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Complexin-1 and foxp1 expression changes are novel brain effects of
alpha-synuclein pathology
(2014)
As the second most frequent neurodegenerative disorder of the aging population, Parkinson’s disease (PD) is characterized by progressive deficits in spontaneous movement, atrophy of dopaminergic midbrain neurons and aggregation of the protein alpha-synuclein (SNCA). To elucidate molecular events before irreversible cell death, we studied synucleinopathy-induced expression changes in mouse brain and identified 49 midbrain/brainstem-specific transcriptional dysregulations. In particular complexin-1 (Cplx1), Rabl2a and 14-3-3epsilon (Ywhae) downregulation, as well as upregulation of the midbrain-specific factor forkhead box P1 (Foxp1) and of Rabgef1, were interesting as early mRNA level effects of alpha-synuclein triggered pathology. The protein levels of complexin-1 were elevated in midbrain/brainstem tissue of mice with A53T-SNCA overexpression and of mice with SNCA-knockout. The response of CPLX1 and Foxp1 levels to SNCA deficiency supports the notion that these factors are regulated by altered physiological function of alpha-synuclein. Thus, their analysis might be useful in PD stages before the advent of Lewy pathology. Because both alpha-synuclein and complexin-1 modulate vesicle release, our findings support presynaptic dysfunction as an early event in PD pathology.
The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.
Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.
Purpose: To evaluate the effect of chronic liver disease (CLD) in a multivariate analysis of associated risk factors in patients with hepatocellular carcinoma (HCC) using transarterial chemoembolization (TACE). Materials and methods: A total of 145 patients with HCC (99 men, 46 women; mean age: 63 years ±8.1; age range: 46-84 years) underwent 598 TACE procedures. The presence of CLD, number and location of lesions, tumor size, Child-Pugh score, vascularity, portal involvement and alpha fetoprotein value were analyzed using the multivariate regression model. Cox regression was used for survival analysis. Results: The median survival time was 26.7 months, and 78.6% of all treated lesions showed tumor responses. The presence of CLD (OR 2.12, P=0.004), Child-Pugh score B (OR 2.24, P=0.002), alpha fetoprotein >100ng/dl (OR 1.18, P<0.001), multinodularity (≥3 lesions) (OR 4.41, P=0.003), lesion size >5cm (OR 4.12, P=0.002) and hypervascularity (OR 7.94, P=0.003) were significant effective factors for a local response when analyzed using a multivariate logistic model. Multivariate survival analysis using Cox's regression model during the median follow-up period of 25 months (range: 1-42 months) demonstrated a significant difference in survival rates (P values <0.05). No significant difference in responses was noted for males, locations of lesions and portal involvements statistically. Conclusion: The presence of chronic liver disease as well as associated risk factors including Child-Pugh score B, alpha fetoprotein 100ng/dl, multinodularity (≥3 lesions), lesion size >5cm and hypervascularity statistically led to a significant effect in tumor response in HCC patients treated with TACE. Patient gender, location of lesion and involvement of portal vein showed no significant difference in response.
Introduction: Currently there are several advanced guiding techniques for pathoanatomical diagnosis of incidental solitary pulmonary nodules (iSPN): Electromagnetic navigation (EMN) with or without endobronchial ultrasound (EBUS) with miniprobe, transthoracic ultrasound (TTUS) for needle approach to the pleural wall and adjacent lung and computed tomography (CT) -guidance for (seldom if ever used) endobronchial or (common) transthoracical approach. In several situations one technique is not enough for efficient diagnosis, therefore we investigated a new diagnostic technique of endobronchial guided biopsies by a Cone Beam Computertomography (CBCT) called DynaCT (SIEMENS AG Forchheim, Germany). Method and Material: In our study 33 incidental solitary pulmonary nodules (iSPNs) (28 malignant, 5 benign; mean diameter 25 +/-12mm, shortest distance to pleura 25+/-18mm) were eligible according to in- and exclusion criteria. Realtime and onsite navigation were performed according to our standard protocol.22 All iSPN were controlled with a second technique when necessary and clinical feasible in case of unspecific or unexpected histological result. In all cases common guidelines of treatment of different iSPNs were followed in a routine manner. Results: Overall navigational yield (ny) was 91% and diagnostic yield (dy) 70%, dy for all accomplished malignant cases (n=28) was 82%. In the subgroup analysis of the invisible iSPN (n=12, 11 malignant, 1 benign; mean diameter 15+/-3mm) we found an overall dy of 75%. For the first time we describe a significant difference in specifity of biopsy results in regards to the position of the forceps in the 3-dimensional volume (3DV) of the iSPN in the whole sample group. Comparing the specifity of biopsies of a 3D-uncentered but inside the outer one third of an iSPN-3DV with the specifity of biopsies of centered forceps position (meaning the inner two third of an iSPN-3DV) reveals a significant (p=0,0375 McNemar) difference for the size group (>1cm) of 0,9 for centered biopsies vs. 0,3 for uncentered biopsies. Therefore only 3D-centered biopsies should be relied on especially in case of a benign result. Conclusion:The diagnostic yield of DynaCT navigation guided transbronchial biopsies (TBB) only with forceps is at least up to twofold higher than conventional TBB for iSPNs <2cm. The diagnostic yield of DynaCT navigation guided forceps TBB in invisible SPNs is at least in the range of other navigation studies which were performed partly with multiple navigation tools and multiple instruments. For future diagnostic and therapeutic approaches it is so far the only onsite and realtime extrathoracic navigation approach (except for computed tomography (CT)-fluoroscopy) in the bronchoscopy suite which keeps the working channel open. The system purchase represents an important investment for hospitals but it is a multidisciplinary and multinavigational tool with possible access via bronchial airways, transthoracical or vascular approach at the same time and on the same table without the need for an expensive disposable instrument use.
Die kutane Larva migrans ist eine in ihrem klinischen Bild typische Hautinfektion, die durch aktives Eindringen und anschließende epidermale Wanderung von Nematodenlarven hervorgerufen wird. Dieses typische klinische Bild wird durch Larven von Hakenwürmern, meist Ancylostoma braziliense, selten andere bei Kaniden und Feliden vorkommende Hakenwurmarten, verursacht.
Ziele der Leitlinie sind die Verbesserung der Versorgung der Patienten durch Optimierung von Diagnostik und Therapie bei Infektionen mit Larva migrans cutanea sowie die Verbesserung der Kenntnisse von Ärztinnen und Ärzte über aktuelle Therapieoptionen.
We present an approach for combining high resolution MRI-based myelin mapping with functional information from electroencephalography (EEG) or magnetoencephalography (MEG). The main contribution to the primary currents detectable with EEG and MEG comes from ionic currents in the apical dendrites of cortical pyramidal cells, aligned perpendicularly to the local cortical surface. We provide evidence from an in-vivo experiment that the variation in MRI-based myeloarchitecture measures across the cortex predicts the variation of the current density over individuals and thus is of functional relevance. Equivalent current dipole locations and moments due to pitch onset evoked response fields (ERFs) were estimated by means of a variational Bayesian algorithm. The myeloarchitecture was estimated indirectly from individual high resolution quantitative multi-parameter maps (MPMs) acquired at 800 μm isotropic resolution. Myelin estimates across cortical areas correlated positively with dipole magnitude. This correlation was spatially specific: regions of interest in the auditory cortex provided significantly better models than those covering whole hemispheres. Based on the MPM data we identified the auditory cortical area TE1.2 as the most likely origin of the pitch ERFs measured by MEG. We can now proceed to exploit the higher spatial resolution of quantitative MPMs to identify the cortical origin of M/EEG signals, inform M/EEG source reconstruction and explore structure–function relationships at a fine structural level in the living human brain.
he aim of this study was to evaluate the effect of controlled intraoral grinding and polishing on the roughness of full-contour zirconia compared to classical veneered zirconia. Thirty bar-shaped zirconia specimens were fabricated and divided into two groups (n=15). Fifteen specimens (group 1) were glazed and 15 specimens (group 2) were veneered with feldspathic ceramic and then glazed. Prior to grinding, maximum roughness depth (Rmax) values were measured using a profilometer, 5 times per specimen. Simulated clinical grinding and polishing were performed on the specimens under water coolant for 15 s and 2 N pressure. For grinding, NTI diamonds burs with grain sizes of 20 µm, 10 µm, and 7.5 µm were used sequentially. The ground surfaces were polished using NTI kits with coarse, medium and fine polishers. After each step, Rmax values were determined. Differences between groups were examined using one-way analysis of variance (ANOVA). The roughness of group 1 was significantly lower than that of group 2. The roughness increased significantly after coarse grinding in both groups. The results after glazing were similar to those obtained after fine grinding for non-veneered zirconia. However, fine-ground veneered zirconia had significantly higher roughness than venerred, glazed zirconia. No significant difference was found between fine-polished and glazed zirconia, but after the fine polishing of veneered zirconia, the roughness was significantly higher than after glazing. It can be concluded that for full-contour zirconia, fewer defects and lower roughness values resulted after grinding and polishing compared to veneered zirconia. After polishing zirconia, lower roughness values were achieved compared to glazing; more interesting was that the grinding of glazed zirconia using the NTI three-step system could deliver smooth surfaces comparable to untreated glazed zirconia surfaces.
Aim: The cytokine receptor tumor necrosis factor receptor superfamily member 9 (TNFRSF9) is mainly considered to be a co-stimulatory activation marker in hematopoietic cells. Several preclinical models have shown a dramatic beneficial effect of treatment approaches targeting TNFRSF9 with agonistic antibodies. However, preliminary clinical phase I/II studies were stopped after the occurrence of several severe deleterious side effects. In a previous study, it was demonstrated that TNFRSF9 was strongly expressed by reactive astrocytes in primary central nervous system (CNS) tumors, but was largely absent from tumor or inflammatory cells. The aim of the present study was to address the cellular source of TNFRSF9 expression in the setting of human melanoma brain metastasis, a highly immunogenic tumor with a prominent tropism to the CNS.
Methods: Melanoma brain metastasis was analyzed in a cohort of 78 patients by immunohistochemistry for TNFRSF9 and its expression was correlated with clinicopathological parameters including sex, age, survival, tumor size, number of tumor spots, and BRAF V600E expression status.
Results: Tumor necrosis factor receptor superfamily member 9 was frequently expressed independently on both melanoma and endothelial cells. In addition, TNFRSF9 was also present on smooth muscle cells of larger vessels and on a subset of lymphomonocytic tumor infiltrates. No association between TNFRSF9 expression and patient survival or other clinicopathological parameters was seen. Of note, several cases showed a gradual increase in TNFRSF9 expression on tumor cells with increasing distance from blood vessels, an observation that might be linked to hypoxia-driven TNFRSF9 expression in tumor cells.
Conclusion: The findings indicate that the cellular source of TNFRSF9 in melanoma brain metastasis largely exceeds the lymphomonocytic pool, and therefore further careful (re-) assessment of potential TNFRSF9 functions in cell types other than hematopoietic cells is needed. Furthermore, the hypothesis of hypoxia-driven TNFRSF9 expression in brain metastasis melanoma cells requires further functional testing.
Heterogenous subtypes of breast cancer need to be analyzed separately. Pooling of datasets can provide reasonable sample sizes but dataset bias is an important concern. We assembled a combined dataset of 579 Affymetrix microarrays from triple negative breast cancer (TNBC) in Gene Expression Omnibus (GEO) series GSE31519. We developed a method for selecting comparable datasets and to control for the amount of dataset bias of individual probesets.
Background and Purpose. Leukocyte migration into alveolar space plays a critical role in pulmonary inflammation resulting in lung injury. Acute ethanol (EtOH) exposure exerts anti-inflammatory effects. The clinical use of EtOH is critical due to its side effects. Here, we compared effects of EtOH and ethyl pyruvate (EtP) on neutrophil adhesion and activation of cultured alveolar epithelial cells (A549). Experimental Approach. Time course and dose-dependent release of interleukin- (IL-) 6 and IL-8 from A549 were measured after pretreatment of A549 with EtP (2.5–10 mM), sodium pyruvate (NaP, 10 mM), or EtOH (85–170 mM), and subsequent lipopolysaccharide or IL-1beta stimulation. Neutrophil adhesion to pretreated and stimulated A549 monolayers and CD54 surface expression were determined. Key Results. Treating A549 with EtOH or EtP reduced substantially the cytokine-induced release of IL-8 and IL-6. EtOH and EtP (but not NaP) reduced the adhesion of neutrophils to monolayers in a dose- and time-dependent fashion. CD54 expression on A549 decreased after EtOH or EtP treatment before IL-1beta stimulation. Conclusions and Implications. EtP reduces secretory and adhesive potential of lung epithelial cells under inflammatory conditions. These findings suggest EtP as a potential treatment alternative that mimics the anti-inflammatory effects of EtOH in early inflammatory response in lungs.
Malignant gliomas are intrinsic brain tumors with a dismal prognosis. They are well-adapted to hypoxic conditions and poorly immunogenic. NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DL).
Here we evaluated the impact of miRNA on the expression of NKG2DL in glioma cells including stem-like glioma cells. Three of the candidate miRNA predicted to target NKG2DL were expressed in various glioma cell lines as well as in glioblastomas in vivo: miR-20a, miR-93 and miR-106b. LNA inhibitor-mediated miRNA silencing up-regulated cell surface NKG2DL expression, which translated into increased susceptibility to NK cell-mediated lysis. This effect was reversed by neutralizing NKG2D antibodies, confirming that enhanced lysis upon miRNA silencing was mediated through the NKG2D system. Hypoxia, a hallmark of glioblastomas in vivo, down-regulated the expression of NKG2DL on glioma cells, associated with reduced susceptibility to NK cell-mediated lysis. This process, however, was not mediated through any of the examined miRNA. Accordingly, both hypoxia and the expression of miRNA targeting NKG2DL may contribute to the immune evasion of glioma cells at the level of the NKG2D recognition pathway. Targeting miRNA may therefore represent a novel approach to increase the immunogenicity of glioblastoma.
Endoscopic retrograde cholangiopancreatography (ERCP) offers an effective interventional option for treating symptomatic chronic pancreatitis. Endoscopic pancreatic sphincterotomy is performed to facilitated endoscopic treatment. Pancreatic duct strictures can be treated by inserting plastic stents, and a 10 Fr endoprosthesis is adequate in many cases. Before stent insertion, hydrostatic balloon dilation is needed in some cases. Pancreatic stones can be removed with a dormia basket, but combining ERCP and extracorporeal shockwave lithotripsy (ESWL) is often most effective.
Standard and advanced endoscopic treatment approaches are delineated in this article and include stricture dilation with a Soehendra retriever, cSEMS placement and multi-stenting.
BACKGROUND: Recent findings support the idea that interleukin (IL)-22 serum levels are related to disease severity in end-stage liver disease. Existing scoring systems--Model for End-Stage Liver Disease (MELD), Survival Outcomes Following Liver Transplantation (SOFT) and Pre-allocation-SOFT (P-SOFT)--are well-established in appraising survival rates with or without liver transplantation. We tested the hypothesis that IL-22 serum levels at transplantation date correlate with survival and potentially have value as a predictive factor for survival.
MATERIAL AND METHODS: MELD, SOFT, and P-SOFT scores were calculated to estimate post-transplantation survival. Serum levels of IL-22, IL-6, IL-10, C-reactive protein (CRP), and procalcitonin (PCT) were collected prior to transplantation in 41 patients. Outcomes were assessed at 3 months, 1 year, and 3 years after transplantation.
RESULTS: IL-22 significantly correlated with MELD, P-SOFT, and SOFT scores (Rs 0.35, 0.63, 0.56 respectively, p<0.05) and with the discrimination in post-transplantation survival. IL-6 showed a heterogeneous pattern (Rs 0.40, 0.63, 0.57, respectively, p<0.05); CRP and PCT did not correlate. We therefore added IL-22 serum values to existing scoring systems in a generalized linear model (GLM), resulting in a significantly improved outcome prediction in 58% of the cases for both the P-SOFT (p<0.01) and SOFT scores (p<0.001).
CONCLUSIONS: Further studies are needed to address the concept that IL-22 serum values at the time of transplantation provide valuable information about survival rates following orthotopic liver transplantation.
Caspase-2 represents the most conserved member of the caspase family, which exhibits features of both initiator and effector caspases. Using ribonucleoprotein (RNP)-immunoprecipitation assay, we identified the proapoptotic caspase-2L encoding mRNA as a novel target of the ubiquitous RNA-binding protein HuR in DLD-1 colon carcinoma cells. Unexpectedly, crosslinking-RNP and RNA probe pull-down experiments revealed that HuR binds exclusively to the caspase-2-5' untranslated region (UTR) despite that the 3' UTR of the mRNA bears several adenylate- and uridylate-rich elements representing the prototypical HuR binding sites. By using RNAi-mediated loss-of-function approach, we observed that HuR regulates the mRNA and in turn the protein levels of caspase-2 in a negative manner. Silencing of HuR did not affect the stability of caspase-2 mRNA but resulted in an increased redistribution of caspase-2 transcripts from RNP particles to translational active polysomes implicating that HuR exerts a direct repressive effect on caspase-2 translation. Consistently, in vitro translation of a luciferase reporter gene under the control of an upstream caspase-2-5'UTR was strongly impaired after the addition of recombinant HuR, whereas translation of caspase-2 coding region without the 5'UTR is not affected by HuR confirming the functional role of the caspase-2-5'UTR. Functionally, an elevation in caspase-2 level by HuR knockdown correlated with an increased sensitivity of cells to apoptosis induced by staurosporine- and pore-forming toxins as implicated by their significant accumulation in the sub G1 phase and an increase in caspase-2, -3 and poly ADP-ribose polymerase cleavage, respectively. Importantly, HuR knockdown cells remained insensitive toward STS-induced apoptosis if cells were additionally transfected with caspase-2-specific siRNAs. Collectively, our findings support the hypothesis that HuR by acting as an endogenous inhibitor of caspase-2-driven apoptosis may essentially contribute to the antiapoptotic program of adenocarcinoma cells by HuR.
Katamnese und Lebenszufriedenheit von Kindern und Jugendlichen mit Geschlechtsidentitätsstörungen
(2014)
Die Behandlung von Kindern und Jugendlichen mit Geschlechtsidentitätsstörungen (GIS) wird seit dem Beginn der pubertätshemmenden Hormontherapie in den neunziger Jahren international kontrovers diskutiert. Diese Störung scheint bei Kindern durch psychotherapeutische Intervention besser behandelbar als bei Jugendlichen. Erwartet wurden weniger psychopathologische Auffälligkeiten und eine höhere Lebenszufriedenheit bei umfassender psychotherapeutischer Begleitung. Des Weiteren wurden die Hypothesen geprüft, dass sich ein Geschlechtswechsel ebenfalls positiv auf Lebenszufriedenheit und Psychopathologie auswirkt.
Es nahmen insgesamt 37 Kinder, Jugendliche und Erwachsene an der schriftlichen Nachuntersuchung teil, die mindestens drei Jahre vor Studienbeginn aufgrund der Diagnose GIS des Kindes- und Jugendalters in der KJP Frankfurt vorgestellt wurden. Erfasst wurden Daten zur Geschlechtsidentität, zum Behandlungsverlauf und zur sexuellen Orientierung, zur Ausprägung der Psychopathologie laut altersangemessenem Screening-Inventar (CBCL, YSR, YASR) und zur Lebenszufriedenheit mithilfe des Inventars zur Erfassung der Lebensqualität bei Kindern und Jugendlichen (ILK). Außerdem wurden die Ausprägung der Psychopathologie (erfasst mit dem CBCL und oder YSR) bei der Erstvorstellung in der Klinik mit der jetzigen Einschätzung verglichen.
Die erhobenen Daten geben keinen Hinweis darauf, dass umfangreiche Psychotherapie oder ein Geschlechtswechsel zu einer höheren Lebenszufriedenheit und einer Verbesserung der Psychopathologie führen. Im Laufe der Zeit kam es zu einer signifikanten Reduktion der Werte der Syndromskalen soziale Probleme und aggressives Verhalten bei allen Studienteilnehmern. Allerdings wurde ein signifikanter Zusammenhang zwischen der Lebenszufriedenheit im Bereich seelische Gesundheit und der Zufriedenheit mit ihrer Psychotherapie gefunden. Die Drop-out-Analyse zeigte, dass Betroffene mit einer unbewältigten Problematik im Zusammenhang mit ihrer GIS eher nicht bereit waren, an dieser Studie teilzunehmen. Des Weiteren ergab sich, dass sich in der Gruppe der Studienteilnehmer signifikant mehr Personen für einen Geschlechtswechsel entschieden haben als in der Gruppe der Studienabbrecher.
Aus den Ergebnissen lässt sich ableiten, dass alle Teilnehmer der Nachuntersuchung mit ihrem Lebensweg gleichsam zufrieden sind, unabhängig vom Ausmaß der Psychotherapie und der Entscheidung für einen Geschlechtswechsel. Außerdem haben alle Personen der Stichprobe heute weniger Probleme mit aggressivem Verhalten und weniger soziale Probleme.
Da von einer Verzerrung der Stichprobe durch einen systematischen Ausfall von Teilnehmern auszugehen ist, sind weitere Nachuntersuchungen nötig, um die Hypothesen dieser Arbeit weiter zu überprüften. Darüber hinaus gilt es zu klären, ob bestimmte Psychotherapieformen bei einigen Patienten effektiver als andere sind.
BACKGROUND: Transient episodes of ischemia in a remote organ or tissue (remote ischemic preconditioning, RIPC) can attenuate myocardial injury. Myocardial damage is associated with tissue remodeling and the matrix metalloproteinases 2 and 9 (MMP-2/9) are crucially involved in these events. Here we investigated the effects of RIPC on the activities of heart tissue MMP-2/9 and their correlation with serum concentrations of cardiac troponin T (cTnT), a marker for myocardial damage.
METHODS: In cardiosurgical patients with cardiopulmonary bypass (CPB) RIPC was induced by four 5 minute cycles of upper limb ischemia/reperfusion. Cardiac tissue was obtained before as well as after CPB and serum cTnT concentrations were measured. Tissue derived from control patients (N = 17) with high cTnT concentrations (≥0.32 ng/ml) and RIPC patients (N = 18) with low cTnT (≤0.32 ng/ml) was subjected to gelatin zymography to quantify MMP-2/9 activities.
RESULTS: In cardiac biopsies obtained before CPB, activities of MMP-2/9 were attenuated in the RIPC group (MMP-2: Control, 1.13 ± 0.13 a.u.; RIPC, 0.71 ± 0.12 a.u.; P < 0.05. MMP-9: Control, 1.50 ± 0.16 a.u.; RIPC, 0.87 ± 0.14 a.u.; P < 0.01), while activities of the pro-MMPs were not altered (P > 0.05). In cardiac biopsies taken after CPB activities of pro- and active MMP-2/9 were not different between the groups (P > 0.05). Spearman's rank tests showed that MMP-2/9 activities in cardiac tissue obtained before CPB were positively correlated with postoperative cTnT serum levels (MMP-2, P = 0.016; MMP-9, P = 0.015).
CONCLUSIONS: Activities of MMP-2/9 in cardiac tissue obtained before CPB are attenuated by RIPC and are positively correlated with serum concentrations of cTnT. MMPs may represent potential targets for RIPC mediated cardioprotection.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00877305.
The question of whether most gliomas are infected with human cytomegalovirus (HCMV) has been under dispute for more than 10 years. We recently reported our failure to detect HCMV in gliomas in Neuro-Oncology.1 Our article was accompanied by 2 related editorials,2,3 one of which boldly criticized our approach.3 Instead of fighting a petty, ivory tower dispute, we would like to lobby for a serious collaborative approach to providing conclusive evidence on the presence of HCMV in glioma (and other cancers). Since we developed the concept of oncomodulation (ie, that HCMV …
Background & Aims: Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy.
Methods: Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group).
Results: Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6–53.0; P < .001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir.
Conclusions: In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.
OBJECTIVES: Outcome of aortic valve replacement may be influenced by the choice of bioprosthesis. Pericardial heart valves are described to have a favourable haemodynamic profile compared with porcine valves, although the clinical notability of this finding is still controversially debated. Herein, we compared the long-term results of two commonly implanted bioprosthesis at a single centre.
METHODS: All consecutive patients undergoing isolated aortic valve replacement with either a Carpentier-Edwards Magna pericardial prosthesis or a Medtronic Mosaic porcine prosthesis between 2002 and 2008 were analysed regarding preoperative characteristics, short- and long-term survival, valve-related complications and echocardiographic findings.
RESULTS: The Medtronic Mosaic was implanted in 163 patients and the Carpentier-Edwards Magna in 295 patients. The sizes of implanted valves were 22.4 ± 1.5 mm for the Mosaic and 21.8 ± 1.8 mm for the Magna (P = 0.001). The long-term survival rate was 76 and 56% after 5 and 10 years for the Medtronic Mosaic, which was comparable with the Carpentier-Edwards Magna (77 and 57%; P = 0.92). Overall long-term survival was comparable with an age- and sex-matched Austrian general population for both groups. Valve-related adverse events were similar between groups. The postoperative mean transvalvular gradient was significantly increased in the Mosaic group (24 ± 9 mmHg vs 17 ± 7 mmHg; P < 0.001).
CONCLUSIONS: Both types of aortic bioprostheses offer excellent results after isolated aortic valve replacement. Despite relevant differences in gradients, long-term survival was comparable with the expected normal survival for both bioprostheses. Patients with a porcine heart valve had a higher postoperative transvalvular gradient.
Polo-like kinase 1 regulates the stability of the mitotic centromere-associated kinesin in mitosis
(2014)
Proper bi-orientation of chromosomes is critical for the accurate segregation of chromosomes in mitosis. A key regulator of this process is MCAK, the mitotic centromere-associated kinesin. During mitosis the activity and localization of MCAK are regulated by mitotic key kinases including Plk1 and Aurora B. We show here that S621 in the MCAK’s C-terminal domain is the major phosphorylation site for Plk1. This phosphorylation regulates MCAK’s stability and facilitates its recognition by the ubiquitin/proteasome dependent APC/CCdc20 pathway leading to its D-box dependent degradation in mitosis. While phosphorylation of S621 does not directly affect its microtubule depolymerising activity, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by stabilizing MCAK, leading to an increased level of protein. Interfering with phosphorylation at S621 causes spindle formation defects and chromosome misalignments. Therefore, this study suggests a new mechanism by which Plk1 regulates MCAK: by regulating its degradation and hence controlling its turnover in mitosis.
Objective: To investigate the impact of HPV status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received surgery and cisplatin-based postoperative radiochemotherapy.
Materials and methods: For 221 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity treated at the 8 partner sites of the German Cancer Consortium, the impact of HPV DNA, p16 overexpression and p53 expression on outcome were retrospectively analysed. The primary endpoint was loco-regional tumour control; secondary endpoints were distant metastases and overall survival.
Results: In the total patient population, univariate analyses revealed a significant impact of HPV16 DNA positivity, p16 overexpression, p53 positivity and tumour site on loco-regional tumour control. Multivariate analysis stratified for tumour site showed that positive HPV 16 DNA status correlated with loco-regional tumour control in patients with oropharyngeal carcinoma (p = 0.02) but not in the oral cavity carcinoma group. Multivariate evaluation of the secondary endpoints in the total population revealed a significant association of HPV16 DNA positivity with overall survival (p < 0.01) but not with distant metastases.
Conclusions: HPV16 DNA status appears to be a strong prognosticator of loco-regional tumour control after postoperative cisplatin-based radiochemotherapy of locally advanced oropharyngeal carcinoma and is now being explored in a prospective validation trial.
Late stage cancer is often associated with reduced immune recognition and a highly immunosuppressive tumor microenvironment. The presence of tumor infiltrating lymphocytes (TILs) and specific gene-signatures prior to treatment are linked to good prognosis, while the opposite is true for extensive immunosuppression. The use of adenoviruses as cancer vaccines is a form of active immunotherapy to initialise a tumor-specific immune response that targets the patient’s unique tumor antigen repertoire. We report a case of a 68-year-old male with asbestos-related malignant pleural mesothelioma who was treated in a Phase I study with a granulocyte-macrophage colony‑stimulating factor (GM-CSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in prominent infiltration of CD8C lymphocytes to tumor, marked induction of systemic antitumor CD8C T-cells and induction of Th1- type polarization in the tumor. These results indicate that ONCOS-102 treatment sensitizes tumors to other immunotherapies by inducing a T-cell positive phenotype to an initially T-cell negative tumor.
Plus Puls : 2014, 3
(2014)
Plus Puls : 2014, 2
(2014)
Hintergrund: Das Monitoring von unfraktioniertem Heparin (UFH) bei extrakorporaler Zirkulation (EKZ) erfolgt standardmäßig mit Phospholipid-abhängigen Gerinnungstests wie „Activated Clotting Time“ [ACT, (sec)] bzw. „aktivierte partielle Prothrombinzeit“ [aPTT, (sec)]. Durch die im Rahmen von Autoimmunerkrankungen wie dem Antiphospholipid-Syndrom (APLS) auftretenden Antiphospholipid-Antikörper (aPL) ist die Aussagekraft dieser Tests bei solchen Patienten durch eine Verlängerung der Gerinnungszeit deutlich eingeschränkt. Die Wirkung von UFH kann auch mit der photometrischen Messung der aXa-Aktivität bestimmt werden. Ziel der vorliegenden Studie war es zu erfassen, ob die aXa-Aktivitiät mit der ACT korreliert und ob es Cut-off-Werte gibt, die bei der Steuerung der Antikoagulation von kardiochirurgischen Patienten z.B. mit Antiphospholipid-Antikörpern während EKZ hilfreich sein können.
Methodik: Nach einem positiven Ethikvotum wurden in diese prospektive Studie Patienten eingeschlossen, die sich einem erstmaligen elektiv geplanten kardiochirurgischen Eingriff unterzogen. Ausschlusskriterien waren Alter < 18 Jahren, bekanntes Antiphospholipidsyndrom, bekannte Heparin-induzierte Thrombozytopenie und Schwangerschaft. Die ACT-gesteuerte Antikoagulation mit UFH (ACT > 400 sec während EKZ) und dessen Reversierung mit Protamin (ACT ≤ 100 sec) wurden auf der Grundlage klinikinterner Standards durchgeführt. Für jeden perioperativ analysierten ACT-Wert (prä-, intra- und postoperativ) wurde die korrespondierende aXa-Aktivität erfasst. Abhängig von EKZ-Dauer ergaben sich bis zu 14 Messzeitpunkte mit insgesamt 144 Messungen. Die statistische Auswertung umfasste u.a. Spearman Rangkorrelation und die Receiver Operative Characteristic (ROC)-Kurve.
Ergebnisse: Es wurden die Daten von n = 15 Patienten in dieser Studie ausgewertet. Das Hauptergebnis zeigte eine hochsignifikante lineare Korrelation (r = 0.771, p < 0.0001) zwischen den Ergebnissen der ACT und der jeweils korrespondierenden aXa-Aktivität. Der optimale Cut-off-Wert der aXa-Aktivität zur Indikation einer ACT > 400 sec betrug 1.135 IU/ml (Fehlklassifikationsrate: 9.4%). Die Fläche unter der ROC betrug 0.899. Es wurde ein optimaler Cut-off-Wert von 0.55 IU/ml (Fehlerklassifikation: 13.3%, AUC: 0.867) analysiert, der eine ACT von ≤ 100 sec vor der Gabe von UFH und nach der Gabe von Protamin indiziert.
Zusammenfassung: Die aXa-Aktivität korreliert mit der ACT und kann für das Monitoring der Antikoagulation mit UFH während EKZ geeignet sein. Die im Rahmen dieser Studie ermittelten aXa-Cut-off-Werte können dazu beitragen, die Antikoagulation mittels UFH zu steuern, wenn die Messwerte von aPTT und ACT nicht aussagekräftig sind
Neben ihrer Rolle in der DNA Mismatch Reparatur wird eine Beteiligung von MMR Proteinen an der Apoptoseinduktion, der Antikörperbildung sowie an der Mitose und Meiose beschrieben. Untersuchungen zu Partnerproteinen des MMR Proteins MLH1 zeigten darüber hinaus eine Interaktion von MLH1 zu einigen Zytoskelett-assoziierten Proteinen. In der vorliegenden Arbeit sollte der Zusammenhang von MLH1 und nicht-erythroidem Spectrin alpha II (SPTAN1) auf Proteinebene untersucht und eine mögliche Beteiligung von SPTAN1 am DNA Mismatch Reparaturprozess mittels eines in vitro MMR-Assays analysiert werden. Die vergleichenden in vitro Analysen der MLH1 und SPTAN1 Expression erfolgten in fünf verschiedenen MLH1-profizienten und zwei MLH1-defizienten Zelllinien. Zudem wurde in vivo die Expression von MLH1 und SPTAN1 exemplarisch am Beispiel eines sporadischen sowie eines MLH1-defizienten Kolonkarzinomgewebes und des jeweils zugehörigen Normalgewebes durchgeführt. Im MMR-Assay wurden Kernextrakte aus HEK293T Zellen eingesetzte, in denen MLH1 und PMS2 bzw. MLH1, PMS2 sowie SPTAN1 überexprimiert wurde oder solche in denen die SPTAN1 Menge durch siRNA Behandlung zuvor reduziert worden war. Während die Untersuchungen hinsichtlich einer Beteiligung von SPTAN1 an der DNA Mismatch Reparatur keine eindeutigen Ergebnisse erbrachten, zeigten die Analysen der Expression von MLH1 und SPTAN1 interessanterweise sowohl in vitro als auch in vivo, dass die Proteinkonzentration von SPTAN1 bei MLH1-Profizienz deutlich höher war, als bei MLH1-Defizienz. Da SPTAN1 ein überaus wichtiges, filamentöses Gerüstprotein darstellt, an der Aktin-Vernetzung und der Stabilisierung der Plasmamembran beteiligt und mitverantwortlich für Organisation der intrazellulären Organellen ist, könnten die Expressions-unterschiede in MLH1-defizienten und MLH1-profizienten Zellen für die Progression und das Metastasierungsverhalten entsprechender Kolontumore eine wichtige Rolle spielen. Weiterführende Untersuchungen, die im Anschluss an diese Arbeit hinsichtlich des Einflusses der SPTAN1 Menge auf das Migrationsverhalten entsprechender Zellen durchgeführt wurden, zeigen, dass MLH1-defiziente Zellen SPTAN1 abhängig weniger stark migrieren, als die MLH1-profizienten Vergleichszellen. Möglicherweise ist die MLH1 abhängige Expression von SPTAN1 Grund dafür, dass Kolontumoren mit MLH1-Defizienz signifikant weniger zur Metastasierung neigen, als sporadische Kolonkarzinome, die MLH1 exprimieren. Ob dies wirklich zutrifft muss allerdings durch weitere nachfolgende Experimente noch weiter untersucht werden.
Vorhofflimmern ist die am weitesten verbreitete Herzrhythmusstörung. Die bisherige antiarrhythmische Therapie ist durch erhebliche kardiale und extrakardiale Nebenwirkungen nur wenig zufriedenstellend. Die Erforschung neuer antiarrhythmischer Substanzen ist aufgrund begrenzt zur Verfügung stehenden menschlichen Probematerials erschwert. Vorhofgewebe wird z.B. bei Herzoperationen gewonnen und kann dann für Forschungszwecke eingesetzt werden. Die Herzzellen sind allerdings sehr empfindlich, weswegen sie meist bereits nach einigen Stunden nicht mehr für weitere Untersuchungen zu gebrauchen sind. Man ist daher auf das Tiermodell angewiesen. Da das Schweineherz dem des Menschen sehr ähnlich ist, stellt es hier ein ideales Testsystem für neue Antiarrhythmika dar. In neuesten Studien wurde in Schweineherzen der IK,PO als ein vielversprechenden Angriffspunkt vorhofselektiver Antiarrhythmika beschrieben. Die diesem Strom zugrundeliegenden Kanaleinheiten sind jedoch zum jetzigen Zeitpunkt nicht genau erforscht.
Ziel der Arbeit war, ein stabiles Modell der Zellkultur mit atrialen Kardiomyozyten zu etablieren. An den kultivierten Herzzellen sollten elektrophysiologische aber auch molekular- und proteinbiologische Methoden angewandt werden. Das Modell sollte mit Zellen aus Schweineherzen erprobt werden und dazu dienen Untersuchungen an Zellen aus einer Gewebepräparation über mehrere Tage durchzuführen. Darüber hinaus sollte die Zellkultur dazu dienen einen Gen-„Knockdown“ anwenden zu können. Der IK,PO und dem diesem Strom möglicherweise zugrundeliegenden Kanaluntereinheiten Kv1.5, Kv4.3, KChIP2 und TASK-1 sollten hierbei charakterisiert werden.
Atriumzellen aus Schweineherzen wurden isoliert und direkt nach Zellisolation sowie unter dem Einfluss der Zellkultur nach bis zu 48 Stunden untersucht. Es kamen die Patch-Clamp-Technik, Real-time-PCR- und Western-Blot-Analysen zum Einsatz. Die Wirkung verschiedener Substanzen auf den IK,PO wurde getestet. Das Kv1.5-Protein wurde dargestellt und mRNA-Analysen für Kv1.5, Kv4.3, KChIP2 und TASK-1 durchgeführt.
Ein Teil der Zellen wurde mit einer gegen Kv1.5 gerichteten siRNA behandelt und anschließend mRNA-Analysen durchgeführt sowie der IK,PO–Strom gemessen.
Die atrialen Kardiomyozyten des Schweines in Kultur zeigten bis zu 48 Stunden vitale Eigenschaften und zeigten sich für die Patch-Clamp-Technik, Real-time-PCR und Western-Blot-Analysen als geeignet. Im Vergleich zu den frisch präparierten Zellen war eine signifikante Zunahme der Stromdichte für den IK,PO zu messen. Die Kinetik des IK,PO-Stroms sowie das Verhalten gegenüber den Substanzen AV0118, Heteropodatoxin und PAP-1 blieben im Vergleich zu den frisch präparierten Zellen unverändert. In Western-Blot-Analysen war im Vergleich zu frisch isolierten Zellen eine Zunahme des Kv1.5-Proteins zu sehen. Die mRNA-Expression des Kv1.5 war dagegen auf ca. ein Sechstel verringert. Eine Abnahme der mRNA-Expression auf ein Zehntel konnte für die Kanaleinheit KChIP2 gesehen werden. Kv4.3 wurde hingegen bis fast auf ein Zweieinhalbfaches vermehrt exprimiert, während die RNA-Expression für TASK-1 konstant blieb. Ein „Knockdown“ des Kv1.5 mit siRNA zeigte eine weitere Reduktion der Kv1.5 mRNA ohne eine messbare zusätzliche Veränderung des IK,PO.
Die Arbeit hat gezeigt, dass primäre Kulturen atrialer Kardiomyozyten des Schweines für elektrophysiologische sowie molekularbiologische Versuche geeignet sind. Der im Interesse stehende Strom IK,PO hat sich unter Kulturbedingungen zwar vergrößert, jedoch blieben Kinetik und vor allem die Eigenschaft auf verschiedene Substanzen zu reagieren unverändert. Es ist somit möglich neue Substanzen in der Entwicklung von Antiarrhythmika an kultivierten Herzzellen zu testen und somit die Anzahl der für die Experimente benötigten Tiere zu verringern. Die Ergebnisse deuten darauf hin, dass neben dem Kv1.5 die Kanaleinheiten der Kv4.3 und KChIP2 wesentlich zum IK,PO betragen. Die vorliegenden Ergebnisse deuten darauf, dass Kv1.5 den Grundstrom des IK,PO bildet und Kv4.3 vornehmlich den Spitzenstrom des IK,PO ausmacht. Kv1.5 wird dabei vermutlich wesentlich durch KChIP2 gehemmt. KChIP2 spielt eine nachweisliche Rolle in der Pathogenese von Herzrhythmusstörungen und zeigt im Vergleich zu Kv1.5 und Kv4.3 eine höhere Gewebespezifität. KChIP2-Blocker könnten in der Entwicklung vorhofselektiver Antiarrhythmika vielversprechende Ergebnisse liefern.
The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molecular anticancer therapy. While the preclinical results are encouraging, the clinical outcomes are rather less inspiring by showing limited anticancer activity. It is thus of importance to identify molecules and mechanisms responsible for the sensitivity of Polo-like kinase 1 inhibition. We have recently shown that p21Cip1/CDKN1A is involved in the regulation of mitosis and its loss prolongs the mitotic duration accompanied by defects in chromosome segregation and cytokinesis in various tumor cells. In the present study, we demonstrate that p21 affects the efficacy of Polo-like kinase 1 inhibitors, especially Poloxin, a specific inhibitor of the unique Polo-box domain. Intriguingly, upon treatment with Polo-like kinase 1 inhibitors, p21 is increased in the cytoplasm, associated with anti-apoptosis, DNA repair and cell survival. By contrast, deficiency of p21 renders tumor cells more susceptible to Polo-like kinase 1 inhibition by showing a pronounced mitotic arrest, DNA damage and apoptosis. Furthermore, long-term treatment with Plk1 inhibitors induced fiercely the senescent state of tumor cells with functional p21. We suggest that the p21 status may be a useful biomarker for predicting the efficacy of Plk1 inhibition.
The transcription factor Tal1 is a critical activator or repressor of gene expression in hematopoiesis and leukaemia. The mechanism by which Tal1 differentially influences transcription of distinct genes is not fully understood. Here we show that Tal1 interacts with the peptidylarginine deiminase IV (PADI4). We demonstrate that PADI4 can act as an epigenetic coactivator through influencing H3R2me2a. At the Tal1/PADI4 target gene IL6ST the repressive H3R2me2a mark triggered by PRMT6 is counteracted by PADI4, which augments the active H3K4me3 mark and thus increases IL6ST expression. In contrast, at the CTCF promoter PADI4 acts as a repressor. We propose that the influence of PADI4 on IL6ST transcription plays a role in the control of IL6ST expression during lineage differentiation of hematopoietic stem/progenitor cells. These results open the possibility to pharmacologically influence Tal1 in leukaemia.
Predominant polarity in bipolar disorder and validation of the polarity index in a German sample
(2014)
Background: A large number of patients with bipolar disorder (BD) can be characterized by predominant polarity (PP), which has important implications for relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339¿346, 2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in treatment of BD. In the present retrospective study, we aimed to validate this Index in a large and well characterized German bipolar sample.
Methods: We investigated 336 bipolar patients (BP) according to their PP and calculated the PI for each patient in order to prove if maintenance treatment differs according to their PP. Furthermore, we analysed whether PP is associated with demographic and clinical characteristics of BP.
Results: In our sample, 63.9% of patients fulfilled criteria of PP: 169 patients were classified as depressive predominant polarity (DPP), 46 patients as manic predominant polarity (MPP). The two groups differed significantly in their drug regime: Patients with DPP were more often medicated with lamotrigine and antidepressants, patients with MPP were more often treated with lithium, valproate, carbamazepine and first generation antipsychotics. However, patients with DPP and MPP did not differ significantly with respect to the PI, although they received evidence-based and guideline-driven treatment.
Conclusion: The reason for this negative finding might well be that for several drugs, which were used frequently, no PI value is available. Nevertheless we suggest PP as an important concept in the planning of BD maintenance treatment.
Background: In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.
Methods: 268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.
Results: Overall, 47.1% of patients (95% confidence interval (CI): 39.9–54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0–6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.
Conclusions: HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.
This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-α general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients.
Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells
(2014)
The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.
Use of drug-eluting balloon coronary intervention prior to living donor kidney transplantation
(2014)
Background: Kidney transplantation is the gold standard of therapy in patients with terminal renal insufficiency. Living donor transplantation is a well-established option in this field. Enlarging the donor's pool implicates the acceptance of an increased rate of comorbidities. Among them, coronary artery disease is a growing problem. An increasing number of patients, undergoing living donation, receive antiplatelet therapies due to coronary disease.
Case presentation: Here we report about the perioperative treatment with a drug-eluting balloon in a patient with major cardiac risk factors who underwent kidney transplantation.
Conclusion: At the current time no recommendation can be given for the routine use of drug-eluting balloons.
Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes.
Das Thoraxtrauma beim Kind
(2014)
Die vorliegende Studie soll einen Überblick geben über Epidemiologie, Unfallursachen, Verletzungsmuster, Therapie und Outcome von Kindern mit thorakalen Verletzungen und einen Vergleich zwischen kindlichen Traumapatienten mit und ohne thorakaler Beteiligung ermöglichen.
Hierfür wurden zwischen September 2002 und Juli 2006 alle Schockraumpatienten der Klinik für Unfall-, Hand- und Wiederherstellungschirurgie der Johann Wolfgang Goethe-Universität Frankfurt am Main mittels eines standardisierten Schockraumprotokolls („TraumaWatch“) prospektiv erfasst. Die Dokumentation der Daten im Schockraum erfolgte durch einen unabhängigen Dokumentationsassistenten zeitgleich mittels Tableau-PC. Die Verlaufsdaten der Patienten wurden durch retrospektive Auswertung der Patientenakten erhoben und tabellarisch erfasst. In die Studie eingeschlossen wurden alle Patienten bis einschließlich dem 17. Lebensjahr, die lebend eingeliefert wurden und nicht direkt im Anschluss an die Schockraumdiagnostik wieder nach Hause entlassen werden konnten. Insgesamt erfüllten 256 Patienten die Einschlusskriterien. Für die Auswertung wurden zwei Gruppen gebildet: Gruppe A umfasste alle Kinder mit Thoraxtrauma (n = 46), Gruppe B alle Kinder, bei denen keine thorakale Beteiligung vorlag (n = 210).
In beiden Gruppen waren Jungen mit 69,6 % bzw. 64,8 % häufiger betroffen als Mädchen. Das Durchschnittsalter lag in Gruppe A mit 12,4 ± 4,9 Jahren signifikant höher als in Gruppe B mit 8,0 ± 5,2 Jahren. Es handelte sich fast ausschließlich um stumpfe Traumen (95,7 % bzw. 95,2 %). Verkehrsunfälle stellten in beiden Gruppen die häufigste Unfallursache dar, kamen in Gruppe A jedoch signifikant häufiger vor (65,2 % vs. 35,2 %). An zweiter Stelle lagen in beiden Gruppen Stürze, wobei in Gruppe A Stürze aus großer Höhe häufiger vorkamen. Beim Thoraxtrauma stehen demnach Unfallmechanismen mit massiverer Gewalteinwirkung im Vordergrund.
Die häufigste Thoraxverletzung war die Lungenkontusion (56,5 %), gefolgt vom Pneumothorax (34,8 %). Ein isoliertes Thoraxtrauma wurde selten beobachtet (4,3 %); die häufigste Begleitverletzung stellte das Schädel-Hirn-Trauma dar (71,7 %). Auch in Gruppe B war das Schädel-Hirn-Trauma die häufigste Verletzung (54,3 %), gefolgt von Extremitätenverletzungen (37,6 %). Verletzungen des Abdomens und Beckens wurden in Gruppe A signifikant häufiger gesehen.
Der mittlere ISS lag in Gruppe A mit 26,7 ± 15,8 signifikant höher als in Gruppe B mit 8,1 ± 6,8. Damit ist das Thoraxtrauma ein Marker für eine hohe Verletzungsschwere.
Die mittlere initiale GCS als Marker für den neurologischen Status war in Gruppe A signifikant niedriger als in Gruppe B (9,4 ± 5,1 vs. 13,0 ± 3,7). Somit treten schwere Schädel-Hirn-Traumata bei Kindern häufiger in Zusammenhang mit einem Thoraxtrauma auf.
Die Letalität war in Gruppe A höher als in Gruppe B (6,5 % vs. 1,9 %). Bei den Todesursachen stand in beiden Gruppen das Schädel-Hirn-Trauma im Vordergrund.
Sowohl die mittlere Intensivliegezeit (8,0 ± 8,1 Tage vs. 1,9 ± 5,0 Tage) als auch die Gesamtdauer des stationären Aufenthalts (13,6 ± 9,7 Tage vs. 7,9 ± 9,6 Tage) waren in Gruppe A signifikant länger als in Gruppe B. Kinder mit Thoraxtrauma mussten häufiger beatmet werden als Kinder ohne Thoraxtrauma (76,1 % vs. 26,7 %); die mittlere Beatmungsdauer war signifikant länger (5,2 ± 4,8 Tage vs. 2,7 ± 3,7 Tage). Eine präklinische Intubation war in Gruppe A ebenfalls signifikant häufiger erforderlich als in Gruppe B (56,5 % vs. 15,2 %). Kinder mit Thoraxtrauma wurden signifikant häufiger operativ versorgt (68,9 % vs. 42,9 %); unfallchirurgische Operationen standen in beiden Gruppen im Vordergrund. Komplikationen wurden in Gruppe A signifikant häufiger gesehen (52,2 % vs. 12,9 %); die häufigste Komplikation war in beiden Gruppen die respiratorische Insuffizienz (39,1 % vs. 5,2 %). In Gruppe A konnten signifikant weniger Patienten nach Hause entlassen werden als in Gruppe B (50,0 % vs. 89,0 %).
Das Thoraxtrauma stellt damit einen Marker für eine hohe Verletzungsschwere und das Vorliegen weiterer schwerer Verletzungen dar und kann somit als negativer prädiktiver Faktor angesehen werden, der die Mortalität und Morbidität bei kindlichen Traumapatienten beeinflusst.
Ziel: Die Evaluation der DEGUM-Mammasonografiekurse nach objektivierbaren Kriterien war Ziel dieser Arbeit. Damit sollte die Qualität der Kurse überprüft werden, um eine flächendeckende Fort- und Weiterbildung auf hohem Niveau anzubieten.
Material und Methoden: 10 Qualitätskriterien, orientierend an den Vorgaben der KBV-Ultraschallvereinbarungen wurden als Qualitätsparameter definiert. Alle Kursleiter des Arbeitskreises Mammasonografie der DEGUM wurden angeschrieben. Dabei wurden die 10 definierten Qualitätskriterien überprüft.
Ergebnisse: Alle Kurse erfüllten die Voraussetzungen bezüglich der Qualität des Kursleiters, der Kursdauer und Unterrichtseinheiten sowie der Anzahl an Kursteilnehmern pro Ultraschallgerät. In 1 von 9 Kursen wurde die Zeit der praktischen Übungen, gefordert sind 50 %, unterschritten. Die Voraussetzungen für den Abschlusskurs (200 selbst durchgeführte und dokumentierte Fälle) sind in den Kursankündigungen zum Teil nicht klar definiert. Ein strukturierter Lehrkatalog fehlt.
Schlussfolgerung: Die DEGUM-Mammasonografiekurse werden auf hohem Niveau angeboten und erfüllen zum größten Teil die Anforderungen der KBV. Trotz der hohen Qualität der DEGUM-Kurse sind Optimierungsoptionen im Bereich Kursankündigung und strukturierter Lehrkatalog möglich.
Die Wahrnehmung von Schmerzen ermöglicht es dem Organismus, auf noxische Reize zu reagieren. Der akute nozizeptive Schmerz hat somit eine natürliche Warnfunktion. Bei länger anhaltenden bzw. chronischen Schmerzen oder Nervenschädigungen kann es jedoch zu pathophysiologischen Veränderungen im Nervensystem kommen, die zur Verselbständigung des Schmerzes führen können. Unter diesen Umständen gilt der Schmerz nicht mehr als Warnsignal, sondern als eigenes Krankheitsbild. Die „International Association for the Study of Pain (IASP)“ definiert Schmerz als „ein unangenehmes Sinnes- und Gefühlserlebnis, das mit aktueller oder potenzieller Gewebsschädigung verknüpft ist oder mit Begriffen einer solchen Schädigung beschrieben wird“. Da bisher verfügbare Arzneimittel chronische Schmerzen in vielen Fällen nicht ausreichend reduzieren können und teilweise zu schwerwiegenden Nebenwirkungen führen, ist es unverzichtbar, an der Entwicklung neuer und noch spezifischer wirkenden Analgetika festzuhalten. Um Pharmaka zu entwickeln, die gezielt in den Mechanismus der Schmerzverarbeitung eingreifen können, ist es notwendig, diesen auf molekularer Ebene zu kennen und zu verstehen.
Seven years after the launch of the European Paediatric Medicine Regulation, limited progress in paediatric oncology drug development remains a major concern amongst stakeholders – academics, industry, regulatory authorities, parents, patients and caregivers. Restricted increases in early phase paediatric oncology trials, legal requirements and regulatory pressure to propose early Paediatric Investigation Plans (PIPs), missed opportunities to explore new drugs potentially relevant for paediatric malignancies, lack of innovative trial designs and no new incentives to develop drugs against specific paediatric targets are some unmet needs. Better access to new anti-cancer drugs for paediatric clinical studies and improved collaboration between stakeholders are essential. The Cancer Drug Development Forum (CDDF), previously Biotherapy Development Association (BDA), with Innovative Therapy for Children with Cancer Consortium (ITCC), European Society for Paediatric Oncology (SIOPE) and European Network for Cancer Research in Children and Adolescents (ENCCA) has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Union (EU) Commission, with an urgent remit to improve paediatric oncology drug development. The Paediatric Oncology Platform proposes to recommend immediate changes in the implementation of the Regulation and set the framework for its 2017 revision; initiatives to incentivise drug development against specific paediatric oncology targets, and repositioning of drugs not developed in adults. Underpinning these changes is a strategy for mechanism of action and biology driven selection and prioritisation of potential paediatric indications rather than the current process based on adult cancer indications. Pre-competitive research and drug prioritisation, early portfolio evaluation, cross-industry cooperation and multi-compound/sponsor trials are being explored, from which guidance for innovative trial designs will be provided.
Background: Despite improvements in liver surgery over the past decades, hemostasis during hepatic resections remains challenging. This multicenter randomized study compares the hemostatic effect of a collagen hemostat vs. a carrier-bound fibrin sealant after hepatic resection.
Methods: Patients scheduled for elective liver resection were randomized intraoperatively to receive either the collagen hemostat (COLL) or the carrier-bound fibrin sealant (CBFS) for secondary hemostasis. The primary endpoint was the proportion of patients with hemostasis after 3 min. Secondary parameters were the proportions of patients with hemostasis after 5 and 10 min, the total time to hemostasis, and the complication rates during a 3 months follow-up period.
Results: A total of 128 patients were included. In the COLL group, 53 out of 61 patients (86.9 %) achieved complete hemostasis within 3 min after application of the hemostat compared to 52 out of 65 patients (80.0 %) in the CBFS group. The 95 % confidence interval for this difference [−6.0 %, 19.8 %] does not include the lower noninferiority margin (−10 %). Thus, the COLL treatment can be regarded as noninferior to the comparator. The proportions of patients with hemostasis after 3, 5, and 10 min were not significantly different between the two study arms. Postoperative mortality and morbidity were similar in both treatment groups.
Conclusion: The collagen hemostat is as effective as the carrier-bound fibrin sealant in obtaining secondary hemostasis during liver resection with a comparable complication rate.
A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.
Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.
Molecular tumour targeting has significantly improved anti-cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of Rapamycin (mTOR) and histone deacetylase (HDAC) inhibition has been shown not only to enhance anti-tumour potential, but also to prevent resistance development seen under mono-drug therapy. This investigation was designed to evaluate whether cross-communication exists between mTOR signalling and epigenetic events regulated by HDAC. DU-145 prostate cancer cells were treated with insulin-like growth factor (IGF) to activate the Akt-mTOR cascade or with the HDAC-inhibitor valproic acid (VPA) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, mTOR, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between mTOR and the epigenetic machinery. IGF activated mTOR, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGFr blockade and knock-down blocked the Akt-mTOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up-regulated histone acetylation, but also activated mTOR-Akt signalling. HDAC1 and 2 knock-down revealed that the interaction with the mTOR system is initiated by histone H3 acetylation. HDAC-mTOR communication, therefore, is apparent whereby tumour-promoting (Akt/mTORhigh, aH3/aH4low) and tumour-suppressing signals (Akt/mTORlow, aH3/aH4high) are activated in parallel. Combined use of an HDAC- and mTOR inhibitor might then diminish pro-tumour effects triggered by the HDAC- (Akt/mTORhigh) or mTOR inhibitor (aH3/aH4low) alone.
Background: HER2 status assessment is a prerequisite for the establishment of an appropriate treatment strategy in gastric cancer. Gastric cancers are very heterogeneous and separate evaluations of gene amplification and protein expression lead to uncertainties in localizing distinct clones and are time consuming. This study evaluates the equivalence of the novel method combining both gene and protein platforms on one slide.
Methods: Immunohistochemistry (IHC) and HER2 dual-colour silver in situ hybridization (SISH) as single methods (IHC/SISH) and gene-protein platform combining both methods on one slide (gene/protein) were performed in randomly collected 100 cases of gastric adenocarcinoma. Results of IHC/SISH were compared with gene/protein staining.
Results: 96 of 100 samples were assessable. In the gene/protein staining, pathologists were able to assess gene amplification and consequent protein expression at the single cell level. In comparison trials, gene amplification was observed in 14.6% by both, conventional SISH and gene/protein platform (agreement 100%; Kappa-coefficient κ = 1.0). Protein expression scores by IHC were 70.8% (0), 10.4% (1+), 9.4% (2+), and 9.4% (3+). Protein expression by gene/protein method were: 70.8% (0), 11.5% (1+), 7.3% (2+) and 10.4% (3+) of patients. There were complete concordances in IHC assessment of cases with score 0 (100.0%; κ = 1). High concordances are shown in score 1+ (98.96%; κ = 0.947) and 3+ (96.88%; κ = 0.825) cases and good concordances in 2+ cases (95.83%; κ = 0.728).
Conclusions: This novel combined platform has the advantage of being able to evaluate both gene and the protein status in the same cancer cell and may be of particular interest for research and patient's care.