Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with ...many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.
Cancer is often regarded as a process of asexual evolution driven by genomic and genetic instability. Mutation, selection and adaptation are by convention thought to occur primarily within, and to a ...lesser degree outside, the primary tumour. However, disseminated cancer cells that remain after 'curative' surgery exhibit extreme genomic heterogeneity before the manifestation of metastasis. This heterogeneity is later reduced by selected clonal expansion, suggesting that the disseminated cells had yet to acquire key traits of fully malignant cells. Abrogation of the cells' progression outside the primary tumour implies new challenges and opportunities for diagnosis and adjuvant therapies.
The use of intraoperative cell salvage and autologous blood transfusion has become an important method of blood conservation. The main aim of autologous transfusion is to reduce the need for ...allogeneic blood transfusion and its associated complications. Allogeneic blood transfusion has been associated with increased risk of tumour recurrence, postoperative infection, acute lung injury, perioperative myocardial infarction, postoperative low-output cardiac failure, and increased mortality. We have reviewed the current evidence for cell salvage in modern surgical practice and examined the controversial issues, such as the use of cell salvage in obstetrics, and in patients with malignancy, or intra-abdominal or systemic sepsis. Cell salvage has been demonstrated to be safe and effective at reducing allogeneic blood transfusion requirements in adult elective surgery, with stronger evidence in cardiac and orthopaedic surgery. Prolonged use of cell salvage with large-volume autotransfusion may be associated with dilution of clotting factors and thrombocytopenia, and regular laboratory or near-patient monitoring is required, along with appropriate blood product use. Cell salvage should be considered in all cases where significant blood loss (>1000 ml) is expected or possible, where patients refuse allogeneic blood products or they are anaemic. The use of cell salvage in combination with a leucocyte depletion filter appears to be safe in obstetrics and cases of malignancy; however, further trials are required before definitive guidance may be provided. The only absolute contraindication to the use of cell salvage and autologous blood transfusion is patient refusal.
We present a European land‐only daily high‐resolution gridded data set for precipitation and minimum, maximum, and mean surface temperature for the period 1950–2006. This data set improves on ...previous products in its spatial resolution and extent, time period, number of contributing stations, and attention to finding the most appropriate method for spatial interpolation of daily climate observations. The gridded data are delivered on four spatial resolutions to match the grids used in previous products as well as many of the rotated pole Regional Climate Models (RCMs) currently in use. Each data set has been designed to provide the best estimate of grid box averages rather than point values to enable direct comparison with RCMs. We employ a three‐step process of interpolation, by first interpolating the monthly precipitation totals and monthly mean temperature using three‐dimensional thin‐plate splines, then interpolating the daily anomalies using indicator and universal kriging for precipitation and kriging with an external drift for temperature, then combining the monthly and daily estimates. Interpolation uncertainty is quantified by the provision of daily standard errors for every grid square. The daily uncertainty averaged across the entire region is shown to be largely dependent on the season and number of contributing observations. We examine the effect that interpolation has on the magnitude of the extremes in the observations by calculating areal reduction factors for daily maximum temperature and precipitation events with return periods up to 10 years.
Equilibrium climate sensitivity, the global surface temperature response to CO
2 doubling, has been persistently uncertain. Recent consensus places it likely within 1.5–4.5 K. Global climate models ...(GCMs), which attempt to represent all relevant physical processes, provide the most direct means of estimating climate sensitivity via CO
2 quadrupling experiments. Here we show that the closely related effective climate sensitivity has increased substantially in Coupled Model Intercomparison Project phase 6 (CMIP6), with values spanning 1.8–5.6 K across 27 GCMs and exceeding 4.5 K in 10 of them. This (statistically insignificant) increase is primarily due to stronger positive cloud feedbacks from decreasing extratropical low cloud coverage and albedo. Both of these are tied to the physical representation of clouds which in CMIP6 models lead to weaker responses of extratropical low cloud cover and water content to unforced variations in surface temperature. Establishing the plausibility of these higher sensitivity models is imperative given their implied societal ramifications.
Plain Language Summary
The severity of climate change is closely related to how much the Earth warms in response to greenhouse gas increases. Here we find that the temperature response to an abrupt quadrupling of atmospheric carbon dioxide has increased substantially in the latest generation of global climate models. This is primarily because low cloud water content and coverage decrease more strongly with global warming, causing enhanced planetary absorption of sunlight—an amplifying feedback that ultimately results in more warming. Differences in the physical representation of clouds in models drive this enhanced sensitivity relative to the previous generation of models. It is crucial to establish whether the latest models, which presumably represent the climate system better than their predecessors, are also providing a more realistic picture of future climate warming.
Key Points
Climate sensitivity is larger on average in CMIP6 than in CMIP5 due mostly to a stronger positive low cloud feedback
This is due to greater reductions in low cloud cover and weaker increases in low cloud water content, primarily in the extratropics
These changes are related to model physics differences that are apparent in unforced climate variability
Tumor Cell Invasion in Glioblastoma Vollmann-Zwerenz, Arabel; Leidgens, Verena; Feliciello, Giancarlo ...
International journal of molecular sciences,
03/2020, Letnik:
21, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain ...cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches.
Unusually long latency periods between the treatment of primary tumors and metastatic recurrences are commonly thought to prove the existence and relevance of clinical tumor dormancy. However, ...careful consideration of disease courses and cancer growth rates leads to the conclusion that clinical dormancy may be everything from non-existent to much more frequent than originally thought. On the other hand, cellular dormancy defined as a non-productive state of disseminated tumor cells is very frequent, while homeostatic mechanisms such as angiogenic and immunological control contribute to the chronicity of cancer. This review attempts to provide a conceptual framework for the study of dormancy, which may guide clinical and experimental research.
Wild bee populations are declining due to human activities, such as land use change, which strongly affect the composition and diversity of available plants and food sources. The chemical composition ...of food (i.e., nutrition) in turn determines the health, resilience, and fitness of bees. For pollinators, however, the term 'health' is recent and is subject to debate, as is the interaction between nutrition and wild bee health. We define bee health as a multidimensional concept in a novel integrative framework linking bee biological traits (physiology, stoichiometry, and disease) and environmental factors (floral diversity and nutritional landscapes). Linking information on tolerated nutritional niches and health in different bee species will allow us to better predict their distribution and responses to environmental change, and thus support wild pollinator conservation.
The diversity, abundance, and health of wild bees is jeopardized primarily by land-use modifications, among other global change drivers.Defining and measuring health in wild bees requires an integrative approach across disciplines.We use elements from chemistry, stoichiometry, ecology, physiology, pathology, and genetics to (i) contribute to a more comprehensive definition of wild bee 'health', and (ii) define a framework linking bee health with floral resource/nutritional landscapes through assessing species-specific nutritional niches.We suggest a novel and holistic approach for capturing bee health through combining field and laboratory tools.Knowledge gained by applying this framework will serve as a blueprint for stakeholders engaged in pollinator conservation.
Antifibrinolytic drugs have become almost ubiquitous in their use during major surgery when bleeding is expected or commonplace. Inhibition of the fibrinolytic pathway after tissue injury has been ...consistently shown to reduce postoperative or traumatic bleeding. There is also some evidence for a reduction of perioperative blood transfusion. However, evidence of complications associated with exaggerated thrombosis also exists, although this appears to be influenced by the choice of the individual agent and the dose administered. There is controversy over the use of the serine protease inhibitor aprotinin, whose license was recently withdrawn but may shortly become available on the market again. In the UK, tranexamic acid, a tissue plasminogen and plasmin inhibitor, is most commonly used, with evidence for benefit in cardiac, orthopaedic, urological, gynaecological, and obstetric surgery. In the USA, ▸-aminocaproic acid, which also inhibits plasmin, is commonly used. We have reviewed the current literature for this increasingly popular class of drugs to support clinical judgement in daily anaesthetic practice.
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