Precision medicine and personalized breast cancer: combination pertuzumab therapy

Trastuzumab (Herceptin), a monoclonal antibody directed against the human epidermal growth-factor receptor 2 (HER2), is the poster child for antibody-based targeted therapy in breast cancer. Pertuzumab, another humanized monoclonal antibody, binds to a different domain of HER2 and prevents the formation of HER2:HER3 dimers, which is the most potent heterodimer in the HER family. The combination of trastuzumab and pertuzumab has synergistic activity, and is associated with improved clinical outcomes. The US Food and Drug Administration (FDA) approved pertuzumab in combination with trastuzumab-based chemotherapy originally as first-line therapy for metastatic HER2-positive breast cancer in 2012, and more recently as neoadjuvant therapy for localized disease in 2013. Pertuzumab is the first neoadjuvant drug to receive accelerated approval by the FDA based on pathological complete response as the primary end point. In this article, we review the mechanism of action, pharmacokinetics, clinical efficacy, safety, and current role of pertuzumab in the management of breast cancer, as well as ongoing clinical trials and future directions regarding the utility of pertuzumab as a personalized therapeutic option for HER2-positive breast cancer. In the coming years, we anticipate increased utilization of neoadjuvant trials for drug development, biomarker discovery, and validation, and envision conduct of personalized breast cancer clinics in which therapies will be routinely selected based on genetic alterations in the tumor. Regardless of the targeted therapy combinations employed based on tumor genomic profile, trastuzumab and pertuzumab will likely continue to form the backbone of the personalized regimen for HER2-positive breast cancer

Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor.

Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.Leverhulme Trus

Food Resilience Toolkit

This toolkit is intended to help community leaders and technical support professionals assess and build food system resilience in their regions. The toolkit is available in English and Spanish and in written and video format. In the introduction, we explore the concept of resilience and the Community Capitals framework and suggest possible indicators of food system resilience. In Chapter 2, we outline four tools for assessing community advantages and challenges and developing plans to address them. These tools are: asset mapping, focus groups, nominal groups, and strategic planning. While many research techniques can be deployed for resilience building, we have found these four to be especially useful in building purpose-driven, directed initiatives that are responsive to community needs and assets. Chapter 3 explores the role of policy in building (or obstructing) resilience, and in responding to shocks. We take a birds-eye view of disaster experiences in both Vermont and Puerto Rico and review how political actors responded differently in each region. We use the Multiple Streams Approach as a lens for understanding how policy decisions happen and where there are opportunities to advocate for change. In the final chapter, we offer lessons from our own resilience research efforts in Puerto Rico and Vermont. We connect our findings with food system resilience indicators and community capitals to offer real-world examples of strengths and vulnerabilities in the face of crisis

Food Resilience Toolkit

This toolkit is intended to help community leaders and technical support professionals assess and build food system resilience in their regions. The toolkit is available in English and Spanish and in written and video format. In the introduction, we explore the concept of resilience and the Community Capitals framework and suggest possible indicators of food system resilience. In Chapter 2, we outline four tools for assessing community advantages and challenges and developing plans to address them. These tools are: asset mapping, focus groups, nominal groups, and strategic planning. While many research techniques can be deployed for resilience building, we have found these four to be especially useful in building purpose-driven, directed initiatives that are responsive to community needs and assets. Chapter 3 explores the role of policy in building (or obstructing) resilience, and in responding to shocks. We take a birds-eye view of disaster experiences in both Vermont and Puerto Rico and review how political actors responded differently in each region. We use the Multiple Streams Approach as a lens for understanding how policy decisions happen and where there are opportunities to advocate for change. In the final chapter, we offer lessons from our own resilience research efforts in Puerto Rico and Vermont. We connect our findings with food system resilience indicators and community capitals to offer real-world examples of strengths and vulnerabilities in the face of crisis

ERPs and their brain sources in perceptual and conceptual prospective memory tasks: commonalities and differences between the two tasks

The present study examined whether Event-Related Potential (ERP) components and their neural generators are common to perceptual and conceptual prospective memory (PM) tasks or specific to the form of PM cue involved. We used Independent Component Analysis (ICA) to study the contributions of brain source activities to scalp ERPs across the different phases of two event-based PM-tasks: (1) holding intentions during a delay (monitoring) (2) detecting the correct context to perform the delayed intention (cue detection) and (3) carrying out the action (realisation of delayed intentions). Results showed that monitoring for both perceptual and conceptual PM-tasks was characterised by an enhanced early occipital negativity (N200). In addition the conceptual PM-task showed a long-lasting effect of monitoring significant around 700 ms. Perceptual PM-task cues elicited an N300 enhancement associated with cue detection, whereas a midline N400-like response was evoked by conceptual PM-task cues. The Prospective Positivity associated with realisation of delayed intentions was observed in both conceptual and perceptual tasks. A common frontal-midline brain source contributed to the Prospective Positivity in both tasks and a strong contribution from parieto-frontal brain sources was observed only for the perceptually cued PM-task. These findings support the idea that: (1) The enhanced N200 can be understood as a neural correlate of a ‘retrieval mode’ for perceptual and conceptual PM-tasks, and additional strategic monitoring is implemented according the nature of the PM task; (2) ERPs associated with cue detection are specific to the nature of the PM cues; (3) Prospective Positivity reflects a general PM process, but the specific brain sources contributing to it depend upon the nature of the PM task

Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, have been associated with severe adverse side-effects, and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems to provide a more complete understanding of glucagon receptor signaling, considering the effect of multiple ligands, association with the receptor-interacting protein receptor activity-modifying protein-2 (RAMP2), and the role of individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.This work was supported by a Warwick Impact Fund (C.W., G.L.), the BBSRC (G.L. - BB/G01227X/1), (T.S., G.R., D.R. - BB/F008392/1), (D.P. - BB/M007529/1 and BB/M000176/1), Warwick Research Development Fund (C.W., G.L.) grant number (RD13301) and the Birmingham Science City Research Alliance (G.L).This is the final version of the article. It first appeared from ASBMB at http://dx.doi.org/10.1074/jbc.M114.62460

Polo kinase Cdc5 associates with centromeres to facilitate the removal of centromeric cohesin during mitosis

Sister chromatid cohesion is essential for tension-sensing mechanisms that monitor bipolar attachment of replicated chromatids in metaphase. Cohesion is mediated by the association of cohesins along the length of sister chromatid arms. In contrast, centromeric cohesin generates intrastrand cohesion and sister centromeres, while highly cohesin enriched, are separated by >800 nm at metaphase in yeast. Removal of cohesin is necessary for sister chromatid separation during anaphase, and this is regulated by evolutionarily conserved polo-like kinase (Cdc5 in yeast, Plk1 in humans). Here we address how high levels of cohesins at centromeric chromatin are removed. Cdc5 associates with centromeric chromatin and cohesin-associated regions. Maximum enrichment of Cdc5 in centromeric chromatin occurs during the metaphase-to-anaphase transition and coincides with the removal of chromosome-associated cohesin. Cdc5 interacts with cohesin in vivo, and cohesin is required for association of Cdc5 at centromeric chromatin. Cohesin removal from centromeric chromatin requires Cdc5 but removal at distal chromosomal arm sites does not. Our results define a novel role for Cdc5 in regulating removal of centromeric cohesins and faithful chromosome segregation

Preparing Parents for Discharge from Hospital with their Infant After Complex Cardiac Surgery Using the Congenital Heart Assessment Tool. An Online Learning Resource for Health Care Professionals

Introduction The aim of this session is to present an online learning resource developed within a portfolio of research around the Congenital Heart Assessment Tool (CHAT). The CHAT, an early warning tool for parents to use at home to monitor their infant following the first stage of surgery for complex Congenital Heart Disease (CHD), was developed in 2012 and implemented within a feasibility Study (phase one) at one specialist centre during 2013-2015 (Gaskin, Daniels & Barron 2016; Gaskin Wray & Barron, 2018). Phase two of the project was to evaluate the CHAT in four children’s cardiac centres in the UK as part of a Health Improvement Project during 2017 (Smith et al, 2018), resulting in an updated version of the tool (CHAT2). Methods This third phase of the project involved development of an online learning resource, which was funded by the University and created in collaboration with Little Hearts Matter, a UK CHD Charity. The aim being to enable wider implementation of CHAT across the UK, through consistent education of health care professionals who are involved in the preparation of parents and families for their infant’s discharge. The learning objectives of the online learning resource are for health care professionals to have: • Enhanced knowledge and understanding of complex CHD in order to teach parents how to spot signs of clinical deterioration in their infant whilst at home • Developed an understanding of the CHAT, who it is for, what it does, and why it is used • Learnt how to use CHAT when teaching parents prior to discharge • Learnt how to use CHAT to support decision making when taking telephone calls from families at home The online learning resource recognises different learning styles and incorporates a range of self directed activities, video clips demonstrating how to use CHAT and links to a breadth of supporting resources. The resource is currently being piloted and a staged implementation and evaluation strategy is being planned for 2019. Results This session will provide an update on the progress of the implementation of this e-learning resource, which could subsequently be made available internationally