Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive ...method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.
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► Invading cells exhibit EMT in an autochthonous model of pancreatic cancer ► Mutant cells enter the circulation before cancer is found on histology ► Circulating pancreatic cells (CPCs) express cancer stem cell-associated markers ► Inflammation is necessary and sufficient for EMT, invasion, and dissemination
Prior to detectable pancreatic tumor formation, pancreatic cells invade and enter the bloodstream, explaining why many cancer patients develop metastatic disease despite complete removal of small tumors.
Proposals submitted to the FDA for MSC-based products are undergoing a rapid expansion that is characterized by increased variability in donor and tissue sources, manufacturing processes, proposed ...functional mechanisms, and characterization methods. Here we discuss the diversity in MSC-based clinical trial product proposals and highlight potential challenges for clinical translation.
Each day, all organisms are subjected to changes in light intensity because of the Earth’s rotation around its own axis. To anticipate this geo-physical variability, and to appropriately respond ...biochemically, most species, including mammals, have evolved an approximate 24-hour endogenous timing mechanism known as the circadian clock (CC). The ‘clock’ is self-sustained, cell autonomous and present in every cell type. At the core of the clock resides the CC-oscillator, an exquisitely crafted transcriptional-translational feedback system. Remarkably, components of the CC-oscillator not only maintain daily rhythmicity of their own synthesis, but also generate temporal variability in the expression levels of numerous target genes through transcriptional, post-transcriptional and post-translational mechanisms, thus, ensuring proper chronological coordination in the functioning of cells, tissues and organs, including the liver. Indeed, a variety of physiologically critical hepatic functions and cellular processes are CC-controlled. Thus, it is not surprising that modern lifestyle factors (e.g. travel and jet lag, night and rotating shift work), which force ‘circadian misalignment’, have emerged as major contributors to global health problems including obesity, non-alcoholic fatty liver disease and steatohepatitis. Herein, we provide an overview of the CC-dependent pathways which play critical roles in mediating several hepatic functions under physiological conditions, and whose deregulation is implicated in chronic liver diseases including non-alcoholic steatohepatitis and alcohol-related liver disease.
Evaluating scenarios toward zero plastic pollution Lau, Winnie W Y; Shiran, Yonathan; Bailey, Richard M ...
Science (American Association for the Advancement of Science),
09/2020, Letnik:
369, Številka:
6510
Journal Article
Recenzirano
Odprti dostop
Plastic pollution is a pervasive and growing problem. To estimate the effectiveness of interventions to reduce plastic pollution, we modeled stocks and flows of municipal solid waste and four sources ...of microplastics through the global plastic system for five scenarios between 2016 and 2040. Implementing all feasible interventions reduced plastic pollution by 40% from 2016 rates and 78% relative to "business as usual" in 2040. Even with immediate and concerted action, 710 million metric tons of plastic waste cumulatively entered aquatic and terrestrial ecosystems. To avoid a massive build-up of plastic in the environment, coordinated global action is urgently needed to reduce plastic consumption; increase rates of reuse, waste collection, and recycling; expand safe disposal systems; and accelerate innovation in the plastic value chain.
Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of ...pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
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•IL-17+ T cells are recruited to the pancreas in response to Kras and inflammation•IL-17A overexpression accelerates PanIN initiation and progression•Inhibition of IL-17 signaling effectively prevents PanIN initiation and progression•Kras activates expression of functional IL-17 receptors on PanIN epithelium
McAllister et al. show that KrasG12D induces IL-17 receptors expression on PanIN epithelial cells and stimulates infiltration of IL-17-producing immune cells in a murine PanIN model, the latter of which is confirmed in human PanIN and that inhibition of IL-17 signaling prevents pancreatic neoplasia initiation.
Over the last few decades, plastic waste has become an increasing environmental concern as it accumulates in every environment on our planet. Though traditionally seen as a macroscopic problem (i.e., ...large plastic debris), plastic pollution is also evident at smaller scales. Indeed, the intentional industrial production of small plastic particles and the physical degradation of larger plastic debris have overtime resulted in an increased environmental prevalence of smaller plastic particles, including microplastics. While the effects of these small polymers on marine biota have been an important research focus, recent global surveys indicate that our freshwater lakes and rivers are also plagued by microplastics. However, despite these discoveries we currently have a limited understanding of the impact these particles may have on freshwater animals, particularly on vertebrate species. Thus, the aim of the present study was to assess the impact of high concentrations of microplastics (5 and 20 mg.L−1) on the early life stages in zebrafish, a model freshwater vertebrate model. To do this, we exposed embryonic and larval zebrafish to fluorescently labelled polyethylene microspheres for up to 14 days and assessed their microplastic content, growth, hatching and oxygen consumption rates. We then explored the molecular underpinnings of the microplastic response by RNA sequencing. Over the course of the exposure, we observed a consistent accumulation of microplastics in the gastrointestinal tract of the fish in a concentration dependent manner, but could not detect any detrimental effects of these particles on larval development, growth or metabolism. However, whole animal transcriptomics revealed that microplastics induced a transient and extensive change in larval gene expression within 48 h exposure, which largely disappeared by 14 days. However, as these transcriptional changes occurred during a critical period of larval development, we suggest that an evaluation of the potential long-term impact of these particles is warranted.
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•No effects of MP (microplastics) on hatching, mortality and growth in zebrafish•No effects of MP on O2 consumption rates•Large transcriptomic changes after 2 days of MP exposure•Downregulated genes involved with neural development and function•Most gene expression differences disappeared at 14 days of MP exposure
Short term exposure of developing zebrafish to polyethylene microplastics induces extensive transcriptomic perturbations with no apparent immediate effects on larval development and physiology.
In a randomized trial involving 4000 patients in the ICU who required sedation for mechanical ventilation, dexmedetomidine had no benefit on 90-day mortality as compared with usual care and was ...associated with more adverse events. Additional drugs were required for prescribed sedation levels in the two groups.
Filamentous fungi represent an incredibly rich and rather overlooked reservoir of natural products, which often show potent bioactivity and find applications in different fields. Increasing the ...naturally low yields of bioactive metabolites within their host producers can be problematic, and yield improvement is further hampered by such fungi often being genetic intractable or having demanding culturing conditions. Additionally, total synthesis does not always represent a cost-effective approach for producing bioactive fungal-inspired metabolites, especially when pursuing assembly of compounds with complex chemistry. This review aims at providing insights into heterologous production of secondary metabolites from filamentous fungi, which has been established as a potent system for the biosynthesis of bioactive compounds. Numerous advantages are associated with this technique, such as the availability of tools that allow enhanced production yields and directing biosynthesis towards analogues of the naturally occurring metabolite. Furthermore, a choice of hosts is available for heterologous expression, going from model unicellular organisms to well-characterised filamentous fungi, which has also been shown to allow the study of biosynthesis of complex secondary metabolites. Looking to the future, fungi are likely to continue to play a substantial role as sources of new pharmaceuticals and agrochemicals—either as producers of novel natural products or indeed as platforms to generate new compounds through synthetic biology.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but ...its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
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