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Therapeutische Konzepte der Radioiodtherapie bei der Autoimmunhyperthyreose vom Typ Morbus Basedow
(2004)
In der vorliegenden Arbeit wurden retrospektiv Ergebnisse einer Radioiodtherapie bei 126 konsekutiven Patienten (19 Männer; 107 Frauen, Alter 50,9±14,6, Median 51,5 Jahre) analysiert, die im Zeitraum von 1992 bis 2001 wegen einer Autoimmuthyreopathie vom Typ M. Basedow in der Klinik für Nuklearmedizin der Gutenberg Universität Mainz behandelt wurden. Ziel der Arbeit war es, die Effektivität unterschiedlicher Therapieansätze zu vergleichen sowie Faktoren, welche einen Einfluss auf die Therapieergebnisse haben könnten, zu ermitteln, wobei Anamnese, Schilddrüsenvolumen, Stoffwechsellage und Thyreostase zum Zeitpunkt der Therapie besondere Berücksichtigung fanden. Bei 47 Patienten erfolgte die Radioiodtherapie nach einem funktionsoptimierten Konzept mit dem Ziel (150 Gy), eine Euthyreose zu erreichen. 79 Patienten wurden nach ablativem Konzept mit dem Ziel einer posttherapeutischen Hypothyreose behandelt. Die Dosis in dieser Gruppe betrug bei 19 Patienten 200 Gy; bei 29 Patienten 250 Gy; bei 15 Patienten 275 Gy und bei 16 Patienten 300 Gy. In 21% aller Fälle erfolgte die Therapie bei Erstmanifestation, bei 15% nach dem 1. Rezidiv und bei 64 % nach dem 2. Rezidiv. Bezüglich der Thyreostase, der Stoffwechsellage und des prätherapeutischen Radioiod-Uptakes waren die Gruppen nicht signifikant unterschiedlich. Entsprechend den Therapiekonzepten wurde bei funktionsorientiertem Konzept im Median 372 MBq als Aktivität errechnet und 400 MBq appliziert (14,3 MBq/ml). Für Patienten mit ablativem Therapiekonzept wurden im Median 514 MBq errechnet und 600 MBq appliziert (28,6 MBq/ml). Erreicht wurden in der ersten Gruppe Organdosen zwischen 80 und 380 Gy (Median 180 Gy). Bei 7 Patienten (14%) wurde dabei der angestrebte Bereich nicht erreicht, bei 27 Patienten (57%) erreicht und bei 13 Patienten (29%) überschritten. Der Variationskoeffizient lag bei 52%. In der Gruppe mit ablativem Ziel erreichten die Organdosen 56-685 Gy (Median 275 Gy). Bei 67 der 79 Patienten (85%) lag die erreichte Dosis wie geplant oder höher, bei 12 Patienten (15%) wurde die angestrebte Dosis nicht erreicht. Nur bei 3 der 47 Patienten (6%) wurde eine Euthyreose erreicht. Eine Hyperthyreose lag dagegen bei 22 Patienten (47%) vor. 22 Patienten (47%) wiesen posttherapeutisch eine Hypothyreose auf. Dagegen waren in der Gruppe mit ablativer Therapie 61 Patienten (77%) wie erwünscht hypothyreot und 18 (23%) hatten eine Resthyperthyreose. Patienten, die nach der ablativen Radioiodtherapie eine erwünschte Hypothyreose erreichten, hatten eine kürzere eff. HWZ und einen höherer Radioiod-Uptake (4,7 Tage; 52%) als Therapieversager (5,4 Tage; 49%) sowie ein geringeres Schilddrüsenvolumen nach der Behandlung (7,2±4,7 vs. 21,5±13,3 ml). Zehn Patienten nach ablativer Therapie (n=10) hatten trotz erreichter Dosis >250 Gy eine Resthyperthyreose. Das Schilddrüsenvolumen lag bei diesen Patienten zwischen 14 und 70 ml (Mittelwert: 29,5 ml). Die posttherapeutische Volumenreduktion war bei funktionsorientierter Therapie geringer als bei ablativem Konzept (um 55% vs. 65%). Die TRAK und anti-TPO-AK-Titer waren in beiden Gruppen gegenüber dem Ausgangswert angestiegen. Dabei waren die posttherapeutischen Konzentrationen bei funktionsoptimiertem Konzept höher als nach ablativer Therapie. Die Radioiodtherapie wurde in beiden Gruppen gut toleriert. Beschwerden durch eine strahleninduzierte Thyreoiditis zeigten sich bei 13 Patienten (10%), die mit Eiskrawatte und nichtsteroidale Antiphlogistika behandelt wurden. Unter Cortisonprophylaxe (n=29) wurde nur bei einem Patienten eine Verschlechterung der vorbestehenden EO beobachtet. Das Schilddrüsenvolumen wurde als wesentlicher, den Therapieerfolg bestimmender Parameter bei ablativem Konzept in der multivariaten Analyse identifiziert. So hatten Patienten mit einem Schilddrüsenvolumen ab 25 ml ein 10-fach höheres Risiko für ein Versagen der Radioiodtherapie in Relation zu Patienten, die eine Schilddrüse <25 ml hatten. Die Radioiodtherapie mit ablativen Dosen erweist sich in einem Iodmangelgebiet gegenüber der funktionsorientierten Behandlung als eine effektivere Therapie. Dieses Konzept geht mit niedrigerem Risiko der Verschlechterung einer vorbestehenden EO (unter Cortisonprophylaxe) einher. Es stellt sich bei diesem Konzept heraus, dass die Thyreostase in niedriger Dosierung keinen bedeutenden Einfluss auf den Therapieerfolg hatte. Die Auswertung der Daten bestätigt, dass die aktuell verwendete individuelle Dosisplanung mittels Radioiodtest eine präzise Abschätzung der notwendigen Aktivität erlaubt. Ausgehend von Ergebnissen diese Studie erscheint bei ablativem Konzept eine volumenadaptierte Korrektur der Zieldosis sinnvoll: während bei Schilddrüsenvolumina zwischen 25-40 ml eine Dosis von 250 Gy (entsprechend aktuellen Empfehlungen der Leitlinie der DGN) optimal ist, sollten bei Volumina > 40 ml höhere Zieldosen gewählt werden. Bei Patienten mit Schilddrüsenvolumina < 20 ml ist eine Dosis von 200 Gy ausreichend.
Prognostische Faktoren und das Outcome von Patienten mit einem primären Glioblastom sind in der Fachliteratur gut beschrieben. Im Gegensatz dazu gibt es wenige vergleichbare Informationen zu Patienten mit einem sekundären Glioblastom. Das Ziel dieser Arbeit war es, das Outcome von Patienten mit einem sekundären Glioblastom zu beurteilen und prognostische Faktoren in Be-zug auf das Gesamtüberleben zu identifizieren.
Dazu wurde die interne Datenbank des Universitätsklinikums Frankfurt/Main von Patienten mit Hirntumoren retrospektiv nach klinischen Daten durchsucht. Alle Patienten hatten ein histologisch gesichertes WHO Grad II oder III Gliom und anschließend ein WHO Grad IV sekundäres Glioblastom. Paraffiniertes Hirntumorgewebe wurde auf Mutationen der Isocitrat Dehydrogenase-1 (IDH1) mittels einer immunhistochemischen Färbung mit einem R132H (clone H09) spezifischen Antikörper untersucht. Eine uni- und multivariate statistische Analyse wurde durchgeführt, um Faktoren zu ermitteln, die potentiell das Gesamt-überleben beeinflussen könnten.
Es wurden 45 Patienten mit einem histologisch gesicherten sekundären Glioblastom untersucht. Das mediane Alter betrug 41 Jahre. 14 Patienten unterzogen sich einer radiologisch kompletten Resektion des sekundären Glioblastoms, 31 Patienten wurden subtotal reseziert oder biopsiert. Initial ist bei 37 Patienten ein astrozytärer Tumor nachgewiesen worden und die restlichen Patienten litten an Oligodendrogliomen oder gemischten Gliomen; bei der initialen Diagnose wurden 17 WHO Grad II und 28 WHO Grad III Tumoren fest-gestellt. Die mediane Zeit zwischen Ursprungstumor und dem Auftreten des sekundären Glioblastoms betrug 158,9 Wochen. Das mediane Gesamtüberleben betrug 445 Tage nach der Diagnose eines sekundären Glioblastoms. Mutationen des IDH1 (R132H) Proteins wurden bei 24 Patienten festgestellt und fehlten bei 17 Patienten; bei 4 Patienten konnte keine IDH1 immunhistochemische Färbung durchgeführt werden.
In der univariaten Analyse konnte der Zeitraum zwischen initialer Läsion und dem Progress zu einem sekundären Glioblastom als statistisch signifikanter Einflussfaktor identifiziert werden- Patienten mit einem Zeitraum von mehr als 2 Jahren hatten ein besseres Gesamtüberleben (460 vs. 327 Tage, p = 0,011). Außerdem konnte bei Patienten, die eine kombinierte Radiochemotherapie bekamen, ein besseres Gesamtüberleben nachgewiesen werden als bei Patienten, welche ausschließlich eine Therapieform erhielten (611 vs. 380 Tage, p < 0,001). Weiterhin konnten ein WHO Grad II Ursprungstumor (472 vs. 421 Tage, p = 0,05) und eine Frontalllappenlokalisation des Glioblastoms (472 vs. 425 Ta-ge, p = 0,031) das Überleben steigern.
In der multivariaten Analyse konnte gezeigt werden, dass die Mutation des IDH1 (R132H) Proteins in statistisch signifikanter Weise mit einem längeren Gesamtüberleben assoziiert war (p = 0,012); statistische Signifikanz für ein län-geres Gesamtüberleben bei Patienten mit initial einem WHO Grad II (p = 0,047) und einer Frontallappenlokalisation des Glioblastoms (p = 0,042) stellte sich auch ein. In Bezug auf die Patienten spezifischen Daten wurden zwei Prognosegruppen erstellt; Patienten in der guten Prognosegruppe scheinen einen Benefit von einer totalen Tumorresektion zu haben (p = 0,02), während eine Resektion für die andere Prognosegruppe keine große Rolle spielte (p = 0,926).
Trotz des relativ geringen Erkrankungsalters haben sekundäre Glioblastom Patienten eine schlechte Prognose. Die Ergebnisse dieser Arbeit unterstreichen die Wichtigkeit und den prognostischen Wert der IDH1 Diagnostik, die Notwendigkeit einer kombinierten Radiochemotherapie und eine Risikostratifizierung für eine Prognoseabschätzung anhand der Patienten spezifischen Einflussfaktoren.
Objectives: To discuss optimal management of recurrent urinary tract infections (UTIs) in women. About every second woman experiences at least one UTI in her lifetime, of those 30% experience another UTI, and 3% further recurrences. Especially young healthy women without underlying anatomical deficiencies suffer from recurrent UTIs (rUTI), which are associated with significant morbidity and reduction in quality of life.
Methods: This is a narrative review, investigating publications dealing with recurrent UTI in women. Risk factors and options for management are discussed.
Results: The increased susceptibility of women to rUTI is based on the female anatomy in addition to behavioural, genetic, and urological factors. However, why some women are more likely than others to develop and maintain rUTI remains to be clarified. Invasive characteristics of certain uropathogenic Escherichia coli that are able to form extra- and intracellular biofilms and may therefore cause delayed release of bacteria into the bladder, may play a role in this setting. Treatment recommendations for an acute episode of rUTI do not differ from those for isolated episodes. Given the nature of rUTI, different prophylactic approaches also play an important role. Women with rUTI should first be counselled to use non-antibiotic strategies including behavioural changes, anti-adhesive treatments, antiseptics, and immunomodulation, before antibiotic prophylaxis is considered. In addition to the traditional treatment and prophylactic therapies, new experimental strategies are emerging and show promising effects, such as faecal microbiota transfer (FMT), a treatment option that transfers microorganisms and metabolites of a healthy donor’s faecal matter to patients using oral capsules, enemas, or endoscopy. Initial findings suggest that FMT might be a promising treatment approach to interrupt the cycle of rUTI. Furthermore, bacteriophages, infecting and replicating in bacteria, have been clinically trialled for UTIs.
Conclusion: Due to the limitation of available data, novel treatment options require further clinical research to objectify the potential in treating bacterial infections, particularly UTIs.
The role and timing of radiotherapy (RT) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) remains controversial. While recent trials support the oncological safety of early salvage RT (SRT) compared to adjuvant RT (ART) in selected patients, previous randomized studies demonstrated that ART might improve recurrence-free survival in patients at high risk for local recurrence based on adverse pathology. Although ART might improve survival, this approach is characterized by a risk of overtreatment in up to 40% of cases. SRT is defined as the administration of RT to the prostatic bed and to the surrounding tissues in the patient with PSA recurrence after surgery but no evidence of distant metastatic disease. The delivery of salvage therapies exclusively in men who experience biochemical recurrence (BCR) has the potential advantage of reducing the risk of side effects without theoretically compromising outcomes. However, how to select patients at risk of progression who are more likely to benefit from a more aggressive treatment after RP, the exact timing of RT after RP, and the use of hormone therapy and its duration at the time of RT are still open issues. Moreover, what the role of novel imaging techniques and genomic classifiers are in identifying the most optimal post-operative management of PCa patients treated with RP is yet to be clarified. This narrative review summarizes most relevant published data to guide a multidisciplinary team in selecting appropriate candidates for post-prostatectomy radiation therapy.
Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.
Die Bande q23 auf Chromosom 11 ist in zahlreiche reziproke chromosomale Translokationen verwickelt. Diese sind dominant mit dem Krankheitsphänotyp einer AML, ALL und seltener mit malignen Lymphomen und myelodysplastischen Syndromen assoziiert. Mittlerweile sind fünfundachtzig cytogenetische Aberrationen der Bande 11q23 bekannt. Das auf 11q23 betroffene Gen wird als das Mixed Lineage Leukemia (MLL), Acute Lymphoblastic Leukemia (ALL-1), Human Homolog of trithorax (HRX) oder als Human Trithorax 1 (Htrx1) bezeichnet. Die häufigsten Partnergene des MLL sind AF4 (40 %), AF9 (27 %), sowie ENL, AF6, ELL und AF10 (4-7 %).
Die Bruchpunkte von t(11;V) Translokationen sind nicht gleichmäßig über das gesamte, 92 kb große humane MLL-Gen verteilt, sondern liegen alle in der 8,3 kb großen Bruchpunktsregion Bpr. Auch innerhalb der Bpr ist die Verteilung der Translokationsbruchpunkte nicht homogen. Die Bruchpunkte von Patienten mit de novo Leukämien und einem Alter über einem Jahr liegen mehrheitlich in der 5’-Hälfte der Bpr, dem Subcluster I. Dagegen liegen die Bruchpunkte von Patienten mit therapiebedingten Leukämien und einem Alter unter einem Jahr überwiegend in der 3’-Hälfte der Bpr, dem Subcluster II.
Neuere Forschungsergebnisse zeigten, daß DNA-Doppelstrangbrüche auf zwei verschiedenen Chromosomen eine hinreichende Voraussetzung für das Entstehen chromosomaler Translokationen sind. Aufgrund der inhomogenen Verteilung der Translokationsbruchpunkte im MLL-Gen stellte sich die Frage, ob bestimmte Regionen dieses Gens für DNA-Doppelstrangbrüche prädisponiert sind. Interessanterweise ist Subcluster II extrem sensitiv gegenüber DNA-Doppelstrangbrüchen, die durch cytotoxische Agenzien oder Apoptose-auslösende Ereignisse induziert werden können. In unserer Arbeitsgruppe konnte eine etwa 200 bp große Region lokalisiert werden, über die sich nahezu alle Etoposid-induzierten DNA-Doppelstrangbrüche verteilten.
In dieser Arbeit konnte gezeigt werden, daß die Bildung von DNA-Doppelstrangbrüchen in dieser Region durch die Gabe eines Caspase-Inhibitors gehemmt werden kann. Eine Etoposid-induzierte Protein-DNA-Wechselwirkung konnte allerdings nicht nachgewiesen werden. In der Literatur fanden sich Hinweise darauf, daß Subcluster II im Gegensatz zu Subcluster I eine verstärkte Histonacetylierung aufweist. Basierend auf diesen Hinweisen sollte die Arbeitshypothese untersucht werden, ob Subcluster II einen geninternen Promotor des MLL-Gens darstellt.
Die potentielle Promotorregion wurde zunächst durch Computeranalysen eingegrenzt. Mit RT-PCR Experimenten wurde anschließend der potentielle geninterne Promotor des murinen Mll-Gens in einer murinen Fibroblastenzellinie lokalisiert, die einen Transkriptionsstop und eine Polyadenylierungssequenz in Exon 4 des Mll-Gens trug. Um die am Mausmodell gewonnenen Erkenntnisse auch im humanen System zu überprüfen, wurde die geninterne Promotorregion des humanen MLL Gens vor ein Luciferasereportergen kloniert. Durch RTPCR konnte der geninterne Transkriptionsstart im Subcluster II des humanen MLL-Gens lokalisiert werden. Damit konnte zum ersten Mal gezeigt werden, daß Transkriptionsinitiation und genetische Instabilität im Subcluster II des humanen MLL-Gens kolokalisieren.
Durch Deletionsmutanten wurde die Bedeutung der einzelnen Module dieser Promotorregion ermittelt. Dabei zeigte sich, daß die Anwesenheit von zwei retromobilen Elementen eine Enhancer-Funktion haben. Demgegenüber zeigte die homologe murine Sequenz, die in unserer Arbeitsgruppe gleichzeitig von S. Scharf untersucht wurde und für die keine erhöhte Anfälligkeit für DNA-Doppelstrangbrüche bekannt ist, nur eine schwache Promotoraktivität. Dies weist auf einen Zusammenhang zwischen der genetischen Instabilität von Subcluster II und der Rate geninterner Transkriptionsinitiationsprozesse hin.
Das Protein, für das das Transkript des geninternen murinen Promotors kodiert, wurde mittels immunhistologischer und Western Blot Experimente nachgewiesen. Dabei konnte gezeigt werden, daß dieses Protein, wie auch das MLL-Protein, proteolytisch durch Taspase1 und daß sich ein Mini-MLL-Komplex bildet.
Objective: Area postrema (AP) syndrome (defined as: nausea and/or emesis and/or singultus at onset of brainstem dysfunction) comprises complex pathophysiologic mechanisms triggered by different entities. The first objective was to assess the frequency of AP syndrome as a clinical feature in brainstem encephalitis (BE). Finding an especially high prevalence of AP syndrome in Bickerstaff brainstem encephalitis (BBE), we also analyzed the frequency of AP syndrome in other autoimmune diseases with anti‐ganglioside antibodies (Guillain–Barré syndrome (GBS) and its variants).
Methods: We systematically evaluated the prevalence of AP syndrome in BE in all patients treated at our university hospital during a 15‐year period. In a second step, BBE patients were compared to GBS and Miller Fisher syndrome (MFS) patients as clinical subtypes of a disease continuum without brainstem dysfunction.
Results: We found AP syndrome in 8 of 21 BE patients, including 3 of 7 BBE and in 4 of 112 GBS/MFS patients. AP syndrome was as a frequent but under‐recognized feature of BE with a significant impact on patients’ well being.
Interpretation: Manifestation of AP syndrome in BBE but also in GBS and its subtypes point toward a role of autoimmune antibodies that should be investigated in future studies. Considerable misdiagnosis or nonrecognition complicates diagnostic and therapeutic management. Therefore, AP syndrome should be considered in any episode of otherwise unexplained nausea, emesis, or singultus.
Regorafenib CSF penetration, efficacy, and MRI patterns in recurrent malignant glioma patients
(2019)
(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas.
(2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients’ serum and CSF.
(3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients.
(4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.
Immune profile and radiological characteristics of progressive multifocal leukoencephalopathy
(2021)
Background and purpose: Progressive multifocal leukoencephalopathy (PML) constitutes a severe disease with increasing incidence, mostly in the context of immunosuppressive therapies. A detailed understanding of immune response in PML appears critical for the treatment strategy. The aim was a comprehensive immunoprofiling and radiological characterization of magnetic resonance imaging (MRI) defined PML variants.
Methods: All biopsy-confirmed PML patients (n = 15) treated in our department between January 2004 and July 2019 were retrospectively analysed. Data from MRI, histology as well as detailed clinical and outcome data were collected. The MRI-defined variants of classical (cPML) and inflammatory (iPML) PML were discriminated based on the intensity of gadolinium enhancement. In these PML variants, intensity and localization (perivascular vs. parenchymal) of inflammation in MRI and histology as well as the cellular composition by immunohistochemistry were assessed. The size of the demyelinating lesions was correlated with immune cell infiltration.
Results: Patients with MRI-defined iPML showed a stronger intensity of inflammation with an increased lymphocyte infiltration on histological level. Also, iPML was characterized by a predominantly perivascular inflammation. However, cPML patients also demonstrated certain inflammatory tissue alterations. Infiltration of CD163-positive microglia and macrophage (M/M) subtypes correlated with PML lesion size.
Conclusions: The non-invasive MRI-based discrimination of PML variants allows for an estimation of inflammatory tissue alterations, although exhibiting limitations in MRI-defined cPML. The association of a distinct phagocytic M/M subtype with the extent of demyelination might reflect disease progression.
Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.
We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.
We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.
In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
Im EU-Projekt „Regulatory Control Networks of Synthetic Lethality“ (SYNLET) wurden durch Vergleich der Genexpressionsprofile auf Transkriptionsebene von parentalen sensitiven Neuroblastom-Zelllinien und ihren Vincristin-resistenten Sublinien bioinformatisch 40 Kandidatengene ermittelt, die für Vincristin-Resistenz und damit Zellüberleben essentiell sein könnten. Diese Kandidatengene wurden im Rahmen dieser Dissertation einzeln in Neuroblastomzellen der Vincristin-resistenten Sublinie UKF-NB-2rVCR20 herunterreguliert durch Transfektion (Elektroporation) von small interfering RNAs (siRNAs; knock down). Anschließend wurden die Zellen ohne und mit verschiedenen Vincristin-Konzentrationen auf Zellviabilitätsveränderungen getestet. Beim Kandidatengen mit den niedrigsten Zellviabilitäten (SMARCC1) wurde ein Western Blot gemacht, um die Herunterregulierung zu bestätigen. Zu Beginn wurde das effektivste Programm zur Elektroporation der UKF-NB-2rVCR20-Zellen durch eine Transfektionsoptimierung ermittelt. Alle Kandidatengene wurden 2x transfiziert, bei unklaren oder besonders interessanten Ergebnissen auch 3x. Als positive Kontrolle wurde der ABC-Transporter MDR1 herunterreguliert, da hier die Auswirkungen auf die Resistenz gegen Vincristin bekannt sind. Bei 10 von 40 Kandidatengenen waren die Zellviabilitäten ohne Vincristin und/oder bei mindestens einer Vincristin-Konzentration extrem verändert (FOXJ1, MAP2K1, NFYB, RICS, SMARCA1, SMARCB1, SMARCC1, STK35, TOCA1 und TPM2). Das entspricht einem Prozentsatz von 25 % Kandidatengenen, bei denen die bioinformatisch vorhergesagte Wirkung in vitro bestätigt werden konnte. Allerdings sind bei diesen 10 effektiven Kandidatengenen auch 2 Gene dabei, nach deren Herunterregulierung es zu einer erhöhten Zellviabilität kam (FOXJ1 und RICS). Bei der Frage, welche Gene das Absterben der Tumorzellen beschleunigen und als ein mögliches Therapieziel in Frage kommen könnten, bleiben also 8 Kandidatengene (20 % aller Kandidatengene). Das interessanteste Kandidatengen ist SMARCC1, da die Herunterregulierung alleine (ohne Zugabe von Vincristin) zu einer massiven Abnahme der Zellviabilität führte. Damit stellt SMARCC1 ein interessantes Ziel zur Therapie in Tumorzellen dar.
Aim: Left ventricular non-compaction (LVNC) is perceived as a rare high-risk cardiomyopathy characterized by excess left ventricular (LV) trabeculation. However, there is increasing evidence contesting the clinical significance of LV hyper-trabeculation and the existence of LVNC as a distinct cardiomyopathy. The aim of this study is to assess the association of LV trabeculation extent with cardiovascular morbidity and all-cause mortality in patients undergoing clinical cardiac magnetic resonance (CMR) scans across 57 European centers from the EuroCMR registry.
Methods and Results: We studied 822 randomly selected cases from the EuroCMR registry. Image acquisition was according to international guidelines. We manually segmented images for LV chamber quantification and measurement of LV trabeculation (as per Petersen criteria). We report the association between LV trabeculation extent and important cardiovascular morbidities (stroke, atrial fibrillation, heart failure) and all-cause mortality prospectively recorded over 404 ± 82 days of follow-up. Maximal non-compaction to compaction ratio (NC/C) was mean (standard deviation) 1.81 ± 0.67, from these, 17% were above the threshold for hyper-trabeculation (NC/C > 2.3). LV trabeculation extent was not associated with increased risk of the defined outcomes (morbidities, mortality, LV CMR indices) in the whole cohort, or in sub-analyses of individuals without ischaemic heart disease, or those with NC/C > 2.3.
Conclusion: Among 882 patients undergoing clinical CMR, excess LV trabeculation was not associated with a range of important cardiovascular morbidities or all-cause mortality over ~12 months of prospective follow-up. These findings suggest that LV hyper-trabeculation alone is not an indicator for worse cardiovascular prognosis.
Inflammation is a highly regulated biological response of the immune system that is triggered by assaulting pathogens or endogenous alarmins. It is now well established that some soluble extracellular matrix constituents, such as small leucine-rich proteoglycans (SLRPs), can act as danger signals and trigger aseptic inflammation by interacting with innate immune receptors. SLRP inflammatory signaling cascade goes far beyond its canonical function. By choosing specific innate immune receptors, coreceptors, and adaptor molecules, SLRPs promote a switch between pro- and anti-inflammatory signaling, thereby determining disease resolution or chronification. Moreover, by orchestrating signaling through various receptors, SLRPs fine-tune inflammation and, despite their structural homology, regulate inflammatory processes in a molecule-specific manner. Hence, the overarching theme of this review is to highlight the molecular and functional specificity of biglycan-, decorin-, lumican-, and fibromodulin-mediated signaling in inflammatory and autoimmune diseases.
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.
Background: Evidence from animal studies suggests that leptin metabolism is associated with zinc (Zn) status. However, research investigating this relationship in adolescents and young adults with anorexia nervosa (AN) is scarce; the present study aims to fill that gap.
Methods: Serum concentrations of leptin, the soluble leptin receptor (sOB-R) and the free leptin index (FLI) were obtained in healthy control subjects (n=19), acutely ill individuals (n=14) and recovered patients with AN (n=15). Serum Zn concentrations noted in previous research data were also incorporated for all groups.
Results: Leptin, FLI and Zn concentrations were higher in recovered subjects with AN when compared with acutely ill AN patients. Remitted patients showed higher sOB-R concentrations but no difference in FLI compared with the control group. Leptin and FLI were lower in the acutely ill patients compared with the control subjects, who showed no differences in Zn concentrations. Zn concentrations were not correlated with leptin, sOB-R or FLI concentrations in any of the three investigated subgroups.
Conclusions: The present investigation does not entirely support an association between Zn, Leptin and FLI concentrations in subjects with AN, possibly due to limited statistical power. Further research and replication of the present findings related to the interaction between leptin and Zn is warranted. However, with respect to serum leptin levels the data of the present investigation indicate that acutely ill and remitted patients with AN differ as regards serum leptin concentrations and FLI, which is in line with previous research.
Simple Summary: Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection.
Abstract: There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.
Forewarned is forearmed
(2009)
Obesity is considered as a type of chronic inflammation. It enhances the risk of developing cardiovascular disease, diabetes, and some cancers. The key players in the induction of inflammation in adipose tissue are macrophages. However the mechanism of macrophage activation in obese fat tissue is still not fully understood. Elevated level of saturated fatty acids in adipose tissue promotes inflammation and insulin resistance. Exposure of macrophages to saturated fatty acids stimulates pro-inflammatory c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-kB) signaling, and production of pro-inflammatory cytokines, such as IL-6, IL-8, IL-1β, and TNFα. Palmitate is a major saturated free fatty acid released by adipocytes. It activates inflammatory pathways through Toll-like receptors (TLR) 2 and 4, provokes endoplasmic reticulum (ER) stress and increases levels of diacylglycerols (DAGs) and ceramides. Saturated fatty acids also affect cellular oxidative metabolism. Thus, mitochondrial fatty acid oxidation reduces ER-stress and expression of inflammatory cytokines in palmitate-treated macrophages. On the other hand mitochondrial reactive oxygen species (ROS) promote palmitate-mediated pro-inflammatory cytokine production. Recently, mitochondrial functions were linked to their morphology. Mitochondrial fission has been reported in β-cells and myocytes in response to high levels of glucose and free fatty acids, and was associated with disruption of mitochondrial functions, increased ROS level, and cell death. The aim of this study was to investigate the role of mitochondrial fragmentation in palmitate-induced inflammation in human macrophages. In our settings fatty acids, independently of their saturation, affected mitochondrial morphology. Mixtures of long chain saturated and unsaturated fatty acids as well as triglyceride-rich lipoprotein lipolysis products promoted mitochondrial fission. Mitochondrial fragmentation in palmitate-treated macrophages revealed a time- and concentration-dependent character, and was reversible upon palmitate removal. This observation, together with unaltered levels of mitochondrial protein and DNA content, and intact mitochondrial respiration, suggested that mitochondria were not damaged and were functionally active. Mechanistically, palmitate-induced mitochondrial fragmentation was not regulated by ER stress or loss of mitochondrial membrane potential. However, inhibition of palmitate incorporation into mitochondrial membrane phospholipids decreased mitochondrial fragmentation. Other approach to prevent mitochondrial fission was the inhibition of dynamin-related protein 1 (DRP1) activity, which drives mitochondrial fission by forming ring- like structures around mitochondria and constricting mitochondrial membranes. Palmitate altered mitochondrial membrane lipid composition and promoted DRP1-oligomerization. The inhibition of palmitate-induced mitochondrial fragmentation enhanced mitochondrial ROS production, c-Jun phosphorylation, and upregulated expression of pro-inflammatory cytokines. Taken together, these results suggest that mitochondrial fragmentation is a protective mechanism attenuating palmitate-induced inflammatory responses. Future experiments will be required to investigate the role of mitochondrial fragmentation in obesity-associated diseases in vivo.
Hintergrund: Seit mehr als 50 Jahren werden in Deutschland Herzschrittmacher-Implantationen durchgeführt, mittlerweile mit mehr als 100.000 Implantationen pro Jahr. Obwohl es sich um einen gängigen Eingriff handelt, existieren wenig prospektiv randomisierte Studien zu technischen Aspekten der Implantation, insbesondere dem Wundverschluss am Ende der Operation. Ziel der vorliegenden Arbeit war es, an einem Kollektiv von Patienten unerwünschte Ereignisse und kosmetische Ergebnisse, in Abhängigkeit des beim Hautverschluss verwendeten Nahtmaterials (resorbierbarer bzw. nicht-resorbierbarer Faden), miteinander zu vergleichen.
Methoden: In einem Zeitraum von Juli 2018 bis April 2019 wurden Patienten mit geplanter de novo Herzschrittmacher-Implantation ohne Defibrillationstherapie prospektiv in die Studie eingeschlossen und anhand einer Randomisierungliste in zwei Probandengruppen eingeteilt: nicht-resorbierbares Nahtmaterial (Gruppe Prolene®) bzw. resorbierbares Nahtmaterial (Gruppe Monocryl®).
Ein Tag (Beobachtungszeitpunkt 1), sechs Wochen (Beobachtungszeitpunkt 2) und ein Jahr post-OP (Beobachtungszeitpunkt 3) erfolgte die Beurteilung der Narbe bezüglich des kosmetischen Ergebnisses und klinisch relevanter, unerwünschter Ereignisse. Zur kosmetischen Beurteilung diente die Wundbreite in mm, eine auftretende Kelloidbildung und die „Patient and Observer Scar Assessment Scale“ (POSA-Score). Dieser wurde zu Beobachtungszeitpunkt 1 seitens des Patienten auf zwei Fragen (Schmerzhaftigkeit, Juckreiz) reduziert. Die erhobenen klinisch relevanten Parameter waren Nachblutungen, Infektionen, Insuffizienz der Naht und Revisions-OP aufgrund eines Lokalbefundes.
Ergebnisse: Es konnten 114 Patienten in die Studie eingeschlossen werden. Zu Beobachtungszeitpunkt 2 und Beobachtungszeitpunkt 3 belief sich die Anzahl auf jeweils 92 Probanden. Zu allen drei Beobachtungszeitpunkten konnte zwischen beiden Gruppen weder ein signifikanter Unterschied im kosmetischen Ergebnis noch im Auftreten klinisch relevanter Ereignisse festgestellt werden.
Schlussfolgerung: Anhand der vorliegenden Studie scheint das verwendete Nahtmaterial keinen großen Einfluss auf das kosmetische Ergebnis der Narbe, sowie auf das Auftreten von unerwünschten Ereignissen zu haben. Eine multizentrische prospektiv randomisierte Studie mit größerer Patientenanzahl ist notwendig, um die hier erhobenen Daten zu verifizieren.
Bei der Analyse der Diffusion von Gallensäuren durch Lipiddoppelmembranen (SUV´s, LUVET´s) erweisen sich die lipophilen Gallensäuren als besonders diffusionsfreudig. Zu diesen können die LC, CDC und die DC gezählt werden. Die deutlich hydrophilere und therapeutisch bedeutende UDC permeiert ebenfalls durch Liposomenmembranen, hat jedoch eine geringere Geschwindigkeitskonstante. Konjugierte Gallensäuren zeigen dagegen nur eine minimale Diffusionsrate. Weiterhin wurde nachgewiesen, daß eine deutliche Abhängigkeit der Permeation von der Gallensäurenkonzentration besteht. Mit steigender Konzentration erhöht sich die Geschwindigkeit. Auch bei diesen Experimenten sind die lipophileren Substanzen die schnelleren. Zudem kann festgehalten werden, daß auch eine Temperaturerhöhung bis auf 37 °C und ein Abfall des pH- Wertes auf 5,4 einen positiven Einfluß auf die Permeabilitätsrate von Gallensäuren haben. Umgekehrt verhält es sich bei einer Temperaturminderung auf 10 °C und einer pH- Erhöhung auf 9,4. Eine gleichzeitige pH- Minderung und Temperaturerhöhung hat einen additiven Effekt auf die Diffusion. Geschwindigkeitssteigernd erweist sich auch die Verwendung größerer Liposomen. Eine Steigerung des Liposomendurchmessers geht mit einer Zunahme der Permeabilität einher. Auch die Zugabe von Ethanol bewirkt eine Zunahme der Diffusion durch Liposomenmembranen. Eine herabgesetzte Diffusionsrate kann bei Änderungen in der Lipidkomposition von Lipiddoppelmembranen beobachtet werden. Ein Einbau von Cholesterin führt eine deutliche Minderung der Permeation aller Gallensäuren herbei, wobei die lipophilen Gallensäuren auch weiterhin rascher permeieren. Ein Cholesteringehalt von 20% (w/w) wirkt dabei stärker hemmend als ein Gehalt von 10% (w/w). Im zweiten Abschnitt der vorliegenden Arbeit konzentrieren sich die Beobachtungen auf den Einfluß von Ethanol auf Lipiddoppelmembranen. Es kann gezeigt werden, daß Ethanol einen membrandestabilisierenden Effekt hat, der um so stärker ist, je höher die Ethanolkonzentration gewählt wird. Die DPH- Fluoreszenzversuche lassen zudem erkennen, daß Ethanol zu einer Reduktion der Membranordnung führt und damit zu einer Zunahme der Membranfluidität. Ein Einbau von UDC in die Liposomenmembran hat dagegen einen membran-stabilisierenden Effekt und reduziert die Ethanolwirkung. Dieser Effekt ist zu der Menge der in der Membran eingebauten UDC proportional. Der Cholesterineinbau in die Membran zeigt ähnliche Effekte wie der Einbau von UDC. Die Ergebnisse dieser Arbeit liefern zusätzliche Erklärungen für Phänomene beim therapeutischen Einsatz von Gallensäuren, die bisher nur mangelhaft zu verstehen waren. So kann aus den Diffusionsstudien die Erkenntnis gewonnen werden, daß bei der Diffusion von mehr apolaren Gallensäuren, wie z.B. der CDC, eine leichtere Diffusion durch Membranen möglich ist als für die mehr polaren Moleküle. In der PBC sind vor allem die mehr apolaren Gallensäuren nachweisbar und stellen somit einen vielleicht wichtigen pathophysiologischen Faktor dar, der sich eventuell durch Einbau von Cholesterin in Membranen oder durch Applikation von UDC mindern läßt. UDC scheint jedoch auch gegen andere schädigende Substanzen eine protektive Wirkung zu haben. Ethanolinduzierte Schädigungen an Membranen konnten z.B. durch die Anwendung von UDC deutlich reduziert werden. Eine wenig geschädigte oder sogar intakte Membran kann ihren vielfältigen Funktionen gerecht werden, z.B. die Funktion von Transportsystemen aufrechterhalten. Dies könnte erklären, warum UDC bei primär biliären Leberkrankheiten eine Cholestase vermindert oder sogar aufheben kann, die heute weitgehend mit einer Schädigung membranständiger Carriersysteme erklärt wird.
Background. Intervertebral disc degeneration (IDD) at the cervicothoracic junction of spine is clinically relevant, however, little attention had been paid. T2 mapping and magnetic transfer ratio (MTR) are useful magnetic resonance imaging (MRI) techniques to quantitatively evaluate IDD, revealing the biochemical changes within the intervertebral disc. To compare T2 mapping with MTR imaging regarding their accuracy to quantitatively diagnose intervertebral disc degeneration at the cervicothoracic junction, influences of anatomical level, gender, age, and Pfrrmann grade of T2 relaxation time values and MTR values were evaluated.
Methods. Sixty-seven patients with neck and upper back pain were included and examined with both T2 mapping andMTR imaging. Te Pfrrmann grade, T2 relaxation time values, and MTR value of each disc between C7 and T3 were measured. Diferences were investigated among diferent segmental levels, genders, age ranges, and Pfrrmann grades. Te diagnostic accuracy of both MRI techniques was compared using the receiver operating characteristic (ROC) curves.
Results. No signifcant diference was detected comparing T2 relaxation time values or MTR values among diferent anatomical levels, genders, and segmental levels. And we generally found that T2 relaxation time values decreased, while MTR value increased with increasing age. Importantly, we demonstrated the signifcant correlation between either T2 relaxation time values or MTR value and Pfrrmann grade.
Conclusion. We proved the better accuracy of T2 mapping over MTR imaging to quantitatively evaluate the intervertebral disc degeneration of the cervicothoracic junction.
Poster presentation: 28th Annual Scientific Meeting of the Society for Immunotherapy of Cancer (SITC)
Significant progress has been made over the last decade towards realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells, and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also continuously expanding cytotoxic cell lines such as NK-92 are being considered for adoptive cancer immunotherapy. High cytotoxicity of NK-92 has previously been shown against malignant cells of hematologic origin in preclinical studies, and general safety of infusion of NK-92 cells has been established in phase I clinical trials. To enhance their therapeutic utility, we genetically modified NK-92 cells to express chimeric antigen receptors (CAR) specific for tumor-associated surface antigens. Such CAR were composed of a tumor-specific scFv antibody fragment fused via hinge and transmembrane domains to intracellular signaling moieties such as CD3 zeta chain, or composite fusion molecules also containing a costimulatory protein domain in addition to CD3 zeta. For development towards clinical applications, here a codon-optimized second generation CAR was constructed that consists of an ErbB2-specific scFv antibody domain fused via a linker to a composite CD28-CD3 zeta signaling domain. GMP-compliant protocols for vector production, lentiviral transduction and expansion of a genetically modified NK-92 single cell clone (NK-92/5.28.z) were established. Functional analysis of NK-92/5.28.z cells revealed high and stable CAR expression, selective cytotoxicity against ErbB2-expressing but otherwise NK-resistant tumor cells of different origins in vitro, as well as homing to ErbB2-expressing tumors in vivo. Furthermore, antigen specificity and selective cytotoxicity of these cells were retained in vivo, resulting in antitumoral activity against subcutaneous and intracranial glioblastoma xenografts in NSG mice. Ongoing work now focuses on the development of these cells for adoptive immunotherapy of ErbB2-positive glioblastoma.
Background: The MRI Breast Imaging-Reporting and Data System (BI-RADS) lexicon recommends that a breast MRI proto-col contain T2-weighted and dynamic contrast-enhanced (DCE) MRI sequences. The addition of diffusion-weighted imag-ing (DWI) significantly improves diagnostic accuracy. This study aims to clarify which descriptors from DCE-MRI, DWI, andT2-weighted imaging are most strongly associated with a breast cancer diagnosis.Purpose/Hypothesis: To develop a multiparametric MRI (mpMRI) model for breast cancer diagnosis incorporating Ameri-can College of Radiology (ACR) BI-RADS recommended descriptors for breast MRI with DCE, T2-weighted imaging, andDWI with apparent diffusion coefficient (ADC) mapping.Study Type: Retrospective.Subjects: In all, 188 patients (mean 51.6 years) with 210 breast tumors (136 malignant and 74 benign) who underwentmpMRI from December 2010 to September 2014.Field Strength/Sequence: IR inversion recovert DCE-MRI dynamic contrast-enhanced magnetic resonance imaging VIBEVolume-Interpolated-Breathhold-Examination FLASH turbo fast-low-angle-shot TWIST Time-resolved angiography withstochastic Trajectories.Assessment: Two radiologists in consensus and another radiologist independently evaluated the mpMRI data. Charac-teristics for mass (n = 182) and nonmass (n = 28) lesions were recorded on DCE and T2-weighted imaging accordingto BI-RADS, as well as DWI descriptors. Two separate models were analyzed, using DCE-MRI BI-RADS descriptors, T2-weighted imagines, and ADCmean as either a continuous or binary form using a previously published ADC cutoffvalue of ≤1.25 × 10−3mm2/sec for differentiation between benign and malignant lesions. Histopathology was the stan-dard of reference.Statistical Tests: χ2test, Fisher’s exact test, Kruskal–Wallis test, Pearson correlation coefficient, multivariate logistic regres-sion analysis, Hosmer–Lemeshow test of goodness-of-fit, receiver operating characteristics analysis.Results: In Model 1, ADCmean (P = 0.0031), mass margins with DCE (P = 0.0016), and delayed enhancement with DCE(P = 0.0016) were significantly and independently associated with breast cancer diagnosis; Model 2 identified ADCmean(P = 0.0031), mass margins with DCE (P = 0.0012), initial enhancement (P = 0.0422), and delayed enhancement with DCE(P = 0.0065) to be significantly independently associated with breast cancer diagnosis. T2-weighted imaging variables werenot included in the final models
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
Background: Compound flaps offer the advantage of one stage defect reconstruction respecting all relevant tissues and early functional recovery by optimal vascularity of all components. Due to its specific vascular anatomy and the three-dimensional donor site, compound flaps with bone components may result in higher complication rates compared to soft tissue compound flaps. The meta-analysis summarizes the available evidence and evaluates whether bone components are a risk factor for periprocedural complications in upper extremity multidimensional defect reconstruction. Method: PubMed and Embase were searched for all publications addressing compound free flaps for upper extremity defect reconstruction with bone or soft tissue components published between January 1988 and May 2018. The methodological quality was assessed with the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies. Flap loss, thrombosis rate, early infection, hematoma, seroma, as well as donor site complications were extracted and analyzed. Results: Twelve out of 1157 potentially eligible studies (evidence-III) comprising 159 patients were finally included with publication bias for all summarized complication rates. Complication rates for flaps with/ without bone components were: total flap loss 5%, 95% CI = 3%–10% (6%/5%); partial flap loss 8%, 95% CI = 5%–15%, (9%/8%); arterial/venous thrombosis 7%, 95% CI = 4%–12%, (8%/5%)/14%, 95% CI = 9%–21% (16%/6%, P < .05) with higher risk for flaps with bone components; infection 6%, 95% CI = 3%–12% (6%/6%); hematoma 6%, 95% CI = 3%–11% (6%/5%); seroma 5%, 95% CI = 3%–10% (5%/5%); dehiscence 10%, 95% CI = 6%–17% (11%/9%). Conclusion: Compound flaps for upper extremity defect reconstruction including bone components have a higher venous thrombosis rate compared to compound soft-tissue flaps.
Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa.
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efcient diagnostic algorithms.
Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age,
66 ± 6.6 years) were included in the study. Patients sufered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open–source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms.
Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and
ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of 0.93 ± 0.04, 0.91 ± 0.06, and 0.92 ± 0.05, respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02–0.06 for ERG and PIN-4.
Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classifcation. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classifcation methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine.
Reciprocal t(9;22) ABL/BCR fusion proteins: leukemogenic potential and effects on B cell commitment
(2009)
Background: t(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph+) determine formation of different fusion genes that are associated with either Ph+ acute lymphatic leukemia (Ph+ ALL) or chronic myeloid leukemia (CML). The "minor" breakpoint in Ph+ ALL encodes p185BCR/ABL from der22 and p96ABL/BCR from der9. The "major" breakpoint in CML encodes p210BCR/ABL and p40ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96ABL/BCR and p40ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL. Methodology: All t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR. Principal Findings: Both p96ABL/BCR and p40ABL/BCR increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96ABL/BCR and to a minor extent p40ABL/BCR forced the B-cell commitment of SL-cells and UCBC. Conclusions/Significance: Our here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22) in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their influence on the lineage commitment.
Clinical application of transcranial Doppler for detection of cerebral emboli during cardiac surgery
(2010)
Objective: Neurologic injury is one of the most damaging complications for cardiac surgery. How to decrease neurologic impairment by improving perioperative monitoring remains a challenge for both cardiac surgeons and anesthetists. For this reason, transcranial doppler (TCD) has been widely used in cerebral monitoring during cardiac surgery. In this study, two experiments of clinical application of TCD for detection of cerebral emboli during cardiac surgery were to be done. One was “Solid and gaseous cerebral emboli during valvular surgery are significantly reduced with axillary artery cannulation”. The other was “Do intraoperative cerebral embolic signals differ between valvular surgery (VS) and CABG”. Methods: In experiment one, 20 valve and combined procedures with aortic cannulation (AoC group) were compared to 18 procedures with axillary cannulation (AxC group) in a prospective non-randomized study. In experiment two, 18 VS patients and 18 CABG patients were matched by extracorporeal circulation (ECC) time retrospectively. Intraoperative monitoring of both middle cerebral arteries was performed with TCD discriminating between solid and gaseous embolic signals (ES). Results: In experiment one, the AxC group had less solid ES than the AoC group (38±22 vs 55±25, P<0.05), but no significant difference was found in gaseous (501±271 vs 538±333, P>0.05) and total (539 ± 279 vs 593 ± 350, P>0.05) ES. The AxC group had less solid ES during arterial cannulation (2.1±1.5 vs 6.6±3.6, P<0.05) and during aortic cross-clamp time (4.4 ±3.1 vs 10.2 ± 5.1, P<0.05) than the AoC group. During ECC, gaseous ES was not significantly different between groups (398±210 vs 448±291, P>0.05). However, AxC showed less gaseous ES (85±68 vs 187±148, P<0.05) and less gaseous ES per minute (1.8±1.5 vs 4.5±3.2, P<0.05) during weaning off extracorporeal circulation than the AoC group. No significant difference in gaseous ES (313±163 vs 261±189, P>0.05) and gaseous ES per minute (3.1±2.2 vs 2.8±2.2, P>0.05) was found between groups from bypass start to aortic declamping. No neurologic complications occurred. In experiment two, no significant difference was found in solid (38±20 vs 40±26, P>0.05) or gaseous (457±263 vs 412±157, P>0.05) ES between the VS and CABG group during the whole recording time. During ECC, solid ES (20±10 vs 24±19, P>0.05) and gaseous ES (368±230 vs 317±157, P>0.05) were comparable between groups. Specifically, during weaning off ECC, the VS group had more gaseous ES/min (5.6±3.6 vs 3.1±1.2, P<0.05) than the CABG group. But this difference in gaseous ES/min was not significant during the period from bypass start to aortic declamping (2.5±1.8 vs 3.0±1.8, P>0.05). Conclusion: Cerebral embolization does occur during cardiac surgery. Through these two experiments, we demonstrated the feasibility and importance of clinical application of transcranial doppler for detection of cerebral emboli during cardiac surgery. Due to the diversity in clinical application of TCD, it is impossible to compare the number of ES between different research centers. More unified standards should be drawn in order to make wider clinical application possible. Up till now, no robust evidence shows the correlation between intraoperative ES and postoperative neurological impairment. The research on intraoperative ES and postoperative neurological impairment should rely on a complete concept.
Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes
(2018)
Previous identification of the inducible nitric oxide synthase (NOS2) gene as a risk allele for psoriasis (Ps) and psoriatic arthritis (PsA) suggests a possible pathogenic role of nitric oxide (NO). Using a mouse model of mannan-induced Ps and PsA (MIP), where macrophages play a regulatory role by releasing reactive oxygen species (ROS), we found that NO was detectable before disease onset in mice, independent of a functional nicotinamide adenine dinucleotide phosphate oxidase 2 complex. MIP was suppressed by either deletion of Nos2 or inhibition of NO synthases with NG-nitro-L-arginine methyl ester, demonstrating that Nos2-derived NO is pathogenic. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-γ–stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1α (IL-1α) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS.
Slack (sequence like a Ca2+ -activated K + channel; also termed Slo2.2, Kcnt1, or KNa 1.1) is a Na+ -activated K + channel that is highly expressed in the peripheral and central nervous system. Previous studies have shown that Slack is enriched in the isolectin B4binding, non-peptidergic subpopulation of C-fiber sensory neurons and that Slack controls the sensory input in neuropathic pain. Recent single-cell RNA-sequencing studies suggested that Slack is highly co-expressed with transient receptor potential (TRP) ankyrin 1 (TRPA1) in sensory neurons. By using in situ hybridization and immunostaining we confirmed that Slack is highly co-localized with TRPA1 in sensory neurons, but only to a minor extent with TRP vanilloid 1. Mice lacking Slack globally or conditionally in sensory neurons (SNS-Slack─/─ ), but not mice lacking Slack conditionally in neurons of the spinal dorsal horn (Lbx1-Slack─/─ ), displayed increased pain behavior after intraplantar injection of the TRPA1 activator allyl isothiocyanate. Patch-clamp recordings with cultured primary neurons and in a HEK-293 cell line transfected with TRPA1 and Slack revealed that Slack-dependent K + currents are modulated in a TRPA1-dependent manner. Taken together, these findings highlight Slack as a modulator of TRPA1-mediated activation of sensory neurons.
Furthermore, we investigated the contribution of Slack in the spinal dorsal horn to pain processing. Lbx1-Slack ─/─ mice demonstrated normal basal pain sensitivity and Complete Freund’s Adjuvant-induced inflammatory pain. Interestingly, we observed a significantly increased spared nerve injury (SNI)-induced neuropathic pain hypersensitivity in Lbx1-Slack ─/─ mutants compared to control littermates. Moreover, we tested the effects of pharmacological Slack activation in the SNI model. Systemic and intrathecal, but not intraplantar administration of the Slack opener loxapine significantly alleviated SNI-induced hypersensitivity in control mice, but only slightly in Lbx1Slack ─/─ mice, further supporting the inhibitory function of Slack in spinal dorsal horn neurons in neuropathic pain processing.
Altogether, our data suggest that Slack in sensory neurons controls TRPA1-induced pain, whereas Slack in spinal dorsal horn neurons inhibits peripheral nerve injury induced neuropathic pain. These data provide further insights into the molecular mechanisms of pain sensation.
Cardiovascular disease (CVD) remains the leading cause of cardiac morbidity and mortality in the entire world population. Heart failure (HF) is the fastest growing cardiac diagnosis, with an annual incidence of 10 cases per 1000 people in individuals older than 65 [1]. This is partly a reflection of an aging population and success of treatment of acute coronary syndromes with reduced premature mortality due to ischaemic heart disease (IHD), as well as increasing ability to recognise non-ischaemic - intrinsic myocardial processes- due to advances in genetics and imaging. The conventional imaging predictors of outcome in CVD patients primarily include left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE) using cardiovascular magnetic resonance (CMR). LVEF represents the main universal, as well as the multimodality biomarker of risk stratification. ...
Thioredoxin 1 and thioredoxin 2 have opposed regulatory functions on hypoxia-inducible factor-1α
(2007)
Hypoxia inducible factor 1 (HIF-1), a key regulator for adaptation to hypoxia, is composed of HIF-1alpha and HIF-1beta. In this study, we present evidence that overexpression of mitochondria-located thioredoxin 2 (Trx2) attenuated hypoxia-evoked HIF-1alpha accumulation, whereas cytosolic thioredoxin 1 (Trx1) enhanced HIF-1alpha protein amount. Transactivation of HIF-1 is decreased by overexpression of Trx2 but stimulated by Trx1. Inhibition of proteasomal degradation of HIF-1alpha in Trx2-overexpressing cells did not fully restore HIF-1alpha protein levels, while HIF-1alpha accumulation was enhanced in Trx1-overexpressing cells. Reporter assays showed that cap-dependent translation is increased by Trx1 and decreased by Trx2, whereas HIF-1alpha mRNA levels remained unaltered. These data suggest that thioredoxins affect the synthesis of HIF-1alpha. Trx1 facilitated synthesis of HIF-1alpha by activating Akt, p70S6K, and eIF-4E, known to control cap-dependent translation. In contrast, Trx2 attenuated activities of Akt, p70S6K, and eIF-4E and provoked an increase in mitochondrial reactive oxygen species production. MitoQ, a mitochondria specific antioxidant, reversed HIF-1alpha accumulation as well as Akt activation under hypoxia in Trx2 cells, supporting the notion of translation control mechanisms in affecting HIF-1alpha protein accumulation.
Formalin‐fixed, paraffin‐embedded (FFPE ), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here, we developed a pressure cycling technology (PCT )‐SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PC a) and diffuse large B‐cell lymphoma (DLBCL ) samples. We show that the proteome patterns of FFPE PC a tissue samples and their analogous fresh‐frozen (FF ) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PC a tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between 1 and 15 years in a biobank and show a high degree of the proteome pattern similarity between two types of histological regions in small FFPE samples, that is, punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of a certain degree of biological variations. Applying the method to two independent DLBCL cohorts, we identified myeloperoxidase, a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PC a and DLBCL have been discovered.
Highlights
• Deletion of SPPL3 promotes resistance of malignant B cells to NK cell cytotoxicity
• Loss of SPPL3 blocks ligand binding to NK receptors via increased N-glycosylation
• B3GNT2 deletion reduces LacNAc addition and restores SPPL3-KO cell sensitivity to NK cells
• SPPL3-deficient cells are enriched in tetra-antennary N-glycans with LacNAc elongations
Summary
Natural killer (NK) cells are primary defenders against cancer precursors, but cancer cells can persist by evading immune surveillance. To investigate the genetic mechanisms underlying this evasion, we perform a genome-wide CRISPR screen using B lymphoblastoid cells. SPPL3, a peptidase that cleaves glycosyltransferases in the Golgi, emerges as a top hit facilitating evasion from NK cytotoxicity. SPPL3-deleted cells accumulate glycosyltransferases and complex N-glycans, disrupting not only binding of ligands to NK receptors but also binding of rituximab, a CD20 antibody approved for treating B cell cancers. Notably, inhibiting N-glycan maturation restores receptor binding and sensitivity to NK cells. A secondary CRISPR screen in SPPL3-deficient cells identifies B3GNT2, a transferase-mediating poly-LacNAc extension, as crucial for resistance. Mass spectrometry confirms enrichment of N-glycans bearing poly-LacNAc upon SPPL3 loss. Collectively, our study shows the essential role of SPPL3 and poly-LacNAc in cancer immune evasion, suggesting a promising target for cancer treatment.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complex membrane protein complexes. The enzyme contributes substantially to oxidative energy-conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. Here, we report the X-ray structure of mitochondrial complex I at 3.6- 3.9 Å resolution describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the ‘deactive’ form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site rendering support for a two-state stabilization-change mechanism of protonpumping.
Microsurgical free flap reconstruction in acute burn care offers the option of reconstructing even challenging defects in a single stage procedure. Due to altered rheological and hemodynamic conditions in severely burned patients, it bears the risk of a higher complication rate compared to microsurgical reconstruction in other patients. To avoid failure, appropriate indications for free flap reconstruction should be reviewed thoroughly. Several aspects concerning timing of the procedure, individual flap choice, selection and preparation of the recipient vessels, and perioperative measures must be considered. Respecting these specific conditions, a low complication rate, comparable to those seen in microsurgical reconstruction of other traumatic limb defects, can be observed. Hence, the free flap procedure in acute burn care is a relatively safe and reliable tool in the armamentarium of acute burn surgery. In reconstructive burn care, microsurgical tissue transfer is routinely used to treat scar contractures. Due to the more robust perioperative condition of patients, even lower rates of complication are seen in microsurgical reconstruction.
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Hintergrund: Am Fachbereich Medizin der Universität Frankfurt werden jedes Jahr zwischen 15 und 20 neue Projekte zur Verbesserung der Lehre durch den Studienausschuss gefördert. Portfolios zur Skizzierung der Projekte werden von den Zentren und Instituten eingereicht. Diese Projekte haben u.a. die Neustrukturierung von Kursen und Praktika, die Implementierung und Evaluation von Prüfungen (z. B. objective structured clinical evaluation), die Förderung der didaktischen Aus- und Weiterbildung von Dozenten und Tutoren oder die curriculare Einbindung von elektronischen Medien in die Lehre zum Inhalt.
Um diese Projekte untereinander zu koordinieren, wurde im Juni 2006 das Frankfurter Ideenforum für Lehre und Unterricht – kurz FILU – geschaffen.
Ziele des Frankfurter Ideenforums für Lehre und Unterricht
1. Das Forum FILU bietet eine Informationsplattform für die Projektleiter der Lehrverbesserungsprojekte.
2. Das Forum übernimmt die Funktion eines Kondensators für thematisches und informationelles Vernetzungspotential der Projekte untereinander.
3. Übersteigt der Arbeits- und Koordinationsbedarf die Möglichkeiten des Forums, initiiert das FILU neue interdisziplinäre Arbeitsgruppen.
4. Der "Journal Club" innerhalb der Treffen des FILU läßt alle Teilnehmer an der aktuellen Studienlage in Ausbildungsforschung teilhaben.
5. Das Forum FILU engagiert sich dafür, die Aktivitäten zur Lehre innerhalb des Fachbereiches Medizin und darüber hinaus bekannt zu machen.
Methode: Koordination und Organisation des Forums übernimmt eine ärztliche wissenschaftliche Mitarbeiterin. Die Treffen finden in 4-Wochenrhythmen à 2 Stunden statt. Pflichtmitglieder sind die Initiatoren und Leiter der Lehrverbesserungsprojekte; weitere interessierte Akteure des Fachbereiches nehmen ebenfalls teil.
Pro Termin werden maximal zwei Lehrverbesserungsprojekte vorgestellt und diskutiert. In einem Journal Club wird eine aktuelle und für den Fachbereich relevante Studie aus den einschlägigen Journalen der Ausbildungsforschung und Medizindidaktik vorgestellt. Nach jedem Treffen erfolgt eine freiwillige Befragung der Mitglieder hinsichtlich Zielvorstellungen, Veranstaltungsankündigungen und Vortragswünschen. Halbjährig erfolgt ein Bericht an den Studienausschuss. [Ein Organigramm stellt bildhaft die Strukturen dar.]
Ergebnisse: Insgesamt haben bisher bei 9 Terminen 202 Personen teilgenommen. Aus der Befragung der Mitglieder initiierten sich ein interdisziplinäres Promotions- und Studienkolleg für Ausbildungsforschung und ein Lehrverbesserungsprojekt zur zentrumsübergreifenden Koordination von Simulationspatienten in OSCE.
Innerhalb des Forums entstand die Planung zur Präsentation der Lehre-Aktivitäten auf einer Veranstaltung der Frankfurter Medizinischen Gesellschaft. Der Fachbereich verfügt durch Anregung aus dem Gremium inzwischen über ein eigenes Online-Portal, einen virtuellen "Treffpunkt Lehre".
[Teilnehmerzahlen, Herkunftszentren der Teilnehmer, Themen der LV-Projekte über die letzten zwei Jahre]
Schlussfolgerung: Das "Frankfurter Ideenforum für Lehre und Unterricht", FILU, bietet seit seiner Implementierung eine lebendige Austausch- und Kommunikationsplattform für die Leiter der Lehrverbesserungsprojekte am Fachbereich. Über das Forum wird eine gemeinsame Nutzung der vorhandenen Ressourcen in der Lehre möglich. Die interdisziplinäre Zusammenarbeit der Akteure wird maßgeblich gefördert und bietet die Möglichkeit, sinnvolle thematische und personelle Synergien zu finden.
Reisen sind aus verschiedenen Gründen mit erhöhten gesundheitlichen Risiken verbunden, insbesondere dann, wenn damit lange Reisezeiten, beengte Reiseverhältnisse, klimatische und Ernährungsumstellungen sowie vermehrte physische und psychische Belastungen verbunden sind. Besonders gefährdet sind Reisende, deren Leistungsfähigkeit durch bedeutsame chronische Erkrankungen eingeschränkt sind, wozu die Erkrankungen des kardiovaskulären Formenkreises zählen. Häufig verzichten herzkranke Patienten deshalb auf Urlaubsreisen, weil sie das damit verbundene Gesundheitsrisiko scheuen. Die Deutsche Herzstiftung e. V. und die Deutsche Gesellschaft für Prävention und Rehabilitation von Herz-Kreislauferkrankungen (DGPR) empfehlen daher speziell für Herzkranke angebotene Reisen. Diese sogenannten „Herzreisen“ werden nach strengen Richtlinien durchgeführt und verstehen sich als ärztlich begleitete Gruppenreisen, die spezielle Angebote für Herzkranke enthalten. Hierzu zählen, ähnlich wie in den ambulanten Herzgruppen (AHG), ein tägliches Bewegungs- und Entspannungsprogramm, die Durchführung von Arzt-Patient-Seminaren, Arztsprechstunden sowie spezielle diätetische Angebote und cholesterinreduzierte Mahlzeiten. Diese Reisen und alle in diesem Zusammenhang organisierten Ausflüge werden von 2 bis 3 in der Notfallmedizin erfahrenen Ärzten begleitet, die immer eine Notfallausrüstung (Notfallkoffer, EKG-Gerät, Defibrillator) mit sich führen. Über das Auftreten von Erkrankungen, Komplikationen, Verletzungen und erforderliche ärztliche Kontrolluntersuchungen bei Herzkranken und nicht herzkranken Vergleichspersonen bei Urlaubs- bzw. Herzreisen lagen jedoch bisher keine wissenschaftlichen Daten vor. Ziel dieser prospektiven Untersuchung war es, Erkenntnisse über die Art und Häufigkeit kardiovaskulärer und anderer Komplikationen oder Erkrankungen zu gewinnen, die im Rahmen kommerzieller Urlaubsreisen bei Herz-Kreislaufpatienten auftreten und wie sie von den begleitenden Ärzten allein oder mit Hilfe der medizinischen Einrichtungen vor Ort gelöst werden können. Deshalb wurden die Daten aller Herzpatienten und Begleitpersonen analysiert (n = 588), die in den Jahren 2000 und 2001 an Urlaubsreisen der Firma Kalina, Köln, unter ärztlicher Betreuung teilgenommen haben. Die Datenerfassung der hauptsächlich als Flugreisen angebotenen Herzreisen war durch einen speziell entwickelten Anamnesebogen und ein Sprechstunden-/Betreuungsprotokoll möglich, die vor den Reisen an die begleitenden Ärzte ausgegeben wurden. 421 Herzpatienten (71,6 %) und 165 Begleitpersonen (28,1 %) nahmen an den untersuchten Herzreisen teil. Die Geschlechtsverteilung der Herzpatienten war sehr ausgeglichen ( 48,0 %, 51,8 %), unter den Begleitpersonen befanden sich jedoch deutlich mehr Frauen (82,4 %). Das mittlere Alter der Herzpatienten lag bei 66,5 Jahren, das der Begleitpersonen bei 60,9 Jahren. Die evaluierte Gruppe der Herzpatienten bestand aus teilweise schwer kardial erkrankten Personen, die häufig sogar an mehreren kardialen Erkrankungen gleichzeitig litten. Sie unterschieden sich von den Begleitpersonen vor allem im Bezug auf die Prävalenz von Begleiterkrankungen, (kardialen) Risikofaktoren und die Einnahme kardial wirksamer Medikamente. Wie zu erwarten war, kam es auf Herzreisen zu kardiovaskulären und auch anderen Zwischenfällen, die mit dem speziellen Patientenkollektiv und seinen Vorerkrankungen in Verbindung gebracht werden konnten. Alle Zwischenfälle wurden von den begleitenden Ärzten jedoch sicher gelöst, so dass die ständige Anwesenheit eines Arztes inklusive Notfallausrüstung zu Recht gefordert wird. Nur in Ausnahmefällen kam es zu schwereren Komplikationen, die die begleitenden Ärzten nicht selbst behandeln konnten und die eine ambulante Behandlung bei einem anderen Arzt oder eine stationäre Aufnahme im Krankenhaus notwendig machten. Die auf den Reisen aufgetretenen Komplikationen sind jedoch selten und unterscheiden sich zahlenmäßig nicht von denen, die im Rahmen anderer kardiologischer Rehabilitationen oder der ambulanten Herzgruppen auftreten. Auf Herzreisen muss allerdings aufgrund des speziellen Gefahrenpotentials von Herzpatienten schon aus statistischen Gründen immer mit Komplikationen gerechnet werden. Anders als in Berichten von Krasemann und Laubinger kam es während des 2-jährigen Untersuchungszeitraumes von Herzreisen zu keinem tödlichen Zwischenfall oder zum Auftreten eines Myokard- oder Reinfarktes. Im Vergleich zu den Begleitpersonen traten jedoch überdurchschnittlich mehr allgemeine und leichtere kardiale Probleme und auch medizinisch kritischere Komplikationen auf. Die Ergebnisse unserer Untersuchung bestätigen die Annahmen anderer Autoren, dass Herzreisen sicher durchführbar sind. Sie tragen dem Bedürfnis der Herzpatienten Rechnung, auch im Urlaub ein subjektives Gefühl der Sicherheit durch einen Arzt vermittelt zu bekommen und einen medizinischen Ansprechpartner zu haben, der im Notfall eingreifen kann. Die Herzreisen entsprechen damit wichtigen Zielen in der kardiologischen Rehabilitation und tragen zu einer weiteren Wiedereingliederung in den Alltag bei. Den Patienten wird es trotz Herzerkrankung ermöglicht, mit reduziertem Risiko, betreut in den Urlaub zu fahren und krankheitsangepasste Freizeitaktivitäten durchzuführen. Somit kann die Herzreise einen wichtigen Beitrag in der kardiologischen Rehabilitation leisten.
Introduction: Cesarean section (CS) rates are increasing worldwide. One constant indication is the breech presentation at term. By offering external cephalic version (ECV) and vaginal breech delivery CS rates can be further reduced. Objective: This study aimed to analyze the ECV at 38 weeks of gestation with the associate uptake rate, predicting factors, success rate, and complications at a tertiary healthcare provider in Germany specializing in vaginal breech delivery. Methods: We conducted a prospective cohort study with retrospective data acquisition. All women with a singleton fetus in breech presentation presenting after 34 weeks of gestation for counseling between 2013 and 2017 were included. ECV impact factors were analyzed using logistic regression. Results: A total of 1,598 women presented for breech birth planning. ECV was performed on 353 patients. The overall success rate was 22.4%. A later week of gestation (odds ratio [OR] 1.69), an abundant amniotic fluid index (AFI score) (OR 5.74), fundal (OR 3.78) and anterior (OR 0.39) placental location, and an oblique lie (OR 9.08) were significantly associated with successful ECV in our population. No major complications were observed. The overall vaginal delivery rates could be increased to approximately 14% with ECV. Conclusion: The demand for alternative birth modes other than CS for breech birth is high in the area of Frankfurt, Germany. Our study offers evidence of the safety of ECV at 38 weeks. Centers with expertise in vaginal breech delivery and ECV can reduce CS-rates. To further establish vaginal breech delivery and ECV as alternate options, the required knowledge and skill should be implemented in the revised curricula.
Die Häufigkeitsrate atopischer Erkrankungen bei Kindern, wie Heuschnupfen, Asthma, Neurodermitis (atopische Dermatitis), nimmt weltweit zu. Die Gründe sind vielschichtig. Gesichert ist der Zusammenhang zwischen der erblichen Überempfindlichkeit gegenüber natürlichen Substanzen (Atopie) und vermehrter Allergen- und Passivrauch-Exposition sowie Zunahme der Ein-Kind-Familien, Veränderung der mikrobiologischen Besiedlung des Darmes und Infektexposition. Besonders gut untersucht wurden diese Zusammenhänge von Erika von Mutius in einer Studie, in der sie von 1991 bis 1992 die Häufigkeit von Asthma in München (5030 Kinder) und Leipzig/Bitterfeld (2623 Kinder) verglichen hat.
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)
Strong dose response after immunotherapy with PQ grass using conjunctival provocation testing
(2019)
Background: Pollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose.
Methods: Patients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31–41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship.
Results: In total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature.
Conclusions: PQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.