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    Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi-episode schizophrenia. 

    Papiol, S; Popovic, D.; Keeser, D.; Hasan, A.; Schneider-Axmann, T.; Degenhardt, F.; Rossner, M. J.; Bickeböller, H.; Schmitt, A.; Falkai, P.; et al.
    Malchow, B.
    Translational psychiatry 2017-06-27; 7(6): Art. e1159
    Preliminary studies suggest that, besides improving cognition, aerobic exercise might increase hippocampal volume in schizophrenia patients; however, results are not consistent. Individual mechanisms of volume changes are unknown but might be connected to the load of risk genes. Genome-wide association studies have uncovered the polygenic architecture of schizophrenia. The secondary analysis presented here aimed to determine the modulatory role of schizophrenia polygenic risk scores (PRSs) on volume changes in the total hippocampus and cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG) and subiculum over time. We studied 20 multi-episode schizophrenia patients and 23 healthy controls who performed aerobic exercise (endurance training) combined with cognitive remediation for 3 months and 21 multi-episode schizophrenia patients allocated to a control intervention (table soccer) combined with cognitive remediation. Magnetic resonance imaging-based assessments were performed at baseline and after 3 months with FreeSurfer. No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis. We hypothesize that a high polygenic risk may negatively influence neuroplasticity in CA4/DG during aerobic exercise in schizophrenia.
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    Protection of Mice from Acute Graft-versus-Host Disease Requires CD28 Co-stimulation on Donor CD4+ Foxp3+ Regulatory T Cells. 

    Uri, Anna; Werner, Sandra; Lühder, Fred; Hünig, Thomas; Kerkau, Thomas; Beyersdorf, Niklas
    Frontiers in immunology 2017; 8: Art. 721
    Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell plus T cell transplantation (allo-HSCT). In this study, we investigated the requirement for CD28 co-stimulation of donor CD4+ conventional (CD4+CD25-Foxp3-, Tconv) and regulatory (CD4+CD25+Foxp3+, Treg) T cells in aGvHD using tamoxifen-inducible CD28 knockout (iCD28KO) or wild-type (wt) littermates as donors of CD4+ Tconv and Treg. In the highly inflammatory C57BL/6 into BALB/c allo-HSCT transplantation model, CD28 depletion on donor CD4+ Tconv reduced clinical signs of aGvHD, but did not significantly prolong survival of the recipient mice. Selective depletion of CD28 on donor Treg did not abrogate protection of recipient mice from aGvHD until about day 20 after allo-HSCT. Later, however, the pool of CD28-depleted Treg drastically declined as compared to wt Treg. Consequently, only wt, but not CD28-deficient, Treg were able to continuously suppress aGvHD and induce long-term survival of the recipient mice. To our knowledge, this is the first study that specifically evaluates the impact of CD28 expression on donor Treg in aGvHD. Moreover, the delayed kinetics of aGvHD lethality after transplantation of iCD28KO Treg provides a novel animal model for similar disease courses found in patients after allo-HSCT.
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    Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia. 

    Witt, S. H.; Streit, F.; Jungkunz, M.; Frank, J.; Awasthi, S.; Reinbold, C. S.; Treutlein, J.; Degenhardt, F.; Forstner, A. J.; Heilmann-Heimbach, S.; et al.
    Dietl, L.Schwarze, C. E.Schendel, D.Strohmaier, J.Abdellaoui, A.Adolfsson, R.Air, T. M.Akil, H.Alda, M.Alliey-Rodriguez, N.Andreassen, O. A.Babadjanova, G.Bass, N. J.Bauer, M.Baune, B. T.Bellivier, F.Bergen, S.Bethell, A.Biernacka, J. M.Blackwood, D. H. R.Boks, M. P.Boomsma, D. I.Børglum, A. D.Borrmann-Hassenbach, M.Brennan, P.Budde, M.Buttenschøn, H. N.Byrne, E. M.Cervantes, P.Clarke, T.-K.Craddock, N.Cruceanu, C.Curtis, D.Czerski, P. M.Dannlowski, U.Davis, T.de Geus, E. J. C.Di Florio, A.Djurovic, S.Domenici, E.Edenberg, H. J.Etain, B.Fischer, S. B.Forty, L.Fraser, C.Frye, M. A.Fullerton, J. M.Gade, K.Gershon, E. S.Giegling, I.Gordon, S. D.Gordon-Smith, K.Grabe, H. J.Green, E. K.Greenwood, T. A.Grigoroiu-Serbanescu, M.Guzman-Parra, J.Hall, L. S.Hamshere, M.Hauser, J.Hautzinger, M.Heilbronner, U.Herms, S.Hitturlingappa, S.Hoffmann, P.Holmans, P.Hottenga, J.-J.Jamain, S.Jones, I.Jones, L. A.Juréus, A.Kahn, R .S.Kammerer-Ciernioch, J.Kirov, G.Kittel-Schneider, S.Kloiber, S.Knott, S. V.Kogevinas, M.Landén, M.Leber, M.Leboyer, M.Li, Q. S.Lissowska, J.Lucae, S.Martin, N. G.Mayoral-Cleries, F.McElroy, S. L.McIntosh, A. M.McKay, J. D.McQuillin, A.Medland, S. E.Middeldorp, C. M.Milaneschi, Y.Mitchell, P. B.Montgomery, G. W.Morken, G.Mors, O.Mühleisen, T. W.Müller-Myhsok, B.Myers, R. M.Nievergelt, C. M.Nurnberger, J. I.O'Donovan, M. C.Loohuis, L. M. O.Ophoff, R.Oruc, L.Owen, M. J.Paciga, S. A.Penninx, B. W. J. H.Perry, A.Pfennig, A.Potash, J. B.Preisig, M.Reif, A.Rivas, F.Rouleau, G. A.Schofield, P. R.Schulze, T. G.Schwarz, M.Scott, L.Sinnamon, G. C. B.Stahl, E. A.Strauss, J.Turecki, G.Van der Auwera, S.Vedder, H.Vincent, J. B.Willemsen, G.Witt, C. C.Wray, N. R.Xi, H. S.Tadic, A.Dahmen, N.Schott, B. H.Cichon, S.Nöthen, M. M.Ripke, S.Mobascher, A.Rujescu, D.Lieb, K.Roepke, S.Schmahl, C.Bohus, M.Rietschel, M.
    Translational psychiatry 2017-06-20; 7(6): Art. e1155
    Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
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    Types and Strains: Their Essential Role in Understanding Protein Aggregation in Neurodegenerative Diseases. 

    Wemheuer, Wiebke M.; Wrede, Arne; Schulz-Schaeffer, Walter J.
    Frontiers in aging neuroscience 2017; 9: Art. 187
    Protein misfolding and aggregation is a key event in diseases like Alzheimer's disease (AD) or Parkinson's disease (PD) and is associated with neurodegeneration. Factors that initiate protein misfolding and the role of protein aggregation in the pathophysiology of disease pose major challenges to the neuroscientific community. Interestingly, although the accumulation of the same misfolded protein, e.g., α-synuclein is detectable in all idiopathic PD patients, the disease spectrum covers a variety of different clinical presentations and disease courses. In a more recent attempt this clinical variance is being explained in analogy to prion diseases by different protein aggregate conformations. In prion diseases a relationship between protein aggregate conformation properties and the clinical disease course was shown by relating different prion types to a dementia and an ataxic disease course in Creutzfeldt-Jakob patients. This principle is currently transferred to AD, PD and other neurodegenerative diseases with protein aggregation. However, differences in protein aggregate conformation are frequently addressed as disease strains. The term "strain" also derives from prion research and evolved by adopting the virus terminology at a time when transmissible spongiform encephalopathies (TSEs; later called prion diseases) were assumed to be caused by a virus. The problem is that in virus taxonomy the term "type" refers to properties of the disease agent itself and the term "strain" refers to host associated factors that interact with the disease agent and may moderately modify the clinical disease presentation. Strain factors can be discovered only after transmission and passaging of the agent in a host of a different species. The incorrect use of the terminology confuses disease agent and host factors and hampers the understanding of the pathophysiology of protein aggregate-associated neurodegenerative diseases. In this review article the discoveries are reviewed that explain how the terms "type" and "strain" emerged for unconventional disease agents. This may help to avoid confusion in the terminology of protein aggregation diseases and to reflect correctly the impact of protein aggregate conformation as well as host factor contribution on different clinical variations of AD, PD and other neurodegenerative diseases.
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    Rab Interacting Molecules 2 and 3 Directly Interact with the Pore-Forming CaV1.3 Ca2+ Channel Subunit and Promote Its Membrane Expression. 

    Picher, Maria M; Oprişoreanu, Ana-Maria; Jung, SangYong; Michel, Katrin; Schoch, Susanne; Moser, Tobias
    Frontiers in cellular neuroscience 2017; 11: Art. 160
    Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca2+ channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca2+ channel complex, the key signaling element at the AZ. Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). Co-expressing full-length RIM2α with a Ca2+ channel complex closely resembling that of IHCs (CaV1.3α1-CaVß2a) in HEK293 cells doubled the Ca2+-current and shifted the voltage-dependence of Ca2+ channel activation by approximately +3 mV. Co-expression of the short RIM isoform RIM3γ increased the CaV1.3α1-CaVß2a-mediated Ca2+-influx in HEK293 cells, but disruption of RIM3γ in mice left Ca2+-influx in IHCs and hearing intact. In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.
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    Immune and myodegenerative pathomechanisms in inclusion body myositis. 

    Keller, Christian W.; Schmidt, Jens; Lünemann, Jan D.
    Annals of clinical and translational neurology 2017-06; 4(6) p.422-445
    Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.
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    Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice. 

    Meyer-Kovac, Judit; Kolbe, Isa; Ehrhardt, Lea; Leliavski, Alexei; Husse, Jana; Salinas, Gabriela; Lingner, Thomas; Tsang, Anthony H.; Barclay, Johanna L.; Oster, Henrik
    Molecular metabolism 2017-06; 6(6) p.512-523
    OBJECTIVE: Circadian Clock gene mutant mice show dampened 24-h feeding rhythms and an increased sensitivity to high-fat diet (HFD) feeding. Restricting HFD access to the dark phase counteracts its obesogenic effect in wild-type mice. The extent to which altered feeding rhythms are causative for the obesogenic phenotype of Clock mutant mice, however, remains unknown. METHODS: Metabolic parameters of wild-type (WT) and ClockΔ19 mutant mice (MT) were investigated under ad libitum and nighttime restricted HFD feeding. Liver circadian clock function was partially rescued by hydrodynamic tail vein delivery of WT-Clock DNA vectors in mutant mice and transcriptional, metabolic, endocrine and behavioral rhythms studied. RESULTS: Nighttime-restricted feeding restored food intake, but not body weight regulation in MT mice under HFD, suggesting Clock-dependent metabolic dysregulation downstream of circadian appetite control. Liver-directed Clock gene therapy partially restored liver circadian oscillator function and transcriptome regulation without affecting centrally controlled circadian behaviors. Under HFD, MT mice with partially restored liver clock function (MT-LR) showed normalized body weight gain, rescued 24-h food intake rhythms, and WT-like energy expenditure. This was associated with decreased nighttime leptin and daytime ghrelin levels, reduced hepatic lipid accumulation, and improved glucose tolerance. Transcriptome analysis revealed that hepatic Clock rescue in MT mice affected a range of metabolic pathways. CONCLUSION: Liver Clock gene therapy improves resistance against HFD-induced metabolic impairments in mice with circadian clock disruption. Restoring or stabilizing liver clock function might be a promising target for therapeutic interventions in obesity and metabolic disorders.
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    Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia. 

    Jaramillo, S.; Benner, A.; Krauter, J.; Martin, H.; Kindler, T.; Bentz, M.; Salih, H. R.; Held, G.; Köhne, C.-H.; Götze, K.; et al.
    Lübbert, M.Kündgen, A.Brossart, P.Wattad, M.Salwender, H.Hertenstein, B.Nachbaur, D.Wulf, G.Horst, H.-A.Kirchen, H.Fiedler, W.Raghavachar, A.Russ, G.Kremers, S.Koller, E.Runde, V.Heil, G.Weber, D.Göhring, G.Döhner, K.Ganser, A.Döhner, H.Schlenk, R. F.
    Blood cancer journal 2017-05-26; 7(5): Art. e564
    The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P<0.0001, each), and further reduced by 2 days (P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P<0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.
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    Primary Progressive Multiple Sclerosis: Putting Together the Puzzle. 

    Abdelhak, Ahmed; Weber, Martin S.; Tumani, Hayrettin
    Frontiers in neurology 2017; 8: Art. 234
    The focus of multiple sclerosis research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors such as genetic susceptibility, age, and Epstein-Barr virus (EBV) infection may interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter as well as of the meninges with inflammatory cells such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies may be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future.
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    Experimental Porcine Toxoplasma gondii Infection as a Representative Model for Human Toxoplasmosis. 

    Nau, Julia; Eller, Silvia Kathrin; Wenning, Johannes; Spekker-Bosker, Katrin Henrike; Schroten, Horst; Schwerk, Christian; Hotop, Andrea; Groß, Uwe; Däubener, Walter
    Mediators of inflammation 2017; 2017: Art. 3260289
    Porcine infections are currently not the state-of-the-art model to study human diseases. Nevertheless, the course of human and porcine toxoplasmosis is much more comparable than that of human and murine toxoplasmosis. For example, severity of infection, transplacental transmission, and interferon-gamma-induced antiparasitic effector mechanisms are similar in pigs and humans. In addition, the severe immunosuppression during acute infection described in mice does not occur in the experimentally infected ones. Thus, we hypothesise that porcine Toxoplasma gondii infection data are more representative for human toxoplasmosis. We therefore suggest that the animal model chosen must be critically evaluated for its assignability to human diseases.
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    The ribosome biogenesis factor yUtp23/hUTP23 coordinates key interactions in the yeast and human pre-40S particle and hUTP23 contains an essential PIN domain. 

    Wells, Graeme R.; Weichmann, Franziska; Sloan, Katherine E.; Colvin, David; Watkins, Nicholas J.; Schneider, Claudia
    Nucleic acids research 2017-05-05; 45(8) p.4796-4809
    Two proteins with PIN endonuclease domains, yUtp24(Fcf1)/hUTP24 and yUtp23/hUTP23 are essential for early pre-ribosomal (r)RNA cleavages at sites A0, A1/1 and A2/2a in yeast and humans. The yUtp24/hUTP24 PIN endonuclease is proposed to cleave at sites A1/1 and A2/2a, but the enzyme cleaving at site A0 is not known. Yeast yUtp23 contains a degenerate, non-essential PIN domain and functions together with the snR30 snoRNA, while human hUTP23 is associated with U17, the human snR30 counterpart. Using in vivo RNA-protein crosslinking and gel shift experiments, we reveal that yUtp23/hUTP23 makes direct contacts with expansion sequence 6 (ES6) in the 18S rRNA sequence and that yUtp23 interacts with the 3΄ half of the snR30 snoRNA. Protein-protein interaction studies further demonstrated that yeast yUtp23 and human hUTP23 directly interact with the H/ACA snoRNP protein yNhp2/hNHP2, the RNA helicase yRok1/hROK1(DDX52), the ribosome biogenesis factor yRrp7/hRRP7 and yUtp24/hUTP24. yUtp23/hUTP23 could therefore be central to the coordinated integration and release of ES6 binding factors and likely plays a pivotal role in remodeling this pre-rRNA region in both yeast and humans. Finally, studies using RNAi-rescue systems in human cells revealed that intact PIN domain and Zinc finger motifs in human hUTP23 are essential for 18S rRNA maturation.
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    Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration. 

    Zhang, Jian-Nan; Koch, Jan C
    Neural regeneration research 2017-05; 12(5) p.692-695
    Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2 (CRMP2) might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases.
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    p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo. 

    Alexandrova, Evguenia M.; Mirza, Safia A.; Xu, Sulan; Schulz-Heddergott, Ramona; Marchenko, Natalia D.; Moll, Ute M.
    Cell death & disease 2017-03-09; 8(3): Art. e2661
    Missense mutations in TP53 comprise >75% of all p53 alterations in cancer, resulting in highly stabilized mutant p53 proteins that not only lose their tumor-suppressor activity, but often acquire oncogenic gain-of-functions (GOFs). GOF manifests itself in accelerated tumor onset, increased metastasis, increased drug resistance and shortened survival in patients and mice. A known prerequisite for GOF is mutant p53 protein stabilization, which itself is linked to aberrant protein conformation. However, additional determinants for mutant p53 stabilization likely exist. Here we show that in initially heterozygous mouse tumors carrying the hotspot GOF allele R248Q (p53Q/+), another necessary prerequisite for mutant p53 stabilization and GOF in vivo is loss of the remaining wild-type p53 allele, termed loss-of-heterozygosity (LOH). Thus, in mouse tumors with high frequency of p53 LOH (osteosarcomas and fibrosarcomas), we find that mutant p53 protein is stabilized (16/17 cases, 94%) and tumor onset is significantly accelerated compared with p53+/- tumors (GOF). In contrast, in mouse tumors with low frequency of p53 LOH (MMTV-Neu breast carcinomas), mutant p53 protein is not stabilized (16/20 cases, 80%) and GOF is not observed. Of note, human genomic databases (TCGA, METABRIC etc.) show a high degree of p53 LOH in all examined tumor types that carry missense p53 mutations, including sarcomas and breast carcinomas (with and without HER2 amplification). These data - while cautioning that not all genetic mouse models faithfully represent the human situation - demonstrate for the first time that p53 LOH is a critical prerequisite for missense mutant p53 stabilization and GOF in vivo.
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    Nano-formulated curcumin accelerates acute wound healing through Dkk-1-mediated fibroblast mobilization and MCP-1-mediated anti-inflammation 

    Dai, Xinyi; Liu, Juan; Zheng, Huaiyuan; Wichmann, Johannes; Hopfner, Ursula; Sudhop, Stefanie; Prein, Carina; Shen, Yi; Machens, Hans-Günther; Schilling, Arndt F
    NPG Asia Materials 2017; 9(3): Art.
    Turmeric, a product of Curcuma longa, has a very long history of being used for the treatment of wounds in many Asian countries. Curcumin, the principal curcuminoid of turmeric, has recently been identified as a main mediator of turmeric’s medicinal properties. However, the inherent limitations of the compound itself, such as hydrophobicity, instability, poor absorption and rapid systemic elimination, pose big hurdles for translation to wider clinical application. We present here an approach for engineering curcumin/gelatin-blended nanofibrous mats (NMs) by electrospinning to adequately enhance the bioavailability of the hydrophobic curcumin for wound repair. Curcumin was successfully formulated as an amorphous nanosolid dispersion and favorably released from gelatin-based biomimetic NMs that could be easily applied topically to experimental wounds. We show synergistic signaling by the released curcumin during the healing process: (i) mobilization of wound site fibroblasts by activating the Wnt signaling pathway, partly mediated through Dickkopf-related protein-1, and (ii) persistent inhibition of the inflammatory response through decreased expression of monocyte chemoattractant protein-1 by fibroblasts. With a combination of these effects, the curcumin/gelatin-blended NMs enhanced the regenerative process in a rat model of acute wounds, providing a method for translating this ancient medicine for use in modern wound therapy
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    Combination of general anesthesia and peripheral nerve block with low-dose ropivacaine reduces postoperative pain for several days after outpatient arthroscopy: A randomized controlled clinical trial. 

    Büttner, Benedikt; Mansur, Ashham; Hinz, José; Erlenwein, Joachim; Bauer, Martin; Bergmann, Ingo
    Medicine 2017; 96(6): Art. e6046
    BACKGROUND: Effective methods for postoperative pain relief are an important concern in outpatient surgery. For arthroscopies we combine a single-shot peripheral nerve block using low-volume, low-concentration ropivacaine with general anesthesia. We hypothesized that the patients would have less postoperative pain and be more rapidly home ready than after general anesthesia alone. METHODS: Patients (American Society of Anesthesiologists I-III, 18-80 years old) scheduled for outpatient arthroscopy on the upper or lower extremity were randomized to have either a combination of peripheral nerve block and general anesthesia (NB + GA, study group) or general anesthesia alone (GA, control group). The relevant nerve was localized by ultrasound and 10 mL ropivacaine 0.2% was injected. General anesthesia was with propofol and remifentanil. Numeric rating scales were used to assess pain and patient satisfaction in the recovery room, on the evening of surgery, and on the following 2 days. RESULTS: A total of 120 patients participated in the study (NB + GA: 61; GA: 59). The percentage of patients reporting relevant pain in the recovery room were 0% versus 44% (P < 0.001), on the evening after surgery 3% versus 80% (P < 0.001), and on days 1 and 2 postsurgery 12% versus 73% and 12% versus 64% (NB + GA vs GA, respectively). Median time to home discharge was NB + GA 34.5 min (range 15-90) versus GA 55 min (20-115) (P < 0.001). CONCLUSIONS: The combination of a peripheral nerve block with low-dose ropivacaine and general anesthesia reduced postoperative pain compared with general anesthesia alone for several days after outpatient arthroscopy. It also shortened the time to home discharge.
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    Predicting primary progressive aphasias with support vector machine approaches in structural MRI data. 

    Bisenius, Sandrine; Mueller, Karsten; Diehl-Schmid, Janine; Fassbender, Klaus; Grimmer, Timo; Jessen, Frank; Kassubek, Jan; Kornhuber, Johannes; Landwehrmeyer, Bernhard; Ludolph, Albert; et al.
    Schneider, AnjaAnderl-Straub, SarahStuke, KatharinaDanek, AdrianOtto, MarkusSchroeter, Matthias L.
    NeuroImage. Clinical 2017; 14 p.334-343
    Primary progressive aphasia (PPA) encompasses the three subtypes nonfluent/agrammatic variant PPA, semantic variant PPA, and the logopenic variant PPA, which are characterized by distinct patterns of language difficulties and regional brain atrophy. To validate the potential of structural magnetic resonance imaging data for early individual diagnosis, we used support vector machine classification on grey matter density maps obtained by voxel-based morphometry analysis to discriminate PPA subtypes (44 patients: 16 nonfluent/agrammatic variant PPA, 17 semantic variant PPA, 11 logopenic variant PPA) from 20 healthy controls (matched for sample size, age, and gender) in the cohort of the multi-center study of the German consortium for frontotemporal lobar degeneration. Here, we compared a whole-brain with a meta-analysis-based disease-specific regions-of-interest approach for support vector machine classification. We also used support vector machine classification to discriminate the three PPA subtypes from each other. Whole brain support vector machine classification enabled a very high accuracy between 91 and 97% for identifying specific PPA subtypes vs. healthy controls, and 78/95% for the discrimination between semantic variant vs. nonfluent/agrammatic or logopenic PPA variants. Only for the discrimination between nonfluent/agrammatic and logopenic PPA variants accuracy was low with 55%. Interestingly, the regions that contributed the most to the support vector machine classification of patients corresponded largely to the regions that were atrophic in these patients as revealed by group comparisons. Although the whole brain approach took also into account regions that were not covered in the regions-of-interest approach, both approaches showed similar accuracies due to the disease-specificity of the selected networks. Conclusion, support vector machine classification of multi-center structural magnetic resonance imaging data enables prediction of PPA subtypes with a very high accuracy paving the road for its application in clinical settings.
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    Predicting behavioral variant frontotemporal dementia with pattern classification in multi-center structural MRI data. 

    Meyer, Sebastian; Mueller, Karsten; Stuke, Katharina; Bisenius, Sandrine; Diehl-Schmid, Janine; Jessen, Frank; Kassubek, Jan; Kornhuber, Johannes; Ludolph, Albert C.; Prudlo, Johannes; et al.
    Schneider, AnjaSchuemberg, KatharinaYakushev, IgorOtto, MarkusSchroeter, Matthias L.
    NeuroImage. Clinical 2017; 14 p.656-662
    PURPOSE: Frontotemporal lobar degeneration (FTLD) is a common cause of early onset dementia. Behavioral variant frontotemporal dementia (bvFTD), its most common subtype, is characterized by deep alterations in behavior and personality. In 2011, new diagnostic criteria were suggested that incorporate imaging criteria into diagnostic algorithms. The study aimed at validating the potential of imaging criteria to individually predict diagnosis with machine learning algorithms. MATERIALS & METHODS: Brain atrophy was measured with structural magnetic resonance imaging (MRI) at 3 Tesla in a multi-centric cohort of 52 bvFTD patients and 52 healthy control subjects from the German FTLD Consortium's Study. Beside group comparisons, diagnosis bvFTD vs. controls was individually predicted in each subject with support vector machine classification in MRI data across the whole brain or in frontotemporal, insular regions, and basal ganglia known to be mainly affected based on recent meta-analyses. Multi-center effects were controlled for with a new method, "leave one center out" conjunction analyses, i.e. repeatedly excluding subjects from each center from the analysis. RESULTS: Group comparisons revealed atrophy in, most consistently, the frontal lobe in bvFTD beside alterations in the insula, basal ganglia and temporal lobe. Most remarkably, support vector machine classification enabled predicting diagnosis in single patients with a high accuracy of up to 84.6%, where accuracy was highest in a region-of-interest approach focusing on frontotemporal, insular regions, and basal ganglia in comparison with the whole brain approach. CONCLUSION: Our study demonstrates that MRI, a widespread imaging technology, can individually identify bvFTD with high accuracy in multi-center imaging data, paving the road to personalized diagnostic approaches in the future.
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    The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer. 

    Rühlmann, Felix; Nietert, Manuel; Sprenger, Thilo; Wolff, Hendrik A.; Homayounfar, Kia; Middel, Peter; Bohnenberger, Hanibal; Beissbarth, Tim; Ghadimi, B. Michael; Liersch, Torsten; et al.
    Conradi, Lena-Christin
    Journal of Cancer 2017; 8(7) p.1229-1237
    The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity. For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up. The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up. High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.
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    Prevalence of 'Food Addiction' as Measured with the Yale Food Addiction Scale 2.0 in a Representative German Sample and Its Association with Sex, Age and Weight Categories. 

    Hauck, Carolin; Weiß, Annegret; Schulte, Erica Marla; Meule, Adrian; Ellrott, Thomas
    Obesity facts 2017; 10(1) p.12-24
    BACKGROUND/AIMS: To assess the prevalence and correlates of addictive-like eating behavior in Germany. METHODS: The German version of the Yale Food Addiction Scale (YFAS) 2.0 was used to investigate, for the first time, the prevalence of 'food addiction' in a representative sample aged 18-65 years (N = 1,034). RESULTS: The prevalence of 'food addiction' measured by the YFAS 2.0 was 7.9%. Individuals meeting criteria for 'food addiction' had higher BMI and were younger than individuals not meeting the threshold. Underweight (15.0%) and obese (17.2%) individuals exhibited the highest prevalence rate of 'food addiction'. Addictive-like eating was not associated with sex, education level, or place of residence. CONCLUSION: YFAS 2.0 'food addiction' was met by nearly 8% of the population. There is a non-linear relationship between addictive-like eating and BMI, with the highest prevalence among underweight and obese persons. These findings suggest that 'food addiction' may be a contributor to overeating but may also reflect a distinct phenotype of problematic eating behavior not synonymous with obesity. Further, the elevated prevalence of YFAS 2.0 'food addiction' among underweight individuals may reflect an overlap with eating disorders and warrants attention in future research.
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    Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms. 

    Garcia-Esparcia, Paula; López-González, Irene; Grau-Rivera, Oriol; García-Garrido, María Francisca; Konetti, Anusha; Llorens, Franc; Zafar, Saima; Carmona, Margarita; Del Rio, José Antonio; Zerr, Inga; et al.
    Gelpi, EllenFerrer, Isidro
    Frontiers in neurology 2017; 8: Art. 89
    OBJECTIVES: The goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology. METHODS: Real-time quantitative PCR, mitochondrial enzymatic assays, and analysis of β-amyloid, tau, and synuclein species were used. RESULTS: The main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer's disease. Altered solubility and aggregation of α-synuclein, increased β-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble β-amyloid are found in DLB. However, increased soluble β-amyloid 1-40 and β-amyloid 1-42, and increased TNFα mRNA and protein expression, distinguish rpDLB. CONCLUSION: Molecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response.
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