated and that attention should now be devoted to environmental causes. © 2012 Elsevier B.V.
Graham T.A.,Cancer Research UK Research Institute |
McDonald S.A.C.,Blizard Institute of Cell and Molecular Science
Biochemical Society Transactions | Year: 2010
Recent investigations into Barrett's oesophagus at the level of individual crypts have found significant genetic heterogeneity within a single lesion. Furthermore, this genetic diversity has been shown to predict cancer development. In the present article, we review the genetic alterations implicated in disease progression in Barrett's oesophagus and discuss how genetic diversity could arise during tumorigenesis. Three arguments are discussed: a high mutation rate coupled with strong selection, clonal interaction driving progression, and a hitherto unidentified alteration that disrupts epithelial cell homoeostasis. Suggestions are made for future research to distinguish which of these theories is the predominant mechanism in Barrett's oesophagus-associated tumorigenesis. ©The Authors.
Etemadifar M.,Isfahan University of Medical Sciences |
Etemadifar M.,Blizard Institute of Cell and Molecular Science |
Maghzi A.-H.,Isfahan University of Medical Sciences
Multiple Sclerosis Journal | Year: 2011
Background: The epidemiology of multiple sclerosis (MS) has changed in recent decades.Objectives: This study aimed to give an update on the prevalence and incidence of MS in Isfahan, Iran.Methods: The study population was all residents of Isfahan province during the period from April 2003 to July 2010. In April 2003, a registry of MS patients was created at the Isfahan MS Society (IMSS), which is the only referral center for MS patients in the province. Nearly all MS patients in Isfahan province are now registered with IMSS and were included in the analysis.Results: Among the 3522 registered patients, 2716 were female and 806 were male (sex ratio: 3.37 : 1), and 431 were diagnosed in 2009. This results in a prevalence figure of 73.3 (95% CI: 70.9-75.8) and an incidence of 9.1 (95% CI: 8.3-10.0) per 100,000.Conclusion: The reported prevalence and incidence figures in our study were higher than in our previous report of 2007, in which the prevalence and incidence of MS were reported to be 43.8 and 3.64 per 100,000, respectively. This dramatic increase in the prevalence of MS puts Isfahan amongst the regions with the highest prevalence of MS in Asia and Oceania and is mostly due to changing environmental factors, amongst which vitamin D deficiency seems an important factor in our population. © The Author(s) 2011.
Zeki S.S.,Blizard Institute of Cell and Molecular Science
Discovery medicine | Year: 2011
Barrett's esophagus is a columnar metaplasia conferring an increased risk of adenocarcinoma development. Evidence suggests that this increased risk is due to field cancerization - the formation of histologically undistinguishable field of clonally derived, mutant cells within the Barrett's segment. Field cancerization can occur prior to both dysplasia and invasive neoplasia and potentially provides a mechanism for the development of multifocal and metachronous tumors. In the gastrointestinal tract, mutant clones spread predominately by crypt fission; the same is likely to be true in Barrett's lesions. Epithelial interactions in the form of cooperation or competition between epithelial clones, as well as with stromal cells, may further drive clone growth. Field cancerization is a clinically relevant phenomenon, knowledge of which could influence the size of resection margins to enhance prognosis after curative surgery, as well as provide a rationale for the development of effective biomarkers for neoplasia risk in Barrett's esophagus. This may provide a foundation for streamlined surveillance programs to prevent the development of invasive tumors.