Metastatic cancer cells acquire energy-intensive processes including increased invasiveness and chemoresistance. However, how the energy demand is met and the molecular drivers that coordinate an ...increase in cellular metabolic activity to drive epithelial-mesenchymal transition (EMT), the first step of metastasis, remain unclear. Using different in vitro and in vivo EMT models with clinical patient's samples, we showed that EMT is an energy-demanding process fueled by glucose metabolism-derived adenosine triphosphate (ATP). We identified angiopoietin-like 4 (ANGPTL4) as a key player that coordinates an increase in cellular energy flux crucial for EMT via an ANGPTL4/14-3-3γ signaling axis. This augmented cellular metabolic activity enhanced metastasis. ANGPTL4 knockdown suppresses an adenylate energy charge elevation, delaying EMT. Using an in vivo dual-inducible EMT model, we found that ANGPTL4 deficiency reduces cancer metastasis to the lung and liver. Unbiased kinase inhibitor screens and Ingenuity Pathway Analysis revealed that ANGPTL4 regulates the expression of 14-3-3γ adaptor protein via the phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase signaling pathways that culminate to activation of transcription factors, CREB, cFOS and STAT3. Using a different mode of action, as compared with protein kinases, the ANGPTL4/14-3-3γ signaling axis consolidated cellular bioenergetics and stabilized critical EMT proteins to coordinate energy demand and enhanced EMT competency and metastasis, through interaction with specific phosphorylation signals on target proteins.
The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic ...immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.
Purpose
Guidelines recommend teaching of lung ultrasound for critical care, though little information exists on how much training is required for independent practice, especially for non-physician ...trainees. We thus aimed to elucidate a threshold number of cases above which competency for independent practice may be attained for respiratory therapists (RTs).
Methods
We conducted a prospective audit of lung ultrasound training between July 2014 and April 2015 in our 20-bed medical intensive care unit. Following theoretical instruction and self-learning, trainees acquired images from 12 lung zones under direct supervision and classified images into six patterns. Assistance during image acquisition and correct interpretation of ultrasound images were recorded.
Results
Eleven ultrasound-naïve RTs scanned an average of 15 patients each (170 patients in total). Among supervisor-adjudicated lung ultrasound findings, 35.5 % were abnormal. Blinded verification of the adjudicated findings was done for the first 92 patients (1104 images), with an agreement of 95.4 %. As RTs scanned more patients, there was a significant decrease in the proportion of images requiring supervisor assistance (Cuzick’s
P
< 0.001), and a significant increase in the proportion of correctly identified images (Cuzick’s
P
= 0.008). After trainees performed at least ten scans, less than 2 % of images required assistance with acquisition and less than 5 % were wrongly interpreted.
Conclusions
Our training method allowed RTs to independently perform lung ultrasound after at least ten directly supervised scans. Given that RTs are likely to have less ultrasound knowledge and less clinical know-how compared to physicians, we believe that the same threshold number of scans may be also safely applied to the latter.
Biodegradable nanocomposites were prepared from poly(butylene succinate) (PBS) and organo-montmorillonite (OMMT), in the presence of maleic anhydride-grafted PBS (PBS-g-MA) as compatibiliser. The ...effects of OMMT loading and PBS-g-MA on the biodegradability of PBS nanocomposites were investigated. Soil burial testing was carried out for 180 days in natural organic humus compost soil under controlled conditions. It is noted that the weight loss of nanocomposites was lower than that of neat PBS, due to the enhanced barrier properties after addition of OMMT. However, the addition of PBS-g-MA increased the weight loss of nanocomposite. The mechanical properties of PBS nanocomposites were significantly reduced after the soil burial. Biodegradation of the material was further confirmed by the decreased molecular weight through gel permeation chromatography (GPC), and changes in the chemical structure as verified by Fourier transform infrared (FTIR) spectroscopy. This was supported by the degraded surface of PBS and the nanocomposites observed under scanning electron microscopy (SEM). The effects of biodegradation on the thermal properties were studied through the differential scanning calorimetry (DSC). In addition, the biodegradation rate of the materials was determined by measuring the carbon dioxide (CO2) evolution. The degraded samples were recovered and PBS-degrading bacteria were found to be present in the exposed samples.
Improving wastewater treatment processes is becoming increasingly important, due to more stringent effluent quality requirements, the need to reduce energy consumption and chemical dosing. This can ...be achieved by applying artificial intelligence. Machine learning is implemented in two domains: (1) predictive control and (2) advanced analytics. This is currently being piloted at the integrated validation plant of PUB, Singapore's National Water Agency. (1) Primarily, predictive control is applied for optimised nutrient removal. This is obtained by application of a self-learning feedforward algorithm, which uses load prediction and machine learning, fine-tuned with feedback on ammonium effluent. Operational results with predictive control show that the load prediction has an accuracy of ≈88%. It is also shown that an up to ≈15% reduction of aeration amount is achieved compared to conventional control. It is proven that this load prediction-based control leads to stable operation and meeting effluent quality requirements as an autopilot system. (2) Additionally, advanced analytics are being developed for operational support. This is obtained by application of quantile regression neural network modelling for anomaly detection. Preliminary results illustrate the ability to autodetect process and instrument anomalies. These can be used as early warnings to deliver data-driven operational support to process operators.
The molecular mechanisms underlying constitutive nuclear factor-κB (NF-κB) activation in solid tumors has not been elucidated. We show that Annexin-1 (ANXA1) is involved in this process, and ...suppression of ANXA1 in highly metastatic breast cancer cells impedes migration and metastasis capabilities in vitro and in vivo. ANXA1 expression correlates with NF-κB activity, suggesting that ANXA1 may be required for the constitutive activity of IκB kinase (IKK) and NF-κB in highly metatstatic breast cancer. Gel-filtration analysis demonstrated that ANXA1 co-elutes with the members of the IKK complex and NF-κB signaling pathway, and immunoprecipitation confirmed that ANXA1 can bind to and interact with IKKγ or NEMO, but not IKKα or IKKβ. Importantly, silencing of ANXA1 prevents the interaction of NEMO and RIP1, which indicates that ANXA1 is required for the recruitment of RIP1 to the IKK complex, which may be important for the activation of NF-κB. Downstream targets of NF-κB include uPA and CXCR4, which can be modulated by ANXA1 silencing. CXCR4-mediated migration of breast cancer cell lines in response to CXCL12 was significantly modulated by ANXA1, indicating its importance in the tissue-specific migration of breast cancer cells. Chromatin immunoprecipitation experiments confirmed that in ANXA1 overexpressed cells, NF-κB was recruited to CXCR4 promoter without external stimulation, indicating that ANXA1 is critical for the constitutive activation of NF-κB in breast cancer to promote metastasis. Finally, we show that ANXA1 overexpression enhances metastasis and reduces survival in an intracardiac metastasis model, while ANXA1-deficient mice crossed with MMTV-PyMT mice display significantly less metastasis than their heterozygous littermates, indicating that ANXA1 is an important gene in breast cancer metastasis. Our data reveal that ANXA1 can constitutively activate NF-κB in breast cancer cells through the interaction with the IKK complex, and suggests that modulating ANXA1 levels has therapeutic potential to suppress breast cancer metastasis.
A directional audio-capturing device is highly desirable for normal communication in a noisy environment, and to enhance the quality of speech signal for the hearing impaired. In this paper, we ...propose a compact directional audio-capturing device which reduces the background noise in relation to speech signal which originates from a desired direction. This device contains three functional units: (1) a differential microphone formed by two omni-directional microphones connected in an endfire orientation, (2) adaptive beamforming and (3) echo shaping of the residual output signals to further improve the signal-to-noise ratio. The adaptation is based on a control scheme using the differences in the spatial responses between the omni-directional and the differential microphone signals. A post-processing scheme using echo-shaping filter is used to further suppress any residual interferences. A real-time implementation of our proposed scheme has been constructed and its performance measured. The experiments indicate a polar pattern with good interference cancellation, with an average interference suppression of as much as 22
dB. Our experiments also indicate lower speech distortion using our proposed system. In term of speech quality, the improvement is indicated by the mean-opinion-score (MOS) scale. The MOS has been obtained from both subjective tests conducted using ten listeners, as well as using the perceptual evaluation of speech quality tool indicated in ITU-T standards document.
Background
Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect ...patient outcome.
Aim
To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU.
Findings
Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources.
Conclusions
Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.
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