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Introduction Minimally invasive surgery (i.e., laparoscopy) and minimally invasive anesthesia (i.e., caudal anesthesia with spontaneous respiration) have separately shown benefits for inguinal hernia repair in infants, yet to what degree these techniques can be combined remains unknown. This study investigated whether laparoscopy impacts the feasibility of performing caudal anesthesia with spontaneous respiration in infants. Methods Prospectively collected data of all infants less than 12 months old and over 3 kg weight who underwent laparoscopic indirect hernia repair (LAP) at our department from 2019 to 2021 were compared with a historical control-matched group of infants who underwent open repair (OPEN) from 2017 to 2021. We assessed the patients' characteristics, anesthesia, and surgical data as well as intra- and postoperative complications. Results A total of 87 infants were included (LAP n = 29, OPEN n = 58). Caudal anesthesia with spontaneous respiration was feasible in 62.1% of cases (LAP n = 55.2%, OPEN n = 65.5%; nonsignificant). Neither group registered anesthetic intra- or postoperative complications. Sedatives were utilized in 97% of LAP patients versus 56.9% of OPEN patients (p Conclusion This is the first comparative study on caudal anesthesia and spontaneous respiration in infants undergoing laparoscopic versus open inguinal hernia surgery. Laparoscopy increased the need for ventilatory support and sedatives but did not significantly impair the feasibility of caudal anesthesia and spontaneous respiration.

The surface polysacharide arabinomannan (AM) and related glycolipid lipoarabinomannan (LAM) play critical roles in tuberculosis pathogenesis. Human antibody responses to AM/LAM are heterogenous and knowledge of reactivity to specific glycan epitopes at the monoclonal level is limited, especially in individuals who can control M. tuberculosis infection. We generated human IgG mAbs to AM/LAM from B cells of two asymptomatic individuals exposed to or latently infected with M. tuberculosis. Here, we show that two of these mAbs have high affinity to AM/LAM, are non-competing, and recognize different glycan epitopes distinct from other anti-AM/LAM mAbs reported. Both mAbs recognize virulent M. tuberculosis and nontuberculous mycobacteria with marked differences, can be used for the detection of urinary LAM, and can detect M. tuberculosis and LAM in infected lungs. These mAbs enhance our understanding of the spectrum of antibodies to AM/LAM epitopes in humans and are valuable for tuberculosis diagnostic and research applications., Elise Ishida et al. generate human monoclonal antibodies that can selectively recognize specific oligosaccharide epitopes of the polysaccharides arabinomannan and lipoarabinomannan, which are critical for M. tuberculosis pathogenesis. The authors demonstrate the utility of these antibodies in both diagnostic and laboratory settings, making them important tools for M. tuberculosis research.

Euro-centric psychiatric conceptualizations often ignore the interplay of local with universal factors in psychological suffering. Emic, locally focused perspectives can enrich etic knowledge to provide culturally sensitive care and to better elucidate the role of culture in mental illness. This study explored the idiom Tsûsa ǃNaeǃkhais xa hâǃnâ/mâǃnâ/ǂgâǃnâhe hâ (a terrible event has entered a person and remains standing inside), which was understood to relate to experiences of trauma and post-traumatic stress, among speakers of Khoekhoegowab, a southern-African click language. Semi-structured interviews were conducted with 16 participants from six urban and rural communities in Namibia. Questions probed perceptions of the idiom in terms of etiology, course, and risk and resilience factors from a socio-ecological framework. Five key themes were identified using thematic analysis: origin in a shocking event; intrusive recurrence of memories, “it keeps on coming back”; the close interplay between mental and physical suffering; the importance of active engagement in healing through prayer and acceptance; and the role of the community in both alleviating and amplifying distress. Our findings highlight local norms and strategies for adaptive coping, and the benefits of exploring local idioms to elucidate the braiding together of universal and cultural elements in psychological distress.

Designing a flood early warning system for West Africa, a region with significant climatic and cultural diversity, is challenging. Stakeholders agree on prioritising a system that delivers accurate, clear, timely and accessible information.

Impaired wound healing represents an unsolved medical need with a high impact on patients´ quality of life and global health care. Even though its causes are diverse, ischemic-hypoxic conditions and exacerbated inflammation are shared pathological features responsible for obstructing tissue restoration. In line with this, it has been suggested that promoting a normoxic pro-regenerative environment and accelerating inflammation resolution, by reinstating the lymphatic fluid transport, could allow the wound healing process to be resumed. Our group was first to demonstrate the functional use of scaffolds seeded with photosynthetic microorganisms to supply tissues with oxygen. Moreover, we previously proposed a photosynthetic gene therapy strategy to create scaffolds that deliver other therapeutic molecules, such as recombinant human growth factors into the wound area. In the present work, we introduce the use of transgenic Synechococcus sp. PCC 7002 cyanobacteria (SynHA), which can produce oxygen and lymphangiogenic hyaluronic acid, in photosynthetic biomaterials. We show that the co-culture of lymphatic endothelial cells with SynHA promotes their survival and proliferation under hypoxic conditions. Also, hyaluronic acid secreted by the cyanobacteria enhanced their lymphangiogenic potential as shown by changes to their gene expression profile, the presence of lymphangiogenic protein markers and their capacity to build lymph vessel tubes. Finally, by seeding SynHA into collagen-based dermal regeneration materials, we developed a viable photosynthetic scaffold that promotes lymphangiogenesis in vitro under hypoxic conditions. The results obtained in this study lay the groundwork for future tissue engineering applications using transgenic cyanobacteria that could become a therapeutic alternative for chronic wound treatment. Statement of significance In this study, we introduce the use of transgenic Synechococcus sp. PCC 7002 (SynHA) cyanobacteria, which were genetically engineered to produce hyaluronic acid, to create lymphangiogenic photosynthetic scaffolds for dermal regeneration. Our results confirmed that SynHA cyanobacteria maintain their photosynthetic capacity under standard human cell culture conditions and efficiently proliferate when seeded inside fibrin-collagen scaffolds. Moreover, we show that SynHA supported the viability of co-cultured lymphatic endothelial cells (LECs) under hypoxic conditions by providing them with photosynthetic-derived oxygen, while cyanobacteria-derived hyaluronic acid stimulated the lymphangiogenic capacity of LECs. Since tissue hypoxia and impaired lymphatic drainage are two key factors that directly affect wound healing, our results suggest that lymphangiogenic photosynthetic biomaterials could become a treatment option for chronic wound management.

In our laboratory, we employ two biphoton sources for quantum key distribution. The first is based on cw parametric down-conversion of photons at 404 nm in PPKTP waveguide chips, while the second is based on the pulsed parametric down-conversion of 775 nm photons in PPLN waveguides. The spectral characterization is important for the determination of certain side-channel attacks. A Hong-Ou-Mandel experiment employing the first photon source revealed a complex structure of the common Hong-Ou-Mandel dip. By measuring the spectra of the single photons at 808 nm, we were able to associate these structures to the superposition of different transverse modes of the pump photons in our waveguide chips. The pulsed source was characterized by means of single-photon spectra measured by a sensitive spectrum analyzer as well as dispersion-based measurements. Finally, we also describe Hong-Ou-Mandel experiments using the photons from the second source.

Euro-centric psychiatric conceptualizations often ignore the interplay of local with universal factors in psychological suffering. Emic, locally focused perspectives can enrich etic knowledge to provide culturally sensitive care and to better elucidate the role of culture in mental illness. This study explored the idiom

This paper suggests innovative investment strategies drawing on return seasonalities. By means of an out-of-sample study of the German stock market, we report that these long–short investment strategies earn on average raw returns up to 233 basis points per month throughout two decades from 1998 to 2017. On a monthly basis, this documents an outperformance of the corresponding Heston and Sadka (J Financ Econ 87(2):418–445, 2008) strategy by 66%. This outperformance is robust in magnitude even after adjusting for common risk factors along both the three-factor Fama and French (J Financ Econ 33(1):3–56, 1993) model and the four-factor Carhart (J Finance 52(1):57–82, 1997) model. Categorizing stocks into three risk profiles lets us conclude that long–short momentum portfolios of stocks with a low-risk profile generate robust investment performance.

Background and Objectives: Appendiceal carcinoids are rare neuroendocrine tumors and mainly found incidentally during histopathological examination following appendectomy. This observational cohort study was performed to determine the prevalence, treatment modalities and outcomes in children diagnosed with an appendiceal carcinoid tumor. Materials and Methods: Data from the largest German statutory health insurance “Techniker Krankenkasse” were analyzed within an 8-year period: January 2010 to December 2012 and January 2016 to December 2020. Patient characteristics, surgical technique, type of surgical department, diagnostic management, and postoperative morbidity were analyzed. Results: Out of 40.499 patients following appendectomy, appendiceal carcinoids were found in 44 children, resulting in a prevalence of 0.11%. Mean age at appendectomy was 14.7 (±2.6) years. Laparoscopic approach was performed in 40 (91%) cases. Right-sided hemicolectomy was performed in 8 (18%) patients. Additional diagnostic work-up (CT and MRI) was recorded in 5 (11%) children. Conclusions: This large nationwide pediatric study shows that 1 in 1000 patients was found to have a neuroendocrine tumor of the appendix (prevalence 0.11%), emphasizing its low prevalence in the pediatric age group. The majority of patients were treated with appendectomy only. However, treatment modalities are still variable. Longer follow-up analyses are needed to evaluate published guidelines and recommendations to aim for a limited surgical approach.

Climate change is projected to increase flood risks in West Africa. The EU Horizon 2020 project FANFAR co-designed a pre-operational flood forecasting and alert system for West Africa in four workshops with 50–60 stakeholders from 17 countries, adopting a Multi-Criteria Decision Analysis (MCDA) process. Firstly, we aimed to find a robust configuration of the FANFAR system. We document empirical evidence of MCDA, including stakeholder analysis, jointly creating 10 objectives, and 11 FANFAR system configurations. Stakeholders found it most important that the system produces accurate, clear, and accessible flood risk information, well before floods. Monte Carlo simulation and sensitivity analyses helped identifying three configurations that were robust despite uncertainty of expert predictions and different stakeholder preferences, elicited in group sessions. Secondly, we investigated if problem structuring helps focus early technical system development. Although partly achieved, full MCDA was necessary to provide convincingly robust configurations. Thirdly, we critically analyzed MCDA based on literature from sustainability science and transdisciplinary research. Our proposed framework consists of three steps: co-design (joint problem framing), co-production (doing research), and co-dissemination and evaluation of integrated knowledge. MCDA met many requirements, but not all. In step 1, participatory MCDA with problem structuring provides a consistent methodology, and can identify stakeholders and shared objectives to foster joint understanding. MCDA successfully contributes to step 2 by combining interdisciplinary expert knowledge, integrating conflicting stakeholder preferences, handling uncertainty, and providing unambiguous, shared results. Many elements of step 3 are not met by MCDA. We discuss this framework and using MCDA for transdisciplinary hydrology research that engages with stakeholders and society.

Jedes Produktionsgut muss irgendwie in die Produktionsanlage gelangen. Genau das macht Zuführtechnik. Sie ist ein wichtiger Bestandteil der automatisierten Produktion. Technologische Felder wie Digitale Zwillinge und künstliche Intelligenz bieten heute die Möglichkeit zur Digitalisierung der Zuführtechnik. Der Beitrag befasst sich mit innovativen digitalen Prozessen zur Machbarkeitsanalyse einer Zuführaufgabe, zur Entwicklung von Zuführsystemen sowie zum After Sales & Service. Als Maschinenbasis für die Digitalisierung der Zuführtechnik dienen zwei vibrationsförderbasierte Zuführsysteme.

Climate change is projected to increase flood risks in West Africa. The EU Horizon 2020 project FANFAR co-designed a pre-operational flood forecasting and alert system for West Africa in three lively workshops with 50–60 stakeholders, adopting a transdisciplinary framework from Multi-Criteria Decision Analysis (MCDA). We aimed to (i) exemplify MCDA as a structured transdisciplinary process; (ii) prioritize suitable FANFAR system configurations; and (iii) document and discuss empirical evidence. We used various interactive problem structuring methods in stakeholder sessions to generate 10 objectives and design 11 FANFAR system configurations. The non-additive MCDA model combined expert predictions about system performance with stakeholder preferences elicited in group sessions. All groups preferred a system producing accurate, clear, and accessible flood risk information that reaches recipients well before floods. To receive this, most groups would trade off higher operation and maintenance costs, development time, and implementing several languages. We accounted for uncertainty in expert predictions with Monte Carlo simulation. Sensitivity analyses tested the results’ robustness for changing MCDA aggregation models and diverging stakeholder preferences. Despite many uncertainties, three FANFAR system configurations achieved 63–70 % of the ideal case over all objectives in all stakeholder groups, and outperformed other options in cost-benefit visualizations. Stakeholders designed these best options to work reliably under difficult West African conditions rather than incorporating many advanced features. The current FANFAR system combines important features increasing system performance. Most respondents of a small online survey are satisfied, and willing to use the system in future. We discuss our learning drawing from design principles of transdisciplinary research. We attempted to over-come “unbalanced ownership” and “insufficient legitimacy” by including key West African institutions as consortium partners and carrying out co-design workshops with mandated representatives from 17 countries. MCDA overcomes challenges such as “lack of technical integration”, or “vagueness and ambiguity of results”. Whether FANFAR will have a “societal impact” depends on long term financing and system uptake by West African institutions after termination of EU sponsoring. We hope that our promising results will have a “scientific impact” and motivate further stakeholder engagement in hydrology research.

Nanophase separation during injection molding of high density polyethylene (HDPE) together with polyethylene reactor blend (RB) additives that have ultrabroad bimodal molar mass distribution and a high content of ultrahigh molar mass polyethylene (UHMWPE), produces thermoplastic all-polyethylene composites reinforced with extended-chain UHMWPE nanostructures formed in situ. Neither alien fibers, inorganic fillers, hazardous nanoparticles nor modified single- and multi-step molding processes are required to convert HDPE into higher performance engineering plastics. The RB40 additive is readily tailored by ethylene polymerization on silica-supported chromium two-site catalysts and contains 40 wt% UHMWPE (Mw = 1.5 × 106 g∙mol−1) dispersed in 50 wt% HDPE wax (Mw = 1.1 × 103 g∙mol−1). The presence of disentangled nanophase-separated UHMWPE together with HDPE wax serving as a processing aid enables injection molding of all-PE composites with high UHMWPE content of up to 24 wt% without changing processing parameters typical for HDPE. As verified by both scanning electron microscopic analyses of samples etched with hot xylene and thermal analysis, the HDPE matrix is efficiently reinforced by in situ formed polyethylene shish-kebab fibers where flow-induced crystallization yields extended-chain UHMWPE nanostructures as shish nucleating the crystallization of HDPE kebab. For the first time, by etching quenched samples, it was possible to completely suppress kebab formation and to image in situ extended-chain UHMWPE shish with an average diameter of 80 nm. Upon increasing the UHMPE content the average total diameter of shish-kebab fiber-like structures drastically decreases from micron to nanometer range, forming non-woven-like architectures. This self-reinforcement simultaneously improves toughness, stiffness and strength parameters unparalleled by conventional melt-blending HDPE with micron-sized UHMWPE and HDPE wax. Compared to HDPE, the addition of 60 wt% RB40 increases the Young's modulus to 4.2 GPa, tensile strength to 160 MPa and impact strength to 20 kJ/m2. This sustainable route to self-reinforced all-PE composite composites preserves the high energy, resource, cost and eco-efficiencies typical for pure hydrocarbon resins. Here, we examine the impact of RB40 addition on in situ nanostructure formation and its correlation with thermal and mechanical properties of all-PE composites.

Tailored polyethylene reactor blend additives (RB) with ultrabroad bimodal molar mass distributions comprise nanophase-separated ultrahigh molar mass polyethylene (UHMWPE) uniformly dispersed in polyethylene wax. During injection molding of high-density polyethylene (HDPE) together with variable amounts of the nanophase-separated HDPE wax/UHMWPE (70/30) additive (RB30) flow-induced oriented crystallization affords shish-kebab fiber-like UHMWPE nanostructures accounting for efficient HDPE self-reinforcement. RB additives are readily prepared by ethylene polymerization on silica-supported two-site chromium catalysts which simultaneously produce HDPE wax together with disentangled nanoplatelet-like UHMWPE. The presence of HDPE wax is essential for lowering melt viscosity at high UHMWPE content. Since HDPE wax crystallizes onto extended-chain UHMWPE shish to form kebab structures, high HDPE wax content is tolerated without encountering emission problems and impairing mechanical properties as observed in the a...

The Sudan virus (SUDV), an ebolavirus, causes severe hemorrhagic fever with human case fatality rates of ~50%. Previous work from our lab demonstrated the synthetic antibody F4 potently inhibits viral entry and protects against lethal virus challenge in mice [Chen et al., ACS Chem. Biol., 2014, 9, 2263–2273]. Here, we explore mechanistic requirements as well as contribution of the Fc region and function on neutralization and in vivo protection. Live cell imaging demonstrates that the antibody colocalizes with vesicular stomatitis virus particles containing the Sudan virus glycoprotein (VSV-GP(SUDV)) and that the antibody is rapidly degraded within cellular endosomes. A viral escape mutant contained substitutions on the N-heptad repeat (NHR) segment of GP2, the fusion subunit. Truncation studies indicated that the size of the Fc impacts virus neutralization potential. Finally, we examined the protective efficacy of Fc-null mutants in mice, and found that Fc function was not required for high levels of protection. Altogether, these results indicate that neutralization of SUDV GP-mediated cell entry likely involves blockade of viral membrane fusion within endosomes, and that inhibition of viral entry is the likely mechanism of in vivo protection.

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two E2 mAbs between the β-connector region and the B-domain. Two of the E2-specific mAbs conferred protection in vivo in a stringent lethal challenge mouse model of CHIKV infection, whereas the E1 mAbs did not. These results provide insight into human antibody response to CHIKV and identify candidate mAbs for therapeutic intervention., Author summary Chikungunya virus (CHIKV) is a globally emerging virus that can cause significant disease, including a prolonged and painful arthritis. The virus is spread by mosquitoes that circulate in many regions of the world including the United States. Currently, there are no available vaccines or therapies to treat CHIKV infection. In this report, we identified and characterized a large panel of antibodies against CHIKV from two donors that contracted the viral infection in the Dominican Republic. These antibodies target a number of different regions of the membrane proteins that coat the surface of the virus, and many can inhibit the ability of CHIKV to infect cells. Two of the antibodies were shown to protect mice from a lethal dose of CHIKV. These antibodies have therapeutic potential, and provide insight into the human immune response that may facilitate vaccine development.

Zusammenfassung In diesem Artikel möchten wir unseren, seit 2012 jährlich durchgeführten „Schmökerabend“ näher beleuchten. Dies soll mit Hauptaugenmerk auf die folgenden drei Aspekte geschehen: – Das Angebot von Programmpunkten und Workshops vor Ort, – Ziele und Nutzwert dieser und ähnlicher von der TH und Hochschulbibliothek durchgeführten Veranstaltungen, – der betriebene Arbeitsaufwand und Hilfsmittel (z. B. Projektmanagement Tools), die für Vorbereitung und Organisation solcher Veranstaltungen interessant oder hilfreich sein können.

Patterned homeotropic alignment using nanoparticles (NPs) was achieved using inkjet printing. Two types of gold NPs, one smaller and one larger in core diameter (2 and 5 nm) capped with a monolayer of dodecanethiol, and emissive carbon dots with a core diameter of 2.5 nm featuring a mixed ligand shell of carboxylic acid groups and aliphatic hydrocarbon chains were tested on both rigid glass and flexible polycarbonate substrates. To define the director across the entire cell and not just in the NP-printed areas, alignment ‘underlayers’ were tested, and 30° obliquely evaporated SiOx as alignment ‘underlayer’ generally provided the best results with the highest quality of the homeotropic alignment as well as the best contrast at the boundary between printed and non-printed (i.e. homeotropic and planar) domains of the fabricated cells. We also report that the chemical nature of the nematic liquid crystal (LC) used, the number of layers printed and the composition of the nano-ink need to be adjusted to...

Dispersions of chemically and thermally robust carbon dots (2.5 ± 0.5 nm in core diameter) were prepared and investigated by polarised optical microscopy, electro-optic measurements including dynamic tests and numerical simulations as well as fluorescence confocal microscopy. The carbon dots were prepared by a straightforward thermal decomposition method from citric acid and hexadecylamine, and they show typical excitation wavelength-dependent photoluminescence behaviour. All dispersions, ranging from 0.5 to 5.0 wt.%, showed lower values for isotropic–nematic phase transition temperature and broader isotropic–nematic biphasic temperature intervals with increasing carbon dot content in comparison to the neat material. Doping of the nematic host with the carbon dots resulted in lower values for the apparent threshold voltage and the elastic constants, but higher values for the rotational viscosity. At 2.5 wt.% and higher, carbon dots residing at the confining interfaces in planar cells induce an inc...

Background: HER2+, hormone receptor-positive (HR+) breast cancer is a distinct subtype associated with good prognosis but poor response to standard chemotherapy + anti-HER2 (single or dual blockade). Substantial overtreatment by poly-chemotherapy combined with anti-HER2 therapy is suspected in this subtype. Yet, the efficacy of combining endocrine therapy (ET) with anti-HER2 therapy or novel antibody drug conjugates like T DM1 without systemic chemotherapy remains unclear. Methods: ADAPT HER2+/HR+ is a phase II, randomized, neoadjuvant, 3-arm trial (12 weeks) in patients with cT1c-cT3, cN0/+ HER2+, ER+ and/or PR+ early BC. Arm A: T-DM1 (3.6 mg/kg) alone; Arm B: T DM1 + ET (premenopausal: tamoxifen, postmenopausal: AI); Arm C: trastuzumab + ET. Postoperative chemotherapy is recommended together with completion of one year of trastuzumab. Initial and serial core biopsies were obtained prior to therapy and after 3 weeks. First translational analysis of the trial run-in phase (n=130) focuses on dynamics of HER2, Ki67, ER and PR. Results: 162 tumors, HR+ and HER2+ by local pathology, were screened; n=130 were HR+ and HER2+ by central pathology and randomized at 40 trial sites in Germany between 11/2012 and 03/2014 (Arm A/B/C: 37/49/44). Median age was 49 years; 60% were cT2-3, 32% cN+, 75% central G3; median baseline Ki67 was 30%; 49 patients were treated by TAM and 44 postmenopausal patients by AI in ET containing arms. Three-week core biopsies were available in 117 patients (arm A/B/C: n=33/43/41), n=99 with invasive tumor tissue (61/76 (80%) in T-DM1 containing arms and 38/41(93%) in trastuzumab + ET arm). Three-week Ki67 could only be analyzed in n=73 (53% of patients in T-DM1-containing arms, 81% in the T+ET arm) due to a lacking amount of cells for counting ( Median fractional decrease in proliferation (Ki67) after 3 weeks of therapy was 40% in the T-DM1 + ET arm (B) as compared to 14% and 25% in the T-DM1 (A) and T+ET (C) arms, respectively. Among postmenopausal patients, the contrast (52% (B) vs. 0% (A) and 28% (B)) was significant. Mean PR expression change (absolute, measured in %) was -15 in the B Arm vs. 7 and -7 in the A and C arms, respectively (p=0.04) – particularly in postmenopausal women ( 25 vs. +13 and -10, respectively, p=0.04). Baseline ER expression was positively associated with early proliferation response (fractional Ki67 decrease), e.g., by logistic regression using 30% decrease as response criterion. Data on the impact of gene mutations and further molecular markers on proliferation response will be available for presentation at the meeting. Conclusions: In the unique neoadjuvant ADAPT HER2+/HR+ trial, the combination of T-DM1 with ET (particularly AI) seems to be associated with a strong early proliferation response and PR expression drop in anti-HER2 antibody (drug conjugate) +/- ET, without systemic pre-operative chemotherapy. Interim analysis is scheduled after 130 completely treated patients. The high percentage of non-invasive tissue biopsied after 3 weeks in the T-DM1 arms is intriguing, as it would be consistent with higher pathological complete response rates. Citation Format: Oleg Gluz, Ulrike Nitz, Kuemmel Sherko, Kraemer Stefan, Michael Braun, Claudia Schumacher, Bahriye Aktas, Helmut Forstbauer, Toralf Reimer, Peter Fasching, Jochem Potenberg, Daniel Hofmann, Ronald E Kates, Rachel Wuerstlein, Matthias Christgen, Hans H Kreipe, Nadia Harbeck. Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-01.

Background: In early HR+, HER2-negative breast cancer (BC), the 2013 St. Gallen Consensus recommends adjuvant chemotherapy (CT) for patients with nodal involvement, Recurrence Score (RS) >25, grade G3, or high Ki67. However, risk assessment by these factors may be discordant; e.g., in PlanB, about 60% of centrally G3 tumors did not have RS >25. Here, we present first cumulative outcome data from PlanB for evaluation of different risk assessment tools. Methods: The WSG-PlanB trial was designed to evaluate anthracyline-free adjuvant CT, 6 x TC vs. 4 x EC - 4 x Doc in HER2-negative BC. Since an early amendment (August, 2009), HR+ patients with 0-3 involved nodes and RS≤11 were selected to omit CT, receiving only adjuvant endocrine therapy. The primary trial endpoint is event-free survival (EFS, events: relapse, second malignancy, death); secondary endpoints include relapse-free (RFS) and overall survival (OS). Central grade and luminal B classification were centrally assessed by an independent trial pathologist. Results: From April 2009 to December 2011, 3198 patients were recruited; of these, 2449 were randomized to chemotherapy. Median age was 56 years; 84.1% were HR+ by local pathology, 60.8% node-negative. The central tumor bank population reported here included 3071 cases. RS was available in 2566/2741 cases registered as HR+; of these, 18% had Recurrence Score of 0-11, 60.4% RS 12-25, and 11.6% RS >25. In 343 patients (14.1% of pN0-1 patients after amendment), CT was omitted based on RS ≤11. By central assessment, in HR+ disease, grade was distributed as follows: G1/G2/G3: 5.3%/62.6%/32.1%; only 43.5% of central G3 tumors were locally G3; overall concordance between central and local grade was 65.6%. 41.7% of (central) HR+ patients, had "luminal B" tumors (central Ki67≥20% and/or PR≤20%). After 35 months median follow-up, 131 events, including 103 relapses, have been documented; 3-year EFS and RFS in the no-chemotherapy group were 98.4% and 99.0%, respectively. In the central HR+ population, EFS was substantially poorer in patients with RS >25 than in others (3y EFS: 92% vs. 98% in both RS 12-25 and RS 0-11; p Discussion: In spite of receiving no adjuvant CT, patients with RS 0-11 (HR+ HER2- pN0-1) had excellent 3y-EFS. The excellent outcome of patients with RS 12-25 receiving CT suggests potential CT overtreatment in a subgroup. The ongoing WSG-ADAPT trial addresses this issue. Early results of WSG-PlanB suggest that quality-assured pathology together with Oncotype DX® are essential in identifying high-risk patients to avoid undertreatment. Citation Format: Ulrike Nitz, Oleg Gluz, Ronald E Kates, Daniel Hofmann, Hans H Kreipe, Matthias Christgen, Steve Shak, Michael Clemens, Stefan Kraemer, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Manfred Kusche, Volker Heyl, Fatemah Lorenz-Salehi, Marianne Just, Cornelia Liedtke, Rachel Wuerstlein, Nadia Harbeck. Prognostic impact of discordance between different risk assessment tools in early breast cancer (recurrence score, central grade, Ki67): Early outcome analysis from the prospective phase III WSG-PlanB trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-01.

Filoviruses (family Filoviridae) include five ebolaviruses and Marburg virus. These pathogens cause a rapidly progressing and severe viral disease with high mortality rates (generally 30-90%). Outbreaks of filovirus disease are sporadic and, until recently, were limited to less than 500 cases. However, the 2013-2016 epidemic in western Africa, caused by Ebola virus (EBOV), illustrated the potential of filovirus outbreaks to escalate to a much larger scale (over 28,000 suspected cases). mAbs against the envelope glycoprotein represent a promising therapeutic platform for managing filovirus infections. However, mAbs that exhibit neutralization or protective properties against multiple filoviruses are rare. Here we examined a panel of engineered bi- and trispecific antibodies, in which variable domains of mAbs that target epitopes from multiple filoviruses were combined, for their capacity to neutralize viral infection across filovirus species. We found that bispecific combinations targeting EBOV and Sudan virus (another ebolavirus), provide potent cross-neutralization and protection in mice. Furthermore, trispecific combinations, targeting EBOV, Sudan virus, and Marburg virus, exhibited strong neutralization potential against all three viruses. These results provide important insights into multispecific antibody engineering against filoviruses and will inform future immunotherapeutic discoveries.

Recently main requirements for power conversion system are further downsizing and higher efficiency. To satisfy these requirements, enhanced power density of power modules should be the key to succeed. In this paper, 3.3kV SiC-Hybrid module with High Power next Core package, which can realize enhanced power density, has been described.

Analysis of monoclonal antibodies (MAbs) derived from single B cell cloning has been highly beneficial for antimicrobial immunotherapy, vaccine design, and advancing our understanding of pathogen-triggered effects on the human immunoglobulin repertoire. Sequencing of variable domains of single B cells, and characterization of binding and functional activities of MAbs derived from those sequences, provides in-depth insight not only into sites of susceptibility for antibody-mediated neutralization or opsonization of the pathogen but also into the dynamics of protective antibody evolution during infection. This information can be utilized to rapidly develop novel immunotherapies of completely human origin and provides a roadmap for structure-based vaccine design that aims to elicit similar protective antibody responses. Here, we summarize recent aspects of the single B cell cloning approach.

Background: Prosigna is a standardized test measuring expression levels of 50 classifier genes (PAM50) in breast tumor tissue using nCounter® Technology (Nanostring Technologies, Inc.). It provides intrinsic subtype and risk of recurrence (ROR) score predicting 10-year recurrence probability. WSG prospectively evaluated Prosigna's impact on therapy decisions in EBC and the quality assurance at its implementation in clinical routine. Methods: The study recruited 201 consecutive postmenopausal patients in 11 centers with ER+ HER- N0 EBC (10/2013 to 10/2014). Its primary objective was to assess the extent to which the Prosigna (Breast Cancer Intrinsic Subtype Test (BCIST)) affects the oncologists' treatment recommendations regarding adjuvant chemotherapy (CT) and actual treatments received for EBC patients. Changes in treatment recommendations include (1) endocrine therapy alone, (2) endocrine therapy plus CT, and (3) changes in types of CT before/after the test and confidence in this treatment decision from physician and patient at a 6-month follow up. Secondary objectives included information on (1) physicians' confidence in the recommendations before/after the test, and by cancer recurrence risk groups, (2) rate of CT related adverse events stratified by administration of CT, and (3) patients' decisional conflict status, anxiety levels, and functional status before/after Prosigna's results. As a secondary endpoint for quality assurance, we repeated Prosigna in a second decentralized pathology laboratory in Germany for inter-observation control. Results: In the total evaluable cohort (n=198), 114 (57.6%) of tumors were classified by Prosigna as Luminal A, 79 (39.9%) Luminal B, 3 (1.5%) Basal-like and 2 (1%) HER2-E. Median Prosigna ROR score was 45 (0-94). There was a 29.3% discordance in intrinsic subtyping between Prosigna and IHC. Concordance between central pathology and the second lab regarding molecular subtype was 95.5% with only 9 discordant samples, all within the luminal group. Concordance regarding ROR risk group classification was 92.9%; no clinically relevant differences (low-high or vice versa) were seen. Overall, there was a change of treatment choice (change in CT indication and change in regimens) in 18.2% compared to the pre-Prosigna decision. Post-Prosigna, 87.8% of physicians felt more confident with their prognostic assessment and 89.4% with their intended treatment. 94.8% of the patients expected to stick to their decision after discussing the Prosigna results. Six-month follow up (actual CT administered, its morbidity, perceptions by physicians and patients) will be presented at SABC. Conclusion: Overall, there was a change of treatment choice (change in CT indication and change in CT regimens) in 18.2% compared to the pre-Prosigna decision. Substantial discordance between Prosigna (PAM50) and local IHC underlines the importance of molecular subtyping prior adjuvant treatment decisions. High concordance of Prosigna results between central and decentralized lab testing were found. Results of WSG study can be pooled with two similar European studies and may thus help to improve our understanding of treatment decision making and adherence in EBC. Citation Format: Wuerstlein R, Sotlar K, Gluz O, Hofmann D, Otremba B, Von Schumann R, Witzel I, Schindlbeck C, Janni W, Schem C, Bauerfeind I, Hasmueller S, Tesch H, Paulenz A, Morel P, Cowens W, Hornberger J, Kates RE, Pelz E, Harbeck N. Prosigna® results impact on adjuvant decision making in early breast cancer (EBC): Final analysis of the prospective WSG study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-07-03.

Purpose The 21-gene Recurrence Score (RS) assay is a validated prognostic/predictive tool in early hormone receptor–positive breast cancer (BC); however, only a few prospective outcome results have been available so far. In the phase III PlanB trial, RS was prospectively used to define a subset of patients who received only endocrine therapy. We present 3-year outcome data and concordance analysis (among biomarkers/RS). Patients and Methods Central tumor bank was established prospectively from PlanB (intermediate and high-risk, locally human epidermal growth factor receptor 2–negative BC). After an early amendment, HR-positive, pN0-1 patients with RS ≤ 11 were recommended to omit chemotherapy. Results From 2009 to 2011, PlanB enrolled 3,198 patients with a median age of 56 years; 41.1% had node-positive and 32.5% grade 3 disease. In 348 patients (15.3%), chemotherapy was omitted based on RS ≤ 11. After 35 months median follow-up, 3-year disease-free survival in patients with RS ≤ 11 and endocrine therapy alone was 98% versus 92% and 98% in RS > 25 and RS 12 to 25 in chemotherapy-treated patients, respectively. Nodal status, central and local grade, the Ki-67 protein encoded by the MKI67 gene, estrogen receptor, progesterone receptor, tumor size, and RS were univariate prognostic factors for disease-free survival; only nodal status, both central and local grade, and RS were independent multivariate factors. Histologic grade was discordant between central and local laboratories in 44%. RS was positively but moderately correlated with the Ki-67 protein encoded by the MKI67 gene and grade and negatively correlated with progesterone receptor and estrogen receptor. Conclusion In this prospective trial, patients with enhanced clinical risk and omitted chemotherapy on the basis of RS ≤ 11 had excellent 3-year survival. The substantial discordance observed between traditional prognostic markers and RS emphasizes the need for standardized assessment and supports the potential integration of standardized, well-validated genomic assays such as RS with clinicopathologic prognostic factors for chemotherapy indication in early hormone receptor–positive BC.

The influence of distinct carbon based nanofillers: expanded graphite (EG), conducting carbon black (CB), thermally reduced graphene oxide (TRGO) and multi-walled carbon nanotubes (CNT) on the thermal, dielectric, electrical and rheological properties of polybutylene terephthalate (PBT) was examined. The glass transition temperature (Tg) of PBT nanocomposites is independent of the filler type and content. The carbon particles act as nucleation agents and significantly affect the melting temperature (Tm), the crystallization temperature (Tc) and the degree of crystallinity of PBT composites. PBT composites with EG show insulating behaviour over the tested concentration range of 0.5 to 2 wt.-% and hardly changed rheological behaviour. CB, CNT and TRGO induce electrical conductivity to their particular PBT composites by forming a conducting particle network within the polymer matrix. CNT reached the percolation threshold at the lowest concentration (

535 Background: Prosigna is a standardized test measuring expression levels of 50 classifier genes (PAM50) in formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue using nCounter Technology ...

Background: Early therapy response is currently not regarded for further treatment decisions as standard of care in the treatment of breast cancer (BC). Predictive markers for the success of a certain therapy could support the physician’s choice of adequate and beneficial therapies by simultaneous reduction of unnecessary toxicity. Proliferation makers as Ki-67 seem to be a suitable tool, as dynamic changes of proliferation (as result of induction therapy) have been shown to be most important for outcome of neoadjuvant chemotherapy prediction in patients with pCR in distinct BC subtypes (luminal B, TNBC, HER2+). Methods: Trial design: ADAPT combines early assessment of prognosis by conventional markers (e.g. molecular classification, nodal status) with dynamic measurement of proliferation changes during a 3-week induction therapy, using baseline diagnostic core biopsy and a second biopsy after induction therapy. ADAPT consists of an umbrella trial and five different sub-trials (HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-, Elderly) and is set up as prospective, multi-center, controlled, non-blinded, randomized phase II/III trial. Subtype-specific treatment across the sub-trials is highly innovative and involves the following treatment strategies: • HR+/HER2-: endocrine therapy (ET) vs. chemotherapy (4xPac q2w – 4xEC q2w vs. 8xNab-Pac q1w – 4xEC q2w) + ET, depending on risk classification/early response. • HER2+/HR+: T-DM1 vs. T-DM1 + ET vs. trastuzumab + ET. • HER2+/HR-: Trastuzumab + Pertzumab ± Paclitaxel q1w. • TN: Nab-Paclitaxel + Gemcitabine vs. nab-Pac + Carboplatin. • Elderly: 2xMyocet + Cyclophosphamide q3w, depending on cPR/cCR or NC/toxicity the treatment will be continued for two more cycles or changed to 6xPac q1w. Adaptation/change in therapy regimens can be made by interim analysis after n=130 in each sub-trial. Eligibility criteria: Histologically confirmed unilateral primary invasive BC with known HR-/HER2-status (central pathology) for allocation to the respective sub-trial. Pts requiring chemo- or targeted (anti-HER2) therapy must have adequate laboratory values and organ function and must have no contraindications for the planned treatment. Primary endpoints: Evaluation of dynamic test for outcome prediction/prospective comparison of 5yr EFS in responders (intermediate risk (RS 12-25) / good response to short-term ET in HR+/HER2- or pts with pCR in HER2+/TN BC) compared to low risk HR+/HER2- (RS≤11, N0-1) pts (control group). Statistical methods: Assumption across sub-protocols: adjuvant CTx can be spared in HR+/HER2- or pCR be achieved in HER2+/TN in expected 1120 (HR+/HER2-) or 170 (HER2+/TN) pts, respectively. Outcome will be compared to the control group (expected n=640 HR+/HER2- pts: low risk (by RS), i.e. no CTx). Assuming 94% 5yr survival in control group, one-sided test of non-inferiority at 95% CI will have 80% power for survival non-inferiority margin of 3.2% (i.e. 90.8% survival). Present and target accrual: By June 2014, 73 active sites have recruited 1820 pts for ADAPT HR+/HER2-. Target accrual is 4000 pts. 190 of 380 pts were successfully randomized for ADAPT HER2+/HR+. ADAPT HER2+/HR- has included 17 of 220 pts and ADAPT Triple Negative has recruited 150 of 336 pts. Citation Format: Ulrike Nitz, Oleg Gluz, Raquel von Schumann, Daniel Hofmann, Ronald E Kates, Sherko Kuemmel, Michael Braun, Claudia Schumacher, Benno Nuding, Bahriye Aktas, Helmut Forstbauer, Nicolai Maass, Mahdi Rezai, Stefan Kraemer, Mathias Warm, Rachel Wuerstlein, Nadia Harbeck. ADAPT - Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-04.

Background: Current diagnostic tools for breast cancer (BC), including screening, diagnostic breast imaging and biopsy, do not provide information about subtype classification. However, the subtype classification is crucial for the assessment of the recurrence risk and for the choice of optimal adjuvant treatment. A vast amount of data from recent research, clinical trials, and peer reviewed publications support the value of intrinsic subtyping based on gene expression analyses to assess prognosis and treatment options for patients with early BC. Trial design: The multicenter (n=8), prospective study examines whether the Prosigna™ test influences physician and patient adjuvant treatment selection over and above currently used prognostic factors. It also examines the impact of the test results on patients’ reported outcomes including their decisional conflict status, anxiety levels, and functional status. Prosigna™ is a standardized test measuring the expression levels of 50 classifier genes in formalin-fixed, paraffin-embedded tissue samples and provides a subtype classification based on the fundamental biology of individual patient’s tumor (intrinsic subtyping), as well as a prognostic score (risk of recurrence (ROR) score) that predicts the probability of cancer recurrence over 10 years. Eligibility criteria: Postmenopausal women with resected N0, estrogen-receptor-positive (ER) (by immunohistochemistry (IHC); >1% of stained tumor cells is considered positive), HER2-negative (IHC and/or in-situ fluorescence hybridization by local laboratory), early-stage invasive BC (T1-T2, pN0 (i+/mol+), M0). Patients must be able to give consent and must be eligible for treatment with adjuvant chemotherapy (Ctx) (ECOG performance status ≤1). Patients with non-invasive (e.g. Paget’s disease, DCIS), ER-negative or HER2-positive BC must not be included. Metastatic disease and contraindications for adjuvant Ctx (age, ECOG >1, significant comorbidities) are exclusion criteria. Patients unable to complete patient reported outcome surveys will be excluded. Specific aims: Primary endpoint is the proportion of patients whose choice of treatment is changed as a result of receiving the Prosigna™ result. Secondary endpoints include the proportion of patients whose choice of treatment is changed stratified by ROR groups (low, intermediate, high) and who have cancer recurrence risk proximal to the cutoff points between risk strata (± 5% from cutoff point). Investigators’ confidence in treatment recommendations before/after Prosigna™ results and change in patients’ decisional conflict status, anxiety levels, and functional status, stratified by cancer recurrence risk strata, will be investigated. Rate and severity of treatment-related adverse events stratified by whether patient received adjuvant Ctx and agreement in molecular subtyping between Prosigna™ and local IHC will be evaluated. Statistical methods: Sample size of 200 produces a one-sided 95% lower-limit CI with a distance from the sample proportion to the lower limit that is equal to 0.05 when the sample proportion is 0.25. Present and target accrual: A total of 200 patients will be included, current accrual is n=111 as of 3rd June 2014. Citation Format: Rachel Wuerstlein, Karl Sotlar, Burkhard Otremba, Oleg Gluz, Enrico Pelz, Daniel Hofmann, Ronald E Kates, Isabelle Witzel, Christian Schindlbeck, Wolfgang Janni, Christian Schem, Hans Tesch, Nadia Harbeck. Prospective observational study of clinical outcomes for the NanoString® technologies Prosigna™ test by the West German Study Group [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-03.