julilili42/papers huggingface dataset:
Incidence of Histologically Proven Pelvic and Para-Aortic Lymph Node Metastases and Rate of Upstaging in Patients with Locally Advanced Cervical Cancer: Results of a Prospective Randomized Trial
2017-01-01

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Surgical staging is associated with a significant rate of upstaging compared to clinical/radiological staging in patients with locally advanced cervical cancer. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To analyze the stage-specific percentage of pelvic and para-aortic lymph node metastases and the upstaging ratio in a prospective randomized trial (Uterus-11). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; FIGO stage IIB-IVA cervical cancer patients were randomized to surgical staging (arm A) or to clinical staging and primary chemoradiation (arm B). Arm B patients underwent CT-guided biopsy of suspicious para-aortic lymph nodes. Confirmed para-aortic metastasis patients received extended-field radiation therapy. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A total of 234 patients were enrolled, including 120 (arm A) and 114 (arm B) treated per protocol. The groups were well balanced. Pelvic and para-aortic lymph node metastases were identified after surgical staging in 51 and 24% of patients, respectively (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). Pelvic and para-aortic lymph node metastases were confirmed in 45 and 20% of IIB patients and in 71 and 37% of IIIB patients, respectively. Upstaging occurred in 39/120 (33%) in arm A and in 9/114 (8%) in arm B (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The histological results in both groups led to a considerable rate of upstaging. Oncological data from the Uterus-11 study may reveal whether modified therapy translates into a survival benefit.
Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death
2017-01-01

Suicidal erythrocyte death or eryptosis contributes to or even accounts for anemia in a wide variety of clinical conditions, such as iron deficiency, dehydration, hyperphosphatemia, vitamin D excess, chronic kidney disease (CKD), hemolytic-uremic syndrome, diabetes, hepatic failure, malignancy, arteriitis, sepsis, fever, malaria, sickle-cell disease, beta-thalassemia, Hb-C and G6PD-deficiency, Wilsons disease, as well as advanced age. Moreover, eryptosis is triggered by a myriad of xenobiotics and endogenous substances including cytotoxic drugs and uremic toxins. Eryptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the erythrocyte surface. Triggers of eryptosis include oxidative stress, hyperosmotic shock, and energy depletion. Signalling involved in the regulation of eryptosis includes Ca2+ entry, ceramide, caspases, calpain, p38 kinase, protein kinase C, Janus-activated kinase 3, casein kinase 1α, cyclin-dependent kinase 4, AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein kinase, mitogen- and stress-activated kinase MSK1/2, and ill-defined tyrosine kinases. Inhibitors of eryptosis may prevent anaemia in clinical conditions associated with enhanced eryptosis and stimulators of eryptosis may favourably influence the clinical course of malaria. Additional experimentation is required to uncover further clinical conditions with enhanced eryptosis, as well as further signalling pathways, further stimulators, and further inhibitors of eryptosis. Thus, a detailed description of the methods employed in the analysis of eryptosis may help those, who enter this exciting research area. The present synopsis describes the experimental procedures required for the analysis of phosphatidylserine exposure at the cell surface with annexin-V, cell volume with forward scatter, cytosolic Ca2+ activity ([Ca2+]i) with Fluo3, oxidative stress with 2′,7′-dichlorodihydrofuorescein diacetate (DCFDA), glutathione (GSH) with mercury orange 1(4-chloromercuryphenyl-azo-2-naphthol), lipid peroxidation with BODIPY 581/591 C11 fluorescence, and ceramide abundance with specific antibodies. The contribution of kinases and caspases is defined with the use of the respective inhibitors. It is hoped that the present detailed description of materials and methods required for the analysis of eryptosis encourages further scientists to enter this highly relevant research area.
Online Recognition of Driver-Activity Based on Visual Scanpath Classification
2017-01-01

The next step towards the fully automated vehicle is the level of conditional automation, where the automated driving system can take over the control and responsibility for a limited time interval. Nevertheless, take-over situations may occur, forcing the driver to resume the driving task. Despite such situations, the driver is able to perform secondary tasks during conditionally automated driving, hence a low take-over quality must be expected. Methods for Driver-Activity Recognition (DAR) usually extract features for the classification within a moving time window. In this paper, the first DAR architecture based on the driver's scanpath, which is extracted by means of dynamic clustering and symbolic aggregate approximation patterns, is introduced. To demonstrate the potential of this approach, it is compared to a state-of-the-art method based on the data of a driving simulator study with 82 subjects. The classification performance of both DAR approaches was examined for decreasing window sizes with regard to the recognition of different secondary tasks and the separability of drivers using a handheld or hands-free device. Compared to the state-of-the-art approach, the proposed method shows a classification accuracy increase of nearly 20%, a significant improvement of the overall classification performance, and is able to classify the secondary tasks of the driver even for short windows of a duration of 5 s, i.e. with little information.
German Guidelines on Screening, Diagnosis and Treatment of Alcohol Use Disorders
2017-01-01

Evidence-based strategies for screening, diagnosing and treating alcohol use disorders (AUD) are instrumental in the early and better management of individuals at risk for or suffering from AUD. However, existing guidelines vary and may be biased by conflicts of interests. Unbiased recommendations can be achieved only if sufficient detail is provided on the composition and representativeness of author groups, methodological rigor, handling of potential conflicts of interest and financing. This paper presents the first evidence-based guidelines for AUD from German-speaking countries. These guidelines are based on the work of delegates from a representative sample of 46 scientific societies (mostly medical) from Austria, Germany and Switzerland dealing with AUD. It also included patients and relatives. Recommendations were derived from a standardised hierarchical process involving quality controls drawn from existing guidelines, de novo literature searches and/or expert experience. Potential conflicts of interest were assessed yearly and led to exclusion from voting in specific areas. An overall cost of more than 400,000€ (for alcohol and tobacco guidelines) were exclusively covered by the participating societies and academic institutions. More than 100 recommendations on screening, diagnostics and treatment of AUD are outlined in this paper, and their scientific background is given in the online supplementary material. Tables of aggregated study synopses (in English) and the full version of guidelines (in German) are available (see “Links”).
c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity
2017-01-01

Regulatory T (Treg) cells are critical for the shutdown of immune responses and have emerged as valuable targets of immunotherapies. Treg cells can rapidly proliferate; however, the homeostatic processes that limit excessive Treg cell numbers are poorly understood. Here, we show that, compared to conventional T cells, Treg cells have a high apoptosis rate ex vivo correlating with low c-FLIP expression. Treg-specific deletion of c-FLIP in mice resulted in fatal autoimmune disease of a scurfy-like phenotype characterized by absent peripheral Treg cells, activation of effector cells, multi-organ immune cell infiltration, and premature death. Surprisingly, blocking CD95L did not rescue Treg survival in vivo, suggesting additional survival functions of c-FLIP in Treg cells in addition to its classical role in the inhibition of death receptor signaling. Thus, our data reveal a central role for c-FLIP in Treg cell homeostasis and prevention of autoimmunity.
Biomarkers for Hearing Dysfunction: Facts and Outlook
2017-01-01

In medicine, biomarkers are a metric for disease state. More generally, a biomarker is anything that can be used as an indicator for a particular disease state or any physiological state of an organism. Here, we introduce functional and molecular biomarkers that are useful for categorizing defined subtypes of hearing disorder, which can help to selectively trace a particular dysfunction of the inner ear and the auditory pathway to disease.
The Role of Radical Prostatectomy and Radiotherapy in Treatment of Locally Advanced Prostate Cancer: A Systematic Review and Meta-Analysis
2017-01-01

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; The role of radical prostatectomy (RP) is still controversial for locally advanced prostate cancer (PC). Radiotherapy (RT) and hormonal therapy (HT) are usually used as a primary treatment. &lt;b&gt;&lt;i&gt;Material and Methods: &lt;/i&gt;&lt;/b&gt;A systematic online search was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Eligible publications reporting the overall survival (OS) and/or disease-specific survival (DSS) were included. A total of 14 studies, including 17,869 patients, were considered for analysis. The impact of therapeutic modalities on survival was assessed, with a risk of bias assessment according to the Newcastle Ottawa Scale. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; For RP, RT, and HT, the mean 10-year OS was 70.7% (95% CI 61.3-80.2), 65.8% (95% CI 48.1-83.3), and 22.6% (95% CI 4.9-40.3; &lt;i&gt;p&lt;/i&gt; = 0.001), respectively. The corresponding 10-year DSS was 84.1% (95% CI 75.1-93.2), 89.4% (95% CI 70.1-108.6), and 50.4% (95% CI 31.2-69.6; &lt;i&gt;p&lt;/i&gt; = 0.0127), respectively. Among all treatment combinations, RP displayed significant improvement in OS when included in the treatment (Z = 4.01;&lt;i&gt; p&lt;/i&gt; &lt; 0.001). Adjuvant RT significantly improved DSS (Z = 2.7; &lt;i&gt;p&lt;/i&gt; = 0.007). Combination of RT and HT favored better OS in comparison to monotherapy with RT or HT (Z = 3.61; &lt;i&gt;p&lt;/i&gt; &lt; 0.001). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Improved outcomes in advanced PC were detected for RP plus adjuvant RT vs. RP alone and RT plus adjuvant HT vs. RT alone with comparable survival results between both regimens. RP with adjuvant RT may present the modality of choice when HT is contraindicated.
Electrophysiological Evidence of the Basilar-Membrane Travelling Wave and Frequency Place Coding of Sound in Cochlear Implant Recipients
2017-01-01

&lt;b&gt;&lt;i&gt;Aim:&lt;/i&gt;&lt;/b&gt; To obtain direct evidence for the cochlear travelling wave in humans by performing electrocochleography from within the cochlea in subjects implanted with an auditory prosthesis. &lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Sound induces a travelling wave that propagates along the basilar membrane, exhibiting cochleotopic tuning with a frequency-dependent phase delay. To date, evoked potentials and psychophysical experiments have supported the presence of the travelling wave in humans, but direct measurements have not been made. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Electrical potentials in response to rarefaction and condensation acoustic tone bursts were recorded from multiple sites along the human cochlea, directly from a cochlear implant electrode during, and immediately after, its insertion. These recordings were made from individuals with residual hearing. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Electrocochleography was recorded from 11 intracochlear electrodes in 7 ears from 6 subjects, with detectable responses on all electrodes in 5 ears. Cochleotopic tuning and frequency-dependent phase delay of the cochlear microphonic were demonstrated. The response latencies were slightly shorter than those anticipated which we attribute to the subjects' hearing loss. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Direct evidence for the travelling wave was observed. Electrocochleography from cochlear implant electrodes provides site-specific information on hair cell and neural function of the cochlea with potential diagnostic value.
Slack KNa channels influence dorsal horn synapses and nociceptive behavior
2017-01-01

The sodium-activated potassium channel Slack (Kcnt1, Slo2.2) is highly expressed in dorsal root ganglion neurons where it regulates neuronal firing. Several studies have implicated the Slack channel in pain processing, but the precise mechanism or the levels within the sensory pathway where channels are involved remain unclear. Here, we furthered the behavioral characterization of Slack channel knockout mice and for the first time examined the role of Slack channels in the superficial, pain-processing lamina of the dorsal horn. We performed whole-cell recordings from spinal cord slices to examine the intrinsic and synaptic properties of putative inhibitory and excitatory lamina II interneurons. Slack channel deletion altered intrinsic properties and synaptic drive to favor an overall enhanced excitatory tone. We measured the amplitudes and paired pulse ratio of paired excitatory post-synaptic currents at primary afferent synapses evoked by electrical stimulation of the dorsal root entry zone. We found a substantial decrease in the paired pulse ratio at synapses in Slack deleted neurons compared to wildtype, indicating increased presynaptic release from primary afferents. Corroborating these data, plantar test showed Slack knockout mice have an enhanced nociceptive responsiveness to localized thermal stimuli compared to wildtype mice. Our findings suggest that Slack channels regulate synaptic transmission within the spinal cord dorsal horn and by doing so establishes the threshold for thermal nociception.
Double cuticle barrier in two global pests, the whiteflyTrialeurodes vaporariorumand the bedbugCimex lectularius
2017-01-01

The integument protects the organism against penetration of xenobiotics and water that would potentially interfere with homeostasis. In insects that play key roles in a variety of agricultural and ecological habitats this inward barrier is barely investigated. In order to advance in this field, we studied integumental barrier (cuticle) permeability in the two global pests Trialeurodes vaporariorum (greenhouse whitefly) and Cimex lectularius (bedbug) applying a simple dye-penetration assay. In agreement with our recent findings in Drosophila melanogaster, we show that the surface of these insects is regionalised. We also show that, in contrast to the single barrier in D. melanogaster, two barriers with distinct temperature-sensitive and lipid-based phyisco-chemical material properties act in parallel to protect these insects against penetration of hydrophilic molecules. These findings imply the existence of unexplored mechanisms by which the cuticle acts as a protective coat against penetration of water and xenobiotics including pollutants and insecticides.
Baseline toxicity and ion-trapping models to describe the pH-dependence of bacterial toxicity of pharmaceuticals
2017-01-01

The pH-dependence of cytotoxicity of diverse acidic, basic and multiprotic pharmaceuticals could be explained by baseline toxicity after invoking mixture effects of all species and delayed uptake of charged species.
Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells
2017-01-01

Background/Aims: Key properties of tumor cells include enhanced glycolytic flux with excessive consumption of glucose and formation of lactate. As glycolysis is highly sensitive to cytosolic pH, maintenance of glycolysis requires export of H+ ions, which is in part accomplished by Na+/H+ exchangers, such as NHE1. The carrier is sensitive to oxidative stress. Growth of tumor cells could be suppressed by the polyphenol Ellagic acid, which is found in various fruits and vegetables. An effect of Ellagic acid on transport processes has, however, never been reported. The present study thus elucidated an effect of Ellagic acid on cytosolic pH (pHi), NHE1 transcript levels, NHE1 protein abundance, Na+/H+ exchanger activity, and lactate release. Methods: Experiments were performed in Ishikawa cells without or with prior Ellagic acid (20 μM) treatment. NHE1 transcript levels were determined by qRT-PCR, NHE1 protein abundance by Western blotting, pHi utilizing (2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein [BCECF] fluorescence, Na+/H+ exchanger activity from Na+ dependent realkalinization after an ammonium pulse, cell volume from forward scatter in flow cytometry, reactive oxygen species (ROS) from 2’,7’-dichlorodihydrofluorescein fluorescence, glucose uptake utilizing 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose, and lactate concentration in the supernatant utilizing a colorimetric (570 nm)/ fluorometric enzymatic assay. Results: A 48 hour treatment with Ellagic acid (20 μM) significantly decreased NHE1 transcript levels by 75%, NHE1 protein abundance by 95%, pHi from 7.24 ± 0.01 to 7.02 ± 0.01, Na+/H+ exchanger activity by 77%, forward scatter by 10%, ROS by 82%, glucose uptake by 58%, and lactate release by 15%. Conclusion: Ellagic acid (20μM) markedly down-regulates ROS formation and NHE1 expression leading to decreased Na+/H+ exchanger activity, pHi, glucose uptake and lactate release in endometrial cancer cells. Those effects presumably contribute to reprogramming and growth inhibition of tumor cells.
Energy-Efficiency Optimization of Torque Vectoring Control for Battery Electric Vehicles
2017-01-01

We propose a novel torque vectoring concept for battery electric vehicles propelled by wheelindividual electric machines. Under consideration of vehicle dynamics and electric machine efficiency, this paper focuses on taking advantage of the provided degrees of freedom to reduce energy consumption. The proposed approach improves energy efficiency by introducing two functional elements: Firstly, an optimization problem based on a detailed nonlinear four-wheel vehicle model is solved to create reference sideslip angle and yaw rate that minimize the energy consumption due to wheel slip. A subsequent Linear Quadratic Controller calculates a yaw torque around the vehicle's vertical axis to follow the desired reference. To generate both, the acceleration demanded by the driver and the yaw torque requested by the LQR, a torque allocation algorithm is required. The proposed torque allocation algorithm takes into account the energy efficiency characteristics of the electric machines to provide the required propulsion force and the yaw torque with minimized loss power. Based on experimental results, the proposed torque vectoring control system leads to an energy consumption reduction of around 10% for many typical driving situations containing both, high and low lateral acceleration scenarios.
Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients
2017-01-01

Background: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orai1, a pore forming channel protein accomplishing store operated Ca2+ entry (SOCE). Increased Orai1 expression and SOCE have been shown to confer survival of tumor cells. SOCE could be up-regulated by lithium. The present study explored, whether SOCE and/or apoptosis are altered in ChAc fibroblasts and could be modified by lithium treatment. Methods: Fibroblasts were isolated from ChAc patients and age-matched healthy volunteers. Cytosolic Ca2+ activity ([Ca2+]i) was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 μM), and apoptosis from annexin-V/propidium iodide staining quantified in flow cytometry. Results: SOCE was significantly smaller in ChAc fibroblasts than in control fibroblasts. Lithium (2 mM, 24 hours) significantly increased and Orai1 blocker 2-Aminoethoxydiphenyl Borate (2-APB, 50 μM, 24 hours) significantly decreased SOCE. Annexin-V-binding and propidium iodide staining were significantly higher in ChAc fibroblasts than in control fibroblasts. In ChAc fibroblasts annexin-V-binding and propidium iodide staining were significantly decreased by lithium treatment, significantly increased by 2-APB and virtually lithium insensitive in the presence of 2-APB. Conclusions: In ChAc fibroblasts, downregulation of SOCE contributes to enhanced susceptibility to apoptosis. Both, decreased SOCE and enhanced apoptosis of ChAc fibroblasts can be reversed by lithium treatment.
Extracellular Cyclophilin A Augments Platelet-Dependent Thrombosis and Thromboinflammation
2017-01-01

Abstract Cyclophilin A (CyPA) is involved in the pathophysiology of several inflammatory and cardiovascular diseases. To our knowledge, there is no specific inhibitor targeting extracellular CyPA without affecting other extracellular cyclophilins or intracellular CyPA functions. In this study, we developed an antibody-based inhibitor of extracellular CyPA and analysed its effects in vitro and in vivo. To generate a specific antibody, mice and rats were immunized with a peptide containing the extracellular matrix metalloproteinase inducer binding site and various antibody clones were selected and purified. At first, antibodies were tested for their binding capacity to recombinant CyPA and their functional activity. The clone 8H7-mAb was chosen for further experiments. 8H7-mAb reduced the CyPA-induced migration of inflammatory cells in vitro and in vivo. Furthermore, 8H7-mAb revealed strong antithrombotic effects by inhibiting CyPA-dependent activation of platelets and thrombus formation in vitro and in vivo. Surprisingly, 8H7-mAb did not influence in vivo tail bleeding time or in vitro whole blood coagulation parameters. Our study provides first evidence that antibody-based inhibition of extracellular CyPA inhibits thrombosis and thromboinflammation without affecting blood homeostasis. Thus, 8H7-mAb may be a promising compound for thrombi modulation in inflammatory diseases to prevent organ dysfunction.
Pyrazolates advance cerium chemistry: a CeIII/CeIV redox equilibrium with benzoquinone
2017-01-01

Homoleptic Ce<sup>IV</sup> and Ce<sup>III</sup> 3,5-dimethylpyrazolate (L) complexes react with 1,4-hydroquinone (H<sub>2</sub>hq) and 1,4-benzoquinone (bq), respectively, to form a new O<sub>2</sub>N<sub>2</sub> diolato ligand (phcd) by means of a Ce<sup>III</sup>/Ce<sup>IV</sup> redox equilibrium.