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Abstract To improve the prognosis of bladder and prostate cancer, highly specific and sensitive biomarkers are needed for early detection, prognosis prediction, and therapeutic stratification. Extracellular vesicles (EV) from plasma could fill this gap due to their potential to serve as cancer biomarkers. However, the enrichment of EV is a major challenge, because the highly abundant plasma proteins are interfering with analytical downstream applications like mass spectrometry (MS). Therefore, the purity requirements of the EV samples must be carefully considered when selecting or developing a suitable EV enrichment method. The aim of this study was to compare a self-designed EV enrichment method based on density cushion centrifugation (DCC) combined with size exclusion chromatography (SEC) and concentration (method 1) with the exoRNeasy midi kit from Qiagen (method 2) and with unprocessed plasma. Furthermore, the single steps of method 1 were evaluated for their effectiveness to enrich EV from plasma. The results showed that the EV samples enriched with method 1 contained the highest levels of EV and exosome markers with simultaneously low levels of highly abundant plasma proteins. In summary, the combination of DCC, SEC and concentration proved to be a promising approach to discover EV-based biomarkers from plasma of cancer patients.

Abstract Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.

Abstract Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM-like organoid (LEGO: Laboratory Engineered Glioblastoma-like Organoid) models and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides new human GBM models and a research path toward effective GBM therapy.

Abstract Background Despite multiple therapeutic modalities, the overall survival of patients with gastric adenocarcinoma remains poor, especially for advanced tumor stages. Although the tyrosine kinase MerTK has shown therapeutic relevance in several tumor entities, its potential effects in gastric adenocarcinoma have not yet been sufficiently characterized. Methods MerTK expression and its influence on patient survival were evaluated by immunohistochemistry in a cohort of 140 patients with gastric adenocarcinoma. CRISPR/Cas9 knockout and siRNA knockdown of MerTK in the gastric cancer cell lines SNU1, SNU5, and MKN45 was used to analyze protein expression, growth, migration, and invasion properties in vitro and in a murine xenograft model. MerTK was pharmacologically targeted with the small molecule inhibitor UNC2025 in vitro and in vivo. Results In patients, high MerTK expression was associated with decreased overall survival (OS) and lymph node metastasis especially in patients without neoadjuvant therapy (p

Abstract Epithelial membrane protein 3 (EMP3) is an N-glycosylated tetraspanin with a putative trafficking function. It is highly expressed in isocitrate dehydrogenase-wild-type glioblastoma (IDH-wt GBM), and its high expression correlates with poor survival. However, the exact trafficking role of EMP3 and how it promotes oncogenic signaling in GBM remain unclear. Here, we show that EMP3 promotes EGFR/CDK2 signaling by regulating the trafficking and enhancing the stability of EGFR. BioID2-based proximity labeling revealed that EMP3 interacts with endocytic proteins involved in the vesicular transport of EGFR. EMP3 knockout (KO) enhances epidermal growth factor (EGF)-induced shuttling of EGFR into RAB7 + late endosomes, thereby promoting EGFR degradation. Increased EGFR degradation is rescued by the RAB7 negative regulator and novel EMP3 interactor TBC1D5. Phosphoproteomic and transcriptomic analyses further showed that EMP3 KO converges into the inhibition of the cyclin-dependent kinase CDK2 and the repression of EGFR-dependent and cell cycle transcriptional programs. Phenotypically, EMP3 KO cells exhibit reduced proliferation rates, blunted mitogenic response to EGF, and increased sensitivity to the pan-kinase inhibitor staurosporine and the EGFR inhibitor osimertinib. Furthermore, EGFR-dependent patient-derived glioblastoma stem cells display a transcriptomic signature consistent with reduced CDK2 activity, as well as increased susceptibility to CDK2 inhibition upon EMP3 knockdown. Lastly, using TCGA data, we showed that GBM tumors with high EMP3 expression have increased total and phosphorylated EGFR levels. Collectively, our findings demonstrate a novel EMP3-dependent mechanism by which EGFR/CDK2 activity is sustained in GBM. Consequently, EMP3’s stabilizing effect provides an additional layer of tumor cell resistance against targeted kinase inhibition.

Abstract Background Colorectal cancer ranks second in terms of cancer associated deaths worldwide, whereas miRNA play a pivotal role in the etiology of cancer and its metastases. Aims Studying the expression and cellular function of miR‐18a in metastatic colorectal cancer and association to progression‐free survival. Methods and Results Colorectal liver metastases (N = 123) and primary colorectal cancer (N = 27) where analyzed by RT‐PCR and correlated with clinical follow up data. Invasion and migration assays were performed with the liver metastatic cell line LIM2099 after miR‐18a knockdown. Cell viability under FOLFOX treatment and knockdown was measured. We found that the expression of miR‐18a was increased 4.38‐fold in liver metastases and 3.86‐fold in colorectal tumor tissue compared to healthy liver tissue and colorectal mucosa, respectively (p ≤ .001). Patients with a high miR‐18a expression in liver metastases had a progression‐free survival (PFS) of 13.6 months versus 8.9 months in patients with low expression (N = 123; p = .024). In vitro migration of LIM2099 cells was reduced after miR‐18a knockdown and cell viability was significantly increased after miR‐18a knockdown and treatment with folinic acid or oxaliplatin. Subgroup analysis of PFS revealed significant benefits for patients with high miR‐18a expression receiving 5‐FU, folinic acid or oxaliplatin. Conclusions High expression of miR‐18a in colorectal liver metastases might have a protective effect after resection of metastases and FOLFOX treatment regarding PFS.

Abstract Background Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes. Methods Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into ‘highly active’ and’not-highly active’(≥ /

To cope with the megatrends electrification, automated driving, and connectivity, new functionalities and electric and/or electronic systems must be developed, which require a safe power supply. This leads to increased functional safety requirements for the power supply system, particularly regarding availability. Fault tolerance measures can be implemented to comply with a safety goal (SG) specifying a safety-related availability requirement. To verify an architecture concerning the residual risk of an SG violation, several quantitative target values are provided in ISO 26262. This technical elaboration presents a systematic and holistic approach how to gain benefit in the quantitative evaluation from cyclic safety mechanisms (SMs)– in a fault tolerant item– which have a fault handling time interval (FHTI) longer than the fault tolerant time interval. Modelling cyclic SMs only based on conventional AND-gates is not sufficient. Instead, the fault sequence is differentiated to enable ISO 26262-compliance. Within this paper, an innovative approach including its mathematical background is presented how cyclic SMs can be modelled in a fault tree analysis– with focus on multiple-point faults. The results are verified by a Monte-Carlo-Simulation. Besides the scalability of the approach regarding the number of considered cyclic SMs, the relevant FHTI of each cyclic SM can be considered in a traceable and comprehensible manner.

For textile-based electronic systems with multiple contacts distributed over a large area, it is very complex to create reliable electrical and mechanical interconnections. In this work, we report for the first time on the use of rotating ultrasonic polymer welding for the continuous integration and interconnection of highly conductive ribbons with textile-integrated conductive tracks. For this purpose, the conductive ribbons are prelaminated on the bottom side with a thermoplastic film, which serves as an adhesion agent to the textile carrier, and another thermoplastic film is laminated on the top side, which serves as an electrical insulation layer. Experimental tests are used to investigate the optimum welding process parameters for each material combination. The interconnects are initially electrically measured and then tested by thermal cycling, moisture aging, buckling and washing tests, followed by electrical and optical analyses. The interconnects obtained are very low ohmic across the materials tested, with resulting contact resistances between 1 and 5 mOhm. Material-dependent results were observed in the reliability tests, with climatic and mechanical tests performing better than the wash tests for all materials. In addition, the development of a heated functional prototype demonstrates a first industrial application.

Existing optogenetic silencing methods affect membrane potential, biochemistry or protein integrity. Here, the authors demonstrate an approach for silencing synaptic transmission that combines fast activation and reversibility, by using nondisruptive, reversible, light-evoked clustering of synaptic vesicles, which they validate in Caenorhabditis elegans, zebrafish, and murine cell culture.

Summary: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of aggressive lymphoid malignancies. Here, we explore the contribution of RNA editing to DLBCL pathogenesis. We observed that DNA mutations and RNA editing events are often mutually exclusive, suggesting that tumors can modulate pathway outcomes by altering sequences at either the genomic or the transcriptomic level. RNA editing targets transcripts within known disease-driving pathways such as apoptosis, p53 and NF-κB signaling, as well as the RIG-I-like pathway. In this context, we show that ADAR1-mediated editing within MAVS transcript positively correlates with MAVS protein expression levels, associating with increased interferon/NF-κB signaling and T cell exhaustion. Finally, using targeted RNA base editing tools to restore editing within MAVS 3′UTR in ADAR1-deficient cells, we demonstrate that editing is likely to be causal to an increase in downstream signaling in the absence of activation by canonical nucleic acid receptor sensing.

mTORC1 blocks lysosomal nutrient generation. Here, the authors show that mTORC1 inactivation triggers V-ATPase assembly, which rapidly initiates lysosomal acidification and degradation of protein contents throughout the lysosomal population.

Here the authors show that antibody-dependent phagocytosis of ring-stage P. falciparum parasites is mediated by merozoite antigens and is a strong predictor of protection following challenge in a controlled human malaria infection study in semi-immune Kenyan adults.

Minimizing and quantifying the uncertainty of wind simulations are essential for the wind energy industry during the planning phase of wind farm projects and for financial considerations. Measurements at 118 sites onshore and offshore in Germany are analyzed and used for the verification of wind simulations with the mesoscale model WRF. In order to minimize the difference between simulations and observations a correction of the annual cycle is applied and a remodeling approach is developed which allows for a correction of the simulated wind speed time series. The remodeling methodology is based on a linear regression analysis of simulated and observed wind speed time series accounting for sub‑grid variations of orography and roughness. Averaging the regression parameter for 26 measurement sites results in an overall global parameter set which is applied to the wind atlas data. While the “raw” data (without optimization) before any correction showed differences of up to 30 % with respect to the annual mean wind speed the remodeling process reduced the bias to below 5 % for the majority of measurements. When being compared with data from the NEWA wind atlas and the EMD‑WRF Europe+ data set an overall bias between 0.6 m/s and 0.8 m/s is found for the NEWA, EMD‑WRF Europe+ and anemos “raw” data. This bias is reduced to zero with a small standard deviation when the remodeling process and the site-specific adaptation are applied.

Abstract Background MicroRNAs (miRNAs) and isomiRs play important roles in tumorigenesis as essential regulators of gene expression. 5’isomiRs exhibit a shifted seed sequence compared to the canonical miRNA, resulting in different target spectra and thereby extending the phenotypic impact of the respective common pre-miRNA. However, for most miRNAs, expression and function of 5’isomiRs have not been studied in detail yet. Therefore, this study aims to investigate the functions of miRNAs and their 5’isomiRs. Methods The expression of 5’isomiRs was assessed in The Cancer Genome Atlas (TCGA) breast cancer patient dataset. Phenotypic effects of miR-183 overexpression in triple-negative breast cancer (TNBC) cell lines were investigated in vitro and in vivo by quantifying migration, proliferation, tumor growth and metastasis. Direct targeting of E2F1 by miR-183-5p|+2 was validated with a 3’UTR luciferase assay and linked to the phenotypes of isomiR overexpression. Results TCGA breast cancer patient data indicated that three variants of miR-183-5p are highly expressed and upregulated, namely miR-183-5p|0, miR-183-5p|+1 and miR-183-5p|+2. However, TNBC cell lines displayed reduced proliferation and invasion upon overexpression of pre-miR-183. While invasion was reduced individually by all three isomiRs, proliferation and cell cycle progression were specifically inhibited by overexpression of miR-183-5p|+2. Proteomic analysis revealed reduced expression of E2F target genes upon overexpression of this isomiR, which could be attributed to direct targeting of E2F1, specifically by miR-183-5p|+2. Knockdown of E2F1 partially phenocopied the effect of miR-183-5p|+2 overexpression on cell proliferation and cell cycle. Gene set enrichment analysis of TCGA and METABRIC patient data indicated that the activity of E2F strongly correlated with the expression of miR-183-5p, suggesting transcriptional regulation of the miRNA by a factor of the E2F family. Indeed, in vitro, expression of miR-183-5p was regulated by E2F1. Hence, miR-183-5p|+2 directly targeting E2F1 appears to be part of a negative feedback loop potentially fine-tuning its activity. Conclusions This study demonstrates that 5’isomiRs originating from the same arm of the same pre-miRNA (i.e. pre-miR-183-5p) may exhibit different functions and thereby collectively contribute to the same phenotype. Here, one of three isomiRs was shown to counteract expression of the pre-miRNA by negatively regulating a transcriptional activator (i.e. E2F1). We speculate that this might be part of a regulatory mechanism to prevent uncontrolled cell proliferation, which is disabled during cancer progression. Graphical Abstract

Background Liver metastases severely reduce the long term survival of colorectal cancer patients. Long non-coding RNAs (lncRNAs) CCAT1 and CCAT2 have previously been found to be associated with impaired patient outcomes in primary colorectal cancer. We aimed to elucidate the role of CCAT1 and CCAT2 in colorectal liver metastases. Methods Total RNA was isolated from 97 human tissue samples of colorectal liver metastases and adjacent normal liver tissue. Gene expression analysis was performed by RT-qPCR and Multiplex ELISA and correlated with patient characteristics and survival. Gene expression, cancer cell migration, invasion, and proliferation were studied after siRNA-mediated knockdown of CCAT1, CCAT2, and MYC in metastatic colorectal cancer cell lines Colo205 and HROC277Met2. Results Elevated expression levels of lncRNAs CCAT1 and CCAT2, and their common target MYC in colorectal liver metastases were associated with prolonged progression-free survival after liver resection. High expression of CCAT1 was likewise associated with prolonged overall survival. Knockdown of CCAT1, CCAT2, and MYC resulted in increased migratory and invasive potential in metastatic colorectal cancer cell lines. Gene expression analysis revealed alterations in constituents of Wnt signaling following knockdown. Conclusion Our findings demonstrate tumor-suppressive functions of lncRNAs CCAT1 and CCAT2 in colorectal liver metastases. They suppress Wnt signaling directly and indirectly through target gene MYC and might prevent further metastatic spread from colorectal liver metastases.

Purpose The overarching goal of the FOCUS (biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer (CRC) recurrence and survival) Consortium is to unravel the effect of folate and folate-mediated one-carbon metabolism (FOCM) biomarkers on CRC prognosis to provide clinically relevant advice on folate intake to cancer patients and define future tertiary prevention strategies.Participants The FOCUS Consortium is an international, prospective cohort of 2401 women and men above 18 years of age who were diagnosed with a primary invasive non-metastatic (stages I–III) CRC. The consortium comprises patients from Austria, two sites from the Netherlands, Germany and two sites from the USA. Patients are recruited after CRC diagnosis and followed at 6 and 12 months after enrolment. At each time point, sociodemographic data, data on health behaviour and clinical data are collected, blood samples are drawn.Findings to date An increased risk of cancer recurrences was observed among patients with higher compared with lower circulating folic acid concentrations. Furthermore, specific folate species within the FOCM pathway were associated with both inflammation and angiogenesis pathways among patients with CRC. In addition, higher vitamin B6 status was associated with better quality of life at 6 months post-treatment.Future plans Better insights into the research on associations between folate and FOCM biomarkers and clinical outcomes in patients with CRC will facilitate the development of guidelines regarding folate intake in order to provide clinically relevant advice to patients with cancer, health professionals involved in patient care, and ultimately further tertiary prevention strategies in the future. The FOCUS Consortium offers an excellent infrastructure for short-term and long-term research projects and for combining additional biomarkers and data resulting from the individual cohorts within the next years, for example, microbiome data, omics and multiomics data or CT-quantified body composition data.

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1–/–, Phd2+/–, Phd3–/–, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1–/– mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3–/– mice, colitis activity and CAC growth remained unaltered. In Phd2+/– mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal–regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth.

Cu-Cu direct interconnects are highly desirable for the microelectronic industry as they allow for significant reductions in the size and spacing of microcontacts. The main challenge associated with using Cu is its tendency to rapidly oxidize in air. This research paper describes a method of Cu passivation using a self-assembled monolayer (SAM) to protect the surface against oxidation. However, this approach faces two main challenges: the degradation of the SAM at room temperature in the ambient atmosphere and the monolayer desorption technique prior to Cu-Cu bonding. In this paper, the systematic investigation of these challenges and their possible solutions are presented. The methods used in this study include thermocompression (TC) bonding, X-ray photoelectron spectroscopy (XPS), shear strength testing, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDX). The results indicate nearly no Cu oxidation (4 at.%) for samples with SAM passivation in contrast to the bare Cu surface (27 at.%) after the storage at −18 °C in a conventional freezer for three weeks. Significant improvement was observed in the TC bonding with SAM after storage. The mean shear strength of the passivated samples reached 65.5 MPa without storage. The average shear strength values before and after the storage tests were 43% greater for samples with SAM than for the bare Cu surface. In conclusion, this study shows that Cu-Cu bonding technology can be improved by using SAM as an oxidation inhibitor, leading to a higher interconnect quality.

Abstract Background Portal venous embolization (PVE) is a minimal invasive preoperative strategy that aims to increase future liver remnant (FLR) in order to facilitate extended hemihepatectomy. We analyzed our data retrospectively regarding complications and degree of hypertrophy (DH). Methods: 88 patients received PVE either by particles / coils (n = 77) or by glue / oil (n = 11), supported by 7 right hepatic vein embolizations (HVE) by coils or occluders. All complications were categorized by the Clavien- Dindo (CD) and the CIRSE classification. Results In 88 patients (median age 68 years) there was one intervention with a biliary leak and subsequent drainage (complication grade 3 CD, CIRSE 3), two with prolonged hospital stay (grade 2 CD, grade 3 CIRSE) and 13 complications grade 1 CD, but no complications of grade 4 or higher neither in Clavien- Dindo nor in CIRSE classification. The median relative increase in FLR was 47% (SD 35%). The mean pre-intervention standardized FLR rose from 23% (SD 10%) to a post-intervention standardized FLR of 32% (SD 12%). The degree of hypertrophy (DH) was 9,3% (SD 5,2%) and the kinetic growth rate (KGR) per week was 2,06 (SD 1,84). Conclusion PVE and, if necessary, additional sequential HVE were safe procedures with a low rate of complications and facilitated sufficient preoperative hypertrophy of the future liver remnant.

BackgroundImpairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (

ObjectivesIn this in-vitro study, teeth were imaged using photoacoustic tomography (PAT), cone-beam computed tomography (CBCT), and micro-computed tomography (μ-CT). The study had aim: to identify the best wavelength for PAT images to determine the accuracy of the three imaging methods, and to determine whether PAT images of teeth can achieve acceptable reconstruction quality.MethodsNineteen human mandibular single-rooted incisors were extracted from patients with trauma or periodontitis. To determine the best wavelength for acquiring photoacoustic images, all 19 teeth were scanned in vitro with PAT, using different laser wavelengths between 680 and 960 nm. The images were analyzed using image analysis software. To assess the accuracy of PAT and compare it with the accuracy of CBCT, each tooth was also scanned in vitro using CBCT and the reference standard technique of μ-CT. Subsequently, three different three-dimensional models, one for each imaging technique, were created for each tooth. Finally, the three different three-dimensional models acquired for the same tooth were matched and analyzed regarding volume and surface.ResultsThe highest quality tooth images were achieved using the 680 nm wavelength, which showed the best contrast ratio. The full geometry of the dental root (μ-CT compared with PAT) could be visualized with relative standard deviations of 0.12 mm for the surface and -7.33 mm3 for the volume (n = 19). The full geometry of the dental root (μ-CT compared with CBCT) could be visualized with relative standard deviations of 0.06 mm for the surface and -14.56 mm3 for the volume (n = 19). The difference between the PAT-μ-CT group and CBCT-μ-CT group regarding the total average of the root surface area was not significant (p>0.06).ConclusionImages, which were acquired using PAT at 680nm showed the best contrast ration, enabling the identification of dentin, cementum and the dental pulp. No significant differences were found between the PAT-μ-CT group and CBCT-μ-CT group regarding the total average of the RSA and the total volume. Thus, three-dimensional reconstructions based on in-vitro PAT are already of acceptable reconstruction quality.

Digital federated platforms and data cooperatives for secure, trusted and sovereign data exchange will play a central role in the construction industry of the future. With the help of platforms, cooperatives and their novel value creation, the digital transformation and the degree of organization of the construction value chain can be taken to a new level of collaboration. The goal of this research project was to develop an experimental prototype for a federated innovation data platform along with a suitable exemplary use case. The prototype is to serve the construction industry as a demonstrator for further developments and form the basis for an innovation platform. It exemplifies how an overall concept is concretely implemented along one or more use cases that address high-priority industry pain points. This concept will create a blueprint and a framework for further developments, which will then be further established in the market. The research project illuminates the perspective of various governance innovations to increase industry collaboration, productivity and capital project performance and transparency as well as the overall potential of possible platform business models. However, a comprehensive expert survey revealed that there are considerable obstacles to trust-based data exchange between the key stakeholders in the industry value network. The obstacles to cooperation are predominantly not of a technical nature but rather of a competitive, predominantly trust-related nature. To overcome these obstacles and create a pre-competitive space of trust, the authors therefore propose the governance structure of a data cooperative model, which is discussed in detail in this paper.

Introduction Women with gestational diabetes mellitus (GDM) have a higher risk of developing type 2 diabetes mellitus compared with women who never had GDM. Consequently, the question of structured aftercare for GDM has emerged. In all probability, many women do not receive care according to the guidelines. In particular, the process and interaction between obstetrical, diabetic, gynaecological, paediatric and general practitioner care lacks clear definitions. Thus, our first goal is to analyse the current aftercare situation for women with GDM in Germany, for example, the participation rate in aftercare diabetes screening, as well as reasons and attitudes stated by healthcare providers to offer these services and by patients to participate (or not). Second, we want to develop an appropriate, effective and patient-centred care model.Methods and analysis This is a population-based mixed methods study using both quantitative and qualitative research approaches. In various working packages, we evaluate data of the GestDiab register, of the Association of Statutory Health Insurance Physicians of North Rhine and the participating insurance companies (AOK Rheinland/Hamburg, BARMER, DAK Gesundheit, IKK classic, pronova BKK). In addition, quantitative (postal surveys) and qualitative (interviews) surveys will be conducted with randomly selected healthcare providers (diabetologists, gynaecologists, paediatricians and midwives) and affected women, to be subsequently analysed. All results will then be jointly examined and evaluated.Ethics and dissemination The study was approved by the ethics committee of the Faculty of Medicine, Heinrich-Heine-University Düsseldorf (Ethics Committee No.: 2019-738). Participants of the postal surveys and interviews will be informed in detail about the study and the use of data as well as the underlying data protection regulations before voluntarily participating. The study results will be disseminated through peer-reviewed journals, conferences and public information.Trial registration number DRKS00020283.

The aim of this pilot experiment was to compare the effect of resistance training (rt) versus static stretching (ss) on hamstring flexibility. Study was conducted on 18 volunteers (n=18), cadet hockey players with average age 14y. Hamstring flexibility was measured by thomayers test and both active and passive range of motion (rom) of hip joint. After prestesting mentioned parameters, volunteers were randomized to rt group (n= 10) and ss gorup (n= 8). Both groups were given 2 hamstring exercises, perfmored in full rom. After 6 weeks of following exercise protocol, both groups were tested. Then four- week training pause was implemented, with pretesting players afterwards. Volunteers were swapped to another group, exercising for next 6 weeks. Last measurements were done at the end. All players improved significantly in both active and passive hip flexion, ignoring the methods. Both methods noticed improvements in every measurment, however, not all of them were statistically significant. Results of ss group were superior to st group. The ss group noticed significant changes in every observed parameter, except for active flexion of the left hip. The st group observed significant changes in passive flexion of the right hip, both active and passive flexion of the left hip. Results show, that resistance training might be beneficial for improving hamstring flexibility of young hockey players. Major limitation of this study were the sample size and duration of experiment. More research needs to be done to confirm or disprove our results.

Purpose: Obesity is associated with increased incidence and mortality in rectal cancer (RC). However, an obesity paradox in the sense of a protective effect of obesity is discussed controversially. We evaluated whether adipose tissue distribution has an impact on medical (MC) and surgical complications (SC) after RC surgery. Methods: A total of 296 RC patients underwent oncological surgery and multidetector CT with quantification of total (TAT), visceral (VAT), and subcutaneous adipose tissue (SAT). Logistic regressions on SC (anastomotic leakage [n = 26], wound infection [n = 58], bleeding [n = 12], abscess [n = 32], bladder dysfunction [n = 24], burst abdomen [n = 10]), and MC (pulmonary [n = 22], cardiac [n = 18], urinary tract infection [n = 9], sepsis [n = 5]) were performed. Results: High pelvicVAT was associated with reduced risk for overall SC (OR = 0.915, p = 0.012) and anastomotic leakage (OR = 0.587, p = 0.024, CI: 0.369/0.934). In contrast, CT-quantified obesity was associated with increased risk for wound infection, bladder dysfunction, burst abdomen, overall MC, and cardiac complications (ORs up to 1.423). BMI was not associated with any SC or MC. Conclusion: An obesity paradox with a protective effect of CT-quantified adipose tissue was confirmed for anastomotic leakage and overall SC. In contrast, high adipose tissue was associated with higher risk for other SC and MC. These results show a more complex influence of body composition on MC and SC. CT-quantified obesity is able to provide deeper insights to explain the obesity paradox beyond BMI.

Wind measurements are rare in heights of interest in terms of wind turbines. Consequently, well-verified model simulations of the wind conditions are fundamental during the planning stage of wind farms. In this paper, a new approach is presented where data from operational wind turbines is used to verify these wind simulations. Several issues are discussed: model wind speed has to be combined with the power curve from the wind turbine in order to be comparable with the turbine data. Furthermore, in operational mode a turbine does not perfectly perform at any time step. Thus, those time steps have to be identified and replaced by missing values since a model cannot reproduce an unsual turbine operation. In addition, wind turbines are influenced by surrounding turbines resulting in a reduction of power production at some time steps. Consequently, a wake model is applied on the model simulation. In a next step, the edited turbine power data is compared to the power time series resulting from a mesoscale simulation for Germany with the mesoscale model WRF. The simulation is improved by a remodelling-method during the post-processing. This method alters the model wind speed and particularly results in a reduced wind speed bias. Comparing these model simulation's power production time series to the turbine production data reveals that they correlate well with most values in the range of 0.82 to 0.87 for an hourly temporal resolution. The relative bias for the simulations is between 10 to 25 % in terms of power. Finally, a comparison with a model verification with wind measurement data is carried out. It is shown that the verification with data from operational wind turbines and from wind measurements are in the same range in terms of correlations.

Anastomotic leakage (AL) accounts for a major part of in-house mortality in patients undergoing colorectal surgery. Local ischemia and abdominal sepsis are common risk factors contributing to AL and are characterized by upregulation of the hypoxia-inducible factor (HIF) pathway. The HIF pathway is critically regulated by HIF-prolyl hydroxylases (PHDs). Here, we investigated the significance of PHDs and the effects of pharmacologic PHD inhibition (PHI) during anastomotic healing. Ischemic or septic colonic anastomoses were created in mice by ligation of mesenteric vessels or lipopolysaccharide-induced abdominal sepsis, respectively. Genetic PHD deficiency (Phd1–/–, Phd2+/–, and Phd3–/–) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2 haplodeficiency (Phd2+/–) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only Phd2+/– (but not PHI or Phd1–/–) protected from sepsis-related mortality. Mechanistically, PHI and Phd2+/– induced immunomodulatory (M2) polarization of macrophages, resulting in increased collagen content and attenuated inflammation-driven immune cell recruitment. We conclude that PHI improves healing of colonic anastomoses in ischemic or septic conditions by Phd2+/–-mediated M2 polarization of macrophages, conferring a favorable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI.

Adverse effects of drug combinations and their underlying mechanisms are highly relevant for safety evaluation, but often not fully studied. Hydroxychloroquine (HCQ) and azithromycin (AZM) were used as a combination therapy in the treatment of COVID-19 patients at the beginning of the pandemic, leading to higher complication rates in comparison to respective monotherapies. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ, AZM, and their combination on the structure and functionality of cardiomyocytes, and to better understand the underlying mechanisms. Our results demonstrate synergistic adverse effects of AZM and HCQ on electrophysiological and contractile function of iPSC-CMs. HCQ-induced prolongation of field potential duration (FPDc) was gradually increased during 7-day treatment period and was strongly enhanced by combination with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, more pronounced contractile dysfunctions, and more elevated conduction velocity, compared to respective monotreatments. Mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased cellular accumulation of HCQ and AZM as well as increased Cx43- and Nav1.5-protein levels.

Abstract Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HRhet = 0.82, 95% CI: 0.68–0.99 and rs2847149: HRhet = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet = 1.28, 95% CI: 1.07–1.53; HRhzv = 2.02, 95% CI:1.46–2.80; HRlogAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P

Safety is a crucial issue in hydrogen energy applications due to the unique properties of hydrogen. Accordingly, a suitable hydrogen sensor for leakage detection must have at least high sensitivity and selectivity, rapid response/recovery, low power consumption and stable functionality, which requires further improvements on the available hydrogen sensors. In recent years, the mature development of nanomaterials engineering technologies, which facilitate the synthesis and modification of various materials, has opened up many possibilities for improving hydrogen sensing performance. Current research of hydrogen detection sensors based on both conservational and innovative materials are introduced in this review. This work mainly focuses on three material categories, i.e., transition metals, metal oxide semiconductors, and graphene and its derivatives. Different hydrogen sensing mechanisms, such as resistive, capacitive, optical and surface acoustic wave-based sensors, are also presented, and their sensing performances and influence based on different nanostructures and material combinations are compared and discussed, respectively. This review is concluded with a brief outlook and future development trends.

Abstract Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5′-Hydroxymethyl-2′-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions. Pretreatment or single intraperitoneal lavage with YC-1 significantly reduced postoperative adhesion formation without prompting systemic adverse effects. Expression analyses of cytokines in peritoneal tissue and fluid and in vitro assays applying macrophages and peritoneal fibroblasts indicated that this effect was cooperatively mediated by various putatively HIF-1α-dependent mechanisms, comprising attenuated pro-inflammatory activation of macrophages, impaired recruitment and activation of peritoneal fibroblasts, mitigated epithelial-mesenchymal-transition (EMT), as well as enhanced fibrinolysis and impaired angiogenesis. Thus, this study identifies prevention of postsurgical peritoneal adhesions as a novel and promising field for the application of HIF inhibitors in clinical practice.

Abstract Background Epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSC) contribute to tumour progression and metastasis. Assessment of transcription factors involved in these two mechanisms can help to identify new targets for an oncological therapy. In this study, we focused on the evaluation of the transcription factor Six1 (Sine oculis 1). This protein is involved in embryologic development and its contribution to carcinogenesis has been described in several studies. Methods Immunohistochemistry against Six1 was performed on a tissue microarray containing specimens of primary pancreatic ductal adenocarcinomas (PDAC) of 139 patients. Nuclear and cytoplasmic expression was evaluated and correlated to histopathological parameters. Expression of Six1 was inhibited transiently by siRNA in Panc1 and BxPc3 cells and stably by shRNA in Panc1 cells. Expression analysis of CDH1 and Vimentin mRNA was performed and cell motility was tested in a migration assay. Panc1 cells transfected with Six1 shRNA or scrambled shRNA were injected subcutaneously into nude mice. Tumour growth was observed for four weeks. Afterwards, tumours were stained against Six1, CD24 and CD44. Results Six1 was overexpressed in the cytoplasm and cellular nuclei in malignant tissues (p

Multiple reports have highlighted the importance of the local immunological cellular composition (i.e. the density of effector T cells and macrophage polarization state) in predicting clinical outcome in advanced metastatic stage of colorectal cancer. However, in spite of the general association between a high effector T cell density and improved outcome, our recent work has revealed a specific lymphocyte-driven cancer cell-supporting signal. Indeed, lymphocyte-derived CCL5 supports CCR5-positive tumor cell proliferation and thereby fosters tumor growth in metastatic liver lesions. Upon systematic analysis of CCR5 expression by tumor cells using immunohistochemistry, we observed that the intensity of CCR5 increases with primary tumor size and peaks in T4 tumors. In liver metastases however, though CCR5 expression intensity is globally heightened compared to primary tumors, alterations in the expression patterns appear, leading to “patchiness” of the stain. CCR5 patchiness is, therefore, a signature of liver metastases in our cohort (n = 97 specimens) and relates to globally decreased expression intensity, but does not influence the extent of the response to CCR5 inhibitor Maraviroc in patients. Moreover, CCR5 patchiness relates to a poor immune landscape characterized by a low cytotoxic-to-regulatory T cell ratio at the invasive margin and enriched cellular and molecular markers of macrophage M2 polarization. Finally, because higher numbers of PD-1- and CTLA-4-positive cells surround tumors with patchy CCR5 expression, one can speculate that these tumors potentially respond to immune checkpoint blockade. This hypothesis is corroborated by the prolonged disease-free survival and disease-specific survival observed in patients with low gene expression of CCR5 in metastases from two publically available cohorts. These observations highlight the complex role of the CCL5-CCR5 axis in CRC metastatic progression and warrant further investigations.

Summary: Lymphatic vessels (LVs) are important in the regulation of tissue fluid homeostasis and the pathogenesis of tumor progression. We investigated the innervation of LVs and the response to agonists and antagonists of the autonomic nervous system in vivo. While skin-draining collecting LVs express muscarinic, α1- and β2-adrenergic receptors on lymphatic endothelial cells and smooth muscle cells, intestinal lacteals express only β-adrenergic receptors and muscarinic receptors on their smooth muscle cells. Quantitative in vivo near-infrared imaging of the exposed flank-collecting LV revealed that muscarinic and α1-adrenergic agonists increased LV contractility, whereas activation of β2-adrenergic receptors inhibited contractility and initiated nitric oxide (NO)-dependent vasodilation. Tumor-draining LVs were expanded and showed a higher innervation density and contractility that was reduced by treatment with atropine, phentolamine, and, most potently, isoproterenol. These findings likely have clinical implications given the impact of lymphatic fluid drainage on intratumoral fluid pressure and thus drug delivery. : Bachmann et al. use in vivo imaging to demonstrate that muscarinic and α1-adrenergic agonists increase lymphatic contractility, whereas activation of β2-adrenergic receptors inhibits contractility and mediates NO-dependent vasodilation. Tumor-draining lymphatics have a denser innervation and increased contractility, which can be diminished by β2-adrenergic agonists. Keywords: lymphatic vessels, contractility, autonomic nervous system, Ca2+ imaging, tumor-draining lymphatics

ObjectivesSalinomycin is a polyether antibiotic with selective activity against human cancer stem cells. The impact of salinomycin on patient-derived primary human colorectal cancer cells has not been investigated so far. Thus, here we aimed to investigate the activity of salinomycin against tumor initiating cells isolated from patients with colorectal cancer.MethodsPrimary tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma were exposed to salinomycin and compared to treatment with 5-FU and oxaliplatin. TICs were injected subcutaneously into NOD/SCID mice to induce a patient-derived mouse xenograft model of colorectal cancer. Animals were treated either with salinomycin, FOLFOX regimen, or salinomycin and FOLFOX. Human colorectal cancer cells were used to delineate an underlying molecular mechanism of salinomycin in this tumor entity.ResultsApplying TICs isolated from human patients with colorectal liver metastases or from human primary colon carcinoma, we demonstrated that salinomycin exerts increased antiproliferative activity compared to 5-fluorouracil and oxaliplatin treatment. Consistently, salinomycin alone or in combination with FOLFOX exerts superior antitumor activity compared to FOLFOX therapy in a patient-derived mouse xenograft model of colorectal cancer. Salinomycin induces apoptosis of human colorectal cancer cells, accompanied by accumulation of dysfunctional mitochondria and reactive oxygen species. These effects are associated with expressional down-regulation of superoxide dismutase-1 (SOD1) in response to salinomycin treatment.ConclusionCollectively, the results of this pre-clinical study indicate that salinomycin alone or in combination with 5-fluorouracil and oxaliplatin exerts increased antitumoral activity compared to common chemotherapy.

Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups—patients who suffered from postoperative complications (n = 30) and those without complication (n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications (p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans. The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism p = 0.04; pFDR = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.

To optimize the process of base fertilisation in the context of Precision Farming, IT support for the corresponding service processes was developed as part of a research project. Applying the methods of service engineering, a software system that supports an efficient and transparent service provision was developed in the IPS project (Information Production System for Precision Farming). The paper shows the methodological approach of the project, the potential for innovation of the developed software system and discusses the results. Thereby, the findings presented in this paper can be regarded as an exemplary application of service engineering which may also be advantageous for similar service-orientated agricultural sectors.

Colorectal cancer (CRC) survival has environmental and inherited components. The expression of specific genes can be inferred based on individual genotypes—so called expression quantitative trait loci. In this study, we used the PrediXcan method to predict gene expression in normal colon tissue using individual genotype data from 91 CRC patients and examined the correlation ρ between predicted and measured gene expression levels. Out of 5434 predicted genes, 58% showed a negative ρ value and only 16% presented a ρ higher than 0.10. We subsequently investigated the association between genotype-based gene expression in colon tissue for genes with ρ > 0.10 and survival of 4436 CRC patients. We identified an inverse association between the predicted expression of ARID3B and CRC-specific survival for patients with a body mass index greater than or equal to 30 kg/m2 (HR (hazard ratio) = 0.66 for an expression higher vs. lower than the median, p = 0.005). This association was validated using genotype and clinical data from the UK Biobank (HR = 0.74, p = 0.04). In addition to the identification of ARID3B expression in normal colon tissue as a candidate prognostic biomarker for obese CRC patients, our study illustrates the challenges of genotype-based prediction of gene expression, and the advantage of reassessing the prediction accuracy in a subset of the study population using measured gene expression data.

Fan-out wafer-level packaging (FOWLP) is an interesting platform for Microelectromechanical systems (MEMS) sensor packaging. Employing FOWLP for MEMS sensor packaging has some unique challenges, while some originate merely from the fabrication of redistribution layers (RDL). For instance, it is crucial to protect the delicate structures and fragile membranes during RDL formation. Thus, additive manufacturing (AM) for RDL formation seems to be an auspicious approach, as those challenges are conquered by principle. In this study, by exploiting the benefits of AM, RDLs for fan-out packaging of capacitive micromachined ultrasound transducers (CMUT) were realized via drop-on-demand inkjet printing technology. The long-term reliability of the printed tracks was assessed via temperature cycling tests. The effects of multilayering and implementation of an insulating ramp on the reliability of the conductive tracks were identified. Packaging-induced stresses on CMUT dies were further investigated via laser-Doppler vibrometry (LDV) measurements and the corresponding resonance frequency shift. Conclusively, the bottlenecks of the inkjet-printed RDLs for FOWLP were discussed in detail.

Background: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients. Methods: A total of 138 newly diagnosed CRC patients underwent CT scans at diagnosis and completed questionnaires prior to and six and twelve months post-surgery. We investigated the associations of VFA, SFA, and SMM with HRQoL at multiple time points. Results: A higher VFA was associated with increased pain six and twelve months post-surgery (β = 0.06, p = 0.04 and β = 0.07, p = 0.01) and with worse social functioning six months post-surgery (β = −0.08, p = 0.01). Higher SMM was associated with increased pain twelve months post-surgery (β = 1.03, p < 0.01). Conclusions: CT-quantified body composition is associated with HRQoL scales post-surgery. Intervention strategies targeting a reduction in VFA and maintaining SMM might improve HRQoL in CRC patients during the first year post-surgery.

A novel capacitive sensor for measuring the water-level and monitoring the water quality has been developed in this work by using an enhanced screen printing technology. A commonly used environment-friendly conductive polymer poly(3,4-ethylenedioxythiophene):poly (styrenesulfonate) (PEDOT:PSS) for conductive sensors has a limited conductivity due to its high sheet resistance. A physical treatment performed during the printing process has reduced the sheet resistance of printed PEDOT:PSS on polyethylenterephthalat (PET) substrate from 264.39 Ω/sq to 23.44 Ω/sq. The adhesion bonding force between printed PEDOT:PSS and the substrate PET is increased by using chemical treatment and tested using a newly designed adhesive peeling force test. Using the economical conductive ink PEDOT:PSS with this new physical treatment, our capacitive sensors are cost-efficient and have a sensitivity of up to 1.25 pF/mm.

BACKGROUND:Ethiopia bears a high burden of visceral leishmaniasis (VL). Early access to VL diagnosis and care improves clinical prognosis and reduces transmission from infected humans; however, significant obstacles exist. The approximate 250,000 seasonal mobile workers (MW) employed annually in northwestern Ethiopia may be particularly disadvantaged and at risk of VL acquisition and death. Our study aimed to assess barriers, and recommend interventions to increase access, to VL diagnosis and care among MWs. METHODOLOGY/PRINCIPAL FINDINGS:In 2017, 50 interviews and 11 focus group discussions were conducted with MWs, mobile residents, VL patients and caretakers, community leaders and healthcare workers in Kafta Humera District, Tigray. Participants reported high vulnerability to VL among MWs and residents engaged in transitory work. Multiple visits to health facilities were consistently needed to access VL diagnosis. Inadequate healthcare worker training, diagnostic test kit unavailability at the primary healthcare level, lack of VL awareness, insufficient finances for care-seeking and prioritization of income-generating activities were significant barriers to diagnosis and care. Social (decision-making and financial) support strongly and positively influenced care-seeking; workers unable to receive salary advances, compensation for partial work, or peer assistance for contract completion were particularly disadvantaged. Participants recommended the government/stakeholders intervene to ensure: MWs access to bed-nets, food, shelter, water, and healthcare at farms or sick leave; decentralization of diagnostic tests to primary healthcare facilities; surplus medications/staff during the peak season; improved referral/feedback/reporting/training within the health system; free comprehensive healthcare for all VL-related services; and community health education. CONCLUSIONS/SIGNIFICANCE:Contrary to what health policy for VL dictates in this endemic setting, study participants reported very poor access to diagnosis and, consequently, significantly delayed access to treatment. Interventions tailored to the socio-economic and health needs of MWs (and other persons suffering from VL) are urgently needed to reduce health disparities and the VL burden.

DNA mismatch repair (MMR)-deficient cancers accumulate high numbers of coding microsatellite mutations, which lead to the generation of highly immunogenic frameshift peptide (FSP) neoantigens. MMR-deficient cells can grow out to clinically manifest cancers either if they evade immune cell attack or if local T-cells get exhausted. Therefore, a subset of MSI cancer patients responds particularly well to treatment with immune checkpoint inhibitors. We analyzed whether immune evasion in MMR-deficient cancer mediated by loss of HLA class I or II antigens is related to local immune cell activation status. Microsatellites located in Beta2-microglobulin (B2M) and the HLA class II-regulatory genes RFX5 and CIITA were analyzed for mutations in MMR-deficient colorectal cancers (n = 53). The results were related to CD3-positive and PDCD1 (PD-1)-positive T-cell infiltration. PDCD1 (PD-1)-positive T-cell counts were significantly higher in B2M-mutant compared to B2M-wild type tumors (median: 22.2 cells per 0.25 mm2 vs. 2.0 cells per 0.25 mm2, Wilcoxon test p = 0.002). Increasing PDCD1 (PD-1)-positive T-cell infiltration was significantly related to an increased likelihood of B2M mutations (OR = 1.81). HLA class II antigen expression status was significantly associated with enhanced overall T-cell infiltration, but not related to PDCD1 (PD-1)-positive T-cells. These results suggest that immune evasion mediated by B2M mutation-induced loss of HLA class I antigen expression predominantly occurs in an environment of activated PDCD1 (PD-1)-positive T cell infiltration. If B2M mutations interfere with anti-PDCD1 (PD-1)/CD274 (PD-L1) therapy success, we predict that resistance towards anti-PDCD1 (PD-1) therapy may – counterintuitively – be particularly common in patients with MMR-deficient cancers that show high PDCD1 (PD-1)-positive T cell infiltration.

Abstract Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation‐dependent manner. Following p53–p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy‐induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5‐FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1‐specific inhibitors and their use in combination with chemotherapy.

Star polymers are one example of three-dimensional macromolecules containing several arms with similar molecular weight connected to a central core. Due to their compact structure and their enhanced segment density in comparison to linear polymers of the same molecular weight, they have attracted significant attention during recent years. The preparation of block-arm star copolymers with a permanently hydrophilic block and an “environmentally” sensitive block, which can change its nature from hydrophilic to hydrophobic, leads to nanometer-sized responsive materials with unique properties. These polymers are able to undergo a conformational change or phase transition as a reply to an external stimulus resulting in the formation of core–shell nanoparticles, which further tend to aggregate. Star-shaped copolymers with different cores were synthesized via atom transfer radical polymerization (ATRP). The core-first method chosen as synthetic strategy allows good control over the polymer architecture. First of all the multifunctional initiators were prepared by esterification reaction of the hydroxyl groups with 2-chloropropionyl chloride. Using β-cyclodextrin as core molecules, which possess a well-defined number of functional groups up to 21, allows defining the number of arms per star polymer. In order to prepare stimuli-responsive multi-arm copolymers, containing a stimuli-responsive (poly(N-isopropylacrylamide) (PNIPAAm)) and a non-responsive block (poly(N,N-dimethylacrylamide) (PDMAAm)), consecutive ATRP was carried out. The polymers were characterized intensively using NMR spectroscopy and size exclusion chromatography (SEC), whereas the temperature-depending aggregation behavior in aqueous solution was determined via turbidimetry and differential scanning calorimetry (DSC).