Optimization of the indications for allogeneic stem cell transplantation in Acute Myeloid Leukemia based on interactive diagnostic strategies

The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling. Keywords: Acute Myeloid Leukemia (AML), Allogeneic Stem Cell Transplantation (SCT), Indication, Cytogenetics, Polymerase Chain Reaction (PCR

Effects of temperature variability on community structure in a natural microbial food web

Climate change research has demonstrated that changing temperatures will have an effect on community-level dynamics by altering species survival rates, shifting species distributions, and ultimately, creating mismatches in community interactions. However, most of this work has focused on increasing temperature, and still little is known about how the variation in temperature extremes will affect community dynamics. We used the model aquatic community held within the leaves of the carnivorous plant, Sarracenia purpurea, to test how food web dynamics will be affected by high temperature variation. We tested the community response of the first (bacterial density), second (protist diversity and composition), and third trophic level (predator mortality), and measured community respiration. We collected early and late successional stage inquiline communities from S. purpurea from two North American and two European sites with similar average July temperature. We then created a common garden experiment in which replicates of these communities underwent either high or normal daily temperature variation, with the average temperature equal among treatments. We found an impact of temperature variation on the first two, but not on the third trophic level. For bacteria in the high-variation treatment, density experienced an initial boost in growth but then decreased quickly through time. For protists in the high- variation treatment, alpha-diversity decreased faster than in the normal-variation treatment, beta-diversity increased only in the European sites, and protist community composition tended to diverge more in the late successional stage. The mortality of the predatory mosquito larvae was unaffected by temperature variation. Community respiration was lower in the high-variation treatment, indicating a lower ecosystem functioning. Our results highlight clear impacts of temperature variation. A more mechanistic understanding of the effects that temperature, and especially temperature variation, will have on community dynamics is still greatly needed

Top predators affect the composition of naive protist communities, but only in their early-successional stage

Introduced top predators have the potential to disrupt community dynamics when prey species are naive to predation. The impact of introduced predators may also vary depending on the stage of community development. Early-succession communities are likely to have small-bodied and fast-growing species, but are not necessarily good at defending against predators. In contrast, late-succession communities are typically composed of larger-bodied species that are more predator resistant relative to small-bodied species. Yet, these aspects are greatly neglected in invasion studies. We therefore tested the effect of top predator presence on early- and late-succession communities that were either naive or non-naive to top predators. We used the aquatic community held within the leaves of Sarracenia purpurea. In North America, communities have experienced the S. purpurea top predator and are therefore non-naive. In Europe, this predator is not present and its niche has not been filled, making these communities top-predator naive. We collected early- and late-succession communities from two non-naive and two naive sites, which are climatically similar. We then conducted a common-garden experiment, with and without the presence of the top predator, in which we recorded changes in community composition, body size spectra, bacterial density, and respiration. We found that the top predator had no statistical effect on global measures of community structure and functioning. However, it significantly altered protist composition, but only in naive, early-succession communities, highlighting that the state of community development is important for understanding the impact of invasion

Azadiphosphaindane-1,3-diyls: A Class of Resonance-Stabilized Biradicals

Conversion of 1,2-bis(dichlorophosphino)benzene with sterically demanding primary amines led to the formation of 1,3-dichloro-2-aza-1,3-diphosphaindanes of the type C6H4(μ-PCl)2N-R. Reduction yielded the corresponding 2-aza-1,3-diphosphaindane-1,3-diyls (1), which can be described as phosphorus-centered singlet biradical(oid)s. Their stability depends on the size of the substituent R: While derivatives with R=Dmp (2,6-dimethylphenyl) or Ter (2,6-dimesitylphenyl) underwent oligomerization, the derivative with very bulky R=tBuBhp (2,6-bis(benzhydryl)-4-tert-butylphenyl) was stable with respect to oligomerization in its monomeric form. Oligomerization involved activation of the fused benzene ring by a second equivalent of the monomeric biradical and can be regarded as formal [2+2] (poly)addition reaction. Calculations indicate that the biradical character in 1 is comparable with literature-known P-centered biradicals. Ring-current calculations show aromaticity within the entire ring system of 1. © 2020 The Authors. Angewandte Chemie International Edition published by Wiley-VCH Gmb

Interactions of "Sarracenia purpurea" and its inquilines: comparing Europe and North America

Sarracenia purpurea is a carnivorous pitcher plant from North America and a model system for aquatic communities. After the pitchers fill up with rainwater, a food web forms in these detritus-fueled ecosystems ranging from bacteria to insect larvae, including the top predator Wyeomyia smithii. Two weeks after opening this food webs consists only of a handful of small and fast dispersing species (early succession). After four weeks more species that are larger and more competitive have arrived (late succession). At this time point all functional levels of the food webs are present. In North America this includes several endemic insect larvae and a mite. In Europe, S. purpurea was introduced by seed, however the native food web (and its top predator) were not imported, resulting in all levels of the food web being filled by local species with exception to the insect niche. Thus the European Sarracenia inquiline communities share shorter evolutionary trajectories with the plant and are also top predator naive. Also in Switzerland the plant was introduced in several bogs and fens, most of them situated in the Jura and Alps above 1000m. In chapter two the interaction of S. purpurea with the European spider-genera Agelena and Dolomedes was examined. Dolomedes uses the pitchers as hunting ground and a hiding place. Agelena distribution curiously follows the insect-attraction pattern of S. purpurea, which peaks ca. 4 weeks after pitcher opening. In chapter three the effect of top predator presence on early and late succession protist communities that were either naive or non-naive to the top predator was tested. Early and late succession communities from four climatically similar sites were collected. Two of these sites were from North America (non-naive) and two sites were from Europe (naive). Finally a common garden experiment was conducted in which the changes in the protist community composition, as well as bacterial numbers, with and without the presence of the top predator were followed through time. Additionally the respiration of the whole communities at the end of the experiment was measured. In chapter four, the effects of climate change related increased temperature variations on early and late succession communities from both continents were tested. Once again conducted a common garden experiment was conducted, in which we increased the daily temperature variations in one group to extreme values (4-35°C) while the control group was treated with average temperature variations ranging from 10 to 21°C. However the average temperature among treatments for both experimental groups was equal (15.5°C). Also in this experiment the changes in protist community composition, as well as bacterial numbers were followed through time. Interestingly an impact of temperature variation on the bacteria and the protists (first and second trophic level) could be detected, however not on the mosquito-larvae (third trophic level). Bacterial density in the high variation treatment showed an initial boost in growth but then decreased quickly through time. For protists in the high variation treatment, alpha-diversity decreased faster than in the normal variation treatment, however beta-diversity increased only in the European sites showing that these communities changed their composition. In general protist community composition tended to diverge more in the late successional stage of both continents.Sarracenia purpurea ist eine fleischfressende Pflanze aus Nordamerika und gilt als Modellsystem für aquatische Lebensgemeinschaften. Nachdem die Kannenblätter sich mit Regenwasser gefüllt haben, entwickelt sich ein Nahrungsnetz in diesen auf Detritus basierenden Ökosystemen welches von Bakterien bis zu Insektenlarven reicht und den Top-Prädator Wyeomyia smithii einschliesst. Zwei Wochen nach dem Öffnen der Kannen bestehen diese Nahrungsnetze nur aus einer Handvoll kleiner Arten, die zudem schnell neue Lebensräume besiedeln können (frühes Sukzessionsstadium). Nach vier Wochen sind bereits mehr Arten, die auch größer und konkurrenzfähiger sind vorhanden (späteres Sukzessionsstadium). Zu diesem Zeitpunkt sind fast alle funktionellen Ebenen des Nahrungsnetzes vorhanden. In Nordamerika umfasst dieses einige einheimische Insektenlarven und eine Milbe. Nach Europa wurde S. purpurea aber als Samen eingeführt. Dadurch wurde das ursprüngliche Nahrungsnetz (und auch der Top-Prädator) nicht importiert. Allen trophischen Ebenen des Nahrungsnetzes, mit Ausnahme der Nische der Insekten, sind daher durch lokale Arten besetzt. Aus diesem Grund hatten die europäischen Sarracenia-bewohnenden Gesellschaften kürzere evolutionäre Entwicklungszeiten mit der Pflanze als die amerikanischen und sind zudem nicht an die Präsenz eines Top-Prädators gewöhnt. Auch in der Schweiz wurde die Pflanze in mehrere Mooren eingeführt. Die meisten von ihnen befinden sich im Jura und den Alpen in über 1000 Meter Höhe. Im zweiten Kapitel wurde die Interaktion von S. purpurea mit den europäischen Spinnengattungen Agelena und Dolomedes untersucht. Dolomedes nutzt die Kannen als Jagdrevier und Versteck. Die Verteilung der Netze von Agelena folgt interessanterweise proportional dem Muster der Insektenanlockung von S. purpurea, und erreicht ca. 4 Wochen nach der Öffnung der Kannenblätter ihren Höchststand. In Kapitel drei wurde die Wirkung der Top-Prädatorenpräsenz auf das frühe und spätere Sukzessionsstadium der Protisten-Gesellschaften untersucht. Diese waren entweder an Prädatoren gewöhnt oder eben nicht. Frühe und spätere Sukzessionsstadien von vier klimatisch ähnlichen Sarracenia-Standorten wurden gesammelt. Zwei dieser Standorte befanden sich in Nordamerika (an Prädatoren gewöhnt) und zwei weitere in Europa (nicht an Prädatoren gewöhnt). In einem „common garden” Experiment wurden die Änderungen in der Zusammensetzung der Protistengesellschaften sowie in der Bakterienanzahl, mit und ohne die Anwesenheit eines Top-Prädators über mehrere Tage verfolgt. Zusätzlich wurde am Ende des Experiments die Atmung der gesamten Lebensgemeinschaft gemessen. In Kapitel vier wurden die Auswirkungen des Klimawandels (erhöhte Temperaturschwankungen) auf frühe und spätere Sukzessionsstadium der Gesellschaften aus beiden Kontinenten getestet. Dazu wurde ein weiteres „common garden” Experiment durchgeführt, bei dem die täglichen Temperaturschwankungen in einer Gruppe auf Extremwerte (4-35 °C) erhöht wurden, während die Kontrollgruppe lediglich durchschnittlichen Temperaturschwankungen von 10 bis 21 °C ausgesetzt wurde. Die Durchschnittstemperatur für beiden Versuchsgruppen war mit (15,5 ° C) genau gleich. Auch in diesem Experiment wurden die Änderungen in der Zusammensetzung der Protistengesellschaften sowie die Anzahl der Bakterien über mehrere Tage hinweg beobachtet. Interessanterweise konnten Auswirkungen der Temperaturschwankungen auf die Bakterien und Protisten (erste und zweite Trophieebene) jedoch nicht auf dem Moskito-Larven (dritte Trophieebene) nachgewiesen werden. Die Bakteriendichte in der Versuchsgruppe der hohen Temperaturschwankungen zeigte einen anfänglichen Wachstumsschub, fiel dann aber stark ab. Bei den Protisten in der gleichen Gruppe verringerte sich die Alpha-Diversität schneller als in der normalen Versuchsgruppe. Die Beta-Diversität erhöhte sich allerdings nur in den europäischen Standorten, was zeigt, dass nur diese Gemeinschaften ihre Zusammensetzung veränderten. Im Allgemeinen neigten die Protisten Gesellschaften beider Kontinente dazu in der Zusammensetzung ihrer späten Sukzessionsstadien stärker zu divergieren

Farber disease: clinical presentation, pathogenesis and a new approach to treatment

<p>Abstract</p> <p>Background</p> <p>Farber Disease is an autosomal-recessively inherited, lysosomal storage disorder caused by acid ceramidase deficiency and associated with distinct clinical phenotypes. Children with significant neurological involvement usually die early in infancy, whereas patients without or only mild neurological findings suffer from progressive joint deformation and contractures, subcutaneous nodules, inflammatory, periarticular granulomas, a hoarse voice and finally respiratory insufficiency caused by granuloma formation in the respiratory tract and interstitial pneumonitis leading to death in the third or fourth decade of live. As the inflammatory component of this disorder is caused by some kind of leukocyte dysregulation, allogeneic hematopoietic stem cell transplantation can restore a healthy immune system and thus may provide a curative option in Farber Disease patients without neurological involvement. Previous stem cell transplantations in two children with severe neurological involvement had resulted in a disappointing outcome, as both patients died of progressive deterioration of their neurological status. As a consequence, stem cell transplantation does not appear to be able to abolish or even reduce the neurotoxic effects of the abundant ceramide storage in the brain.</p> <p>Methods</p> <p>After myeloablative, busulfan-based preparative regimens, four Farber Disease patients without neurological involvement received an allogeneic hematopoietic stem cell transplantation from related and unrelated donors. Stem cell source was BM in three patients and PBSC in one patient; GvHD-prophylaxis consisted of CsA and short course MTX.</p> <p>Results and discussion</p> <p>In all patients, HSCT resulted in almost complete resolution of granulomas and joint contractures, considerable improvement of mobility and joint motility without relevant therapy-related morbidities. All patients are alive and well at this point with stabile donor cell chimerism and without evidence of chronic GvHD or other late sequelae of stem cell transplantation.</p> <p>Conclusion</p> <p>Allogeneic hematopoietic stem cell transplantation provides a promising approach for Farber Disease patients without neurological involvement.</p

The Role of Allogeneic Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma Patients

Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15–20% of patients remain refractory to chemoradiotherapy, and 20–40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies

Molecular Diagnostics, Targeted Therapy, and the Indication for Allogeneic Stem Cell Transplantation in Acute Lymphoblastic Leukemia

In recent years, the panel of known molecular mutations in acute lymphoblastic leukemia (ALL) has been continuously increased. In Philadelphia-positive ALL, deletions of the IKZF1 gene were identified as prognostically adverse factors. These improved insights in the molecular background and the clinical heterogeneity of distinct cytogenetic subgroups may allow most differentiated therapeutic decisions, for example, with respect to the indication to allogeneic HSCT within genetically defined ALL subtypes. Quantitative real-time PCR allows highly sensitive monitoring of the minimal residual disease (MRD) load, either based on reciprocal gene fusions or immune gene rearrangements. Molecular diagnostics provided the basis for targeted therapy concepts, for example, combining the tyrosine kinase inhibitor imatinib with chemotherapy in patients with Philadelphia-positive ALL. Screening for BCR-ABL1 mutations in Philadelphia-positive ALL allows to identify patients who may benefit from second-generation tyrosine kinase inhibitors or from novel compounds targeting the T315I mutation. Considering the central role of the molecular techniques for the management of patients with ALL, efforts should be made to facilitate and harmonize immunophenotyping, cytogenetics, and molecular mutation screening. Furthermore, the potential of high-throughput sequencing should be evaluated for diagnosis and follow-up of patients with B-lineage ALL

Investigation of the kinetic regularities of the reaction of dry reforming of methane using nickel-containing catalysts based on cerium-zirconium oxides

In this study, we performed an investigation of the kinetics of the reaction of dry reforming of methane (DRM). For this work we used nickel-containing cerium-zirconium oxides. The catalysts were prepared in supercritical iso-propanol and characterized by means of XRD, TEM, XPS. It was found that the rate of DRM reaction becomes first order in methane and zero order in carbon dioxide. The dependences of the conversions of the reactants and product yields were obtained as a function of the contact time and the concentration of the initial mixture. In addition, the effective activation energy was calculated. It was shown that the most active and stable catalyst is 5wt% Ni/Ce0.5Zr0.5O[2]