An antibody fragment-decorated liposomal conjugate targets Philadelphia-like acute lymphoblastic leukemia.

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is an aggressive B-ALL malignancy associated with high rates of relapse and inferior survival rate. While targeted treatments against the cell surface proteins CD22 or CD19 have been transformative in the treatment of refractory B-ALL, patients may relapse due to antigen loss, necessitating targeting alternative antigens. Cytokine receptor-like factor 2 (CRLF2) is overexpressed in half of Ph-like ALL cases conferring chemoresistance and enhancement of leukemia cell survival. Therefore, targeting CRLF2 may reduce the likelihood of relapse associated with antigen loss. We developed a CRLF2-targeting single-chain variable fragment modified by the fragment crystallizable region (CRLF2 scFv-Fc) conjugated to a drug maytansinoid 1 (DM1)-DOPC liposomal conjugate, creating homogeneous CRLF2-targeted liposomes (CRLF2-DM1 LIP). Cellular association and internalization studies in a Ph-like ALL cell line, MHH-CALL-4, compared to its lentivirally transduced CRLF2-knockdown counterpart (KD-CALL-4) revealed excellent CRLF2-targeting efficiency of CRLF2-DM1 LIP. Moreover, CRLF2-DM1 LIP showed selective association and internalization ex vivo using Ph-like ALL patient-derived xenograft (PDX) cells with minimal reactivity with non-target cells. Cell apoptosis assays demonstrated the CRLF2-dependent potency of CRLF2-DM1 LIP in Ph-like ALL cell lines. This study is the first to highlight the therapeutic potential of a CRLF2-directed scFv-Fc-liposomal conjugate for targeting Ph-like ALL.

Feasibility Study for Finding Mathematical Approaches to Describe the Optimal Operation Point of Sensor-Based Sorting Machines for Plastic Waste.

At present, sensor-based sorting machines are usually not operated at the optimal operation point but are either overrun or underrun depending on the availability of waste streams. Mathematical approaches for predefined ideal mixtures can be found based on the input stream composition and the throughput rate. This scientific article compares whether and under what conditions these approaches can be applied to sensor-based sorting machines. Existing data for predefined ideal mixtures are compared with newly generated data of real waste on three sensor-based sorting setups in order to make significant statements. Five samples of 3D plastics at regular intervals were taken in a processing plant for refuse-derived fuels. With the comparison of all these results, four hypotheses were validated, related to whether the same mathematical approaches can be transferred from ideal mixtures to real waste and whether they can be transferred to sensor-based sorting machines individually or depending on the construction type. The developed mathematical approaches are regression models for finding the optimal operation point to achieve a specific sensor-based sorting result in terms of purity and recovery. For a plant operator, the main benefit of the findings of this scientific article is that purity could be increased by 20% without substantially adapting the sorting plant.

PIK3CA-mutations in breast cancer.

PURPOSE: Phosphatidylinositide-3-kinase (PI3K) regulates proliferation and apoptosis; somatic PIK3CA-mutations may activate these processes. Aim of this study was to determine the prevalence of PIK3CA-mutations in a cohort of early stage breast cancer patients and the association to the course of disease. PATIENTS AND METHODS: From an unselected cohort of 1270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT01592825) 1123 tumours were tested for the three PIK3CA hotspot-mutations H1047R, E545K, and E542K by qPCR. Primary objectives were the prevalence of somatic PIK3CA-mutations and their association to tumour characteristics. Secondary objective was the association of PIK3CA-mutations to recurrence-free interval (RFI) and overall survival. RESULTS: PIK3CA-mutation rate was 26.7% (300 of 1123). PIK3CA-mutations were significantly more frequent in steroid hormone-receptor (SHR)-positive HER2-negative (31.4%), and G1 and G2 tumours (32.8%). Overall, we did not observe a significant association of PIK3CA-mutations to RFI. In SHR-positive BCs with PIK3CA-mutations, a strong trend for impaired  RFI was observed (adjusted HR 1.64, 95% CI 0.958-2.807), whilst in SHR-negative BCs PIK3CA-mutations were insignificantly associated with improved RFI (adjusted HR 0.49; 95% CI 0.152-1.597). Of note, we observed a significantly detrimental prognostic impact of PIK3CA-mutations on RFI in SHR-positive, HER2-negative BCs if only aromatase inhibitors were administered as adjuvant therapy (adjusted HR 4.44, 95% CI 1.385-13.920), whilst no impact was observed in tamoxifen treated patients. CONCLUSION: This cohort study speficies the overall mutation rate of PIK3CA in early breast cancer. The impact of PIK3CA-mutations on RFI and OS was heterogeneous. Our results suggest that estrogen deprivation failes to be active in case of PIK3CA-mutation.

Evaluation of Improvements in the Separation of Monolayer and Multilayer Films via Measurements in Transflection and Application of Machine Learning Approaches.

Small plastic packaging films make up a quarter of all packaging waste generated annually in Austria. As many plastic packaging films are multilayered to give barrier properties and strength, this fraction is considered hardly recyclable and recovered thermally. Besides, they can not be separated from recyclable monolayer films using near-infrared spectroscopy in material recovery facilities. In this paper, an experimental sensor-based sorting setup is used to demonstrate the effect of adapting a near-infrared sorting rig to enable measurement in transflection. This adaptation effectively circumvents problems caused by low material thickness and improves the sorting success when separating monolayer and multilayer film materials. Additionally, machine learning approaches are discussed to separate monolayer and multilayer materials without requiring the near-infrared sorter to explicitly learn the material fingerprint of each possible combination of layered materials. Last, a fast Fourier transform is shown to reduce destructive interference overlaying the spectral information. Through this, it is possible to automatically find the Fourier component at which to place the filter to regain the most spectral information possible.

Lifecycle Assessment for Recycling Processes of Monolayer and Multilayer Films: A Comparison.

This work covers a lifecycle assessment of monolayer and multilayer films to quantify the environmental impacts of changing the management of plastic film waste. This lifecycle assessment offers the possibility of quantifying the environmental impacts of processes along the lifecycle of monolayer and multilayer films and mapping deviating impacts due to changed process parameters. Based on the status quo, the changes in global warming potential and abiotic fossil resource depletion were calculated in different scenarios. The changes included collecting, sorting, and recycling mono- and multilayer films. The "Functional Unit" under consideration comprised 1000 kg of plastic film waste, generated as post-consumer waste in Austria and captured in the lightweight packaging collection system. The results showed the reduction of environmental impacts over product lifecycles by improving waste management and creating a circular economy. Recycling all plastic film reduced global warming potential by 90% and abiotic fossil resource consumption by 93%. The necessary optimisation steps to meet the politically required recycling rates by 2025 and 2030 could be estimated, and the caused environmental impacts are presented. This work shows the need for increased collection, recycling, and significant improvement in the sorting of films to minimise global warming potential and resource consumption.

Latent Recycling Potential of Multilayer Films in Austrian Waste Management.

This work presents a hand sorting trial of Austrian plastic packaging, which showed that according to an extrapolation of the 170,000 t separately collected waste collected in Austria, 30 wt% are flexible 2D plastic packaging. Further, the applications for these materials have been catalogued. The composition of these films was evaluated via Fourier-Transformed Infrared Spectroscopy, which showed that 31% of all films were made of polyethene, 39% of polypropylene, 11% of polyethene-polyethene terephthalate composite, and 8% of a polyethene-polypropylene composite, further resulting in the calculation that of all flexible packaging, 20 wt% are multilayer films. These findings were used to calculate the latent potential for raising the current recycling quota of 25.7% to the mandated rate of 55% in 2030. To this end, scenarios depicting different approaches to sorting and recycling small films were evaluated. It was calculated that through improving the sorting of films the recycling rate could be increased to 35.5%. This approach allows for the recycling of monolayer films by avoiding contamination with foreign materials introduced by multilayer films that impede the recyclates' mechanical properties. The evaluation showed that sorting multilayer films of this fraction could raise the recycling quota further to 38.9%.

A New Three-Component Photo-Initiating System for Visible Light Recording of Volume Holograms with Single-Pulsed Laser.

Versatile substituted electron-deficient trichloromethylarenes can easily be synthesized and combined with a Safranine O/triarylalkylborate salt to form a highly efficient three-component photo-initiation system that starts free radical polymerization to finally form holographic gratings with a single-pulsed laser. The mechanism of this photo-initiation most likely relies on an electron transfer from the borate salt into the semi-occupied HOMO of the excited dye molecule Safranine O, which after fragmentation generates an initiating alkyl radical and longer-lived dye radical species. This dye radical is most probably oxidized by the newly introduced trichloromethylarene derivative as an electron acceptor. The two generated radicals from one absorbed photon initiate the photopolymerization and form index gratings in a suitable holographic recording material. This process is purely photonic and does not require further non-photonic post treatments.

A recombinant antibody fragment directed to the thymic stromal lymphopoietin receptor (CRLF2) efficiently targets pediatric Philadelphia chromosome-like acute lymphoblastic leukemia.

Antibody fragments are promising building blocks for developing targeted therapeutics, thus improving treatment efficacy while minimising off-target toxicity. Despite recent advances in targeted therapeutics, patients with Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), a high-risk malignancy, lack specific and effective targeted treatments. Cytokine receptor-like factor 2 (CRLF2) is overexpressed in 50% of Ph-like ALL cases, conferring the survival of leukemia blasts through activation of the JAK/STAT signalling pathway. Targeting such a vital cell-surface protein could result in potent anti-leukaemic efficacy and reduce the likelihood of relapse associated with antigen loss. Herein, we developed a novel single-chain variable fragment (scFv) against CRLF2 based on a monoclonal antibody raised against the recombinant extracellular domain of human TSLPRα chain. The scFv fragment demonstrated excellent binding affinity with CRLF2 protein in the nanomolar range. Cellular association studies in vitro using an inducible CRLF2 knockdown cell line and ex vivo using patient-derived xenografts revealed the selective association of the scFv with CRLF2. The fragment exhibited significant receptor antagonistic effects on STAT5 signalling, suggesting possible therapeutic implications in vivo. This study is the first to describe the potential use of a novel scFv for targeting Ph-like ALL.

Influence of material alterations and machine impairment on throughput related sensor-based sorting performance.

Experiments with sensor-based sorting (SBS) machinery provide insight into the effect of throughput rate and input composition on the sorting performance. For this purpose, material mixtures with certain compositions and particle size distributions were created from waste fractions and sorted at various throughput rates. To evaluate the sorting performance of the SBS unit (using near infrared technology) in dependence of the applied load, four assessment factors concerning the output fractions were studied: yield, product purity, recovery/product quantity and incorrectly discharged share of reject particles. The influences on the assessment parameters of light twodimensional (2D) particles in the input of a sorting stage and failing air valves in an SBS unit were evaluated for various input compositions at different throughput rates. It was found that a share of approximately 5 wt% 2D particles in the input had a similar negative effect on the yield as the malfunction of 20% of all air valves in an SBS machine at high throughput rates. Additionally, the failure of the air valves reduced the product purity of the sorting stage at increased throughput rates. Furthermore, qualitative observations concerning systematic effects of prior studies could be confirmed. Resulting graphs for a specific input composition of an SBS unit at varying throughput rates could be used to adjust the throughput rate to meet the exact demands for a sorting stage.

Substantial Genetic Progress in the International Apis mellifera carnica Population Since the Implementation of Genetic Evaluation.

The Apis mellifera carnica subspecies of the honeybee has long been praised for its gentleness and good honey yield before systematic breeding efforts began in the early 20th century. However, before the introduction of modern techniques of genetic evaluation (best linear unbiased prediction, BLUP) and a computerized data management in the mid 1990s, genetic progress was slow. Here, the results of the official breeding value estimation in BeeBreed.eu are analyzed to characterize breeding progress and inbreeding. From about the year 2000 onward, the genetic progression accelerated and resulted in a considerable gain in honey yield and desirable properties without increased inbreeding coefficients. The prognostic quality of breeding values is demonstrated by a retrospective analysis. The success of A. m. carnica breeding shows the potential of BLUP-based breeding values and serves as an example for a large-scale breeding program.

Effects of copper-impregnated collagen implants on local pro- and anti-inflammatory and regenerative tissue reactions following implantation in rats.

Combining collagen, an established regenerative biomaterial, and copper (Cu) with its known antibacterial and angiogenic effects could improve wound healing. However, Cu is also cytotoxic. Thus, this study aimed at examining the tissue reactions after simultaneous intramuscular implantation of collagen discs either without Cu (controls) or impregnated in 2, 20, or 200 mmol/L Cu acetate in 24 rats. After 7, 14, and 56 days, implants with peri-implant tissue were retrieved from 8 rats/day for immunohistochemical detection of CD68+ monocytes/macrophages and CD163+ macrophages, MHC-II+ cells, T lymphocytes and nestin as tissue regeneration marker. CD68+ monocytes/macrophages around implants increased with Cu amount but decreased over time except for the highest Cu amount, while CD163+ macrophages increased over time around and within implants. MHC-II+ cells were similar to CD68+ monocytes/macrophages. T lymphocyte numbers around implants were higher for Cu-impregnated samples vs. controls on day 7 and highest on day 14, but declined afterwards. Nestin expression around and within implants was largely unaffected by Cu. In conclusion, pro-inflammatory reactions around implants were dose-dependently influenced by Cu but mostly decreased over time, while Cu did not negatively affect anti-inflammatory and regenerative reactions. These results suggest that Cu-impregnated collagen could be beneficial in wound treatment.

Controlled fermentation of rapeseed presscake by Rhizopus, and its effect on some components with relevance to human nutrition.

The use of rapeseed protein could contribute to meeting the increasing demand for plant proteins with high biological value in human nutrition. In order to make rapeseed presscake fit for human consumption, the presscake was fermented by using the tempeh mould, Rhizopus microsporus var. oligosporus. Fermentation was satisfactory at initial levels of added acetic acid of 40-60 mmoles/Kg, aw of 0.97, pasteurization, surface inoculation and incubation at 32 °C and 90-95% relative humidity. It was crucial to stop the fermentation once the mould had grown and metabolized sufficiently but before a major rise in pH and subsequent growth of acid-sensitive sporeforming bacteria occurred. Some degradation of glucosinolates, cell wall polysaccharides and phenolic compounds was found, but there was some evidence that growth and metabolism of the mould also depended on the texture of the presscake, as these factors affect the oxygen supply to the mould. In conclusion, it is possible to ferment rapeseed presscake by using the "Tempeh starter" Rhizopus oligosporus, but in order to use the resulting product to enrich various foods with protein or replace other proteins, the degree of degradation of undesired compounds should be further standardized, especially by the control of the pH, oxygen supply, and fermentation time.

The Chemistry and Physics of Bayfol® HX Film Holographic Photopolymer.

Holographic photopolymers are a new technology to create passive diffractive optical elements by a pure laser interference recording. In this review, we explain the chemistry concepts of light harvesting in an interference pattern and the subsequent grating formation as chemical response. Using the example of the newly developed Bayfol® HX film we discuss the reaction-diffusion driven photo-polymerization process for an index modulation formation to create volume phase gratings. Further we elucidate the selection of monomer chemistry and discuss details of the recording conditions based on the concept of exposure dosage and exposure time. Influences ranging from high dosage recording to low power recording are explained and how to affect the desired diffraction efficiency. Finally, we outline and demonstrate the process to mass manufacturing of volume phase gratings.

Factors Associated with Worse Lung Function in Cystic Fibrosis Patients with Persistent Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. METHODS: Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. RESULTS: 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). CONCLUSIONS: In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00669760.

High performance photoinitiating systems for holography recording: need for a full control of primary processes.

Optimization of holography recording in photopolymers was studied from the point of view of a quite general process, that is, the photogeneration of radicals. On the basis of a dye/coinitiator photoinitiating system, the effect of primary events and their relative efficiency was investigated with respect to the final overall properties, such as the diffraction efficiency. Quenching of the dye excited states by the borate salts coinitiators exhibits important differences depending on the dye used (Rose Bengal or Safranine O). Keeping in mind that both singlet and triplet states of the dyes can react, and taking into account the viscosity of the matrix, a method to evaluate the overall quantum yield of radicals released is proposed. It is found that this quantum yield well correlates with the maximum rate of photopolymerization. More interestingly, the dose required to obtain a given diffraction efficiency was found to be also governed by the radical quantum yield, showing that the final property is directly governed by primary events. This shed some light on the efficiency of photochemical pathway to generate radicals for use in organic or polymer areas.

Time-sequential autostereoscopic 3-D display with a novel directional backlight system based on volume-holographic optical elements.

A novel directional backlight system based on volume-holographic optical elements (VHOEs) is demonstrated for time-sequential autostereoscopic three-dimensional (3-D) flat-panel displays. Here, VHOEs are employed to control the direction of light for a time-multiplexed display for each of the left and the right view. Those VHOEs are fabricated by recording interference patterns between collimated reference beams and diverging object beams for each of the left and right eyes on the volume holographic recording material. For this, self-developing photopolymer films (Bayfol® HX) were used, since those simplify the manufacturing process of VHOEs substantially. Here, the directional lights are similar to the collimated reference beams that were used to record the VHOEs and create two diffracted beams similar to the object beams used for recording the VHOEs. Then, those diffracted beams read the left and right images alternately shown on the LCD panel and form two converging viewing zones in front of the user's eyes. By this he can perceive the 3-D image. Theoretical predictions and experimental results are presented and the performance of the developed prototype is shown.

Traditional 'air-dried' fermented sausages from Central Germany.

Traditional varieties of fermented pork sausages from Central Germany are different from related meat products in various aspects. First, they are prepared from "warm" pork immediately after slaughter. The meat is then minced, mixed with spices and minimal amounts of sugars, salt and nitrate, and the stuffed sausages ripen for a minimum of 6-8 weeks at temperatures below 15 °C. Second, surface mould growth during ripening is regularly removed or suppressed. The manufacturing methods require a minimum of investments and labour and reflect the socio-economic situation in the manufacturing area. The sausages have a good record of safety, and a preliminary risk assessment indicates that pathogens are kept under sufficient control by the extended ripening at low temperatures. Small-scale (artisanal) manufacture of these products is only possible with a flexible interpretation of the hygienic principles set up in current legislation.

Early dialogue between the developers of new technologies and pricing and reimbursement agencies: a pilot study.

It is common practice for developers of new health care technologies to engage in early dialogue with the major regulatory agencies; such discussions frequently center around the proposed clinical trial designs to support the registration of new interventions and suggestions on their improvement. Pricing and reimbursement agencies are increasingly using the results from health technology assessments to inform their decision making for new technologies. Such assessments are invariably underpinned by the phase 3 clinical trial evidence which may not provide answers to the key questions. Technology developers are beginning to realize that direct, early dialogue on the evidence requirements of the major pricing and reimbursement agencies, before phase 3 clinical trial designs for their key development compounds have been finalized, may be beneficial. This article reports on the pioneering efforts of one technology developer in seeking early dialogue with seven pricing and reimbursement agencies in five countries globally in 2007-2008 on their likely evidence requirements for a new oral treatment for patients with chronic plaque psoriasis. The pilot project demonstrated that a feasible process of early dialogue could be established, through a face-to-face meeting with prior circulation of a briefing book. Although there was some variation in the advice the similarities far outweighed the differences. More experience of early dialogue needs to be accumulated, involving a wider range of pricing and reimbursement agencies and compounds. The conclusion of this study, however, was that early dialogue can be a worthwhile process for all parties and can lead to a common understanding about evidence development for market access.

From the surface to volume: concepts for the next generation of optical-holographic data-storage materials.

Optical data storage has had a major impact on daily life since its introduction to the market in 1982. Compact discs (CDs), digital versatile discs (DVDs), and Blu-ray discs (BDs) are universal data-storage formats with the advantage that the reading and writing of the digital data does not require contact and is therefore wear-free. These formats allow convenient and fast data access, high transfer rates, and electricity-free data storage with low overall archiving costs. The driving force for development in this area is the constant need for increased data-storage capacity and transfer rate. The use of holographic principles for optical data storage is an elegant way to increase the storage capacity and the transfer rate, because by this technique the data can be stored in the volume of the storage material and, moreover, it can be optically processed in parallel. This Review describes the fundamental requirements for holographic data-storage materials and compares the general concepts for the materials used. An overview of the performance of current read-write devices shows how far holographic data storage has already been developed.

Comparison of a new self developing photopolymer with AA/PVA based photopolymer utilizing the NPDD model.

The development of suitable recording media for applications such as holographic optical elements and holographic data storage are of significant research and commercial interest. In this paper, a photopolymer material developed by Bayer MaterialScience is examined using various optical techniques and then characterised using the Non-local Photo-polymerization Driven Diffusion model. This material demonstrates the capabilities of a new class of photopolymer offering high index modulation, full colour recording, high light sensitivity and environmental stability. One key result of this study is the material's high spatial frequency resolution, indicating a very low non-local effect, thus qualifying it as a very good storage medium.