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"text": "\n164081\nHarmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma.\n\nBowden, JA\n\nHeckert, A\n\nUlmer, CZ\n\nJones, CM\n\nKoelmel, JP\n\nAbdullah, L\n\nAhonen, L\n\nAlnouti, Y\n\nArmando, AM\n\nAsara, JM\n\nBamba, T\n\nBarr, JR\n\nBergquist, J\n\nBorchers, CH\n\nBrandsma, J\n\nBreitkopf, SB\n\nCajka, T\n\nCazenave-Gassiot, A\n\nCheca, A\n\nCinel, MA\n\nColas, RA\n\nCremers, S\n\nDennis, EA\n\nEvans, JE\n\nFauland, A\n\nFiehn, O\n\nGardner, MS\n\nGarrett, TJ\n\nGotlinger, KH\n\nHan, J\n\nHuang, Y\n\nNeo, AH\n\nHyötyläinen, T\n\nIzumi, Y\n\nJiang, H\n\nJiang, H\n\nJiang, J\n\nKachman, M\n\nKiyonami, R\n\nKlavins, K\n\nKlose, C\n\nKöfeler, HC\n\nKolmert, J\n\nKoal, T\n\nKoster, G\n\nKuklenyik, Z\n\nKurland, IJ\n\nLeadley, M\n\nLin, K\n\nMaddipati, KR\n\nMcDougall, D\n\nMeikle, PJ\n\nMellett, NA\n\nMonnin, C\n\nMoseley, MA\n\nNandakumar, R\n\nOresic, M\n\nPatterson, R\n\nPeake, D\n\nPierce, JS\n\nPost, M\n\nPostle, AD\n\nPugh, R\n\nQiu, Y\n\nQuehenberger, O\n\nRamrup, P\n\nRees, J\n\nRembiesa, B\n\nReynaud, D\n\nRoth, MR\n\nSales, S\n\nSchuhmann, K\n\nSchwartzman, ML\n\nSerhan, CN\n\nShevchenko, A\n\nSomerville, SE\n\nSt John-Williams, L\n\nSurma, MA\n\nTakeda, H\n\nThakare, R\n\nThompson, JW\n\nTorta, F\n\nTriebl, A\n\nTrötzmüller, M\n\nUbhayasekera, SJK\n\nVuckovic, D\n\nWeir, JM\n\nWelti, R\n\nWenk, MR\n\nWheelock, CE\n\nYao, L\n\nYuan, M\n\nZhao, XH\n\nZhou, S\n\nBeiträge in Fachzeitschriften\nISI:000416963900004\n28986437.0\n10.1194/jlr.M079012\nPMC5711491\nAs the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1, 27 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.\n Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.\n\nKöfeler, Harald\n\nTrötzmüller, Martin\n\n\n"
},
{
"text": "\n164714\nGenome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.\n\nJiang, X\n\nO'Reilly, PF\n\nAschard, H\n\nHsu, YH\n\nRichards, JB\n\nDupuis, J\n\nIngelsson, E\n\nKarasik, D\n\nPilz, S\n\nBerry, D\n\nKestenbaum, B\n\nZheng, J\n\nLuan, J\n\nSofianopoulou, E\n\nStreeten, EA\n\nAlbanes, D\n\nLutsey, PL\n\nYao, L\n\nTang, W\n\nEcons, MJ\n\nWallaschofski, H\n\nVölzke, H\n\nZhou, A\n\nPower, C\n\nMcCarthy, MI\n\nMichos, ED\n\nBoerwinkle, E\n\nWeinstein, SJ\n\nFreedman, ND\n\nHuang, WY\n\nVan Schoor, NM\n\nvan der Velde, N\n\nGroot, LCPGM\n\nEnneman, A\n\nCupples, LA\n\nBooth, SL\n\nVasan, RS\n\nLiu, CT\n\nZhou, Y\n\nRipatti, S\n\nOhlsson, C\n\nVandenput, L\n\nLorentzon, M\n\nEriksson, JG\n\nShea, MK\n\nHouston, DK\n\nKritchevsky, SB\n\nLiu, Y\n\nLohman, KK\n\nFerrucci, L\n\nPeacock, M\n\nGieger, C\n\nBeekman, M\n\nSlagboom, E\n\nDeelen, J\n\nHeemst, DV\n\nKleber, ME\n\nMärz, W\n\nde Boer, IH\n\nWood, AC\n\nRotter, JI\n\nRich, SS\n\nRobinson-Cohen, C\n\nden Heijer, M\n\nJarvelin, MR\n\nCavadino, A\n\nJoshi, PK\n\nWilson, JF\n\nHayward, C\n\nLind, L\n\nMichaëlsson, K\n\nTrompet, S\n\nZillikens, MC\n\nUitterlinden, AG\n\nRivadeneira, F\n\nBroer, L\n\nZgaga, L\n\nCampbell, H\n\nTheodoratou, E\n\nFarrington, SM\n\nTimofeeva, M\n\nDunlop, MG\n\nValdes, AM\n\nTikkanen, E\n\nLehtimäki, T\n\nLyytikäinen, LP\n\nKähönen, M\n\nRaitakari, OT\n\nMikkilä, V\n\nIkram, MA\n\nSattar, N\n\nJukema, JW\n\nWareham, NJ\n\nLangenberg, C\n\nForouhi, NG\n\nGundersen, TE\n\nKhaw, KT\n\nButterworth, AS\n\nDanesh, J\n\nSpector, T\n\nWang, TJ\n\nHyppönen, E\n\nKraft, P\n\nKiel, DP\n\nBeiträge in Fachzeitschriften\nISI:000422650500011\n29343764.0\n10.1038/s41467-017-02662-2\nPMC5772647\nVitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16, 25 to 79, 66 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.\n\nMärz, Winfried\n\nPilz, Stefan\n\n\n"
},
{
"text": "\n184673\nDecrease in gynecological cancer diagnoses during the COVID-19 pandemic: an Austrian perspective.\n\nTsibulak, I\n\nReiser, E\n\nBogner, G\n\nPetru, E\n\nHell-Teutsch, J\n\nReinthaller, A\n\nWeirather, C\n\nWeiss, T\n\nBozsa, S\n\nPuschacher, B\n\nHall, M\n\nHittler, D\n\nHrauda, K\n\nThell, E\n\nClauss, S\n\nPozniak, J\n\nAlicke, S\n\nGangl, D\n\nGamperl, G\n\nEbner, C\n\nKnoll, K\n\nLeitner, K\n\nSchilcher, A\n\nSchinnerl, M\n\nSigl, V\n\nSinger, C\n\nAigmüller, T\n\nHofstätter, B\n\nMarth, C\n\nBeiträge in Fachzeitschriften\nISI:000590754900003\n33033166.0\n10.1136/ijgc-2020-001975\nPMC7656153\nOn March 16, 2020, the federal government of Austria declared a nationwide lockdown due to the COVID-19 pandemic. Since the lockdown, screening examinations and routine checkups have been restricted to prevent the spread of the virus and to increase the hospitals' bed capacity across the country. This resulted in a severe decline of patient referrals to the hospitals.\n To assess the impact of the COVID-19 pandemic on the rate of newly diagnosed gynecological and breast cancers in Austria.\n Data of 2077 patients from 18 centers in Austria with newly diagnosed gynecological or breast cancer between January and May 2019 and January and May 2020 were collected. Clinical parameters, including symptoms, performance status, co-morbidities, and referral status, were compared between the time before and after the COVID-19 outbreak.\n Our results showed a slight increase of newly diagnosed cancers in January and February 2020 as compared with 2019 (+2 and +35%, respectively) and a strong decline in newly diagnosed tumors since the lockdown: -24% in March 2020 versus March 2019, -49% in April 2020 versus April 2019, -49% in May 2020 versus May 2019. Two-thirds of patients diagnosed during the pandemic presented with tumor-specific symptoms compared with less than 50% before the pandemic (p<0.001). Moreover, almost 50% of patients in 2020 had no co-morbidities compared with 35% in 2019 (p<0.001). Patients, who already had a malignant disease, were rarely diagnosed with a new cancer in 2020 as compared with 2019 (11% vs 6%; p<0.001).\n The lockdown led to a decreased number of newly diagnosed gynecological and breast cancers. The decreased accessibility of the medical services and postponed diagnosis of potentially curable cancers during the COVID-19 pandemic may be a step backwards in our healthcare system and might impair cancer treatment outcomes. Therefore, new strategies to manage early cancer detection are needed to optimize cancer care in a time of pandemic in the future.\n © IGCS and ESGO 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.\n\nAigmüller, Thomas\n\nPetru, Edgar\n\n\n"
},
{
"text": "\n186593\nDynamic Control of Mitochondrial Ca<sup>2+</sup> Levels as a Survival Strategy of Cancer Cells.\n\nMadreiter-Sokolowski, CT\n\nGottschalk, B\n\nSokolowski, AA\n\nMalli, R\n\nGraier, WF\n\nBeiträge in Fachzeitschriften\nISI:000619013700001\n33614647.0\n10.3389/fcell.2021.614668\nPMC7889948\nCancer cells have increased energy requirements due to their enhanced proliferation activity. This energy demand is, among others, met by mitochondrial ATP production. Since the second messenger Ca2+ maintains the activity of Krebs cycle dehydrogenases that fuel mitochondrial respiration, proper mitochondrial Ca2+ uptake is crucial for a cancer cell survival. However, a mitochondrial Ca2+ overload induces mitochondrial dysfunction and, ultimately, apoptotic cell death. Because of the vital importance of balancing mitochondrial Ca2+ levels, a highly sophisticated machinery of multiple proteins manages mitochondrial Ca2+ homeostasis. Notably, mitochondria sequester Ca2+ preferentially at the interaction sites between mitochondria and the endoplasmic reticulum (ER), the largest internal Ca2+ store, thus, pointing to mitochondrial-associated membranes (MAMs) as crucial hubs between cancer prosperity and cell death. To investigate potential regulatory mechanisms of the mitochondrial Ca2+ uptake routes in cancer cells, we modulated mitochondria-ER tethering and the expression of UCP2 and analyzed mitochondrial Ca2+ homeostasis under the various conditions. Hence, the expression of contributors to mitochondrial Ca2+ regulation machinery was quantified by qRT-PCR. We further used data from The Cancer Genome Atlas (TCGA) to correlate these in vitro findings with expression patterns in human breast invasive cancer and human prostate adenocarcinoma. ER-mitochondrial linkage was found to support a mitochondrial Ca2+ uptake route dependent on uncoupling protein 2 (UCP2) in cancer cells. Notably, combined overexpression of Rab32, a protein kinase A-anchoring protein fostering the ER-mitochondrial tethering, and UCP2 caused a significant drop in cancer cells' viability. Artificially enhanced ER-mitochondrial tethering further initiated a sudden decline in the expression of UCP2, probably as an adaptive response to avoid mitochondrial Ca2+ overload. Besides, TCGA analysis revealed an inverse expression correlation between proteins stabilizing mitochondrial-ER linkage and UCP2 in tissues of human breast invasive cancer and prostate adenocarcinoma. Based on these results, we assume that cancer cells successfully manage mitochondrial Ca2+ uptake to stimulate Ca2+-dependent mitochondrial metabolism while avoiding Ca2+-triggered cell death by fine-tuning ER-mitochondrial tethering and the expression of UCP2 in an inversed manner. Disruption of this equilibrium yields cancer cell death and may serve as a treatment strategy to specifically kill cancer cells.\n Copyright © 2021 Madreiter-Sokolowski, Gottschalk, Sokolowski, Malli and Graier.\n\nGottschalk, Benjamin\n\nGraier, Wolfgang\n\nMadreiter-Sokolowski, Corina\n\nMalli, Roland\n\nSokolowski, Armin\n\n\n"
},
{
"text": "\n186\nDose increase augments response rate to interferon-alpha in chronic hepatitis C.\n\nFerenci, P\n\nStauber, R\n\nPropst, A\n\nFiedler, R\n\nMüller, C\n\nGschwantler, M\n\nSchütze, K\n\nDatz, C\n\nJudmaier, G\n\nVogel, W\n\nKrejs, GJ\n\nGangl, A\n\nBeiträge in Fachzeitschriften\nISI:A1996WC42200015\n9011466.0\n10.1007/BF02087884\nNone\nApproximately 50% of patients with chronic hepatitis C respond to treatment with interferon-alpha. The aim of this randomized controlled trial was to evaluate whether an increase in dose of interferon-alpha augments response rate. One hundred thirty-eight patients with newly diagnosed chronic hepatitis C received a three-month course of 3 MU IFN-alpha2b administered every two days. All patients were anti-HCV and HCV-RNA (PCR) positive. Prior to treatment, a liver biopsy was performed. Complete response was defined by normal serum ALT concentrations and disappearance of HCV-RNA. After three months, 60 nonresponders were randomized (stratified according to histology) either to continue 3 MU interferon-alpha2b every two days for another six months (group A, total dose: 410 MU) or to receive increasing doses of interferon-alpha2b (6 MU every two days for three months, followed by 10 MU every two days for three months) (group B, total dose: 870 MU). Serum ALT concentrations were measured monthly and HCV-RNA at three-month intervals. Liver biopsy was repeated six months after end of treatment. Pretreatment characteristics of the randomized patients were: group A: N = 30; male/female: 20/10; age: 54 +/- 10 years; CPH 9, CAH 8, cirrhosis 13; mean ALT 108 +/- 98 units/liter; group B: N = 30; male/female: 21/9; age: 57 +/- 15 years; CPH 10, CAH 9, cirrhosis 11; mean ALT 90 +/- 40 units/liter. At the end of treatment six patients in group B but none in group A became responders [P = 0.011 (Fisher's exact test), intent-to-treat analysis]. All six responders were noncirrhotics. High-dose interferon was not tolerated by six patients in group B. Noncompliance resulted in five dropouts in group A and one in group B. During the six-month follow-up, four of the six responders relapsed. A patient in group A with increased serum ALT concentration but negative HCV-RNA at the end of treatment became a full responder after six months. Of nonresponders to 3 MU interferon alpha2b every two days for three months, 20% responded to higher interferon doses, but none to continued standard dose. Prolonged treatment with interferon may be necessary to obtain a sustained response. However, treatment with higher-dose interferon was not tolerated in 20% of the patients.\n\nKrejs, Günter Josef\n\nStauber, Rudolf\n\n\n"
},
{
"text": "\n63160\nInterventional occlusion of interatrial communication after modified Fontan operation\n\nGamillscheg, A\n\nBeitzke, A\n\nStein, JI\n\nZobel, G\n\nRödl, S\n\nZartner, P\n\nBeiträge in Fachzeitschriften\nISI:000175254000004\n12063702.0\n10.1007/s003920200031\nNone\nAfter modified Fontan operations various communications between the systemic and pulmonary venous returns may cause persistent or increasing postoperative cyanosis. Interventional closure of these right-to-left shunts may be necessary to eliminate hypoxemia and to reduce the risk of paradoxical embolic complications. PATIENTS AND METHODS: Eighteen patients with a mean age of 5.6 +/- 4.1 (2.5-17.5) years underwent interventional closure of a right-to-left shunt 17.4 +/- 15.8 (3-60) months after a modified Fontan operation. After test balloon occlusion fenestrations were closed in 13 patients using an Amplatzer Septal occluder (n = 7), a Rashkind PDA occluder (n = 3), a CardioSeal umbrella (n = 1) and detachable coils (n = 2). Residual leaks at the suture lines between the interatrial patch and the right atrial wall were closed using detachable coils and a Rashkind PDA occluder in 2 and 1 patients, respectively. In 3 patients intracardiac venous collateral channels were closed by means of detachable coils. RESULTS: The mean aortic oxygen saturation increased from 85 +/- 4.5 (70-89)% to 91.4 +/- 2.8 (83-95)% (p < 0.001) breathing room air and the mean tunnel pressure rose from 10.7 +/- 1.8 (6-14) mmHg to 12.1 +/- 2.4 (6-16) mmHg (p < 0.001). Calculated Qs decreased from 5.15 +/- 2.1 (2.1-11.3) l/min/m2 to 3.6 +/- 1.0 (1.8-5.6) l/min/m2 (p < 0.001). Mixed venous saturation (66.4 +/- 7.4% vs 65 +/- 7%) and mean systemic arterial pressure (73 +/- 8 mmHg vs 73 +/- 9 mmHg) remained unchanged. In one patient an additional leak of the tunnel could not be closed because of an increase to more than 18 mmHg of the mean pressure in the lateral tunnel during balloon test occlusion. In 2 patients residual leaks after umbrella and coil occlusion of a fenestration and an additional venous collateral channel were closed by means of coils after 16 and 21 months, respectively. At a follow-up of 42 +/- 23 (7-99) months, mean oxygen saturation measured by pulse oxymetry was 93 +/- 2 (90-97)%. In 2 patients color-coded Doppler echocardiography revealed a minimal residual right-to-left shunt. In 2 patients contrast echocardiography demonstrated the additional presence of intrapulmonary fistulas. All patients remained free from device migration, thromboembolic events and hemolysis. CONCLUSION: After modified Fontan operations various right-to-left shunts between the systemic and pulmonary venous returns can be successfully closed using umbrella devices or coils to eliminate cyanosis and to reduce the risk of paradoxical embolism.\n\nGamillscheg, Andreas\n\nRoedl, Siegfried\n\n\n"
},
{
"text": "\n151301\n3'-deoxy-3'-18F-fluorothymidine PET and MRI for early survival predictions in patients with recurrent malignant glioma treated with bevacizumab.\n\nSchwarzenberg, J\n\nCzernin, J\n\nCloughesy, TF\n\nEllingson, BM\n\nPope, WB\n\nGeist, C\n\nDahlbom, M\n\nSilverman, DH\n\nSatyamurthy, N\n\nPhelps, ME\n\nChen, W\n\nBeiträge in Fachzeitschriften\nISI:000298660900017\n22159180.0\n10.2967/jnumed.111.092387\nPMC3424269\nWith the dismal prognosis for malignant glioma patients, survival predictions become key elements in patient management. This study compares the value of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and MRI for early outcome predictions in patients with recurrent malignant glioma on bevacizumab therapy.\n Thirty patients treated with bevacizumab combination therapy underwent (18)F-FLT PET immediately before and at 2 and 6 wk after the start of treatment. A metabolic treatment response was defined as a decrease of equal to or greater than 25% in tumor (18)F-FLT uptake (standardized uptake values) from baseline using receiver-operating-characteristic analysis. MRI treatment response was assessed at 6 wk according to the Response Assessment in Neurooncology criteria. (18)F-FLT responses at different times were compared with MRI response and correlated with progression-free survival and overall survival using Kaplan-Meier analysis. Metabolic response based on (18)F-FLT was further compared with other outcome predictors using Cox regression analysis.\n Early and late changes in tumor (18)F-FLT uptake were more predictive of overall survival than MRI criteria (P < 0.001 and P = 0.01, respectively). (18)F-FLT uptake changes were also predictive of progression-free survival (P < 0.001). The median overall survival for responders was 3.3 times longer than for nonresponders based on (18)F-FLT PET criteria (12.5 vs. 3.8 mo, P < 0.001) but only 1.4 times longer using MRI assessment (12.9 vs. 9.0 mo, P = 0.05). On the basis of the 6-wk (18)F-FLT PET response, there were 16 responders (53%) and 14 nonresponders (47%), whereas MRI identified 9 responders (7 partial response, 2 complete response, 31%) and 20 nonresponders (13 stable disease, 7 progressive disease, 69%). In 7 of the 8 discrepant cases between MRI and PET, (18)F-FLT PET was able to demonstrate response earlier than MRI. Among various outcome predictors, multivariate analysis identified (18)F-FLT PET changes at 6 wk as the strongest independent survival predictor (P < 0.001; hazard ratio, 10.051).\n Changes in tumor (18)F-FLT uptake were highly predictive of progression-free and overall survival in patients with recurrent malignant glioma on bevacizumab therapy. (18)F-FLT PET seems to be more predictive than MRI for early treatment response.\n\nSchwarzenberg, Johannes\n\n\n"
},
{
"text": "\n154227\n[Sacral Skin Elasticity - Establishing a Non-Invasive Mechanical Method for Measurement].\n\nDahmann, S\n\nLebo, PB\n\nGörlich, D\n\nMeyer-Marcotty, MV\n\nBeiträge in Fachzeitschriften\nISI:000383278000004\n27547929.0\n10.1055/s-0042-104118\nNone\nSome patients with sacral scars, e. g. those developing after pilonidal sinus surgery, report discomfort when sitting or putting strain on the scars. In order to establish objective criteria for the assessment of this kind of discomfort and for the evaluation of scar quality after various types of surgical interventions, it is of interest to provide a method which enables physicians to assess skin quality in the sacral region. For this purpose, we developed a mechanical, non-invasive, fast and cost-neutral method for the measurement of skin distensibility and mobility. We examined a healthy sample of 100 study participants to establish benchmark values for scar-free skin in the sacral region and to identify the factors which impact skin quality, e. g. age, weight and sex.\n With the participant in a standing position, 4 vertically arranged measurement points, which are exactly spaced in cranial to caudal direction by 10 mm-100 mm-10 mm, are marked in the lumbar and sacral region, respectively. The participant is then asked to bend forward and - with arms and legs fully stretched on both sides - to touch both their patellae with the balls of their hands so that the distance between the measurement points can be measured in this position as well. Then, with the participant standing upright again, another measurement is taken to establish the distance by which the lowest point can be manually moved in cranial direction.\n The sacral-lumbar skin distension quotient (lumbar skin distension / sacral skin distension×100), which can easily be calculated from the measurements, is independent of age and BMI and has a standard range of about 80-93%. Sacral skin mobility ranges from 11 to 18 mm, but is slightly negatively influenced by a high BMI.\n By comparing lumbar and sacral skin distension in the same study participant, we are able to obtain intraindividually valid findings about possible changes in skin and scar quality. Owing to the lack of known published data about sacral skin elasticity, the proposed measurement method, while restricted to a number of special cases, seems to be practicable and independent of the patient's general condition. Compared with devices that have been used for the measurement of elasticity in other skin areas, our procedure is generally available and cost-neutral.\n © Georg Thieme Verlag KG Stuttgart · New York.\n\nLebo, Patricia Beatrice\n\n\n"
},
{
"text": "\n159051\nTopotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR).\n\nSehouli, J\n\nChekerov, R\n\nReinthaller, A\n\nRichter, R\n\nGonzalez-Martin, A\n\nHarter, P\n\nWoopen, H\n\nPetru, E\n\nHanker, LC\n\nKeil, E\n\nWimberger, P\n\nKlare, P\n\nKurzeder, C\n\nHilpert, F\n\nBelau, AK\n\nZeimet, A\n\nBover-Barcelo, I\n\nCanzler, U\n\nMahner, S\n\nMeier, W\n\nBeiträge in Fachzeitschriften\nISI:000392825100015\n27789470.0\n10.1093/annonc/mdw418\nNone\nRandomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC).\n Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m2/ days 1-3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points.\n A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4-10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4-27.6 resp. 26.0-36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia.\n The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.\n © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.\n\nPetru, Edgar\n\n\n"
},
{
"text": "\n163042\nPreparing for the crewed Mars journey: microbiota dynamics in the confined Mars500 habitat during simulated Mars flight and landing.\n\nSchwendner, P\n\nMahnert, A\n\nKoskinen, K\n\nMoissl-Eichinger, C\n\nBarczyk, S\n\nWirth, R\n\nBerg, G\n\nRettberg, P\n\nBeiträge in Fachzeitschriften\nISI:000412135200001\n28974259.0\n10.1186/s40168-017-0345-8\nPMC5627443\nThe Mars500 project was conceived as the first full duration simulation of a crewed return flight to Mars. For 520 days, six crew members lived confined in a specifically designed spacecraft mock-up. The herein described "MIcrobial ecology of Confined Habitats and humAn health" (MICHA) experiment was implemented to acquire comprehensive microbiota data from this unique, confined manned habitat, to retrieve important information on the occurring microbiota dynamics, the microbial load and diversity in the air and on various surfaces. In total, 360 samples from 20 (9 air, 11 surface) locations were taken at 18 time-points and processed by extensive cultivation, PhyloChip and next generation sequencing (NGS) of 16S rRNA gene amplicons.\n Cultivation assays revealed a Staphylococcus and Bacillus-dominated microbial community on various surfaces, with an average microbial load that did not exceed the allowed limits for ISS in-flight requirements indicating adequate maintenance of the facility. Areas with high human activity were identified as hotspots for microbial accumulation. Despite substantial fluctuation with respect to microbial diversity and abundance throughout the experiment, the location within the facility and the confinement duration were identified as factors significantly shaping the microbial diversity and composition, with the crew representing the main source for microbial dispersal. Opportunistic pathogens, stress-tolerant or potentially mobile element-bearing microorganisms were predicted to be prevalent throughout the confinement, while the overall microbial diversity dropped significantly over time.\n Our findings clearly indicate that under confined conditions, the community structure remains a highly dynamic system which adapts to the prevailing habitat and micro-conditions. Since a sterile environment is not achievable, these dynamics need to be monitored to avoid spreading of highly resistant or potentially pathogenic microorganisms and a potentially harmful decrease of microbial diversity. If necessary, countermeasures are required, to maintain a healthy, diverse balance of beneficial, neutral and opportunistic pathogenic microorganisms. Our results serve as an important data collection for (i) future risk estimations of crewed space flight, (ii) an optimized design and planning of a spacecraft mission and (iii) for the selection of appropriate microbial monitoring approaches and potential countermeasures, to ensure a microbiologically safe space-flight environment.\n\nKoskinen Mora, Kaisa\n\nMahnert, Alexander\n\nMoissl-Eichinger, Christine\n\n\n"
},
{
"text": "\n177334\n2019 ARIA Care pathways for allergen immunotherapy\n\nBousquet, J\n\nPfaar, O\n\nTogias, A\n\nSchunemann, HJ\n\nAnsotegui, I\n\nPapadopoulos, NG\n\nTsiligianni, I\n\nAgache, I\n\nAnto, JM\n\nBachert, C\n\nBedbrook, A\n\nBergmann, KC\n\nBosnic-Anticevich, S\n\nBosse, I\n\nBrozek, J\n\nCalderon, M\n\nCanonica, GW\n\nCaraballo, L\n\nCardona, V\n\nCasale, T\n\nCecchi, L\n\nChu, DK\n\nCosta, E\n\nCruz, AA\n\nCzarlewski, W\n\nDurham, SR\n\nDu Toit, G\n\nDykewicz, M\n\nEbisawa, M\n\nFauquert, JL\n\nFernandez-Rivas, M\n\nFokkens, WJ\n\nFonseca, J\n\nFontaine, JF\n\nvan Wijk, RG\n\nHaahtela, T\n\nHalken, S\n\nHellings, PW\n\nIerodiakonou, D\n\nIinuma, T\n\nIvancevich, JC\n\nJacobsen, L\n\nJutel, M\n\nKaidashev, I\n\nKhaitov, M\n\nKalayci, O\n\nTebbe, JK\n\nKlimek, L\n\nKowalski, ML\n\nKuna, P\n\nKvedariene, V\n\nLa Grutta, S\n\nLarenas-Linemann, D\n\nLau, S\n\nLaune, D\n\nLe, L\n\nCarlsen, KL\n\nLourenco, O\n\nMalling, HJ\n\nMarien, G\n\nMenditto, E\n\nMercier, G\n\nMullol, J\n\nMuraro, A\n\nO'Hehir, R\n\nOkamoto, Y\n\nPajno, GB\n\nPark, HS\n\nPanzner, P\n\nPassalacqua, G\n\nPham-Thi, N\n\nRoberts, G\n\nRolland, C\n\nRosario, N\n\nRyan, D\n\nSamolinski, B\n\nSanchez-Borges, M\n\nScadding, G\n\nShamji, MH\n\nSheikh, A\n\nSturm, GJ\n\nBom, AT\n\nToppila-Salmi, S\n\nValentin-Rostan, M\n\nValiulis, A\n\nValovirta, E\n\nVentura, MT\n\nWahn, U\n\nWalker, S\n\nWallace, D\n\nWaserman, S\n\nYorgancioglu, A\n\nZuberbier, T\n\nBeiträge in Fachzeitschriften\nISI:000484750400003\nNone\n10.5414/ALX02096\nNone\nAllergen immunotherapy (MT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence- based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including health professionals. The decision to prescribe MT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as on the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomaikers that can predict MT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate phannacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow up of patients.\n\nSturm, Gunter\n\n\n"
},
{
"text": "\n181325\nComputational modeling of cardiac growth and remodeling in pressure overloaded hearts-Linking microstructure to organ phenotype.\n\nNiestrawska, JA\n\nAugustin, CM\n\nPlank, G\n\nBeiträge in Fachzeitschriften\nISI:000527368300003\n32058078.0\n10.1016/j.actbio.2020.02.010\nPMC7311197\nCardiac growth and remodeling (G&R) refers to structural changes in myocardial tissue in response to chronic alterations in loading conditions. One such condition is pressure overload where elevated wall stresses stimulate the growth in cardiomyocyte thickness, associated with a phenotype of concentric hypertrophy at the organ scale, and promote fibrosis. The initial hypertrophic response can be considered adaptive and beneficial by favoring myocyte survival, but over time if pressure overload conditions persist, maladaptive mechanisms favoring cell death and fibrosis start to dominate, ultimately mediating the transition towards an overt heart failure phenotype. The underlying mechanisms linking biological factors at the myocyte level to biomechanical factors at the systemic and organ level remain poorly understood. Computational models of G&R show high promise as a unique framework for providing a quantitative link between myocardial stresses and strains at the organ scale to biological regulatory processes at the cellular level which govern the hypertrophic response. However, microstructurally motivated, rigorously validated computational models of G&R are still in their infancy. This article provides an overview of the current state-of-the-art of computational models to study cardiac G&R. The microstructure and mechanosensing/mechanotransduction within cells of the myocardium is discussed and quantitative data from previous experimental and clinical studies is summarized. We conclude with a discussion of major challenges and possible directions of future research that can advance the current state of cardiac G&R computational modeling. STATEMENT OF SIGNIFICANCE: The mechanistic links between organ-scale biomechanics and biological factors at the cellular size scale remain poorly understood as these are largely elusive to investigations using experimental methodology alone. Computational G&R models show high promise to establish quantitative links which allow more mechanistic insight into adaptation mechanisms and may be used as a tool for stratifying the state and predict the progression of disease in the clinic. This review provides a comprehensive overview of research in this domain including a summary of experimental data. Thus, this study may serve as a basis for the further development of more advanced G&R models which are suitable for making clinical predictions on disease progression or for testing hypotheses on pathogenic mechanisms using in-silico models.\n Copyright © 2020. Published by Elsevier Ltd.\n\nAugustin, Christoph\n\nNiestrawska, Justyna Anna\n\nPlank, Gernot\n\n\n"
},
{
"text": "\n182324\nLoss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma.\n\nCubero, FJ\n\nMohamed, MR\n\nWoitok, MM\n\nZhao, G\n\nHatting, M\n\nNevzorova, YA\n\nChen, C\n\nHaybaeck, J\n\nde Bruin, A\n\nAvila, MA\n\nBoekschoten, MV\n\nDavis, RJ\n\nTrautwein, C\n\nBeiträge in Fachzeitschriften\nISI:000538096600005\n32490320.0\n10.1002/hep4.1495\nPMC7262317\nTargeted inhibition of the c-Jun N-terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO)hepatocyte-specific knockout (Δhepa) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMOΔhepa/JNK1Δhepa mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMOΔhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.\n © 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.\n\nHaybäck, Johannes\n\n\n"
},
{
"text": "\n182935\nFetal Inflammatory Response Syndrome and Cerebral Oxygenation During Immediate Postnatal Transition in Preterm Neonates.\n\nWolfsberger, CH\n\nBruckner, M\n\nBaik-Schneditz, N\n\nSchwaberger, B\n\nMileder, LP\n\nAvian, A\n\nUrlesberger, B\n\nPichler, G\n\nBeiträge in Fachzeitschriften\nISI:000559351800001\n32793528.0\n10.3389/fped.2020.00401\nPMC7387571\nIntroduction: Fetal inflammatory response syndrome (FIRS), defined as elevated umbilical cord blood interleukin-6 (IL-6) values > 11 pg/ml, is associated with an increased risk of neonatal morbidity and mortality. The primary aim of the present study was to evaluate a potential influence of FIRS on cerebral oxygen saturation (crSO2) and fractional tissue oxygen extraction (cFTOE) during immediate postnatal transition in preterm neonates. The secondary aim was to analyze the potential influence of FIRS on cerebral injury and mortality. Methods: Secondary outcome parameters of prospective observational studies were analyzed. Preterm neonates with measured IL-6 values from umbilical cord blood and cerebral near-infrared spectroscopy (NIRS) measurements during immediate transition after birth were included. Preterm neonates with FIRS (FIRS group) were matched 1:1 for gestational age (± 1 week) to preterm neonates without FIRS (non-FIRS group). crSO2, cFTOE, arterial oxygen saturation (SpO2), heart rate (HR), and fraction of inspired oxygen (FiO2) were compared between both groups. In addition, cerebral injury and mortality were compared between both groups. Results: A total of 46 preterm neonates were included. Twenty-three neonates in the FIRS group [median gestational age 32.1 (IQR 30.3-33.0) weeks; median IL-6 19.7 (IQR 12.2-37.0) pg/ml] were compared to 23 neonates in the non-FIRS group [gestational age: 32.0 (30.4-33.1) weeks; IL-6: 5.4 (3.0-6.7) pg/ml]. cFTOE showed significantly lower values within the first 4 min and a trend toward lower values in minute 5 after birth in the FIRS group. There were no significant differences in crSO2 within the first 15 min after birth between the two groups. SpO2 was significantly lower in minutes 5 and 6 and HR was significantly lower in minutes 2 and 4 after birth in the FIRS group compared to the non-FIRS group. Survival without cerebral injury was similar in both groups. Conclusion: In preterm neonates with FIRS the crSO2 was similar despite significantly lower cFTOE values during the first minutes after birth. This observation may be a result of compromised oxygen consumption and delivery in the first minutes after birth in neonates with FIRS.\n Copyright © 2020 Wolfsberger, Bruckner, Baik-Schneditz, Schwaberger, Mileder, Avian, Urlesberger and Pichler.\n\nAvian, Alexander\n\nBaik-Schneditz, Nariae\n\nBruckner, Marlies\n\nMileder, Lukas Peter\n\nPichler, Gerhard\n\nSchwaberger, Bernhard Christian\n\nUrlesberger, Berndt\n\nWolfsberger, Christina H.\n\n\n"
},
{
"text": "\n87\nA rapid immunocytochemical assay for CMV detection in peripheral blood of organ-transplanted patients in clinical practice.\n\nHalwachs, G\n\nZach, R\n\nPogglitsch, H\n\nHolzer, H\n\nTiran, A\n\nIberer, F\n\nWasler, A\n\nTscheliessnigg, HP\n\nLanzer, G\n\nFölsch, B\n\nBeiträge in Fachzeitschriften\nISI:A1993LT25000016\n8395099.0\n10.1097/00007890-199308000-00016\nNone\nThis study describes clinical experience with a rapid method for diagnosis of cytomegalovirus infection in organ-transplanted patients, based on the detection of CMV-specific antigens in peripheral polymorphonuclear cells with a mixture of monoclonal antibodies. This CMV-pp65 assay was formerly called the "CMV immediate early antigen assay." A group of 180 organ-transplanted patients were examined with this assay; 75 of them could be observed from the date of transplantation. These 75 patients consisted of two groups: 59 kidney transplant patients receiving no CMV hyperimmunoglobulin prophylaxis (group I), 13 heart-transplanted patients, and 3 liver transplanted patients receiving prophylaxis (group II). Group III consisted of 105 patients who had been transplanted ca. 2 years before starting this study. In group I, 26 (44%) were CMV-pp65-positive (13 primary and 13 secondary infections). Fifteen of these 26 (58%) positive patients showed clinical symptoms of CMV infection. Eleven of these 15 (73%) were primary infections. Symptomatic patients had significantly more CMV-pp65-positive cells than asymptomatic patients; 12 patients showed a high number of positive cells and 11 of them developed severe CMV illness. Thirty-three patients were CMV-pp-65-negative (22 CMV IgG-sero-positive, 11 CMV IgG-seronegative). None of them had symptoms of CMV infection. In all patients of group I there were 36 periods of graft dysfunction in which CMV infection had to be differentiated from transplant rejection. In 10 out of 36 there was a CMV-pp65-positive test result and subsequent seroconversion. Treatment of viral infection resulted in improvement of clinical problems. In the remaining 26 episodes no CMV-pp65-positive cells were detected: in 17 cases graft dysfunction was caused by rejection, in 9 cases by other complications. In group II, 13 of 16 patients (81%) were positive in the CMV-pp65 assay (6 primary infections, 7 secondary infections). However, none of them showed clinical signs of CMV infection, regardless of the number of positive cells. No CMV-related graft dysfunction was observed. In group III, CMV infections did not play an important role. The experiences described suggest that this test is a valuable tool in early CMV diagnosis and in differentiating CMV-dependent graft dysfunction from other graft dysfunctions. It allows prompt therapeutic intervention.\n\nHolzer, Herwig\n\nLanzer, Gerhard\n\n\n"
},
{
"text": "\n6275\nRisk factors for vertebral deformities in men: relationship to number of vertebral deformities. European Vertebral Osteoporosis Study Group.\n\nIsmail, AA\n\nO'Neill, TW\n\nCooper, C\n\nSilman, AJ\n\nBeiträge in Fachzeitschriften\nISI:000085212800011\n10703929.0\n10.1359/jbmr.2000.15.2.278\nNone\nRecent epidemiological studies suggest a similar overall prevalence of vertebral deformity in men to that in women, though the influence of increasing age on the prevalence of vertebral deformity is less marked in men. However, most affected men have only a single or two vertebral deformities, which may be unrelated to osteoporosis. The aim of this study was to examine the role of risk factors, previously demonstrated to be associated with vertebral osteoporosis in females, in men with single/dual deformities compared to those with multiple deformities. Age stratified random samples of men aged 50 years and over were recruited from population registers in 30 European centers as part of the European Vertebral Osteoporosis Study (EVOS). Subjects had a lateral spinal radiograph and the presence of vertebral deformity was determined using the McCloskey algorithm. Lifestyle and other risk factor data were obtained from an interviewer-administered questionnaire. In all 6937 men with a mean age of 64.4 (SD = 8.5) years were studied of whom 738 (10.6%) subjects had one or two deformities, and 109 (1.6%) subjects had three or more deformities. There was a marked increase in the prevalence of multiple vertebral deformities with increasing age, but only a modest effect of age on the prevalence of single deformities. Associations between various risk factors for osteoporosis and vertebral deformity were analyzed separately in men with single/dual vertebral deformity from those with three or more deformities using logistic regression. After adjustment for age, there were statistically significant associations between the following risk factors and multiple deformities: previous hip fracture (odds ratio [OR] 10.5), lack of regular physical activity (OR 2.9), low body mass (OR 2.5), and previous steroid use (OR 2.3). By contrast, there were only weak associations with these same variables in males with single/dual deformities and, apart from poor self-reported general health, all of the 95% confidence intervals spanned unity. There was no difference in the reporting of very heavy levels of physical activity under the age of 50 years between men with single/dual deformities and those with multiple deformities. In conclusion, men with multiple deformities showed a similar pattern of risk factor association to those seen in women with vertebral deformity, in contrast to men with single/dual deformities.\n\nWeber, Kurt\n\n\n"
},
{
"text": "\n8778\nEffect of exogenous 5,8,11,14,17-eicosapentaenoic acid on cardiac anaphylaxis.\n\nJuan, H\n\nPeskar, BA\n\nSimmet, T\n\nBeiträge in Fachzeitschriften\nISI:A1987F840200004\n2881590.0\n10.1111/j.1476-5381.1987.tb08961.x\nPMC1916950\nThe effects of infusions of eicosapentaenoic acid (EPA) (6 X 10(-8) mol min-1 and 15 X 10(-8) mol min-1) on the coronary constriction and the release of immunoreactive sulphidopeptide-leukotrienes (SP-LT), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) from perfused anaphylactic guinea-pig hearts were investigated. EPA dose-dependently inhibited the profound early coronary flow reduction after antigen injection. The less pronounced late phase of anaphylactic coronary flow reduction was, however, not significantly affected. EPA (15 X 10(-8) mol min-1) significantly shortened the average duration of antigen-induced arrhythmias. EPA dose-dependently decreased release of immunoreactive TXB2 and 6-keto-PGF1 alpha from anaphylactic guinea-pig hearts. Release of immunoreactive SP-LT was dose-dependently increased after antigen challenge in the presence of EPA. Inhibiton of the release of SP-LT by the lipoxygenase inhibitor esculetin (1 X 10(-7) mol min-1) was accompanied by a significant attenuation of flow reduction during the late phase of anaphylactic vasoconstriction. Reversed phase h.p.l.c. of perfusates from anaphylactic guinea-pig hearts revealed immunoreactivity comigrating with authentic leukotriene C4 (LTC4), LTD4, and LTE4. In perfusates from hearts treated with EPA infusions, additional immunoreactivity was detected comigrating with LTC5, LTD5 and LTE5. In addition to immunoreactivity migrating with LTB4, as observed in control heart perfusates, in perfusates from EPA-treated hearts, a second peak was observed, which coincides with the retention time described for LTB5. Exogenous LTC5 (1 X 10(-12) mol min-1 and 20 X 10(-12) mol min-1) induced dose-dependent reductions of coronary flow and was found to be a slightly weaker constrictor than LTC4, but no significant differences were observed. Coronary vasoconstriction elicited by infusion of exogenous LTC4 (20 X 10(-12) mol min-1) was dose-dependently inhibited by infusions of EPA. However, the negative inotropic effect of LTC4 remained unaffected. Thus, in the isolated anaphylactic heart of the guinea-pig exogenous EPA was effectively metabolized via the 5-lipoxygenase pathway whereas the cyclo-oxygenase pathway of polyunsaturated fatty acid metabolism was found to be inhibited. The results are in agreement with the suggestion that cyclo-oxygenase products are mediators of the early phase of the anaphylactic coronary constriction, while vasoconstrictor SP-LT are involved in the later phase. However, in spite of enhanced release of SP-LT, EPA infusion did not result in increased coronary constriction.(ABSTRACT TRUNCATED AT 400 WORDS)\n\nPeskar, Bernhard\n\n\n"
},
{
"text": "\n88052\nThrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.\n\nHacke, W\n\nKaste, M\n\nBluhmki, E\n\nBrozman, M\n\nDávalos, A\n\nGuidetti, D\n\nLarrue, V\n\nLees, KR\n\nMedeghri, Z\n\nMachnig, T\n\nSchneider, D\n\nvon Kummer, R\n\nWahlgren, N\n\nToni, D\n\nECASS Investigators\n\nBeiträge in Fachzeitschriften\nISI:000259440900003\n18815396.0\n10.1056/NEJMoa0804656\nNone\nBACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke. METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)\n\n\n"
},
{
"text": "\n147617\nWhite Matter Lesion Progression: Genome-Wide Search for Genetic Influences.\n\nHofer, E\n\nCavalieri, M\n\nBis, JC\n\nDeCarli, C\n\nFornage, M\n\nSigurdsson, S\n\nSrikanth, V\n\nTrompet, S\n\nVerhaaren, BF\n\nWolf, C\n\nYang, Q\n\nAdams, HH\n\nAmouyel, P\n\nBeiser, A\n\nBuckley, BM\n\nCallisaya, M\n\nChauhan, G\n\nde Craen, AJ\n\nDufouil, C\n\nvan Duijn, CM\n\nFord, I\n\nFreudenberger, P\n\nGottesman, RF\n\nGudnason, V\n\nHeiss, G\n\nHofman, A\n\nLumley, T\n\nMartinez, O\n\nMazoyer, B\n\nMoran, C\n\nNiessen, WJ\n\nPhan, T\n\nPsaty, BM\n\nSatizabal, CL\n\nSattar, N\n\nSchilling, S\n\nShibata, DK\n\nSlagboom, PE\n\nSmith, A\n\nStott, DJ\n\nTaylor, KD\n\nThomson, R\n\nTöglhofer, AM\n\nTzourio, C\n\nvan Buchem, M\n\nWang, J\n\nWestendorp, RG\n\nWindham, BG\n\nVernooij, MW\n\nZijdenbos, A\n\nBeare, R\n\nDebette, S\n\nIkram, MA\n\nJukema, JW\n\nLauner, LJ\n\nLongstreth, WT\n\nMosley, TH\n\nSeshadri, S\n\nSchmidt, H\n\nSchmidt, R\n\nCohorts for Heart and Aging Research in Genomic Epidemiology Consortium\n\nBeiträge in Fachzeitschriften\nISI:000363974500004\n26451028.0\n10.1161/STROKEAHA.115.009252\nPMC4749149\nWhite matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.\n Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.\n A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.\n Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.\n © 2015 American Heart Association, Inc.\n\nBirkl-Töglhofer, Anna Maria\n\nCavalieri, Margherita\n\nHofer, Edith\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n152127\nEGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.\n\nScheipl, S\n\nBarnard, M\n\nCottone, L\n\nJorgensen, M\n\nDrewry, DH\n\nZuercher, WJ\n\nTurlais, F\n\nYe, H\n\nLeite, AP\n\nSmith, JA\n\nLeithner, A\n\nMöller, P\n\nBrüderlein, S\n\nGuppy, N\n\nAmary, F\n\nTirabosco, R\n\nStrauss, SJ\n\nPillay, N\n\nFlanagan, AM\n\nBeiträge in Fachzeitschriften\nISI:000383594300008\n27102572.0\n10.1002/path.4729\nPMC4922416\nChordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.\n © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.\n\nLeithner, Andreas\n\nScheipl, Susanne\n\n\n"
}
]
}