New Markers for Management of Mesothelioma.

In this review, we provide an update on the status of cancer biomarkers for the clinical management of pleural mesothelioma, an aggressive cancer associated with asbestos exposure. Mesothelioma can be difficult to diagnose, and response to treatment is transient, even with recently adopted immune checkpoint inhibitor (ICI) combinations. Identification of mesothelioma-specific biomarkers could facilitate early diagnosis and tailor treatment strategies. Mesothelioma is characterized by frequent loss or alteration of the tumor suppressor genes cyclin-dependent kinase inhibitor 2A (CDKN2A) and BRCA1-associated protein-1 (BAP1). Accumulating data show these genes and/or their related protein products will be valuable tissue-based biomarkers for mesothelioma. Loss of BAP1, CDKN2A, p16, or methylthioadenosine phosphorylase provide pathologists with a reliable means of differentiating between mesothelioma and reactive mesothelial cell proliferations. This can aid diagnosis in difficult cases and is requisite for the identification of the new pathological entity malignant mesothelioma in situ. However, limited progress in identifying clinically useful soluble biomarkers in this cancer type has been made, with mesothelin remaining the benchmark. To date, results from studies to identify predictive biomarkers for ICI response have been disappointing. A recent retrospective study demonstrated BAP1 loss was predictive of improved survival following combination pemetrexed- and platinum-based chemotherapy. Validation of this result could have important clinical implications. Clinical trials aimed at targeting therapy based on biomarker expression are generally in the early phase setting, with overall results being moderate. The identification of biomarkers for mesothelioma remains a key research question due to their potential to improve patient outcomes in this deadly cancer.

The Inhibitory Activity of Anthraquinones against Pathogenic Protozoa, Bacteria, and Fungi and the Relationship to Structure.

Plant-derived anthraquinones were evaluated in cell assays for their inhibitory activities against the parasitic protozoa Trichomonas vaginalis human strain G3 that causes the sexually transmitted disease trichomoniasis in women, Tritrichomonas foetus bovine strain D1 that causes sexually transmitted diseases in farm animals (bulls, cows, and pigs), Tritrichomonas foetus-like strain C1 that causes diarrhea in domestic animals (cats and dogs), and bacteria and fungi. The anthraquinones assessed for their inhibitory activity were anthraquinone, aloe-emodin (1,8-dihydroxy-3-hydroxymethylanthraquinone), anthrarufin (1,5-dihydroxyanthraquinone), chrysazin (1,8-dihydroxyanthraquinone), emodin (1,3,8-trihydroxy-6-methylanthraquinone), purpurin (1,2,4-trihydroxyanthraquinone), and rhein (1,8-dihydroxy-3-carboxyanthraquinone). Their activities were determined in terms of IC50 values, defined as the concentration that inhibits 50% of the cells under the test conditions and calculated from linear dose response plots for the parasitic protozoa, and zone of inhibition for bacteria and fungi, respectively. The results show that the different substituents on the anthraquinone ring seem to influence the relative potency. Analysis of the structure-activity relationships in protozoa indicates that the aloe-emodin and chrysazin with the highest biological activities merit further study for their potential to help treat the diseases in women and domestic and farm animals. Emodin also exhibited antifungal activity against Candida albicans. The suggested mechanism of action and the additional reported beneficial biological properties of anthraquinones suggest that they have the potential to ameliorate a broad spectrum of human diseases.

A Molecular Strategy to Lock-in the Conformation of a Perylene Bisimide-Derived Supramolecular Polymer.

Locking-in the conformation of supramolecular assemblies provides a new avenue to regulate the (opto)electronic properties of robust nanoscale objects. In the present contribution, we show that the covalent tethering of a perylene bisimide (PBI)-derived supramolecular polymer with a molecular locker enables the formation of a locked superstructure equipped with emergent structure-function relationships. Experiments that exploit variable-temperature ground-state electronic absorption spectroscopy unambiguously demonstrate that the excitonic coupling between nearest neighboring units in the tethered superstructure is preserved at a temperature (371 K) where the pristine, non-covalent assembly exists exclusively in a molecularly dissolved state. A close examination of the solid-state morphologies reveals that the locked superstructure engenders the formation of hierarchical 1D materials which are not achievable by unlocked assemblies. To complement these structural attributes, we further demonstrate that covalently tethering a supramolecular polymer built from PBI subunits enables the emergence of electronic properties not evidenced in non-covalent assemblies. Using cyclic voltammetry experiments, the elucidation of the potentiometric properties of the locked superstructure reveals a 100-mV stabilization of the conduction band energy when compared to that recorded for the non-covalent assembly.

Determinants for concomitant anxiety and depression in people living with chronic obstructive pulmonary disease.

OBJECTIVE: Anxiety and depression are common comorbidities in people diagnosed with chronic obstructive pulmonary disease (COPD). Despite concomitant psychological symptomatology being reported in 22-48% of people with COPD, most literature focuses on identifying the risk factors for anxiety or depression separately. Therefore, our objective was to determine whether there is an association between people living with concomitant anxiety and depression and sociodemographic risk factors in people and living with COPD. METHODS: This was a cross-sectional study of 242 people living with COPD. Symptomatology of anxiety and depression were assessed using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI-II). Univariate and multivariable logistic regression models were used to test the association between symptomatology and demographic predictor variables. Odds ratios and 95% confidence intervals were derived. RESULTS: Of the 242 people included, 48.8% (n = 118) had no symptoms of anxiety or depression and 33.5%% (n = 81) had symptomatology for both. Multivariable modelling suggested younger age, having a carer, having a previous psychological medical history, having a higher number of comorbidities and poorer quality of life were associated with concomitant anxiety and depression compared to those without symptomatology. CONCLUSION: Further work should be done to build upon our results which adds to the limited literature surrounding risk factors for concomitant psychological symptomatology to facilitate future discussion surrounding reducing these detrimental comorbidities in people with COPD.

Investigating the Extent Realistic Moulage Impacts on Immersion and Performance Among Undergraduate Paramedicine Students in a Simulation-based Trauma Scenario: A Pilot Study.

INTRODUCTION: Many healthcare education commentators suggest that moulage can be used in simulation to enhance scenario realism. However, few studies investigate to what extent using moulage in simulation impacts learners. We undertook a mixed-methods pilot study investigating how moulage influences student immersion and performance in simulation. METHODS: Fifty undergraduate paramedicine students were randomized into two groups completing a trauma-based scenario with or without patient moulage. Task immersion was determined via a self-report questionnaire (National Aeronautics and Space Administration Task Load Index), eye-tracking, and postsimulation interviews. Performance was measured via independent observation of video by two paramedic clinical educators and time-to-action-when students first applied pressure to the primary wound. RESULTS: Eye-tracking suggested that students attended to the thigh wound more often with the inclusion of moulage than without. National Aeronautics and Space Administration Task Load Index data suggested that the inclusion of moulage heightened students' feeling of being rushed throughout the scenario. This elicited an expedited performance of tasks with moulage present compared with not. Students experienced greater immersion with the inclusion of moulage. However, including moulage enhanced scenario difficulty to the extent that overall clinical performance was negatively affected. However, no differences were found when more heavily weighting items felt to contribute most to the survivability of the patient. CONCLUSIONS: Including moulage engendered immersion and a greater sense of urgency and did not sacrifice performance of key life-saving interventions. As a result of undertaking this pilot project, we suggest that a large-scale randomized controlled trial is feasible and should be undertaken before implementing change to curricula.

Discriminant validity of the Hospital Anxiety and Depression Scale, Beck Depression Inventory (II) and Beck Anxiety Inventory to confirmed clinical diagnosis of depression and anxiety in patients with chronic obstructive pulmonary disease.

The objective of this study was to investigate the discriminant validity of commonly used depression and anxiety screening tools in order to determine the most suitable tool for patients with chronic obstructive pulmonary disease (COPD). COPD patients (n = 56) completed the Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI-II) and Beck Anxiety Inventory (BAI). These scores were compared to confirmed clinical diagnoses of depression and anxiety using the Mini Neuropsychiatric Interview. HADS depression subscale (HADS-D) sensitivity/specificity was 78/81%; BDI-II 89/77%; HADS anxiety subscale (HADS-A) 71/81%; and BAI 89/62%. HADS-D sensitivity/specificity was improved (100/83%) with the removal of Q4 'I feel as if I am slowed down' and adjusted cut-off (≥5). Removal of BDI-II Q21 'Loss of interest in sex' with adjusted cut-off ≥12 resulted in similar improvement (100/79%). No problematic items were identified for HADS-A or BAI. Previously reported low sensitivity/specificity of the HADS for COPD patients was not replicated. Furthermore, simple modifications of the HADS-D markedly improved sensitivity/specificity for depression.BDI-II, HADS-A and BAI produced acceptable sensitivity/specificity unmodified. Pending further research for COPD patients we recommend continued use of the HADS-A with standard cut-off (≥8) and removal of Q4 of the HADS-D with lower cut-off ≥5.

Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1.

Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT). Letrozole-resistant breast cancer cells (LTLT-Ca) were treated with a novel phytoalexin, glyceollin I, and exhibited morphological characteristics synonymous with an epithelial phenotype and decreased proliferation. Letrozole-resistance increased Zinc Finger E-Box Binding Homeobox 1 (ZEB1) expression (4.51-fold), while glyceollin I treatment caused a -3.39-fold reduction. Immunofluorescence analyses resulted of glyceollin I-induced increase and decrease in E-cadherin and ZEB1, respectively. In vivo studies performed in ovariectomized, female nude mice indicated that glyceollin treated tumors stained weakly for ZEB1 and N-cadherin and strongly for E-cadherin. Compared to letrozole-sensitive cells, LTLT-Ca cells displayed enhanced motility, however in the presence of glyceollin I, exhibited a 68% and 83% decrease in invasion and migration, respectively. These effects of glyceollin I were mediated in part by inhibition of ZEB1, thus indicating therapeutic potential of glyceollin I in targeting EMT in letrozole resistant breast cancer.

Impact of a point-of-sale tobacco display ban on smokers' spontaneous purchases: comparisons from postpurchase interviews before and after the ban in Western Australia.

OBJECTIVE: To assess the impact of the Western Australian tobacco point-of-sale display ban on spontaneous purchase behaviours. METHODS: Daily adult smokers (n=402) observed purchasing cigarettes were recruited via exit interviews either 2 months before or after the implementation of the display ban. Smokers were asked if they had intended to purchase cigarettes before entering the store to assess spontaneous purchase behaviours. Whether smokers had noticed the displays before their purchase and the extent to which this influenced their purchase decision was also assessed via non-prompting questions. RESULTS: When compared with before the ban, fewer smokers after the ban noticed the displays (27.1% vs 1.1%, p<0.001), fewer reported making spontaneous purchases (28.2% vs 19.8%, p<0.05) and fewer claimed the displays influenced their purchase decisions (free recall 5.0% vs 1.1%, p<0.05; cued recall 22.1% vs 3.8%, p<0.001). Before the ban, spontaneous purchasers were more likely than planned purchasers to suggest the displays influenced their purchase decisions (free recall 9.7% vs 3.2%, p<0.05; cued recall 40.0% vs 17.9%, p<0.01). After the ban, spontaneous purchasers nominating the influence of displays fell substantially (free recall 9.7% vs 5.6%, p=NS; cued recall 40.0% vs 11.1%, p<0.01) as it did for planned purchasers (free recall 3.2% vs 0.0%, p<0.05; cued recall 17.9% vs 2.1%, p<0.01). CONCLUSIONS: We observed a 30% reduction in smokers making spontaneous tobacco purchases after implementation of the Western Australian tobacco display ban and between a fivefold and sixfold reduction in the proportion suggesting displays influenced their decision to purchase cigarettes. These data are consistent with previous research suggesting tobacco displays encourage spontaneous purchases and their removal corresponds to reductions in the same.

Combination of allele-specific detection techniques to quantify minority resistance variants in hepatitis B infection: a novel approach.

Detection of minor variant viral quasispecies of the rtV173L+rtL180M+rtM204V combination mutation in the hepatitis B virus (HBV) polymerase mediating both lamivudine resistance and vaccine escape is potentially important for tracking the development and evolution of resistance within both individuals and populations. A highly sensitive and specific assay to quantitate HBV genomes was developed with this mutation combination directly from viral DNA in serum using allele-specific quantitative PCR with locked nucleic acid primers and a minor groove binder probe. This combination of primers and probe yields a linear detection range down to 150 copies. This strategy has 100% specificity even in mixtures of predominately wild type genomes. The assay accurately detected 3×10² copies of the triple mutant spiked into 3 × 108 copies of the wild-type genomes (0.0001%), while maintaining 100% specificity. This approach was validated using serum from a subject infected with known lamivudine-resistant HBV. The triple mutant viral population was quantitated at 2.86 × 108 copies/ml within a total viral concentration of 1.03 × 10¹° copies/ml of serum (2.8%). This quantitative allele-specific PCR strategy therefore is a useful method for highly sensitive and specific detection of point mutation combinations that are clinically important in the pathogenesis of drug resistance and/or immune escape.

Measuring the effect of cigarette plain packaging on transaction times and selection errors in a simulation experiment.

INTRODUCTION: Australia has introduced legislation to force all cigarette packaging to be generic from 2012 onwards. The tobacco retail industry estimates this will result in transaction times increasing by 15-45 s per pack and is spending at least $A10 million of tobacco industry funds on an advertising campaigns claiming that the increased time and errors associated with plain packaging will ultimately cost small businesses $A 461 million per annum and endanger 15,000 jobs. We undertook an objective experiment to test these claims. METHODOLOGY: Participants (n=52) were randomly assigned to stand in front of a display of either 50 plain or coloured cigarette packets and then were read a randomly ordered list of cigarette brands. The time participants took to locate each packet was recorded and all selection errors were noted. After 50 'transactions', participants repeated the entire experiment with the alternative plain/coloured packs. Afterwards, participants were asked in an open-ended manner whether plain or coloured packaging was easier to locate and why. RESULTS: The average transaction was significantly quicker for plain compared with coloured packs (2.92 vs 3.17 s; p=0.040). One or more mistakes were made by 40.4% of participants when selecting coloured packaging compared with only 17.3% for plain packaging (p=0.011). Qualitative results suggested that the colours and inconsistent location of brand names often served to distract when participants scanned for brands. CONCLUSION: Rather than plain packaging requiring an additional 45 s per transaction, our results suggest that it will, if anything, modestly decrease transaction times and selection errors.

An independent assessment of the Australian food industry's Daily Intake Guide 'Energy Alone' label.

ISSUES ADDRESSED: A single thumbnail variant of the food industry's voluntary front-of-package Daily Intake Guide (DIG)--called the 'Energy Alone' thumbnail (DIG kJ)--has recently appeared on many energy-dense, nutrient-poor foods and beverages, especially soft drinks and confectionery. However, there is no published data to date that has assessed its merit. METHOD: A quota sample of 58 Australian adults (50% female; 47% blue collar; mean age 35 years, range 18-59) was presented with photographs of three food packages alternatively labelled with DIG kJ, full DIG (five thumbnails) and Traffic Lights (TL) systems. Participants ranked each labelling system along seven-point scales for the following dimensions: 'interpretable, 'noticeable', 'useful' 'and' a deterrent to purchasing unhealthy snack foods: Participants were afterwards brought together in eight focus groups of 7-8 to discuss the merits of each system. RESULTS: Paired samples t-tests suggested the DIG kJ was rated significantly less "noticeable" ,'useful'or'a deterrent'than either the full DIG or TL systems. The TL system was also rated as significantly more'interpretable"and"a deterrent'than either variant of DIG. In the focus groups, participants described the DIG kJ as too small to be noticeable, too abstract to be meaningful, and of little practical use. Higher energy on food labels was also associated with positive health, rather than as a risk for overconsumption. CONCLUSION: The DIG kJ performed poorly against the TL and full DIG. Our results suggest it is an ineffective food labelling system, that is unlikely to affect consumer knowledge, awareness, attitudes, purchasing or consumption behaviours.