Blending different low molecular weight gelators (LMWGs) provides a convenient route to tune the properties of a gel and incorporate functionalities such as fluorescence. Blending a series of ...gelators having a common bis‐urea motif, and functionalised with different amino acid‐derived end‐groups and differing length alkylene spacers is reported. Fluorescent gelators incorporating 1‐ and 2‐pyrenyl moieties provide a probe of the mixed systems alongside structural and morphological data from powder diffraction and electron microscopy. Characterisation of the individual gelators reveals that although the expected α‐urea tape motif is preserved, there is considerable variation in the gelation properties, molecular packing, fibre morphology and rheological behaviour. Mixing of the gelators revealed examples in which: 1) the gels formed separate, orthogonal networks maintaining their own packing and morphology, 2) the gels blended together into a single network, either adopting the packing and morphology of one gelator, or 3) a new structure not seen for either of the gelators individually was created. The strong binding of the urea functionalities to anions was exploited as a means of breaking down the gel structure, and the use of fluorescent gel blends provides new insights into anion‐mediated gel dissolution.
It all adds up: Low molecular weight gelators containing a common bis‐urea motif have been blended together to produce both orthogonal assemblies and new mixed gelator structures with distinct morphologies and packing arrangements (see graphic). The use of fluorescent gel blends provides new insights into gel formation and anion‐mediated gel dissolution.
Microfluidic devices (MFDs) printed in 3-D geometry using digital light projection to polymerize monomers often have surfaces that are not as hydrophobic as MFDs made from polydimethylsiloxane. ...Droplet microfluidics in these types of devices are subject to droplet adhesion and aqueous spreading on less hydrophobic MFD surfaces. We have developed a post-processing technique using hydrophobic monomers that renders the surfaces of these devices much more hydrophobic. The technique is fast and easy, and involves flowing monomer without initiator into the channels and then exposing the entire device to UV light that generates radicals from the initiator molecules remaining in the original 3-D polymerization. After treatment the channels can be cleared and the surface is more hydrophobic, as evidenced by higher contact angles with aqueous droplets. We hypothesize that radicals generated near the previously printed surfaces initiate polymerization of the hydrophobic monomers on the surfaces without bulk polymerization extending into the channels. The most hydrophobic surfaces were produced by treatment with an alkyl acrylate and a fluorinated acrylate. This technique could be used for surface treatment with other types of monomers to impart unique characteristics to channels in MFDs.
Background: Alcoholic liver disease is known to be associated with abnormal iron homeostasis, and iron metabolism itself is regulated by the liver‐derived peptide hepcidin. Both CCAAT enhancer ...binding protein alpha (C/EBPα) and interleukin 6 (IL‐6) have been shown to regulate hepcidin gene transcription.
Aim: To investigate mechanisms underlying alcohol‐induced disturbances in iron homeostasis by measuring the expression of hepcidin and C/EBPα mRNA using in vivo and in vitro models of alcoholic liver injury.
Methods: Male rats were pair‐fed an alcoholic liquid diet for 12 weeks. RT‐PCR was performed on liver tissue using specific primers for hepcidin and C/EBPα. The effect of alcohol on hepcidin and C/EBPα gene expression was also determined in isolated hepatocytes, HuH‐7 cells and HepG2 cells treated with 50 mM ethanol, 200 μM acetaldehyde, and/or 20 ng/ml IL‐6.
Results: Hepcidin and C/EBPα mRNA expression were significantly decreased in alcohol‐fed rats compared with pair‐fed controls (6‐fold p<0.001 and 2.2‐fold p<0.0002 reduction, respectively) and hepatic lipid peroxidation was increased by 32.5% (p<0.05) in alcohol‐fed rats compared with controls. Hepcidin gene expression was not altered significantly in cells cultured in the presence of 50 mM ethanol. Following 24 hour stimulation by IL‐6, there was a 4‐fold increase in hepcidin expression in hepatocytes and a 9‐fold increase in HuH‐7 cells. Ethanol (50 mM) attenuated the IL‐6‐induced increase in hepcidin expression in HuH‐7 cells (9‐fold to a 4‐fold increase) but not in hepatocytes. Acetaldehyde had no effect on hepcidin gene expression in cells in culture.
Conclusion: The down‐regulation of hepcidin and C/EBPα gene expression shown in vivo implies disturbed iron sensing contributing to the hepatosiderosis seen in alcoholic liver disease, possibly by mechanisms involving the IL‐6 signaling cascade.
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic malignancy. HCC is one of the leading causes of cancer deaths worldwide. The oral multi-tyrosine kinase inhibitor Sorafenib ...is the standard first-line therapy in patients with advanced unresectable HCC. Despite the significant survival benefit in HCC patients post treatment with Sorafenib, many patients had progressive disease as a result of acquiring drug resistance. Circumventing resistance to Sorafenib by exploring and targeting possible molecular mechanisms and pathways is an area of active investigation worldwide. Epithelial-to-mesenchymal transition (EMT) is a cellular process allowing epithelial cells to assume mesenchymal traits. HCC tumour cells undergo EMT to become immune evasive and develop resistance to Sorafenib treatment. Immune checkpoint molecules control immune escape in many tumours, including HCC. The aim of this study is to investigate whether combined inhibition of EMT and immune checkpoints can re-sensitise HCC to Sorafenib treatment. Post treatment with Sorafenib, HCC cells PLC/PRF/5 and Hep3B were monitored for induction of EMT and immune checkpoint molecules using quantitative reverse transcriptase (qRT)- PCR, western blot, immunofluorescence, and motility assays. The effect of combination treatment with SB431542, a specific inhibitor of the transforming growth factor (TGF)-
receptor kinase, and siRNA mediated knockdown of programmed cell death protein ligand-1 (PD-L1) on Sorafenib resistance was examined using a cell viability assay. We found that three days of Sorafenib treatment activated EMT with overexpression of TGF-
1 in both HCC cell lines. Following Sorafenib exposure, increase in the expression of PD-L1 and other immune checkpoints was observed. SB431542 blocked the TGF-
1-mediated EMT in HCC cells and also repressed PD-L1 expression. Likewise, knockdown of PD-L1 inhibited EMT. Moreover, the sensitivity of HCC cells to Sorafenib was enhanced by combining a blockade of EMT with SB431542 and knockdown of PD-L1 expression. Sorafenib-induced motility was attenuated with the combined treatment of SB431542 and PD-L1 knockdown. Our findings indicate that treatment with Sorafenib induces EMT and expression of immune checkpoint molecules, which contributes to Sorafenib resistance in HCC cells. Thus, the combination treatment strategy of inhibiting EMT and immune checkpoint molecules can re-sensitise HCC cells to Sorafenib.
Purpose of Review
Climate change poses a serious threat to human health and well-being. Australia is not immune to the public health impacts and continues to be underprepared, putting the population ...health at risk. However, there is a dearth in knowledge about how the Australian public health system will address the impacts of climate change.
Recent Findings
This integrative review synthesises tools, frameworks, and guidance material suitable for climate change adaptation from a preventive public health perspective. The literature search was conducted in electronic databases MEDLINE, PubMed, CINAHL, and Web of Science. Of 4507 articles identified, 19 articles met the inclusion criteria that focused on operational methods in public health and excluded the clinical context and reactive disaster response approaches.
Summary
This review revealed that Australia is ill-prepared to manage climate change adverse health impacts due to ineffective adaptation strategies. The review highlights that Australia urgently requires effective adaptation strategies such as undertaking a National Adaptation Plan process and an improved understanding in managing complex health risks. Taking this action will strengthen the public health system and build health resilience especially for vulnerable populations. These findings will help understand and develop of the necessary adaptive strategies in Australia.
Background The aim of this study was to quantify the changes over time in general surgical residents' operative experience as surgeon, first assistant, and teaching assistant. The introduction of ...work hour restrictions in July 2003 raised concern that residents' operative experience might decline. Early studies evaluating the mean number of operations performed as surgeon reported no major change. The experiences of residents as first assistant and teaching assistant have not been closely examined. Study Design The Accreditation Council for Graduate Medical Education Resident Statistics Summary reports from academic year 1992 to 1993 through the present were reviewed. The mean number of cases reported as total surgeon, surgeon chief, and surgeon junior for academic year 2001 to 2002 through 2005 to 2006 were analyzed for total major operations. The median number of cases reported as total surgeon, first assistant, and teaching assistant for academic year 1992 to 1993 through 2005 to 2006 were analyzed for total major operations. Results Since the implementation of the 80-hour work duty restrictions, the number of total major operations reported by residents as surgeon decreased from 930 to 909 (2.3% decrease, p < 0.0001), surgeon chief operations decreased from 252 to 231 (8.3% decrease, p <0.0001), and surgeon junior operations remained essentially unchanged, from 677 to 678. From academic year 1992 to 1993 through 2005 to 2006, the median number of first assistant and teaching assistant cases declined from 231 to 49 (79% decrease) and from 67 to 23 (66% decrease), respectively. Conclusions Since duty hour restrictions were introduced, there have been small but notable declines in the number of total surgeon and surgeon chief operative cases reported by graduating residents. Over a longer time period, operative cases reported by graduating residents in the roles of first assistant and teaching assistant declined dramatically. Although some of these declines were gradual, recent declines may have been accelerated by the 80-hour duty hour restrictions. These trends must be considered as we plan the education of present and future surgical residents.
Sorafenib, an oral multi-tyrosine kinase inhibitor, has been the first-line therapy for the treatment of patients with advanced HCC, providing a survival benefit of only three months in approximately ...30% of patients. Cancer stem cells (CSCs) are a rare tumour subpopulation with self-renewal and differentiation capabilities, and have been implicated in tumour growth, recurrence and drug resistance. The process of epithelial-to-mesenchymal transition (EMT) contributes to the generation and maintenance of the CSC population, resulting in immune evasion and therapy resistance in several cancers, including HCC. The aim of this study is to target the chemoresistant CSC population in HCC by assessing the effectiveness of a combination treatment approach with Sorafenib, an EMT inhibitor and an immune checkpoint inhibitor (ICI). A stem-cell-conditioned serum-free medium was utilised to enrich the CSC population from the human HCC cell lines Hep3B, PLC/PRF/5 and HepG2. The anchorage independent spheres were characterised for CSC features. The human HCC-derived spheres were assessed for EMT status and expression of immune checkpoint molecules. The effect of combination treatment with SB431542, an EMT inhibitor, and siRNA-mediated knockdown of programmed cell death protein ligand-1 (PD-L1) or CD73 along with Sorafenib on human HCC-derived CSCs was examined with cell viability and apoptosis assays. The three-dimensional spheres enriched from human HCC cell lines demonstrated CSC-like features. The human HCC-derived CSCs also exhibited the EMT phenotype along with the upregulation of immune checkpoint molecules. The combined treatment with SB431542 and siRNA-mediated PD-L1 or CD73 knockdown effectively enhanced the cytotoxicity of Sorafenib against the CSC population compared to Sorafenib alone, as evidenced by the reduced size and proliferation of spheres. Furthermore, the combination treatment of Sorafenib with SB431542 and PD-L1 or CD73 siRNA resulted in an increased proportion of an apoptotic population, as evidenced by flow cytometry analysis. In conclusion, the combined targeting of EMT and immune checkpoint molecules with Sorafenib can effectively target the CSC tumour subpopulation.
Mesenchymal stem/stromal cells (MSCs) present a promising tool in cell‐based therapy for treatment of various diseases. Currently, optimization of treatment protocols in clinical studies is ...complicated by the variations in cell dosing, diverse methods used to deliver MSCs, and the variety of methods used for tracking MSCs in vivo. Most studies use a dose escalation approach, and attempt to correlate efficacy with total cell dose. Optimization could be accelerated through specific understanding of MSC distribution in vivo, long‐term viability, as well as their biological fate. While it is not possible to quantitatively detect MSCs in most targeted organs over long time periods after systemic administration in clinical trials, it is increasingly possible to apply pharmacokinetic modeling to predict their distribution and persistence. This Review outlines current understanding of the in vivo kinetics of exogenously administered MSCs, provides a critical analysis of the methods used for quantitative MSC detection in these studies, and discusses the application of pharmacokinetic modeling to these data. Finally, we provide insights on and perspectives for future development of effective therapeutic strategies using pharmacokinetic modeling to maximize MSC therapy and minimize potential side effects. Stem Cells Translational Medicine 2018;7:78–86
The dosing regimen can be considered the Achilles' heel of mesenchymal stem/stromal cell (MSC)‐based therapies. The establishment of optimal dosage and route of administration of MSCs requires the ability to visualize and quantitatively determine their in vivo distribution. It is increasingly possible to apply pharmacokinetic modelling to predict their distribution and persistence.
Summary
Background
The alginate–antacid, Gaviscon Double Action (Gaviscon DA; Reckitt Benckiser, Slough, UK) suppresses reflux after meals by creating a gel‐like barrier that caps and displaces the ...acid pocket distal to the oesophago‐gastric junction. The effect of Gaviscon DA on reflux and dyspepsia symptoms has not yet been demonstrated with a modern trial design.
Aim
A pilot study to assess the efficacy and safety of Gaviscon DA compared with matched placebo for decreasing upper gastrointestinal symptoms in symptomatic gastro‐oesophageal reflux disease (GERD) patients.
Methods
A randomised, double‐blind, parallel group study was performed in 110 patients with symptoms of GERD. Patients received Gaviscon DA or placebo tablets for 7 consecutive days. The primary endpoint compared the change in overall Reflux Disease Questionnaire (RDQ) symptom score (combined heartburn/regurgitation/dyspepsia). Secondary endpoints assessed individual dimensions, GERD dimension (heartburn and regurgitation) and overall treatment evaluation (OTE).
Results
There was a greater decrease in overall RDQ symptom score in the Gaviscon DA group compared with the placebo group (Least Squares Mean difference −0.55; P = 0.0033), and for each of the dimensions independently. Patients in the Gaviscon DA group evaluated their overall treatment response higher than patients in the placebo group mean (standard deviation) OTE 4.1 (2.44) vs. 1.9 (3.34); P = 0.0005. No differences in the incidence of adverse events were observed between treatment groups.
Conclusions
Gaviscon DA decreases reflux and dyspeptic symptoms in GERD patients compared with matched placebo and has a favourable benefit‐risk balance. Larger scale clinical investigations of medications targeting the acid pocket are warranted. (EudraCT, 2012‐002188‐84)
Multiphoton microscopy (MPM) has become increasingly popular and widely used in both basic and clinical liver studies over the past few years. This technology provides insights into deep live tissues ...with less photobleaching and phototoxicity, which helps us to better understand the cellular morphology, microenvironment, immune responses and spatiotemporal dynamics of drugs and therapeutic cells in the healthy and diseased liver. This review summarizes the principles, opportunities, applications and limitations of MPM in hepatology. A key emphasis is on the use of fluorescence lifetime imaging (FLIM) to add additional quantification and specificity to the detection of endogenous fluorescent species in the liver as well as exogenous molecules and nanoparticles that are applied to the liver in vivo. We anticipate that in the near future MPM‐FLIM will advance our understanding of the cellular and molecular mechanisms of liver diseases, and will be evaluated from bench to bedside, leading to real‐time histology of human liver diseases.
Multiphoton microscopy is a new tool which provides insights into deep live tissues to understand the cellular morphology, microenvironment, immune responses and spatiotemporal dynamics of drugs and therapeutic cells in the liver. This review summarizes its principles, opportunities, applications and limitations in hepatology. A key emphasis is on the use of fluorescence lifetime imaging to add additional quantification and specificity to the detection of fluorescent species in the liver.
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