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Purpose: BN-CV301 is a poxviral-based vaccine comprised of recombinant (rec.) modified vaccinia Ankara (MVA-BN-CV301; prime) and rec. fowlpox (FPV-CV301; boost). Like its predecessor PANVAC, BN-CV301 contains transgenes encoding tumor-associated antigens MUC1 and CEA as well as costimulatory molecules (B7.1, ICAM-1, and LFA-3). PANVAC was reengineered to make it safer and more antigenic. Patients and Methods: This open-label, 3+3 design, dose-escalation trial evaluated three dose levels (DL) of MVA-BN-CV301: one, two, or four subcutaneous injections of 4 × 108 infectious units (Inf.U)/0.5 mL on weeks 0 and 4. All patients received FPV-CV301 subcutaneously at 1 × 109 Inf.U/0.5 mL every 2 weeks for 4 doses, then every 4 weeks. Clinical and immune responses were evaluated. Results: There were no dose-limiting toxicities. Twelve patients enrolled on trial [dose level (DL) 1 = 3, DL2 = 3, DL3 = 6). Most side effects were seen with the prime doses and lessened with subsequent boosters. All treatment-related adverse events were temporary, self-limiting, grade 1/2, and included injection-site reactions and flu-like symptoms. Antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most patients. Single-agent BN-CV301 produced a confirmed partial response (PR) in 1 patient and prolonged stable disease (SD) in multiple patients, most notably in KRAS-mutant gastrointestinal tumors. Furthermore, 2 patients with KRAS-mutant colorectal cancer had prolonged SD when treated with an anti-PD-L1 antibody following BN-CV301. Conclusions: The BN-CV301 vaccine can be safely administered to patients with advanced cancer. Further studies of the vaccine in combination with other agents are planned. See related commentary by Repáraz et al., p. 4871

Le present essai propose une theorie du poeme lyrique qui differe fortement de la definition traditionnelle de la poesie qui considere le vers comme critere principal de la poesie. Au centre de la theorie developpee par Dieter Lamping se trouve la definition du poeme lyrique comme discours singulier en vers. Selon la theorie presente, pour qu’un texte appartienne au genre du poeme lyrique, il est obligatoire qu’il reponde a deux conditions : d’une part, le poeme lyrique – un terme qui est employe comme synonyme du terme poesie – est a distinguer a la fois du poeme dramatique et du poeme epique puisqu’il est concu comme discours singulier en vers. D’autre part, le poeme lyrique doit reunir le critere formel de la composition en vers et le critere structurel du discours singulier. Ces criteres sont relies a la forme et a la structure du discours. Cette definition minimale d’un texte lyrique comme discours singulier en vers, qui envisage une relation constitutive entre forme et structure du poeme, correspond a la complexite esthetique et a la pluralite de la poesie. Elle offre et une description de poesie de validite universelle et une distinction du poeme lyrique des autres formes de discours poetique. Elle propose notamment une approche pertinente pour etudier la poesie moderne qui se degage des traditions poetiques et vise une liberation.

Because the surface connects a material to its environment, the functionalization, modification, and patterning of surfaces is key to a wide range of materials applied in microelectronics, displays, sensing, microarrays, photovoltaics, catalysis, and other fields. Self-assembled monolayers (SAMs), which can be deposited on a wide range of inorganic materials, are only a few nanometers thick, yet they can radically change the properties of the resulting interface. Alternatively, thin polymer films composed of polymer brushes grown from the surface provide a more robust molecular modification of inorganic materials. For many applications, patterned SAMs or polymer brushes are desired. Over the past decade, our group has shown that both SAMs as well as polymer brushes can be patterned very efficiently using microcontact printing. In microcontact printing, a molecular "ink" is deposited on a suitable substrate using a microstructured elastomer stamp, which delivers the ink exclusively in the area of contact between stamp and substrate. In contrast to most types of lithography, microcontact printing does not require expensive equipment. Our work has shown that "microcontact chemistry" is a powerful additive surface patterning method, in which molecular inks react with a precursor SAM during printing so that surfaces can be modified with various orthogonal functional groups or molecular recognition sites in microscale patterns. Functional groups include reactive groups for click chemistry or photochemistry and initiators for radical polymerization. Molecular recognition sites include host-guest chemistry as well as biochemical ligands such as carbohydrates and biotin. In this Account, we present an overview of our research in this area including selected examples of work by other groups. In the first part, we review our work on the patterning of SAMs using microcontact chemistry, with a focus on click chemistry and photochemistry. We will show how cycloadditions, thiol-ene reactions, and tetrazole chemistry can be used to obtain versatile surface patterns. In the second part, we demonstrate that microcontact chemistry can be used to pattern polymer brushes. Among others, initiators for surface-induced nitroxide-mediated polymerization and atom transfer polymerization were printed and used to grow patterned polymer brushes with molecular recognition groups suitable for responsive surface adhesion. In the third part, we describe how SAMs and polymer brushes can be printed on microparticles instead of flat substrates so that Janus particles with functional patches can be obtained. Finally, we present a brief outlook on further developments expected in this field.

Purpose: The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors. Patients and Methods: Subjects (n = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort (n = 37 with every 4-week dosing). Results: The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade ≥3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 μg/kg. A time-dependent rise in IFNγ and an associated rise in IL10 were observed following NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on T-cell receptor sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed after treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6–30+ months). Conclusions: NHS-IL12 was well tolerated up to a dose of 16.8 μg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors. See related commentary by Lyerly et al., p. 9

Three supramolecular adhesive systems based on the host–guest interaction of β-cyclodextrins (β-CD) with photoresponsive arylazopyrazoles (AAP) are reported. Glass substrates and silicon wafers were functionalized either with β-CD or AAP containing polymer brushes by microcontact printing and surface initiated atom transfer radical polymerization (SI-ATRP). Two host or guest surfaces were glued by incubation with the complementary guest or host polymer. In addition, complementary surfaces functionalized with guest and host polymer brushes were glued together. The adhesion strength of the three systems was investigated in air as well as under water and UV irradiation. All systems show strong supramolecular adhesion in air due to multivalent host–guest interaction. The system based on two complementary surfaces has excellent water resistance, adhesion can be de-activated by irradiation with UV light, and adhesion can be reversed using a competitive guest, but no direct photo-release was observed due to a hindered photo-isomerization in the nanoscale confinement of the polymer brushes sandwiched between two adhering substrates.

The field of antimicrobials is considered to be facing a crisis. Increasing microbial resistance is creating a demand for new drugs, which however is not being matched by privately funded R&D. The reasons for this market failure are of a technical and economic nature. The present article analyzes what changes to IP-based incentives are conceivable in the European Union (EU) in order to address the antimicrobial crisis. Since the assessment of the suitability of the analyzed options depends on interdisciplinary research, this article also proposes a research agenda to be considered for the implementation of public policies in this field.

Purpose Precision oncology holds the promise of improving patient outcome. It is based on the idea that the testing of genomic biomarkers can lead to the recommendation of a treatment option tailored to the specific patient. To derive treatment recommendations from molecular profiles, interdisciplinary molecular tumor boards (MTBs) have been established recently in many academic institutions. The recommendation process in MTBs, however, has not been well defined, which limits applicability to larger clinical trials and patient populations. Methods We created four fictional patients on the basis of recent real cases with genomic information on mutations, fusions, copy numbers, and gene expression. We identified 29 tumor boards from nine countries worldwide and asked them to provide treatment recommendations for the sample patients. In addition, a questionnaire regarding the setup and methods used by MTBs was circulated. Results Five MTBs from four countries provided treatment recommendations and answered the questionnaire. For one patient, three tumor board treatment recommendations were identical, and two tumor boards had identical treatment strategies for the other three patients. There was heterogeneity in the interpretation of tumor and germline aberrations as well as in standards of prioritization. Conclusion Differences in the interpretation and recommendation process contribute to heterogeneity in MTB recommendations. Additional comparative analyses of recommendations could help improve rational decision making and lead to standardization.

Telomerases elongate the ends of chromosomes required for cell immortality through their reverse transcriptase activity. By using the model organism Saccharomyces cerevisiae we defined the order in which the holoenzyme matures. First, a longer precursor of the telomerase RNA, TLC1 is transcribed and exported into the cytoplasm, where it associates with the protecting Sm-ring, the Est- and the Pop-proteins. This partly matured telomerase is re-import into the nucleus via Mtr10 and a novel TLC1-import factor, the karyopherin Cse1. Remarkably, while mutations in all known transport factors result in short telomere ends, mutation in CSE1 bypasses this defect and become Type I like survivors. Interestingly, both import receptors contact the Sm-ring for nuclear import, which therefore resembles a quality control step in the maturation process of the telomerase. The re-imported immature TLC1 is finally trimmed into the ~1150 nucleotide long mature form. TMG-capping of TLC1 finalizes maturation, leading to mature telomerase.

The importance of Southern Ocean sea ice has come into the focus of polar research in the last couple of decades. Especially in West Antarctica, where sea ice has declined, its distribution and evolution play a critical role for the stability of nearby ice shelves. Organic geochemical analyses of marine surface sediments from the West Antarctic continental shelves permit a biomarker-based reconstruction of sea surface conditions in these vulnerable areas. We analysed highly branched isoprenoids (HBIs), such as the sea-ice proxy IPSO25 and phytoplankton-derived HBI-trienes, but also phytosterols and isoprenoidal glycerol dialkyl glycerol tetraethers (GDGTs), which are established tools for the reconstruction of primary productivity and sea surface temperatures, respectively. The combination of IPSO25 with a phytoplankton marker results in the semi-quantitative sea-ice index PIPSO25, which provides useful reconstructions of sea-ice conditions, avoiding misleading over- or underestimations of sea-ice cover. Comparisons of the biomarker-based sea-ice distribution patterns and GDGT-based temperatures with (1) sea-ice distributions obtained from satellite observations and (2) estimated sea-ice patterns and SSTs deduced from modelled data are in reasonable agreement, but also highlight specific aspects that need to be considered when interpreting biomarker data. We further discuss IPSO25 concentrations in the vicinity of ice shelves, where elevated values could be related to the occurrence of ice shelf basal melt water and platelet ice under landfast sea ice.

Fusarium keratoplasticum is arguably the most common Fusarium solani species complex (FSSC) species associated with human infections. Invasive fusariosis is a life-threatening fungal infection that is difficult to treat with conventional azole antifungals. Azole drug resistance is often caused by the increased expression of pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters of the ABCG sub-family. Most investigations of Fusarium ABC transporters associated with azole antifungal drug resistance are limited to plant pathogens. Through the manual curation of the entire ABCG protein family of four FSSC species including the fully annotated genome of the plant pathogen Nectria haematococca we identified PDR transporters ABC1 and ABC2 as the efflux pump candidates most likely to be associated with the innate azole resistance phenotype of Fusarium keratoplasticum. An initial investigation of the transcriptional response of logarithmic phase F. keratoplasticum cells to 16 mg/L voriconazole confirmed strong upregulation (372-fold) of ABC1 while ABC2 mRNA levels were unaffected by voriconazole exposure over a 4 h time-period. Overexpression of F. keratoplasticum ABC1 and ABC2 in the genetically modified Saccharomyces cerevisiae host ADΔΔ caused up to ∼1,024-fold increased resistance to a number of xenobiotics, including azole antifungals. Although ABC1 and ABC2 were only moderately (20% and 10%, respectively) expressed compared to the Candida albicans multidrug efflux pump CDR1, overexpression of F. keratoplasticum ABC1 caused even higher resistance levels to certain xenobiotics (e.g., rhodamine 6G and nigericin) than CDR1. Our investigations suggest an important role for ABC1 orthologues in the innate azole resistance phenotype of FSSC species.

Kinneretia sp. strain DAIF2 was isolated from a eutrophic freshwater pond. The genome consists of a single chromosome (6,010,585 bp) with a GC content of 69.3%. The whole-genome-based phylogeny of DAIF2 revealed a closest relation to the genus Kinneretia.

Kinneretia sp. strain DAIF2 was isolated from a eutrophic freshwater pond. The genome consists of a single chromosome (6,010,585 bp) with a GC content of 69.3%. The whole-genome-based phylogeny of DAIF2 revealed a closest relation to the genus Kinneretia .

Pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters of the ABCG family are eukaryotic membrane proteins that pump an array of compounds across organelle and cell membranes. Overexpression of the archetype fungal PDR transporter Cdr1 is a major cause of azole antifungal drug resistance in Candida albicans, a significant fungal pathogen that can cause life-threatening invasive infections in immunocompromised individuals. To date, no structure for any PDR transporter has been solved. The objective of this project was to investigate the role of the 23 Cdr1 cysteine residues in the stability, trafficking, and function of the protein when expressed in the eukaryotic model organism, Saccharomyces cerevisiae. The biochemical characterization of 18 partially cysteine-deficient Cdr1 variants revealed that the six conserved extracellular cysteines were critical for proper expression, localization, and function of Cdr1. They are predicted to form three covalent disulfide bonds that stabilize the large extracellular domains of fungal PDR transporters. Our investigations also revealed a novel nucleotide-binding domain motif, GX2[3]CPX3NPAD/E, at the peripheral cytosolic apex of ABCG transporters that possibly contributes to the unique ABCG transport cycle. With this knowledge, we engineered an “almost cysteine-less,” yet fully functional, Cdr1 variant, Cdr1P-CID, that had all but the six extracellular cysteines replaced with serine, alanine, or isoleucine (C1106I of the new motif). It is now possible to perform cysteine-cross-linking studies that will enable more detailed biochemical investigations of fungal PDR transporters and confirm any future structure(s) solved for this important protein family. IMPORTANCE Overexpression of the fungal pleiotropic drug resistance (PDR) transporter Cdr1 is a major cause of antifungal drug resistance in Candida albicans, a significant fungal pathogen that can cause life-threatening invasive infections in immunocompromised individuals. To date, no structure for any PDR ABC transporter has been solved. Cdr1 contains 23 cysteines; 10 are cytosolic and 13 are predicted to be in the transmembrane or the extracellular domains. The objective of this project was to create, and biochemically characterize, CDR1 mutants to reveal which cysteines are most important for Cdr1 stability, trafficking, and function. During this process we discovered a novel motif at the cytosolic apex of PDR transporters that ensures the structural and functional integrity of the ABCG transporter family. The creation of a functional Cys-deficient Cdr1 molecule opens new avenues for cysteine-cross-linking studies that will facilitate the detailed characterization of an important ABCG transporter family member.

Objective We present the Berlin-Tübingen-Oncology corpus (BRONCO), a large and freely available corpus of shuffled sentences from German oncological discharge summaries annotated with diagnosis, treatments, medications, and further attributes including negation and speculation. The aim of BRONCO is to foster reproducible and openly available research on Information Extraction from German medical texts. Materials and Methods BRONCO consists of 200 manually deidentified discharge summaries of cancer patients. Annotation followed a structured and quality-controlled process involving 2 groups of medical experts to ensure consistency, comprehensiveness, and high quality of annotations. We present results of several state-of-the-art techniques for different IE tasks as baselines for subsequent research. Results The annotated corpus consists of 11 434 sentences and 89 942 tokens, annotated with 11 124 annotations for medical entities and 3118 annotations of related attributes. We publish 75% of the corpus as a set of shuffled sentences, and keep 25% as held-out data set for unbiased evaluation of future IE tools. On this held-out dataset, our baselines reach depending on the specific entity types F1-scores of 0.72–0.90 for named entity recognition, 0.10–0.68 for entity normalization, 0.55 for negation detection, and 0.33 for speculation detection. Discussion Medical corpus annotation is a complex and time-consuming task. This makes sharing of such resources even more important. Conclusion To our knowledge, BRONCO is the first sizable and freely available German medical corpus. Our baseline results show that more research efforts are necessary to lift the quality of information extraction in German medical texts to the level already possible for English.

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients., Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

Since it was announced on 5 May 2021 that the Biden/Harris administration supported the proposition to wave intellectual property rights (i.e. the so-called “TRIPS waiver”) linked to COVID-19 initiated by India and South Africa in front of the WTO, the subject of the patent waiver has come to the forefront of public debate. We would like to shed some light on this debate.

This article deals with the establishment and evolution of intellectual property rights in Latin America. It goes through the contexts in which these rights have been in-corporated into the domestic legal framework. Although Latin American economies are more or less fragile from the point of view of intellectual property, the conclusions indicate that there are several challenges to be faced, but that the countries of the region have the potential to overcome them and advance in the protection and use of their intellectual assets.

In this Statement, the authors take a position on the waiver of intellectual property (IP) protection currently being considered by the members of the World Trade Organisation. The waiver was initiated by India and South Africa as a measure to enable rapid access to affordable medical products that are necessary to combat Covid-19. The initiative gained momentum after the US decided to support it. The authors do not consider this path to be expedient. The Statement presents factual and legal arguments why a comprehensive waiver of IP protection is unlikely to be a necessary and suitable measure towards the pursued objective. Overall, it argues that IP rights may so far have played an enabling and facilitating rather than hindering role in overcoming Covid-19. The global community might not be better off if IP rights are waived, neither during nor after the pandemic. There are more efficient and direct ways to supply developing countries with vaccines quickly – if the industrialised countries are willing to do their share. The Statement can be supported by filling in the form: https://forms.gle/c4kc8m9JE44AwjoJ7.

The reconstruction of past Antarctic sea ice coverage through the application of diatom assemblages is often hampered in near coastal environments due to silica dissolution effects. The more recently established approach of using highly branched isoprenoid biomarkers to identify past sea ice conditions seems a valid method to overcome this limitation and that may also provide insight into ice-shelf dynamics. Here, we evaluate the so-called PIPSO25 index applied to modern surface sediments from the Amundsen Sea, the Drake Passage and Bransfield Strait, and the Weddell Sea. The comparison of biomarker-based sea ice estimates with satellite-derived sea ice concentrations supports the potential of the proxy approach. In a next step, we generated biomarker records using two sediment cores from the western and eastern Weddell Sea to track sea ice variability over late Pleistocene glacial-interglacial cycles. Consideration of additional data such as XRF and multi-sensor core logging records as well as micropaleontological investigations enables a comprehensive assessment of the environmental changes in the Weddell Sea in response to large-scale climate transitions. While magnetic susceptibility and density data obtained for both cores display similar patterns, we note distinct differences between the biomarker records highlighting local feedback mechanisms affecting sea ice cover.

This portfolio conveys some of the author���s principal views regarding second language (L2) teaching and learning. These views have been developed and informed by studying the research literature, personal language learning experience, language teaching observations, and language teaching experience. The first section, teaching perspectives, contains an explanation of the environment envisioned by the author while writing this portfolio, his teaching philosophy statement, and a summary of classroom observations. The second section, research perspectives, contains two research papers and an annotated bibliography that support the author���s language teaching philosophy.

This dissertation analyses the effect of behavioural aspects on the decision-making in healthcare. The objective is to determine factors influencing the perception of the value of health in Germany. Results indicate that the perception of the value of health in Germany is affected by determinants besides the (perceived) benefit of the intervention. This result is found on an institutional level (pharmaceutical price negotiation) and on an individual level (willingness to pay).