Adoptive Immunotherapy in Chimeras with Donor Lymphocytes

Allogeneic stem cell transplantation has a well-defined indication in the treatment of hematological malignancies. The beneficial immune effect of allogeneic marrow transplantation has long been known, but only recently have methods been developed to separate the graft-versus-leukemia (GVL) effect from graft-versus-host disease (GVHD). Animal experiments have shown that lymphocytes from the marrow donor can be transfused without causing severe GVHD if stable chimerism and tolerance is established. First clinical studies have been preformed in patients with recurrent chronic myelogenous leukemia. In these patients complete molecular remissions were induced that persist without further maintenance treatment. These results have been confirmed in larger multicenter studies in Europe and the USA. The best results were obtained in chronic myelogenous leukemia (CML); repeated successes have been reported in relapsing acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma (MMY), and rare responses were reported for acute lymphoid leukemia. Contrary to animal experiments GVHD has been observed in human patients although to a lesser extent than expected in transplants not given immunosuppression. Secondly myelosuppression has been observed in patients treated with relapsing CML. In CML the incidence of GVHD could be reduced by depleting CD8(+) T cells from the donor lymphocyte concentrate. Alternatively only small numbers of T lymphocytes can be transfused and in the case of failing responses, the numbers of donor lymphocytes may be increased. Results in recurrent AML have been improved by the use of low-dose cytosine arabinoside, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor mobilized blood cells as compared to lymphocytes only. In MMY the response rate is higher than in AML, but the remissions are of limited duration in most patients. Several protocols have been designed to include preemptive donor lymphocyte transfusion in patients with a high relapse risk after transplantation. Problems remain to avoid chronic GVHD and to circumvent the immune escape mechanisms of leukemia. Copyright (C) 2003 S. Karger AG, Basel

Expression of immune checkpoint molecules TIGIT and TIM-3 by tumor-infiltrating lymphocytes predicts poor outcome in sinonasal mucosal melanoma

Background: Sinonasal mucosal melanoma (SNMM) is a rare but aggressive tumor with a poor prognosis. The coinhibitory receptors T cell immunoglobulin and mucinodomain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3) and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) are promising new targets in anti-cancer immunotherapy. The expression profiles of these immune checkpoint molecules (ICMs) and potential prognostic implications have not been characterized in SNMM yet. Methods: Immunohistochemical staining for TIGIT, LAG-3 and TIM-3 was performed on tumor tissue samples from 27 patients with primary SNMM. Associations between ICM expression and demographic parameters, AJCC tumor stage, overall survival, and recurrence-free survival were retrospectively analyzed. Results: SNMM patients with low numbers of TIGIT+ and TIM-3+ tumor infiltrating lymphocytes (TILs) in the primary tumor survived significantly longer than patients with a high degree of TIGIT+ and TIM-3+ TILs. High infiltration with TIM-3+ or TIGIT+ lymphocytes was associated with the higher T4 stage and decreased 5-year survival. Conclusion: We identified high densities of TIM-3+ and TIGIT+ TILs as strong negative prognostic biomarkers in SNMM. This suggests that TIM-3 and TIGIT contribute to immunosuppression in SNMM and provides a rationale for novel treatment strategies based on this next generation of immune checkpoint inhibitors. Prospective studies with larger case numbers are warranted to confirm our findings and their implications for immunotherapy

Useful knowledge, 'industrial enlightenment', and the place of India

Research is now turning to the missing place of technology and ‘useful knowledge’ in the debate on the ‘great divergence’ between East and West. Parallel research in the history of science has sought the global dimensions of European knowledge. Joel Mokyr's recent The Enlightened Economy (2009) argued the place of an exceptional ‘industrial enlightenment’ in Europe in explaining industrialization there, but neglected the wide geographic framework of European investigation of the arts and manufactures. This article presents two case studies of European industrial travellers who accessed and described Indian crafts and industries at the time of Britain's industrial revolution and Europe's Enlightenment discourse on crafts and manufactures. The efforts of Anton Hove and Benjamin Heyne to ‘codify’ the ‘tacit’ knowledge of a part of the world distant from Europe were hindered by the English East India Company and the British state. Their accounts, only published much later, provide insight into European perceptions of India's ‘useful knowledge’

Investigation of hippocampal synaptic transmission and plasticity in mice deficient in the actin-binding protein Drebrin

The dynamic regulation of the actin cytoskeleton plays a key role in controlling the structure and function of synapses. It is vital for activity-dependent modulation of synaptic transmission and long-term changes in synaptic morphology associated with memory consolidation. Several regulators of actin dynamics at the synapse have been identified, of which a salient one is the postsynaptic actin stabilising protein Drebrin (DBN). It has been suggested that DBN modulates neurotransmission and changes in dendritic spine morphology associated with synaptic plasticity. Given that a decrease in DBN levels is correlated with cognitive deficits associated with ageing and dementia, it was hypothesised that DBN protein abundance instructs the integrity and function of synapses. We created a novel DBN deficient mouse line. Analysis of gross brain and neuronal morphology revealed no phenotype in the absence of DBN. Electrophysiological recordings in acute hippocampal slices and primary hippocampal neuronal cultures showed that basal synaptic transmission, and both long-term and homeostatic synaptic plasticity were unchanged, suggesting that loss of DBN is not sufficient in inducing synapse dysfunction. We propose that the overall lack of changes in synaptic function and plasticity in DBN deficient mice may indicate robust compensatory mechanisms that safeguard cytoskeleton dynamics at the synapse

uni-con² – universal concrete construction

Die Umsetzung der Ziele des DFG-Schwerpunktprogramms (SPP) 1542 „Leicht Bauen mit Beton – Grundlagen für das Bauen der Zukunft mit bionischen und mathematischen Entwurfsprinzipien“ erfordert eine Anpassung grundlegender, im Stahlbetonbau etablierter Konstruktionsformen. Ein Beispiel hierfür ist die Stahlbetonskelettbauweise. Aktuelle Konstruktionen weisen klare Strukturen aus Stützen, Unterzügen und Decken, im Regelfall mit rechteckigen, über die Bauteillänge konstanten Querschnitten auf. Um diese typischen Konstruktionen zu optimieren, können die im Rahmen des SPP 1542 an der TU Braunschweig entwickelten Bauteil-, Füge- und Herstellungstechnologien genutzt werden. Um dies exemplarisch zu zeigen, wurde der Demonstrator uni-con² entwickelt und hergestellt. Der Demonstrator stellt einen Ausschnitt eines innovativen Tragwerks aus Hochleistungsbeton dar, das aus Platten- und Stabelementen, die nach dem Prinzip „form follows force“ an die einwirkenden Beanspruchungen angepasst werden, zusammengesetzt wird (Bild 1). Die vorgefertigten Elemente werden trocken gefügt. So kann der Aufbau beschleunigt und eine direkte Belastung ermöglicht werden. Die Verwendung von Trockenfugen erfordert eine hohe Präzision bei der Herstellung der Bauteile. Dies kann durch den Einsatz von hochpräzise hergestellten Schalungen sichergestellt werden. Der symmetrische Aufbau der Tragkonstruktion sowie die gleichbleibenden Spannweiten ermöglichen die multiple Verwendung der komplexen Schalungen. In Kombination mit der Reduktion des Zementverbrauchs ermöglicht dies zudem die Einsparung von natürlichen Ressourcen und Energie.The implementation of the objectives of the DFG Priority Programme (SPP) 1542 “Concrete light – Future concrete structures using bionic, mathematical and engineering formfinding principles” requires the modification of fundamental structural forms established in reinforced concrete construction. An example of this is the reinforced concrete framework construction. Current constructions show distinct structures consisting of columns, beams and slabs, usually having rectangular cross-sections that are constant over the entire length of the component. In order to optimise these standard structures, the construction, joining and manufacturing technologies developed within the scope of SPP 1542 at Technical University (TU) Braunschweig can be used. The demonstrator uni-con² was developed and manufactured to exemplify this. The demonstrator represents a cutout of an innovative load-bearing structure made of high-performance concrete, which is composed of slab and beam elements designed according to the “form follows force” principle and adapted to the relevant stresses (Fig. 1). The prefabricated elements are joined dry. In this way the assembly can be accelerated and a direct loading can be made possible. The use of dry joints requires high precision in the production of the components. This can be achieved by high precision formwork. The symmetrical configuration of the structure and the constant spans allow the multiple use of the complex formwork. In combination with the reduction of cement consumption, this also enables the saving of natural resources and energy

Clonal karyotype evolution involving ring chromosome 1 with myelodysplastic syndrome subtype RAEB-t progressing into acute leukemia

s Karyotypic evolution is a well-known phenomenon in patients with malignant hernatological disorders during disease progression. We describe a 50-year-old male patient who had originally presented with pancytopenia in October 1992. The diagnosis of a myelodysplastic syndrome (MDS) FAB subtype RAEB-t was established in April 1993 by histological bone marrow (BM) examination, and therapy with low-dose cytosine arabinoside was initiated. In a phase of partial hernatological remission, cytogenetic assessment in August 1993 revealed a ring chromosome 1 in 13 of 21 metaphases beside BM cells with normal karyotypes {[}46,XY,r(1)(p35q31)/46,XY]. One month later, the patient progressed to an acute myeloid leukemia (AML), subtype M4 with 40% BM blasts and cytogenetic examination showed clonal evolution by the appearance of additional numerical aberrations in addition to the ring chromosome{[}46,XY,r(1),+8,-21/45,XY,r(1),+8,-21,-22/46, XY]. Intensive chemotherapy and radiotherapy was applied to induce remission in preparation for allogeneic bone marrow transplantation (BMT) from the patient's HLA-compatible son. After BMT, complete remission was clinically, hematologically and cytogenetically (normal male karyotype) confirmed. A complete hematopoietic chimerism was demonstrated. A relapse in January 1997 was successfully treated using donor lymphocyte infusion and donor peripheral blood stem cells (PB-SC) in combination with GM-CSF as immunostimulating agent in April 1997, and the patient's clinical condition remained stable as of January 2005. This is an interesting case of a patient with AML secondary to MDS. With the ring chromosome 1 we also describe a rare cytogenetic abnormality that predicted the poor prognosis of the patient, but the patient could be cured by adoptive immunotherapy and the application of donor's PB-SC. This case confirms the value of cytogenetic analysis in characterizing the malignant clone in hernatological neoplasias, the importance of controlling the quality of an induced remission and of the detection of a progress of the disease. Copyright (c) 2006 S. Karger AG, Basel

Magnetische Ausrichtung von Mikro- Stahldrahtfasern in UHPFRC

Ausgangspunkt für dieses Anschlussprojekt am Institut für Tragwerksplanung der TU Braunschweig war der Wunsch, die Effektivität des Faseranteils derjenigen Betonbauteile zu erhöhen, die zuvor im SPP-Projekt Entwicklung neuartiger Verbindungen für komplexe Stab-, Flächen- und Raumtragelemente aus UHPFRC (S. 50 ff . in diesem Buch) hergestellt und untersucht wurden. Voruntersuchungen und Versuche zum Thema der magnetische Faserausrichtung in UHPFRC werden am ITE seit 2014 kontinuierlich durchgeführt [1]–[4]. Diese Voruntersuchungen berührten bereits zentrale Aspekte dieses Forschungsvorhabens und lieferten konkrete Hinweise auf die zu erwartenden Ergebnisse zur robotergestützten, magnetischen Ausrichtung und Verteilung der Mikrostahlfasern (MSF). Im Fokus der Forschung standen zum einen die Möglichkeiten der digitalen und robotergestützten Bauteilfertigung und zum anderen das Potenzial der Faserausrichtung zur Steigerung der Materialeffizienz von UHPFRC. In der Entwicklung des Verfahrens der magnetischen Faserausrichtung (MFA) wurden diese beiden Ansätze zusammengeführt.The starting point for this follow-up project, which was carried out at the Institute of Structural Design at the Technical University of Braunschweig, was the desire to increase the effectiveness of the fibre content of the type of concrete components that were previously manufactured and investigated in the SPP project Development of novel jointing systems for complex beam surface and spatial elements made of UHPFRC (p. 50 et seq. in this book). Preliminary investigations and tests on the topic of magnetic fiber alignment in UHPFRC have been carried out continuously at ITE since 2014 [1]–[4]. These preliminary investigations already touched upon central aspects of this research project and provided concrete indications of the expected fi ndings on robot-assisted magnetic alignment and distribution of the micro steel fi bres (MSF). The research focused on the possibilities of digital and robot based component production on the one hand and the potential of fibre orientation to increase the material efficiency of UHPFRC on the other. In the development of the magnetic fibre alignment (MFA) process, these two approaches were brought together

Magnetic Alignment of Microsteel Fibers as Strategy for Reinforcing UHPFRC

The objective of this paper is to provide an insight into current basic research at ITE on the manufacturing process of resource-efficient components through the controlled, automated magnetic distribution and alignment of steel fibers in UHPFRC (Ultra-High Performance Fibre-Reinforced Concrete). The method for distributing and aligning steel fibers in UHPFRC is based on the physical phenomenon of magnetism. Since steel fibers are ferromagnetic, magnetic fields can selectively change their position in the fresh concrete and align them according to the force flow and the maxim "form follows force". The magnetic fiber alignment (MFA) process developed on this principle combines the capabilities of digital and automized component manufacturing with the potential of targeted fiber alignment to increase the material efficiency of UHPFRC. It is highlighted at four levels: UHPFRC At the material level, studies were conducted on the composite properties of different brand-new and recycled microsteel fibers (MSF), formwork designs suitable for the MFA process were developed, flux densities of different magnets were simulated with special software solutions and measured in practice, and an end effector was fabricated that was implemented on 3- and 6-axis kinematics. At the process level, the interaction of the main parameters of the MFA process was evaluated by visual analysis on transparent glucose syrup-based solutions, and series of specimens were analyzed by micro-CT scans. At the component level, centric tensile tests were performed on a wide variation of dog-bones to provide an assessment of the potential increase in tensile performance of UHPFRC by the MFA process. At an economic and environmental evaluation level, the results from the tensile tests were used to assess and quantify the potential savings from reducing the fiber content and using recycled steel fibers