Pseudomonas aeruginosa causes severe and persistent infections in immune compromised individuals and cystic fibrosis sufferers. The infection is hard to eradicate as P. aeruginosa has developed ...strong resistance to most conventional antibiotics. The problem is further compounded by the ability of the pathogen to form biofilm matrix, which provides bacterial cells a protected environment withstanding various stresses including antibiotics. Quorum sensing (QS), a cell density-based intercellular communication system, which plays a key role in regulation of the bacterial virulence and biofilm formation, could be a promising target for developing new strategies against P. aeruginosa infection. The QS network of P. aeruginosa is organized in a multi-layered hierarchy consisting of at least four interconnected signaling mechanisms. Evidence is accumulating that the QS regulatory network not only responds to bacterial population changes but also could react to environmental stress cues. This plasticity should be taken into consideration during exploration and development of anti-QS therapeutics.
The Antarctic Conservation Biogeographic Regions (ACBRs), originally proposed in 2012, are now established as an important tool in Antarctic science, conservation, management and policy. Here, we ...provide a revised version of the ACBRs, reflecting updates in underlying spatial layers, together with the results of new analyses justifying the inclusion of a 16th bioregion. This updated version now covers all iceâfree areas of Antarctica and is publicly available through the Australian Antarctic Data Centre. In light of the interest in the ACBRs across a variety of research fields, we also provide a new set of summary statistics for the updated spatial layer, including landscape metrics, climate data, protected area coverage and an overview of human activity. The updated ACBRs represent a contemporary, practical and evidenceâbased foundation for understanding, conserving and managing Antarctic biodiversity at a continental scale.
•Very low concentrations offloating macro and microplastics found around Antarctica.•Mean densities of 0.03 macrolitter items·km−2 and 187.6 microplastics·km−2.•Plastic densities are one order of ...magnitude lower than in adjacent temperate waters.•The Subtropical Front seems to be a barrier to the dispersal of drifting plastics.
While macroplastics have been washing up on Southern Ocean islands for decades and microplastics have been found in seabirds from the region since 1960, there are still relatively few quantitative data on the amount of plastic pollution, especially with regard to floating plastics, at high southern latitudes. We present a baseline estimate of the abundance of floating plastics around the Southern Ocean from a survey of floating macro-, meso- and microplastic pollution conducted during the Antarctic Circumnavigation Expedition in 2016/17. A total of 40 net trawls and 626 h of observation were performed during this survey. Of these, 33 net samples and 552 h of observation were made in polar waters south of the Subtropical Front (STF). Only 5 microplastics and 17 macrolitter items were observed south of the STF, confirming the Southern Ocean as the region with the lowest concentrations of plastic pollution globally. The mean concentrations of floating macrolitter (0.02–0.03 items·km−2) and small plastic fragments (188 ± 589 particles·km−2) south of the STF were one order of magnitude lower than in adjacent temperate waters north of the STF, which suggests that the STF acts as a barrier to the southward transport of floating debris. Despite their much lower density, the mass of macroplastics was similar to that of floating microplastics in the Southern Ocean.
Background
Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older ...women. This is an updated version of a Cochrane review first published in 2005.
Objectives
To assess effects of long‐term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment.
Search methods
We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews.
Selection criteria
We included randomised double‐blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route.
Data collection and analysis
Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods.
Main results
We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well‐conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.
In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow‐up: from 5 per 1000 to between 6 and 13 per 1000).
Oestrogen‐only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow‐up time.
Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long‐term use.
Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen‐only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer.
One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen‐only HT versus similar‐sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause.
For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms.
Authors' conclusions
Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short‐term use of low‐dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen‐only HT is well documented.
HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non‐oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long‐term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age.
An increasing number of logistics service providers act as freight integrators in offering one-stop solutions to customers in recent years. Most mathematical models of intermodal network design have ...been developed with a single objective of cost minimisation. This study focuses on developing innovative approaches in the area of enhanced intermodal network design provided by freight integrators. The overall aim of this paper is to demonstrate an original optimisation model that can be employed by freight integrators to address cost minimisation, transit time minimisation, and carbon footprint to better meet market needs. To achieve the aim, this paper develops a bi-objective optimisation model to minimise cost and transit time for the tactical planning of intermodal container flows with constrained carbon emission. The results and analysis of the example of China offer practical insights on the impact of trade-offs between cost and transit time, and the effect of different carbon emission restrictions on intermodal network design.
•Freight integrators can meet diversified customer and environmental needs.•Aids investment and service planning before foreign market entry.•Carbon emission limit significantly affects the feasible solutions.
Tyrosine kinase inhibitors such as erlotinib are commonly used as a therapeutic agent against cancer due to its relatively low side-effect profile and, at times, greater efficacy. However, erlotinib ...resistance (ER) in non-small cell lung cancer is being recognized as a major problem. Therefore, understanding the mechanism behind ER and developing effective regimens are needed. Autophagy's role in cancer has been controversial and remains unclear. In this study, we examined the effectiveness of low dose erlotinib-cisplatin combination in erlotinib resistant lung adenocarcinoma (ERPC9) cells and the role of autophagy in ER. ERPC9 cells were established from erlotinib sensitive PC9 cells. Appropriate treatments were done over two days and cell survival was quantified with Alamar Blue assay. LC3II and regulatory proteins of autophagy were measured by western blot. Small interfering RNA (siRNA) was utilized to inhibit translation of the protein of interest. In ERPC9 cells, combination treatment induced synergistic cell death and a significant decrease in autophagy. At baseline, ERPC9 cells had a significantly higher LC3II and lower p-mTOR levels compared to PC9 cells. The addition of rapamycin increased resistance and 3-methyladenine sensitized ERPC9 cells, indicating autophagy may be acting as a protective mechanism. Further examination revealed that ERPC9 cells harbored high baseline Atg3 levels. The high basal Atg3 was targeted and significantly lowered with combination treatment. siRNA transfection of Atg3 resulted in the reversal of ER; 42.0% more cells died in erlotinib-alone treatment with transfection compared to non-transfected ERPC9 cells. We reveal a novel role for Atg3 in the promotion of ER as the inhibition of Atg3 translation was able to result in the re-sensitization of ERPC9 cells to erlotinib-alone treatment. Also, we demonstrate that combination erlotinib-cisplatin is an effective treatment against erlotinib resistant cancer by targeting (down-regulating) Atg3 mediated autophagy and induction of apoptotic cell death.
Antarctic terrestrial biodiversity occurs almost exclusively in ice-free areas that cover less than 1% of the continent. Climate change will alter the extent and configuration of ice-free areas, yet ...the distribution and severity of these effects remain unclear. Here we quantify the impact of twenty-first century climate change on ice-free areas under two Intergovernmental Panel on Climate Change (IPCC) climate forcing scenarios using temperature-index melt modelling. Under the strongest forcing scenario, ice-free areas could expand by over 17,000 km
by the end of the century, close to a 25% increase. Most of this expansion will occur in the Antarctic Peninsula, where a threefold increase in ice-free area could drastically change the availability and connectivity of biodiversity habitat. Isolated ice-free areas will coalesce, and while the effects on biodiversity are uncertain, we hypothesize that they could eventually lead to increasing regional-scale biotic homogenization, the extinction of less-competitive species and the spread of invasive species.
Microfibers are ubiquitous contaminants of emerging concern. Traditionally ascribed to the "microplastics" family, their widespread occurrence in the natural environment is commonly reported in ...plastic pollution studies, based on the assumption that fibers largely derive from wear and tear of synthetic textiles. By compiling a global dataset from 916 seawater samples collected in six ocean basins, we show that although synthetic polymers currently account for two-thirds of global fiber production, oceanic fibers are mainly composed of natural polymers. µFT-IR characterization of ~2000 fibers revealed that only 8.2% of oceanic fibers are synthetic, with most being cellulosic (79.5%) or of animal origin (12.3%). The widespread occurrence of natural fibers throughout marine environments emphasizes the necessity of chemically identifying microfibers before classifying them as microplastics. Our results highlight a considerable mismatch between the global production of synthetic fibers and the current composition of marine fibers, a finding that clearly deserves further attention.
Abstract Combination treatment for non–small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are ...efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose erlotinib-cisplatin combination in NSCLC in vitro and in vivo . In NSCLC cells harboring epidermal growth factor receptor (EGFR) mutations, combination erlotinib-cisplatin treatment led to synergistic cell death, but there was minimal efficacy in NSCLC cells with wild-type EGFR. In xenograft models, combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment. The anti-tumor effect observed was secondary to the targeting of angiogenesis, evidenced by decreased vascular endothelial growth factor (VEGF) levels and decreased levels of CD31 and microvessel density. Combination treatment targets angiogenesis through down-regulation of the c-MYC/hypoxia inducible factor 1-alpha (HIF-1α) pathway. In fact, cell lines with EGFR exon 19 deletions expressed high basal levels of c-MYC and HIF-1α and correlate with robust responses to combination treatment. These results suggest that low dose erlotinib-cisplatin combination exhibits its anti-tumor activity by targeting angiogenesis through the modulation of the c-MYC/HIF-1α/VEGF pathway in NSCLC with EGFR exon 19 deletions. These findings may have significant clinical implications in patients with tumors harboring EGFR exon 19 deletions as they may be particularly sensitive to this regimen.
•Quantitatively investigates the port–hinterland container transportation network resilience against man-made unconventional emergency events.•Propose to enhance resilience by strategic investment in ...vulnerability reduction.•Adopt the network game theory to model the complex business relationships among players.•Provide managerial insights on resilience improvement through theoretical discussions and numerical experiments.
China's “Belt and Road” strategy emphasizes the significance of maritime logistics. To ensure the efficiency and safety of landside maritime logistics, this study aims to investigate the strategic investment of players in a port–hinterland container transportation network to enhance network resilience to man-made unconventional emergency events by reducing vulnerability. Given the complexity of the involvement of multiple players and their interacting complementary and competitive business relationships, network game theory is adopted. Results show that the complementary influence Bonacich centrality of players plays a critical role in determining their investment decisions and serves as basis from which useful managerial insights can be derived.
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