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ZusammenfassungAnhand des von der Deutschen Forschungsgemeinschaft (DFG) geförderten Projekts „Digitalisierung des Darmstädter Tagblatts“ (DDAT) wird ein Workflow für die Digitalisierung komplexer und umfangreicher Periodika vorgestellt. Das Projekt wird in Kollaboration zwischen der Universitäts- und Landesbibliothek Darmstadt (ULB) und dem Institut für Sprach- und Literaturwissenschaften der Technischen Universität Darmstadt (TU Darmstadt) durchgeführt. Die Arbeitsschritte umfassen dabei die Bild-Erstellung vom Original, die digitale Weiterverarbeitung bis hin zum maschinenlesbaren Volltext mit linguistischen Basisannotationen, die öffentlich zugängliche Präsentation im Internet und die ausführliche Recherche nach Rechteinhabern einzelner Artikel und Fotografien wie sie in §§ 61 ff. UrhG vorgeschrieben ist („sorgfältige Suche“).

Acute graft-versus-host disease is a frequent complication associated with allogeneic hematopoietic stem cell transplantation. Patients that become refractory to initial steroid treatment have a poor prognosis. apceth-201 consists of human allogeneic mesenchymal stromal cells, engineered by lentiviral transduction to express the protease inhibitor alpha-1 antitrypsin, to augment the anti-inflammatory potential of the mesenchymal stromal cells. We show that apceth-201 mesenchymal stromal cells efficiently suppress T cell proliferation and polarize macrophages to an anti-inflammatory M2 type, in vitro. To assess the in vivo efficacy of apceth-201, it was tested in two different mouse models of acute graft-versus-host disease. Control animals in a humanized model succumbed quickly to disease, whereas median survival was doubled in apceth-201-treated animals. The product was also tested in a graft-versus-host disease model system that closely mimics haploidentical hematopoietic stem cell transplantation, an approach that is now being evaluated for use in the clinic. Control animals succumbed quickly to disease, whereas treatment with apceth-201 resulted in long-term survival of 57% of the animals. Within 25 days after the second injection, clinical scores returned to baseline in responding animals, indicating complete resolution of graft-versus-host disease. These promising data have led to planning of a phase I study using apceth-201.

Chimeric antigen receptor (CAR) redirected T cells are efficacious in the treatment of leukemia/lymphoma, however, showed less capacities in eliminating solid tumors which is thought to be partly due to the lack of cytokine support in the tumor lesion. In order to deliver supportive cytokines, we took advantage of the inherent ability of mesenchymal stem cells (MSCs) to actively migrate to tumor sites and engineered MSCs to release both IL7 and IL12 to promote homeostatic expansion and Th1 polarization. There is a mutual interaction between engineered MSCs and CAR T cells, in presence of CAR T cell released IFN-&gamma, and TNF-&alpha, chronic inflammatory Th2 MSCs shifted towards a Th17/Th1 pattern with IL2 and IL15 release that mutually activated CAR T cells with extended persistence, amplification, killing and protection from activation induced cell death. MSCs releasing IL7 and IL12 were superior over non-modified MSCs in supporting the CAR T cell response and improved the anti-tumor attack in a transplant tumor model. Data demonstrate the first use of genetically modified MSCs as vehicles to deliver immuno-modulatory proteins to the tumor tissue in order to improve the efficacy of CAR T cells in the treatment of solid malignancies.

Phrasal compounds are taken to be word-level structures that combine a lexical head with a phrasal non-head. Several claims have emerged from the pertinent literature: phrasal compounds allegedly only have nominal heads, can host a variety of syntactic structures in non-head position, are determinative, and are instances of expressive morphology. The existence of adjectival phrasal compounds is either explicitly denied in the literature, or considered a marginal phenomenon at best. This article presents data from theCorpus of Contemporary American English(COCA; Davies 2008) that show that adjectival phrasal compounds do exist in English. We demonstrate that they are similar to non-phrasal adjectival compounds and to nominal phrasal compounds. At the same time, they crucially differ from nominal compounds in the prototypical semantic relations between head and non-head: adjectival phrasal compounds are mostly similative-intensifying as opposed to determinative. We argue that this property is also found in noun–adjective compounds and follows naturally from the semantics of the head category in question, viz. adjectives as mostly gradable predicates. In turn, the majority of adjectival phrasal compounds in our data feature a strong expressive component, a characteristic they share with other phrasal compounds.

In English, the position of the AP in the nominal phrase is determined by its form: only structurally simpler phrases are said to be licit in prenominal position, more complex ones have to follow the noun. Recent studies have reported an increasing use of nominal premodifiers in English, so the question arises whether this trend affects only simpler phrases or whether a new structural option emerges – complex APs in prenominal position. Drawing on data from COHA, this article investigates which types of AP occur prenominally. The data show that certain types of complex APs are gaining ground in the prenominal position. Most of these can be analyzed as complex words rather than complex phrases and hence do not indicate major syntactic changes in the English NP. However, some of the attestations, such as easy-predicates with a to-infinitival clause, are complex phrases. It is argued that it is the dependency relation between their rightmost element, a lexical verb, and the noun they modify which makes them occur in prenominal position.

// Jobst C. von Einem 1 , Sylvia Peter 2 , Christine Gunther 2 , Hans-Dieter Volk 3 , Gerald Grutz 3 , Christoph Salat 4 , Oliver Stoetzer 4 , Peter J. Nelson 5 , Marlies Michl 1 , Dominik P. Modest 1 , Julian W. Holch 1 , Martin Angele 6 , Christiane Bruns 7 , Hanno Niess 6,* and Volker Heinemann 1,* 1 Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, LMU, Munich, Germany 2 Apceth GmbH & Co. KG, Munich, Germany 3 Institute for Medical Immunology and Berlin-Brandenburg Center for Regenerative Medicine, Charite-Universitatsmedizin, Berlin, Germany 4 Haemato-Onkologische Schwerpunktpraxis Prof. Salat, Dr. Stoetzer, Munich, Germany 5 Department of Medicine IV, University Hospital of Munich, LMU, Munich, Germany 6 Department of Surgery, University Hospital Grosshadern, LMU, Munich, Germany 7 General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany * These authors have contributed equally to this article Correspondence to: Jobst C. von Einem, email: // Keywords : mesenchymal stem cells, gastrointestinal cancer, CCC, CRC, GDEPT Received : May 10, 2017 Accepted : August 26, 2017 Published : September 16, 2017 Abstract Purpose: This phase I, first in human, first in class clinical study aimed at evaluating the safety, tolerability and efficacy of treatment with genetically modified mesenchymal stromal cells (MSC) in combination with ganciclovir (GCV). MSC_apceth_101 are genetically modified autologous MSCs used as vehicles for a cell-based gene therapy in patients with advanced gastrointestinal adenocarcinoma. Experimental design: The study design consisted of a dose-escalation 3 + 3 design. All patients ( n = 6) were treated with up to three applications of MSC_apceth_101, followed by GCV infusions given on three consecutive days starting 48 hours after injection of MSC_apceth_101. Three of six patients received a total dose of 1.5 × 10 6 cells/kg. Two patients received three doses of 1 × 10 6 cells/kg, while one patient received only two doses of 1 × 10 6 cells/kg due to a SADR. Results: Six patients received MSC_apceth_101. No IMP-related serious adverse events occurred. Adverse-events related to IMP-injection were increased creatinine, cough, fever, and night sweat. TNF, IL-6, IL-8, IL-10 and sE-Selectin, showed that repeated application is immunologically safe, but induces a switch of the functional properties of monocytes to an inflammatory phenotype. Treatment induced stable disease in 4/6 patients, and progressive disease in 2/6 patients. Conclusion: Treatment with MSC_apceth_101 in combination with GCV demonstrated acceptable safety and tolerability in patients with advanced gastrointestinal adenocarcinoma.

The integrity of the vasculature plays an important role in the success ofallogeneic organ and haematopoietic stem cell transplantation. Endothelial cells(EC) have previously been shown to be the target of activated cytotoxic Tlymphocytes (CTL) resulting in extensive cell lysis. Mesenchymal stromal cells(MSC) are multipotent cells which can be isolated from multiple sites, eachdemonstrating immunomodul atory capabilities. They are explored herein fortheir potential to protect EC from CTL-targeted lys is. CD8+T cells isolated fromhuman PBMC were stimulated with mitotically inactive cells of a humanmicrovascular endothelial cell line (CDC/EU.HMEC-1, further referred to asHMEC) for 7 days. Target HMEC were cultured in the presence or absence ofMSC for 24 h before exposure to activated allogeneic CTL for 4 h. EC were thenanalysed for cytotoxic lysis by flow cytometry. Culture of HMEC with MSC inthe efferent immune phase (24 h before the assay) led to a decrease in HMEClysis. This lysis was determined to be MHC Class I restricted linked and furtheranalysis suggested that MSC contact is important in abrogation of lysis, asprotection is reduced where MSC are separated in transwell experiments. Theefficacy of multiple sources of MSC was also confirmed, and the collaborativeeffect of MSC and the endothelium protective drug defibrotide were determined,with defibrotide enhancing the protection provided by MSC. These resultssupport the use of MSC as an adjuvant cellular therapeutic in transplantmedicine, alone or in conjunction with EC protective agents such as defibrotide. Science Foundation Ireland Bayerische Forschungsstiftung (Bavarian Research Foundation) Wilhelm Sander Foundation Servier Laboratories

Measles virus (MV) infection may lead to severe chronic CNS disease processes, including MV-induced encephalitis. Because the intracellular Ca(2+) concentration ([Ca(2+)](i)) is a major determinant of the (patho-)physiological state in all cells we asked whether important Ca(2+) conducting pathways are affected by MV infection in cultured cortical rat neurons. Patch-clamp measurements revealed a decrease in voltage-gated Ca(2+) currents during MV-infection, while voltage-gated K(+) currents and NMDA-evoked currents were unaffected. Calcium-imaging experiments using 50mM extracellular KCl showed reduced [Ca(2+)](i) increases in MV-infected neurons, confirming a decreased activity of voltage-gated Ca(2+) channels. In contrast, the group-I metabotropic glutamate receptor (mGluR) agonist DHPG evoked changes in [Ca(2+)](i) that were increased in MV-infected cells. Our results show that MV infection conversely regulates Ca(2+) signals induced by group-I mGluRs and by voltage-gated Ca(2+) channels, suggesting that these physiological impairments may contribute to an altered function of cortical neurons during MV-induced encephalitis.

This article analyses adjectival modification in elliptical NPs based on a corpus analysis. It illustrates the fact that descriptive adjectives can be used without nominal heads in English. Whereas in spoken language adjectives denoting more inherent properties feature prominently when the referents are present in the text-external world, no particular types of adjectives appear in written language. In terms of the latter, two major types of linguistic contexts are identified which do not require the use of a nominal head. It is argued that a conception of ‘contrast’ as a ‘non-identity’ condition cannot account for the variation betweenone-replacement and noun ellipsis since it holds for both phenomena. Similarly, partitivity is argued not to be a relevant requirement for the use of adjectives without nouns.

The development of nonviral gene delivery systems is a great challenge to enable safe gene therapy. In this study, ligand-modified nanoparticles based on human serum albumin (HSA) were developed and optimized for an efficient gene therapy. Different glutaraldehyde cross-linking degrees were investigated to optimize the HSA nanoparticles for gene delivery. The peptide sequence arginine-glycine-aspartate (RGD) and the HIV-1 transactivator of transduction sequence (Tat) are well-known as promising targeting ligands. Plasmid DNA loaded HSA nanoparticles were covalently modified on their surface with these different ligands. The transfection potential of the obtained plasmid DNA loaded RGD- and Tat-modified nanoparticles was investigated in vitro, and optimal incubation conditions for these preparations were studied. It turned out that Tat-modified HSA nanoparticles with the lowest cross-linking degree of 20% showed the highest transfection potential. Taken together, ligand-functionalized HSA nanoparticles represent promising tools for efficient and safe gene therapy.

INTRODUCTION In addition to its effects on platelet function, recent studies suggest that inhaled nitric oxide (NO) also influences the function of circulating leukocytes. Therefore, the aim of this work was to investigate the formation of platelet-leukocyte aggregates (PLAs) and platelet and leukocyte cell surface receptor expression during NO therapy in patients with acute respiratory distress syndrome. METHODS In 16 patients responding to NO therapy with an improvement in oxygenation (NO group) and in four nonresponders (control), platelet P-selectin expression, platelet fibrinogen binding, the expression CD11a on leukocytes, and the formation of PLAs were investigated at 0, 60, 120, and 180 mins of therapy or at corresponding time points by means of flow cytometry. In addition, PLA was investigated in 30 healthy volunteers during NO inhalation, in five mechanically ventilated patients without acute respiratory distress syndrome and without NO inhalation, and during NO incubation in platelet-rich plasma of ten healthy volunteers in vitro. RESULTS NO therapy inhibited PLA formation at 60 (13% +/- 4% in the NO group vs. 19% +/- 7% in the control group, p

Imatinib induces remissions in approximately 30% of patients with chronic myeloid leukemia (CML) in myeloid blast crisis (M-BC). Because most patients eventually relapse, allogeneic stem cell transplantation (SCT) in remission offers the best chance for cure. Remission induction with imatinib alone would seem ideal because it is less toxic than conventional chemotherapy. Conversely, patients unlikely to respond may benefit from combination therapy up front. To identify prognostic factors, we studied the mRNA expression of genes related to drug resistance and apoptosis in leukemic cells from patients with M-BC and their in vitro sensitivity to imatinib, and analyzed the results with other baseline factors for their impact on response. We show that high levels of BAX, low levels of MRP-1, and a high platelet count are independently predictive of response to imatinib. Combined into a score, these parameters may be clinically useful for risk-adapted patient stratification.

Background Adenocarcinoma originating from the digestive system is a major contributor to cancer-related deaths worldwide. Tumor recurrence, advanced local growth and metastasis are key factors that frequently prevent these tumors from curative surgical treatment. Preclinical research has demonstrated that the dependency of these tumors on supporting mesenchymal stroma results in susceptibility to cell-based therapies targeting this stroma. Methods/Design TREAT-ME1 is a prospective, uncontrolled, single-arm phase I/II study assessing the safety and efficacy of genetically modified autologous mesenchymal stromal cells (MSC) as delivery vehicles for a cell-based gene therapy for advanced, recurrent or metastatic gastrointestinal or hepatopancreatobiliary adenocarcinoma. Autologous bone marrow will be drawn from each eligible patient after consent for bone marrow donation has been obtained (under a separate EC-approved protocol). In the following ~10 weeks the investigational medicinal product (IMP) is developed for each patient. To this end, the patient’s MSCs are stably transfected with a gamma-retroviral, replication-incompetent and self-inactivating (SIN) vector system containing a therapeutic promoter - gene construct that allows for tumor-specific expression of the therapeutic gene. After release of the IMP the patients are enrolled after given informed consent for participation in the TREAT-ME 1 trial. In the phase I part of the study, the safety of the IMP is tested in six patients by three treatment cycles consisting of re-transfusion of MSCs at different concentrations followed by administration of the prodrug Ganciclovir. In the phase II part of the study, sixteen patients will be enrolled receiving IMP treatment. A subgroup of patients that qualifies for surgery will be treated preoperatively with the IMP to verify homing of the MSCs to tumors as to be confirmed in the surgical specimen. Discussion The TREAT-ME1 clinical study involves a highly innovative therapeutic strategy combining cell and gene therapy and is conducted at a high level of pharmaceutical quality ensuring patient safety. This patient-tailored approach represents the first clinical study worldwide utilizing genetically engineered MSCs in humans. Trial registration EU Clinical Trials Register/European Union Drug Regulating Authorities Clinical Trials Database number: 2012-003741-15

It has previously been shown that a combination of macrophage inflammatory protein-1alpha (MIP-1alpha) and interleukin (IL)-3 maintained human bone marrow (BM)-derived long-term culture-initiating cells (LTC-IC) for at least 8 weeks in vitro. We investigated colony- and cobblestone area-formation potential of peripheral blood progenitor cells (PBPC) at week 6 of long-term culture (LTC) in the absence of exogenous MIP-1alpha. but using cells which had been pre-incubated in the presence of MIP-1alpha for 40 h in liquid culture. The recovery of colony-forming cells (CFC) and cobblestone-area-forming cells (CAFC) after pre-incubation of PBPC with MIP-1alpha was up to threefold higher (P

N,N-Diethyl-1,2-O-isopropyliden-3,5-di-O-mesyl-α-D-glucofuranuronsaureamid (2b) reagiert mit Azid-Ionen unter SN2-Substitution und Inversion am C-5 zur L-ido-Verbindung 3. Eine Nachbargruppenreaktion der N,N-Diethylcarboxamidgruppe, wie sie beim Einsatz von Acetat-Ionen beobachtet wird, tritt nicht ein. Die Konfiguration von 3 wurde durch Rontgenstrukturanalyse bestimmt. Die Elementarzelle der Kristalle von 3 enthalt zwei symmetrie-unabhangige Molekule, die unterschiedliche Konformationen aufweisen. Der Furanosering zeigt in einem Molekul eine E4- im anderen eine 3T4-Konformation. Die Aminonitrilsynthese des D-ribo-Aldehyds 8 liefert ein 1:1-Gemisch der D-allo- und L-talo-Aminonitrile 10a und 11a. Monosaccharides Containing Nitrogen in the Ring, XXXV. Investigations into the Synthesis of 5-Amino-5-deoxyhexuronic Acids The reaction of N,N-diethyl-1,2-O-isopropylidene-3,5-di-O-mesyl-α-D-glucofuranuronamide (2b) with azide ions proceeds via an SN2 substitution with inversion at C-5 and yields the L-ido derivative 3. A neighbouring-group participation of the N,N-diethylcarboxamide group does not occur, as observed by the application of acetate ions. The configuration of 3 was determined by X-ray structure analysis. The crystals of 3 have two symmetrically independent molecules per unit, each of them having different conformations. The furanoid rings correspond with the E4 conformation and with the 3T4 conformation, respectively. The aminonitrile synthesis of the D-ribo aldehyde 8 yields a 1:1 mixture of D-allo- and L-talo-aminonitriles 10a and 11a.

Adrenergic stimulation of the adenylate cyclase (AC)-cAMP-system and 14C-aminopyrine accumulation, an indirect measure of parietal cell H+-production, was studied in a different preparations of gastric mucosal cells. The beta 2-adrenoceptor agonist hexoprenaline activated AC of crude homogenates from the gastric corpus of mouse, rat, guinea-pig, hog, dog and man. In isolated rat gastric cells (20% parietal cells), treated by low power sonication, 10(-8) to 10(-3) mol/l adrenaline and hexoprenaline activated AC equally potently and efficaciously by maximally 170%. Isoprenaline proved to be less effective activating up to 80%. 5.10(-5) mol/l GMP-PNP augmented basal activity 8.5 times and reduced the maximal efficacy. Adrenaline and hexoprenaline activated AC by maximally 120%, isoprenaline by 40%. The potency of adrenaline was 4 times lower, that of hexoprenaline 2 and that of isoprenaline 4 times higher in the presence of GMP-PNP. Adrenergic stimulation was inhibited by the beta-adrenoceptor antagonist propranolol, the effect of alpha-adrenoceptor-blockade by phenoxybenzamine was less pronounced. In fractions with 7-80% of parietal cells, prepared by isopycnic centrifugation with Percoll, adrenaline and hexoprenaline activated AC or hexoprenaline enhanced the cellular levels of cAMP in parietal cell poor and rich fractions. The degree of activation in response to histamine correlated with the number of parietal cells. 14C-Aminopyrine uptake was increasingly stimulated through 10(-8) to 10(-5) mol/l hexoprenaline, maximally by doubling the basal accumulation. 10(-4) mol/l histamine was 8 times more effective. 3.10(-7) mol/l propranolol inhibited the effect of 10(-5) mol/l hexoprenaline by 80%. The data suggest the localization of beta-adrenoceptors (likely beta 2-adrenoceptors) on parietal and other nonidentified gastric cells. At the parietal cell, adrenaline and hexoprenaline initiate activation of AC and hexoprenaline leads to H+-production. The responses are small compared to the effect of histamine. Thus, beta-adrenoceptor agonists exert intrinsic activity in relation to H+-production. Their influence on stimulated secretion of isolated cells remains to be elucidated.