julilili42/papers huggingface dataset:
Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen
2017-08-24

<b>Purpose:</b> Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual's capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings. <b>Methods:</b> CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (<i>N</i> = 678), Middle-Eastern Arab (<i>N</i> = 77), and Asian (<i>N</i> = 153) origin. Robust coefficients of determination (<i>R</i><sup>2</sup>) were estimated for endoxifen (E) or metabolic ratio endoxifen/desmethyl-TAM (E/DMT) as dependent and different CYP2D6 phenotype assignments as independent variables. Allele activity scores (ASs) were modified with respect to a reduced <sup>∗</sup>10 allele activity. Predictability of endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL was investigated by receiver operating characteristic (ROC) analysis. <b>Results:</b> CYP2D6 diplotypes (<i>N</i> = 898) were strongly associated with E and E/DMT independent of age (<i>P</i> < 10<sup>-15</sup>). Across all ethnicities, 68-82% inter-patient variability of E/DMT was explained by CYP2D6 diplotype, while plasma endoxifen was predictable by 39-58%. The previously used codeine specific phenotype classification showed worse prediction for both endpoints particularly in Asians (median <i>R</i><sup>2</sup>< 20%; <i>P</i> < 10<sup>-9</sup>). Downgrading of <sup>∗</sup>10 activity slightly improved the explanatory value of metabolizer phenotype (<i>P</i> < 0.002). Endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL were achieved in 82.3% of patients and were predictable (96% sensitivity, 57% specificity) by CYP2D6 diplotypes with AS > 0.5, i.e., omitting PM/PM and PM/IM patients. <b>Conclusion:</b> The CYP2D6 explanatory power for active drug level assessment is maximized by TAM-specific phenotype assignments while a genotype cutoff that separates PM/PM and PM/IM from the remaining patients may improve clinical benefit via increased endoxifen concentrations.
Developmentally Regulated GTP binding protein 1 (DRG1) controls microtubule dynamics
2017-08-24

Abstract The mitotic spindle, essential for segregating the sister chromatids into the two evolving daughter cells, is composed of highly dynamic cytoskeletal filaments, the microtubules. The dynamics of microtubules are regulated by numerous microtubule associated proteins. We identify here Developmentally regulated GTP binding protein 1 (DRG1) as a microtubule binding protein with diverse microtubule-associated functions. In vitro , DRG1 can diffuse on microtubules, promote their polymerization, drive microtubule formation into bundles, and stabilize microtubules. HeLa cells with reduced DRG1 levels show delayed progression from prophase to anaphase because spindle formation is slowed down. To perform its microtubule-associated functions, DRG1, although being a GTPase, does not require GTP hydrolysis. However, all domains are required as truncated versions show none of the mentioned activities besides microtubule binding.
Oxidant sensor in the cGMP-binding pocket of PKGIα regulates nitroxyl-mediated kinase activity
2017-08-24

Abstract Despite the mechanisms for endogenous nitroxyl (HNO) production and action being incompletely understood, pharmacological donors show broad therapeutic promise and are in clinical trials. Mass spectrometry and site-directed mutagenesis showed that chemically distinct HNO donors 1-nitrosocyclohexyl acetate or Angeli’s salt induced disulfides within cGMP-dependent protein kinase I-alpha (PKGIα), an interdisulfide between Cys42 of the two identical subunits of the kinase and a previously unobserved intradisulfide between Cys117 and Cys195 in the high affinity cGMP-binding site. Kinase activity was monitored in cells transfected with wildtype (WT), Cys42Ser or Cys117/195Ser PKGIα that cannot form the inter- or intradisulfide, respectively. HNO enhanced WT kinase activity, an effect significantly attenuated in inter- or intradisulfide-deficient PKGIα. To investigate whether the intradisulfide modulates cGMP binding, real-time imaging was performed in vascular smooth muscle cells expressing a FRET-biosensor comprising the cGMP-binding sites of PKGIα. HNO induced FRET changes similar to those elicited by an increase of cGMP, suggesting that intradisulfide formation is associated with activation of PKGIα. Intradisulfide formation in PKGIα correlated with enhanced HNO-mediated vasorelaxation in mesenteric arteries in vitro and arteriolar dilation in vivo in mice. HNO induces intradisulfide formation in PKGIα, inducing the same effect as cGMP binding, namely kinase activation and thus vasorelaxation.
Short-term adaptation of saccades does not affect smooth pursuit eye movement initiation
2017-08-24

Scrutiny of the visual environment requires saccades that shift gaze to objects of interest. In case the object should be moving, smooth pursuit eye movements (SPEM) try to keep the image of the object within the confines of the fovea in order to ensure sufficient time for its analysis. Both saccades and SPEM can be adaptively changed by the experience of insufficiencies, compromising the precision of saccades or the minimization of object image slip in the case of SPEM. As both forms of adaptation rely on the cerebellar oculomotor vermis (OMV), most probably deploying a shared neuronal machinery, one might expect that the adaptation of one type of eye movement should affect the kinematics of the other. In order to test this expectation, we subjected two monkeys to a standard saccadic adaption paradigm with SPEM test trials at the end and, alternatively, the same two monkeys plus a third one to a random saccadic adaptation paradigm with interleaved trials of SPEM. In contrast to our expectation, we observed at best marginal transfer which, moreover, had little consistency across experiments and subjects. The lack of consistent transfer of saccadic adaptation decisively constrains models of the implementation of oculomotor learning in the OMV, suggesting an extensive separation of saccade- and SPEM-related synapses on P-cell dendritic trees.
Mass spectrometry-based identification of a naturally presented receptor tyrosine kinase-like orphan receptor 1-derived epitope recognized by CD8 + cytotoxic T cells
2017-08-24

Despite recent treatment improvements with the approval of cell signaling pathway inhibitors, additional treatment options are needed for patients with relapsed/refractory high-risk chronic lymphocytic leukemia (CLL). An emerging immunotherapeutic strategy for CLL is based on the adoptive transfer
Differential induction of ATF3 and HO-1 in myeloid cells and keratinocytes via Dimethylfumarate or Cyclosporine A
2017-08-24

Important inflammatory skin diseases such as psoriasis, lichen planus or atopic dermatitis are characterized by a hyperplasia of the epidermis. In these diseases, proliferation is controlled and only rarely leads to cancer development which can be supported by an inflammatory microenvironment. One key factor which controls and regulates proliferation is the activating transcription factor 3 (ATF3). ATF3 is a dual function protein as it suppresses pro-inflammatory IL-6 and IL-8, but also acts as a pro-oncogenic factor by the suppression of p53. To dissect the bi-modal role of ATF3 we pharmacologically induced ATF3 and analyzed its influence on cytokine expression and secretion in a cell type specific manner comparing myeloid cells with keratinocytes. Since inflammatory skin diseases can be treated systemically with Cyclosporin A (CsA) or Dimethylfumarate (DMF), but only CsA treatment increases the risk of non-melanoma skin cancer, we used those drugs for the induction of ATF3. In the present study, we showed that ATF3 is induced in PBMCs by DMF, while CsA is the most prominent inducer of ATF3in keratinocytes without enhancing HO-1 transcription. Further we could show that LPS treatment elevates IL-1u03b2 and IL-6 and weakly ATF3 transcription in PBMCs. While transcription of both cytokines is elevated, LPS treatment mediates IL-6 secretion with only little IL-1u03b2 secretion. Treatment with DMF dampens LPS-induced transcription.Taken together, our results shed light into the different carcinogenic potential of CsA and DMF, which both target ATF3. Collectively our data demonstrate that CsA strongly induces pro-carcinogenic ATF3 in keratinocytes, whereas ATF3 induction by DMF in myeloid cells acts anti-inflammatory.
The Arabidopsis Leucine-Rich Repeat Receptor Kinase BIR3 Negatively Regulates BAK1 Receptor Complex Formation and Stabilizes BAK1
2017-08-25

BAK1 is a coreceptor and positive regulator of multiple ligand binding leucine-rich repeat receptor kinases (LRR-RKs) and is involved in brassinosteroid (BR)-dependent growth and development, innate immunity, and cell death control. The BAK1-interacting LRR-RKs BIR2 and BIR3 were previously identified by proteomics analyses of in vivo BAK1 complexes. Here, we show that BAK1-related pathways such as innate immunity and cell death control are affected by BIR3 in <i>Arabidopsis thaliana</i> BIR3 also has a strong negative impact on BR signaling. BIR3 directly interacts with the BR receptor BRI1 and other ligand binding receptors and negatively regulates BR signaling by competitive inhibition of BRI1. BIR3 is released from BAK1 and BRI1 after ligand exposure and directly affects the formation of BAK1 complexes with BRI1 or FLAGELLIN SENSING2. Double mutants of <i>bak1</i> and <i>bir3</i> show spontaneous cell death and constitutive activation of defense responses. BAK1 and its closest homolog BKK1 interact with and are stabilized by BIR3, suggesting that <i>bak1 bir3</i> double mutants mimic the spontaneous cell death phenotype observed in <i>bak1 bkk1</i> mutants via destabilization of BIR3 target proteins. Our results provide evidence for a negative regulatory mechanism for BAK1 receptor complexes in which BIR3 interacts with BAK1 and inhibits ligand binding receptors to prevent BAK1 receptor complex formation.
Downregulation of endometrial mesenchymal marker SUSD2 causes cell senescence and cell death in endometrial carcinoma cells
2017-08-25

The cause of death among the majority of endometrial cancer patients involves migration of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into neighbouring organs. It is, thereby, important to identify factors that mediate metastasis. Cell adhesion and migration are modified by the mesenchymal stem cell (MSC) marker Sushi domain containing 2 (SUSD2), a type I transmembrane protein that participates in the orchestration of cell adhesion and migration through interaction with its partner Galactosidase-binding soluble-1 (LGALS1). MSCs have emerged as attractive targets in cancer therapy. Human endometrial adenocarcinoma (Ishikawa) cells were treated with TGFβ (10 ng/ml) for 72h. SUSD2, LGALS1 and MKI67 transcript levels were quantified using qRT-PCR. The proportion of SUSD2 positive (SUSD2+) cells and SMAD2/3 abundance were quantified by FACS and Western blotting, respectively. Senescent cells were identified with β-galactosidase staining; cell cycle and cell death were quantified using Propidium Iodide staining. Treatment of endometrial cancer cells (Ishikawa cells) with TGFβ (10 ng/ml) significantly decreased SUSD2 transcript levels and the proportion of SUSD2 positive cells. Silencing of SUSD2 using siRNA resulted in senescence and cell death of Ishikawa cells via activation of SMAD2/3. These findings suggest that SUSD2 counteracts senescence and cell death and is thus a potential chemotherapeutic target in human endometrial cancer.
Distinct metabolomic signature in cerebrospinal fluid in early parkinson's disease
2017-08-26

Abstract Objective: The purpose of this study was to profile cerebrospinal fluid (CSF) from early‐stage PD patients for disease‐related metabolic changes and to determine a robust biomarker signature for early‐stage PD diagnosis. Methods: By applying a non‐targeted and mass spectrometry‐driven approach, we investigated the CSF metabolome of 44 early‐stage sporadic PD patients yet without treatment (DeNoPa cohort). We compared all detected metabolite levels with those measured in CSF of 43 age‐ and gender‐matched healthy controls. After this analysis, we validated the results in an independent PD study cohort (Tübingen cohort). Results: We identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher ( P &lt; .05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n = 18) as well as in a third and completely independent validation set (n = 36). The biomarker signature is composed of the three markers—mannose, threonic acid, and fructose—and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800. Conclusion: We identified PD‐specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. Our results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to early‐stage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early‐stage PD. © 2017 International Parkinson and Movement Disorder Society
A large, open source dataset of stroke anatomical brain images and manual lesion segmentations
2017-08-26

Abstract Stroke is the leading cause of adult disability worldwide, with up to two-thirds of individuals experiencing long-term disabilities. Large-scale neuroimaging studies have shown promise in identifying robust biomarkers (e.g., measures of brain structure) of long-term stroke recovery following rehabilitation. However, analyzing large rehabilitation-related datasets is problematic due to barriers in accurate stroke lesion segmentation. Manually-traced lesions are currently the gold standard for lesion segmentation on T1-weighted MRIs, but are labor intensive and require anatomical expertise. While algorithms have been developed to automate this process, the results often lack accuracy. Newer algorithms that employ machine-learning techniques are promising, yet these require large training datasets to optimize performance. Here we present ATLAS (Anatomical Tracings of Lesions After Stroke), an open-source dataset of 304 T1-weighted MRIs with manually segmented lesions and metadata. This large, diverse dataset can be used to train and test lesion segmentation algorithms and provides a standardized dataset for comparing the performance of different segmentation methods. We hope ATLAS release 1.1 will be a useful resource to assess and improve the accuracy of current lesion segmentation methods.
Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity
2017-08-28

Cystic Fibrosis (CF) is the most common monogenic disease among people of Western European descent and caused by mutations in the CFTR gene. However, the disease severity is immensely variable even among patients with similar CFTR mutations due to the possible effect of 'modifier genes'. To identify genetic modifiers, we applied RNA-seq based transcriptomic analyses in CF patients with a mild and severe lung phenotype. Global gene expression and enrichment analyses revealed that genes of the type I interferon response and ribosomal stalk proteins are potential modifiers of CF related lung dysfunction. The results provide a new set of CF modifier genes with possible implications as new therapeutic targets for the treatment of CF.
Sports Participation and Social Capital Formation During Adolescence*
2017-08-28

Objective National and international policies claim that young people's sports participation improves their social capital. This article is the first to examine if sports participation has a causal effect on social capital formation during adolescence and whether such effects depend on the organizational format or the type of sports practiced. Methods Propensity score matching is employed in the analysis with possible endogeneity removed by exploiting the information in, and the structure of, the German Socio‐Economic Panel. Results Regular sports participation positively impacts adolescents’ social capital through volunteering, helping friends, and civic involvement. Furthermore, these effects seem to develop predominantly in sports clubs (in contrast to other organizational formats). Conclusion The empirical evidence of this study is suggestive of the relevant societal role of nonprofit clubs as institutions for practicing sport.
Glaucoma, Stem Cells, and Gene Therapy: Where Are We Now?
2017-08-28

Glaucoma is the second most common cause of blindness, affecting 70∼80 million people around the world. The death of retinal ganglion cells (RGCs) is the main cause of blindness related to this disease. Current therapies do not provide enough protection and regeneration of RGCs. A novel opportunity for treatment of glaucoma is application of technologies related to stem cell and gene therapy. In this perspective we will thus focus on emerging approaches to glaucoma treatment including stem cells and gene therapy.
More Dispersion, Higher Bonuses? On Differentiation in Subjective Performance Evaluations
2017-08-28

We investigate the claim that supervisors do not differentiate enough between high- and low-performing employees when evaluating performance. In a first step, this claim is illustrated in a formal model showing that rating compression reduces performance and subsequent bonus payments. The effect depends on the precision of performance information and may be reversed when cooperation is important. We then investigate panel data spanning different banks and find that stronger differentiation indeed increases subsequent bonus payments. The effect tends to be larger for larger spans of control and at higher hierarchical levels but is reversed at the lowest levels.
Impaired Cerebellum to Primary Motor Cortex Associative Plasticity in Parkinson’s Disease and Spinocerebellar Ataxia Type 3
2017-08-28

Corticocortical CB → M1 PAS can induce bidirectional motor cortical plasticity in M1 for healthy aged subjects. The modulation may be independent of the inhibitory neurocircuits, such as SICI and CBI, and the facilitatory mechanism like ICF. Both patients with PD and SCA3 showed impairment of such plasticity, suggesting significant functional perturbation of the CDTC circuit.
Deceleration capacity of heart rate predicts 1‐year mortality of patients undergoing transcatheter aortic valve implantation
2017-08-28

Background Risk prediction in patients with severe aortic stenosis ( AS ) undergoing transcatheter aortic valve implantation ( TAVI ) is challenging. Development of novel markers for patient risk assessment is of great clinical value. Deceleration capacity ( DC ) of heart rate is a strong risk predictor in post‐infarction patients. Hypothesis DC provides prognostic information in patients undergoing TAVI . Methods We enrolled 374 consecutive patients with severe AS undergoing TAVI . All patients received 24‐hour Holter recording or continuous heart‐rate monitoring to assess DC before intervention. Primary endpoint was all‐cause mortality after 1 year. Results Forty‐nine patients (13.1%) died within 1 year. DC was significantly lower in nonsurvivors than in survivors (1.2 ± 4.8 ms vs 3.3 ± 2.9 ms; P &lt; 0.001), whereas the logistic EuroSCORE and EuroSCORE II were comparable between groups (logistic EuroSCORE : 27.3% ± 17.0% vs 22.9% ± 14.2%; P = 0.122; EuroSCORE II : 8.0% ± 6.9% vs 6.7% ± 4.8%, P = 0.673). One‐year mortality in the 116 patients with impaired DC (&lt;2.5 ms) was significantly higher than in patients with normal DC (23.3% vs 8.5%; P &lt; 0.001). In multivariate Cox regression analysis that included DC , sex, paroxysmal atrial fibrillation, hemoglobin level before TAVI , and logistic EuroSCORE , DC was the strongest predictor of 1‐year mortality (hazard ratio: 0.88, 95% confidence interval: 0.85‐0.94, P &lt; 0.001). DC yielded an AUC in the ROC analysis of 0.645. Conclusions DC of heart rate is a strong and independent predictor of 1‐year mortality in patients with severe AS undergoing TAVI .
Modulation of the earliest visual evoked potential by attention: now you see it, now you don’t
2017-08-28

Baumgartner and colleagues (this issue) report a replication of an ERP study by Kelly, Gomez-Ramirez, and Foxe (2008). Unlike the original authors, they failed to observe a significant modulation of the C1 by visuo-spatial attention. They conclude that initial afferent processing in V1 is impermeable to visuo-spatial attention. Although their study, like any replication effort, is valuable and important, there are some uncertainties at the methodological and statistical levels suggesting that the absence of evidence is not evidence of absence in the present case.
SOMFlow: Guided Exploratory Cluster Analysis with Self-Organizing Maps and Analytic Provenance
2017-08-29

Clustering is a core building block for data analysis, aiming to extract otherwise hidden structures and relations from raw datasets, such as particular groups that can be effectively related, compared, and interpreted. A plethora of visual-interactive cluster analysis techniques has been proposed to date, however, arriving at useful clusterings often requires several rounds of user interactions to fine-tune the data preprocessing and algorithms. We present a multi-stage Visual Analytics (VA) approach for iterative cluster refinement together with an implementation (SOMFlow) that uses Self-Organizing Maps (SOM) to analyze time series data. It supports exploration by offering the analyst a visual platform to analyze intermediate results, adapt the underlying computations, iteratively partition the data, and to reflect previous analytical activities. The history of previous decisions is explicitly visualized within a flow graph, allowing to compare earlier cluster refinements and to explore relations. We further leverage quality and interestingness measures to guide the analyst in the discovery of useful patterns, relations, and data partitions. We conducted two pair analytics experiments together with a subject matter expert in speech intonation research to demonstrate that the approach is effective for interactive data analysis, supporting enhanced understanding of clustering results as well as the interactive process itself.