Research in the past decade has greatly expanded our understanding of the pathogenesis of inflammatory bowel disease, which includes Crohn's disease and ulcerative colitis. In addition to the ...sophisticated network of immune response, the epithelial layer lining the mucosa has emerged as an essential player in the development and persistence of intestinal inflammation. As the frontline of numerous environmental insults in the gut, the intestinal epithelial cells are subject to various cellular stresses. In eukaryotic cells, disturbance of endoplasmic reticulum homeostasis may lead to the accumulation of unfolded and misfolded proteins in the ER lumen, a condition called ER stress. This cellular process activates the unfolded protein response, which functions to enhance the ER protein folding capacity, alleviates the burden of protein synthesis and maturation, and activates ER-associated protein degradation. Paneth and goblet cells, 2 secretory epithelial populations in the gut, are particularly sensitive to ER stress on environmental or genetic disturbances. Recent studies suggested that epithelial ER stress may contribute to the pathogenesis of Crohn's disease and ulcerative colitis by compromising protein secretion, inducing epithelial cell apoptosis and activating proinflammatory response in the gut. Our knowledge of ER stress in intestinal epithelial function may open avenue to new inflammatory bowel disease therapies by targeting the ER protein folding homeostasis in the cells lining the intestinal mucosa.
The choice of general anaesthetics may affect postoperative cognitive outcomes. This study was designed to compare the potential impact of propofol-based vs sevoflurane-based general anaesthesia on ...the development of delayed neurocognitive recovery in older adults early after major cancer surgery.
Older adults (aged ≥65 and <90 yr) who were scheduled to undergo major cancer surgery (≥2 h) were randomised to receive either propofol- or sevoflurane-based general anaesthesia. Cognitive function was assessed before and 1 week after surgery with a battery of neuropsychological tests. Age- and education-matched non-surgical controls were recruited, and their cognitive functions were tested at comparable time intervals in order to adjust for learning effects from repeated tests. Delayed neurocognitive recovery was diagnosed according to the International Study of Postoperative Cognitive Dysfunction 1 definition.
From April 1, 2015 to October 15, 2016, 392 patients were enrolled and randomised. Of these patients, 387 completed the intervention and 30-day follow-up, and 379 completed 1-week neuropsychological tests. Fifty-nine control subjects were enrolled and completed repeated neuropsychological tests. The incidence of delayed neurocognitive recovery at 1 week was significantly lower in the propofol group 14.8% (28/189) than in the sevoflurane group 23.2% (44/190); odds ratio=0.577; 95% confidence interval, 0.342–0.975; P=0.038. Safety outcomes did not differ between the two groups.
When compared with sevoflurane-based general anaesthesia, propofol-based general anaesthesia might decrease the incidence of delayed neurocognitive recovery in older adults after major cancer surgery.
NCT02662257; Chinese Clinical Trial Registry (identifier: ChiCTR-IPR-15006209).
In eukaryotic cells, protein folding and modification in the endoplasmic reticulum (ER) is highly sensitive to disturbances of homeostasis. The accumulation of unfolded and misfolded proteins in the ...ER lumen, termed ER stress, activates intracellular signaling pathways to resolve the protein-folding defect. This unfolded protein response (UPR) increases the capacity of ER protein folding, reduces global protein synthesis, and activates ER-associated protein degradation. If ER stress is too severe or chronic, or the UPR is compromised and not able to restore ER protein-folding homeostasis, numerous apoptotic signaling pathways are activated. Preclinical and clinical studies in the past decade indicate that ER stress and the UPR have a significant impact on the pathogenesis of inflammatory bowel disease. Paneth and goblet cells, 2 epithelial cell populations in the gut, rely on a robust ER function for protein folding and secretion. Several immune cells are orchestrated by ER stress and the UPR for differentiation, activation, migration, and survival. In addition, a variety of exogenous and endogenous molecules in the intestinal lumen affect ER function, making ER stress and the UPR relevant cellular signals in intestinal homeostasis. Recent studies demonstrated that unresolved ER stress and/or dysregulated UPR may cause inflammatory bowel disease by inducing epithelial cell death, impairing mucosal barrier function, and activating proinflammatory response in the gut. With our increased understanding of ER stress in inflammatory bowel disease pathogenesis, it is now possible to develop novel therapies to improve ER protein-folding homeostasis and target-specific UPR pathways in cells residing in the intestinal mucosa.
The construction of fast reliable low‐dimensional models is important for monitoring and control of ventilation applications. We employ a discrete Green’s function approach to derive a linear ...low‐dimensional ventilation model directly from the governing equations for indoor ventilation (i.e., the Navier–Stokes equations supplemented with a transport equation for indoor‐pollutant concentration). It is shown that the flow equations decouple from the concentration equation when the ratio α of air‐mass‐flow rate to pollutant‐mass‐flow rate increases to infinity. A low‐dimensional discrete representation of the Green’s function of the concentration equation can then be constructed, based on either numerical simulations or experiments. This serves as a linear model that allows for the reconstruction of concentration fields resulting from any type of pollutant‐source distribution. We employ a suite of Reynolds‐averaged Navier–Stokes (RANS) simulations to illustrate the methodology. We focus on a simple benchmark ventilation case under constant‐density conditions. Discrete linear ventilation models for the concentration are then derived and compared with coupled RANS simulations. An analysis of errors in the discrete linear model is presented: Dependence of the error on the (low‐dimensional) resolution in the discrete model is quantified, and errors introduced by too low values of α are also investigated.
Practical Implications
The paper introduces the derivation and construction of linear low‐dimensional ventilation models, which allow reconstructing concentration fields resulting from any type of indoor‐pollutant‐source distribution. Once constructed, these ventilation models are very efficient to estimate indoor contaminant concentration distributions, compared to direct CFD simulation approaches. Therefore, these models can facilitate monitoring and control of ventilation systems, to remove indoor contaminants.
Although significant advances have recently been made in the diagnosis and treatment of cervical carcinoma, the long-term survival rate for advanced cervical cancer remains low. Therefore, an urgent ...need exists to both uncover the molecular mechanisms and identify potential therapeutic targets for the treatment of cervical cancer. MicroRNAs (miRNAs) have important roles in cancer progression and could be used as either potential therapeutic agents or targets. miR-506 is a component of an X chromosome-linked miRNA cluster. The biological functions of miR-506 have not been well established. In this study, we found that miR-506 expression was downregulated in approximately 80% of the cervical cancer samples examined and inversely correlated with the expression of Ki-67, a marker of cell proliferation. Gain-of-function and loss-of-function studies in human cervical cancer, Caski and SiHa cells, demonstrated that miR-506 acts as a tumor suppressor by inhibiting cervical cancer growth in vitro and in vivo. Further studies showed that miR-506 induced cell cycle arrest at the G1/S transition, and enhanced apoptosis and chemosensitivity of cervical cancer cell. We subsequently identified Gli3, a hedgehog pathway transcription factor, as a direct target of miR-506 in cervical cancer. Furthermore, Gli3 silencing recapitulated the effects of miR-506, and reintroduction of Gli3 abrogated miR-506-induced cell growth arrest and apoptosis. Taken together, we conclude that miR-506 exerts its anti-proliferative function by directly targeting Gli3. This newly identified miR-506/Gli3 axis provides further insight into the pathogenesis of cervical cancer and indicates a potential novel therapeutic agent for the treatment of cervical cancer.
Therapeutic Advances in Pancreatic Cancer Paulson, Andrew Scott; Tran Cao, Hop S; Tempero, Margaret A ...
Gastroenterology (New York, N.Y. 1943)
144, Številka:
6
Journal Article
Recenzirano
Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward ...increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5–10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of “borderline resectable pancreatic cancer”—a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future.
Abstract
In antiferromagnets, the efficient transport of spin-waves has until now only been observed in the insulating antiferromagnet hematite, where circularly (or a superposition of pairs of ...linearly) polarized spin-waves diffuse over long distances. Here, we report long-distance spin-transport in the antiferromagnetic orthoferrite YFeO
3
, where a different transport mechanism is enabled by the combined presence of the Dzyaloshinskii-Moriya interaction and externally applied fields. The magnon decay length is shown to exceed hundreds of nanometers, in line with resonance measurements that highlight the low magnetic damping. We observe a strong anisotropy in the magnon decay lengths that we can attribute to the role of the magnon group velocity in the transport of spin-waves in antiferromagnets. This unique mode of transport identified in YFeO
3
opens up the possibility of a large and technologically relevant class of materials, i.e., canted antiferromagnets, for long-distance spin transport.
The growing plethoras of social media outlets have sparked both opportunity and concern in how organizations manage their corporate image. While previous research has examined the various problems ...associated with negative, word-of-mouth transference of information occurring simultaneously throughout many networks in social media, this paper seeks to address social media usage in impression management (IM). Specifically, we seek to answer two questions: Do IM direct-assertive strategies in social media impact a firm's financial performance? And which social media strategies impact a firm's financial performance? To analyze these questions in depth, we use text mining to collect and analyze text from a variety of social network platforms, including blogs, forums, and corporate websites, to assess how such IM strategies impact financial performance. Our results provide text mining validation that social media have a positive impact on IM. We also provide further understanding of how social media strengthens organizations' communication with various internal and external stakeholders. Lastly, we provide future research ideas concerning social media's usage in IM.
► Text mining shows the relationship between social media use and performance. ► Social media use generally positively impacts financial performance. ► Support for the association between impression management and financial performance.
Background
Enhanced Recovery After Surgery (ERAS) has been widely applied in liver surgery since the publication of the first ERAS guidelines in 2016. The aim of the present article was to update the ...ERAS guidelines in liver surgery using a modified Delphi method based on a systematic review of the literature.
Methods
A systematic literature review was performed using MEDLINE/PubMed, Embase, and the Cochrane Library. A modified Delphi method including 15 international experts was used. Consensus was judged to be reached when >80% of the experts agreed on the recommended items. Recommendations were based on the Grading of Recommendations, Assessment, Development and Evaluations system.
Results
A total of 7541 manuscripts were screened, and 240 articles were finally included. Twenty-five recommendation items were elaborated. All of them obtained consensus (>80% agreement) after 3 Delphi rounds. Nine items (36%) had a high level of evidence and 16 (64%) a strong recommendation grade. Compared to the first ERAS guidelines published, 3 novel items were introduced: prehabilitation in high-risk patients, preoperative biliary drainage in cholestatic liver, and preoperative smoking and alcohol cessation at least 4 weeks before hepatectomy.
Conclusions
These guidelines based on the best available evidence allow standardization of the perioperative management of patients undergoing liver surgery. Specific studies on hepatectomy in cirrhotic patients following an ERAS program are still needed.
Artificial neural network is a powerful tool in the forecast of solar irradiance. In order to gain higher forecasting accuracy, artificial neural network and wavelet analysis have been combined to ...develop a new method of the forecast of solar irradiance. In this paper, the data sequence of solar irradiance as samples is mapped into several time-frequency domains using wavelet transformation, and a recurrent back-propagation (BP) network is established for each domain. The solar irradiance forecasted equals the algebraic sum of the components, which were predicted correspondingly by the established networks, of all the time-frequency domains. A discount coefficient method is adopted in updating the weights and biases of the networks so that the late forecasts play more important roles. On the basis of the principle of combination of artificial neural networks and wavelet analysis, a model is completed for fore-casting solar irradiance. Based on the historical day-by-day records of solar irradiance in Shanghai an example of forecasting total irradiance is presented. The results of the example indicate that the method makes the forecasts much more accurate than the forecasts using the artificial neural networks without combination with wavelet analysis.
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