A novel study on the functional relevance of junctional adhesion molecule -A in breast cancer.

Breast cancer, a disease that arises from the epithelial cells within breast tissue, is a common illness that can affect all age groups. Each year it is diagnosed in an estimated 1 million women worldwide, and accounts for over 450,000 deaths. Despite advancements in breast cancer screening and treatment, breast cancer still remains one of the leading causes of female deaths worldwide. Breast cancer is a heterogeneous disease encompassing many subtypes, which differ both in terms of their molecular backgrounds and clinical prognosis. Cancer initiation and progression is a multistep process involving dysregulations in cell adhesion, proliferation, survival and migration. Breast epithelial cells contain several multi-protein adhesion complexes at two principal sites, between neighbouring cells and between cells and their extracellular matrix. Adhesion proteins regulate a variety of cellular functions, and dysregulation of cellular adhesion has been implicated in the events that accompany cancer initiation and progression. Proteins of the intercellular tight junction have been found to be de-regulated in several human cancers including breast, and have recently been suggested as promising targets for cancer therapy. This thesis is focused on exploring the contribution of one tight junction protein, junctional adhesion molecule-A (JAM-A) to breast cancer progression. In this thesis we used two isogenic breast cancer cell line models, HMT-3522 and Hs578T, both of which have \u22non-tumorigenic\u22 and \u22tumorigenic\u22 variants. We observed that tumorigenic HMT- 3522 T4-2 cells had tighter junctions compared to non- tumorigenic cells, and that the tumorigenic variant of Hs578T cells expressed a higher level of JAM-A. JAM-A expression was also higher in primary breast cultures from tumour relative to non-tumour samples, and highest in aggressive high grade turnours. Interestingly, we detected high levels of soluble JAM-A in serum samples of breast cancer patients with benign disease compared to patients with invasive ductal carcinomas. Functional inhibition of JAM-A was found to decrease protein levels of JAM-A in both nontumorigenic and tumorigenic cells and to significantly reduce ceII migration. In 3-dimensional cultures mimicking the in vivo microenvironment, JAM-A inhibition was found to decrease cell number and 3-dimensional spheroid formation and, for the first time, to partially normalise the ahomalltumorigenic phenotype of invasive cells. Taken together, our study provides novel evidence suggesting that JAM-A may be involved in breast cancer progression and have potential as a biomarker of disease progression or as a therapeutic target

High-Risk Breast Lesions

It is well known that certain types of pre-malignant lesions can predispose some women to increased risk of breast cancer. These certain types of pre-malignant lesions are generally classified as high-risk breast lesions. These lesions become invasive cancers in about 15% of patients and hence the management and treatment of these lesions warrant a significant discussion. There are several categories of these lesions, to include atypical hyperplasia of the breast (atypical ductal hyperplasia and atypical lobular hyperplasia); carcinoma in situ (ductal carcinoma in situ and lobular carcinoma in situ); columnar cell pre-malignant lesions; lobular intraepithelial neoplasia (LIN III); radial scar/complex sclerosing lesion; sclerosing adenosis and papillary lesions of the breast. These lesions are morphologically, radiologically, histologically and clinically heterogeneous and early identification can help to prevent progression to invasive cancers. The management of these lesions has been debated internationally for years by experts as to the best treatment modality with surgical excision of the lesion often not considered necessary. It is thus important to evaluate each patient on an individual case-by-case basis. The characteristics of these high-risk breast lesions are further discussed in this chapter

Emotional intelligence assessment in a graduate entry medical school curriculum.

BACKGROUND: The management of emotions in the workplace is a skill related to the ability to demonstrate empathic behaviour towards patients; to manage emotional reactions in oneself and to lead others as part of a team. This ability has been defined as emotional intelligence (EI) and doctor\u27s EI may be related to communication skills and to patient satisfaction levels. This study reports on the use of two assessments of EI as part of a course on Personal and Professional Development (PPD) in a graduate medical school curriculum. METHODS: Fifty one graduate entry medical students completed an eight session course on PPD between December 2005 and January 2006. Students completed two measures of EI: self-report (EQ-i) and ability (MSCEIT V2.0) over a two year study period. The data gathered were used to explore the relationship between self-report and ability EI and between EI and student demographics, academic performance and change over time. RESULTS: Analysis of the EI data demonstrated that self-report EI did not change over time and was not related to ability EI. Females scored higher than males on a number of self-report and ability EI scores. Self-reported self-awareness was found to deteriorate in males and females over time. High self-reported EI was found to be associated with poor performance on clinical competency assessments but with good performance on a number of bio-medical knowledge based assessments. CONCLUSIONS: This report concludes that assessments of EI can be incorporated into a medical school curriculum as part of a PPD programme and that the concept of EI may be associated with performance in medical school

Junctional Adhesion Molecules (JAMs) - New Players in Breast Cancer?

Worldwide, breast cancer remains a leading cause of death amongst women. Annually, it i sestimated that breast cancer is diagnosed in over a million women (Kasler et al., 2009) with over 450,000 deaths worldwide (Tirona et al., 2010). The incidence of the disease is highest in economically-developed countries, with lower rates in developing countries. Despite continual advances in breast cancer care which have led to reduced mortality, however, the incidence of the disease is still rising. The decrease in breast cancer-specific mortality has been attributed to improvements in screening techniques which permit earlier detection, surgical and radiotherapy interventions, better understanding of disease pathogenesis and utilization of traditional chemotherapies in a more efficacious manner. Consequently, early stage breast cancer is now a curable disease while advanced breast cancer remains asignificant clinical problem. Breast cancer is a heterogeneous disease encompassing many subtypes, which differ both in terms of their molecular backgrounds and clinical prognosis. These breast cancer subtypes range from pre-invasive early stage disease to advanced invasive disease. The simplest classifications of disease subdivide breast cancer into pre-invasive and invasive forms; with the pre-invasive forms being ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Carcinoma in situ is proliferation of cancer cells within the epithelial tissue without invasion of the surrounding stromal tissue (Bland & Copeland, 1998). DCIS arises in the terminal ductal lobular units (TDLU) and in extra-lobular ducts while LCIS occurs in the breast lobules, and is recognisable histopathologically by the presence of populations of aberrant cells with small nuclei (Hanby & Hughes, 2008). Invasive breast cancers are subclassified into invasive ductal breast cancer, invasive lobular breast cancer, inflammatory breast cancer and Paget's disease. Invasive ductal carcinoma (IDC) is the most common formof invasive breast cancer, accounting for around 85% of all cases. DCIS is frequently considered as an obligate precursor to IDC, progressing from lower to higher grades and then onto invasive cancer with progressive accumulation of genomic changes (Farabegoli et al ., 2002). However it has alternately been suggested that there exist genetically-distinct subgroups of DCIS, only some of which have the potential to progress to invasion (Shackney & Silverman, 2003). Long-term natural history studies of DCIS have provided supportive evidence for both possibilities (Page et al., 1995; Collins et al ., 2005; Sanders et al ., 2005). Despite such controversies, the large extent to which the genome is altered in DCIS strongly suggests that genomic instability precedes phenotypic evidence of invasion (Hwang et al ., 2004). This serves to underline the fact that malignant transformation in a heterogeneous disease like breast cancer is a dynamic process evolving through multiple multi-step pathway models. Many factors are thought to be responsible for the development of breast cancer. Genetic factors play a vital role in the predisposition to breast cancer, with mutations of BRCA1 and BRCA2 genes accounting for 5–10% of breast cancer cases and being responsible for 80% of inherited breast cancers (Nathanson et al., 2001). On a more complex level, much insight has been gained from the genetic profiling of thousands of tumours to generate gene signatures of prognostic value (Sorlie et al., 2001; van 't Veer et al., 2002; van de Vijver et al ., 2002), which have spurred the development of commercially-available diagnostic tests. The importance of reproductive factors in the aetiology of breast cancer is also well recognised with early onset of menarche, nulliparity, late menopause, endogenous and exogenous hormones representing the main risk factors (Reeves et al ., 2000; Key et al., 2001; Howell & Evans, 2011). Several other studies have reported anincreased risk of breast cancer with lack of physical activity (especially in pre menopausal women), as well as increasing age and obesity (Clarke et al ., 2006; Walker & Martin, 2007; Harrison et al., 2009; Rod et al., 2009; Awatef et al ., 2011). These risk factors accentuate the abnormal growth control of cells by increasing the circulating levels of oestrogen thereby promoting tumourigenesis within the breast microenvironment. A proper understandingof the breast cancer microenvironment is essential for understanding breast cancer, and will be explored in detail in the next sections. </p

An Irish Experience in Establishing and Evaluating an Intern Led Teaching Programme.

Near-Peer Teaching is a relatively new and expanding area of medical education. The benefit to medical students has been demonstrated in numerous contexts around the world. Our aim was to establish a structured Intern-Led Teaching (ILT) programme in the context of an Irish Intern Training Network affiliated to an Irish Medical School. We then sought to evaluate the success of this programme. Seventy interns were enrolled in the ILT programme and completed a Train the Trainer course involving teaching methods and skills of effective feedback. Following this, the intern tutors delivered several one-hour teaching sessions in small groups to final year medical students on a weekly basis. At the end of each teaching block, a feedback questionnaire was distributed to participating students to evaluate their experiences of this new teaching modality. Tutorial topics were varied. They included clinical examination, history taking, prescribing, and emergencies. Eighty-one percent of students found the intern-led tutorials to be beneficial compared to tutorials run by more senior doctors. Additionally, students felt that with intern led tutorials they could ask questions they otherwise would not. There was a more comfortable environment, and information taught was considered more relevant. A significant number of students felt less nervous about the final medical examinations after the intern-led tutorials. The establishment of a structured intern-led teaching programme was well received by final year medical students. This project shows that interns are a valuable teaching resource in the medical school and should be included in medical schools’ curricula

Tight junctions: a barrier to the initiation and progression of breast cancer?

Breast cancer is a complex and heterogeneous disease that arises from epithelial cells lining the breast ducts and lobules. Correct adhesion between adjacent epithelial cells is important in determining the normal structure and function of epithelial tissues, and there is accumulating evidence that dysregulated cell-cell adhesion is associated with many cancers. This review will focus on one cell-cell adhesion complex, the tight junction (TJ), and summarize recent evidence that TJs may participate in breast cancer development or progression. We will first outline the protein composition of TJs and discuss the functions of the TJ complex. Secondly we will examine how alterations in these functions might facilitate breast cancer initiation or progression; by focussing on the regulatory influence of TJs on cell polarity, cell fate and cell migration. Finally we will outline how pharmacological targeting of TJ proteins may be useful in limiting breast cancer progression. Overall we hope to illustrate that the relationship between TJ alterations and breast cancer is a complex one; but that this area offers promise in uncovering fundamental mechanisms linked to breast cancer progression

Gender Matters:Understanding Transitions in Surgical Education

INTRODUCTION: Diverse transitions are elemental to medical career trajectories. The effective navigation of such transitions influences a sense of belonging and wellbeing, positive relationships, and good engagement and attainment within new contexts. Using Multiple and Multidimensional Transitions (MMT) theory as an analytical lens, this paper aims to answer the research question: “What gendered transitions do female surgeons experience, and how do these gendered transitions impact them?” METHODS: We conducted a qualitative study drawing on narrative inquiry, with face-to-face and online semi-structured interviews with 29 female surgeons across nine surgical specialities in Ireland and Scotland. This paper is part of a larger study including male surgeons, other colleagues and patients of female surgeons. The female surgeons in this paper were purposively sampled using maximum variation sampling across several levels (consultants, trainees and middle-grade doctors), as well as six who had transitioned out of surgery. Framework analysis was employed to interrogate the interview data. RESULTS: Five overarching types of transitions were identified across surgical education but only three of these transitions—work, culture and health—were primarily experienced by female surgeons (not male surgeons so were considered gendered), thereby impacting social, academic, and psychological domains. The remaining two types of transition—education and geography—were seemingly experienced equally by female and male surgeons, so are beyond the scope of this paper focused on female surgeons’ gendered experiences. CONCLUSION: This novel qualitative study drawing on MMT theory illustrates how multiple gendered transitions interact and impact female surgeons across the surgical education continuum. Aligned with MMT theory, family members and others are also purportedly affected by female surgeons’ transitions. Healthcare educators, leaders and policymakers need to better understand gendered transitions and their impacts to improve support for female surgical trainees on their educational journeys

In the era of Black Lives Matters, what skills need to be taught to help students tackle racism in healthcare?

The death of George Floyd brought the topic of Black Lives Matter (BLM) to a global platform. Communication in healthcare curricula focuses on communication between learners and patients, peers, and health care team members. Issues of racism, micro-aggressions and implicit bias can have a significant impact on all these healthcare interactions. This student panel discussion will explore the implications of black lives matter for learning about communication in healthcare. Students from different racial/ethnic backgrounds, different medical schools, different countries and different levels of training will share their experiences with and perspectives on health professional learning and support needs in the context of black lives matter issues. Discussion will include current and potential curricular needs and approaches to BLM issues, including inclusion of student voices in the curriculum, as well as student experiences with racism and implicit bias. This session should be of interest to health professional educators and researchers as well as health professional learners