| 1. |
- Best, Myron G., et al.
(författare)
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RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics
- 2015
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 28:5, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies".
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| 2. |
- Best, Myron G., et al.
(författare)
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Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets
- 2017
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Ingår i: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 32:2, s. 238-252
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.
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| 3. |
- Cooper, Ian R., et al.
(författare)
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Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors
- 2016
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 26:17, s. 4179-4183
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.
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| 4. |
- Huss, Jessica C., et al.
(författare)
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Climate-Dependent Heat-Triggered Opening Mechanism of Banksia Seed Pods
- 2018
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Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Heat-triggered fruit opening and delayed release of mature seeds are widespread among plants in fire-prone ecosystems. Here, the material characteristics of the seed-containing follicles of Banksia attenuata (Proteaceae), which open in response to heat frequently caused by fire, are investigated. Material analysis reveals that long-term dimensional stability and opening temperatures of follicles collected across an environmental gradient increase as habitats become drier, hotter, and more fire prone. A gradual increase in the biaxial curvature of the hygroscopic valves provides the follicles in the driest region with the highest flexural rigidity. The irreversible deformation of the valves for opening is enabled via a temperature-dependent reduction of the elastic modulus of the innermost tissue layer, which then allows releasing the stresses previously generated by shrinkage of the fiber bundles in the adjacent layer during follicle drying. These findings illustrate the level of sophistication by which this species optimizes its fruit opening mechanism over a large distribution range with varying environmental conditions, and may not only have great relevance for developing biomimetic actuators, but also for elucidating the species' capacity to cope with climatic changes.
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| 5. |
- Manning, Victoria, et al.
(författare)
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Improved Quality of Life Following Addiction Treatment Is Associated with Reductions in Substance Use
- 2019
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- People seeking treatment for substance use disorders (SUD) ultimately aspire to improve their quality of life (QOL) through reducing or ceasing their substance use, however the association between these treatment outcomes has received scant research attention. In a prospective, multi-site treatment outcome study (Patient Pathways'), we recruited 796 clients within one month of intake from 21 publicly funded addiction treatment services in two Australian states, 555 (70%) of whom were followed-up 12 months later. We measured QOL at baseline and follow-up using the WHOQOL-BREF (physical, psychological, social and environmental domains) and determined rates of SUD treatment success (past-month abstinence or a statistically reliable reduction in substance use) at follow-up. Mixed effects linear regression analyses indicated that people who achieved SUD treatment success also achieved significantly greater improvements in QOL, relative to treatment non-responders (all four domains p < 0.001). Paired t-tests indicated that non-responders significantly improved their social (p = 0.007) and environmental (p = 0.033) QOL; however, their psychological (p = 0.088) and physical (p = 0.841) QOL did not significantly improve. The findings indicate that following treatment, QOL improved in at least some domains, but that reduced substance use was associated with both stronger and broader improvements in QOL. Addressing physical and psychological co-morbidities during treatment may facilitate reductions in substance use.
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| 6. |
- Manning, Victoria, et al.
(författare)
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Substance use outcomes following treatment : Findings from the Australian Patient Pathways Study
- 2017
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Ingår i: Australian and New Zealand journal of psychiatry (Print). - : SAGE Publications. - 0004-8674 .- 1440-1614. ; 51:2, s. 177-189
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Our understanding of patient pathways through specialist Alcohol and Other Drug treatment and broader health/welfare systems in Australia remains limited. This study examines how treatment outcomes are influenced by continuity in specialist Alcohol and Other Drug treatment, engagement with community services and mutual aid, and explores differences between clients who present with a primary alcohol problem relative to those presenting with a primary drug issue.Method: In a prospective, multi-site treatment outcome study, 796 clients from 21 Alcohol and Other Drug services in Victoria and Western Australia completed a baseline interview between January 2012 and January 2013. A total of 555 (70%) completed a follow-up assessment of subsequent service use and Alcohol and Other Drug use outcomes 12-months later. Results: Just over half of the participants (52.0%) showed reliable reductions in use of, or abstinence from, their primary drug of concern. This was highest among clients with meth/amphetamine (66%) as their primary drug of concern and lowest among clients with alcohol as their primary drug of concern (47%), with 31% achieving abstinence from all drugs of concern. Continuity of specialist Alcohol and Other Drug care was associated with higher rates of abstinence than fragmented Alcohol and Other Drug care. Different predictors of treatment success emerged for clients with a primary drug problem as compared to those with a primary alcohol problem; mutual aid attendance (odds ratio=2.5) and community service engagement (odds ratio=2.0) for clients with alcohol as the primary drug of concern, and completion of the index treatment (odds ratio=2.8) and continuity in Alcohol and Other Drug care (odds ratio=1.8) when drugs were the primary drugs of concern.Conclusion: This is the first multi-site Australian study to include treatment outcomes for alcohol and cannabis users, who represent 70% of treatment seekers in Alcohol and Other Drug services. Results suggest a substantial proportion of clients respond positively to treatment, but that clients with alcohol as their primary drug problem may require different treatment pathways, compared to those with illicit drug issues, to maximise outcomes.
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| 7. |
- Paige, Ellie, et al.
(författare)
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Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction : An Individual-Participant-Data Meta-Analysis
- 2017
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 186:8, s. 899-907
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Forskningsöversikt (refereegranskat)abstract
- The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.
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| 8. |
- Schalkwijk, Stein, et al.
(författare)
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Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:5, s. 1348-1356
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Tidskriftsartikel (refereegranskat)abstract
- Background: Darunavir 800mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available. Objectives: To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women. Patients and methods: A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC(0-tau) and C-trough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure. Results: Simulations predicted that total darunavir exposure (AUC(0-tau)) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC(0-tau) was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%). Conclusions: The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.
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