| 1. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 2. |
- Bergström, Christel A. S., et al.
(författare)
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Early pharmaceutical profiling to predict oral drug absorption : Current status and unmet needs
- 2014
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57, s. 173-199
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Tidskriftsartikel (refereegranskat)abstract
- Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silica and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. (C) 2013 Elsevier B.V. All rights reserved.
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| 3. |
- Bergström, Christel, 1973-, et al.
(författare)
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Biorelevant intrinsic dissolution profiling in early drug development : Fundamental, methodological, and industrial aspects
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 139, s. 101-114
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Forskningsöversikt (refereegranskat)abstract
- Intrinsic dissolution rate (IDR) is the surface specific dissolution rate of a drug. In early drug development, this property (among other parameters) is measured in order to compare different polymorphs and salt forms, guide formulation decisions, and to provide a quality marker of the active pharmaceutical ingredient (API) during production. In this review, an update on different methods and small-scale techniques that have recently evolved for determination of IDR is provided. The importance of biorelevant media and the hydrodynamic conditions of dissolution are also discussed. Different preparation techniques for samples are presented with a focus on disc, particle- and crystal-based methods. A number of small-scale techniques are then described in detail, and their applicability domains are identified. Finally, an updated industrial perspective is provided about IDR's place in the early drug development process.
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| 4. |
- Bodin, Örjan, et al.
(författare)
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Theorizing benefits and constraints in collaborative environmental governance : a transdisciplinary social-ecological network approach for empirical investigations
- 2016
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Ingår i: Ecology & Society. - 1708-3087. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- When environmental processes cut across socioeconomic boundaries, traditional top-down government approaches struggle to effectively manage and conserve ecosystems. In such cases, governance arrangements that foster multiactor collaboration are needed. The effectiveness of such arrangements, however, depends on how well any ecological interdependencies across governed ecosystems are aligned with patterns of collaboration. This inherent interdisciplinary and complex problem has impeded progress in developing a better understanding of how to govern ecosystems for conservation in an increasingly interconnected world. We argue for the development of empirically informed theories, which are not only able to transcend disciplinary boundaries, but are also explicit in taking these complex social-ecological interdependences into account. We show how this emerging research frontier can be significantly improved by incorporating recent advances in stochastic modeling of multilevel social networks. An empirical case study from an agricultural landscape in Madagascar is reanalyzed to demonstrate these improvements.
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| 5. |
- Cook, David C., et al.
(författare)
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Plant biosecurity policy-making modelled on the human immune system: What would it look like?
- 2014
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Ingår i: Environmental Science and Policy. - : Elsevier BV. - 1462-9011. ; 41, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- This paper takes inspiration from the field of bio-mimicry to suggest what a plant biosecurity system might look like if it was modelled on the human immune system. We suggest structural and institutional changes to current biosecurity systems that would facilitate adaptive preparation and response policies, focusing particularly on the Australian plant biosecurity system. By improving information exchanges, interpretation and managing overlapping complementary response capabilities of this system, novel policies emerge that increase resilience to harmful weeds, pests and diseases. This is achieved by adding an element of flexibility in invasion response to cope with different circumstances and contexts, rather than a 'one size fits all' approach. While we find bio-mimicry to be a potentially useful system design tool, there are key differences between the immune and biosecurity systems that the analogy makes clear. Perhaps the most important of these stems from the inability of immune systems to imagine future threats. (C) 2014 Elsevier Ltd. All rights reserved.
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| 6. |
- Darwich, Adam S., et al.
(författare)
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IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3 : Identifying gaps in system parameters by analysing In Silico performance across different compound classes
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 626-642
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Tidskriftsartikel (refereegranskat)abstract
- Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.
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| 7. |
- Elkabets, Moshe, et al.
(författare)
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Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice
- 2011
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 121:2, s. 784-799
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Tidskriftsartikel (refereegranskat)abstract
- Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Scal(+)cKit(-) hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Scal(+)cKit(-) BMCs relative to counterpart control cells. The GRN(+) BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets.
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| 8. |
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| 9. |
- Hens, Bart, et al.
(författare)
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Leveraging Oral Drug Development to a Next Level : Impact of the IMI-Funded OrBiTo Project on Patient Healthcare
- 2021
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Ingår i: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 8
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Forskningsöversikt (refereegranskat)abstract
- A thorough understanding of the behavior of drug formulations in the human gastrointestinal (GI) tract is essential when working in the field of oral drug development in a pharmaceutical company. For orally administered drug products, various GI processes, including disintegration of the drug formulation, drugrelease, dissolution, precipitation, degradation, dosage form transit and permeation, dictate absorption into the systemic circulation. These processes are not always fully captured in predictive in vitro and in silico tools, as commonly applied in the pre-clinical stage of formulation drug development. A collaborative initiative focused on the science of oral biopharmaceutics was established in 2012 between academic institutions and industrial companies to innovate, optimize and validate these in vitro and in silico biopharmaceutical tools. From that perspective, the predictive power of these models can be revised and, if necessary, optimized to improve the accuracy toward predictions of the in vivo performance of orally administered drug products in patients. The IMI/EFPIA-funded “Oral Bioavailability Tools (OrBiTo)” project aimed to improve our fundamental understanding of the GI absorption process. The gathered information was integrated into the development of new (or already existing) laboratory tests and computer-based methods in order to deliver more accurate predictions of drug product behavior in a real-life setting. These methods were validated with the use of industrial data. Crucially, the ultimate goal of the project was to set up a scientific framework (i.e., decision trees) to guide the use of these new tools in drug development. The project aimed to facilitate and accelerate the formulation development process and to significantly reduce the need for animal experiments in this area as well as for human clinical studies in the future. With respect to the positive outcome for patients, high-quality oral medicines will be developed where the required dose is well-calculated and consistently provides an optimal clinical effect. In a first step, this manuscript summarizes the setup of the project and how data were collected across the different work packages. In a second step, case studies of how this project contributed to improved knowledge of oral drug delivery which can be used to develop improved products for patients will be illustrated.
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| 10. |
- Margolskee, Alison, et al.
(författare)
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IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1 : Characterisation of the OrBiTo database of compounds
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 598-609
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Tidskriftsartikel (refereegranskat)abstract
- Predicting oral bioavailability (F-oral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9 L/h (interquartile range: 11.6-43.6 L/h; n = 23), volume of distribution was 80.8 L (54.5-239 L; n = 23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n = 22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.
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| 11. |
- Margolskee, Alison, et al.
(författare)
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IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2 : An introduction to the simulation exercise and overview of results
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 610-625
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Tidskriftsartikel (refereegranskat)abstract
- Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.
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| 12. |
- McAllister, Mark, et al.
(författare)
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Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923 .- 1999-4923. ; 14:5, s. 1010-1010
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Tidskriftsartikel (refereegranskat)abstract
- A webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webinars, to discuss progress in the field, emerging trends, and areas for continued collaboration and harmonisation. Each webinar also hosted a Q&A session where participants could discuss the shared topic and information. Although it was clear from the presentations and Q&A sessions that we continue to make progress in the field of CRDSs and the utility/success of PBBM, there is also a need to continue the momentum and dialogue between the industry and regulators. Five key areas were identified which require further discussion and harmonisation.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Vinarov, Zahari, et al.
(författare)
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Current challenges and future perspectives in oral absorption research : An opinion of the UNGAP network
- 2021
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Ingår i: Advanced Drug Delivery Reviews. - : Elsevier. - 0169-409X .- 1872-8294. ; 171, s. 289-331
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Forskningsöversikt (refereegranskat)abstract
- Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
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| 17. |
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| 18. |
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| 19. |
- Watts, Nick, et al.
(författare)
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The 2020 report of The Lancet Countdown on health and climate change : responding to converging crises
- 2021
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 397:10269, s. 129-170
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Forskningsöversikt (refereegranskat)abstract
- The Lancet Countdown is an international collaboration established to provide an independent, global monitoring system dedicated to tracking the emerging health profile of the changing climate.The 2020 report presents 43 indicators across five sections: climate change impacts, exposures, and vulnerabilities; adaptation, planning, and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement. This report represents the findings and consensus of the 35 leading academic institutions and UN agencies that make up The Lancet Countdown, and draws on the expertise of climate scientists, geographers, engineers, experts in energy, food, and transport, economists, social, and political scientists, data scientists, public health professionals, and doctors.
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| 20. |
- Yuh, Esther L, et al.
(författare)
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Pathological computed tomography features associated with adverse outcomes after mild traumatic brain injury : A TRACK-TBI study with external validation in CENTER-TBI.
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 78:9, s. 1137-1148
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood.OBJECTIVE: To identify pathological CT features associated with adverse outcomes after mTBI.DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021.EXPOSURES: Acute nonpenetrating head trauma.MAIN OUTCOMES AND MEASURES: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months.RESULTS: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study.CONCLUSIONS AND RELEVANCE: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.
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