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Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. Methods: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. Results: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226-3p in 50% (p ≤ 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR-148a-3p/miR-125a-5p/miR-1226-3p only 33% (p ≤ 0.015). Several resistance-relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p ≤ 0.006). Conclusion: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions.We acknowledge support by Open Access Publication Fund of University of Muenster.
Kirsten Lindner was supported by a Research Fellowship of the Dean´s Office of the Faculty of Medicine,
Westfälische Wilhelms-Universität Münster (“Flexible Forschungszeit für Nachwuchswissenschaftler zur
Erhöhung der Forschungsleitung von Frauen in klinischen Fächern”; No. 15-003). Ann-Kathrin Eichelmann
was supported by a Research Fellowship of the Faculty of Medicine, Westfälische Wilhelms-Universität Münster.
Richard Hummel was supported by funding from the German Research Foundation (DFG) in the context of
a Research Grant (Hu 1763/4-1)
Molecular tweezers with a rotationally restricted linker and freely rotating porphyrin moieties
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This journal is © The Royal Society of Chemistry 2018.The effect of the degree of conformational rigidity and/or flexibility on preorganisation in artificial molecular
receptors continues to be actively explored by supramolecular chemists. This work describes a bisporphyrin
architecture, linked via a rigid polycyclic backbone, in which a sterically bulky 2,3,5,6-tetramethylphenyl
diimide core restricts rotation to afford two non-interconvertible tweezer conformations;
syn- and anti-. After separation, the host–guest chemistry of each conformation was studied independently.
The difference in host geometry allows only the syn-conformation to form a strong 1 : 1 bis-porphyrin
complex with the diamino ligand 1,4-diazabicyclo[2.2.2]octane (DABCO) (K11 = 1.25 × 108 M−1),
with the anti-conformation adopting a 2 : 2 sandwich complex with DABCO (K22 = 5.57 × 1017 M−3)
Safety and feasibility of a first-person view, full-body interaction game for telerehabilitation post-stroke
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This journal is published by the University Library System of the University of Pittsburgh as part of its D-Scribe Digital Publishing Program and is cosponsored by the University of Pittsburgh Press.This study explored the feasibility and safety of pairing the Microsoft Kinect® sensor with the Oculus Rift® Head Mounted Display (HMD) as a telerehabilitation technology platform for persons post-stroke. To test initial safety, fourteen participants without disabilities (age 30 ± 8.8 years) engaged in a game-based task using the Microsoft Kinect® with a first-person view using the Oculus Rift®. These tasks were repeated for five participants post-stroke (age 56 ± 3.0 years). No significant adverse events occurred in either study population. When using the Oculus Rift® HMD, three participants without disabilities reported dizziness and nausea. All of the participants post-stroke required hands-on assistance for balance and fall prevention. The intensive nature of physical support necessary for this type of interaction limits the application as a telerehabilitation intervention. Given the increasing availability of HMDs for commercial use, it is crucial that the safety of immersive games and technologies for telerehabilitation is fully explored
Microbial micropatches within microbial hotspots
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access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.The spatial distributions of organism abundance and diversity are often heterogeneous. This includes the sub-centimetre distributions of microbes, which have ‘hotspots’ of high abundance, and ‘coldspots’ of low abundance. Previously we showed that 300 μl abundance hotspots, coldspots and background regions were distinct at all taxonomic levels. Here we build on these results by showing taxonomic micropatches within these 300 μl microscale hotspots, coldspots and background regions at the 1 μl scale. This heterogeneity among 1 μl subsamples was driven by heightened abundance of specific genera. The micropatches were most pronounced within hotspots. Micropatches were dominated by Pseudomonas, Bacteroides, Parasporobacterium and Lachnospiraceae incertae sedis, with Pseudomonas and Bacteroides being responsible for a shift in the most dominant genera in individual hotspot subsamples, representing up to 80.6% and 47.3% average abundance, respectively. The presence of these micropatches implies the ability these groups have to create, establish themselves in, or exploit heterogeneous microenvironments. These genera are often particle-associated, from which we infer that these micropatches are evidence for sub-millimetre aggregates and the aquatic polymer matrix. These findings support the emerging paradigm that the microscale distributions of planktonic microbes are numerically and taxonomically heterogeneous at scales of millimetres and less. We show that microscale microbial hotspots have internal structure within which specific local nutrient exchanges and cellular interactions might occur.This research was supported by a CSIRO
Land and Water Top-Up PhD Scholarship (LD), a
CSIRO consumables grant (LD), an APA to LD and
Australian Research Council grants, www.arc.gov.
au, LP-130100508 and DP-150103018 to JGM
Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians
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access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.The Human T-Lymphotropic Virus type 1 (HTLV-1) infects up to 20 million people
worldwide who predominantly reside in resource-limited areas. The virus is associated
with a haematological malignancy (adult T-cell leukaemia/lymphoma, ATL), and inflammatory
diseases involving organ systems including the spinal cord, eyes and lungs. Determining
the outcomes of infection in most HTLV-1 endemic areas is extremely difficult;
however, the virus is highly endemic to central Australia where the Indigenous population
has access to sophisticated medical facilities. We prospectively followed a large hospitalbased
cohort of Indigenous Australian adults that was well characterized with regard to
base-line comorbid conditions, HTLV-1 serostatus and HTLV-1 proviral load (pVL). A
higher baseline HTLV-1 pVL was strongly associated with an increased risk of airway
inflammation (bronchitis/bronchiolitis and bronchiectasis) and death, which most often
resulted from complications of bronchiectasis. Increased mortality due to an HTLV-1-
associated inflammatory condition has not been demonstrated previously. The morbidity
and mortality associated with HTLV-1 infection may therefore be substantially higher
than has been assumed from an analysis of cohorts of subjects with adult T-cell leukaemia
or HTLV-1-associated myelopathy. These findings have important implications for epidemiological
research and for determining health care priorities in resource-limited settings.This study received funding from the
National Health and Medical Research Council of
Australia (NHMRC project grant 1012945) and the Northern Territory Rural Clinical School, an
initiative of the Australian Department of Health and
Ageing. CRMB is a Wellcome Trust Senior
Investigator
Prediction of beauty and liking ratings for abstract and representational paintings using subjective and objective measures
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access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.Recent research on aesthetics has challenged the adage that ªbeauty is in the eye of the
beholderº by identifying several factors that predict ratings of beauty. However, this research
has emerged in a piecemeal fashion. Most studies have examined only a few predictors of
beauty, and measured either subjective or objective predictors, but not both. Whether the
predictors of ratings of beauty versus liking differ has not been tested, nor has whether predictors
differ for major distinctions in art, such as abstract vs. representational paintings.
Finally, past studies have either relied on experimenter-generated stimuliÐwhich likely yield
pallid aesthetic experiencesÐor on a curation of high-quality artÐthereby restricting the
range of predictor scores. We report a study (N = 598) that measured 4 subjective and 11
objective predictors of both beauty ratings and liking ratings, for 240 abstract and 240 representational
paintings that varied widely in beauty. A crossover pattern occurred in the ratings,
such that for abstract paintings liking ratings were higher than beauty ratings, whereas
for representational paintings beauty ratings were higher than liking ratings. Prediction was
much better for our subjective than objective predictors, and much better for our representational
than abstract paintings. For abstract paintings, liking ratings were much more predictable
than beauty ratings. Implications and directions for future research are discussed.The Natural Sciences and Engineering
Research Council of Canada supported this
research through Discovery Grant RGPIN 238599-
2015 to Glen E. Bodner
Changes in the Elemental and Metabolite Profile of Wheat Phloem Sap during Grain Filling Indicate a Dynamic between Plant Maturity and Time of Day
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).The long distance transport of Fe and Zn in the phloem sap of wheat (Triticum aestivum L.)
is the key route for seed supply, due to wheat having a xylem discontinuity. To date, our knowledge
is limited on Fe and Zn homeostasis in the phloem sap during the reproductive and grain filling
stages. With the use of aphid stylectomy to collect samples of phloem sap, we explored maturity and
morning versus afternoon (within-day) changes in nutrient and metabolite profiles. Phloem exudate
was collected from a wheat breeding line, SAMNYT16, at three times during the grain filling period
and at both midday and mid-afternoon. There were significant changes in the concentration of Mg, K,
Fe and Zn during the course of grain loading and there were also significant within-day differences
for Fe and K concentrations in the phloem exudate during the early phases of grain development. We
found that, for K and Fe, there was an increase of 1.1- and 1.4-fold, respectively, for samples taken
prior to midday to those from mid-afternoon. There was also a significant decrease in K, Fe and Zn
phloem sap concentration of 1.5-, 1.4- and 1.1-fold, respectively, from the start of peak grain loading
to the end of grain loading. Of the 79 metabolites detected within samples of phloem exudate, 43 had
significant maturity differences and 38 had significant within-day variability. Glutamine was found
to increase by 3.3–5.9-fold from midday to mid-afternoon and citric acid was found to decrease by
1.6-fold from the start of grain loading to the end of grain loading. These two metabolites are of
interest as they can complex metal ions and may play a role in long distance transport of metal ions.
The work presented here gives further insight into the complex composition of the phloem sap and
variability that can occur during the day and also with increasing maturity.This research received no external funding
How does fatty mouthfeel, saltiness or sweetness of diets contribute to dietary energy intake?
Get PDF© 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).As “taste” is a primary driver of food choice, the objective of this study was to understand how the sensory properties of diets relate to energy intake (EI). A database of 720 frequently consumed foods, described by a trained panel for basic tastes (sweetness, saltiness) and fatty mouthfeel, was systematically applied to all foods reportedly consumed in 24hr recalls as part of the 2011–2012 Australian National Nutrition and Physical Activity Survey (n = 12,153 adults and children). Food groups were classified according to the Australian Guide to Healthy Eating, and their contribution to total nutrient and sensory intake estimated. There were significant positive correlations between the nutrient and sensory properties of diets, for example, for adults, EI and fatty mouthfeel r = 0.740; EI and saltiness r = 0.623 and EI and sweetness r = 0.517 (all p < 0.01). Core foods (e.g. fruits, vegetables, grains, dairy) can provide similar sensory stimulation whilst being of lower energy content than discretionary foods (e.g. confectionary, snacks). Regression models in adults, controlling for age, sex and BMI, revealed that fatty mouthfeel (β = 0.492), saltiness (β = 0.161) and sweetness (β = 0.138) were significant predictors of EI, explaining 56% variance (p < 0.01). Similar results were found for children. Fatty mouthfeel was the primary driver of energy intake but such sensory stimulation can be derived from core (e.g. dairy foods), rather than discretionary foods, at lower energy content
Extended-Release Morphine for Chronic Breathlessness in Pulmonary Arterial Hypertension—A Randomized, Double-Blind, Placebo-Controlled, Crossover Study
Get PDFThis author accepted manuscript is made available following 12 month embargo from date of publication (July 2019) in accordance with the publisher’s archiving policy.
This manuscript
version is made available under the CC-BY-NC-ND 4.0
license:
http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Context
Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH.
Objectives
This randomized, placebo-controlled, double-blind, crossover study
aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness.
Methods
Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness “right now”—morning and evening—measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291).
Results
Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness “right now” was higher on morphine compared with placebo both for morning [mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = −0.22 (−0.6 to 0.2)] and evening [(M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = −0.33 (−0.8 to 0.1)]. All secondary measures of breathlessness were higher with morphine as were nausea and constipation.
Conclusion
This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms.This work was supported by discretionary funds held by the Discipline, Palliative and Supportive Services, Flinders University, Adelaide, Australia
Evidence that decreased expression of sinusoidal bile acid transporters accounts for the inhibition by rapamycin of bile flow recovery following liver ischemia
Get PDFThis author accepted manuscript is made available following 12 month embargo from date of publication (Sept 2018) in accordance with the publisher’s archiving policy.
This manuscript version is made
available under the CC-BY-NC-ND 4.0 license:
http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Rapamycin is employed as an immunosuppressant following organ transplant and, in patients with hepatocellular carcinoma, to inhibit cancer cell regrowth following liver surgery. Preconditioning the liver with rapamycin to induce the expression of antioxidant enzymes is a potential strategy to reduce ischemia reperfusion (IR) injury. However, pre-treatment with rapamycin inhibits bile flow, especially following ischemia. The aim was to investigate the mechanisms involved in this inhibition. In a rat model of segmental hepatic ischemia and reperfusion, acute administration of rapamycin by intravenous injection did not inhibit the basal rate of bile flow. Pre-treatment of rats with rapamycin for 24 h by intraperitoneal injection inhibited the expression of mRNA encoding the sinusoidal influx transporters Ntcp, Oatp1 and 2 and the canalicular efflux transporter Bsep, and increased expression of canalicular Mrp2. Dose-response curves for the actions of rapamycin on the expression of Bsep and Ntcp in cultured rat hepatocytes were biphasic, and monophasic for effects on Oatp1. In cultured tumorigenic H4IIE liver cells, several bile acid transporters were not expressed, or were expressed at very low levels compared to hepatocytes. In H4IIE cells, rapamycin increased expression of Ntcp, Oatp1 and Mrp2, but decreased expression of Oatp2. It is concluded that the inhibition of bile flow recovery following ischemia observed in rapamycin-treated livers is principally due to inhibition of the expression of sinusoidal bile acid transporters. Moreover, in tumorigenic liver tissue the contribution of tumorigenic hepatocytes to total liver bile flow is likely to be small and is unlikely to be greatly affected by rapamycin.This research was produced with the financial support of Cancer Council S.A.s Beat Cancer Project (grant number 1026478) on behalf of its donors and the State Government of South Australia through the Department of Health. The work was also supported by grants from the Flinders Foundation and Flinders University of South Australia