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Institut
- Medizin (380) (entfernen)
A recent report showed PINK1 transcript levels to be up- or down-regulated by the gain or loss of Ataxin-2 function, respectively, in human blood, in a human neural cell line and in mouse tissues. These observations may have profound implications for the regulation of cell growth and may be medically exploited for the treatment of cancer and neural atrophy...
Alzheimer’s disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aβ/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not β-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.
Background: Research has implicated that changes in zinc (Zn) metabolism may be associated with the biological underpinnings of eating disorders, in particular anorexia nervosa. However, to date research on the role of Zn in patients with bulimia nervosa (BN) is scarce.
Objective: We aimed to explore serum Zn concentrations in young patients with BN, with a focus on the stage of the disorder, comparing acutely ill and recovered patients with BN with healthy controls.
Methods: Serum Zn concentrations were obtained from healthy controls and from acutely ill and remitted young patients with BN. Mean duration of remission was 4.0±3.5 years.
Results: Remitted patients showed elevated serum Zn concentrations when compared to controls (Cohen’s d=2.022), but concentrations were still in the normal range. Acutely ill patients also had higher serum Zn levels when compared to controls (all values still being within the reference range, Cohen’s d=0.882). There was no difference between acutely ill and remitted patients with BN in serum Zn concentrations. Of note, remitted patients had a significantly higher body weight when compared to the other two groups. Overall, there were no significant differences in dietary preferences with regard to Zn containing foods between the groups.
Conclusion: The present study provides preliminary evidence that the underlying factors for changes in Zn serum concentrations in young patients with BN do not vary with regard to the stage of illness (acute versus remitted BN). Further prospective research is needed in order to disentangle the possible interplay between serum Zn status and bulimic eating behaviors.
Hypoxia-induced miR-210 displays a pro-survival, cytoprotective and pro-angiogenic role in several in vitro systems. In vivo, we previously found that miR-210 inhibition increases ischemic damage. Here we describe the generation of a versatile transgenic mouse model allowing the evaluation of miR-210 therapeutic potential in ischemic cardiovascular diseases. We generated a Tet-On miR-210 transgenic mouse strain (TG-210) by targeted transgenesis in the ROSA26 locus. To functionally validate miR-210 transgenic mice, hindlimb ischemia was induced by femoral artery dissection. Blood perfusion was evaluated by power Doppler while tissue damage and inflammation were assessed by histological evaluation. We found that miR-210 levels were rapidly increased in TG-210 mice upon doxycycline administration. miR-210 overexpression was maintained over time and remained within physiological levels in multiple tissues. When hindlimb ischemia was induced, miR-210 overexpression protected from both muscular and vascular ischemic damage, decreased inflammatory cells density and allowed to maintain a better calf perfusion. In conclusion, we generated and functionally validated a miR-210 transgenic mouse model. Albeit validated in the context of a specific cardiovascular ischemic disease, miR-210 transgenic mice may also represent a useful model to assess the function of miR-210 in other physio-pathological conditions.
Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.
The former and current multiple sclerosis (MS) classifications are essential for describing different phenotypes and disease dynamics. To establish personalized treatment regimes, further clinical and paraclinical parameters have to be considered such as imaging, cerebrospinal fluid (CSF) findings, past disease-modifying therapies (DMTs), and disease activity under these therapies. In clinical practice, this information is often difficult to overview. Especially, patients with a long course of disease offer an extensive medical history so that comprehending all of the necessary information can be very time consuming.
Introduction: The 2017 update to the Global Initiative for Obstructive Lung Disease (GOLD) strategy document includes recommendations for treatment intensification or step-down in chronic obstructive pulmonary disease (COPD), although recognises that limited supporting information is available.
DACCORD is an ongoing observational, non-interventional study, recruiting patients following COPD maintenance treatment change or initiation, a subset of whom were receiving a long-acting β2-agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) on entry. Since there were no requirements in terms of prior medication (and no washout before commencing LABA/LAMA FDC), this provides an opportunity to generate "real world" data to test the GOLD 2017 recommendations.
Methods: To reduce heterogeneity, the current analyses include patients receiving indacaterol/glycopyrronium at baseline, and who, prior to the study, were receiving no COPD maintenance medication ("none"), LABA or LAMA monotherapy ("mono"), LABA plus inhaled corticosteroid (ICS; "LABA/ICS"), or triple therapy ("triple"). At the baseline visit, data collected included: demographic and disease characteristics; COPD Assessment Test (CAT); and exacerbations in the 6 months prior to entry. At 3, 6, 9 and 12 months data on exacerbations were collected, with CAT recorded at 3 and 12 months.
Results: A total of 2724 patients were included in the baseline analyses: 795, 954, 598 and 377 in the "none", "mono", "LABA/ICS" and "triple" subgroups, respectively. There were no clinically relevant differences in baseline demographics between the four groups. In terms of disease characteristics, the "triple" group had the highest proportion of patients with a disease duration of more than 1 year since diagnosis and with severe/very severe airflow limitation, but a similar percentage of non-exacerbators compared to the "none" group.
Over the 1-year follow-up, the majority of patients in all four subgroups did not exacerbate (exacerbation rates 0.16, 0.19, 0.21, and 0.26 in the "none", "mono", "LABA/ICS" and "triple" groups, respectively). At 12 months, 61.4%, 65.0%, 71.0% and 52.4% of patients had a clinically relevant improvement in CAT score.
Conclusions: Overall, the results support the GOLD recommendations in suggesting that a switch from a mono-bronchodilator or LABA plus ICS to LABA/LAMA FDC is a valid treatment option for patients with COPD. The results also validate the use of a LABA/LAMA FDC as initial maintenance treatment for COPD, and provide first "real world" evidence to support the newly added "step down" recommendation (from triple to LABA/LAMA FDC).
The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source—such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)—as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy—suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.
Glioblastoma multiforme accounts for more than 80% of all malignant gliomas in adults and a minor fraction of new annual cases occurs in children. In the last decades, research shed light onto the molecular patterns underlying human malignancies which resulted in a better understanding of the disease and finally an improved long term survival for cancer patients. However, malignancies of the central nervous system and especially glioblastomas are still related to poor outcomes with median survivals of less than 6 months despite extensive surgery, chemotherapy and radiation. Hence, a better understanding of the molecular mechanism driving and sustaining cancerous mutations in glioblastomas is crucial for the development of targeted therapies. Apoptosis, a form of programmed cell death, is an important feature of eukaryotic cells and crucial for the maintenance of multicellular homeostasis. Because apoptosis is a highly complex and tightly regulated signaling pathway, resisting apoptotic stimuli and avoiding cell death is a hallmark of the cancerous transformation of cells. Hence, targeting molecular structures to reestablish apoptotic signaling in tumor cells is a promising approach for the treatment of malignancies. Smac mimetics are a group of small molecular protein inhibitors that structurally derive from an intracellular protein termed Smac and selectively block Inhibitor of apoptosis (IAP) proteins, which are often aberrantly expressed in cancer. Several studies confirmed the antitumoral effects of Smac mimetics in different human malignancies, including glioblastoma, and give rationales for the development of potent Smac mimetics and Smac mimetic-based combination protocols. This study investigates the antitumoral activity of the bivalent Smac mimetic BV6 in combination with Interferon α. Latter is a well characterized cytokine with an essential role in immunity, cell differentiation and apoptosis. This study further aims to address the molecular mechanisms underlying the antitumoral activity of the combination treatment by using well established molecular cell death assays, flow cytometry, western blot analysis, genetic approaches and selective pharmacological inhibition. Since different Smac mimetics and Smac mimetic-based combination therapies are currently under clinical evaluations, findings of this study may have broad implications for the application of Smac mimetics as clinical cancer therapeutics.
Das T-lymphoblastische Lymphom (T-LBL) ist eine seltene Form des Non-Hodgkin-Lymphoms (NHL). Als wirksamste Behandlung haben sich intensive Therapien analog zu Protokollen für die akute lymphoblastische Leukämien (ALL) etabliert. Auch bei Erwachsenen werden inzwischen hohe CR-Raten erreicht. Aufgrund einer Rezidivrate von 20–35 % und einem Überleben von 45–75% besteht jedoch der Bedarf einer weiteren Therapieoptimierung. Dieses Ziel wird von der multizentrischen deutschen Studiengruppe für die ALL des Erwachsenen (GMALL) verfolgt, die prospektive Studien durchgeführt und eigene Therapieempfehlungen evaluiert hat.
In der vorliegenden Arbeit wurde die Effektivität der GMALL-Studientherapie T-LBL 1/2004 und der GMALL-Konsensus-Empfehlung für die Therapie neu diagnostizierter T-LBL bei Erwachsenen untersucht. Hauptaugenmerk lag auf der Auswertung der Gesamtergebnisse und der Evaluierung potentiell prognostischer Faktoren. Eine weitere wesentliche Fragestellung war es, die Bedeutung der Mediastinalbestrahlung in der Erstlinientherapie für das Therapieergebnis zu evaluieren. Ein weiterer Schwerpunkt war die Evaluation der Bedeutung eines Interimstagings mittels PET. Zusätzlich wurde die Wirksamkeit verschiedener Salvageansätze bei primärem Therapieversagen und Rezidiv evaluiert.
Ausgewertet wurden Daten von 149 Patienten, die zwischen 2004 und 2013 in zwei konsekutiven Kohorten gemäß der Studie GMALL T-LBL 01/2004 (Kohorte I; n = 101) oder der GMALL-Therapieempfehlung (Kohorte II; n = 48) behandelt wurden. Die empfohlene Therapie beinhaltete zwei Induktionsblöcke, die Reinduktion sowie sechs Konsolidationsblöcke. Die ZNS-Prophylaxe bestand aus intrathekalen Chemotherapiegaben und eine Schädelbestrahlung mit 24 Gy. Patienten, die gemäß der Studie 01/2004 behandelt wurden, sollten nach der Induktion außerdem eine Mediastinalbestrahlung mit 36 Gy erhalten. Patienten ohne CR/CRu nach dem ersten Konsolidationsblock sollten einer Salvagetherapie außerhalb des Studienprotokolls oder der Therapieempfehlung zugeführt werden. Bei mittels CT bestimmter CRu oder PR zu diesem Zeitpunkt wurde zur Sicherung des Remissionsstatus eine PET empfohlen.
Die CR-Rate der Gesamtpopulation lag bei 76 %. Das Gesamtüberleben und das erkrankungsfreie Überleben nach zwei Jahren lagen bei 72 bzw. 70 %. Die Rezidivrate betrug 28 %, die Überlebenswahrscheinlichkeit ein Jahr nach Rezidivdiagnose lag bei 35 %. Es bestand kein statistisch signifikanter Unterschied zwischen den Überlebensraten von Patienten mit und ohne Mediastinalbestrahlung (bestrahlte Patienten der Kohorte vs. Patienten der Kohorte II). Alle Patienten mit computertomographisch ermittelter CRu nach Konsolidation I, bei denen eine konfirmatorische PET durchgeführt wurde (n=21), waren PET-negativ, d. h. in metabolischer CR. Von den PET-evaluierten Patienten mit computertomographisch ermittelter PR (n = 22) waren 55 % PET-negativ. In der Gesamtpopulation wurden zahlreiche potentielle Prognosefaktoren analysiert. Statistische Signifikanz erreichte dabei nur der Allgemeinzustand. Ein ECOG-Score von 0–1 war mit einem günstigeren erkrankungsfreien Überleben assoziiert.
Die Ergebnisse zeigen eine gute Effektivität der GMALL-Therapie. Der Verzicht auf die Mediastinalbestrahlung in der Therapieempfehlung war nicht mit einer Verschlechterung des Therapieergebnisses verbunden. Die Arbeit verdeutlicht die Komplexität der frühen Remissionsbeurteilung mit verschiedenen Verfahren im Versorgungsstandard und unterstreicht den dringenden Bedarf einer standardisierten Remissionsbeurteilung und Referenzbefundung. Die PET erwies sich als wichtiges Instrument des Interimstagings, um eine remissionsabhängige Therapiestratifikation sinnvoll durchführen zu können. Sie zeigte sich zudem als unerlässlich für die korrekte Bewertung der Effektivität von Salvagestrategien und damit für die Therapieoptimierung bei primärer Refraktärität.
Die in dieser Arbeit ausgewerteten Daten bilden die bisher größte berichtete Population einheitlich behandelter erwachsener T-LBL Patienten ab. Die Ergebnisse stellen eine wichtige Grundlage für die weitere Therapieoptimierung im Rahmen der aktuell laufenden GMALL-Studie 08/2013 dar.