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We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET-2) tended to be more common (P = 0·1078). Five-year progression-free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49–1·47] and overall survival (HR = 0·85; 95% CI = 0·49–1·51) did not differ between the groups after study treatment with PET-2-guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET-2-guided escalated BEACOPP.
Non-standard errors
(2021)
In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in sample estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: non-standard errors. To study them, we let 164 teams test six hypotheses on the same sample. We find that non-standard errors are sizeable, on par with standard errors. Their size (i) co-varies only weakly with team merits, reproducibility, or peer rating, (ii) declines significantly after peer-feedback, and (iii) is underestimated by participants.
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.
Aim: To evaluate the ability of PillCamColon2 to visualize colonic segments missed by incomplete optical colonoscopy (OC) and to assess the diagnostic yield.
Methods: This prospective multicentre study included 81 patients from nine centres who underwent second-generation colon capsule endoscopy (CCE) following incomplete OC performed by an experienced gastroenterologist (> 1000 colonoscopies). Patients with stenosis were excluded. According to patient preferences, CCE was performed the following day (protocol A) after staying on clear liquids and 0.75 L Moviprep in the morning or within 30 d after new split-dose Moviprep (protocol B). Boosts consisted of 0.75 L and 0.25 L Moviprep, and phospho-soda was given as a rescue if the capsule was not excreted after seven hours.
Results: Seventy-four patients were analysed (51% of them in group A; 49% in group B). Bowel cleansing was adequate in 67% of cases, and CCE could visualize colonic segments missed by incomplete colonoscopy in 90% of patients under protocol A and 97% of patients under protocol B (P = 0.35, n.s.). Significant polyps including adenocarcinoma were detected in 24% of cases. Detection rates for all polyps and significant polyps per patient were similar in both protocols. Polyps were found predominantly in the right colon (86%) in segments that were not reached by OC. Extracolonic findings - such as reflux esophagitis, suspected Barrett esophagus, upper GI-bleeding, gastric polyps, gastric erosions and angiectasia - were detected in eight patients. PillCamColon2 capsule was retained in the ileum of one patient (1.4%) without symptoms and removed during an uneventful resection for unknown Crohn’s disease that was diagnosed as the cause of anemia, which was the indication for colonoscopy. CCE was well tolerated. One patient suffered from self-limiting vomiting after consuming the phospho-soda.
Conclusion: Second-generation CCE using a low-volume preparation is useful after incomplete OC, and it allows for the detection of additional relevant findings, but cleansing efficiency could be improved.
In dieser Studie wird der Einfluss überwiegend historischer atmosphärischer Flugaschedepositionen auf physikalische Eigenschaften von Waldböden und insbesondere deren Humusauflagen untersucht. Es werden sechs Leitprofile der Region Oberlausitz mit und ohne Flugascheanreicherungen vorgestellt. Die flugascheangereicherten Standorte sind geprägt durch 1,0 bis 1,5 dm mächtige Durchmischungshorizonte (Humusauflage mit Flugasche), die extrem stark durchwurzelt sind. Die reinen Humusauflagen sind geringmächtiger (< 0,6 dm) und auch weniger stark durchwurzelt. Im Vergleich mit reinen Humusauflagen zeigen die flugascheangereicherten zum Teil signifikant höhere Luftkapazitäten, gesättigte Wasserleitfähigkeiten und Festsubstanzdichten, wohingegen emittentennah die nutzbaren Feldkapazitäten geringer sind. Für die flugascheangereicherten Standorte wurden mineralische Flugascheanreicherungen von 150 bis 280 t/ha berechnet, wobei emittentennähere Standorte höhere Werte aufweisen. Zeitweise Vernässung und anstehendes Ausgangsgestein schränken die Durchwurzelbarkeit stark ein. Die nutzbare Feldkapazität des effektiven Wurzelraums nFKWe ist daher deutlich von den Eigenschaften der Auflagen und des Oberbodens geprägt. Die flugascheangereicherten Humusauflagen stellen 20 bis 42% der nFKWe, die reinen Humusauflagen nur 8 bis 16%.
Naturschutzorganisationen, wie die Umweltstiftung World Wide Fund for Nature (WWF) -Deutschland und die Deutsche Sektion der Föderation der Natur- und Nationalparke Europas (FÖNAD), fordern seit Jahren die Anerkennung eines eigenständigen Berufsbildes "Schutzgebietsbetreuer/in" und die Schaffung einer einheitlichen Aus- und Fortbildungsregelung für die hauptamtlichen Naturwachtmitarbeiter in den Großschutzgebieten der Bundesrepublik Deutschland [Fleckenstein 1995, FÖNAD 1992a). Seit geraumer Zeit bemüht sich auch das Land Sachsen-Anhalt um die Ausbildung entsprechenden Personals für seine Großschutzgebiete (vgl. Kison; Wegener 1996). In diesem Zusammenhang beantragte die Umweltakademie Sachsen-Anhalt e.V. im vergangenen Jahr beim Ministerium für Raumordnung, Landwirtschaft und Umwelt (MRLU) die Förderung eines Projektes, das unter Berücksichtigung des bundesweiten Diskussionsstandes Empfehlungen für Mindestanforderungen an die Qualität der Fort- und Weiterbildung erarbeiten sollte.
Die Verknüpfung des Fahrrades mit dem Öffentlichen Verkehr (ÖV) kann den Umweltverbund stärken, den Übergang von einem Verkehrssystem auf das andere erleichtern und eine attraktive Alternative zum motorisierten Individualverkehr schaffen. Die vorliegende Arbeit repräsentiert den zweiten umfassenden Projektbericht innerhalb des Forschungsprojektes „Verbesserte Integration des Fahrrads in den öffentlichen Verkehr – Systematische Erschließung von Handlungsoptionen und Bewertung von Best-Practices“. Im ersten Projektbericht (ebenfalls in dieser Arbeitspapierreihe erschienen – Nr. 15) wurden die Entwicklungen der letzten Jahre in den infrastrukturellen Themenfeldern Fahrradmitnahme, Fahrradverleihsysteme und Fahrradabstellanlagen aufgearbeitet und Fragen zu Kommunikation und Marketing der Angebote sowie zu Möglichkeiten der fortschreitenden Digitalisierung zur verbesserten Integration von Fahrrad und Öffentlichem Verkehr diskutiert. Darauf aufbauend werden im vorliegenden Bericht die Ergebnisse vertiefender Fallstudien dargestellt, mit dem Ziel, Erfolgsfaktoren und Hemmnisse für die Integration von Fahrrad mit Öffentlichem Verkehr aufzuzeigen und in einem späteren Schritt daraus Handlungsempfehlungen zur Stärkung dieser Integration für Kommunen und Verkehrsanbieter geben zu können. Für die Fallstudien wurden solche Beispiele ausgewählt, die einen Vorbildcharakter haben und als nachahmenswert für andere Städte und Regionen gelten können bzw. aus denen sich Erkenntnisse für die Stärkung der Integration von Fahrradverkehr mit dem ÖV ziehen lassen. Zudem sollten die verschiedenen infrastrukturellen Themenfelder abgedeckt sein. Neben einer Darstellung der jeweils fallspezifischen Besonderheiten wird zu jedem Fallbeispiel das Betreiber- und Geschäftsmodell dargestellt und es erfolgt eine Bewertung, die sowohl die Sicht der Betreiber als auch die der Nutzenden beachtet.
Folgende Fallbeispiele werden behandelt:
Die hessischen Verkehrsverbünde Rhein-Main-Verkehrsverbund (RMV) und Nordhessischer Verkehrsverbund (NVV) bieten eine kosten- und sperrzeitfreie Mitnahmeregelung für Fahrräder an.
Das MVGmeinRad Mainz ist als Fahrradverleihsystem ein Teil des kommunalen ÖPNV-Unternehmens.
Zu den Fahrradabstellanlagen an Bahnhöfen wurden in der Fallstudie drei unterschiedlich große Anlagen einbezogen: Dein Radschloss des Verkehrsverbundes Rhein-Ruhr (VRR) für kleine, das Radhaus Offenburg für mittelgroße und die Radstation Düsseldorf für große Standorte.
München wurde schließlich für eine kommunale Strategie zur verbesserten Verknüpfung von Fahrrad und Öffentlichem Verkehr ausgewählt, da dort eine Vielzahl von Maßnahmen zur Stärkung der Fahrradmobilität sichtbar sind.
Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases
(2016)
Anti-angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716’s FcRn and FccR binding sites disabled the antibodies’ Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential nextgeneration therapy for neovascular indications of the eye.
Simple Summary: Currently, it is unclear which kind of axillary staging surgery breast cancer patients with lymph node metastasis should receive after neoadjuvant chemotherapy. For decades, these patients have been treated with a full axillary lymph node dissection, even if they converted to clinical node negativity. However, the removal of a large number of lymph nodes during the procedure can increase arm morbidity and impact quality of life. Therefore, several studies investigated less radical surgical strategies in this setting, such as sentinel lymph node biopsy or targeted axillary dissection, i.e., removal of a previously marked node combined with sentinel node removal. In this review, we summarize current evidence on the different surgical techniques and compare national and international recommendations. We show that many questions regarding oncological safety of different surgery types and the optimal marking technique remain unanswered and present the multinational prospective cohort study AXSANA that will address these open issues.
Abstract: In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical).
Geometrical frustration among interacting spins combined with strong quantum fluctuations destabilize long-range magnetic order in favor of more exotic states such as spin liquids. By following this guiding principle, a number of spin liquid candidate systems were identified in quasi-two-dimensional (quasi-2D) systems. For 3D, however, the situation is less favorable as quantum fluctuations are reduced and competing states become more relevant. Here we report a comprehensive study of thermodynamic, magnetic and dielectric properties on single crystalline and pressed-powder samples of PbCuTe2O6, a candidate material for a 3D frustrated quantum spin liquid featuring a hyperkagome lattice. Whereas the low-temperature properties of the powder samples are consistent with the recently proposed quantum spin liquid state, an even more exotic behavior is revealed for the single crystals. These crystals show ferroelectric order at TFE ≈ 1 K, accompanied by strong lattice distortions, and a modified magnetic response—still consistent with a quantum spin liquid—but with clear indications for quantum critical behavior.
Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.
Die FOURIER-Nullkomponente der Bindungsmatrix Gij G(0) in 1 Beziehung (5.16) wurde durch Summation spezieller Diagramme in der sogen. „Kettenapproximation“ und der „Wassermelonenapproximation“ näherungsweise berechnet. Auf der Basis von (5.16) in 1 wurde in der Kettenapproximation und der Wassermelonenapproximation die magnetische Suszeptibilität und die Magnetisierung des dreidimensionalen ISING-Modells bestimmt. In der Kettenapproximation wurden ferner die freie Energie, die innere Energie und die Atomwärme des dreidimensionalen ISING-Ferromagneten sowie die Druck-Dichte-Isothermen des dreidimensionalen Gittergases ausgerechnet.
The ion-molecule reactions of thiothionylfluoride have been studied by ion cyclotron resonance spectrometry. The major secondary ions are S2F3+ , S3F+ , and S3F2+. In a consecutive reaction of S3F2+ the tertiary ion S4F2+ is formed. The rate constant of the IMR with the greatest yield S2F2+ + SSF2 → S3F2+ + SF was estimated to k = 2 · 10-9 cm 3 molecule -1 sec -1 . The results were compared with the mass spectrum of thiothionylfluoride. They permit conclusions on chemical reactions of lower sulphurfluorides.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.
Die „Selbstenergien“ Gn in 1 wurden durch näherungsweise Auswertung einer größeren Klasse von Selbstenergiediagrammen approximativ berechnet. Das Gleichungssystem (3.3) in 1 für die renormierten Semiinvarianten wurde umgeformt und durch zusätzliche Näherungsannahmen vereinfacht. Durch Näherungsansätze für die Semiinvarianten M2, M3,... konnten einfache Gleichungen für die Magnetisierung M1 hergeleitet werden. Diese Gleichungen wurden numerisch gelöst. Auf der Grundlage der Beziehungen (3.5) und (4.8) in 1 wurden ferner die innere Energie, die freie Energie und die Atomwärme des zweidimensionalen Ising-Ferromagneten sowie die Druck-Dichte-Isothermen des zweidimensionalen Gittergases numerisch ausgerechnet.
The mass spectrum and the ion molecule reactions of phosphirane and of mixtures of phosphirane with NH3 , NH2D, NHD2 and ND3 have been studied by ion cyclotron resonance spectrometry. Almost all important product ions are formed by PH-group transfer reactions, where ethene is generated as the neutral particle. Only two of the more abundant ions, the protonated molecule, H2P(CH2)2+ and the ion m/e=63, P2H+, are formed via other reaction pathways. Secondary, tertiary and quarternary product ions with the general formula R(PH)n+ (R: phosphirane fragment, n-1, 2, 3) have been detected.
The molecular ion is proved to have a cyclic structure. Two possible structures of the product ions with two and three phosphorus atoms are discussed: a structure with an open phosphorus chain, leaving the phosphirane ring intact and a ring extended structure, produced by a ring extension reaction of the PH-group.
Several rate constants of the ion molecule reactions of the phosphirane molecular ion are given.