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Chronic treatment with the mTOR inhibitor, everolimus, fails long-term in preventing tumor growth and dissemination in cancer patients. Thus, patients experiencing treatment resistance seek complementary measures, hoping to improve therapeutic efficacy. This study investigated metastatic characteristics of bladder carcinoma cells exposed to everolimus combined with the isothiocyanate sulforaphane (SFN), which has been shown to exert cancer inhibiting properties. RT112, UMUC3, or TCCSUP bladder carcinoma cells were exposed short- (24 h) or long-term (8 weeks) to everolimus (0.5 nM) or SFN (2.5 µM), alone or in combination. Adhesion and chemotaxis along with profiling details of CD44 receptor variants (v) and integrin α and β subtypes were evaluated. The functional impact of CD44 and integrins was explored by blocking studies and siRNA knock-down. Long-term exposure to everolimus enhanced chemotactic activity, whereas long-term exposure to SFN or the SFN-everolimus combination diminished chemotaxis. CD44v4 and v7 increased on RT112 cells following exposure to SFN or SFN-everolimus. Up-regulation of the integrins α6, αV, and β1 and down-regulation of β4 that was present with everolimus alone could be prevented by combining SFN and everolimus. Down-regulation of αV, β1, and β4 reduced chemotactic activity, whereas knock-down of CD44 correlated with enhanced chemotaxis. SFN could, therefore, inhibit resistance-related tumor dissemination during everolimus-based bladder cancer treatment.
Objective: Relative to urban populations, rural patients may have more limited access to care, which may undermine timely bladder cancer (BCa) diagnosis and even survival.
Methods: We tested the effect of residency status (rural areas [RA < 2500 inhabitants] vs. urban clusters [UC ≥ 2500 inhabitants] vs. urbanized areas [UA, ≥50,000 inhabitants]) on BCa stage at presentation, as well as on cancer-specific mortality (CSM) and other cause mortality (OCM), according to the US Census Bureau definition. Multivariate competing risks regression (CRR) models were fitted after matching of RA or UC with UA in stage-stratified analyses.
Results: Of 222,330 patients, 3496 (1.6%) resided in RA, 25,462 (11.5%) in UC and 193,372 (87%) in UA. Age, tumor stage, radical cystectomy rates or chemotherapy use were comparable between RA, UC and UA (all p > 0.05). At 10 years, RA was associated with highest OCM followed by UC and UA (30.9% vs. 27.7% vs. 25.6%, p < 0.01). Similarly, CSM was also marginally higher in RA or UC vs. UA (20.0% vs. 20.1% vs. 18.8%, p = 0.01). In stage-stratified, fully matched CRR analyses, increased OCM and CSM only applied to stage T1 BCa patients.
Conclusion: We did not observe meaningful differences in access to treatment or stage distribution, according to residency status. However, RA and to a lesser extent UC residency status, were associated with higher OCM and marginally higher CSM in T1N0M0 patients. This observation should be further validated or refuted in additional epidemiological investigations.
22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans, with a heterogenous clinical presentation including medical, behavioural and psychiatric conditions. Previous neuroimaging studies examining the neuroanatomical underpinnings of 22q11.2DS show alterations in cortical volume (CV), cortical thickness (CT) and surface area (SA). The aim of this study was to identify (1) the spatially distributed networks of differences in CT and SA in 22q11.2DS compared to controls, (2) their unique and spatial overlap, as well as (3) their relative contribution to observed differences in CV. Structural MRI scans were obtained from 62 individuals with 22q11.2DS and 57 age-and-gender-matched controls (aged 6–31). Using FreeSurfer, we examined differences in vertex-wise estimates of CV, CT and SA at each vertex, and compared the frequencies of vertices with a unique or overlapping difference for each morphometric feature. Our findings indicate that CT and SA make both common and unique contributions to volumetric differences in 22q11.2DS, and in some areas, their strong opposite effects mask differences in CV. By identifying the neuroanatomic variability in 22q11.2DS, and the separate contributions of CT and SA, we can start exploring the shared and distinct mechanisms that mediate neuropsychiatric symptoms across disorders, e.g. 22q11.2DS-related ASD and/or psychosis/schizophrenia.
Cabozantinib (Cabometyx®) is a potent multikinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor 2, the mesenchymal-epithelial transition factor (MET) receptor, and the “anexelekto” (AXL) receptor tyrosine kinase. It is approved for the treatment of advanced hepatocellular carcinoma (HCC) after failure of sorafenib in Europe (since November 2018) and in the USA (since January 2019). The approval of cabozantinib was based on results of the randomized, placebo-controlled, phase 3 CELESTIAL trial in patients with unresectable HCC, who received one or two prior lines of treatment including sorafenib. At the second planned interim analysis, the trial was stopped, because the primary end point overall survival was clearly in favor for cabozantinib. Additionally, median progression-free survival was superior to placebo. The most common ≥ grade 3 relevant adverse events in patients with HCC treated with cabozantinib were palmar–plantar erythrodysesthesia, hypertension, fatigue, and diarrhea. In this review, current data on cabozantinib for the treatment of patients with advanced HCC, with a focus on the management of common adverse events and ongoing clinical trials, are discussed.
Cancer‐associated venous thromboembolism (VTE) is a frequent, potentially life‐threatening event that complicates cancer management. Anticoagulants are the cornerstone of therapy for the treatment and prevention of cancer‐associated thrombosis (CAT); factor Xa–inhibiting direct oral anticoagulants (DOACs; apixaban, edoxaban, and rivaroxaban), which have long been recommended for the treatment of VTE in patients without cancer, have been investigated in this setting. The first randomized comparisons of DOACs against low‐molecular‐weight heparin for the treatment of CAT indicated that DOACs are efficacious in this setting, with findings reflected in recent updates to published guidance on CAT treatment. However, the higher risk of bleeding events (particularly in the gastrointestinal tract) with DOACs highlights the need for appropriate patient selection. Further insights will be gained from additional studies that are ongoing or awaiting publication. The efficacy and safety of DOAC thromboprophylaxis in ambulatory patients with cancer at a high risk of VTE have also been assessed in placebo‐controlled randomized controlled trials of apixaban and rivaroxaban. Both studies showed efficacy benefits with DOACs, but both studies also showed a nonsignificant increase in major bleeding events while on treatment. This review summarizes the evidence base for rivaroxaban use in CAT, the patient profile potentially most suited to DOAC use, and ongoing controversies under investigation. We also describe ongoing studies from the CALLISTO (Cancer Associated thrombosis—expLoring soLutions for patients through Treatment and Prevention with RivarOxaban) program, which comprises several randomized clinical trials and real‐world evidence studies, including investigator‐initiated research.
CD4+ T cell lymphopenia predicts mortality from Pneumocystis pneumonia in kidney transplant patients
(2020)
Background: Pneumocystis jirovecii pneumonia (PcP) remains a life-threatening opportunistic infection after solid organ transplantation, even in the era of Pneumocystis prophylaxis. The association between risk of developing PcP and low CD4+ T cell counts has been well established. However, it is unknown whether lymphopenia in the context of post-renal transplant PcP increases the risk of mortality. Methods: We carried out a retrospective analysis of a cohort of kidney transplant patients with PcP (n = 49) to determine the risk factors for mortality associated with PcP. We correlated clinical and demographic data with the outcome of the disease. For CD4+ T cell counts, we used the Wilcoxon rank sum test for in-hospital mortality and a Cox proportional-hazards regression model for 60-day mortality. Results: In univariate analyses, high CRP, high neutrophils, CD4+ T cell lymphopenia, mechanical ventilation, and high acute kidney injury network stage were associated with in-hospital mortality following presentation with PcP. In a receiver-operator characteristic (ROC) analysis, an optimum cutoff of ≤200 CD4+ T cells/µL predicted in-hospital mortality, CD4+ T cell lymphopenia remained a risk factor in a Cox regression model. Conclusions: Low CD4+ T cell count in kidney transplant recipients is a biomarker for disease severity and a risk factor for in-hospital mortality following presentation with PcP.
Complexome profiling is an emerging ‘omics approach that systematically interrogates the composition of protein complexes (the complexome) of a sample, by combining biochemical separation of native protein complexes with mass-spectrometry based quantitation proteomics. The resulting fractionation profiles hold comprehensive information on the abundance and composition of the complexome, and have a high potential for reuse by experimental and computational researchers. However, the lack of a central resource that provides access to these data, reported with adequate descriptions and an analysis tool, has limited their reuse. Therefore, we established the ComplexomE profiling DAta Resource (CEDAR, www3.cmbi.umcn.nl/cedar/), an openly accessible database for depositing and exploring mass spectrometry data from complexome profiling studies. Compatibility and reusability of the data is ensured by a standardized data and reporting format containing the “minimum information required for a complexome profiling experiment” (MIACE). The data can be accessed through a user-friendly web interface, as well as programmatically using the REST API portal. Additionally, all complexome profiles available on CEDAR can be inspected directly on the website with the profile viewer tool that allows the detection of correlated profiles and inference of potential complexes. In conclusion, CEDAR is a unique, growing and invaluable resource for the study of protein complex composition and dynamics across biological systems.
In murine models, the expression of inducible nitric oxide synthase (iNOS) in myocardial infarction (MI) has been reported to be the result of tissue injury and inflammation. In the present study, mRNA expression of iNOS, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was investigated in postmortem human infarction hearts. Since HIF-1α is the inducible subunit of the transcription factor HIF-1, which regulates transcription of iNOS and VEGF, the interrelation between the three genes was observed, to examine the molecular processes during the emergence of MI. iNOS and VEGF mRNAs were found to be significantly upregulated in the affected regions of MI hearts in comparison to healthy controls. Upregulation of HIF-1α was also present but not significant. Correlation analysis of the three genes indicated a stronger and significant correlation between HIF-1α and iNOS mRNAs than between HIF-1α and VEGF. The results of the study revealed differences in the expression patterns of HIF-1 downstream targets. The stronger transcription of iNOS by HIF-1 in the affected regions of MI hearts may represent a pathological process, since no correlation of iNOS and HIF-1α mRNA was found in non-affected areas of MI hearts. Oxidative stress is considered to cause molecular changes in MI, leading to increased iNOS expression. Therefore, it may also represent a forensic marker for detection of early changes in heart tissue.
Purpose: Trauma is the leading cause of death in children. In adults, blood transfusion and fluid resuscitation protocols changed resulting in a decrease of morbidity and mortality over the past 2 decades. Here, transfusion and fluid resuscitation practices were analysed in severe injured children in Germany.
Methods: Severely injured children (maximum Abbreviated Injury Scale (AIS) ≥ 3) admitted to a certified trauma-centre (TraumaZentrum DGU®) between 2002 and 2017 and registered at the TraumaRegister DGU® were included and assessed regarding blood transfusion rates and fluid therapy.
Results: 5,118 children (aged 1–15 years) with a mean ISS 22 were analysed. Blood transfusion rates administered until ICU admission decreased from 18% (2002–2005) to 7% (2014–2017). Children who are transfused are increasingly seriously injured. ISS has increased for transfused children aged 1–15 years (2002–2005: mean 27.7–34.4 in 2014–2017). ISS in non-transfused children has decreased in children aged 1–15 years (2002–2005: mean 19.6 to mean 17.6 in 2014–2017). Mean prehospital fluid administration decreased from 980 to 549 ml without affecting hemodynamic instability.
Conclusion: Blood transfusion rates and amount of fluid resuscitation decreased in severe injured children over a 16-year period in Germany. Restrictive blood transfusion and fluid management has become common practice in severe injured children. A prehospital restrictive fluid management strategy in severely injured children is not associated with a worsened hemodynamic state, abnormal coagulation or base excess but leads to higher hemoglobin levels.
Background: Alterations in the SCN5A gene encoding the cardiac sodium channel Nav1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A > G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the functional impact of the variant to clarify the medical relevance.
Methods: Mutant as well as wild type GFP tagged Nav1.5 channels were expressed in HEK293 cells. We performed functional characterization experiments using patch-clamp technique.
Results: Electrophysiological measurements indicated, that the detected missense variant alters Nav1.5 channel functionality leading to a gain-of-function effect. Cells expressing S106G channels show an increase in Nav1.5 current over the entire voltage window.
Conclusion: The results support the assumption that the detected sequence aberration alters Nav1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.
Of the 16 non-structural proteins (Nsps) encoded by SARS CoV-2, Nsp3 is the largest and plays important roles in the viral life cycle. Being a large, multidomain, transmembrane protein, Nsp3 has been the most challenging Nsp to characterize. Encoded within Nsp3 is the papain-like protease PLpro domain that cleaves not only the viral protein but also polyubiquitin and the ubiquitin-like modifier ISG15 from host cells. We here compare the interactors of PLpro and Nsp3 and find a largely overlapping interactome. Intriguingly, we find that near full length Nsp3 is a more active protease compared to the minimal catalytic domain of PLpro. Using a MALDI-TOF based assay, we screen 1971 approved clinical compounds and identify five compounds that inhibit PLpro with IC50s in the low micromolar range but showed cross reactivity with other human deubiquitinases and had no significant antiviral activity in cellular SARS-CoV-2 infection assays. We therefore looked for alternative methods to block PLpro activity and engineered competitive nanobodies that bind to PLpro at the substrate binding site with nanomolar affinity thus inhibiting the enzyme. Our work highlights the importance of studying Nsp3 and provides tools and valuable insights to investigate Nsp3 biology during the viral infection cycle.
Fokale idiopathische Dystonien stellen die häufigste Dystonieform im Erwachse-nenalter dar. Die Pathophysiologie dieser Erkrankungsgruppe ist weitestgehend unverstanden, wobei die Basalganglien, der Thalamus und das Cerebellum eine zentrale Rolle in der Genese dystoner Bewegungen zu spielen scheinen. Unklar ist, ob Patienten mit fokaler idiopathischer Dystonie mikrostrukturelle Verände-rungen in den oben genannten Arealen aufweisen, die das Störungsbild bedingen könnten.
In dieser Arbeit wurde mittels Methoden der quantitativen Magnetresonanztomographie (qMRT) der Versuch unternommen, Änderungen von Struktur und Eigenschaften des Hirngewebes bei idiopathischen Dystonien im Vergleich zu einer gesunden Kontrollkohorte zu identifizieren. Vorangegangen bildgebende Studien erbrachten bislang widersprüchliche Ergebnisse. Insbesondere der Frage nach möglichen Veränderungen des Eisengehaltes sollte mittels Messung der T2*-Re-laxationszeit nachgegangen werden. Weiterhin wurden Areale der motorischen Kontrolle (Basalganglien, Thalamus, Cerebellum und zerebraler Kortex) auf mög-liche Volumenveränderungen untersucht.
Insgesamt wurden 30 Patienten mit fokaler idiopathischer Dystonie sowie 30 alters- und geschlechtsgematchte Kontrollprobanden mittels multimodaler qMRT untersucht und Parameterkarten für die T1- und T2/T2*-Relaxationszeiten sowie der Protonendichte berechnet. Die Parameterkarten wurden sowohl voxelweise als auch regionenbasiert mit der Frage nach Dystonie-spezifischen Veränderungen statistisch ausgewertet. Zusätzlich erfolgte eine Subgruppenanalyse der ge-nannten Parameter von 17 Patienten mit zervikaler Dystonie im Vergleich zu ei-ner verkleinerten Kontrollgruppe.
Für keinen der untersuchten qMRT-Parameter konnte in der voxelweisen oder der regionenbasierten Analyse signifikante Gruppenunterschiede zwischen Patienten mit fokaler idiopathischer Dystonie und gesunden Kontrollprobanden nachgewiesen werden (p ≥ 0,05). Auch unterschieden sich die untersuchten Hirnregionen nicht hinsichtlich ihres Volumens (p ≥ 0,31). Ebenfalls ausschließlich negative Ergebnisse ergab die Subgruppenanalyse für Patienten mit zervikaler Dystonie (Gewebeparameter p ≥ 0,05, Volumen p ≥ 0,21).
Somit fanden sich entgegen der ursprünglichen Hypothese keine mittels qMRT detektierbaren krankheitsspezifischen mikrostrukturellen Gewebeveränderungen bei Patienten mit fokaler idiopathischer Dystonie. Unter Berücksichtigung der me-thodischen Limitationen und der kleinen Fallzahl ergaben sich keine Hinweise auf Dystonie-assoziierte neurodegenerative Prozesse, erhöhte Eisenablagerungen, Demyelinisierung oder Veränderungen des Wassergehaltes. Die Ergebnisse dieser Studie sind kompatibel mit der Sichtweise, dass idiopathische Dystonien am ehesten aufgrund einer reinen neurofunktionellen Netzwerkstörung der Ba-salganglien und deren kortikalen sowie cerebellären Projektionsareale entstehen. Hierbei ist zu berücksichtigen, dass sehr kleine, feingewebliche Veränderungen, die unterhalb des Auflösungsvermögens der hier verwendeten Bildge-bungsmethode liegen, nicht sicher ausgeschlossen werden können. Weitere quantitativ histologische Untersuchungen in Kombination mit quantitativ bildgebenden Verfahren werden benötigt, um die Pathophysiologie dieser Erkrankungsgruppe besser verstehen zu können.
Die Multiple Sklerose (MS) gehört zu den häufigsten chronisch-entzündlichen Erkrankungen des zentralen Nervensystems in Deutschland und kann durch Sehstörungen, Paresen oder Sensibilitätsstörungen symptomatisch werden.
Konventionelle Magnetresonanztomographie (MRT)-Verfahren leisten in der Diagnostik der MS einen wichtigen Beitrag, da diese die Läsionslast der weißen Substanz gut darstellen können. Frühere Studien deuten an, dass kognitive und psychomotorische Symptome wie Fatigue sowie Konzentrations- und Gedächtnisstörungen bei der MS mit Schädigungen des zerebralen Kortex in Beziehung stehen könnten. Mit konventionellen MRT-Bildgebungsverfahren lässt sich zwar kortikale Atrophie, nicht jedoch die zugrundeliegenden mikrostrukturellen kortikalen Umbauprozesse erfassen. In der vorliegenden Studie wurden daher quantitative MRT(qMRT)-Verfahren verwendet, die eben diese diffusen kortikalen Gewebsveränderungen messen und quantifizieren können. Mithilfe der dabei genutzten Diffusions-Tensor-Bildgebung (DTI) als qMRT-Verfahren konnten Diffusionsanomalien analysiert und charakterisiert werden. Dabei wurden zwei Gewebsparameter im Gehirn bestimmt: die mittlere Diffusivität(MD) und die fraktionelle Anisotropie (FA). Da vorherige Studien uneinheitliche Ergebnisse hinsichtlich Änderungen von DTI-Parametern in der grauen Substanz bei der MS erbrachten, beschäftigten wir uns mit der Frage, ob kortikale MD- und FA-Veränderungen bei Patienten mit schubförmig-remittierender MS (RRMS) mithilfe optimierter DTI-Messtechniken zu detektieren sind, wie diese charakterisiert sind und wie sich diese im Kortex verteilen.
An der vorliegenden Studie nahmen 24 Patienten mit RRMS und 25 gesunde Kontrollprobanden teil. Der Schweregrad der Erkrankung wurde mithilfe des Expanded Disability Status Scale (EDSS) eingestuft.
Bei der MRT-Datenerfassung wurde eine optimierte DTI-Methode mit intrinsischer „Eddy-Current“-Kompensation verwendet. Die MD und die FA wurden für jeden Bildpunkt bestimmt. Kortikale Parameterwerte wurden ausgelesen und in Oberflächendatensätzen gespeichert. Es erfolgte ein oberflächenbasierter statistischer Gruppenvergleich. Kortikale Mittelwerte wurden für die MD und die FA bestimmt und zwischen den Gruppen verglichen.
Für Parameter mit nachgewiesenen globalen Gruppenunterschieden wurde die Korrelation mit dem klinischen Status (quantifiziert durch den EDSS) bestimmt.
Die Analyse kortikaler Mittelwerte zeigte eine Erhöhung der MD in der Patientengruppe. Die MD-Veränderungen waren räumlich ausgedehnt und es fanden sich Cluster mit erhöhten MD-Werten in der Patientengruppe, insbesondere in temporalen, okzipitalen und parietalen Regionen. Des Weiteren konnte eine signifikante positive Korrelation zwischen dem EDSS-Score und der kortikalen MD festgestellt werden. Außerdem ließen sich fokale FA-Erniedrigungen im Temporal- und Okzipitallappen nachweisen. Die MD quantifiziert das Ausmaß und die FA die Gerichtetheit der Diffusion.
Somit bietet die MD möglicherweise Hinweise auf die Intaktheit mikrostruktureller Barrieren und die FA auf die Integrität von Faserverbindungen. Unsere Ergebnisse könnten demnach darauf hinweisen, dass im Kortex von MS-Patienten der Abbau mikrostruktureller Barrieren räumlich ausgedehnter stattfindet als eine Störung axonaler Strukturen. Die Korrelation der MD mit dem klinischen Status legt die Möglichkeit der Quantifizierung klinisch relevanter kortikaler Gewebsveränderungen und somit eine mögliche Relevanz dieser Techniken für klinische Studien nahe.
Circulating monocytes contribute to inflammatory processes. We here validate abnormal expression of inflammation-related genes in monocytes of a large and well-characterised group of MDD patients, and relate the outcomes to pertinent clinical characteristics. Thirty-two genes of a previously established inflammation-related gene signature were assessed in 197 patients with MDD, and 151 controls collected during the EU-MOODINFLAME project. Monocyte gene- expression data were related to age, sex, BMI, depression severity, childhood adversity (CA) and suicide risk (SR). Three distinct gene profiles were identified within the MDD group (downregulated, mixed upregulated and strongly upregulated genes). Patients in the merged upregulated groups had a significantly higher prevalence of CA and high SR. Using hierarchical clustering of the genes, we found a cluster of mainly cytokine (production)-related genes; patients with SR had a significantly higher expression of this cluster than patients without SR (particularly for IL-6, IL1A and IL1B). Such difference did not emerge for patients with and without CA. A downregulated gene profile was found for patients not exposed to CA and without SR (particularly for glucocorticoid-signalling genes NR3C1a and HSPA1/B). No inflammatory changes were observed for healthy controls exposed to CA. Our data show that inflammatory activation in MDD is not uniform, and that immunologically discernible phenotypes of depression can be linked to CA and high SR. The absence of monocyte inflammatory activation in healthy controls exposed to CA suggests an inflammatory involvement in MDD-prone individuals exposed to early stressors, but not healthy controls.
Diese Dissertation soll die Frage beantworten, ob die Forderung der Krankenkassen, die Nabelhernie und die epigastrische Hernie als ambulante Operation zu realisieren, gerechtfertigt bzw. sinnvoll ist. Sie soll ferner Steuergrößen und Maßnahmen identifizieren, die die Überführung des Eingriffs in den ambulanten Rahmen begünstigen können.
Seit den achtziger Jahren des letzten Jahrhunderts wird versucht, durch die kurzstationäre und ambulante Operation verschiedener Krankheitsbilder der Forderung nach Kostenersparnis im Gesundheitswesen nachzukommen. Von den Krankenkassen wird gefordert, den Verschluss einer Hernia umbilicalis: Ohne Plastik: Mit Exstirpation einer Nabelzyste, den Verschluss einer Hernie epigastrica: Ohne Plastik sowie den Verschluss einer Hernia umbilicalis: Mit Plastik im Rahmen einer ambulanten Operation zu korrigieren. Entsprechend wurden diese Eingriffe 2005 in die Liste der ambulant zu erbringenden und stationsersetzenden Maßnahmen aufgenommen. Dennoch liegt die durchschnittliche stationäre Verweildauer nach diesem Eingriff weiterhin bei 3,5 Tagen.
Phylogenetisch ist die Entstehung von Nabelhernien durch anatomisch präformierte Schwachstellen der Bauchwand bedingt, an denen Muskulatur fehlt und nur Aponeurosen und Faszien vorhanden sind. Die Entstehung wird aber auch durch Begleiterkrankungen und Risikofaktoren begünstigt.
In die vorliegende Untersuchung wurden nach Anwendung verschiedener Ausschlusskriterien 95 Patienten aufgenommen, die im Zeitraum zwischen dem 24. August 2009 und dem 24. Juni 2012 mit der Hauptdiagnose einer Nabelhernie bzw. epigastrischen Hernie - Diagnose nach ICD10 - K42.0, K42.1, K42.9, K43.0, K43.1 und K43.9 in der Klinik für Allgemein- und Viszeralchirurgie der Hochtaunuskliniken Bad Homburg operiert wurden. Die selektierten Patienten, welche betrachtet wurden, teilten sich in 61 primäre Nabelhernien, fünf Rezidivnabelhernien, elf epigastrische Hernien, drei Rezidive epigastrischer Hernien und 15 Kombinationseingriffe mit simultaner Operation einer Nabelhernie und einer Leistenhernie auf.
Als Operationsverfahren kam entweder eine Naht Stoß-auf-Stoß (NSAS), die Technik nach Mayo mit einer Fasziendoppelung oder die Implantation von alloplastischem Fremdmaterial entweder mittels eines Ventralex™ Patch oder Proceed™ Patch in Sublay-Technik oder bei ausgedehnten Befunden eine retromuskuläre Mesh Plastik (RMMP) zum Einsatz. Als laparoskopisches Verfahren wurde das Intraperitoneale Onlay Mesh (IPOM) verwendet.
Die Auswertung für die deskriptive Statistik erfolgte mit Microsoft® Excel® 2013. Anschließend wurde die Auswertung der explorativen wie auch der mathematisch/induktiven Statistik mit Hilfe von BiAS. für Windows™ Version 11/2015 durchgeführt.
Nach Analyse des Patientengutes konnte anhand von Korrelationsanalysen herausgearbeitet werden, dass das Alter, die Anzahl der Begleiterkrankungen, die Anzahl der Risikofaktoren und die ASA-Klassifikation (American Society of Anesthesiologists), die Größe der Bruchlücke in Zentimetern und die Schmerzen am zweiten postoperativen Tag einen schwachen Zusammenhang rho (ρ) zwischen 0,23 und 0,39 mit der Liegedauer bei jedoch signifikanten p-Wert p ≤ 0,05 aufwiesen. Einen stärkeren Zusammenhang mit einem Korrelationskoeffizienten ρ von 0,42 und 0,40 im Hinblick auf die Liegedauer zeigten hierbei die Operationsdauer und die Schmerzen am ersten postoperativen Tag. Den stärksten signifikanten Zusammenhang mit einem ρ von 0,64 zeigten die Schmerzen am dritten postoperativen Tag.
Die Verweildauer wurde auch durch die Wahl des Operationsverfahrens beeinflusst. Hier ergab sich eine signifikante Verlängerung der Verweildauer durch unterschiedliche Operationsverfahren sowohl in der Begutachtung des Gesamtkollektivs als auch in der Subgruppe NSAS, Mayo und Patch.
Im Anschluss konnte anhand multivariater Analysen festgestellt werden, dass die Operationsdauer, das Operationsverfahren und die ASA-Klassifikation mit p-Werten ≤ 0,05 mit der Liegedauer signifikant korrelierten. Auch konnte mit Hilfe der multivariaten Analyse aufgezeigt werden, dass die Größe der Bruchlücke in Zentimetern und die Schmerzen am ersten und zweiten postoperativen Tag mit Signifikanzwerten ≤ 0,05 mit der Liegedauer korrelierten.
Nach der durchgeführten Analyse, wie auch nach Betrachtung der Literatur, ist die Grundlage zur Durchführbarkeit einer ambulanten Operation die Erfüllung der medizinischen Voraussetzungen, die Erfüllung der Kriterien für ambulante Operationen und die Erfüllung der Entlassungskriterien. Zudem sollten Patienten mit kardiovaskulären Erkrankungen, insbesondere bei Vorliegen einer Herzinsuffizienz, aber auch bei COPD, Asthma und Schlafapnoesyndrom und einem BMI größer 30 nicht für eine ambulante Operation in Betracht gezogen werden. Auch gelten ein ASA Status größer als 2, Nebenwirkungen der (Allgemein-)Narkose wie PONV, Schwindel, Schläfrigkeit und ein erhöhtes postoperatives Schmerzniveau sowie eine große Defektgröße als hinderlich für die ambulante Durchführung der Operationen.
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Progressive bladder cancer growth is associated with abnormal activation of the mammalian target of the rapamycin (mTOR) pathway, but treatment with an mTOR inhibitor has not been as effective as expected. Rather, resistance develops under chronic drug use, prompting many patients to lower their relapse risk by turning to natural, plant-derived products. The present study was designed to evaluate whether the natural compound, sulforaphane (SFN), combined with the mTOR inhibitor everolimus, could block the growth and proliferation of bladder cancer cells in the short- and long-term. The bladder cancer cell lines RT112, UMUC3, and TCCSUP were exposed short- (24 h) or long-term (8 weeks) to everolimus (0.5 nM) or SFN (2.5 µM) alone or in combination. Cell growth, proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins were evaluated. siRNA blockade was used to investigate the functional impact of the proteins. Short-term application of SFN and/or everolimus resulted in significant tumor growth suppression, with additive inhibition on clonogenic tumor growth. Long-term everolimus treatment resulted in resistance development characterized by continued growth, and was associated with elevated Akt-mTOR signaling and cyclin-dependent kinase (CDK)1 phosphorylation and down-regulation of p19 and p27. In contrast, SFN alone or SFN+everolimus reduced cell growth and proliferation. Akt and Rictor signaling remained low, and p19 and p27 expressions were high under combined drug treatment. Long-term exposure to SFN+everolimus also induced acetylation of the H3 and H4 histones. Phosphorylation of CDK1 was diminished, whereby down-regulation of CDK1 and its binding partner, Cyclin B, inhibited tumor growth. In conclusion, the addition of SFN to the long-term everolimus application inhibits resistance development in bladder cancer cells in vitro. Therefore, sulforaphane may hold potential for treating bladder carcinoma in patients with resistance to an mTOR inhibitor.
Background: Climate change is safe to be one of the biggest challenges of mankind. Human activities, especially the combustion of fossil fuels, contribute to the increase of greenhouse gases in the atmosphere and thus to the pace of climate change. The effects of climate change are already being felt, and the resulting damage will most likely be enormous worldwide. Because global impacts vary widely and will lead to very different national vulnerability to climate impacts, each country, depending on its economic background, has different options to ward off negative impacts. Decisions have to be made to mitigate climate consequences according to the preparedness and the vulnerability of countries against the presumed impacts. This requires a profound scientific basis. To provide sound background information, a bibliometric study was conducted to present global research on climate change using established and specific parameters. Bibliometric standard parameters, established socioeconomic values, and climate change specific indices were used for the analyses. This allowed us to provide an overall picture of the global research pattern not only in terms of general aspects, but also in terms of climate change impacts, its effects and regional differences. For this purpose, we choose representative indices, such as the CO2 emissions for the responsibility of countries, the global climate risk index as a combination value for the different types of damage that countries can expect, the increase in sea level as a specific parameter as a measure of the huge global environmental impacts, and the readiness and vulnerability index for the different circumstances of individual countries under which climate change will take place. We hope to have thus made a comprehensive and representative selection of specific parameters that is sufficient to map the global research landscape. We have supplemented the methodology accordingly.
Results: In terms of absolute publication numbers, the USA was the leading country, followed by the UK, and China in 3rd place. The steep rise in Chinese publication numbers over time came into view, while their citation numbers are relatively low. Scandinavian countries were leading regarding their publication numbers related to CO2 emission and socioeconomic indices. Only three developing countries stand out in all analyses: Costa Rica, the Fiji Atoll, and Zimbabwe, although it is here that the climate impact will be greatest. A positive correlation between countries’ preparedness for the impacts of climate change and their publication numbers could be shown, while the correlation between countries’ vulnerability and their publication numbers was negative.
Conclusions: We could show that there exists an inequity between national research efforts according to the publication output and the demands and necessities of countries related to their socioeconomic status. This inequity calls for a rethink, a different approach, and a different policy to improve countries' preparedness and mitigation capacity, which requires the inclusion of the most affected regions of the world in a strengthened international cooperation network.
Background/Aims: Reliable and especially widely accepted preventive measures are crucial to further reduce the incidence of colorectal cancer (CRC). Colon capsule endoscopy (CCE) might increase the screening numbers among patients unable or unwilling to undergo conventional colonoscopy. This registry trial aimed to document and determine the CCE indications, findings, complications, and adverse events in outpatient practices and clinics throughout Germany.
Methods: Patients undergoing CCE between 2010 and 2015 were enrolled in this prospective multicenter registry trial at six German centers. Patient demographics, outcomes, and complications were evaluated.
Results: A total of 161 patients were included. Of the CCE evaluations, 111 (68.9%) were considered successful. Pathological findings in the colon (n=92, 60.1%) and in the remaining gastrointestinal tract (n=38, 24.8%) were recorded. The main finding was the presence of polyps (n=52, 32.3%). Furthermore, five carcinomas (3.1%) were detected and histologically confirmed later. Adequate bowel cleanliness was more likely to be achieved in the outpatient setting (p<0.0001). Interestingly, 85 patients (55.6%) chose to undergo CCE based on personal motivation.
Conclusions: CCE seems to be a reliable and safe endoscopic tool for screening for CRC and detecting other diseases. Its patient acceptance and feasibility seems to be high, especially in the outpatient setting.
Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections.
Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study.
Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002).
Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections.
Functional genomics studies in model organisms and human cell lines provided important insights into gene functions and their context-dependent role in genetic circuits. However, our functional understanding of many of these genes and how they combinatorically regulate key biological processes, remains limited. To enable the SpCas9-dependent mapping of gene-gene interactions in human cells, we established 3Cs multiplexing for the generation of combinatorial gRNA libraries in a distribution-unbiased manner and demonstrate its robust performance. The optimal number for combinatorial hit calling was 16 gRNA pairs and the skew of a library’s distribution was identified as a critical parameter dictating experimental scale and data quality. Our approach enabled us to investigate 247,032 gRNA-pairs targeting 12,736 gene-interactions in human autophagy. We identified novel genes essential for autophagy and provide experimental evidence that gene-associated categories of phenotypic strengths exist in autophagy. Furthermore, circuits of autophagy gene interactions reveal redundant nodes driven by paralog genes. Our combinatorial 3Cs approach is broadly suitable to investigate unexpected gene-interaction phenotypes in unperturbed and diseased cell contexts.