1,721,118 research outputs found
Evaluation of heated humidifiers for use on intubated patients: a comparative study of humidifying efficiency, flow resistance, and alarm functions using a lung model
No full textObjective: Evaluation of humidification efficiency, flow resistance, and alarm functions of heated humidifiers (HH;(Kendall-Aerodyne-delta, Fisher Paykel-MR 730; Drager-Aquapor, Puritan-Bennett-Cascade II) in accordance with ISO/EN-8185:1997 and on a ventilated lung model in accordance with ISO/EN-9360:2000. Methods: Humidification efficiency was evaluated by (a) measuring the water content of the inspiratory air on perfusion with different gas flows, (b) measuring the water loss of a lung model, and (c) simultaneous measurement of the in- and expiratory water content with a capacitive hybrid sensor. The resistance characteristics were measured, the data were compared with a mathematical approximation. The alarm functions were determined. Results: The humidification efficiency of HHs is a function of gas flow and design characteristics. In HHs with tube heating it is possible to make settings at which the inspiratory humidity falls below the minimal value of 33 mgH(2)O/l stipulated by ISO/EN-8185:1997. The inspiratory resistances extend from 0.5 to 4.4 cmH(2)O l(-1) s(-1); the expiratory flow resistances of the devices are low. The alarm functions of HHs with tube heating are inadequate for cases involving both "dry start" and "running dry." Conclusions: Efficiency data that allow a direct comparison with heat and moisture exchangers data according to ISO/EN9360:2000 can also be determined for HH. HH do not prevent pulmonary water losses in intubated patients. These losses can exceed the physiological range. The airway resistance of the Cascade II prohibits its use in spontaneously breathing patients. The warning and shut-off features of HH are unacceptable and hazardous
Angiogenese bei der Transplantat-gegen-Wirt Reaktion
No full textFor a variety of hematopoietic diseases, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option. Due to numerous improvements in the treatment procedure and the constant expansion of indications, the number of transplanted patients has increased rapidly during the last decades. Despite many achievements, the mortality rate after allo-HSCT is still high. The main and most severe complication after allo-HSCT is the graft- versus-host disease (GVHD) and up to 30% of allo-HSCT recipients die due to GVHD or GVHD-related side effects. GVHD is characterized by a systemic inflammatory reaction that is mainly mediated by alloreactive T cells. Alloreactive T cells cause severe tissue damage in main GVHD target organs colon, liver and skin via different cytotoxic mechanisms. All current treatment options aim at the suppression of T cell function, however, the inhibition of immune responses results in an increased risk for infections and tumor relapse. Therefore, there is a clear medical need in defining alternative targets for the development of therapies that act without hampering immune functions.
Recent work by us and others, identified an important role of the endothelium in the development of acute GVHD (aGVHD). However, the inhibition of vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, key mediators of angiogenesis, led to impaired hematopoietic engraftment, which is essential for a beneficial transplantation outcome. This thesis discusses two new approaches for the treatment of aGVHD after allo-HSCT. The first part of this work deals with an aspect that has not been studied in the context of aGVHD before, namely lymphangiogenesis. It is well known that lymph vessels carry out important immunologic functions and that lymphangiogenesis is involved in inflammation, cancer and graft rejection. However, the influence of lymphangiogenesis on inflammation can be beneficial or harmful and seems to depend on various factors such as the inflammatory trigger and the site of inflammation.
Evaluation of murine and human tissue samples showed a significant increase in lymph vessel density during aGVHD, confirming the clinical relevance of lymphangiogenesis in aGVHD. The inhibition of VEGFR3, a main regulator of lymphangiogenesis, revealed that reduced lymphangiogenesis attenuates clinical and histopathological features of aGVHD, without affecting malignant lymphoma growth.
In the second part of the thesis an alternative pathway of hemangiogenesis is investigated. Besides the prominent vascular endothelial growth factor (VEGF)/VEGFR signaling, an alternative pathway involved in angiogenesis is the transforming growth factor-beta (TGF-b) pathway. Depending on downstream signaling, the TGF-b pathway can initiate or inhibit angiogenesis. A study by Greenwood et al. identified the glycoprotein leucine-rich alpha-2-glycoprotein 1 (Lrg1) as regulator of the angiogenic switch in TGF-b signaling. Elevated serum levels of Lrg1 in samples from patients with inflammatory diseases further confirmed the assumption that Lrg1 is expressed under pathological rather than physiological conditions. The correlation between Lrg1-regulated TGF-b signaling and angiogenesis during aGVHD has not been investigated so far. We show that Lrg1 expression is increased in target organs during aGVHD and that the genetic loss of Lrg1 attenuates aGVHD. Using the additional inflammation models of experimental colitis and paw edema, we could also show that Lrg1 contributes to angiogenesis, altered vessel structure and increased inflammation in these disease models.
With this work, we were able to confirm the crucial role of the lymphatic and blood vascular system during aGVHD. We identified two novel factors that provide potential therapeutic targets to reduce aGVHD without interfering with anti-tumor immunity and immune reconstitution
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Endothelial Progenitor Cells during Allogeneic Stem Cell Transplantation and Tumor-Immunotherapy
No full textImmuntherapien für Krebserkrankungen haben in den letzten Jahrzehnten mehr und
mehr Eingang in die klinische Praxis gefunden. Die allogene hämatopoetische
Stammzelltransplantation (allo-KMT) ist zurzeit die effektivste Immuntherapie
für maligne Erkrankungen. Der therapeutische Nutzen der allo-KMT bei malignen
Erkrankungen ist zum Großteil durch die so genannte graft-versus-tumor (GVT)
Aktivität von Immunzellen des Spenders vermittelt. Leider ist die allo-KMT
kein komplikationsarmes Verfahren: Die graft-versus-host Krankheit (GVHD) ist
eine progressive systemische Entzündung, die vor allem den Darm, die Leber und
die Haut betrifft und erhebliche Morbidität und Mortalität verursacht. Ein
großes klinisches Problem stellt die Prophylaxe und Therapie der GVHD dar.
Heutzutage angewandte therapeutische Strategien beeinträchtigen die T Zell
Funktion und führen zu erhöhtem Risiko eines Tumor Rückfalls. Daher sind wir
an der Entwicklung therapeutischer Strategien interessiert, die sich durch
eine hohe Effektivität gegen die GVHD auszeichnen ohne die GVT Aktivität
negativ zu beeinflussen. Eine von uns neu beschriebene therapeutische
Strategie bei GVHD ist die Hemmung der Neovaskularisierung durch spezifische
Depletion von Endothelialen Progenitorzellen (EPCs). Zur Neovaskularisierung
beim erwachsenen Menschen tragen sowohl die Angiogenese, das Sprießen von
gewebeständigen Endothelzellen (ECs), als auch die Vaskulogenese, die
Rekrutierung von im Knochenmark entstandenen zirkulierenden EPCs, bei. Es
besteht eine Verbindung zwischen der Neovaskularisierung, dem Wachstum von
Blutgefäßen, zu verschiedenen entzündlichen Erkrankungen sowie zu
Tumorerkrankungen. Daher haben wir die Bedeutung von Angiogenese und
Vaskulogenese für Entzündungen in Mausmodellen für die GVHD untersucht. Wir
konnten herausfinden, dass die GVHD durch vermehrte Neovaskularisierung in
GVHD Zielorganen charakterisiert ist. Dabei demonstrierten wir eine besonders
wichtige Bedeutung der Vaskulogenese für die Entzündung während der GVHD. Wir
haben einen monoklonalen Antikörper (E4G10) gegen das vaskuläre endotheliale
Adhesionmolekül VE-cadherin eingesetzt, um EPCs zu depletieren und damit
spezifisch die Vaskulogenese zu hemmen. Als Folge der EPC Depletion haben wir
eine Hemmung der Neovaskularisierung beobachtet, die zur Verbesserung der
systemischen und organspezifischen GVHD mit Überlebensvorteil führte. In
Experimenten, bei denen allo-KMT Empfänger sowohl Tumorzellen als auch
allogene T Zellen intravenös verabreicht bekommen haben, konnten wir einen
simultanen positiven Effekt der EPC Depletion auf Tumorwachstum und GVHD
beobachten, der zu einem erheblichen Überlebensvorteil der E4G10 behandelten
allo-KMT Empfänger führte. Unsere Ergebnisse zeigen, dass die Hemmung der
Vaskulogenese mittels der Depletion von EPCs eine einzigartige Möglichkeit
darstellt, um die beiden wesentlichen Komplikationen der allo-KMT (GVHD und
Tumor Rückfall) mit einer therapeutischen Strategie zu behandeln. Ein weiterer
Ansatz zur Entwicklung von neuen therapeutische Strategien bei der GVHD ist
die Nutzung der hohen Anti-Tumor Aktivität von natürlichen Killerzellen (NK
Zellen). Klinische Daten zeigen, dass die Allo-Reaktivität von Spender NK
Zellen gegen Empfänger Tumorzellen entscheidend zur Anti-Tumor Aktivität einer
allo-KMT beiträgt. Um verschiedene Einflussfaktoren auf die NK Zell Aktivität
nach allo-KMT untersuchen zu können haben wir eine Methode etabliert, mit der
verlässlich und genau die NK Reaktivität gegen Tumorzellen auf einer
Einzelzellebene erfasst werden kann. Unsere Methode beruht auf der
durchflusszytometrischen Erfassung von CD107a, einem Granula-membranprotein,
was bei der Degranulation von NK Zellen an der Zelloberfläche expremiert wird.
Mit dieser Methode konnten wir Einflussfaktoren auf die NK Zell Aktivität nach
allo-KMT nachweisen: 1) Das Konditionierungsregime - wir fanden eine erhöhte
NK Zell Aktivität gegen Tumorzellen nach allo-KMT mit reduzierter
Konditionierung. Die hohe Anti-Tumor Reaktivität von NK Zellen ist eine
mögliche Erklärung der guten klinischen Effektivität der allo-KMT mit
reduzierter Konditionierung. 2) Die T Zell Depletion – wir fanden eine erhöhte
NK Zell Toxizität für Alemtuzumab (Campath) in vivo im Vergleich zu
Thymoglobulin (Kaninchen ATG). Unsere Ergebnisse liefern die
pathophysiologische Grundlage für klinische Berichte über ein erhöhtes Risiko
von Tumorrückfällen nach allo-KMT bei T Zell Depletion mit Alemtuzumab und
legen einen kritischen Umgang mit Alemtuzumab bei der allo-KMT nahe.Neovascularization has been implicated in tumor growth and inflammation. Blood
vessels are either formed by sprouting of resident tissue endothelial cells
(ECs, angiogenesis), or by recruitment of bone marrow-derived circulating
endothelial progenitor cells (EPCs, vasculogenesis). The role of
neovascularization and its mechanisms in graft-versus-host disease (GVHD) and
in tumors after allogeneic bone marrow transplantation (allo-BMT) are not
known. In murine allo-BMT models we analyzed the vascular density, ECs and
EPCs by immunofluorescence microscopy and by flow cytometry. We used an
antibody (E4G10) against monomers of the vascular endothelial adhesion
molecule VE-cadherin to inhibit neovascularization without affecting host
vasculature. We analyzed GVHD by survival, clinical scoring, histopathology,
immunohistochemistry, flow cytometry, cytokine immunoassay and gene array. We
assessed tumors by survival, clinical scoring, histopathology and
bioluminescence imaging. We found increased neovascularization in GVHD target
tissues, such as liver and intestines. Interestingly, neovascularization
during GVHD was mediated by vasculogenesis, as opposed to angiogenesis. We
adoptively transferred selected GFP+ EPCs and observed recruitment to the
neovasculature in the liver and intestines during GVHD, as well as to tumor
neovasculature after allo-BMT. Next, we administered E4G10 to allo-BMT
recipients and found depletion of EPCs as well as inhibition of
neovascularization. We observed that E4G10 administration resulted in
simultaneous beneficial effects on GVHD and tumor growth leading to survival
benefit of tumor bearing allo-BMT recipients. Therapeutic targeting of
neovascularization in allo-BMT recipients is a novel strategy to
simultaneously ameliorate GVHD and inhibit post-transplant tumor growth,
providing a new approach to improve the overall outcome of allogeneic
hematopoietic stem cell transplantation
Real-World Results of CAR-T Cell Therapy for Large B Cell Lymphoma with CNS Involvement: A GLA/DRST Study
No full textCurrent incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients: an EBMT Transplant Complications Working Party study
No full textAbstract The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade ( p < 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS ( p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome
Pathological angiogenesis and endothelial dysfunction in Graft-versus-Host Disease after allogeneic hematopoietic stem cell transplantation
Full text linkDuring past decades, considerable progress has been made in the field of allogeneic hematopoietic stem cell transplantation (allo-HSCT), enabling the procedure as a curative treatment to an increasing number of patients suffering from hematopoietic malignancies or autoimmune diseases. Despite numerous improvements of allo-HSCT, the rates of post-treatment complications are still high: more than half of the transplanted patients develop Graft-versus-Host Disease (GvHD), with an overall mortality up to 40%, making GvHD the major treatment sequelae after allo-HSCT. GvHD can occur acute (aGvHD) or chronic (cGvHD) as a systemic inflammatory disease, affecting various organs and tissues. Chronic inflammation subsequently leads to fibrosis and severe morbidity in cGvHD patients. Common therapeutic approaches aim to suppress alloreactive T cells, the inflammatory mediators of GvHD, but the use of immunosuppressive steroids is accompanied by GVHD-associated complications, as treatment toxicity, tumor relapse or fatal infections. Therefore, an urgent need for alternative therapies exists, which effectively prevent and attenuate GvHD without eliminating the necessary immune responses.
Recent studies proposed the endothelium as a novel target for treatment approaches of GvHD. While angiogenesis, the formation of new blood vessels, is a cause of inflammation during early GvHD, the endothelium is damaged from the persisting inflammation at later GvHD stages. Due to the lack of suitable mouse models, the endothelial participation especially in the cGvHD pathology is inadequately characterized, resulting in limited anti-angiogenic therapies and novel therapeutic endothelial targets. This thesis intends to elicit the mechanisms leading to endothelial GvHD and identify such potential target structures for GvHD treatment.
In the first part of this study, we examined metabolic genes that are differentially regulated during pathologic angiogenesis. By genetic deletion with CRISPR/Cas9, the enzymes Enolase 3 and Glucose-6-phosphate dehydrogenase (G6pdx) were identified to participate in the endothelial regulation under allogeneic conditions and were successfully intervened by specific pharmacologic inhibitors in vitro. Therapy using the G6pdx-inhibitor Polydatin resulted in attenuated inflammation in footpad swelling assays, ameliorated the GvHD morbidity and normalized the vascular integrity in vivo.
The second part of the project deals with the endothelium during cGvHD. Two novel murine and one humanized mouse model of cGvHD were established, which closely resemble the clinical features of cGvHD in patients. Characterizing these models, a decelerated immune and hematopoietic cell reconstitution was found, followed by a massive infiltration of T and B cells and severe tissue sclerosis/ fibrosis in GvHD target organs. Determining the endothelial condition during late cGvHD, a prominent vascular damage and dysfunction was found: Next to a loss of endothelial CD31 and VE-Cadherin and an increase of von-Willebrand factor, the endothelial integrity was disturbed by the loss of tight junction protein Zonula occludens protein-1 and pericyte marker Neuron-glial antigen 2. Additionally there was occurrence of circulating endothelial cells and endothelial progenitor cells in cGvHD. Severe endothelial fibrosis by analysis of alpha-smooth muscle actin and Fibroblast-specific protein-1 was quantified. Hence for the first time, a transformation of endothelial towards a mesenchymal cell type (Endothelial-to-mesenchymal transition) was detected, a process which has not been described in the context of GvHD before. This transition was successfully prevented by administration of Pirfenidone, which normalized the CD31+ vessel quantity and ameliorated the endothelial fibrosis in vivo. Furthermore, a panel of five novel endothelium-related biomarkers (Endostatin, Connective tissue growth factor, Endoglin, Follistatin, Endocan), which were increased in blood serum of cGvHD patients, was proposed and might be beneficial for prognosis and diagnosis of cGvHD in the clinic.
This study helps to provide knowledge about the connection between the endothelium and the GvHD pathology. It identified potential therapeutic targets to ameliorate GvHD without interfering the anti-tumor response after allo-HSCT, normalizing the disturbed vascular function and prevent endothelial fibrosis
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