Insulin-Like Growth Factor-1 Receptor Signaling Increases the Invasive Potential of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Cells via Src-Focal Adhesion Kinase and Forkhead Box Protein M1 s

ABSTRACT Resistance to the human epidermal growth factor receptor (HER2)-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-positive metastatic breast cancer. Increased expression or signaling from the insulin-like growth factor-1 receptor (IGF-1R) has been reported to be associated with trastuzumab resistance. However, the specific molecular and biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined. In this study, we found that the major biologic effect promoted by IGF-1R was invasion, which was mediated by both Src-focal adhesion kinase (FAK) signaling and Forkhead box protein M1 (FoxM1). Cotargeting IGF-1R and HER2 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition. Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and HER2 in trastuzumab-resistant cells. Constitutively active Src blocked the anti-invasive effect of IGF-1R/HER2 cotargeted therapy. Furthermore, knockdown of FoxM1 blocked IGF-1-mediated invasion, and dual targeting of IGF-1R and HER2 reduced expression of FoxM1. Reexpression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab. Overall, our results strongly indicate that therapeutic combinations that cotarget IGF-1R and HER2 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1

Obesity in adults: a 2022 adapted clinical practice guideline for Ireland

This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients' lived experiences; move beyond simplistic approaches of "eat less, move more" and address the root drivers of obesity. People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay

Improved Quality of Life, Fitness, Mental Health and Cardiovascular Risk Factors with a Publicly Funded Bariatric Lifestyle Intervention for Adults with Severe Obesity: A Prospective Cohort Study

Background: Lifestyle modification is the cornerstone of management for patients with severe and complicated obesity, but the effects of structured lifestyle programmes on quality of life, anxiety and depression scores and cardiovascular risk factors are not well-described. We sought to describe changes in self-reported quality of life and mental health-related outcomes as well as cardiovascular risk factors in patients completing a 10-week multidisciplinary lifestyle-modification programme. Methods: We conducted a prospective cohort study of all patients referred from our bariatric service who completed the programme between 2013 and 2019. In addition to weight, body mass index (BMI), blood pressure, HbA1c, lipid profile and functional capacity, we quantified health-related quality of life using the Dartmouth COOP Questionnaire and the European Quality of Life Questionnaire Visual Analogue Scale (EQVAS) and mental health using the Hospital Anxiety and Depression Scale (HADS). Results: Of 1122 patients who started the programme, 877 (78.2%) completed it and were included in per protocol analyses. Mean age was 47.3 ± 11.9 years, 66.9% were female, 34.8% were in full- or part-time employment and 69.4% were entitled to state-provided medical care. BMI decreased from 47.0 ± 7.8 to 46.2 ± 7.8 kg m−2 and weight decreased from 131.6 ± 25.5 to 129.5 ± 25.4 kg (both p p < 0.001). Small but statistically significant reductions in LDL cholesterol, systolic blood pressure and HBA1c were also observed. Conclusions: Adults with severe and complicated obesity completing a specialised bariatric lifestyle-modification programme showed significant improvements in self-reported mental health and quality of life, in addition to reductions in cardiovascular risk factors