Search

Cells and their surrounding extracellular matrix (ECM) are engaged in dynamic reciprocity to maintain tissue homeostasis: cells deposit ECM, which in turn presents the signals that define cell identity. This loop of phenotype is obvious for biochemical signals, such as collagens, which are produced by and presented to cells, but the role of biomechanical signals is also increasingly recognised. In addition, cell shape goes hand in hand with cell function and tissue homeostasis. Aberrant cell shape and ECM is seen in pathological conditions, and control of cell shape in micro-fabricated platforms disclose the causal relationship between cell shape and cell function, often mediated by mechanotransduction. In this manuscript, we discuss the loop of phenotype for tendon tissue homeostasis. We describe cell shape and ECM organization in normal and diseased tissue, how ECM composition influences tenocyte shape, and how that leads to the activation of signal transduction pathways and ECM deposition. We further describe the use of technologies to control cell shape to elucidate the link between cell shape and its phenotypical markers and focus on the causal role of cell shape in the loop of phenotype. The dynamic reciprocity between cells and their surrounding extracellular matrix (ECM) influences biomechanical and biochemical properties of ECM as well as cell function through activation of signal transduction pathways that regulate gene and protein expression. We refer to this reciprocity as Loop of Phenotype and it has been studied and demonstrated extensively by using micro-fabricated platforms to manipulate cell shape and cell fate. In this manuscript, we discuss this concept in tendon tissue homeostasis by giving examples in healthy and pathological tenson tissue. Furthermore, we elaborate this by showing how biomaterials are used to feed this reciprocity to manipulate cell shape and function. Finally, we elucidate the link between cell shape and its phenotypical markers and focus on the activation of signal transduction pathways and ECM deposition. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups. Methods: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 µg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG). Results: Overall, the optimal surveillance strategy was annual FIT (47 µg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 µg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 µg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG). Conclusions: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy. Impact: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors. [ABSTRACT FROM AUTHOR]

Pregnant women undergoing a cesarean section (CS) typically receive antibiotics prior to skin incision to prevent infections. To investigate if the timing of antibiotics influences the infant gut microbiome, we conducted a randomized controlled trial (NCT06030713) in women delivering via a scheduled CS who received antibiotics either before skin incision or after umbilical cord clamping. We performed a longitudinal analysis on 172 samples from 28 infants at 8 post-birth time points and a cross-sectional analysis at 1 month in 79 infants from 3 cohorts. Although no significant associations with bacterial composition, metabolic pathways, short-chain fatty acids, and bile acids were found, we observed subtle differences between the groups at the bacterial strain level and in the load of antibiotic resistance genes. Rather, feeding mode was a predominant and defining factor impacting infant microbial composition. In conclusion, antibiotic administration during CS has only limited effects on the early-life gut microbiome. [Display omitted] • Feeding mode profoundly influences infant gut microbiome and bile acid composition • Prophylactic antibiotics given to mother during CS transfer to infant cord blood • Antibiotics during CS exert minor effects on infant gut microbiome composition • Antibiotics during CS subtly impact strain variability and antibiotic resistance genes Sinha et al. conducted a randomized controlled trial and meta-analysis to assess the effects of maternal antibiotics during cesarean sections on the infant gut microbiome and metabolites. They found that these antibiotics have a minor impact compared with feeding mode but noted minor alterations in bacterial strains and antibiotic resistance genes. [ABSTRACT FROM AUTHOR]

Patients who receive chemoradiotherapy or bioradiotherapy (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often experience high toxicity rates interfering with oral intake, causing tube feeding (TF) dependency. International guidelines recommend gastrostomy insertion when the expected use of TF exceeds 4 weeks. We aimed to develop and externally validate a prediction model to identify patients who need TF ≥ 4 weeks and would benefit from prophylactic gastrostomy insertion. A retrospective multicenter cohort study was performed in four tertiary head and neck cancer centers in the Netherlands. The prediction model was developed using data from University Medical Center Utrecht and the Netherlands Cancer Institute and externally validated using data from Maastricht University Medical Center and Radboud University Medical Center. The primary endpoint was TF dependency ≥4 weeks initiated during CRT/BRT or within 30 days after CRT/BRT completion. Potential predictors were extracted from electronic health records and radiotherapy dose–volume parameters were calculated. The developmental and validation cohort included 409 and 334 patients respectively. Multivariable analysis showed predictive value for pretreatment weight change, texture modified diet at baseline, ECOG performance status, tumor site, N classification, mean radiation dose to the contralateral parotid gland and oral cavity. The area under the receiver operating characteristics curve for this model was 0.73 and after external validation 0.62. Positive and negative predictive value for a risk of 90% or higher for TF dependency ≥4 weeks were 81.8% and 42.3% respectively. We developed and externally validated a prediction model to estimate TF-dependency ≥4 weeks in LAHNSCC patients treated with CRT/BRT. This model can be used to guide personalized decision-making on prophylactic gastrostomy insertion in clinical practice. [ABSTRACT FROM AUTHOR]

A criticism of the French film "Week-end" directed by Jean-Luc Godard and starring Mireille Darc is presented.

Graphical abstract Abstract Human epidermal stem cells initiate terminal differentiation when spreading is restricted on ECM-coated micropatterned islands, soft hydrogels or hydrogel-nanoparticle composites with high nanoparticle spacing. The effect of substrate topography, however, is incompletely understood. To explore this, primary human keratinocytes enriched for stem cells were seeded on a topographical library with over 2000 different topographies in the micrometre range. Twenty-four hours later the proportion of cells expressing the differentiation marker transglutaminase-1 was determined by high content imaging. As predicted, topographies that prevented spreading promoted differentiation. However, we also identified topographies that supported differentiation of highly spread cells. Topographies supporting differentiation of spread cells were more irregular than those supporting differentiation of round cells. Low topography coverage promoted differentiation of spread cells, whereas high coverage promoted differentiation of round cells. Based on these observations we fabricated a topography in 6-well plate format that supported differentiation of spread cells, enabling us to examine cell responses at higher resolution. We found that differentiated spread cells did not assemble significant numbers of hemidesmosomes, focal adhesions, adherens junctions, desmosomes or tight junctions. They did, however, organise the actin cytoskeleton in response to the topographies. Rho kinase inhibition and blebbistatin treatment blocked the differentiation of spread cells, whereas SRF inhibition did not. These observations suggest a potential role for actin polymerization and actomyosin contraction in the topography-induced differentiation of spread cells. Statement of Significance The epidermis is the outer covering of the skin. It is formed by layers of cells called keratinocytes. The basal cell layer contains stem cells, which divide to replace cells in the outermost layers that are lost through a process known as differentiation. In this manuscript we have developed surfaces that promote the differentiation of epidermal stem cells in order to understand the signals that control differentiation. The experimental tools we have developed have the potential to help us to devise new treatments that control diseases such as psoriasis and eczema in which epidermal stem cell proliferation and differentiation are disturbed. [ABSTRACT FROM AUTHOR]

Fibroblasts are abundantly present in the prostate tumor microenvironment (TME), including cancer‐associated fibroblasts (CAFs) which play a key role in cancer development. Androgen receptor (AR) signaling is the main driver of prostate cancer (PCa) progression, and stromal cells in the TME also express AR. High‐grade tumor and poor clinical outcome are associated with low AR expression in the TME, which suggests a protective role of AR signaling in the stroma against PCa development. However, the mechanism of this relation is not clear. In this study, we isolated AR‐expressing CAF‐like cells. Testosterone (R1881) exposure did not affect CAF‐like cell morphology, proliferation, or motility. PCa cell growth was not affected by culturing in medium from R1881‐exposed CAF‐like cells; however, migration of PCa cells was inhibited. AR chromatin immune precipitation sequencing (ChIP‐seq) was performed and motif search suggested that AR in CAF‐like cells bound the chromatin through AP‐1‐elements upon R1881 exposure, inducing enhancer‐mediated AR chromatin interactions. The vast majority of chromatin binding sites in CAF‐like cells were unique and not shared with AR sites observed in PCa cell lines or tumors. AR signaling in CAF‐like cells decreased expression of multiple cytokines; most notably CCL2 and CXCL8 and both cytokines increased migration of PCa cells. These results suggest direct paracrine regulation of PCa cell migration by CAFs through AR signaling. [ABSTRACT FROM AUTHOR]

Surface topography is able to influence cell phenotype in numerous ways and offers opportunities to manipulate cells and tissues. In this work, we develop the Nano-TopoChip and study the cell instructive effects of nanoscale topographies. A combination of deep UV projection lithography and conventional lithography was used to fabricate a library of more than 1200 different defined nanotopographies. To illustrate the cell instructive effects of nanotopography, actin-RFP labeled U2OS osteosarcoma cells were cultured and imaged on the Nano-TopoChip. Automated image analysis shows that of many cell morphological parameters, cell spreading, cell orientation and actin morphology are mostly affected by the nanotopographies. Additionally, by using modeling, the changes of cell morphological parameters could by predicted by several feature shape parameters such as lateral size and spacing. This work overcomes the technological challenges of fabricating high quality defined nanoscale features on unprecedented large surface areas of a material relevant for tissue culture such as PS and the screening system is able to infer nanotopography – cell morphological parameter relationships. Our screening platform provides opportunities to identify and study the effect of nanotopography with beneficial properties for the culture of various cell types. Statement of Significance The nanotopography of biomaterial surfaces can be modified to influence adhering cells with the aim to improve the performance of medical implants and tissue culture substrates. However, the necessary knowledge of the underlying mechanisms remains incomplete. One reason for this is the limited availability of high-resolution nanotopographies on relevant biomaterials, suitable to conduct systematic biological studies. The present study shows the fabrication of a library of nano-sized surface topographies with high fidelity. The potential of this library, called the ‘NanoTopoChip’ is shown in a proof of principle HTS study which demonstrates how cells are affected by nanotopographies. The large dataset, acquired by quantitative high-content imaging, allowed us to use predictive modeling to describe how feature dimensions affect cell morphology. [ABSTRACT FROM AUTHOR]

Summary Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of cholesterol degradation pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4 weeks of treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a 4-fold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background High-density lipoproteins (HDLs) protect against the development of atherosclerotic cardiovascular disease. HDL function represents an emerging concept in cardiovascular research. Objective This study investigated the association between HDL functionality and acute myocardial infarction (MI) independent of HDL-cholesterol plasma levels. Methods Participants (non-ST-segment elevation MI, non-STEMI, n = 41; STEMI, n = 37; non-MI patients, n = 33) from a prospective follow-up study enrolling patients with acute chest pain were matched for age and plasma HDL cholesterol. The in vitro capacity of HDL to (1) mediate cholesterol efflux from macrophage foam cells, (2) prevent low-density lipoprotein oxidation, and (3) inhibit TNF-α-induced vascular adhesion molecule-1 expression in endothelial cells was determined. Results STEMI-HDL displayed reduced cholesterol efflux ( P < .001) and anti-inflammatory functionality ( P = .001), whereas the antioxidative properties were unaltered. Cholesterol efflux correlated with the anti-inflammatory HDL activity ( P < .001). Not C-reactive protein levels, a marker of systemic inflammation, but specifically plasma myeloperoxidase levels were independently associated with impaired HDL function (efflux: P = .022; anti-inflammation: P < .001). Subjects in the higher risk quartile of efflux (odds ratio [OR], 5.66; 95% confidence interval [CI], 1.26–25.00; P = .024) as well as anti-inflammatory functionality of HDL (OR, 5.53; 95% CI, 1.83–16.73; P = .002) had a higher OR for MI vs those in the three lower risk quartiles combined. Conclusion Independent of plasma HDL cholesterol levels, 2 of 3 antiatherogenic HDL functionalities tested were significantly impaired in STEMI patients, namely cholesterol efflux and anti-inflammatory properties. Increased myeloperoxidase levels might represent a major contributing mechanism for decreased HDL functionality in MI patients. [ABSTRACT FROM AUTHOR]

Rapid vascularization of bone graft substitutes upon implantation is one of the most important challenges to overcome in order to achieve successful regeneration of large, critical-size bone defects. One strategy for stimulating vascularization during the regeneration process is to create a hypoxic microenvironment by either directly lowering the local oxygen tension, or by applying hypoxia-mimicking factors. Cells compensate for the hypoxic condition by releasing angiogenic factors leading to new blood vessel formation. In the present study, we explored the potential of cobalt ions (Co 2+ ), known chemical mimickers of hypoxia, to stimulate vascularization within a bone graft substitute in vivo. To this end, Co 2+ ions were incorporated into calcium phosphate (CaPs) coatings deposited on poly(lactic acid) (PLA) particles with their effect on the formation of new blood vessels studied upon intramuscular implantation in goats. PLA particles and CaP-coated particles without Co 2+ ions served as controls. Pathological scoring of the inflammatory response following a 12-week implantation period showed no significant differences between the four types of materials. Based on histological and immunohistochemical analyses, both blood vessel area and number of blood vessels in CaP-coated PLA particles containing Co 2+ were higher than in the uncoated PLA particles and CaP-coated PLA particles without Co 2+ . Analysis of blood vessel size distribution indicated abundant formation of small blood vessels in all the samples, while large blood vessels were predominantly found in PLA particles coated with CaP containing Co 2+ ions. The results of this study support the use of CaPs containing Co 2+ ions to enhance vascularization in vivo. Statement of Significance In this work, we have investigated the potential of cobalt ions, incorporated into thin calcium phosphate (CaP) coatings that were deposited on particles of poly(lactic acid) (PLA), to induce neovascularization in vivo. Qualitative and quantitative histological and immunohistochemical analyses showed that both the number of blood vessels and the total blood vessel area were higher in CaP-coated PLA particles containing cobalt ions as compared to the uncoated PLA particles and CaP-coated PLA particles without the metallic additive. Furthermore, a wider distribution of blood vessel sizes, varying from very small to large vessels was specifically observed in samples containing cobalt ions. This in vivo study will significantly contribute to the existing knowledge on the use of bioinorganics, which are simple and inexpensive inorganic factors that can be used to control relevant biological process during tissue regeneration, such as vascularization. As such, we are convinced that this manuscript will be of interest to the readers of Acta Biomaterialia . [ABSTRACT FROM AUTHOR]

Summary Impaired angiogenesis has been implicated in adipose tissue dysfunction and the development of obesity and associated metabolic disorders. Here, we report the unexpected finding that vascular endothelial growth factor B (VEGFB) gene transduction into mice inhibits obesity-associated inflammation and improves metabolic health without changes in body weight or ectopic lipid deposition. Mechanistically, the binding of VEGFB to VEGF receptor 1 (VEGFR1, also known as Flt1) activated the VEGF/VEGFR2 pathway and increased capillary density, tissue perfusion, and insulin supply, signaling, and function in adipose tissue. Furthermore, endothelial Flt1 gene deletion enhanced the effect of VEGFB, activating the thermogenic program in subcutaneous adipose tissue, which increased the basal metabolic rate, thus preventing diet-induced obesity and related metabolic complications. In obese and insulin-resistant mice, Vegfb gene transfer, together with endothelial Flt1 gene deletion, induced weight loss and mitigated the metabolic complications, demonstrating the therapeutic potential of the VEGFB/VEGFR1 pathway. [ABSTRACT FROM AUTHOR]

The research paradigm in biomaterials science and engineering is evolving from using low-throughput and iterative experimental designs towards high-throughput experimental designs for materials optimization and the evaluation of materials properties. Computational science plays an important role in this transition. With the emergence of the omics approach in the biomaterials field, referred to as materiomics, high-throughput approaches hold the promise of tackling the complexity of materials and understanding correlations between material properties and their effects on complex biological systems. The intrinsic complexity of biological systems is an important factor that is often oversimplified when characterizing biological responses to materials and establishing property-activity relationships. Indeed, in vitro tests designed to predict in vivo performance of a given biomaterial are largely lacking as we are not able to capture the biological complexity of whole tissues in an in vitro model. In this opinion paper, we explain how we reached our opinion that converging genomics and materiomics into a new field would enable a significant acceleration of the development of new and improved medical devices. The use of computational modeling to correlate high-throughput gene expression profiling with high throughput combinatorial material design strategies would add power to the analysis of biological effects induced by material properties. We believe that this extra layer of complexity on top of high-throughput material experimentation is necessary to tackle the biological complexity and further advance the biomaterials field. Statement of Significance In this opinion paper, we postulate that converging genomics and materiomics into a new field would enable a significant acceleration of the development of new and improved medical devices. The use of computational modeling to correlate high-throughput gene expression profiling with high throughput combinatorial material design strategies would add power to the analysis of biological effects induced by material properties. We believe that this extra layer of complexity on top of high-throughput material experimentation is necessary to tackle the biological complexity and further advance the biomaterials field. [ABSTRACT FROM AUTHOR]

Background & Aims Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1 ) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. Methods C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. Results In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1–dependent lipidic-micelle–induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs. Conclusion In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1. [ABSTRACT FROM AUTHOR]

Objective Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. Methods We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid profile, and metabolic fluxes. Gene delivery of FXR variants to Fxr −/− mouse liver was performed to evaluate their role in vivo . The effects of fasting and physical exercise on hepatic Fxr splicing were determined. Results We show that FXR splice isoforms regulate largely different gene sets and have specific effects on hepatic metabolism. FXRα2 (but not α1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXRα2 decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXRα2 expression in Fxr −/− mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRα1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxrα2 expression. Conclusions Our results show that the main FXR variants in human liver (α1 and α2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists. [ABSTRACT FROM AUTHOR]

Surface topographies of materials considerably impact cellular behavior as they have been shown to affect cell growth, provide cell guidance, and even induce cell differentiation. Consequently, for successful application in tissue engineering, the contact interface of biomaterials needs to be optimized to induce the required cell behavior. However, a rational design of biomaterial surfaces is severely hampered because knowledge is lacking on the underlying biological mechanisms. Therefore, we previously developed a high-throughput screening device (TopoChip) that measures cell responses to large libraries of parameterized topographical material surfaces. Here, we introduce a computational analysis of high-throughput materiome data to capture the relationship between the surface topographies of materials and cellular morphology. We apply robust statistical techniques to find surface topographies that best promote a certain specified cellular response. By augmenting surface screening with data-driven modeling, we determine which properties of the surface topographies influence the morphological properties of the cells. With this information, we build models that predict the cellular response to surface topographies that have not yet been measured . We analyze cellular morphology on 2176 surfaces, and find that the surface topography significantly affects various cellular properties, including the roundness and size of the nucleus, as well as the perimeter and orientation of the cells. Our learned models capture and accurately predict these relationships and reveal a spectrum of topographies that induce various levels of cellular morphologies. Taken together, this novel approach of high-throughput screening of materials and subsequent analysis opens up possibilities for a rational design of biomaterial surfaces. [ABSTRACT FROM AUTHOR]