The BCR-ABL1 Kinase Bypasses Selection for the Expression of a Pre–B Cell Receptor in Pre–B Acute Lymphoblastic Leukemia Cells

The BCR-ABL1 kinase expressed in acute lymphoblastic leukemia (ALL) drives malignant transformation of human pre–B cells. Comparing genome-wide gene expression profiles of BCR-ABL1+ pre–B ALL and normal bone marrow pre–B cells by serial analysis of gene expression, many genes involved in pre–B cell receptor signaling are silenced in the leukemia cells. Although normal pre–B cells are selected for the expression of a functional pre–B cell receptor, BCR-ABL1+ ALL cells mostly do not harbor a productively rearranged IGH allele. In these cases, we identified traces of secondary VH gene rearrangements, which may have rendered an initially productive VH region gene nonfunctional. Even BCR-ABL1+ ALL cells harboring a functional VH region gene are unresponsive to pre–B cell receptor engagement and exhibit autonomous oscillatory Ca2+ signaling activity. Conversely, leukemia subclones surviving inhibition of BCR-ABL1 by STI571 restore responsiveness to antigen receptor engagement and differentiate into immature B cells expressing immunoglobulin light chains. BCR-ABL1 kinase activity is linked to defective pre–B cell receptor signaling and the expression of a truncated isoform of the pre–B cell receptor–associated linker molecule SLP65. Also in primary leukemia cells, truncated SLP65 is expressed before but not after treatment of the patients with STI571. We conclude that inhibition of BCR-ABL1 reconstitutes selection for leukemia cells expressing a functional (pre–) B cell receptor

Working to improve the management of sarcoma patients across Europe: a policy checklist

Background: The Sarcoma Policy Checklist was created by a multidisciplinary expert group to provide policymakers with priority areas to improve care for sarcoma patients. Main body: This paper draws on this research, by looking more closely at how France, Germany, Italy, Spain, Sweden and the United Kingdom are addressing each of these priority areas. It aims to highlight key gaps in research, policy and practice, as well as ongoing initiatives that may impact the future care of sarcoma patients in different European countries. A pragmatic review of the published and web-based literature was undertaken. Telephone interviews were conducted in each country with clinical and patient experts to substantiate findings. Research findings were discussed within the expert group and developed into five core policy recommendations. The five identified priority areas were: the development of designated and accredited centres of reference; more professional training; multidisciplinary care; greater incentives for research and innovation; and more rapid access to effective treatments. Most of the countries studied have ongoing initiatives addressing many of these priorities; however, many are in early stages of development, or require additional funding and resources. Conclusion: Gaps in access to quality care are particularly concerning in many of Europe’s lower-resourced countries. Equitable access to information, clinical trials, innovative treatments and quality specialist care should be available to all sarcoma patients. Achieving this across Europe will require close collaboration between all stakeholders at both the national and European level

RWE in Europe Paper II: The use of Real World Evidence in the disease context

Real World Evidence (RWE), the use of data not collected via traditional randomised controlled trials (RCT) for decision-making, is becoming more interesting to market-access and reimbursement decision-makers, despite potential methodological issues around its use. This paper, the second in a series looking at the use of Real World Evidence (RWE) in Europe, analyses the opinions of a number of key experts in pricing and reimbursement from a selection of countries across Europe. Discussion centred on the use of RWE in licensing, commissioning, clinical decision-making and patient and outcome related decision-making in the context of three different treatment areas – chronic disease, oncology and rare diseases. Results of discussion sessions with ‘RWE experts’ indicated that the associated benefits of RWE are becoming more relevant but there is a need for a well-organised, high quality system for data generation, interpretation and use. It is likely that different treatment areas will have differing RWE requirements and differing levels of utility. In the rare disease arena, RWE may have a role in licensing based decisions, but this is unlikely for chronic disease or oncology. In order to enhance the role of RWE, and to ensure it meets its full potential in all treatment areas, a multi-stakeholder approach at the EU level is required, with collaboration between national and supranational organisations and all stakeholders including patient organisations, manufacturers and reimbursement agencies

RWE in Europe Paper III: A Roadmap for RWE

Real world evidence (RWE) has been touted as a remedy for current market access issues, facilitating quicker approvals and increased odds of reimbursement at a good price. It is therefore an attractive avenue for pursuit for manufacturers today. This paper, the third in a series looking at the use of RWE in Europe, outlines the discussions held between key opinion leaders in pricing and reimbursement across a number of European countries at a roundtable-style meeting. The aim of the meeting was to develop a 3-year roadmap, and resulting action plan, of initiatives for the enhanced use of RWE in decision-making in the pharmaceutical industry. Following a series of brainstorming sessions across the areas of commissioning and access, clinical evidence and patients and outcomes, contributors were asked to prioritise the importance of a refined set of initiatives identified in these brainstorming sessions to develop the three-year road map. Finally, four key points from the roadmap were identified for initial action: actively engage in early dialogue with payers on RWE needs; consensus exercise on RWD/E in clinical decisions, develop a definition of patient reported/relevant outcomes and develop a model approach for the collection of patient reported/relevant outcomes data. These action points are seen as the most imperative steps for enhancing the role of RWE. If its use is to become more common addressing these steps, as quickly and efficiently as possible, will be vital for all stakeholders in the pharmaceutical arena

Ovulation is triggered by a cyclical modulation of gonadotropes into a hyperexcitable state

Gonadotropes in the anterior pituitary gland are essential for fertility and provide a functional link between the brain and the gonads. To trigger ovulation, gonadotrope cells release massive amounts of luteinizing hormone (LH). The mechanism underlying this remains unclear. Here, we utilize a mouse model expressing a genetically encoded Ca2+ indicator exclusively in gonadotropes to dissect this mechanism in intact pituitaries. We demonstrate that female gonadotropes exclusively exhibit a state of hyperexcitability during the LH surge, resulting in spontaneous [Ca2+]i transients in these cells, which persist in the absence of any in vivo hormonal signals. L-type Ca2+ channels and transient receptor potential channel A1 (TRPA1) together with intracellular reactive oxygen species (ROS) levels ensure this state of hyperexcitability. Consistent with this, virus-assisted triple knockout of Trpa1 and L-type Ca2+ subunits in gonadotropes leads to vaginal closure in cycling females. Our data provide insight into molecular mechanisms required for ovulation and reproductive success in mammals

Bitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis

The median eminence (ME) is a circumventricular organ at the base of the brain that controls body homeostasis. Tanycytes are its specialized glial cells that constitute the ventricular walls and regulate different physiological states, however individual signaling pathways in these cells are incompletely understood. Here, we identify a functional tanycyte subpopulation that expresses key taste transduction genes including bitter taste receptors, the G protein gustducin and the gustatory ion channel TRPM5 (M5). M5 tanycytes have access to blood-borne cues via processes extended towards diaphragmed endothelial fenestrations in the ME and mediate bidirectional communication between the cerebrospinal fluid and blood. This subpopulation responds to metabolic signals including leptin and other hormonal cues and is transcriptionally reprogrammed upon fasting. Acute M5 tanycyte activation induces insulin secretion and acute diphtheria toxin-mediated M5 tanycyte depletion results in impaired glucose tolerance in diet-induced obese mice. We provide a cellular and molecular framework that defines how bitter taste cells in the ME integrate chemosensation with metabolism

ECCO Essential Requirements for Quality Cancer Care : Soft Tissue Sarcoma in Adults and Bone Sarcoma. A critical review

Background: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Sarcoma: essential requirements for quality care Sarcomas - which can be classified into soft tissue and bone sarcomas - are rare, but all rare cancers make up more than 20% of cancers in Europe, and there are substantial inequalities in access to high-quality care. Sarcomas, of which there are many subtypes, comprise a particularly complex and demanding challenge for healthcare systems and providers. This paper presents essential requirements for quality cancer care of soft tissue sarcomas in adults and bone sarcomas. High-quality care must only be carried out in specialised sarcoma centres (including paediatric cancer centres) which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis and follow-up, to treatment, to improve survival and quality of life for patients. Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for soft tissue sarcomas in adults and bone sarcomas. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams is guaranteed to all patients with sarcoma. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.Peer reviewe

Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells

Pre–B cells undergo apoptosis unless they are rescued by pre–B cell receptor–dependent survival signals. We previously showed that the BCR-ABL1 kinase that is expressed in pre–B lymphoblastic leukemia bypasses selection for pre–B cell receptor–dependent survival signals. Investigating possible interference of BCR-ABL1 with pre–B cell receptor signaling, we found that neither SYK nor SLP65 can be phosphorylated in response to pre–B cell receptor engagement. Instead, Bruton's tyrosine kinase (BTK) is constitutively phosphorylated by BCR-ABL1. Activated BTK is essential for survival signals that otherwise would arise from the pre–B cell receptor, including activation of PLCγ1, autonomous Ca(2+) signaling, STAT5-phosphorylation, and up-regulation of BCLX (L). Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1 (+) leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself. However, BCR-ABL1 cannot directly bind to full-length BTK. Instead, BCR-ABL1 induces the expression of a truncated splice variant of BTK that acts as a linker between the two kinases. As opposed to full-length BTK, truncated BTK lacks kinase activity yet can bind to BCR-ABL1 through its SRC-homology domain 3. Acting as a linker, truncated BTK enables BCR-ABL1–dependent activation of full-length BTK, which initiates downstream survival signals and mimics a constitutively active pre–B cell receptor

Bitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis.

peer reviewedThe median eminence (ME) is a circumventricular organ at the base of the brain that controls body homeostasis. Tanycytes are its specialized glial cells that constitute the ventricular walls and regulate different physiological states, however individual signaling pathways in these cells are incompletely understood. Here, we identify a functional tanycyte subpopulation that expresses key taste transduction genes including bitter taste receptors, the G protein gustducin and the gustatory ion channel TRPM5 (M5). M5 tanycytes have access to blood-borne cues via processes extended towards diaphragmed endothelial fenestrations in the ME and mediate bidirectional communication between the cerebrospinal fluid and blood. This subpopulation responds to metabolic signals including leptin and other hormonal cues and is transcriptionally reprogrammed upon fasting. Acute M5 tanycyte activation induces insulin secretion and acute diphtheria toxin-mediated M5 tanycyte depletion results in impaired glucose tolerance in diet-induced obese mice. We provide a cellular and molecular framework that defines how bitter taste cells in the ME integrate chemosensation with metabolism

The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients

Abstract Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis, aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. Previously surgery was the standard primary treatment modality; however, in recent years a paradigm shift towards a more conservative management has been introduced and an effort to harmonise the strategy amongst clinicians has been made. We present herein an evidence-based, joint global consensus guideline approach to the management of this disease focussing on: molecular genetics, indications for an active treatment, and available systemic therapeutic options. This paper follows a one-day consensus meeting held in Milan, Italy, in June 2018 under the auspices of the European Reference Network for rare solid adult cancers, EURACAN, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) as well as Sarcoma Patients EuroNet (SPAEN) and The Desmoid tumour Research Foundation (DTRF). The meeting brought together over 50 adult and pediatric sarcoma experts from different disciplines, patients and patient advocates from Europe, North America and Japan