Proactive maintenance as success factor for use-oriented product-service systems

In use-oriented Product-Service Systems (PSS) the ownership of the product remains with the provider who is responsible for maintenance, repair and overhaul [1]. Thus the risk of machine unavailability is transferred from the customer towards the PSS provider. In order to minimize this risk the provider needs to reduce unscheduled downtimes to enhance machine availability. Hence proactive maintenance is an important success factor for providing this PSS type [2]. In practice, manufacturing equipment providers struggle to derive the required information for providing proactive maintenance from the existing data and thus potentials remain unused. One of the problems for many companies in this context is the missing knowhow for managing and analyzing this high amount of data. This issue is discussed in research and practice under the topic “Big Data” [3]. This paper focusses on discussing different approaches for data gathering, analysis and interpretation as well as associated challenges. Drivers and hindering factors are introduced and solution approaches are provided. These aspects are analyzed in a case study in collaboration with a material handling manufacturer which was conducted in one of the transfer projects of the Collaborative Research Center Transregio 29 which addressed the dynamic interdependencies of products and services in the production area

Accelerated hyperfractionation plus temozolomide in glioblastoma

Introduction Hyperfractionated (HFRT) or accelerated hyperfractionated radiotherapy (AHFRT) have been discussed as a potential treatment for glioblastoma based on a hypothesized reduction of late radiation injury and prevention of repopulation. HFRT and AHFRT have been examined extensively in the pre-Temozolomide era with inconclusive results. In this study we examined the role of accelerated hyperfractionation in the Temozolomide era. Materials and methods Sixty-four patients who underwent AHFRT (62 of which received Temozolomide) were compared to 67 patients who underwent normofractionated radiotherapy (NFRT) (64 of which received TMZ) between 02/2009 and 10/2014. Follow-up data were analyzed until 01/2015. Results Median progression-free survival (PFS) was 6 months for the entire cohort. For patients treated with NFRT median PFS was 7 months, for patients treated with AHFRT median PFS was 6 months. Median overall survival (OS) was 13 months for all patients. For patients treated with NFRT median OS was 15 months, for patients treated with AHFRT median OS was 10 months. The fractionation regimen was not a predictor of PFS or OS in univariable- or multivariable analysis. There was no difference in acute toxicity profiles between the two treatment groups. Conclusions Univariable and multivariable analysis did not show significant differences between NFRT and AHFRT fractionation regimens in terms of PFS or OS. The benefits are immanent: the regimen does significantly shorten hospitalization time in a patient collective with highly impaired life expectancy. We propose that the role of AHFRT + TMZ should be further examined in future prospective trials

Total body irradiation as part of conditioning regimens in childhood leukemia—long-term outcome, toxicity, and secondary malignancies

Background: Total body irradiation (TBI) is an established part of conditioning regimens prior to stem cell transplantation in childhood leukemia but is associated with long-term toxicity. We retrospectively analyzed survival, long-term toxicity, and secondary malignancies in a pooled cohort of pediatric patients (pts.) treated with the same TBI regimen. Methods: Analyzed were 109 pts. treated between September 1996 and November 2015. Conditioning treatment according to EBMT guidelines and the ALL SCTped 2012 FORUM trial consisted of chemotherapy (CT) and TBI with 2 Gy b.i.d. on 3 consecutive days to a total dose of 12 Gy. Median follow-up was 97.9 months (2-228 months). Results: Overall survival (OS) in our cohort at 2, 5, and 10 years was 86.1, 75.5, and 63.0%, respectively. Median survival was not reached. Long-term toxicity developed in 47 pts. After chronically abnormal liver and kidney parameters in 31 and 7 pts., respectively, growth retardation was the most frequent finding as seen in 13 pts. Secondary malignancies were rare (n = 3). Conclusion: TBI-containing conditioning regimens in pediatric stem cell transplantation (SCT) are highly effective. Efforts to replace TBI- with CT-containing regimens have only been successful in subgroups of pts. Although we could show long-term toxicity in 43% of pts., overall survival was 63% at 10 years. Still, long-term effects such as growth retardation can permanently impact the pts.' quality of life and functioning. Along with new substances, efforts should be undertaken to optimize TBI techniques and accompany the treatment by systematic follow-up programs beyond 5 years to improve detection of rare events

Active matrix-based pressure sensor system with a 4 × 16 printed decoder designed with a flexible hybrid organic process design kit

The innovative field of printed sensor with a demand for high accuracy, sensitivity and durability has enabled a wide application area in sensing, healthcare etc. A large-area printed sensor system on a flexible foil substrate emplying p-type organic field-effect transistors (OFETs) is presented. Thereby, the OFET is fabricated through a hybrid manufacturing process, including photolithographically structured source- and drain-electrodes, ink-jet printed organic semiconductor, and spin-coated dielectric. Moreover, a dedicated device model, derived from the variable range hopping model, is developed and integrated together with process related design rules, materials properties and geometric information into a comprehensive process design kit (FH_OPDK). The FH_OPDK is integrated in a commercial electronic design automation tool and is used to design and perform post-layout simulations on logic gates, such as INV, NAND2, and NOR2 as well as circuitry such as ring oscillators and a 4 × 16 digital decoder. Several circuit topologies have been tested and evaluated in a detailed model-hardware correlation analysis. Finally we have optimized logic gates and the decoder in a PMOS only, pseudo CMOS design style. To demonstrate the feasibility of the full sensor system in hardware a 16 × 16 active matrix pressure sensor on a flexible substrate integrated with a 4 × 16 binary decoder was fabricated and tested. We have integrated our flexible hybrid sensor system with a PCB board and a microcontroller to demonstrate the hardware readout platform capable of detecting the weight of objects and visualizing a digital map of applied forces

CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer

Background: Molecular targeting remains to be a promising approach in oncology. Overexpression of G protein-coupled receptors (GPCRs) in human cancer is offering a powerful opportunity for tumor-selective imaging and treatment employing nuclear medicine. We utilized novel chemerin-based peptide conjugates for chemokine-like receptor 1 (CMKLR1) targeting in a breast cancer xenograft model. Methods: By conjugation with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of five highly specific, high-affinity tracers for hybrid positron emission tomography/magnetic resonance (PET/MR) imaging. A xenograft model with target-positive DU4475 and negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imaging in vivo. We acquired small animal PET/MR images, assessed biodistribution by ex vivo measurements and investigated the tracer specificity by blocking experiments. Results: Five CMKLR1-targeting peptide tracers demonstrated high biological activity and affinity in vitro with EC50 and IC50 values below 2 nM. Our target-positive (DU4475) and target-negative (A549) xenograft model could be validated by ex vivo analysis of CMKLR1 expression and binding. After preliminary PET imaging, the three most promising tracers [68Ga]Ga-DOTA-AHX-CG34, [68Ga]Ga-DOTA-KCap-CG34 and [68Ga]Ga-DOTA-ADX-CG34 with best tumor uptake were further analyzed. Hybrid PET/MR imaging along with concomitant biodistribution studies revealed distinct CMKLR1-specific uptake (5.1% IA/g, 3.3% IA/g and 6.2% IA/g 1 h post-injection) of our targeted tracers in DU4475 tumor tissue. In addition, tumor uptake was blocked by excess of unlabeled peptide (6.4-fold, 5.5-fold and 3.4-fold 1 h post-injection), further confirming CMKLR1 specificity. Out of five tracers, we identified these three tracers with moderate, balanced hydrophilicity to be the most potent in receptor-mediated tumor targeting. Conclusion: We demonstrated the applicability of 68Ga-labeled peptide tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR imaging, paving the way for developing them into theranostics for tumor treatment

Harmonising knowledge for safer materials via the “NanoCommons” Knowledge Base

In mediaeval Europe, the term “commons” described the way that communities managed land that was held “in common” and provided a clear set of rules for how this “common land” was used and developed by, and for, the community. Similarly, as we move towards an increasingly knowledge-based society where data is the new oil, new approaches to sharing and jointly owning publicly funded research data are needed to maximise its added value. Such common management approaches will extend the data’s useful life and facilitate its reuse for a range of additional purposes, from modelling, to meta-analysis to regulatory risk assessment as examples relevant to nanosafety data. This “commons” approach to nanosafety data and nanoinformatics infrastructure provision, co-development, and maintenance is at the heart of the “NanoCommons” project and underpins its post-funding transition to providing a basis on which other initiatives and projects can build. The present paper summarises part of the NanoCommons infrastructure called the NanoCommons Knowledge Base. It provides interoperability for nanosafety data sources and tools, on both semantic and technical levels. The NanoCommons Knowledge Base connects knowledge and provides both programmatic (via an Application Programming Interface) and a user-friendly graphical interface to enable (and democratise) access to state of the art tools for nanomaterials safety prediction, NMs design for safety and sustainability, and NMs risk assessment, as well. In addition, the standards and interfaces for interoperability, e.g., file templates to contribute data to the NanoCommons, are described, and a snapshot of the range and breadth of nanoinformatics tools and models that have already been integrated are presented Finally, we demonstrate how the NanoCommons Knowledge Base can support users in the FAIRification of their experimental workflows and how the NanoCommons Knowledge Base itself has progressed towards richer compliance with the FAIR principles

Genetic Analyses of Heme Oxygenase 1 (HMOX1) in Different Forms of Pancreatitis

Contains fulltext : 107993.pdf (publisher's version ) (Open Access)BACKGROUND: Heme oxygenase 1 (HMOX1) is the rate limiting enzyme in heme degradation and a key regulator of inflammatory processes. In animal models the course of pancreatitis was ameliorated by up-regulation of HMOX1 expression. Additionally, carbon monoxide released during heme breakdown inhibited proliferation of pancreatic stellate cells and might thereby prevent the development of chronic pancreatitis (CP). Transcription of HMOX1 in humans is influenced by a GT-repeat located in the promoter. As such, HMOX1 variants might be of importance in the pathogenesis of pancreatitis. METHODS: The GT-repeat and SNP rs2071746 were investigated with fluorescence labelled primers and by melting curve analysis in 285 patients with acute pancreatitis, 208 patients with alcoholic CP, 207 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and in 289 controls, respectively. GT-repeat analysis was extended to a total of 446 alcoholic CP patients. In addition, we performed DNA sequencing in 145 patients with alcoholic CP, 138 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and 151 controls. Exon 3 screening was extended to additional patients and controls. RESULTS: S- and L-alleles of the GT-repeat, genotypes and alleles of SNP rs2071746 and non-synonymous variants detected by sequencing were found with similar frequencies in all groups. CONCLUSIONS: Although functional data implicate a potential influence of HMOX1 variants on the pathogenesis of pancreatitis, we did not find any association. As rare non-synonymous HMOX1 variants were found in patients and controls, it is rather unlikely that they will have functional consequences essential for pancreatitis development

PINK1 Defect Causes Mitochondrial Dysfunction, Proteasomal Deficit and α-Synuclein Aggregation in Cell Culture Models of Parkinson's Disease

Mutations in PTEN induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. Here, we report that PINK1 exists as a dimer in mitochondrial protein complexes that co-migrate with respiratory chain complexes in sucrose gradients. PARK6 related mutations do not affect this dimerization and its associated complexes. Using in vitro cell culture systems, we found that mutant PINK1 or PINK1 knock-down caused deficits in mitochondrial respiration and ATP synthesis. Furthermore, proteasome function is impaired with a loss of PINK1. Importantly, these deficits are accompanied by increased α-synclein aggregation. Our results indicate that it will be important to delineate the relationship between mitochondrial functional deficits, proteasome dysfunction and α-synclein aggregation

HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients

side effects and long-term results

Einleitung: Die hier durchgeführte retrospektive Analyse bzgl. der Langzeitergebnisse und -nebenwirkungen von 109 Patienten unter dem 19. Lebensjahr, die Ganzkörperbestrahlungen im Rahmen von hämatologischen und lymphatischen Neoplasien, diente zur Evaluierung unserer Therapieergebnisse im Vergleich mit veröffentlichten Ergebnissen anderer Arbeitsgruppen. Es erfolgte eine retrospektive Auswertung des elektronischen Patientenarchivierungsprogramms sowie eine Aktenrecherche. Bzgl. der Überlebensdaten wurden die betreuenden Ärzte bzw. die Patienten selbst kontaktiert. Methodik: Es wurden Daten über Alter, Geschlechterverteilung, Diagnosen, Nachbeobachtungszeitraum, Bestrahlungsenergie, zusätzliche therapeutische Strahlenexposition, chemotherapeutische Konditionierung, Transplantationsart, absolute Häufigkeit von Spätfolgen, Rezidive, Lungenfunktionsstörungen, Nierenfunktionsstörungen, okuläre Komplikationen, Knochen-/Gelenkschäden, Schilddrüsenfunktionsstörungen, Leberfunktionsstörungen, Hyperlipidämie, Herzfunktionsstörungen, arterielle Hypertonie und sekundäre Malignome gesammelt. Statistische Analysen wurden unter Verwendung von IBM SPSS Version 22.0 durchgeführt (Chi-Quadrat- Statistik, Cox Regressions-Analysen, Überlebensanalyse (Gesamtüberleben, Rezidivfreies-Überleben und Progressionsfreies Überleben, Überleben in Bezug auf das Vorhandensein oder nicht Vorhandensein von Toxizitäten). Bei bis zu 42,3% der Patienten entwickelten sich im Langzeitverlauf chronische Erkrankungen in unterschiedlichen Organsystemen. Ergebnisse: Das 5 Jahres Gesamtüberleben für alle Patienten betrug 75,5% das mediane Überleben wurde nicht erreicht. In den Subgruppen zeigte sich in Abhängigkeit von den Bestrahlungsgeräten ein signifikanter Überlebensvorteil für Photonen-Strahlen gegenüber Cobalt-60 Strahlen nach 5 Jahren von 84,6% und 70,1%, einem medianen Überleben von 12,6 Jahren (95%-KI: 10,6 – 14,6 Jahre, Linearbeschleuniger) und 10,6 Jahren (95%-KI: 9,4 – 11,7 Jahre, Cobalt-60) entsprechend. Es konnte gezeigt werden, dass unsere Therapie im Vergleich zu historischen Kollektiven keine erhöhten Raten an Spätfolgen verursachte. Einzelne Nebenwirkungen wie z.B. Kleinwuchs (12%), Schilddrüsendysfunktion (6, 4%), Katarakt (2,7%) oder Hypertonie (1%) traten seltener auf als in vergleichbaren Kollektiven. Schlussfolgerung: Angesichts der guten therapeutischen Ergebnisse und der geringen Gesamtmorbidität der konditionierenden Ganzkörperbestrahlung vor allogener KMT im Vergleich zur Konditionierung durch Chemotherapie muss hinterfragt werden, ob auf die Ganzkörperbestrahlung im Rahmen der Konditionierung wirklich verzichtet werden kann. Neue Techniken wie die exklusive Bestrahlung des Knochenmarks („total marrow“) oder aller Lymphknotenstationen im Körper („total lymphatic irradiation“) könnten weitere Optionen zur Reduktion der akuten Nebenwirkungen und insbesondere auch der Spätfolgen sein.Introduction: The present retrospective analysis evaluated the long-term results and side-effects of whole-body radiation in patients with hematologic and lymphatic neoplasias in 109 patients under the age of 19 years. The findings were compared to published results from other working groups. Data was obtained via review of electronic medical records and paper charts. Information on patients survival was obtained by direct contact of treating physicians or the patients themselves. Method: The following data was collected: age, gender, diagnosis, follow-up duration, radiation energy, additional therapeutic radiation exposure, chemotherapeutic conditioning, type of transplantation, absolute prevalence of late side-effects, disease recurrence, lung and kidney dysfunction, ocular complications, bone and joint damage, thyroid dysfunction, liver dysfunction, hyperlipidemia, cardiac dysfunction, arterial hypertension, and secondary malignancies. Statistical analysis was performed with IBM's SPSS version 22.0 and included Chi-Square statistics, Cox regression analysis and survival analysis (overall surgical, recurrence-free survival, progression-free survival, toxicity-free survival). Results: Up to 42.3% of patients developed chronic illnesses of various organ systems in the long-term follow-up. The 5-year survival for all patients was 75.5%, the median survival was not reached. In the subgroup analysis there was an association between improved survival and photon-beam use as compared to cobalt-60 beam use at 5 years follow-up 84,6% and 70,1%. Median survival was 12.6 years (95% CI 10.6-14.6 years) for the photon beam accelerator and 1.6 years (95% CI 9.4-11.7 years) with Cobalt-60. Conclusion: We could show that our therapy did not cause an increase the rate of late complications when compared to historic cohorts. Selected side-effects such as growth retardation (12%), thyroid dysfunction (6.4%), cataract (2.7%) or hypertension (1%) occurred less frequently than in comparable cohorts. Given the good therapeutic results and low total morbidity of conditioned whole body radiation, one needs to question if whole body radiation in the setting of conditioning before allogenic bone marrow transplantation can be abandoned. New techniques such as the exclusive ration of the bone marrow (“total marrow”) or the lymph node stations in the body ("total lymphatic irradiation") could be additional options to reduce acute and especially long- term side effects