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International audience; Meeting Abstract: P028 - ACTRIMS Forum, New Orleans, LA, feb 2016

International audience; OBJECTIVE:To study long-term outcomes in patients treated with IFNB-1b after clinically isolated syndrome (CIS). BACKGROUND:In BENEFIT, patients with CIS were randomized to IFNB-1b or placebo (PL) treatment. After the second clinical event or after 2 years, all patients were treated with IFNB-1b. Mean delay of IFNB-1b in PL was 1.33 years. Comprehensive clinical, MRI, and PROs at 11 years post-randomization are reported. DESIGN/METHODS:All originally randomized patients were asked to undergo clinical, MRI, laboratory, and PRO assessments 11 years after randomization. RESULTS:281 patients were identified (60[percnt] of originally randomized, 72.6[percnt] of eligible patients at participating sites); 278 enrolled. Baseline characteristics were similar to the original BENEFIT population. At Year 11, patients randomized to IFNB-1b still had lower overall annualized relapse rate (p=0.0018) and longer time to first relapse (p=0.0005) and clinically definite MS (p=0.0012). Median EDSS score was 2.0 (change from baseline 0.5) in both groups. PASAT scores remained high (overall median 56 [IQR 10]). Of the 81.3[percnt] working at CIS start, 73.4[percnt] were still employed (64.4[percnt] fulltime). 12.2[percnt] retired early or were on long-term disability (2.9[percnt] at baseline). 64.0[percnt] did not report any sick leave during the past 12 months. Health-related quality of life remained stable (median [IQR] change from baseline EQ-5D: 0.000 [0.209], FAMS TOI: -7.54 [27.17]. Median (IQR) fatigue (FSMC) score: 45.00 (40.00), 46[percnt] of patients without fatigue (cut-off score\textless43), median (IQR) depression (CES-D) score: 9.00 (15.00). MRI findings were similar across groups: 86.4[percnt] had no gadolinium-enhancing lesions; median (IQR) number of new T2 lesions since 5-year MRI: 2.0 (6.0), T2 volume: 1760.0mm³ (3963.0mm³), cortical lesions: 2.0 (5.0), brain volume 1519.0cm³ (152.0mm³), mean cortical thickness 2.64mm³ (0.56mm³). CONCLUSIONS:Results from BENEFIT11 support a long-term impact of early treatment with IFNB-1b on clinical measures, including cognition and fatigue, and health economic and MRI outcomes. Study Supported by:Bayer HealthCare Pharmaceuticals Disclosure: Dr. Edan has received personal compensation for activities with LFB, Biogenidec, speaking from Serono, Inc., Sanofi, Teva, and Bayer Pharmaceuticals Corporation as a consultant and/or scientific advisory board member. Dr. Freedman has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, and Teva Canada Innovation. Dr. Montalban has received personal compensation for activities with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. Dr. Miller has received personal compensation for activities with UCL Institute of Neurology, Biogen Idec, GlaxoSmithKline Inc., Novartis, Merck & Co. Inc., Chugai, and Mitsubishi Pharma. Dr. Miller has received personal compensation in an editorial capac Dr. Hartung has holds stock and/or stock options from Opexa Therapeutics. Dr. Hemmer has received personal compensation for activities with Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GlaxoSmithKline, Chugai Pharmaceutical, Micromet, and Genzyme as a scientific advisory board member. Dr. Fox has received personal compensation for activities Acorda Therapeutics, Bayer Pharmaceuticals Corporation, Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, GlaxoSmithKline, and Novartis. Dr. Barkhof has received personal compensation for activities with Bayer Schering Pharma, Sanofi, Genzyme, Biogen Idec, Teva, Merck Serono, Novartis, Roche, Synthon BV, and Janssen Research as a consultant. Dr. Schippling has received personal compensation for activities with Novartis. Dr. Schippling has received research support from Bayer Schering and Biogen Idec. Dr. Schulze has received personal compensation for activities with PAREXEL International as an employee. Dr. Pleimes has received personal compensation for activities with Myelo Therapeutics GmbH as an employee, and with Bayer Pharmaceuticals Corp. as an employee and consultant. Dr. Pohl has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Pohl owns stock and/or stock options in Bayer Pharmaceuticals Corporation. Dr. Sandbrink has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Sandbrink holds stock and/or stock options in Bayer Pharmaceuticals Corporation. Dr. Suarez has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Wicklein has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Kappos has received personal compensation for activities with Actelion Pharmaceuticals

Auf neuronaler Ebene besteht zwischen der Wahrnehmung von Schmerzen und dem Empfinden negativer Emotionen eine enge Verbindung. Mit Hilfe einer Metaanalyse sollten Überlappungen in diesen Verarbeitungsnetzwerken dargestellt werden. 138 fMRT-Studien bis einschließlich Februar 2007 wurden analysiert. Es handelte sich dabei um 84 Emotionsstudien und 54 Schmerzstudien, deren Ergebnisse in Hinblick auf ihre Koordinatenangaben in 25 Gehirnregionen miteinander verglichen wurden. Die durchgeführte statistische Auswertung zeigte Ähnlichkeiten innerhalb dieser neuronalen Verarbeitungsprozesse hauptsächlich innerhalb von Strukturen des limbischen Systems. The sensation of physical pain and negative emotions is closely connected on a neuronal basis. A meta-analysis was conducted to find overlapping brain activation in the processing of these two perceptions. 138 fMRT-studies until February 2007 have been analysed for this purpose. 84 were studies dealing with negative emotions and 54 studies with pain. The results from these studies were compared using coordinates in 25 different regions of the human brain. The statistical analyses revealed an overlapping of neuronal activity mainly in limbic structures.

Journal Hochschuldidaktik ; 21. Jahrgang 2010 Heft 1

Journal Hochschuldidaktik ; 21. Jahrgang 2010 Heft 1

Die ER-assoziierte Proteindegradation (ERAD) ist Teil des Qualitätskontrollsystems am ER, um der Akkumulation von fehlgefalteten Proteinen im ER entgegenzuwirken. Hierbei werden ERAD-Substrate mit Hilfe von E3-Ligasen wie z.B. HRD1 ubiquityliert und anschließend durch den p97-Ufd1-Npl4 Komplex aus der ER-Membran extrahiert. Im Zytosol werden diese extrahierten Proteine vom 26S Proteasom abgebaut. Für die Retrotranslokation von ERAD- Substraten werden zudem die Membranproteine Derlin-1 und VIMP benötigt, welche mit p97 assoziieren und einen Proteinkomplex bilden. HERP ist ein ER-lokalisiertes Protein, dessen Synthese durch den UPR (unfolded protein response) als Antwort auf die Akkumulation von fehlgefalteten Proteinen im ER induziert wird. Dies deutet auf eine Rolle von HERP im ERAD hin. Interessanterweise besitzt HERP eine sogenannte UBL-Domäne. Für andere Proteine mit UBL-Domäne konnte eine Interaktion dieser Domäne mit dem Proteasom nachgewiesen werden. Daher kann angenommen werden, dass HERP ebenfalls mit dem Proteasom interagiert und dies zur ER- Membran rekrutiert, wo es für den Abbau von ERAD-Substraten benötigt wird. Das Ziel der vorliegenden Arbeit war es, die Rolle von HERP innerhalb des UPR zu ermitteln. Die hier präsentierten Daten zeigen, dass HERP essentiell für den Abbau des ERAD-Modell- Substrates CD3-delta ist. Somit hat HERP tatsächlich eine Rolle im ERAD. Außerdem wird eine direkte Interaktion von HERP mit der E3-Ligase HRD1 nachgewiesen. Es wird zudem gezeigt, dass HERP und HRD1 einen Proteinkomplex mit p97, Derlin-1 und eventuell auch mit VIMP bilden. Dieser ERAD Komplex ist folglich sowohl für die Ubiquitylierung als auch die Retrotranslokation von ERAD-Substraten verantwortlich und garantiert somit die effiziente Prozessierung von Proteinen aus dem ER. Zudem wird gezeigt, dass die UBL-Domäne von HERP im Gegensatz zu anderen UBL- Domänen nicht mit dem Proteasom interagiert. Somit kann nicht mehr davon ausgegangen werden, dass Proteasombindung eine Gemeinsamkeit aller Proteine mit UBL-Domäne ist. Dagegen wird eine Interaktion der UBL-Domäne von HERP mit dem deubiquitylierenden Enzym USP7 nachgewiesen. Dies deutet darauf hin, dass auch Deubiquitylierung eine wichtige Rolle im ERAD-Prozess spielt. ER-associated protein degradation (ERAD) is part of the ER quality control system dealing with the accumulation of misfolded proteins in the ER. This process requires polyubiquitylation of ERAD substrates involving E3 ligases, such as HRD1, and their subsequent extraction from the ER membrane by the p97-Ufd1-Npl4 complex. Retrotranslocation of substrates into the cytosol for degradation by the 26S proteasome also involves the membrane proteins Derlin-1 and VIMP, which are associated with p97 to form a protein complex. The ER-resident protein HERP was shown to be upregulated by the unfolded protein response pathway (UPR) upon the accumulation of misfolded proteins in the ER. It was therefore considered to function in ERAD. Interestingly, HERP contains a UBL domain. In other proteins this domain facilitates an interaction with the proteasome, suggesting that HERP might recruit the proteasome to the ER membrane for efficient ERAD. The aim of this study was to investigate the function of HERP within the UPR. The findings presented here demonstrate that HERP is essential for the degradation of a model ERAD substrate. Thus, HERP indeed has a role in ERAD. Moreover, the data show that HERP directly interacts with the E3 ligase HRD1 and the two proteins form a common protein complex with p97, Derlin-1 and possibly also with VIMP. This suggests that both ubiquitylation and retrotranslocation of ER proteins are performed by one protein complex, enabling an efficient processing of ERAD substrates. This study also demonstrates that the UBL domain of HERP does not share the proteasome binding property of other UBL domains, suggesting that proteasome binding cannot be considered a general feature of all UBL domains. Instead, the HERP UBL domain is able to interact with the deubiquitylating enzyme USP7. Therefore, deubiquitylation might also be an important aspect in the proteasome-dependent degradation of misfolded ER proteins.

Objective: To assess outcomes for patients treated with interferon beta-1b immediately after clinicallyisolated syndrome (CIS) or after a short delay.Methods: Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment)were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayedtreatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients onplacebo could switch to interferon beta-1b or another treatment. Eleven years after randomization,patients were reassessed.Results: Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible atparticipating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk ofCDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p 50.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931[253, 3,296]; p50.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p50.0018). Only25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiplesclerosis. Expanded Disability Status Scale scores remained low and stable, with no differencebetween treatment arms (median [Q1,Q3]: 2.0 [1.0, 3.0]). The early-treatment group had better PacedAuditory Serial Addition Task–3 total scores (p 5 0.0070). Employment rates remained high, andhealth resource utilization tended to be low in both groups.MRI metrics did not differ between groups.Conclusions: Although the delay in treatment was relatively short, several clinical outcomesfavored earlier treatment. Along with low rates of disability and disease progression in bothgroups, this supports the value of treatment at CIS., NCT01795872.