The use of error-category mapping in pharmacokinetic model analysis of dynamic contrast-enhanced MRI data.

This study introduces the use of 'error-category mapping' in the interpretation of pharmacokinetic (PK) model parameter results derived from dynamic contrast-enhanced (DCE-) MRI data. Eleven patients with metastatic renal cell carcinoma were enrolled in a multiparametric study of the treatment effects of bevacizumab. For the purposes of the present analysis, DCE-MRI data from two identical pre-treatment examinations were analysed by application of the extended Tofts model (eTM), using in turn a model arterial input function (AIF), an individually-measured AIF and a sample-average AIF. PK model parameter maps were calculated. Errors in the signal-to-gadolinium concentration ([Gd]) conversion process and the model-fitting process itself were assigned to category codes on a voxel-by-voxel basis, thereby forming a colour-coded 'error-category map' for each imaged slice. These maps were found to be repeatable between patient visits and showed that the eTM converged adequately in the majority of voxels in all the tumours studied. However, the maps also clearly indicated sub-regions of low Gd uptake and of non-convergence of the model in nearly all tumours. The non-physical condition ve ≥ 1 was the most frequently indicated error category and appeared sensitive to the form of AIF used. This simple method for visualisation of errors in DCE-MRI could be used as a routine quality-control technique and also has the potential to reveal otherwise hidden patterns of failure in PK model applications.This work was supported by GlaxoSmithKline UK, Wellcome Trust, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Cancer Research UKThis is the published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S0730725X1400321X

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

Introduction: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity. Methods and analysis: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-angstrom sberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12. Ethics and dissemination: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Local Resistance in Early Medieval Chinese Historiography and the Problem of Religious Overinterpretation

Official Chinese historiography is a treasure trove of information on local resistance to the centralised empire in early medieval China (third to sixth century). Sinologists specialised in the study of Chinese religions commonly reconstruct the religious history of the era by interpreting some of these data. In the process, however, the primary purpose of the historiography of local resistance is often overlooked, and historical interpretation easily becomes ‘overinterpretation’—that is, ‘fabricating false intensity’ and ‘seeing intensity everywhere’, as French historian Paul Veyne proposed to define the term. Focusing on a cluster of historical anecdotes collected in the standard histories of the four centuries under consideration, this study discusses the supposedly ‘religious’ nature of some of the data they contain

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Untersuchungen zu Nitrilasen der NIT1-Gruppe in glucosinolat-bildenden Pflanzen

Glucosinolate sind typische Sekundärmetabolite der Brassicales, die an der Interaktion dieser Pflanzen mit Herbivoren und vermutlich auch Pathogenen beteiligt sind. Im Falle einer Gewebeläsion werden Glucosinolate durch eine Thioglucosidase (Myrosinase) in biologisch aktive Verbindungen, z.B. Isothiocyanate oder Nitrile, umgesetzt. Für $\textit {Arabidopsis thaliana}$ ist aber auch ein verwundungsunabhängiger Katabolismus von Glucosinolaten beschrieben worden. In dieser Pflanze existiert auch eine Gruppe von Nitrilasen, für die glucosinolat-abgeleitete Nitrile als $\textit {in vitro}$ Substrate beschrieben wurden und die daher vermutlich eine Rolle im Glucosinolatmetabolismus spielen. In dieser Studie wurden Hinweise gefunden, die darauf hindeuten, dass diese Gruppe von Nitrilasen und auch das Vorkommen eines verwundungsunabhängigen Glucosinolatkatabolismus auf die Brassicaceae beschränkt sind. Außerdem wurden Nitrilasen aus zwei weitern Vertretern der Brassicales heterolog exprimiert und $\textit {in vitro}$ untersucht.Glucosinolates are typical secondary metabolites of the Brassicales, which are involved in the interaction of these plants with herbivores and presumably also pathogens. In case of a tissue lesion glucosinolates are converted by a thioglucosidase (myrosinase) into biologically active compounds, for example isothiocyanates or nitriles. For $\textit {Arabidopsis thaliana}$ there are also reports of a wounding independent glucosinolate catabolism. Furthermore there is a group of nitrilases in this plant, for which glucosinolate derived nitriles have been described as $\textit {in vitro}$ substrates and which therefore presumably are involved in glucosinolate metabolism. In this study data were presented, which point to the fact that this group of nitrilases and also the occurrence of a wounding independent glucosinolate catabolism are confined to the Brassicaceae. Apart from that nitrilases from two other members of the Brassicales were heterologously expressed and analysed $\textit {in vitro}$

The Future of adjuvant therapy for renal cell carcinoma

Twenty to thirty percent of patients with stage I-III renal cell carcinoma will relapse within 5 years of surgery. Recent advances in our understanding of the molecular pathogenesis of renal cell carcinoma have led to several large randomized clinical trials investigating the role of molecularly targeted agents in the adjuvant setting. However, there are higher than expected drop-out rates due to the intolerability of side effects compared with treatment given in the metastatic setting. Additionally, significant challenges remain in the area of clinical trial design and the need to assess multiple potential therapies in a time- and cost-efficient manner, and to identify which patients are likely to benefit from adjuvant therapy.12 page(s

Adjuvant Therapy in Renal Cell Carcinoma—Past, Present, and Future

To date, no effective adjuvant treatment for renal cell carcinoma (RCC) has been described, but research in this area is important since the 5-year relapse rate for intermediate- and high-risk early-stage RCC is 30%–40%. Metastatic RCC can be treated successfully with immune therapy and targeted therapy. Adjuvant trials with immune therapy have been conducted, but they reported no benefit in disease-free survival, and clinical trials with targeted agents have not yet reported results. Further advances in our understanding of the molecular pathogenesis of RCC will identify additional potential targets for adjuvant treatment trials. Future challenges will consequently include target identification, as well as trial design to answer multiple trial questions concurrently, comprehensively, and economically. We review the past efforts, summarize the current adjuvant clinical trial landscape, and consider the challenges in adjuvant trials for RCC. Additionally, we identify potential future adjuvant trial treatments and propose an alternative design for future adjuvant clinical trials