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A key challenge for the discovery of novel molecular targets and therapeutics against pediatric bone metastatic disease is the lack of bona fide in vitro cell models. Here, we show that a beta-tricalcium phosphate (β-TCP) multicellular 3D in vitro bone microtissue model reconstitutes key phenotypic and transcriptional patterns of native metastatic tumor cells while promoting their stemness and proinvasive features. Comparing planar with interconnected channeled scaffolds, we identified geometry as a dominant orchestrator of proangiogenic traits in neuroblastoma tumor cells. On the other hand, the β-TCP-determined gene signature was DNA replication related. Jointly, the geometry and chemical impact of β-TCP revealed a prometastatic landscape of the engineered tumor microenvironment. The proposed 3D multicellular in vitro model of pediatric bone metastatic disease may advance further analysis of the molecular, genetic and metabolic bases of the disease and allow more efficient preclinical target validations.

Jahrzehntelangen feministischen Kämpfen, Analysen und Errungenschaften zum Trotz sind Männer und Frauen in Arbeitsmarkt, Beschäftigung oder Sozialversicherung keineswegs gleichgestellt. Der Gender Pay Gap oder die Tatsache, dass insbesondere Frauen von (Alters-)Armut betroffen sind, sind nur einige merkliche Auswirkungen der Geschlechterungleichheit, die auch im 21. Jahrhundert nicht an Wirkmächtigkeit verloren hat. Dieser Band macht sich die Geschichte von Geschlechterhierarchien in Arbeitskontexten zum Gegenstand und stellt sich damit in die lange Tradition frauen- und geschlechterhistorischer Forschungen. Die Beiträge untersuchen, wie Ungleichheit zwischen Männern und Frauen historisch immer wieder neu hergestellt, ausgestaltet und abgesichert wurde. Sie zeigen die vielfältigen Wechselbezüge von Arbeit und Geschlecht auf und analysieren die Verschränkungen mit anderen Differenz- und Ungleichheitskategorien, insbesondere mit Stand/Klasse. Dabei stellen die Autor*innen Akteur*innen in den Mittelpunkt ihres Interesses, die an der Durchsetzung von Hierarchien oder an stillen oder lautstarken Protesten um deren Beseitigung beteiligt waren. Die Protagonistinnen der Beiträge sind meist weibliche Arbeitskräfte, die sich ihren Lebensunterhalt vielfach unter äußerst prekären Umständen organisierten. Damit schreiben die Aufsätze die Geschlechtergeschichte von Ungleichheit, Diskriminierung und Prekarität, aber auch von Handlungsmacht und Eigensinn in Arbeitsverhältnissen fort.

This paper explores the relationship between dirt, gender, and hierarchies in labour contexts based on the example of early modern maids. Using the instruments of historical discourse analysis, it probes how the understanding of dirt in the late Middle Ages around 1500 differs from that of around 1700. Besides gender and labour, one reference point of the search for traces in normative sources is the body as an intersection of diverse categories and an incorporator of dirt. Two opposing movements accompany the shift of dirt from an external stain to an internal essence. While normative theological or lordly sources pushed maids from the interior of households to the exterior of cities, dirt slowly inscribed itself into the maids’ bodies and helped establish a hierarchical labour regime that viewed female labour as inferior because it was performed by women.

Previous studies of magnetic adatom chains on superconducting substrates have mostly focused on the regime of dense chains and classical spins. Here, using scanning tunnelling microscopy, the authors study the excitation spectra of Fe chains on a NbSe2 surface, adatom by adatom, in the regime of quantum spins.

Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US‐enhanced drug delivery. Polymeric MB are highly suitable for these applications because of their acoustic responsiveness, high drug loading capability, and ease of surface functionalization. While many studies have focused on using polymeric MB for diagnostic and therapeutic purposes, relatively little attention has thus far been paid to improving their inherent imaging and drug delivery features. This study here shows that manipulating the polymer chemistry of poly(butyl cyanoacrylate) (PBCA) MB via temporarily mixing the monomer with the monomer‐mimetic butyl cyanoacetate (BCC) during the polymerization process improves the drug loading capacity of PBCA MB by more than twofold, and the in vitro and in vivo acoustic responses of PBCA MB by more than tenfold. Computer simulations and physisorption experiments show that BCC manipulates the growth of PBCA polymer chains and creates nanocavities in the MB shell, endowing PBCA MB with greater drug entrapment capability and stronger acoustic properties. Notably, because BCC can be readily and completely removed during MB purification, the resulting formulation does not include any residual reagent beyond the ones already present in current PBCA‐based MB products, facilitating the potential translation of next‐generation PBCA MB. [ABSTRACT FROM AUTHOR]

Aims: The majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D‐negative CD34‐positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK‐rearrangements in DFSP and plaque‐like CD34‐positive dermal fibroma (P‐LDF). Methods and Results: We searched the archives of academic institutions for cases previously coded as DFSP and P‐LDF. NGS‐naïve or PDGFB‐negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK‐positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of "DFSP" and two "P‐LDF" with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0–2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP‐like cases and FLNA in P‐LDF‐like lesions. ALK FISH was positive in one (of two) cases previously labelled P‐LDF. Methylome profiling of two (of three) ALK‐rearranged DFSP‐like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months). Conclusion: We describe a cohort of novel ALK‐rearranged tumours with morphologic features similar to DFSP. [ABSTRACT FROM AUTHOR]

Assembly of nanoparticles into superlattices yields nanomaterials with novel properties. We have recently shown that engineered protein cages are excellent building blocks for the assembly of inorganic nanoparticles into highly structured hybrid materials, with unprecedented precision. In this study, we show that the protein matrix, composed of surface‐charged protein cages, can be readily tuned to achieve a number of different crystalline assemblies. Simply by altering the assembly conditions, different types of crystalline structures were produced, without the need to further modify the cages. Future work can utilize these new protein scaffolds to create nanoparticle superlattices with various assembly geometries and thus tune the functionality of these hybrid materials. [ABSTRACT FROM AUTHOR]

Cardiovascular tissue engineering is providing many solutions to cardiovascular diseases. The complex disease demands necessitating tissue-engineered constructs with enhanced functionality. In this study, we are presenting the production of a dexamethasone (DEX)-loaded electrospun tubular polymeric poly(l-lactide) (PLA) or poly(d,l-lactide-co-glycolide) (PLGA) construct which contains iPSC-CMs (induced pluripotent stem cell cardiomyocytes), HUVSMCs (human umbilical vein smooth muscle cells), and HUVECs (human umbilical vein endothelial cells) embedded in fibrin gel. The electrospun tube diameter was calculated, as well as the DEX release for 50 days for 2 different DEX concentrations. Furthermore, we investigated the influence of the polymer composition and concentration on the function of the fibrin gels by imaging and quantification of CD31, alpha-smooth muscle actin (αSMA), collagen I (col I), sarcomeric alpha actinin (SAA), and Connexin 43 (Cx43). We evaluated the cytotoxicity and cell proliferation of HUVECs and HUVSMCs cultivated in PLA and PLGA polymeric sheets. The immunohistochemistry results showed efficient iPSC-CM marker expression, while the HUVEC toxicity was higher than the respective HUVSMC value. In total, our study emphasizes the combination of fibrin gel and electrospinning in a functionalized construct, which includes three cell types and provides useful insights of the DEX release and cytotoxicity in a tissue engineering perspective.

Abstract Bone defects stand out as one of the greatest challenges of reconstructive surgery. Fused deposition modelling (FDM) allows for the printing of 3D scaffolds tailored to the morphology and size of bone damage in a patient-specific and high-precision manner. However, FDM still suffers from the lack of materials capable of efficiently supporting osteogenesis. In this study, we developed 3D-printed porous scaffolds composed of polylactic acid/hydroxyapatite (PLA/HA) composites with high ceramic contents (above 20%, w/w) by FDM. The mechanical properties of the PLA/HA scaffolds were compatible with those of trabecular bone. In vitro degradation tests revealed that HA can neutralize the acidification effect caused by PLA degradation, while simultaneously releasing calcium and phosphate ions. Importantly, 3D-printed PLA/HA did not induce the upregulation of activation markers nor the expression of inflammatory cytokines in dendritic cells thus exhibiting no immune-stimulatory properties in vitro. Evaluations using human mesenchymal stem cells (MSC) showed that pure PLA scaffolds exerted an osteoconductive effect, whereas PLA/HA scaffolds efficiently induced osteogenic differentiation of MSC even in the absence of any classical osteogenic stimuli. Our findings indicate that 3D-printed PLA scaffolds loaded with high concentrations of HA are most suitable for future applications in bone tissue engineering.

Purpose: Complex supply chains characterise today's economic life, which is determined by uncertainties and risks. Managing those successfully requires the development of resilient and flexible structures and processes based on information transparency, which enables better decision-making, especially in times of global crises. In this context, supply chain visibility (SCV) is defined as the stakeholders' capability to have access to accurate and timely information about the flow of goods. Although the importance of SCV has been discussed in scientific literature and practice, challenges still inhibit improved SCV, particularly in distribution logistics. These have been scarcely investigated. The purpose of this study is to identify the challenges of SCV in distribution logistics and to provide implications to address them. Methodology: A qualitative content analysis (QCA) spanning 26 scientific articles was used. Results: We found evidence of challenges inhibiting SCV in distribution logistics within the three aggregated dimensions of inappropriate processes & technologies and information systems, lack of communication & trust, and insufficient monitoring & decision-making metrics. The findings show that trust can be seen as both a challenge and a prerequisite. Despite the possibilities of digitalisation, there exist trade-offs between manual processes and new technology implementation. Decision-making can be based on individual experiences, and monitoring can be difficult due to undefined metrics. Conclusion: Practitioners may use the findings to better identify and address the challenges of SCV in distribution logistics. Further studies could extend the findings through empirical studies, which would allow practitioners to assess their level of SCV and derive initial solutions.

Abstract For 3D neural cultures durable hydrogels are required, which persist over a long differentiation period and thus enable the maturation of neuronal networks (NN). Here, 3D models based on human induced pluripotent stem cell‐derived neural progenitor cells that are embedded in hydrogels of either pure alginate or alginate functionalized with the extracellular matrix protein laminin 111 (L111) are established. This study analyzes material characteristics such as porosity, L111 distribution and shear viscosity, cell compatibility of hydrogels by measuring viability and cytotoxicity, and neural function by monitoring cell migration, differentiation as well as NN formation and activity on multielectrode arrays. The addition of L111 increases neural migration and enhances differentiation into neurons and astrocytes as well as synaptogenesis in alginate hydrogels. NN formed in hydrogels are electrically active for up to 206 d and L111‐supplementation further increases electrical activity, network maturation, and synchronicity compared to 2D controls and NN grown in pure alginate hydrogels. L111 addition to alginate gels further accelerates recovery of electrical activity after blockage of sodium channels with tetrodotoxin. In conclusion, NN grown in alginate‐L111 hydrogel blends are promising models for future long‐term applications in disease modeling, drug or chemical evaluation.

Chronic venous insufficiency (CVI) is a leading vascular disease whose clinical manifestations include varicose veins, edemas, venous ulcers, and venous hypertension, among others. Therapies targeting this medical issue are scarce, and so far, no single venous valve prosthesis is clinically available. Herein, we have designed a bi-leaflet transcatheter venous valve that consists of (i) elastin-like recombinamers, (ii) a textile mesh reinforcement, and (iii) a bioabsorbable magnesium stent structure. Mechanical characterization of the resulting biohybrid elastin-like venous valves (EVV) showed an anisotropic behavior equivalent to the native bovine saphenous vein valves and mechanical strength suitable for vascular implantation. The EVV also featured minimal hemolysis and platelet adhesion, besides actively supporting endothelialization in vitro, thus setting the basis for its application as an in situ tissue engineering implant. In addition, the hydrodynamic testing in a pulsatile bioreactor demonstrated excellent hemodynamic valve performance, with minimal regurgitation (

Background and purpose: In rectal cancer patients, radiotherapy in prone position using a belly board can reduce the dose to organs at risk. For this patient group we investigated inter-fraction shape variation of the mesorectal part of the clinical target volume (CTV) and determined planning target volume (PTV) margins. Materials and methods: Patients with rectal cancer receiving neoadjuvant (chemo)radiotherapy were eligible. For each patient a planning computed tomography (pCT) and five cone-beam CT (CBCT) scans were acquired in prone position using a belly board. The mesorectal CTV was delineated on all scans. Mesorectal shape variation was quantified relative to the pCT. PTV margins were derived locally and averaged for separate subregions of the mesorectal CTV. For each patient a total PTV was constructed using our clinical margins for mesorectal and lymph node CTVs. An artificial dose distribution conforming to this PTV was used to calculate the coverage for the mesorectal CTV using the CBCT delineations. Results: In 19 rectal cancer patients the derived PTV margins were smallest in the upper-lateral region (6 mm) and largest in the upper-anterior region (16 mm). PTV margins for the upper-anterior region were larger for female patients (19 mm) compared to male patients (14 mm). Clinical margins for the total PTV were sufficient for a coverage of at least 97% of the mesorectal CTV for all patients. Conclusions: Mesorectal shape variation is heterogeneous and largest in the upper-anterior region, in rectal cancer patients irradiated in prone position and using a belly board.

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Summary: Background and objectives: Malignant sweat gland tumors are rare, with the most common being eccrine porocarcinoma (EP). Approximately 18% of benign eccrine poroma (EPO) transit to EP. Previous research has provided first insights into the mutational landscape of EP. However, only few studies have performed gene expression analyses. This leaves a gap in the understanding of EP biology and potential drivers of malignant transformation from EPO to EP. Methods: Transcriptome profiling of 23 samples of primary EP and normal skin (NS). Findings from the EP samples were then tested in 17 samples of EPO. Results: Transcriptome profiling revealed diversity in gene expression and indicated biologically heterogeneous sub‐entities as well as widespread gene downregulation in EP. Downregulated genes included CD74, NDGR1, SRRM2, CDC42, ANXA2, KFL9 and NOP53. Expression levels of CD74, NDGR1, SRRM2, ANXA2, and NOP53 showed a stepwise‐reduction in expression from NS via EPO to EP, thus supporting the hypothesis that EPO represents a transitional state in EP development. Conclusions: We demonstrated that EP is molecularly complex and that evolutionary trajectories correspond to tumor initiation and progression. Our results provide further evidence implicating the p53 axis and the EGFR pathway. Larger samples are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Background: Recent developments in esophageal cancer treatment, including studies exploring active surveillance following chemoradiotherapy, have led to a need for clear terminology and definitions regarding different multimodal treatment options. Objective: The aim of this study was to reach worldwide consensus on the definitions and semantics of multimodal esophageal cancer treatment. Methods: In total, 72 experts working in the field of multimodal esophageal cancer treatment were invited to participate in this Delphi study. The study comprised three Delphi surveys sent out by email and one online meeting. Input for the Delphi survey consisted of terminology obtained from a systematic literature search. Participants were asked to respond to open questions and to indicate whether they agreed or disagreed with different statements. Consensus was reached when there was ≥75% agreement among respondents. Results: Forty-nine of 72 invited experts (68.1%) participated in the first online Delphi survey, 45 (62.5%) in the second survey, 21 (46.7%) of 45 in the online meeting, and 39 (86.7%) of 45 in the final survey. Consensus on neoadjuvant and definitive chemoradiotherapy with or without surgery was reached for 27 of 31 items (87%). No consensus was reached on follow-up after treatment with definitive chemoradiotherapy. Conclusion(s): Consensus was reached on most statements regarding terminology and definitions of multimodal esophageal cancer treatment. Implementing uniform criteria facilitates comparison of studies and promotes international research collaborations. [ABSTRACT FROM AUTHOR]

Native tissues feature unique hierarchical designs, in which fiber units are arranged from the bottom up in anisotropic patterns. The processing of biomaterials into fibers, followed by their textile‐like assembly into complex patterns, is therefore a promising avenue to engineer native‐like tissue replacements. Here it is shown for the first time the fabrication of meter‐long hydrogel fibers prepared from engineered elastin using a microinjection system and exploiting the catalyst‐free click chemistry. Given their similarity to native elastin, the fabricated elastin‐like fibers achieved excellent stretching (500%) and recoiling performance. Moreover, the fabrication scheme is compatible with the implementation of a salt‐leaching gas‐foaming approach, resulting in highly porous elastin‐like fibers (the first of their kind). From the translation perspective, the fibers can be autoclaved, which allows for sterilization and long‐term storage. Human umbilical vein endothelial cells cultured on autoclaved fibers produced a confluent endothelial layer lining the fiber surface, in which the cells became aligned in response to physiological fiber stretching. It is also shown that these functional fibers can be assembled by weaving, braiding and knitting, with various spatial patterns. Overall, the elastin‐like fibers can be used as building blocks for the reconstruction of functional tissues using the principles of textile technology. [ABSTRACT FROM AUTHOR]

Aims: To assess the potential for precision medicine in type 2 diabetes by quantifying the variability of body weight as response to pharmacological treatment and to identify predictors which could explain this variability. Methods: We used randomized clinical trials (RCTs) comparing glucose‐lowering drugs (including but not limited to sodium‐glucose cotransporter‐2 inhibitors, glucagon‐like peptide‐1 receptor agonists and thiazolidinediones) to placebo from four recent systematic reviews. RCTs reporting on body weight after treatment to allow for calculation of its logarithmic standard deviation (log[SD], i.e., treatment response heterogeneity) in verum (i.e., treatment) and placebo groups were included. Meta‐regression analyses were performed with respect to variability of body weight after treatment and potential predictors. Results: A total of 120 RCTs with a total of 43 663 participants were analysed. A slightly larger treatment response heterogeneity was shown in the verum groups, with a median log(SD) of 2.83 compared to 2.79 from placebo. After full adjustment in the meta‐regression model, the difference in body weight log(SD) was −0.026 (95% confidence interval −0.044; 0.008), with greater variability in the placebo groups. Scatterplots did not show any slope divergence (i.e., interaction) between clinical predictors and the respective treatment (verum or placebo). Conclusions: We found no major treatment response heterogeneity in RCTs of glucose‐lowering drugs for body weight reduction in type 2 diabetes. The precision medicine approach may thus be of limited value in this setting. [ABSTRACT FROM AUTHOR]