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BackgroundThe rate of seroconversion after COVID-19 vaccination in patients with moderate to severe psoriasis requiring systemic treatment is poorly understood.ObjectivesThe aim of this prospective single-center cohort study performed between May 2020 and October 2021 was to determine the rate of seroconversion after COVID-19 vaccination in patients under active systemic treatment for moderate to severe psoriasis.MethodsInclusion criteria were systemic treatment for moderate to severe psoriasis, known COVID-19 vaccination status, and repetitive anti-SARS-CoV-2-S IgG serum quantification. The primary outcome was the rate of anti-SARS-CoV-2-S IgG seroconversion after complete COVID-19 vaccination.Results77 patients with a median age of 55.9 years undergoing systemic treatment for moderate to severe psoriasis were included. The majority of patients received interleukin- (n=50, 64.9%) or tumor necrosis factor (TNF)-α inhibitors (n=16, 20.8%) as systemic treatment for psoriasis; nine patients (11.7%) were treated with methotrexate (MTX) monotherapy, and one patient each received dimethyl fumarate (1.3%), respectively apremilast (1.3%). All included patients completed COVID-19 vaccination with two doses over the course of the study. Serum testing revealed that 74 patients (96.1%) showed an anti-SARS-CoV-2-S IgG seroconversion. While all patients on IL-17A, -12 or -12/23 inhibitors (n=50) achieved seroconversion, three of 16 patients (18.8%) receiving MTX and/or a TNF-α inhibitor as main anti-psoriatic treatment did not. At follow-up, none of the patients had developed symptomatic COVID-19 or died from COVID-19.ConclusionsAnti-SARS-CoV-2-S IgG seroconversion rates following COVID-19 vaccination in psoriasis patients under systemic treatment were high. An impaired serological response, however, was observed in patients receiving MTX and/or TNF-α inhibitors, in particular infliximab.

BackgroundSézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma.ObjectiveTo compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS.MethodsWe utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq).ResultsWe scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as CCR7, IL7R and CD27. In the skin, we detected two major malignant T-cell populations: One subpopulation was closely related to the malignant T cells from the blood, while the other subpopulation expressed genes reminiscent of skin resident effector memory T cells including GZMB and NKG7. Pseudotime analysis indicated crucial transcriptomic changes in the transition of malignant T cells between blood and skin. These changes included the differential regulation of TXNIP, a putative tumor suppressor in CTCL, and the adaptation to the hypoxic conditions in the skin. Tumor cell proliferation in the skin was supported by stimulating interactions between myeloid cells and malignant T cells.ConclusionsUsing scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin.

Computational requirements for deep neural networks (DNNs) have been on a rising trend for years. Moreover, network dataflows and topologies are becoming more sophisticated to address more challenging applications. DNN accelerators cannot adopt quickly to the constantly changing DNNs. In this paper, we describe our approach to make a static accelerator more versatile by adding an embedded FPGA (eFPGA). The eFPGA is tightly coupled to the on-chip network, which allows us to pass data through the eFPGA before and after it is processed by the DNN accelerator. Hence, the proposed solution is able to quickly address changing requirements. To show the benefits of this approach, we propose an eFPGA application that enables dynamic quantization of data. We can fit four number converters on an $1.5mm^2$ eFPGA, which can process 400M data elements per second. We will practically validate our work in the near future, with a SoC tapeout in the ongoing EPI project.

Neuroblastoma (NB) is a tumor of the sympathoadrenal system arising in children under 15 years of age. In Germany, NB accounts for 7% of childhood cancer cases, but 11% of cancer deaths. It originates from highly migratory progenitor cells that leave the dorsal neural tube and contribute neurons and glial cells to sympathetic ganglia, and chromaffin and supportive cells to the adrenal medulla and paraganglia. Clinically, histologically and molecularly, NBs present as extremely heterogeneous, ranging from very good to very poor prognosis. The etiology of NB still remains unclear and needs to be elucidated, however, aberrant auto- and paracrine embryonic cell communications seem to be likely candidates to initiate or facilitate the emergence, progression and regression of NB. The wingless-type MMTV integration site (WNT) family of proteins represents an evolutionary highly conserved signaling system that orchestrates embryogenesis. At least 19 ligands in the human, numerous receptors and co-receptors are known, which control not only proliferation, but also cell polarity, migration and differentiation. Here we seek to interconnect aspects of WNT signaling with sympathoadrenal and paraganglionic development to define new WNT signaling cues in the etiology and progression of NB.

5th International Conference on Particle Physics and Astrophysics, ICPPA 2020, Moscow, Russian Federation, 5 Oct 2020 - 9 Oct 2020; Journal of physics / Conference Series 1690(1), 012104 (1-6) (2020). doi:10.1088/1742-6596/1690/1/012104, The Compressed Baryonic Matter experiment (CBM) performance for proton anisotropic flow measurements is studied with Monte-Carlo simulations using collisions of gold ions at lab momentum of 12A GeV/c employing DCM-QGSM-SMM heavy-ion event generator. Realistic procedures are used for centrality estimation with the number of registered tracks and particle identification with information from Time-Of-Flight detector. Variation of directed flow estimates depending on various combinations of PSD modules is used to evaluate possible systematic biases due to collision symmetry plane estimation., Published by IOP Publ., Bristol

Millions of patients suffer from lymphedema worldwide. Supporting the contractility of lymphatic collectors is an attractive target for pharmacological therapy of lymphedema. However, lymphatics have mostly been studied in animals, while the cellular and molecular characteristics of human lymphatic collectors are largely unknown. We studied epifascial lymphatic collectors of the thigh, which were isolated for autologous transplantations. Our immunohistological studies identify additional markers for LECs (vimentin, CCBE1). We show and confirm differences between initial and collecting lymphatics concerning the markers ESAM1, D2-40 and LYVE-1. Our transmission electron microscopic studies reveal two types of smooth muscle cells (SMCs) in the media of the collectors with dark and light cytoplasm. We observed vasa vasorum in the media of the largest collectors, as well as interstitial Cajal-like cells, which are highly ramified cells with long processes, caveolae, and lacking a basal lamina. They are in close contact with SMCs, which possess multiple caveolae at the contact sites. Immunohistologically we identified such cells with antibodies against vimentin and PDGFRα, but not CD34 and cKIT. With Next Generation Sequencing we searched for highly expressed genes in the media of lymphatic collectors, and found therapeutic targets, suitable for acceleration of lymphatic contractility, such as neuropeptide Y receptors 1, and 5; tachykinin receptors 1, and 2; purinergic receptors P2RX1, and 6, P2RY12, 13, and 14; 5-hydroxytryptamine receptors HTR2B, and 3C; and adrenoceptors α2A,B,C. Our studies represent the first comprehensive characterization of human epifascial lymphatic collectors, as a prerequisite for diagnosis and therapy. Open-Access-Publikationsfonds 2016 peerReviewed

Tumour-induced hem- and lymph-angiogenesis are frequently associated with tumour progression. Vascular Endothelial Growth Factor-C (VEGF-C) is a potent inducer of lymphangiogenesis, while the endogenous soluble splice-variant of VEGF receptor-2, esVEGFR-2, acts as a natural inhibitor. Previously we have shown down-regulation of esVEGFR-2 mRNA in progressed stages of neuro-blastoma (NB), a tumour derived from sympatho-adrenal precursor cells. Here we studied the immunolocalization of esVEGFR-2 in human embryos, infantile adrenal gland and primary NB. We also quantified esVEGFR-2 mRNA in NB cell lines after differentiation-induction by all-trans retinoic acid (ATRA). By immunoperoxidase staining we observed expression of esVEGFR-2 in both the sympathetic trunk and the adrenal medulla. Additionally, esVEGFR-2 was found in spinal ganglia, floor plate of the neural tube, choroid plexus, notochord, arterial endothelium, skeletal muscle, epidermis and gut epithelium. Developing and circulating leukocytes showed the strongest signal. In NB, esVEGFR-2 was considerably stronger in differentiating low grade tumours with neuronal phenotype than in undifferentiated lesions. Differentiation-induction of the NB cell line SMS-Kan with 5-10 µM ATRA resulted in a significant increase of esVEGFR-2 mRNA after 6, 9 and 12 days. We show that esVEGFR-2 is widely expressed in embryonic tissues. Especially, the adrenal medulla and circulating leukocytes seem to be potent inhibitors of lymphangiogenesis. We provide additional evidence for a role of esVEGFR-2 in NB. Thereby, high levels of esVEGFR-2 correlate with a more differentiated phenotype, and may inhibit tumour progression by inhibition of lymphangiogenesis.

The overall mission of the 4S project (Smart Chips for Smart Surroundings) was to define and develop efficient flexible, reconfigurable core building blocks, including the supporting tools, for future Ambient System Devices. Reconfigurability offers the needed flexibility and adaptability, it provides the efficiency needed for these systems, it enables systems that can adapt to rapidly changing environmental conditions, it enables communication over heterogeneous wireless networks, and it reduces risks: reconfigurable systems can adapt to standards that may vary from place to place or standards that have changed during and after product development. In 4S we focused on heterogeneous building blocks such as analogue, hardwired functions, fine and coarse grain reconfigurable tiles and microprocessors. Such a platform can adapt to a wide application space without the need for specialized ASICs. A novel power aware design flow and runtime system was developed. The runtime system decides dynamically about the near-optimal application mapping to the given hardware platform. The overall concept was verified on hardware platforms based on an existing SoC and in a second step with novel silicon. DRM (Digital Radio Mondiale) and MPEG4 Video applications have been implemented on the platforms demonstrating the adaptability of the 4S concept.

Der Einsatz von Nanomaterialien in der medizinischen Diagnostik und Therapie ist etabliert. Einige Metalloxid-Nanopartikel (NP) wie Titandioxid (TiO2) oder Zinkoxid (ZnO) besitzen photokatalytische Eigenschaften. Ziel dieser Studie war die Beurteilung zytotoxischer Effekte durch die Behandlung von Karzinomzellen[for full text, please go to the a.m. URL], 81. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie

Background: Inactivation of the p53 pathway that controls cell cycle progression, apoptosis and senescence, has been proposed to occur in virtually all human tumors and p53 is the protein most frequently mutated in human cancer. However, the mutational status of p53 in melanoma is still controversial; to clarify this notion we analysed the largest series of melanoma samples reported to date. Methodology/Principal Findings: Immunohistochemical analysis of more than 180 melanoma specimens demonstrated that high levels of p53 are expressed in the vast majority of cases. Subsequent sequencing of the p53 exons 5–8, however, revealed only in one case the presence of a mutation. Nevertheless, by means of two different p53 reporter constructs we demonstrate transcriptional inactivity of wild type p53 in 6 out of 10 melanoma cell lines; the 4 other p53 wild type melanoma cell lines exhibit p53 reporter gene activity, which can be blocked by shRNA knock down of p53. Conclusions/Significance: In melanomas expressing high levels of wild type p53 this tumor suppressor is frequently inactivated at transcriptional level.

A network-on-chip (NoC) is an energy-efficient on-chip communication architecture for multi-processor system-on-chip (MPSoC) architectures. In earlier papers we proposed two network-on-chip architectures based on packet-switching and circuit-switching. In this paper we derive an energy model for both NoC architectures to predict their energy consumption per transported bit. Both architectures are also compared with a traditional bus architecture. The energy model is primarily needed to find a near optimal run-time mapping (from an energy point of view) of inter-process communication to NoC links.

Dynamic reconfiguration of digital hardware enables systems to adapt to changing demands of the applications and of the environment. This paper concentrates on a core element of a reconfigurable hardware architecture, which supports a Real-time Operating System in reconfiguring the hardware – the Run-time Reconfiguration (RTR) Manager. The RTR-Manager has been developed to control, monitor and execute dynamic reconfiguration. It enables a fast adaptation of the SoC architecture through context switching between different configurations. Configuration code analysis and observation of the reconfiguration process guarantee a correct reconfiguration and increase the safety of the system. The system was successfully implemented and evaluated by means of the Rapid Prototyping System RAPTOR2000.

The present thesis describes the characterization of T cell responses to melanoma and its modulation by in situ cytokine therapy. Previous studies have shown that antibody cytokine fusion proteins, designated immunocytokines, achieve high cytokine concentrations in the tumor microenvironment and thereby effectively stimulate cellular immune responses against malignancies. Analysis of the T cell receptor repertoire of tumor infiltrating lymphocytes, as presented here, revealed operative differences in the immunomodulatory capacity of two proinflammatory cytokines, i.e., interleukin 2 and lymphotoxin ɑ, if applied targeted to the tumor site. While interleukin 2 is boosting an already established T cell response and enables the recirculation of clonally expanded T cells, lymphotoxin ɑ's modus operandi is relying on newly recruited T cells. Via induction of a tertiary lymphoid organ at the tumor site lymphotoxin a immunocytokines allow the recruitment, priming, and activation of naïve T cells to harness an effective T cell response against the tumor.

In 24 patients with cutaneous T-cell lymphomas (CTCL) the clinical course was documented by determination of a tumour burden index (TBI) on entering the study and six months later. In addition to the first TBI, soluble interleukin-2 receptor levels (slL-2R) in the serum were determined using an ELISA technique in 23 patients. In 18 patients natural killer cell (NK) activity was assessed by a 4 h chromium-51 release assay. Statistical analysis revealed a negative correlation between NK activity and an increase of TBI as well as NK activity and slL-2R. Furthermore, there was a strong positive correlation between the increase of TBI and slL-2R. slL-2R and NK activity might be prognostic factors in CTCL patients.

Background In recent studies, convolutional neural networks (CNNs) outperformed dermatologists in distinguishing dermoscopic images of melanoma and nevi. In these studies, dermatologists and artificial intelligence were considered as opponents. However, the combination of classifiers frequently yields superior results, both in machine learning and among humans. In this study, we investigated the potential benefit of combining human and artificial intelligence for skin cancer classification. Methods Using 11,444 dermoscopic images, which were divided into five diagnostic categories, novel deep learning techniques were used to train a single CNN. Then, both 112 dermatologists of 13 German university hospitals and the trained CNN independently classified a set of 300 biopsy-verified skin lesions into those five classes. Taking into account the certainty of the decisions, the two independently determined diagnoses were combined to a new classifier with the help of a gradient boosting method. The primary end-point of the study was the correct classification of the images into five designated categories, whereas the secondary end-point was the correct classification of lesions as either benign or malignant (binary classification). Findings Regarding the multiclass task, the combination of man and machine achieved an accuracy of 82.95%. This was 1.36% higher than the best of the two individual classifiers (81.59% achieved by the CNN). Owing to the class imbalance in the binary problem, sensitivity, but not accuracy, was examined and demonstrated to be superior (89%) to the best individual classifier (CNN with 86.1%). The specificity in the combined classifier decreased from 89.2% to 84%. However, at an equal sensitivity of 89%, the CNN achieved a specificity of only 81.5% Interpretation Our findings indicate that the combination of human and artificial intelligence achieves superior results over the independent results of both of these systems.

International audience; The empirical law of Moore does not only describe the increasing density of transistors permitted by technological advances. It also imposes new requirements and challenges. Systems complexity increases at the same speed. Nowadays systems could never be designed using the same approaches applied 20 years ago. New architectures are and must be continuously conceived. It is clear now that Moore’s law for the last two decades has enabled three main revolutions. The first revolution in the mid-eighties was the way to embed more and more electronic devices in the same silicon die; it was the era of System On Chip. One main challenge was the way to interconnect all these devices efficiently. For this purpose, the Bus interconnect structure was used for long time. Anyway, in the mid-nineties the industrial and academic communities faced a new challenge when the number of processing cores became two numerous for sharing a single communication medieum. A new interconnection scheme based on the Network Telecom Fabrics, the Network On Chip was born; over the past decade intense research efforts have led to significant improvements.

Bacterial capsular polysaccharides are virulence factors and are considered T cell–independent antigens. However, the capsular polysaccharide Sp1 from Streptococcus pneumoniae serotype 1 has been shown to activate CD4+ T cells in a major histocompatibility complex (MHC) class II–dependent manner. The mechanism of carbohydrate presentation to CD4+ T cells is unknown. We show in live murine dendritic cells (DCs) that Sp1 translocates from lysosomal compartments to the plasma membrane in MHCII-positive tubules. Sp1 cell surface presentation results in reduction of self-peptide presentation without alteration of the MHCII self peptide repertoire. In DM-deficient mice, retrograde transport of Sp1/MHCII complexes resulting in T cell–dependent immune responses to the polysaccharide in vitro and in vivo is significantly reduced. The results demonstrate the capacity of a bacterial capsular polysaccharide antigen to use DC tubules as a vehicle for its transport as an MHCII/saccharide complex to the cell surface for the induction of T cell activation. Furthermore, retrograde transport requires the functional role of DM in self peptide–carbohydrate exchange. These observations open new opportunities for the design of vaccines against microbial encapsulated pathogens., Author Summary Microorganisms are comprised of proteins, carbohydrates, lipids, and nucleic acids. Current immunologic paradigms state that activation of T lymphocytes required for humoral and cellular immune responses resulting in immunologic memory to the pathogens is solely brought about by proteinaceous antigens, processed and degraded to small peptides, loaded onto major histocompatibility complex (MHC) molecules, and transported as MHC/peptide complexes to the cell surface, where the MHC/peptide complex is recognized by the T cell antigen receptor. The findings of the present study elucidate the mechanism of MHC class II (MHCII)–dependent presentation of the bacterial capsular polysaccharide of Streptococcus pneumoniae serotype 1 (Sp1) that results in effective T cell activation. Sp1 is transported in MHCII-positive tubules from lysosomal compartments to the plasma membrane for presentation. In the absence of the DM molecule, known as an editor and catalyst of self and foreign peptide exchange, retrograde transport of carbohydrate/MHCII complexes resulting in dendritic cell engagement with T cells in vitro and T cell–dependent immune responses to the polysaccharide in vivo fail. The results suggest a fundamental shift in the immunologic paradigm, offering previously unrecognized opportunities for the design of new classes of vaccines against infectious diseases.