julilili42/papers huggingface dataset:
Preclinical and Translational PET/MR Imaging
2014-05-15

Combined PET and MR imaging (PET/MR imaging) has progressed tremendously in recent years. The focus of current research has shifted from technologic challenges to the application of this new multimodal imaging technology in the areas of oncology, cardiology, neurology, and infectious diseases. This article reviews studies in preclinical and clinical translation. The common theme of these initial results is the complementary nature of combined PET/MR imaging that often provides additional insights into biologic systems that were not clearly feasible with just one modality alone. However, in vivo findings require ex vivo validation. Combined PET/MR imaging also triggers a multitude of new developments in image analysis that are aimed at merging and using multimodal information that ranges from better tumor characterization to analysis of metabolic brain networks. The combination of connectomics information that maps brain networks derived from multiparametric MR data with metabolic information from PET can even lead to the formation of a new research field that we would call cometomics that would map functional and metabolic brain networks. These new methodologic developments also call for more multidisciplinarity in the field of molecular imaging, in which close interaction and training among clinicians and a variety of scientists is needed.
Cross-Platform Toxicogenomics for the Prediction of Non-Genotoxic Hepatocarcinogenesis in Rat
2014-05-15

In the area of omics profiling in toxicology, i.e. toxicogenomics, characteristic molecular profiles have previously been incorporated into prediction models for early assessment of a carcinogenic potential and mechanism-based classification of compounds. Traditionally, the biomarker signatures used for model construction were derived from individual high-throughput techniques, such as microarrays designed for monitoring global mRNA expression. In this study, we built predictive models by integrating omics data across complementary microarray platforms and introduced new concepts for modeling of pathway alterations and molecular interactions between multiple biological layers. We trained and evaluated diverse machine learning-based models, differing in the incorporated features and learning algorithms on a cross-omics dataset encompassing mRNA, miRNA, and protein expression profiles obtained from rat liver samples treated with a heterogeneous set of substances. Most of these compounds could be unambiguously classified as genotoxic carcinogens, non-genotoxic carcinogens, or non-hepatocarcinogens based on evidence from published studies. Since mixed characteristics were reported for the compounds Cyproterone acetate, Thioacetamide, and Wy-14643, we reclassified these compounds as either genotoxic or non-genotoxic carcinogens based on their molecular profiles. Evaluating our toxicogenomics models in a repeated external cross-validation procedure, we demonstrated that the prediction accuracy of our models could be increased by joining the biomarker signatures across multiple biological layers and by adding complex features derived from cross-platform integration of the omics data. Furthermore, we found that adding these features resulted in a better separation of the compound classes and a more confident reclassification of the three undefined compounds as non-genotoxic carcinogens.
Teachers or Psychologists: Who Should Facilitate Depression Prevention Programs in Schools?
2014-05-15

The current study evaluates a depression prevention program for adolescents led by psychologists vs. teachers in comparison to a control. The universal school-based prevention program has shown its efficacy in several studies when implemented by psychologists. The current study compares the effects of the program as implemented by teachers versus that implemented by psychologists under real-life conditions. A total of 646 vocational track 8th grade students from Germany participated either in a universal prevention program, led by teachers (n = 207) or psychologists (n = 213), or a teaching-as-usual control condition (n = 226). The design includes baseline, post-intervention, and follow-up (at 6 and 12 months post-intervention). The cognitive-behavioral program includes 10 sessions held in a regular school setting in same-gender groups and is based on the social information-processing model of social competence. Positive intervention effects were found on the change in girls’ depressive symptoms up to 12 months after program delivery when the program was implemented by psychologists. No such effects were found on boys or when program was delivered by teachers. The prevention program can successfully be implemented for girls by psychologists. Further research is needed for explanations of these effects.
Radiopurity of CaWO4 crystals for direct dark matter search with CRESST and EURECA
2014-05-15

The direct dark matter search experiment CRESST uses scintillating CaWO \\nsingle crystals as targets for possible WIMP scatterings. An intrinsic\\nradioactive contamination of the crystals as low as possible is crucial for the\\nsensitivity of the detectors. In the past CaWO crystals operated in CRESST\\nwere produced by institutes in Russia and the Ukraine. Since 2011 CaWO \\ncrystals have also been grown at the crystal laboratory of the Technische\\nUniversit\\\\"at M\\\\"unchen (TUM) to better meet the requirements of CRESST and of\\nthe future tonne-scale multi-material experiment EURECA. The radiopurity of the\\nraw materials and of first TUM-grown crystals was measured by ultra-low\\nbackground -spectrometry. Two TUM-grown crystals were also operated as\\nlow-temperature detectors at a test setup in the Gran Sasso underground\\nlaboratory. These measurements were used to determine the crystals' intrinsic\\n -activities which were compared to those of crystals produced at other\\ninstitutes. The total -activities of TUM-grown crystals as low as 1.23\\n 0.06 mBq/kg were found to be significantly smaller than the activities of\\ncrystals grown at other institutes typically ranging between ~15 mBq/kg and ~35\\nmBq/kg.\\n
Exposure control for HDR video
2014-05-15

This paper proposes an algorithm for determining the exposure times for High Dynamic Range (HDR) video by adapting them to the current lighting. Due to the limited capability of the sensor used, only two exposures per frame can be taken. For each image, the histogram for the exposure time of the other image is estimated. When this histogram is subtracted from the original, the result can be used to adjust the exposure time to the current lighting situation by standard exposure control algorithms. The subtraction removes the dynamic range already covered by the other image, thus the exposure time can be optimized for the residual dynamic range. The algorithm has been compared with state-of-the-art algorithms for HDR imaging. It is proven to have comparable results in mean squared error to a ground truth gained from real-world data. Furthermore this algorithm is capable of running during the capturing process of a video, since it doesn't require additional exposures than those already taken.
Neutrophils release extracellular DNA traps in response to exercise
2014-05-16

Intense exercise evokes a rapid and transient increase in circulating cell-free DNA (cf-DNA), a phenomenon that is commonly observed in a variety of acute and chronic inflammatory conditions. In this study, we aimed to shed new light on the release and clearance mechanisms of cf-DNA in response to exercise. We hypothesized that activated neutrophils may primarily contribute to exercise-evoked cf-DNA levels by releasing neutrophil extracellular traps (NETs). Analysis of plasma and/or serum samples from male athletes at rest and in response to exhaustive treadmill exercise revealed an immediate and transient increase in cf-DNA that was concomitantly counterbalanced by an increase in serum DNase activity. Consistently, rapid release and clearance kinetics for cf-DNA could also be observed in response to intensive cycling exercise, with no significant differences between endurance-trained (V̇o 2max &gt;57 ml·min −1 ·kg −1 ) and healthy (V̇o 2max &lt;49 ml·min −1 ·kg −1 ) sedentary individuals. In postexercise blood smear samples, we detected seemingly intact neutrophils displaying morphological signs of NET release, as indicated by abnormal swollen nuclei and emanating DNA fibers. In support, we observed a striking correlation of postexercise cf-DNA concentrations with plasma levels of the granule-derived enzyme myeloperoxidase. Our study indicates that intense exercise induces liberation of NETs, which is sufficiently counterbalanced in healthy individuals by a concomitant rise in serum DNase activity. As aberrant release of NETs has been linked to diverse disease states, monitoring of cf-DNA/DNase levels or activities in response to standardized exercise testing could provide a valuable tool to identify people who are at increased risk for cardiac ischemia, thrombosis, autoimmunity, or chronic fatigue.
Molecular Epidemiology and Genotyping of Hepatitis B Virus of HBsAg-Positive Patients in Oman
2014-05-16

This study shows the distribution of HBV genotypes, therapy resistance, and vaccine escape mutations in HBV-infected patients in Oman. Our findings will have a major impact on therapy management and diagnostics of chronic HBV infections in Oman to control HBV infection in this intermediate HBV-endemic country.
Biomarkers in lower urinary tract symptoms/overactive bladder
2014-05-16

The word biomarker to name all the parameters described above, from bladder wall thickness to urinary molecules, has been introduced to call the attention to a field wherein objective noninvasive parameters were nonexistent. OAB treatment based on a biomarker, in comparison to the treatment based on a diagnosis made from a careful history and exclusion of urinary tract infection, is not supported by current literature.
Platelet Expression of Stromal Cell-Derived Factor-1 Is Associated with the Degree of Valvular Aortic Stenosis
2014-05-16

Valvular AS is associated with enhanced platelet-SDF-1 expression; moreover the degree of valvular AS correlates with SDF-1 platelet surface expression. These findings may have clinical implications in the future.
Upregulation of non-β Cell-derived Vascular Endothelial Growth Factor A Increases Small Clusters of Insulin-producing Cells in the Pancreas
2014-05-16

Pancreatic β cell-derived vascular endothelial growth factor A (VEGF-A) contributes to normal β cell function. We therefore hypothesized that non-β cell-derived VEGF-A may affect its properties in adult mice.We generated transgenic mice expressing human VEGF-A (hVEGF-A) in a visceral smooth muscle cell (SMC)-dominant manner under the control of the transgelin (Tagln/SM22α) promoter via a tamoxifen-induced Cre/loxP recombination system (SM-CreER(T2)/hVEGF mice).SM-CreER(T2)/hVEGF mice received tamoxifen orally followed by microscopic examination of their pancreas 4 weeks after the hVEGF-A induction. The number of clusters of insulin-producing cells (IPCs) in islets, pancreatic ducts, and individual IPCs were counted.The number of small IPC clusters (100-215 μm(2)) in the pancreas increased significantly in SM-CreER(T2)/hVEGF mice compared with SM-CreER(T2)(Ki) mice (473 out of 1 992 counts vs. 199 out of 976 counts, p<0.05), although total IPC area and the number of pancreatic duct IPCs, in proportion to exocrine area, were similar between the 2 groups. Although most small IPC clusters observed in SM-CreER(T2)/hVEGF mice were not accompanied by α and/or δ cells, some were attached to a single or a few α cells. An STZ-induced diabetic state in SM-CreER(T2)/hVEGF mice was slightly ameliorated, with only one point of significance 12 weeks after STZ administration, compared with SM-CreER(T2)(Ki) mice.Upregulation of non-β cell-derived VEGF-A may alter the composition of pancreatic IPCs by increasing the number of small IPC clusters. These findings provide new information on the role of non-β cell-derived VEGF-A to IPC regeneration and insulin production.
SPR analysis of promoter binding of Synechocystis PCC6803 transcription factors NtcA and CRP suggests cross‐talk and sheds light on regulation by effector molecules
2014-05-17

Surface plasmon resonance monitoring of the binding of transcription factors cAMP receptor protein (CRP) and nitrogen control factor of cyanobacteria (NtcA) from Synechocystis sp. PCC6803 to promoter fragments of glnA, glnN (NtcA regulon) and cccS (CRP regulon), revealed exclusive CRP binding to cccS, whereas NtcA was bound to all three promoters with different affinities, which were strongly increased by the NtcA activator 2‐oxoglutarate. Effective NtcA affinity for 2‐oxoglutarate varied with the promoter. High‐affinity promoters and the NtcA‐coactivating protein PII‐interacting protein X (PipX) increased NtcA affinity towards 2‐oxoglutarate, suggesting PipX‐stabilization of the 2‐oxoglutarate‐bound NtcA conformation. PipX binding to NtcA required 2‐oxoglutarate and was much tighter ( K d ≈ 85 nM) than to the PipX‐sequestering PII protein. NtcA appears to require more strongly PipX and 2‐oxoglutarate (2OG) for estimulating gene expression at promoters having “imperfect” NtcA binding sites.
Magnetoencephalographic Signatures of Numerosity Discrimination in Fetuses and Neonates
2014-05-19

Numerosity discrimination has been demonstrated in newborns, but not in fetuses. Fetal magnetoencephalography allows non-invasive investigation of neural responses in neonates and fetuses. During an oddball paradigm with auditory sequences differing in numerosity, evoked responses were recorded and mismatch responses were quantified as an indicator for auditory discrimination. Thirty pregnant women with healthy fetuses (last trimester) and 30 healthy term neonates participated. Fourteen adults were included as a control group. Based on measurements eligible for analysis, all adults, all neonates, and 74% of fetuses showed numerical mismatch responses. Numerosity discrimination appears to exist in the last trimester of pregnancy.
Severe presentation of WDR62 mutation: Is there a role for modifying genetic factors?
2014-05-19

Mutations in WDR62 are associated with primary microcephaly; however, they have been reported with wide phenotypic variability. We report on six individuals with novel WDR62 mutations who illustrate this variability and describe three in greater detail. Of the three, one lacks neuromotor development and has severe pachygyria on MRI, another has only delayed speech and motor development and moderate polymicrogyria, and the third has an intermediate phenotype. We observed a rare copy number change of unknown significance, a 17q25qter duplication, in the first severely affected individual. The 17q25 duplication included an interesting candidate gene, tubulin cofactor D ( TBCD ), crucial in microtubule assembly and disassembly. Sequencing of the non‐duplicated allele showed a TBCD missense mutation, predicted to cause a deleterious p.Phe1121Val substitution. Sequencing of a cohort of five patients with WDR62 mutations, including one with an identical mutation and different phenotype, plus 12 individuals with diagnosis of microlissencephaly and another individual with mild intellectual disability (ID) and a 17q25 duplication, did not reveal TBCD mutations. However, immunostaining with tubulin antibodies of cells from patients with both WDR62 and TBCD mutation showed abnormal tubulin network when compared to controls and cells with only the WDR62 mutation. Therefore, we propose that genetic factors contribute to modify the severity of the WDR62 phenotype and, although based on suggestive evidence, TBCD could function as one of such factors. © 2014 Wiley Periodicals, Inc.
Vorticity survival in magnetized Friedmann universes
2014-05-19

We use a general relativistic approach to investigate the effects of weak\\ncosmological magnetic fields on linear rotational perturbations during the\\nradiation and dust epochs of the universe. This includes ordinary kinematic\\nvorticity, as well as vortex-like inhomogeneities in the density distribution\\nof the cosmic medium. Our study confirms that magnetic fields can source both\\ntypes of perturbations and shows that their presence also helps cosmic rotation\\nto survive longer. In agreement with previous Newtonian studies, we find that\\nduring the dust era vorticity decays slower than in non-magnetised cosmologies.\\nPrior to equipartition the magnetic effect is more pronounced, since it helps\\nthe aforementioned rotational distortions to maintain constant magnitude.\\nOverall, magnetised universes seem to provide a much better environment for the\\nsurvival of cosmic vorticity than their magnetic-free counterparts.\\n
COMBI-d: A randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma
2014-05-20

9011^ Background: As monotherapies, the BRAF inhibitor dabrafenib (D) and the MEK inhibitor trametinib (T) demonstrated superior progression-free survival (PFS) v chemotherapy in pts with BRAFV600 mutant, metastatic melanoma (MM). Resistance develops in most pts, and oncogenic toxicities (e.g., cutaneous squamous carcinoma (cuSCC)) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects in the Phase I/II study of D+T v D (NCT01072175), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01584648) was conducted to confirm the superiority of D+T over D in pts with BRAFV600E/K mutant MM. Methods: Pts were randomized 1:1 to receive D (150 mg twice daily) + T (2 mg once daily) or D+ placebo (P) as first-line therapy. Eligible pts were ≥18 years and ECOG performance status ≤1, with histologically confirmed unresectable stage IIIC or IV, BRAFV600E/K mutant cutaneous melanoma. The primary endpoint was investigator-assessed PFS; secondary endpoints were overall survival (OS), ORR, duration of response, and safety. Cross over was prohibited. The study has 95% power and a one-sided α=0.025 to detect a PFS hazard ratio (HR) of 0.59. Results: From May 2012 to Jan 2013, 423 pts were randomized (211 to D+T, 212 to D+P). Median follow up was 9 mo (0-16 mo). HR for investigator-assessed PFS was 0.75 (95% CI: 0.57, 0.99; p=0.035), in favor of D+T with a median PFS of 9.3 v 8.8 mo with D+P. The confirmed ORR was 67% (complete response [CR] 10%) for D+T and 51% (CR 9%) for D+P (p=0.0015). HR for interim OS was 0.63 (95% CI 0.42, 0.94; p=0.023), in favor of D+T (40 v 55 deaths). Rates of AEs were similar for both arms. More pts had AEs leading to dose modifications with D+T v D+P. Increased incidence (51% v 28%) and severity (grade 3, 6% v 2%) of pyrexia occurred with D+T v D+P. Fewer cutaneous hyperproliferative events occurred with D+T v D+P (CuSCC 2% v 9%; hyperkeratosis 3% v 32%). Conclusions: D+T demonstrated a significant improvement in PFS compared to D+P in pts with BRAFV600E/K mutant MM. Clinical trial information: NCT01072175.
Tetra- and Pentacyclic Triterpene Acids from the Ancient Anti-inflammatory Remedy Frankincense as Inhibitors of Microsomal Prostaglandin E2Synthase-1
2014-05-20

The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3-30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure-activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and -2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the abundance of highly active triterpene acids in frankincence extracts, our findings provide further evidence of the anti-inflammatory potential of frankincense preparations and reveal novel, potent bioactivities of tirucallic acids, roburic acids, and lupeolic acids.
Bevacizumab and improvement of progression-free survival (PFS) for patients with the mesenchymal molecular subtype of ovarian cancer.
2014-05-20

5509 Background: ICON7 demonstrated that the addition of bevacizumab to carboplatin and paclitaxel improves progression free survival (PFS), but not overall survival (OS) in first-line treatment of ovarian cancer. Our aim was to determine if response to bevacizumab was associated with the molecular classification as described by The Cancer Genome Atlas (TCGA) project. Methods: Core biopsies from formalin fixed paraffin embedded (FFPE) tissue blocks were examined to ensure >70% tumor nuclei from 425 of 455 ICON7 patients enrolled in Germany. Quality Illumina Whole-Genome DASL HT global gene expression data was generated to stratify 380 (89%) patients into four TCGA subclassifications. Median PFS with 95% confidence intervals (CI) and log rank tests were used to evaluate treatment effect on PFS in the presence of non-proportional hazards. Results: Molecular classification was as follows: 86 were differentiated (23%), 124 immunoreactive (33%), 73 mesenchymal (19%), and 97 proliferative (25%). The groups were balanced over treatment arms. 267 (70.3%) were of serous histology. Patients with serous carcinomas of mesenchymal subtype obtained the greatest benefit from bevacizumab with an improvement of median PFS of 9.5 months (25.5 [95%CI 21.1, NA] vs. 16 [95%CI 10.5, NA] months, p=0.053). In contrast, the differentiated, immunoreactive and proliferative subtypes demonstrated median PFS improvements of 5.8 (19.4 [18.6, NA] vs. 13.6 [9.7, 32.7], p=0.35), 3.4 (17.9 [15.9, NA] vs. 14.6 [12.4, NA], p=0.38) and 3.2 months (21.5 [19.8, 29] vs. 18.3 [13.8, NA], p=0.76), respectively. Patients with mesenchymal tumors or high risk clinical characteristics (suboptimal stage III, all stage IV) (46% of cohort) demonstrated a 7.3 month improvement in median PFS with bevacizumab (19.8 [18.3, 23.7] vs. 12.5 [10.1, 16.2] months, p<0.01). Conclusions: Assignment to molecular subclassifications based on gene expression signatures was feasible using FFPE tissue. Patients with mesenchymal subtype ovarian cancer may be most likely to obtain sustained benefit from treatment with bevacizumab.