The cancer invasion front (CIF), a spatially-recognized area due to the frequent presence of peritumoral desmoplastic reaction, represents a cancer site where many hallmarks of cancer metastasis occur. It is now strongly suggested that the desmoplastic microenvironment holds crucial information for determining tumor development and progression. Despite extensive research on tumor-host cell interactions at CIFs, the exact paracrine molecular network that is hardwired into the proteome of the stromal and cancer subpopulations remains partially understood. Here, we interrogated the signaling pathways and the molecular functional signatures across the proteome of a desmoplastic coculture model system of colorectal cancer progression. We discovered a group of bone morphogenetic protein (BMP) antagonists that coordinates major biological programs in CIFs, including cell proliferation, invasion, migration and differentiation processes. Using a mathematical model of cancer cell progression, coupled to in vitro cell migration assays, we demonstrated that the prominent BMP antagonist gremlin-1 (GREM1) may trigger motility of cancer cell cohorts. Our data collectively demonstrate that the desmoplastic CIFs deploy a microenvironmental signature, based on BMP antagonism, in order to regulate the motogenic fates of cancer cell cohorts invading the adjacent stroma. 相似文献
Introduction: The cost of in vivo and in vitro screening of ADME properties of compounds has motivated efforts to develop a range of in silico models. At the heart of the development of any computational model are the data; high quality data are essential for developing robust and accurate models. The characteristics of a dataset, such as its availability, size, format and type of chemical identifiers used, influence the modelability of the data.
Areas covered: This review explores the usefulness of publicly available ADME datasets for researchers to use in the development of predictive models. More than 140 ADME datasets were collated from publicly available resources and the modelability of 31 selected datasets were assessed using specific criteria derived in this study.
Expert opinion: Publicly available datasets differ significantly in information content and presentation. From a modelling perspective, datasets should be of adequate size, available in a user-friendly format with all chemical structures associated with one or more chemical identifiers suitable for automated processing (e.g. CAS number, SMILES string or InChIKey). Recommendations for assessing dataset suitability for modelling and publishing data in an appropriate format are discussed. 相似文献
The ideal classification of basal cell carcinoma (BCC) should be able to identify subtypes which correlate with clinical behaviour and treatment requirements. Unfortunately, however, such a classification has yet to be defined. In the interim, the currently most favoured classification is one based predominantly on histological growth pattern. This classification contributes to the useful concept of low- and high-risk histological subtypes of BCC. The latter are characterized by an increased probability of subclinical extension and/or incomplete excision and/or aggressive local invasive behaviour and/or local recurrence. The Royal College of Pathologists has published a minimum dataset for the histopathological reporting of BCC and this has been written to be compatible with the British Association of Dermatologists' management guidelines. Growth patterns to be reported include nodular, superficial, infiltrative/morphoeic and micronodular types, together with differentiation when of severely atypical or malignant squamous type (basosquamous carcinoma). Deep and peripheral excision margins will be reported to be either involved or clear. The latter will include a comment of a clearance of less than 1 mm for close margins and a measured distance in whole millimetres for other excisions. Clinical assessment and histology remain the 'gold standard' for evaluating BCC and cancers in general. However, in the postgenomic era emphasis is changing from the gathering and archiving of genomic data to its analysis and use in guiding clinical practice. In this context, a current goal is to define cancer phenotype in terms of molecular abnormalities and use this as a new gold standard. One way to assess whether this goal is being achieved for BCC is to determine whether our knowledge of its molecular pathology has any relevance to the minimum dataset for histological reporting. Knowledge of BCC molecular pathology has been fuelled by the recent discovery that deregulation of the Hedgehog (Hh) signalling pathway, a key player in embryonic patterning, appears to be fundamental to tumour growth. But despite accrual of a large amount of data concerning Hh pathway molecular alterations in neoplasia, little is known about the functional consequences of these changes in BCC, how they lead to tumour development, or how they relate to non-Hh pathway alterations such as TP53 mutation. Recent work suggests that the cellular localization of beta-catenin gives a degree of credence to the growth pattern classification of BCC. Furthermore, it is possible that beta-catenin may have a pathogenetic role in the invasive behaviour of BCC. This review draws on current evidence to discuss these issues and assess whether they are relevant to the minimum dataset. 相似文献
Title. Benchmarking nurse staffing levels: the development of a nationwide feedback tool. Aim. This paper is a report of a study to develop a methodology that corrects nurse staffing for nursing care intensity in a way that allows nationwide benchmarking of nurse staffing data. Background. Although nurse workload measurement systems are recognized to be informative in nurse staffing decisions, they are rarely used. When these systems are used, however, it is only possible to compare units within hospitals, because currently available instruments are not standardized for comparisons beyond hospital boundaries. The Belgian Nursing Minimum Dataset (B‐NMDS) contains uniformly measured data about the intensity of nursing care and nurse staffing levels for all hospitals in Belgium. Method. We conducted a retrospective multilevel analysis of the B‐NMDS for the year 2003. The sample included 690,258 inpatient days for 298,691 patients, recorded from 1637 acute care nursing units in 115 hospitals. We corrected the number of nursing staff by using different covariates available in the B‐NMDS: intensity of nursing care, type of day (week vs. weekend), service type (general vs. intensive) and hospital type (academic vs. general). Findings. The multilevel approach allowed us to explain about 70% of the variability in the number of nursing staff per nursing unit using hospital type (P = 0·0053); intensity of nursing care (P < 0·0001) and service type (P < 0·0001) as the only covariates. Conclusion. The feedback tool we developed can inform nurse managers and policymakers about nursing intensity‐adjusted nurse staffing levels according to different benchmarks. Our study demonstrates that investing in large nursing datasets is appropriate for the international nursing community. 相似文献
The development of a national cardiac procedures database is in the interest of many groups: cardiac surgeons and interventional cardiologists, participating hospital units, patients, governments, health insurance funds and industry. To date, information about short-term outcomes of coronary interventions has been fragmented and uncoordinated at state and national levels. Long-term outcomes have not yet been systematically addressed in Australia. A highly desirable objective is the development of a dataset of information that is pertinent to the Australian context, with common minimum datasets for surgery and percutaneous intervention. Information will gain added value if it is linked to other national databases such as the National Death Index. Also, risk adjustment should be used to improve the value of outcome data. Development of a ‘common’ Cardiac Procedures Database, in turn, should lead to improved health policy and better health management in an area that currently runs at significant cost. Thus, provided due care is taken to protect the privacy of stakeholders, maintain quality control and entry of only valid information into the database, the resulting outcome will benefit all interested parties; clinicians, hospitals, patients and the wider Australian community. 相似文献