The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer

Current hormonal therapies have benefited millions of patients with breast cancer. Their success, however, is often temporary and limited to a subset of patients whose tumors express estrogen receptor alpha (ER). The therapies are entirely ineffective in ER-negative disease. Recent studies suggest that there are many biological pathways and alterations involved in determining whether ER is expressed and how it is regulated during breast cancer evolution. Improving hormonal therapies, in addition to perfecting current strategies, will also target these newly discovered pathways and alterations, and others yet to be found. The present commentary will briefly highlight a few important observations and unanswered questions regarding ER status and growth regulation during breast cancer evolution, which hopefully will help to stimulate new thinking and progress in this important area of medial research

The feasibility of collecting information from people with Multiple Sclerosis for the UK MS Register via a web portal: characterising a cohort of people with MS.

BACKGROUND: A UK Register of people with Multiple Sclerosis has been developed to address the need for an increased knowledge-base about MS. The Register is being populated via: a web-based portal; NHS neurology clinical systems; and administrative data sources. The data are de-identified and linked at the individual level. At the outset, it was not known whether people with MS would wish to participate in the UK MS Register by personally contributing their data to the Register via a web-based system. Therefore, the research aim of this work was to build an internet-mounted recruitment and consenting technology for people with Multiple Sclerosis, and to assess its feasibility as a questionnaire delivery platform to contribute data to the UK MS Register, by determining whether the information provided could be used to describe a cohort of people with MS. METHODS: The web portal was developed using VB.net and JQuery with a Microsoft SQL 2008 database. UK adults with MS can self-register and enter data about themselves by completing validated questionnaires. Descriptive statistics were used to characterise the respondents. RESULTS: The web portal was launched in May 2011, and in first three months 7,279 individuals registered on the portal. The ratio of men to women was 1:2.4 (n = 5,899), the mean self-reported age at first symptoms was 33.8 (SD 10.5) years, and at diagnosis 39.6 (SD 10.3) years (n = 4,401). The reported types of MS were: 15% primary progressive, 63% relapsing-remitting, 8% secondary progressive, and 14% unknown (n = 5,400). These characteristics are similar to those of the prevalent MS population. Employment rates, sickness/disability rates, ethnicity and educational qualifications were compared with the general UK population. Information about the respondents' experience of early symptoms and the process of diagnosis, plus living arrangements are also reported. CONCLUSIONS: These initial findings from the MS Register portal demonstrate the feasibility of collecting data about people with MS via a web platform, and show that sufficient information can be gathered to characterise a cohort of people with MS. The innovative design of the UK MS register, bringing together three disparate sources of data, is creating a rich resource for research into this condition

Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis

INTRODUCTION: Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers. METHODS: BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate. RESULTS: If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%. CONCLUSION: Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection

Comparing counselling alone versus counselling supplemented with guided use of a well-being app for university students experiencing anxiety or depression (CASELOAD): protocol for a feasibility trial.

BACKGROUND: University counselling services face a unique challenge to offer short-term therapeutic support to students presenting with complex mental health needs and in a setting which suits the academic timetable. The recent availability of mobile phone applications (apps) offers an opportunity to supplement face-to-face therapy and has the potential to reach a wider audience, maintain engagement between therapy sessions, and enhance therapeutic outcomes. The present study, entitled Counselling plus Apps for Students Experiencing Levels of Anxiety or Depression (CASELOAD), aims to explore the feasibility of supplementing counselling with guided use of a well-being app. METHODS/DESIGN: Forty help-seeking university students (aged 18 years and over) with symptoms of moderate anxiety or depression will be recruited from a University Counselling Service (UCS) in the United Kingdom (UK). Participants will be recruited via counsellors who provide the initial clinical assessment and who determine treatment allocation to one of two treatments on the basis of client-treatment fit. The two conditions comprise (1) counselling alone (treatment as usual/TAU) or (2) counselling supplemented with guided use of a well-being app (enhanced intervention). Trained counsellors will deliver up to six counselling sessions in each treatment arm across a 6-month period, and the session frequency will be decided by client-counsellor discussion. Assessments will occur at baseline, every counselling session, post-intervention (3 months after consent) and follow-up (6 months after consent). Assessments will include clinical measures of anxiety, depression, psychological functioning, specific mental health concerns (e.g. academic distress and substance misuse), resilience and therapeutic alliance. The usage, acceptability, feasibility and potential implications of combining counselling with guided use of the well-being app will be assessed through audio recordings of counselling sessions, telephone interviews with participants, focus groups with counsellors and counsellor notes. DISCUSSION: This study will inform the design of a randomised pilot trial and a definitive trial which aim to improve therapy engagement, reduce dropout and enhance clinical outcomes of student counselling. TRIAL REGISTRATION: ISRCTN55102899

Signatures of Selection in Fusion Transcripts Resulting From Chromosomal Translocations in Human Cancer

BACKGROUND: The recurrence and non-random distribution of translocation breakpoints in human tumors are usually attributed to local sequence features present in the vicinity of the breakpoints. However, it has also been suggested that functional constraints might contribute to delimit the position of translocation breakpoints within the genes involved, but a quantitative analysis of such contribution has been lacking. METHODOLOGY: We have analyzed two well-known signatures of functional selection, such as reading-frame compatibility and non-random combinations of protein domains, on an extensive dataset of fusion proteins resulting from chromosomal translocations in cancer. CONCLUSIONS: Our data provide strong experimental support for the concept that the position of translocation breakpoints in the genome of cancer cells is determined, to a large extent, by the need to combine certain protein domains and to keep an intact reading frame in fusion transcripts. Additionally, the information that we have assembled affords a global view of the oncogenic mechanisms and domain architectures that are used by fusion proteins. This can be used to assess the functional impact of novel chromosomal translocations and to predict the position of breakpoints in the genes involved

Serum antibodies against p53 in relation to cancer risk and prognosis in breast cancer: a population-based epidemiological study

To perform an epidemiological evaluation of the predictive value of p53 autoantibodies in breast cancer, we measured antibodies against p53 in serum samples from 165 breast cancer patients in comparison with serum samples from 330 healthy controls, selected from the same population as the cases and matched for age, sex and specimen storage time. Median age of patients was 51 years (range 25–64 years). Presence of serum p53 autoantibodies was analysed by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blotting. The lower ELISA reactivities were similar for cases and controls, but presence of high-level reactivity was more common among cases than among controls [odds ratio (OR) 9.03, 95% confidence interval (CI) 2.40–50.43]. Presence of Western blot-detected p53 autoantibodies had a very similar association (OR 10.8, CI 3.0–59.4). Among the cases, we also studied whether there was any correlation between level of anti-p53 antibodies and stage of the disease or survival. There was no significant correlation between presence of antibodies and stage of the disease. There was a significant negative correlation between presence of p53 antibodies and survival (P= 0.003). A stepwise multivariate Cox regression analysis showed that T-stage, age and presence of anti-p53 antibodies were significant independent prognostic variables, with a dose-dependent negative effect on survival for all three variables. We conclude that presence of anti-p53 antibodies are of significance both for the risk of having breast cancer and the risk of dying from breast cancer. 1999 Cancer Research Campaig

Comparing individual-based approaches to modelling the self-organization of multicellular tissues.

The coordinated behaviour of populations of cells plays a central role in tissue growth and renewal. Cells react to their microenvironment by modulating processes such as movement, growth and proliferation, and signalling. Alongside experimental studies, computational models offer a useful means by which to investigate these processes. To this end a variety of cell-based modelling approaches have been developed, ranging from lattice-based cellular automata to lattice-free models that treat cells as point-like particles or extended shapes. However, it remains unclear how these approaches compare when applied to the same biological problem, and what differences in behaviour are due to different model assumptions and abstractions. Here, we exploit the availability of an implementation of five popular cell-based modelling approaches within a consistent computational framework, Chaste (http://www.cs.ox.ac.uk/chaste). This framework allows one to easily change constitutive assumptions within these models. In each case we provide full details of all technical aspects of our model implementations. We compare model implementations using four case studies, chosen to reflect the key cellular processes of proliferation, adhesion, and short- and long-range signalling. These case studies demonstrate the applicability of each model and provide a guide for model usage

Hip abduction weakness in elite junior footballers is common but easy to correct quickly: a prospective sports team cohort based study

Background: Hip abduction weakness has never been documented on a population basis as a common finding in a healthy group of athletes and would not normally be found in an elite adolescent athlete. This study aimed to show that hip abduction weakness not only occurs in this group but also is common and easy to correct with an unsupervised home based program. Methods: A prospective sports team cohort based study was performed with thirty elite adolescent under-17 Australian Rules Footballers in the Australian Institute of Sport/Australian Football League Under-17 training academy. The players had their hip abduction performance assessed and were then instructed in a hip abduction muscle training exercise. This was performed on a daily basis for two months and then they were reassessed.Results: The results showed 14 of 28 athletes who completed the protocol had marked weakness or a side-to-side difference of more than 25% at baseline. Two months later ten players recorded an improvement of ≥ 80% in their recorded scores. The mean muscle performance on the right side improved from 151 Newton (N) to 202 N (p<0.001) while on the left, the recorded results improved from 158 N to 223 N (p<0.001). Conclusions: The baseline values show widespread profound deficiencies in hip abduction performance not previously reported. Very large performance increases can be achieved, unsupervised, in a short period of time to potentially allow large clinically significant gains. This assessment should be an integral part of preparticipation screening and assessed in those with lower limb injuries. This particular exercise should be used clinically and more research is needed to determine its injury prevention and performance enhancement implications