Design and Structural Requirements of the Potent and Safe TLR-9 Agonistic Immunomodulator MGN1703

Single-stranded oligodeoxynucleotides (ODN), containing nonmethylated cytosine-guanine motifs (CpG ODN), are recognized by the innate immune system as "danger signals." CpG ODN are efficacious immunomodulators but require phosphorothioate (PT) or other backbone modifications for metabolic stability, which cause toxicities in mice and primates. We therefore designed a covalently closed DNA molecule (dSLIM ®) where two single-stranded loops containing CG motifs are connected through a double-stranded stem in the absence of any nonnatural DNA component. The most promising immunomodulator, MGN1703, comprises two loops of 30 nucleotides containing three CG motifs each, and a connecting stem stem of 28 base pairs. MGN1703 stimulates cytokine secretion [interferon (IFN)-α, IFN-γ, interleukin (IL)-12, IL-6, and IL-2] and activates immune cells by increased expression of CD80, CD40, human leukocyte antigen (HLA)-DR and ICAM-1. Efficacy of immunomodulation strictly depends on the descriptive dumbbell shape and size of the molecule. Variations in stem length and loop size lead to reduced potency of the respective members of the dSLIM ® class. In a representative mouse model, toxicities from injections of high amounts of a CpG ODN-PT and of MGN1703 were evaluated. The CpG ODN-PT group showed severe organ damage, whereas no such or other pathologies were found in the MGN1703 group. Oncological clinical trials of MGN1703 already confirmed our design

Antibiotic consumption and antimicrobial resistance in Poland; findings and implications

Background: The problem of inappropriate use of antibiotics and the resulting growth in antimicrobial resistance (AMR) has implications for Poland and the world. The objective of this paper was to compare and contrast antibiotic resistance and antibiotic utilisation in Poland in recent years versus other European countries, including agreed quality indicators, alongside current AMR patterns and ongoing policies and initiatives in Poland to influence and improve antibiotic prescribing. Methods: A quantitative ten-year analysis (2007-2016) of the use of antibiotics based on European Centre for Disease Prevention and Control (ECDC) data combined with a literature review on AMR rates and antimicrobial stewardship initiatives. Results: The system of monitoring AMR and appropriate strategies to address AMR rates remain underdeveloped in Poland. The role of microbiological diagnostics and efforts to prevent infections is currently underestimated by physicians. Overall, Poland had one of the highest rates of total consumption of antibiotics in the analysed European countries. Total consumption of antibacterials for systemic use and relative consumption of beta-lactamase sensitive penicillins were characterized by small but statistically significant average annual increases between 2007 and 2016 (from 22.2DIDs to 23.9 DIDs and from 0.8% to 1.3%, respectively). Conclusions: The integrated activities around appropriate antibiotic prescribing in the pre- and post-graduate training of physicians and dentists seem to be particularly important, as well as changes in policies on prescribing antibiotics within ambulatory care. AMR and appropriate prescribing of antibiotics should be the focus of health policy actions in Poland

Protection of mice against Philadelphia chromosome-positive acute lymphoblastic leukemia by cell-based vaccination using nonviral, minimalistic expression vectors and immunomodulatory oligonucleotides.

PURPOSE: Childhood Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL) has a poor prognosis. Because leukemia cell burden is reduced but not eradicated by polychemotherapy, improved treatment strategies should enhance those immune mechanisms responsible for the maintenance of complete remission. The aim of this study was to evaluate the protection of mice challenged with the syngeneic Ph(+) ALL cell line BM185 using genetically modified leukemia cell vaccines and immunomodulating oligonucleotides. Experimental Design: Because retroviral vectors are ineffective at transducing nondividing primary cells from human hematopoietic malignancies, we first evaluated nonviral techniques (electroporation and ballistic transfer) using minimalistic immunogenically defined gene expression vectors to generate B7.1 or granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing BM185 cells. Subsequently, protective vaccination experiments with these cells were performed in a leukemia challenge mouse model. RESULTS: Electroporation yielded a high transfection rate (82.6% for B7.1) with moderate GM-CSF secretion/1 x 10(6) cells (228 pg), whereas ballistic transfer led to a lower transfection rate (30.9%) with high GM-CSF secretion (614 pg). Secondly, we immunized mice with B7.1/interleukin 2- or B7.1/GM-CSF-expressing BM185 cell vaccines. We observed a better protection of mice that received the B7.1/GM-CSF vaccine compared with these receiving the B7.1/interleukin 2 vaccine. Protection was additionally enhanced by application of a double stem-loop immunomodulating oligonucleotide containing CpG motifs. CONCLUSION: Our data indicate that immunization with B7.1/GM-CSF-expressing cell vaccines generated by electroporation and application of double stem-loop immunomodulating oligonucleotide protected mice against a murine Ph(+) ALL challenge. Ultimately, this approach may also lead to clinical benefit in patients with Ph(+) ALL

Interactive VR-based visualization for material flow simulations

The conventional way of visualizing the material flow in a production system is to use simulation tools and their integrated symbols and pictograms. By going this way, the reference to the real production system is very limited since conventional material flow models provide only an abstract view and are not very comprehensive for the user. This paper introduces a procedure which enables a Virtual Design Review of the planned process layout on a large-screen visualization facility. This enables production planners to conduct a virtual inspection of alternative concepts for a planned production system including the visualized material flow. As a result, planning certainty and system comprehension of all parties involved increase significantly, so that the presented procedure serves as a valuable decision support. This paper describes the steps to be taken from production data to an optimized material flow being verified by a Virtual Design Review

Advancements in matrix-assisted laser desorption ionization mass spectrometry of peptides, proteins and polymers

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1998.Includes bibliographical references (leaves 198-204).by Heinrich J. Köchling.Ph.D

Brainstem abnormalities and vestibular nerve enhancement in acute Neuroborreliosis

BACKGROUND: Borreliosis is a widely distributed disease. Neuroborreliosis may present with unspecific symptoms and signs and often remains difficult to diagnose in patients with central nervous system symptoms, particularly if the pathognomonic erythema chronica migrans does not develop or is missed. Thus, vigilance is mandatory in cases with atypical presentation of the disease and with potentially severe consequences if not recognized early. We present a patient with neuroborreliosis demonstrating brain stem and vestibular nerve abnormalities on magnetic resonance imaging. CASE PRESENTATION: A 28-year-old Caucasian female presented with headaches, neck stiffness, weight loss, nausea, tremor, and gait disturbance. Magnetic resonance imaging showed T2-weighted hyperintense signal alterations in the pons and in the vestibular nerves as well as bilateral post-contrast enhancement of the vestibular nerves. Serologic testing of the cerebrospinal fluid revealed the diagnosis of neuroborreliosis. CONCLUSION: Patients infected with neuroborreliosis may present with unspecific neurologic symptoms and magnetic resonance imaging as a noninvasive imaging tool showing signal abnormalities in the brain stem and nerve root enhancement may help in establishing the diagnosis

Do firms hedge in order to avoid financial distress costs? New empirical evidence using bank data

We present a new approach to test empirically the financial distress costs theory of corporate hedging. We estimate the ex-ante expected financial distress costs, which serve as a starting point to construct further explanatory variables in an equilibrium setting, as a fraction of the value of an asset-or-nothing put option on the firm's assets. Using single-contract data of the derivatives' use of 189 German middle-market companies that stems from a major bank as well as Basel II default probabilities and historical accounting information, we are able to explain a significant share of the observed cross-sectional differences in hedge ratios. Hence, our analysis adds further support for the financial distress costs theory of corporate hedging from the perspective of a financial intermediary