julilili42/papers huggingface dataset:
Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species
2015-01-01

Background/Aims: Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue. Methods: Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor. Results: All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC50 values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat. Conclusion: Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.
NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML
2015-01-01

Natural killer cells have been shown to be relevant in the recognition and lysis of acute myeloid leukemia. In childhood acute lymphoblastic leukemia, it was shown that HLA I expression and KIR receptor-ligand mismatch significantly impact ALL cytolysis. We characterized 14 different primary childhood AML blasts by flow cytometry including NKG2D ligands. Further HLA I typing of blasts was performed and HLA I on the AML blasts was quantified. In two healthy volunteer NK cell donors HLA I typing and KIR genotyping were done. Blasts with high NKG2D ligand expression had significantly higher lysis by isolated NK cells. Grouping the blasts by NKG2D ligand expression led to a significant inverse correlation of HLA I expression and cytolysis in NKG2D low blasts. Furthermore, a significant positive correlation of NKG2D ligand expression and blast cytolysis was shown. No impact of KIR ligand-ligand mismatch was found but a significantly increased lysis of homozygous C2 blasts by KIR2DL1 negative NK cells (donor B) was revealed. In conclusion, NKG2D signaling leads to NK cell mediated lysis of childhood AML despite high HLA I expression.
Platelets and vascular inflammation of the brain
2015-01-01

Summary There is emerging evidence that platelets have an important role in inflammation beyond their involvement in hemostasis. Platelets can contribute to inflammatory reactions via crosstalk both with immune cells and endothelial cells. Inflamed vessels are characterized by the presence of activated endothelial cells. These activated endothelial cells upregulate receptors necessary for leukocyte recruitment, but also for the adhesion of platelets. Subsequently, immune cells can bind to platelets through adhesion receptors presented on the platelet surface, thus supporting leukocyte recruitment to the vessel wall. There are several neurological diseases associated with vascular inflammation including multiple sclerosis (MS) and stroke. Increased markers of platelet activation could be demonstrated in patients suffering from MS compared to healthy individuals. Reports from murine models indicate that platelets may be of importance for disease progression and severity by mediating leukocyte recruitment as one potential underlying mechanism. Blocking platelet function disease severity was considerably ameliorated. Moreover, processes of tissue remodelling may be influenced by platelet derived mediators. Whether a role of platelets for vascular inflammation can be extrapolated to further neurological diseases will have to be investigated in further in depth experimental and clinical trials. Platelets and platelet associated mechanisms may offer novel starting points to understand neurovascular diseases from a different point of view and to develop novel approaches to access the disease.
A Humanized Anti-CD22-Onconase Antibody-Drug Conjugate Mediates Highly Potent Destruction of Targeted Tumor Cells
2015-01-01

Antibody-drug conjugates (ADCs) have evolved as a new class of potent cancer therapeutics. We here report on the development of ADCs with specificity for the B-cell lineage specific (surface) antigen CD22 being expressed in the majority of hematological malignancies. As targeting moiety a previously generated humanized anti-CD22 single-chain variable fragment (scFv) derivative from the monoclonal antibody RFB4 was reengineered into a humanized IgG1 antibody format (huRFB4). Onconase (ranpirnase), a clinically active pancreatic-type ribonuclease, was employed as cytotoxic payload moiety. Chemical conjugation via thiol-cleavable disulfide linkage retained full enzymatic activity and full binding affinity of the ADC. Development of sophisticated purification procedures using size exclusion and ion exchange chromatography allowed the separation of immunoconjugate species with stoichiometrically defined number of Onconase cargos. A minimum of two Onconase molecules per IgG was required for achieving significant in vitro cytotoxicity towards lymphoma and leukemia cell lines. Antibody-drug conjugates with an Onconase to antibody ratio of 3 : 1 exhibited an IC 50 of 0.08 nM, corresponding to more than 18,400-fold increased cytotoxicity of the ADC when compared with unconjugated Onconase. These results justify further development of this ADC as a promising first-in-class compound for the treatment of CD22-positive malignancies.
High-resolution neutron spectroscopy on protein solution samples
2015-01-01

Proteins in solution move subject to a complex superposition of global translational and rotational diffusion as well as internal relaxations covering a wide range of time scales. With the advent of new high-flux neutron spectrometers in combination with enhanced analysis frameworks it has become possible to separate these different contributions. We discuss new approaches to the analysis by presenting example spectra and fits from data recorded on the backscattering spectrometers IN16, IN16B, and BASIS on the same protein solution sample. We illustrate the separation of the rotational and translational diffusion contribution, the accurate treatment of the solvent contribution, and the extraction of information on internal fluctuations. We also exemplify the progress made in passing from second- to third-generation backscattering spectrometers.
A Self-doping Surface Effect and its Influence on the Sensor Performance of Undoped SnO2 Based Gas Sensors
2015-01-01

The variation of the calcination temperature in the fabrication procedure of sol-gel SnO2 thick film gas sensors leads to very different sensing characteristics [1]. In the present studies, the conduction mechanism and electrical characteristics of the surface of undoped SnO2 based sensing materials - calcined at different temperatures - are investigated by performing DC electrical resistance and work function changes measurements. The results show for the first time the existence of an intrinsic surface band bending for undoped SnO2 (calcination temperature 450 °C). Because an intrinsic surface band bending has a big impact on the conduction mechanism and the concentration of surface species, which have an influence on the electrical resistance, the sensing performance is dramatically changed. The effect is similar to 1 at.% Ni surface loading, which showed a huge intrinsic surface band bending and an enhanced sensing performance in comparison to the undoped base material [2].
Levothyroxine Treatment of Euthyroid Children with Autoimmune Hashimoto Thyroiditis: Results of a Multicenter, Randomized, Controlled Trial
2015-01-01

Background: Levothyroxine (L-T4) treatment of euthyroid children with Hashimoto thyroiditis (HT) is a controversial issue. Patients and Methods: We conducted a prospective, randomized, controlled clinical trial. Out of 79 identified euthyroid patients, 59 started the study; 25 patients (21 female, 4 male; age: 11.8 ± 2.3 years) received L-T4 at a mean dose of 1.6 μg/kg (SD, 0.8) daily, and 34 (27 female, 7 male; age: 12.6 ± 1.2 years) were not treated. Patients developing subclinical hypothyroidism during follow-up (n = 13) were treated with L-T4 and removed from the observation group. As the main outcome measures, thyroid gland volume (determined by ultrasound) as well as serum levels of TSH, free T4, and antibodies against thyroid peroxidase and thyroglobulin were assessed every 6 months for 36 months. Results: At the start, the mean thyroid volume (standard deviation score, SDS) was 2.5 in the treatment group and 1.6 in the observation group. There was a constant decline in mean thyroid volume (SDS) from 2.13 (month 12) to 1.12 (month 30) in the treated group, with a delta thyroid volume of -1.01 SDS. In the observation group, the mean delta thyroid volume increased to +0.27 SDS. The change of the delta thyroid volume was statistically significantly different between both groups during the 12- and 30-month time points (p &lt; 0.05). L-T4 had no effect on thyroid function and serum thyroid antibodies. Conclusions: L-T4 treatment can decrease the thyroid volume in euthyroid children with HT, but the effect is limited to a definite time period.
Impact of Phosphorus Restriction and Vitamin D-Substitution on Secondary Hyperparathyroidism in a Proteinuric Mouse Model
2015-01-01

&lt;b&gt;&lt;i&gt;Background/Aims: &lt;/i&gt;&lt;/b&gt;Since the discovery of FGF23, secondary hyperparathyroidism (SHPT) in renal disease has been considered to result primarily from phosphorus retention rather than vitamin D deficiency. However, the impact of phosphorus restriction and vitamin D supplementation on SHPT is still ill defined. &lt;b&gt;&lt;i&gt;Methods: &lt;/i&gt;&lt;/b&gt;We investigated the development of SHPT in a doxorubicin-induced proteinuric mouse model and tested different treatment strategies including a low phosphorus diet and substitution with native or active vitamin D in 129 S1/SvImJ wild-type mice. &lt;b&gt;&lt;i&gt;Results: &lt;/i&gt;&lt;/b&gt;Development of SHPT at day 30 was strongly related to the magnitude of induced proteinuria. In mice with a proteinuria &lt;100 mg/mg creatinine, SHPT was mild (PTH increase 2.4-fold), and serum levels of FGF23, phosphate and urea remained almost stable, whereas mice with heavy proteinuria (&gt;100 mg/mg creatinine) developed marked SHPT (PTH increase 10.1-fold) accompanied by massive increase in FGF23 (27.0-fold increase), hyperphosphatemia (1.8-fold increase), renal failure (7.3-fold urea increase) and depletion of both 25-OH vitamin D and 1,25-OH vitamin D. Substitution with native or active vitamin D was unable to suppress SHPT, whereas a low-phosphorus diet (P&lt;sub&gt;i&lt;/sub&gt; content 0.013%) completely suppressed SHPT in mice with both mild and heavy proteinuria. &lt;b&gt;&lt;i&gt;Conclusions: &lt;/i&gt;&lt;/b&gt;The development of SHPT resulted from phosphate retention in this proteinuric model and could completely be suppressed with a low-phosphorus diet.
Differential toxicity of gold-doxorubicin in cancer cells vs. cardiomyocytes as measured by real-time growth assays and fluorescence lifetime imaging microscopy (FLIM)
2015-01-01

The kinetics of toxicity of doxorubicin (Dox) and gold nanoparticle-conjugated doxorubicin (Au-Dox) were investigated in cultured B16 melanoma cells and cardiomyocytes using real-time cell-growth imaging.
Generation of an alpaca‐derived nanobody recognizing γ‐H2AX
2015-01-01

Post‐translational modifications are difficult to visualize in living cells and are conveniently analyzed using antibodies. Single‐chain antibody fragments derived from alpacas and called nanobodies can be expressed and bind to the target antigenic sites in living cells. As a proof of concept, we generated and characterized nanobodies against the commonly used biomarker for DNA double strand breaks γ‐H2AX. In vitro and in vivo characterization showed the specificity of the γ‐H2AX nanobody. Mammalian cells were transfected with fluorescent fusions called chromobodies and DNA breaks induced by laser microirradiation. We found that alternative epitope recognition and masking of the epitope in living cells compromised the chromobody function. These pitfalls should be considered in the future development and screening of intracellular antibody biomarkers.
Impact of Na+/Ca2+ Exchangers on Therapy Resistance of Ovary Carcinoma Cells
2015-01-01

Background/Aims: According to previous observations, enhanced store-operated Ca2+-entry (SOCE) accomplished by the pore forming ion channel unit Orai1 and its regulator STIM1 contribute to therapy resistance of ovary carcinoma cells. Ca2+ signaling is further shaped by Ca2+ extrusion through K+-independent (NCX) and/or K+-dependent (NCKX) Na+/Ca2+-exchangers. The present study thus explored whether therapy resistance is further paralleled by altered expression and/or function of Na+/Ca2+-exchangers. Methods: In therapy resistant (A2780cis) and therapy sensitive (A2780sens) ovary carcinoma cells transcript levels were estimated from RT-PCR, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, Na+/Ca2+-exchanger activity from the increase of [Ca2+]i (Δ[Ca2+]i) and from whole cell current (Ica) following abrupt replacement of Na+ containing (130 mM) and Ca2+ free extracellular perfusate by Na+ free and Ca2+ containing (2 mM) extracellular perfusate, as well as cell death from PI -staining in flow cytometry. Results: The transcript levels of NCX3, NCKX4, NCKX5, and NCKX6, slope and peak of Δ[Ca2+]i as well as Ica were significantly higher in therapy resistant than in therapy sensitive ovary carcinoma cells. The Na+/Ca2+-exchanger inhibitor KB-R7943 (10 μM) significantly blunted Δ[Ca2+]i and significantly augmented the cisplatin-induced cell death of therapy resistant ovary carcinoma cells without significantly modifying cisplatin-induced cell death of therapy sensitive ovary carcinoma cells. Conclusion: Enhanced Na+/Ca2+-exchanger activity may contribute to the therapy sensitivity of ovary carcinoma cells.
Robot-assisted radical cystectomy and intracorporeal urinary diversion - safe and reproducible?
2015-01-01

RARC with intracorporeal diversion is safe and reproducible in 'non-pioneer' tertiary centers with robotic expertise having acceptable operative time and complications as well as comparable functional and oncologic outcomes.
Pharmacogenetics: Implications for Modern Type 2 Diabetes Therapy
2015-01-01

Many clinical treatment studies have reported remarkable interindividual variability in the response to pharmaceutical drugs, and uncovered the existence of inadequate treatment response, non-response, and even adverse drug reactions. Pharmacogenetics addresses the impact of genetic variants on treatment outcome including side-effects. In recent years, it has also entered the field of clinical diabetes research. In modern type 2 diabetes therapy, metformin is established as first-line drug. The latest pharmaceutical developments, including incretin mimetics, dipeptidyl peptidase 4 inhibitors (gliptins), and sodium/glucose cotransporter 2 inhibitors (gliflozins), are currently experiencing a marked increase in clinical use, while the prescriptions of α-glucosidase inhibitors, sulfonylureas, meglitinides (glinides), and thiazolidinediones (glitazones) are declining, predominantly because of reported side-effects. This review summarizes the current knowledge about gene-drug interactions observed in therapy studies with the above drugs. We report drug interactions with candidate genes involved in the pharmacokinetics (e.g., drug transporters) and pharmacodynamics (drug targets and downstream signaling steps) of the drugs, with known type 2 diabetes risk genes and previously unknown genes derived from hypothesis-free approaches such as genome-wide association studies. Moreover, some new and promising candidate genes for future pharmacogenetic assessment are highlighted. Finally, we critically appraise the current state of type 2 diabetes pharmacogenetics in the light of its impact on therapeutic decisions, and we refer to major problems, and make suggestions for future efforts in this field to help improve the clinical relevance of the results, and to establish genetically determined treatment failure.
Sclerostin Quo Vadis? - Is This a Useful Long-Term Mortality Parameter in Prevalent Hemodialysis Patients?
2015-01-01

&lt;b&gt;&lt;i&gt;Background/Aims: &lt;/i&gt;&lt;/b&gt;Cardiovascular calcification contributes to the increased mortality in hemodialysis patients. Sclerostin was identified as an antianabolic bone factor causing soft tissue calcification. Data on prospective large-scale studies associating sclerostin with mortality in hemodialysis patients are so far inconsistent. &lt;b&gt;&lt;i&gt;Methods: &lt;/i&gt;&lt;/b&gt;In our multicenter prospective longitudinal study following hemodialysis patients, we assessed the associations of sclerostin and bone remodeling markers with long-term mortality. We evaluated the relationship between circulating sclerostin, Fibroblast growth factor 23 (FGF23) and traditional bone remodeling markers. Sclerostin levels in hemodialysis patients were compared with healthy controls. Results: We enrolled 239 hemodialysis patients with a median follow up of 1461 days. In Cox regression analysis, FGF23 (HR 1.40;95%CI 1.11-1.76), parathyroid hormone (PTH) (HR 1.80;95%CI 1.44-2.26) and alkaline phosphatase (AP) (HR 1.50;95%CI 1.10-2.04) per SD, 25(OH)vitamin D (HR 0.42;95%CI 0.23-0.76) per natural log but not sclerostin (HR 1.02;95%CI 0.75-1.38) per SD increase were associated with mortality. FGF23, PTH and AP were negatively associated with sclerostin. Among control and hemodialysis females, sclerostin levels were lower than in men. &lt;b&gt;&lt;i&gt;Conclusion: &lt;/i&gt;&lt;/b&gt;Higher FGF23, PTH, AP and lower 25(OH)vitamin D but not sclerostin predict long-term mortality. Sclerostin was negatively associated with FGF23, PTH and AP and lower in females than in males.
World War II 2.0: Digital memory of fascism in Russia in the aftermath of Euromaidan in Ukraine
2015-01-01

The events in Ukraine in 2013-2014 will have long-lasting ramifications for the future of international security being in essence the end of a post Cold War order. While the scale of Russia's involvement in Ukraine is still debated, the discursive construction of Ukrainian crisis in Russian media undeniably draws heavily on the World War II narrative of fascism. Representing Euromaidan participants as being on the 'wrong side of history' helps bolster an existential threat frame that resonates extremely well on the Post-Soviet space. This paper explores the digital memory of fascism on Russian social media in the aftermath of Euromaidan in Ukraine by analysing debates on Russian segments of social networks, such as Twitter, Livejournal.com and Vkontakte.com.
Pressure Overload by Transverse Aortic Constriction Induces Maladaptive Hypertrophy in a Titin-Truncated Mouse Model
2015-01-01

Mutations in the giant sarcomeric protein titin (TTN) are a major cause for inherited forms of dilated cardiomyopathy (DCM). We have previously developed a mouse model that imitates a TTN truncation mutation we found in a large pedigree with DCM. While heterozygous Ttn knock-in mice do not display signs of heart failure under sedentary conditions, they recapitulate the human phenotype when exposed to the pharmacological stressor angiotensin II or isoproterenol. In this study we investigated the effects of pressure overload by transverse aortic constriction (TAC) in heterozygous (Het) Ttn knock-in mice. Two weeks after TAC, Het mice developed marked impairment of left ventricular ejection fraction<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mo stretchy="false">(</mml:mo><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.05</mml:mn><mml:mo stretchy="false">)</mml:mo></mml:math>, while wild-type (WT) TAC mice did not. Het mice also trended toward increased ventricular end diastolic pressure and volume compared to WT littermates. We found an increase in histologically diffuse cardiac fibrosis in Het compared to WT in TAC mice. This study shows that a pattern of DCM can be induced by TAC-mediated pressure overload in a TTN-truncated mouse model. This model enlarges our arsenal of cardiac disease models, adding a valuable tool to understand cardiac pathophysiological remodeling processes and to develop therapeutic approaches to combat heart failure.
Light sensitivity in a vertebrate mechanoreceptor?
2015-01-01

Using immunohistochemistry and Western blot analysis we demonstrate that melanospin is localised in cells around the central pore of lateral line neuromasts in the African clawed frog, Xenopus laevis. Since melanopsin is a known photoreceptor pigment with diverse functions in vertebrates, we suggest that the lateral line of Xenopus laevis, which is primarily a mechanorecptor, may also be light sensitive. Potential functions of such photosensitivity are discussed, including its role in mediating locomotor responses following dermal illumination.
Bordersearch: An Adaptive Identification of Failure Regions
2015-01-01

The reliability and safety of modern analog devices, e.g. in automotives, aircraft or consumer electronics, is influenced by many input parameters like supply voltage, ambient temperature or load resistances. In certain regions of this large parameter space, the device exhibits degraded performance or it fails completely. The validation of such a device has to find the regions of the input parameter space in which the device misbehaves. However, with several parameters, it is a complex task to determine these regions, especially if parameters interact. In this paper, we present the Bordersearch algorithm, which combines adaptive testing with a machine learning classifier to efficiently determine the border between passing and failing regions in the parameter space. Furthermore, this method enables sophisticated post-processing analysis, e.g. better visualizations and automatic ranking of the parameters according to their influence. This algorithm scales well to a high-dimensional parameter space and is robust against outliers and fuzzy borders. We show the effectiveness of this method on an automotive electromechanical system with eleven input parameters.
Lanthanide complex-incorporated periodic mesoporous organosilica nanospheres with tunable photoluminescence
2015-01-01

Functional DPA (<italic>N</italic>,<italic>N</italic>-bis(trimethoxysilylpropyl)-2,6-pyridine dicarboxamide) can be successfully incorporated into mesoporous silica frameworks of regular spherical morphology to accommodate photoluminescent rare-earth metal centres.