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"text": "\n174698\nEHR problem list clustering for improved topic-space navigation.\n\nKreuzthaler, M\n\nPfeifer, B\n\nVera Ramos, JA\n\nKramer, D\n\nGrogger, V\n\nBredenfeldt, S\n\nPedevilla, M\n\nKrisper, P\n\nSchulz, S\n\nBeiträge in Fachzeitschriften\nISI:000463675400013\n30943968.0\n10.1186/s12911-019-0789-9\nPMC6448176\nThe amount of patient-related information within clinical information systems accumulates over time, especially in cases where patients suffer from chronic diseases with many hospitalizations and consultations. The diagnosis or problem list is an important feature of the electronic health record, which provides a dynamic account of a patient's current illness and past history. In the case of an Austrian hospital network, problem list entries are limited to fifty characters and are potentially linked to ICD-10. The requirement of producing ICD codes at each hospital stay, together with the length limitation of list items leads to highly redundant problem lists, which conflicts with the physicians' need of getting a good overview of a patient in short time. This paper investigates a method, by which problem list items can be semantically grouped, in order to allow for fast navigation through patient-related topic spaces.\n We applied a minimal language-dependent preprocessing strategy and mapped problem list entries as tf-idf weighted character 3-grams into a numerical vector space. Based on this representation we used the unweighted pair group method with arithmetic mean (UPGMA) clustering algorithm with cosine distances and inferred an optimal boundary in order to form semantically consistent topic spaces, taking into consideration different levels of dimensionality reduction via latent semantic analysis (LSA).\n With the proposed clustering approach, evaluated via an intra- and inter-patient scenario in combination with a natural language pipeline, we achieved an average compression rate of 80% of the initial list items forming consistent semantic topic spaces with an F-measure greater than 0.80 in both cases. The average number of identified topics in the intra-patient case (μIntra = 78.4) was slightly lower than in the inter-patient case (μInter = 83.4). LSA-based feature space reduction had no significant positive performance impact in our investigations.\n The investigation presented here is centered on a data-driven solution to the known problem of information overload, which causes ineffective human-computer interactions at clinicians' work places. This problem is addressed by navigable disease topic spaces where related items are grouped and the topics can be more easily accessed.\n\nKreuzthaler, Markus Eduard\n\nKrisper, Peter\n\nPfeifer, Bastian\n\nSchulz, Stefan\n\nVera Ramos, Jose Antonio\n\n\n"
},
{
"text": "\n182804\nIL-33 reduces tumor growth in models of colorectal cancer with the help of eosinophils.\n\nKienzl, M\n\nHasenoehrl, C\n\nValadez-Cosmes, P\n\nMaitz, K\n\nSarsembayeva, A\n\nSturm, E\n\nHeinemann, A\n\nKargl, J\n\nSchicho, R\n\nBeiträge in Fachzeitschriften\nISI:000546801900001\n32923137.0\n10.1080/2162402X.2020.1776059\nPMC7458617\nIn many types of cancer, presence of eosinophils in tumors correlate with an improved disease outcome. In line with this, activated eosinophils have been shown to reduce tumor growth in colorectal cancer (CRC). Interleukin (IL)-33 has recently emerged as a cytokine that is able to inhibit the development of tumors through eosinophils and other cells of the tumor microenvironment thereby positively influencing disease progress. Here, we asked whether eosinophils are involved in the effects of IL-33 on tumor growth in CRC.In models of CT26 cell engraftment and colitis-associated CRC, tumor growth was reduced after IL-33 treatment. The growth reduction was absent in eosinophil-deficient ΔdblGATA-1 mice but was restored by adoptive transfer of ex vivo-activated eosinophils indicating that the antitumor effect of IL-33 depends on the presence of eosinophils. In vitro, IL-33 increased the expression of markers of activation and homing in eosinophils, such as CD11b and Siglec-F, and the degranulation markers CD63 and CD107a. Increased expression of Siglec-F, CD11b and CD107a was also seen in vivo in eosinophils after IL-33 treatment. Viability and cytotoxic potential of eosinophils and their migration properties toward CCL24 were enhanced indicating direct effects of IL-33 on eosinophils. IL-33 treatment led to increased levels of IL-5 and CCL24 in tumors.Our data show that the presence of eosinophils is mandatory for IL-33-induced tumor reduction in models of CRC and that the mechanisms include eosinophil recruitment, activation and degranulation. Our findings also emphasize the potential use of IL-33 as an adjuvants in CRC immunotherapy.\n AOM: azoxymethane; bmRPMI: bone marrow RPMI; CRC: colorectal cancer; CFSE: carboxyfluorescein succinimidyl ester; DSS: dextran sulfate sodium; EPX: eosinophil peroxidase; INF-γ: interferon gamma; ILC: innate lymphoid cell; IL-33: interleukin-33; IL-5: interleukin-5; MDSC: myeloid derived suppressor cells; NK cells: natural killer cells; P/S: penicillin/streptomycin; rm: recombinant mouse; T regs: regulatory T cells; TATE: tumor associated tissue eosinophilia; TNF-α: tumor necrosis factor alpha.\n © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.\n\nHeinemann, Akos\n\nKargl, Julia\n\nKienzl, Melanie\n\nMaitz, Kathrin Stefanie\n\nSarsembayeva, Arailym\n\nSchicho, Rudolf\n\nSturm, Eva\n\nValadez Cosmes, Paulina\n\n\n"
},
{
"text": "\n183347\nMorphometric parameters of muscle and bone in critically ill patients : Post hoc analysis of the VITdAL-ICU trial.\n\nMalle, O\n\nMaurer, D\n\nWagner, D\n\nSchnedl, C\n\nAmrein, S\n\nPieber, T\n\nFahrleitner-Pammer, A\n\nDimai, HP\n\nAmrein, K\n\nBeiträge in Fachzeitschriften\nISI:000570828500002\n32945947.0\n10.1007/s00508-020-01736-4\nNone\nSarcopenia, defined as loss of muscle mass, quality and function, is a part of the frailty syndrome. In critical illness, sarcopenia has rarely been evaluated regarding clinical outcomes. Therefore, we evaluated the association of sarcopenia with both hospital length of stay (HLOS) and 6‑month mortality in critically ill patients using abdominal computed tomography (CT) scans.\n In a post hoc analysis from the high dose vitamin D3 vs. placebo in adult vitamin D deficient patients (VITdAL-ICU) trial, we retrospectively reviewed all available abdominal CT scans (18 women, 19 men). We measured and calculated total psoas area (TPA), psoas muscle density (PMD), skeletal muscle index (SMI) and bone mineral density (BMD) and analyzed the relation of these endpoints with HLOS and mortality. Defining sarcopenia we used cut-off values for TPA as 642.1 mm2/m2 in women and 784 mm2/m2 in men and PMD as 31.1 Hounsfield units (HU) in women and 33.3 HU in men, both measured at the level of L3, as well as for SMI (38.5 cm2/m2 in women and 52.4 cm2/m2 in men). Likely osteoporosis was defined by L1 trabecular attenuation of ≤110 HU. Values for TPA, PMD and SMI could not be obtained in 11 patients and BMD in 1 patient.\n Mean adjusted TPA was lower in women versus men (478 vs. 749 mm2/m2) as well as PMD (34.6 vs. 41.3 HU), SMI (62.36 vs. 76.81 cm2/m2) and BMD (141.1 vs. 157.2 HU). No significant influence on hospital length of stay and on 6‑month mortality was found, irrespective of the morphometric parameter used (TPA, PMD, SMI, BMD; p > 0.05). Survivors showed statistically nonsignificantly better values than nonsurvivors: TPA: 652 vs. 530 mm2/m2 (p = 0.27); PMD: 38.4 vs. 37.4 HU (p = 0.85); SMI: 70.32 vs. 69.54 cm2/m2 (p = 0.91); BMD: 156 vs. 145.8 HU (p = 0.81).\n Although the study is limited by the small sample size, our data do not support a strong predictive value for TPA/PMD/SMI or BMD for HLOS or mortality in critically ill patients with vitamin D deficiency.\n\nAmrein, Karin\n\nDimai, Hans\n\nFahrleitner-Pammer, Astrid\n\nMalle, Oliver\n\nPieber, Thomas\n\nWagner, Doris\n\n\n"
},
{
"text": "\n3888\nThe effects of lifestyle, dietary dairy intake and diabetes on bone density and vertebral deformity prevalence: the EVOS study.\n\nLunt, M\n\nMasaryk, P\n\nScheidt-Nave, C\n\nNijs, J\n\nPoor, G\n\nPols, H\n\nFalch, JA\n\nHammermeister, G\n\nReid, DM\n\nBenevolenskaya, L\n\nWeber, K\n\nCannata, J\n\nO'Neill, TW\n\nFelsenberg, D\n\nSilman, AJ\n\nReeve, J\n\nBeiträge in Fachzeitschriften\nISI:000171206900010\n11580083.0\n10.1007%2Fs001980170069\nNone\nThe risk of low and moderate energy fracture is related to bone mineral density (BMD). Yet it is uncertain whether the epidemiologic determinants of fracture risk are the same as for low bone density. The European Vertebral Osteoporosis Study was a population-based prevalence study of vertebral deformity in 36 age-stratified population samples aged 50-80 years. In nearly 4000 subjects (13 centers), BMD measurements were also made at the spine, femoral neck and femoral trochanter. To investigate whether effects of reported physical activity on spine deformity risk were mediated through BMD, we modeled these and other risk factor data with BMD as the dependent variate after adjusting for age, center, sex and body mass index (BMI). The significant determinants of vertebral deformity risk were also entered into logistic models of deformity risk that included BMD measurements as covariates. Both current and lifetime physical activity were positively associated with BMD. This effect was stronger with hip BMD than with spine BMD. Lifetime smoking exposure was associated with reduced BMD. Type 2 diabetes mellitus was associated with increased BMD. Weak positive associations were found between consumption of dairy products and BMD at the three measured sites and these were strengthened by an interaction with measures of physical activity in men. Physical activity in women had the largest beneficial effect in lean women and in women exposed to hormone replacement therapy. When fracture risk was modeled with BMD as a covariate, the lifestyle and dietary determinants became less strongly related to vertebral deformity risk, suggesting that BMD may have acted as an intermediary variable. However, heavy physical activity in men still increased spine deformity risk after adjusting for BMD. It is concluded that physical activity in both genders and milk consumption in young women might protect against vertebral deformities in later life through their effects on bone density. The adverse effect of smoking on BMD was confirmed. Heavy physical activity in men might increase spine deformity risk even when BMD is normal.\n\nWeber, Kurt\n\n\n"
},
{
"text": "\n67746\nRadial chromatin positioning is shaped by local gene density, not by gene expression\n\nKupper, K\n\nKolbl, A\n\nBiener, D\n\nDittrich, S\n\nvon Hase, J\n\nThormeyer, T\n\nFiegler, H\n\nCarter, NP\n\nSpeicher, MR\n\nCremer, T\n\nCremer, M\n\nBeiträge in Fachzeitschriften\nISI:000246221800006\nNone\n10.1007/s00412-007-0098-4\nNone\nG- and R-bands of metaphase chromosomes are characterized by profound differences in gene density, CG content, replication timing, and chromatin compaction. The preferential localization of gene-dense, transcriptionally active, and early replicating chromatin in the nuclear interior and of gene-poor, later replicating chromatin at the nuclear envelope has been demonstrated to be evolutionary-conserved in various cell types. Yet, the impact of different local chromatin features on the radial nuclear arrangement of chromatin is still not well understood. In particular, it is not known whether radial chromatin positioning is preferentially shaped by local gene density per se or by other related parameters such as replication timing or transcriptional activity. The interdependence of these distinct chromatin features on the linear deoxyribonucleic acid (DNA) sequence precludes a simple dissection of these parameters with respect to their importance for the reorganization of the linear DNA organization into the distinct radial chromatin arrangements observed in the nuclear space. To analyze this problem, we generated probe sets of pooled bacterial artificial chromosome (BAC) clones from HSA 11, 12, 18, and 19 representing R/G-band-assigned chromatin, segments with different gene density and gene loci with different expression levels. Using multicolor 3D flourescent in situ hybridization (FISH) and 3D image analysis, we determined their localization in the nucleus and their positions within or outside the corresponding chromosome territory (CT). For each BAC data on local gene density within 2- and 10-Mb windows, as well as GC (guanine and cytosine) content, replication timing and expression levels were determined. A correlation analysis of these parameters with nuclear positioning revealed regional gene density as the decisive parameter determining the radial positioning of chromatin in the nucleus in contrast to band assignment, replication timing, and transcriptional activity. We demonstrate a polarized distribution of gene-dense vs gene-poor chromatin within CTs with respect to the nuclear border. Whereas we confirm previous reports that a particular gene-dense and transcriptionally highly active region of about 2 Mb on 11p15.5 often loops out from the territory surface, gene-dense and highly expressed sequences were not generally found preferentially at the CT surface as previously suggested.\n\nSpeicher, Michael\n\n\n"
},
{
"text": "\n93338\nA prospective cohort study of close interval computed tomography and magnetic resonance imaging after primary lumbar discectomy: factors associated with recurrent disc herniation and disc height loss.\n\nMcGirt, MJ\n\nEustacchio, S\n\nVarga, P\n\nVilendecic, M\n\nTrummer, M\n\nGorensek, M\n\nLedic, D\n\nCarragee, EJ\n\nBeiträge in Fachzeitschriften\nISI:000269489800007\n19730212.0\n10.1097/BRS.0b013e3181b34a9a\nNone\nStudy Design. Prospective cohort study. Objective. We performed a prospective cohort study with standardized postoperative lumbar imaging every 3 months for a year then annually to assess the incidence and factors associated with same-level recurrent disc herniation. Summary of Background Data. The true incidence of same-level recurrent disc herniation after lumbar discectomy is unclear. Retrospective studies have reported widely varying incidences between 3% and 18%. Prospective controlled studies are lacking. Methods. A total of 108 patients undergoing first-time lumbar discectomy for refractory radiculopathy were enrolled. Baseline lumbar CT and MRI and standardized clinical data were assessed before surgery, and CT and MRI scans repeated 6 weeks, 3, 6, 9, 12, and 24-months after surgery and at the time of recurrent sciatica. Age, weight, preoperative disc volume, and height, volume of disc removed, and size of anular defect were compared with postoperative disc height loss and recurrent disc herniation using regression analysis. Results. One hundred patients (41 +/- 10 years old) were available for 1-year (93%) and 76 (70%) for 2-year follow-up (mean follow-up: 25 +/- 12 months). Improvement in all outcome measures was observed by 6 weeks after surgery (P < 0.005). An 18% loss of disc height was observed 3 months after surgery, progressing to 26% by 2 years. Eleven (10.2%) patients experienced recurrent disc herniation requiring revision discectomy a mean 10.5 months after surgery. Subjects with larger anular defects (P = 0.019) and with smaller percentage of disc volume removed (P = 0.028) were associated with an increased risk of recurrent disc herniation. Conversely, those from whom greater disc volumes were removed (P = 0.024) had more progressive disc height loss by 6 months after surgery. Conclusion. Larger anular defects and less disc removal increased the risk of reherniation. Greater volumes of disc removal were associated with accelerated disc height loss. In the setting of larger anular defects or less aggressive disc removal, concern for recurrent herniation should be increased during outpatient follow-up. In this situation effective anular repair may be helpful.\n\nEustacchio, Sandro\n\nTrummer, Martin\n\n\n"
},
{
"text": "\n142859\nDecreased apelin and apelin-receptor expression in the pulmonary vasculature of nitrofen-induced congenital diaphragmatic hernia.\n\nHofmann, AD\n\nFriedmacher, F\n\nTakahashi, H\n\nHunziker, M\n\nGosemann, JH\n\nPuri, P\n\nBeiträge in Fachzeitschriften\nISI:000330628000011\n24363088.0\n10.1007/s00383-013-3450-1\nNone\nThe high morbidity and mortality in congenital diaphragmatic hernia (CDH) are attributed to severe pulmonary hypoplasia and persistent pulmonary hypertension (PH). PH is characterized by structural changes in pulmonary arteries, resulting in adventitial and medial thickness. These effects are triggered by abnormal apoptosis and proliferation of pulmonary vascular endothelial and smooth muscle cells (SMCs). Apelin (APLN), a target gene of bone morphogenic protein receptor 2 (BMPR2), is known to play an important and manifold role in regulating pulmonary homeostasis promoting endothelial cell (EC) survival, proliferation and migration. In addition to these autocrine effects of apelin, it displays a paracrine function attenuating the response of pulmonary SMCs to growth factors and promoting apoptosis. Apelin exerts its effect via its G-protein-coupled receptor (APLNR) and is solely expressed by pulmonary vascular EC, whereas APLNR is co-localized in pulmonary ECs and SMCs. Dysfunction of BMPR2 and downstream signalling have been shown to disturb the crucial balance of proliferation of SMCs contributing to the pathogenesis of human and experimentally induced PH. We designed this study to investigate the hypothesis that apelin and APLNR signalling are disrupted in the pulmonary vasculature of rats in nitrofen-induced CDH.\n Pregnant rats were exposed to nitrofen or vehicle on D9 of gestation. Foetuses were sacrificed on D21 and divided into nitrofen and control group (n = 32). Pulmonary RNA was extracted and mRNA levels of APLN and APLNR were determined by quantitative real-time PCR. Protein expression of apelin and APLNR was investigated by western blotting. Confocal immunofluorescence double staining for apelin, APLNR and SMCs were performed.\n Relative mRNA level of APLN and APLNR were significantly decreased in the CDH group compared to control lungs. Western blotting and confocal microscopy confirmed the qRT-PCR results showing decreased pulmonary protein expression of apelin and APLNR in lungs of nitrofen-exposed foetuses compared to controls.\n This study provides striking evidence of markedly decreased gene and protein expression of apelin and its receptor APLNR in the pulmonary vasculature of nitrofen-induced CDH. The disruption of the apelin-APLNR signalling axis in the pulmonary vasculature may lead to extensive vascular remodelling and contribute to PPH in the nitrofen-induced CDH model.\n\n\n"
},
{
"text": "\n159320\n<i>Enterococcus durans</i> EP1 a Promising Anti-inflammatory Probiotic Able to Stimulate sIgA and to Increase <i>Faecalibacterium prausnitzii</i> Abundance.\n\nCarasi, P\n\nRacedo, SM\n\nJacquot, C\n\nElie, AM\n\nSerradell, ML\n\nUrdaci, MC\n\nBeiträge in Fachzeitschriften\nISI:000393711700001\n28239378.0\n10.3389/fimmu.2017.00088\nPMC5300979\nEnterococcus species, principally Enterococcus faecium are used as probiotics since a long time with preference in animal applications but safety considerations were updated and also new uses as probiotics can be envisaged. Fifteen Enterococcus strains isolated from different foods were identified and analyzed for virulence factors and antibiotic resistance. Three Enterococcus durans strains were selected to study their immunomodulatory properties on PBMC and Caco2 cells. Two strains presented a profile toward a mild inflammatory Th1 response considering TNF-α/IL-10 and IL-1β/IL-10 cytokines ratios. The third strain EP1, presented an anti-inflammatory potential and was selected for in vivo studies. In mice, the strain was well tolerated and did not cause any adverse effects. EP1 administration increased the amount of IgA+ cells in mesenteric lymph node (MLN) after 7 days of administration. In fecal samples, the IgA content increased gradually and significantly from day 7 to day 21 in treated group. Additionally, IL-17, IL-6, IL-1β, IFN-γ, and CXCL1 gene expression significantly decreased on day 21 in Peyer's patches and IL-17 decreased in MLN. Mice treated with the probiotic showed significant lower mRNA levels of pro-inflammatory cytokines and mucins in the ileum at day 7 while their expression was normalized at day 21. Colonic expression of il-1β, il6, and mucins remain diminished at day 21. Ileum and colon explants from treated mice stimulated in vitro with LPS showed a significant reduction in IL-6 and an increase in IL-10 secretion suggesting an in vivo protective effect of the probiotic treatment against a proinflammatory stimulus. Interestingly, analysis of feces microbiota demonstrated that EP1 administration increase the amount of Faecalibacterium prausnitzii, a butyrate-producing bacteria, which is known for its anti-inflammatory effects. In conclusion, we demonstrated that EP1 strain is a strong sIgA inducer and possess mucosal anti-inflammatory properties. This strain also modulates gut microbiota increasing Faecalibacterium prausnitzii, a functionally important bacterium. Thus, E. durans EP1 is not only a good candidate to increases F. prausnitzii in some cases of dysbiosis but can also be interesting in gut inflammatory disorders therapy.\n\nRacedo, Silvia Maria\n\n\n"
},
{
"text": "\n169749\nKey Messages for a Frailty Prevention and Management Policy in Europe from the ADVANTAGE JOINT ACTION Consortium.\n\nRodríguez Mañas, L\n\nGarcía-Sánchez, I\n\nHendry, A\n\nBernabei, R\n\nRoller-Wirnsberger, R\n\nGabrovec, B\n\nLiew, A\n\nCarriazo, AM\n\nRedon, J\n\nGalluzzo, L\n\nViña, J\n\nAntoniadou, E\n\nTargowski, T\n\nDi Furia, L\n\nLattanzio, F\n\nBozdog, E\n\nTelo, M\n\nBeiträge in Fachzeitschriften\nISI:000446544700004\n30272089.0\n10.1007/s12603-018-1064-y\nNone\nIn the 2015 Ageing Report, the European Commission (EC) and the Economic Policy Committee stated that coping with the challenge posed by an ageing population will require determined policy action in Europe, particularly in reforming pension, health care and long-term care systems. The concern for this situation motivated the EC, the Parliament and many of the Member States (MS) to co-fund, in the 2015 call of the Third European Health Programme of the European Union 2014-2020, the first Joint Action (JA) on the prevention of frailty. ADVANTAGE JA brings together 33 partners from 22 MSs for 3 years. It aims to build a common understanding on frailty to be used in the MSs by policy makers and other stakeholders involved in the management, both at individual and population level, of older people who are frail or at risk for developing frailty throughout the European Union (EU). It is a formidable challenge but also a great opportunity for concerted action resulting in fostering effective and successful policies in frailty prevention and management in the participating MS. The Consortium has 2 years of hard work ahead to contribute to the needed change for frailty related disability free Europe. The first practical step towards this aim was the preparation of a document: the State of the Art on Frailty Report to support an overview of evidence of what works and what does not work on frailty prevention and management. Subsequently, this will be reflected in the advice that the JA will give to policy makers at MS level. Overall, these messages intend to be an instrument of added value to advocate for policy driven decisions on frailty prevention and management in the JA participating MSs and subsequently towards a frailty related disability free older population in Europe. The aim of this paper is to describe ADVANTAGE JA general structure, approach and recommendations towards a European health and social policy which will support frailty prevention in the participating MS.\n\nRoller-Wirnsberger, Regina\n\n\n"
},
{
"text": "\n1347\nInfluence of n-3 fatty acids on the growth of human breast cancer cells in vitro: relationship to peroxides and vitamin-E.\n\nChajès, V\n\nSattler, W\n\nStranzl, A\n\nKostner, GM\n\nBeiträge in Fachzeitschriften\nISI:A1995QT24100002\n7579484.0\n10.1007%2FBF00689711\nNone\nEpidemiological studies suggest a causal relationship of dietary polyunsaturated fatty acids (PUFA's) with the morbidity and mortality from breast cancer. In order to reveal possible underlying mechanisms of these findings, we studied the influence of n-3 and n-6 PUFA's in comparison to oleic acid on the proliferation of well characterized estrogen dependent (MCF-7, ZR-75, T-47-D) and estrogen independent (MDA-MB-231, HBL-100) breast cancer cells in culture. The cell growth inhibitory effect was related to the formation of lipid peroxidation products. Normal human skin fibroblasts served as a control. In fibroblasts, the addition of 20 micrograms/ml of exogenous fatty acids either had no effect or caused an insignificant increase of proliferation. Similar results were obtained with MCF-7 cells. In all other breast cancer cell types, n-3 long-chain PUFA's, eicosapentaenoic and docosahexaenoic acids, were the most effective fatty acids in arresting the cell growth. Alpha-linolenic and gamma-linolenic acid exerted a variable effect on cell proliferation depending on the cell line investigated. Oleic acid significantly stimulated the proliferation of hormone-independent breast cancer cells while it had no effect on the proliferation of hormone-dependent cells. Viability studies by trypan blue excretion indicated that the arrest in cell growth was not due to major cytotoxic effects. The addition of PUFA's to breast cancer cells caused a significant increase in the formation of conjugated dienes and lipid hydroperoxides in the cellular lipids; their content was significantly correlated with the capacity of arresting cell growth. In contrast, the addition of PUFA's to fibroblasts did not increase lipid hydroperoxide formation. The addition of Vitamin E to cancer cells at a concentration of 10 microM to the PUFA-supplemented medium almost completely restored cell growth. Our data indicate that PUFA's significantly interfere with cell proliferation of breast cancer cells in vitro due to the formation of oxidation products. In addition to that, there must be other factors involved, most probably related to the differential metabolism of PUFA's in tumor cells. Our findings may have some impact on treatment and prevention of breast cancer.\n\nKostner, Gerhard\n\nSattler, Wolfgang\n\n\n"
},
{
"text": "\n120406\nImpact of distal ureter management on oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma.\n\nXylinas, E\n\nRink, M\n\nCha, EK\n\nClozel, T\n\nLee, RK\n\nFajkovic, H\n\nComploj, E\n\nNovara, G\n\nMargulis, V\n\nRaman, JD\n\nLotan, Y\n\nKassouf, W\n\nFritsche, HM\n\nWeizer, A\n\nMartinez-Salamanca, JI\n\nMatsumoto, K\n\nZigeuner, R\n\nPycha, A\n\nScherr, DS\n\nSeitz, C\n\nWalton, T\n\nTrinh, QD\n\nKarakiewicz, PI\n\nMatin, S\n\nMontorsi, F\n\nZerbib, M\n\nShariat, SF\n\nUpper Tract Urothelial Carcinoma Collaboration\n\nBeiträge in Fachzeitschriften\nISI:000327766500038\n22579047.0\n10.1016/j.eururo.2012.04.052\nNone\nThere is a lack of consensus regarding the optimal approach to the bladder cuff during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).\n To compare the oncologic outcomes following RNU using three different methods of bladder cuff management.\n Retrospective analysis of 2681 patients treated with RNU for UTUC at 24 international institutions from 1987 to 2007.\n Three methods of bladder cuff excision were performed: transvesical, extravesical, and endoscopic.\n Univariable and multivariable models tested the effect of distal ureter management on intravesical recurrence, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS).\n Of the 2681 patients, 1811 (67.5%) underwent the transvesical approach; 785 (29.3%), the extravesical approach; and 85 (3.2%), the endoscopic approach. There was no difference in terms of RFS, CSS, and OS among the three distal ureteral management approaches. Patients who underwent the endoscopic approach were at significantly higher risk of intravesical recurrence compared with those who underwent the transvesical (p=0.02) or extravesical approaches (p=0.02); the latter two groups did not differ from each other (p=0.40). Actuarial intravesical RFS estimates at 2 and 5 yr after RNU were 69% and 58%, 69% and 51%, and 61% and 42% for the transvesical, extravesical, and endoscopic approaches, respectively. In multivariate analyses, distal ureteral management (p=0.01), surgical technique (open vs laparoscopic; p=0.02), previous bladder cancer (p<0.001), higher tumor stage (trend; p=0.01), concomitant carcinoma in situ (CIS) (p<0.001), and lymph node involvement (trend; p<0.001) were all associated with intravesical recurrence. Excluding patients with history of previous bladder cancer, all variables remained independent predictors of intravesical recurrence.\n The endoscopic approach was associated with higher intravesical recurrence rates. Interestingly, concomitant CIS in the upper tract is a strong predictor of intravesical recurrence after RNU. The association of laparoscopic RNU with intravesical recurrence needs to be further investigated.\n Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n150577\nCombined Assessment of High-Sensitivity Troponin T and Noninvasive Coronary Plaque Composition for the Prediction of Cardiac Outcomes.\n\nGitsioudis, G\n\nSchüssler, A\n\nNagy, E\n\nMaurovich-Horvat, P\n\nBuss, SJ\n\nVoss, A\n\nHosch, W\n\nHofmann, N\n\nKauczor, HU\n\nGiannitsis, E\n\nKatus, HA\n\nKorosoglou, G\n\nBeiträge in Fachzeitschriften\nISI:000359708400008\n25734549.0\n10.1148/radiol.15141110\nNone\nTo determine the risk-stratification ability of plaque volume and composition assessment with cardiac computed tomographic (CT) angiography and high-sensitivity troponin T (hsTnT) in patients at intermediate risk for coronary artery disease (CAD).\n The study complied with the Declaration of Helsinki and was approved by the local ethics committee. All patients gave written informed consent. Five hundred twenty-one consecutive patients (mean age ± standard deviation, 62 years ± 10; 256 men and 265 women) were included in this prospective, observational, longitudinal, single-center study. Quantitative cardiac CT angiography analysis was performed in all patients (for 7690 coronary segments), whereas biomarkers (hsTnT and high-sensitivity C-reactive protein) were available in 408 patients (78%). To evaluate the incremental value of cardiac CT angiography and hsTnT for the prediction of cardiovascular events, multivariate Cox regression and integrated discrimination improvement analysis were applied.\n In 521 patients, 13 hard cardiac events occurred during a mean follow-up period of 2.3 years ± 1.1 (median, 2.4 years; range, 0.5-4.5 years), while 23 patients underwent late coronary revascularization. The Duke clinical score was 51% ± 30, indicating intermediate risk. The presence of no plaques or purely calcified versus noncalcified plaques, plaque volume according to tertiles, and increased hsTnT (≥14 pg/mL) was independently associated with hard cardiac events (hazard ratio [HR] = 26.08, 95% confidence interval [CI]: 2.78, 244.99; HR = 12.14, 95% CI: 1.87, 78.74; and HR = 10.31, 95% CI: 2.72, 39.0, respectively; P < .01 for all). Patients with increased hsTnT and plaque burden (n = 53) showed the highest incidence for hard cardiac events (annual rate, 12.7%), followed by those with either increased hsTnT or plaque burden (n = 145; annual rate = 0.44%, P < .03), while those with lower hsTnT and plaque burden exhibited excellent outcomes and no hard event during the follow-up duration (n = 210; annual rate = 0%, P < .001).\n Use of hsTnT as a marker of myocardial microinjury and cardiac CT angiography as a marker of the total atherosclerotic burden improves the prediction of cardiac outcome in patients with presumably stable CAD and may aid in personalized risk stratification in patients at intermediate risk.\n\nNagy, Eszter\n\n\n"
},
{
"text": "\n164098\nLysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype.\n\nPlastira, I\n\nBernhart, E\n\nGoeritzer, M\n\nDeVaney, T\n\nReicher, H\n\nHammer, A\n\nLohberger, B\n\nWintersperger, A\n\nZucol, B\n\nGraier, WF\n\nKratky, D\n\nMalle, E\n\nSattler, W\n\nBeiträge in Fachzeitschriften\nISI:000418293800002\n29258556.0\n10.1186/s12974-017-1024-1\nPMC5735906\nExtracellular lysophosphatidic acid (LPA) species transmit signals via six different G protein-coupled receptors (LPAR1-6) and are indispensible for brain development and function of the nervous system. However, under neuroinflammatory conditions or brain damage, LPA levels increase, thereby inducing signaling cascades that counteract brain function. We describe a critical role for 1-oleyl-2-hydroxy-sn-glycero-3-phosphate (termed "LPA" throughout our study) in mediating a motile and pro-inflammatory microglial phenotype via LPAR5 that couples to protein kinase D (PKD)-mediated pathways.\n Using the xCELLigence system and time-lapse microscopy, we investigated the migrational response of microglial cells. Different M1 and M2 markers were analyzed by confocal microscopy, flow cytometry, and immunoblotting. Using qPCR and ELISA, we studied the expression of migratory genes and quantitated the secretion of pro-inflammatory cytokines and chemokines, respectively. Different transcription factors that promote the regulation of pro-inflammatory genes were analyzed by western blot. Reactive oxygen species (ROS) and nitric oxide (NO) production, phagocytosis, and microglial cytotoxicity were determined using commercially available assay kits.\n LPA induces MAPK family and AKT activation and pro-inflammatory transcription factors' phosphorylation (NF-κB, c-Jun, STAT1, and STAT3) that were inhibited by both LPAR5 and PKD family antagonists. LPA increases migratory capacity, induces secretion of pro-inflammatory cytokines and chemokines and expression of M1 markers, enhances production of ROS and NO by microglia, and augments cytotoxicity of microglial cell-conditioned medium towards neurons. The PKD family inhibitor blunted all of these effects. We propose that interference with this signaling axis could aid in the development of new therapeutic approaches to control neuroinflammation under conditions of overshooting LPA production.\n In the present study, we show that inflammatory LPA levels increased the migratory response of microglia and promoted a pro-inflammatory phenotype via the LPAR5/PKD axis. Interference with this signaling axis reduced microglial migration, blunted microglial cytotoxicity, and abrogated the expression and secretion of pro-inflammatory mediators.\n\nBernhart, Eva Maria\n\nGöritzer, Madeleine\n\nGraier, Wolfgang\n\nHammer, Astrid\n\nHinteregger, Helga\n\nKratky, Dagmar\n\nLohberger, Birgit\n\nMalle, Ernst\n\nPlastira, Ioanna\n\nSattler, Wolfgang\n\nWintersperger, Andrea\n\n\n"
},
{
"text": "\n164514\nNuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.\n\nRosen, LE\n\nKarrison, T\n\nAnanthanarayanan, V\n\nGallan, AJ\n\nAdusumilli, PS\n\nAlchami, FS\n\nAttanoos, R\n\nBrcic, L\n\nButnor, KJ\n\nGalateau-Sallé, F\n\nHiroshima, K\n\nKadota, K\n\nKlampatsa, A\n\nStang, NL\n\nLindenmann, J\n\nLitzky, LA\n\nMarchevsky, A\n\nMedeiros, F\n\nMontero, MA\n\nMoore, DA\n\nNabeshima, K\n\nPavlisko, EN\n\nRoggli, VL\n\nSauter, JL\n\nSharma, A\n\nSheaff, M\n\nTravis, WD\n\nVigneswaran, WT\n\nVrugt, B\n\nWalts, AE\n\nTjota, MY\n\nKrausz, T\n\nHusain, AN\n\nBeiträge in Fachzeitschriften\nISI:000430404600006\n29327706.0\n10.1038/modpathol.2017.170\nNone\nA recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.\n\nBrcic, Luka\n\nLindenmann, Jörg\n\n\n"
},
{
"text": "\n165396\nImpact of perioperative chemotherapy on survival in patients with advanced primary urethral cancer: results of the international collaboration on primary urethral carcinoma.\n\nGakis, G\n\nMorgan, TM\n\nDaneshmand, S\n\nKeegan, KA\n\nTodenhöfer, T\n\nMischinger, J\n\nSchubert, T\n\nZaid, HB\n\nHrbacek, J\n\nAli-El-Dein, B\n\nClayman, RH\n\nGalland, S\n\nOlugbade, K\n\nRink, M\n\nFritsche, HM\n\nBurger, M\n\nChang, SS\n\nBabjuk, M\n\nThalmann, GN\n\nStenzl, A\n\nEfstathiou, JA\n\nBeiträge in Fachzeitschriften\nISI:000359312100031\n25969370.0\n10.1093/annonc/mdv230\nNone\nTo investigate the impact of perioperative chemo(radio)therapy in advanced primary urethral carcinoma (PUC).\n A series of 124 patients (86 men, 38 women) were diagnosed with and underwent surgery for PUC in 10 referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemo(radio)therapy on overall survival (OS). The median follow-up was 21 months (mean: 32 months; interquartile range: 5-48).\n Neoadjuvant chemotherapy (NAC), neoadjuvant chemoradiotherapy (N-CRT) plus adjuvant chemotherapy (ACH), and ACH was delivered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively. Receipt of NAC/N-CRT was associated with clinically node-positive disease (cN+; P = 0.033) and lower utilization of cystectomy at surgery (P = 0.015). The objective response rate to NAC and N-CRT was 25% and 33%, respectively. The 3-year OS for patients with objective response to neoadjuvant treatment (complete/partial response) was 100% and 58.3% for those with stable or progressive disease (P = 0.30). Of the 26 patients staged ≥cT3 and/or cN+ disease, 16 (62%) received perioperative chemo(radio)therapy and 10 upfront surgery without perioperative chemotherapy (38%). The 3-year OS for this locally advanced subset of patients (≥cT3 and/or cN+) who received NAC (N = 5), N-CRT (N = 3), surgery-only (N = 10) and surgery plus ACH (N = 8) was 100%, 100%, 50% and 20%, respectively (P = 0.016). Among these 26 patients, receipt of neoadjuvant treatment was significantly associated with improved 3-year relapse-free survival (RFS) (P = 0.022) and OS (P = 0.022). Proximal tumor location correlated with inferior 3-year RFS and OS (P = 0.056/0.005).\n In this series, patients who received NAC/N-CRT for cT3 and/or cN+ PUC appeared to demonstrate improved survival compared with those who underwent upfront surgery with or without ACH.\n © The Author 2015. 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\n\n"
},
{
"text": "\n169809\nAn approach towards molecular imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue flow chamber.\n\nvon Elverfeldt, D\n\nMeissner, M\n\nPeter, K\n\nPaul, D\n\nMeixner, F\n\nNeudorfer, I\n\nMerkle, A\n\nHarloff, A\n\nZirlik, A\n\nSchöllhorn, J\n\nMarkl, M\n\nHennig, J\n\nBode, C\n\nvon zur Muhlen, C\n\nBeiträge in Fachzeitschriften\nISI:000301713900012\n22434633.0\n10.1002/cmmi.482\nNone\nThe development of magnetic resonance imaging (MRI) contrast agents targeting epitopes in atherosclerosis is of general interest. In particular, early detection of activated platelets as key players in plaque rupture could provide improved triage of patients. However, so far the efficiency of contrast agents targeting human pathologies can only be examined in animal experiments, which do not necessarily reflect human in vivo conditions. We therefore describe application of a contrast agent targeting activated human platelets in an MRI tissue flow chamber, allowing detection and characterization of contrast agent binding. Microparticles of iron oxide (MPIO) were conjugated to an antibody targeting ligand-induced binding sites (LIBS) on the activated platelet glycoprotein IIb/IIIa-receptor or to control antibody, resulting in LIBS-MPIO or control-MPIO contrast agent. Human endarterectomy specimens from patients with acute stroke or transient ischemic attack were imaged ex vivo before and after contrast agent perfusion using a 9.4 T MRI system. Specimens were measured under static (n = 18) or flow conditions (n = 18) in a specially designed flow chamber setup, simulating physiological conditions in a stenosed vessel. A significant MPIO-induced negative contrast was achieved in MRI by LIBS-MPIO in specimens under static and flow conditions (LIBS-MPIO vs control-MPIO: p < 0.01), and the location of LIBS-MPIO binding corresponded well between histology and MRI (p < 0.05). The number of MPIOs per platelet area on endarterectomy specimens in histology was significantly higher with LIBS-MPIO (p < 0.001). Furthermore, the intensity of contrast agent binding and signal change showed the potential to reflect the severity of clinical symptoms. LIBS-MPIO allows the detection of activated platelets on the surface of symptomatic atherosclerotic human plaques using molecular MRI. Furthermore, the MRI tissue flow chamber setup described could help to evaluate binding properties of contrast agents, and might therefore be an interesting tool for contrast agent development from animal experiments towards clinical application.\n Copyright © 2012 John Wiley & Sons, Ltd.\n\nZirlik, Andreas\n\n\n"
},
{
"text": "\n175735\nA miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling.\n\nGlantschnig, C\n\nKoenen, M\n\nGil-Lozano, M\n\nKarbiener, M\n\nPickrahn, I\n\nWilliams-Dautovich, J\n\nPatel, R\n\nCummins, CL\n\nGiroud, M\n\nHartleben, G\n\nVogl, E\n\nBlüher, M\n\nTuckermann, J\n\nUhlenhaut, H\n\nHerzig, S\n\nScheideler, M\n\nBeiträge in Fachzeitschriften\nISI:000466932600011\n30742779.0\n10.1096/fj.201801385RR\nNone\nThe glucocorticoid receptor (GR) represents the crucial molecular mediator of key endocrine, glucocorticoid hormone-dependent regulatory circuits, including control of glucose, protein, and lipid homeostasis. Consequently, aberrant glucocorticoid signaling is linked to severe metabolic disorders, including insulin resistance, obesity, and hyperglycemia, all of which also appear upon chronic glucocorticoid therapy for the treatment of inflammatory conditions. Of note, long-term glucocorticoid exposure under these therapeutic conditions typically induces glucocorticoid resistance, requiring higher doses and consequently triggering more severe metabolic phenotypes. However, the molecular basis of acquired glucocorticoid resistance remains unknown. In a screen of differential microRNA expression during glucocorticoid-dependent adipogenic differentiation of human multipotent adipose stem cells, we identified microRNA 29a (miR-29a) as one of the most down-regulated transcripts. Overexpression of miR-29a impaired adipogenesis. We found that miR-29a represses GR in human adipogenesis by directly targeting its mRNA, and downstream analyses revealed that GR mediates most of miR-29a's anti-adipogenic effects. Conversely, miR-29a expression depends on GR activation, creating a novel miR-29-driven feedback loop. miR-29a and GR expression were inversely correlated both in murine adipose tissue and in adipose tissue samples obtained from human patients. In the latter, miR-29a levels were additionally strongly negatively correlated with body mass index and adipocyte size. Importantly, inhibition of miR-29 in mice partially rescued the down-regulation of GR during dexamethasone treatment. We discovered that, in addition to modulating GR function under physiologic conditions, pharmacologic glucocorticoid application in inflammatory disease also induced miR-29a expression, correlating with reduced GR levels. This effect was abolished in mice with impaired GR function. In summary, we uncovered a novel GR-miR-29a negative feedback loop conserved between mice and humans, in health and disease. For the first time, we elucidate a microRNA-related mechanism that might contribute to GR dysregulation and resistance in peripheral tissues.-Glantschnig, C., Koenen, M., Gil-Lozano, M., Karbiener, M., Pickrahn, I., Williams-Dautovich, J., Patel, R., Cummins, C. L., Giroud, M., Hartleben, G., Vogl, E., Blüher, M., Tuckermann, J., Uhlenhaut, H., Herzig, S., Scheideler, M. A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling.\n\n\n"
},
{
"text": "\n177248\nDeformation behavior of the iliotibial tract under different states of fixation.\n\nSteinke, H\n\nLingslebe, U\n\nBöhme, J\n\nSlowik, V\n\nShim, V\n\nHädrich, C\n\nHammer, N\n\nBeiträge in Fachzeitschriften\nISI:000310423300002\n22297087.0\n10.1016/j.medengphy.2011.12.009\nNone\nThe iliotibial tract (tract) is an important structure for the biomechanics of both the hip and knee joint. While a detailed characterization of its mechanical properties might help to better understand its specific role in the load transfer from the pelvis to femur and tibia, determination of those properties is complicated by its particular structure of thin fibers in the fresh state. Moreover, although the tracts mechanical properties are often derived from cadaveric material chemically fixed with either ethanol or formaldehyde, the influence of such fixation methods remains to be elucidated. Aim of this study was to determine Young's modulus (tensile modulus, YM) of the tract. We hypothesized that either ethanol or formaldehyde fixation would significantly increase the YM compared to the tracts condition in a fresh state.\n 13 specimens of tract were gained from donators. The ends of the probes were plastinated with resin creating a sharp interface between the clamp and the probe to prevent material slippage. The specimens were measured in their fresh state, under ethanol- and formaldehyde-fixed conditions and re-measured after rinsing with tap water.\n The YM of the fresh probes averaged 397.3N/mm(2) with a standard deviation (SD) of 151.5N/mm(2). The YM of the ethanol-fixed specimens was significantly higher (673.2N/mm(2), SD 328.5N/mm(2), p<0.05). After rinsing with tap water, the YM decreased to 95% of the fresh condition value (377.4N/mm(2), SD 144.5N/mm(2), non-significant change from fresh). After formaldehyde fixation, the YM reached 490.3N/mm(2) (SD 143.0N/mm(2), p<0.05). When the formaldehyde-fixed specimens were rinsed, the YM was 114% of the value of the fresh condition (452.6N/mm(2), SD 115.1N/mm(2), non-significant change from fresh).\n This study found a significant influence of the chemical fixation method on the YM of the IT tract. If such fixation is required, our results suggest using a treatment with ethanol and subsequent rinsing that results in minimal changes to the tracts YM. Furthermore, plastination of the ends of the specimens could be crucial to allow in vitro determination of valid YM of ligaments data that can then be integrated with confidence in further finite element analyses.\n Copyright © 2011 IPEM. Published by Elsevier Ltd. All rights reserved.\n\nHammer, Niels\n\n\n"
},
{
"text": "\n178648\nElexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.\n\nMiddleton, PG\n\nMall, MA\n\nDřevínek, P\n\nLands, LC\n\nMcKone, EF\n\nPolineni, D\n\nRamsey, BW\n\nTaylor-Cousar, JL\n\nTullis, E\n\nVermeulen, F\n\nMarigowda, G\n\nMcKee, CM\n\nMoskowitz, SM\n\nNair, N\n\nSavage, J\n\nSimard, C\n\nTian, S\n\nWaltz, D\n\nXuan, F\n\nRowe, SM\n\nJain, R\n\nVX17-445-102 Study Group\n\nBeiträge in Fachzeitschriften\nISI:000496238300006\n31697873.0\n10.1056/NEJMoa1908639\nPMC7282384\nCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.\n We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.\n A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.\n Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).\n Copyright © 2019 Massachusetts Medical Society.\n\nEber, Ernst\n\n\n"
},
{
"text": "\n186594\nPAM-50 predicts local recurrence after breast cancer surgery in postmenopausal patients with ER+/HER2- disease: results from 1204 patients in the randomized ABCSG-8 trial.\n\nFitzal, F\n\nFilipits, M\n\nFesl, C\n\nRudas, M\n\nGreil, R\n\nBalic, M\n\nMoinfar, F\n\nHerz, W\n\nDubsky, P\n\nBartsch, R\n\nFerree, S\n\nSchaper, C\n\nGnant, M\n\nAustrian Breast and Colorectal Cancer Study Group (ABCSG)\n\nBeiträge in Fachzeitschriften\nISI:000642298200041\n33608712.0\n10.1093/bjs/znaa089\nNone\nThe aim of this study was to investigate whether the PAM-50-based 46-gene assay carries prognostic value for risk of local recurrence of breast cancer.\n The Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 RCT compared 5 years of tamoxifen with tamoxifen for 2 years followed by anastrozole for 3 years in postmenopausal women with endocrine receptor-positive breast cancer. This study included patients from the trial who had breast-conserving surgery for whom tumour blocks were available for PAM-50 analysis.\n Tumour blocks from 1204 patients who had breast-conserving surgery were available for the PAM-50 analysis, and 1034 of these received radiotherapy. After a median follow-up of 10.8 years, 23 local events had been observed, corresponding to an overall local recurrence risk of 2.2 per cent. Univariable competing-risk analysis demonstrated that patients at low risk according to PAM-50 analysis (risk-of-recurrence (ROR) score less than 57) had a significantly lower incidence of local recurrence than those in the high-risk group at 5 years (0.1 (95 per cent c.i. 0 to 0.7) versus 2.2 (0.9 to 4.6) per cent respectively; subhazard ratio (SHR) 17.18, 95 per cent c.i. 2.06 to 142.88; P = 0.009) and 10 years (0.9 (0.4 to 2.0) versus 3.8 (1.9 to 6.6) per cent; SHR 4.76, 1.72 to 13.17; P = 0.003). Multivariable analyses that included ROR score, age, tumour size, nodal status, type of surgery, tumor grade, and trial-specific endocrine therapy confirmed that ROR score was an independent prognostic factor for risk of local recurrence. Analysis of the women randomized to radiotherapy or control after breast conservation showed that PAM-50 was not predictive of radiotherapy effect.\n PAM-50 can be used as a prognostic tool for local recurrence risk in postmenopausal women with hormone receptor-positive breast cancer treated with endocrine therapy. The test was not predictive for the benefit of radiotherapy.\n © The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.\n\nBalic, Marija\n\nMoinfar, Farid\n\n\n"
}
]
}