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\"Reproductive donation is the most contentious area of assisted reproduction. Even within Europe there are wide variations in what is permitted in each country. This multidisciplinary book takes a fresh look at the practices of egg, sperm and embryo donation and surrogacy, bringing together ethical analysis and empirical research. New evidence is offered on aspects of assisted reproduction and the families these create, including non-traditional types. One of the key issues addressed is should children be told of their donor origin? If they do learn the identity of their donor, what kinds of relationships may be forged between families, the donor and other donor sibling families? Should donation involve a gift relationship? Is intra-familial donation too close for comfort? How should we understand the growing trend for 'reproductive tourism'? This lively and informed discussion offers new insights into reproductive donation and the resulting donor families\"--Provided by publisher.

An outstanding challenge in epigenome studies is the estimation of cell-type proportions in complex epithelial tissues. Here, we construct and validate a DNA methylation reference and algorithm for complex tissues that contain epithelial, immune and nonimmune stromal cells. Using this reference, we show that easily accessible tissues such as saliva, buccal and cervix exhibit substantial variation in immune cell (IC) contamination. We further validate our reference in the context of oral cancer, where it correctly predicts an increased IC infiltration in cancer but suppressed in patients with highest smoking exposure. Finally, our method can improve the specificity of differentially methylated CpG calls in epithelial cancer. The degree and variation of IC contamination in complex epithelial tissues is substantial. We provide a valuable resource and tool for assessing the epithelial purity and IC contamination of samples and for identifying differential methylation in such complex tissues.

Nomlabofusp is a recombinant, cell‐penetrating human frataxin (hFXN) fusion protein in development for the treatment of Friedreich's ataxia (FRDA). This study evaluated whether nomlabofusp‐derived hFXN concentrations covary across accessible peripheral matrices and FRDA‐relevant tissues, supporting the feasibility of surrogate tissue sampling to monitor drug‐derived hFXN exposure. Following subcutaneous administration in mice, rats, non‐human primates, and patients with FRDA, we quantified nomlabofusp‐derived hFXN and assessed cross‐tissue correlations across target tissues (brain, heart, skeletal muscle, dorsal root ganglia) and accessible peripheral matrices (skin, buccal cells, platelets). We observed significant and consistent cross‐tissue correlations, with concordant relationships among heart, skeletal muscle, dorsal root ganglia, skin, buccal cells, liver, and mitochondrial fractions, indicating coordinated distribution and/or retention of nomlabofusp‐derived hFXN across these matrices. Correlation patterns were maintained across species, supporting the robustness and translational relevance of the observed relationships. Collectively, these data support the use of peripheral tissues—particularly skin and buccal cells—for cross‐sectional and longitudinal monitoring of hFXN supplementation in FRDA. Study Highlights What is the current knowledge on the topic? Friedreich's ataxia (FRDA) is caused by frataxin (FXN) deficiency with prominent involvement of dorsal root ganglia, heart, and skeletal muscle, but repeated FXN measurement in these target tissues is invasive and impractical for longitudinal trials. Nomlabofusp is a subcutaneously administered recombinant human FXN (hFXN) fusion protein intended for mitochondrial delivery, and early clinical studies show dose‐dependent hFXN increases in accessible matrices (skin, buccal cells, platelets). However, key translational uncertainties persisted: whether peripheral tissues consistently mirror hFXN in FRDA target organs across species and clinical dosing schedules, and whether whole‐tissue measures capture mitochondrial delivery—both prerequisites for using surrogate tissues in longitudinal trials. What question did this study address? Do nomlabofusp‐derived hFXN concentrations in minimally invasive peripheral tissues (skin biopsy, buccal swab, platelets) correlate with hFXN in FRDA‐relevant tissues (brain, heart, skeletal muscle, dorsal root ganglia) across species and dosing regimens? What does this study add to our knowledge? Across mice, rats, non‐human primates, and FRDA patients, nomlabofusp produced increases in hFXN and showed significant, directionally consistent cross‐tissue associations linking peripheral matrices—especially skin and buccal epithelium—with FRDA‐relevant organs. Mouse whole‐liver and liver‐mitochondrial hFXN were strongly concordant (r = 0.88–1.00 early), supporting mitochondrial uptake and interpretability of whole‐tissue measurements. In patients, skin–buccal correlations were strongest with consistent daily dosing (Spearman r = 0.73 in Phase 2). How might this change clinical pharmacology or translational science? Skin and buccal epithelium are supported as practical surrogate tissues for monitoring hFXN and tissue exposure when target‐organ sampling is infeasible. This enables serial assessment to inform dose/regimen optimization and sampling windows while reducing participant burden and strengthening translational bridging for FXN supplementation strategies.

This paper presents the concept, design, construction, and validation of a novel probe based on the hexadic disposition of six pressure sensors suitable for measuring triaxial stress states inside bulky soft materials. The measurement of triaxial stress states inside bulk materials such as brain tissue surrogates is a challenging task needed to investigate internal organs’ stress states and validate FE models. The purpose of the work was the development and validation of a 17 × 17 × 17 mm probe containing six pressure sensors. To do so, six piezoresistive pressure sensors of 6 mm diameter were arranged into an hexad at three cartesian axes and bisecting angles, based on the analytical solution of the stress tensor. The resulting probe was embedded in a soft silicone rubber of known characteristics, calibrated under cyclic compression and shear in three orientations, and statically validated with combined loads. A calibration matrix was computed, and validation tests allowed us to estimate Von Mises stress under combined stress with an error below 6%. Hence, the proposed probe design and method can give indications about the complex stress state developing internally to soft materials under triaxial high-strain fields, opening applications in the analysis of biological models or physical surrogates involving parenchyma organs.

Abstract The prenatal environment contributes to the risk for congenital conditions, including birth defects, developmental disorders, and diseases that manifest in later life. However, our current understanding of prenatal exposures and their impact on disease risk is extremely limited. DNA methylation (DNAm) is a promising biomarker of prenatal exposures because this epigenetic mechanism is developmentally active, environmentally responsive, and imparts chemically stable marks that can be quantified with increasing accuracy and precision. However, development and utilization of DNAm biomarkers are impeded by inadequate understanding of how environmentally responsive prenatal DNAm changes persist across progenitor cell populations and pre- and postnatal development. This review synthesizes current evidence on the impact of the prenatal environment on DNAm, including specific dietary and chemical influences, and persistence of these changes across life stages. We then evaluate the suitability of common surrogate tissues (blood, saliva, and extra-embryonic tissues) from a developmental cell lineage framework for their applicability in prenatal exposure research and outline key considerations in selecting surrogate tissues for epigenome-wide association studies. Finally, using orofacial cleft etiopathogenesis as a model, we illustrate the conceptual application of DNAm biomarkers and highlight the need for longitudinal studies and comparative analysis of target and surrogate tissues. By identifying key knowledge gaps and proposing actionable strategies to address them, this review is directed at advancing the use of DNAm biomarkers in resolving how prenatal exposures contribute to human disease. Graphical Abstract Graphical Abstract

Background The widespread use of accessible peripheral tissues for epigenetic analyses has prompted increasing interest in the study of tissue-specific DNA methylation (DNAm) variation in human populations. To date, characterizations of inter-individual DNAm variability and DNAm concordance across tissues have been largely performed in adult tissues and therefore are limited in their relevance to DNAm profiles from pediatric samples. Given that DNAm patterns in early life undergo rapid changes and have been linked to a wide range of health outcomes and environmental exposures, direct investigations of tissue-specific DNAm variation in pediatric samples may help inform the design and interpretation of DNAm analyses from early life cohorts. In this study, we present a systematic comparison of genome-wide DNAm patterns between matched pediatric buccal epithelial cells (BECs) and peripheral blood mononuclear cells (PBMCs), two of the most widely used peripheral tissues in human epigenetic studies. Specifically, we assessed DNAm variability, cross-tissue DNAm concordance and genetic determinants of DNAm across two independent early life cohorts encompassing different ages. Results BECs had greater inter-individual DNAm variability compared to PBMCs and highly the variable CpGs are more likely to be positively correlated between the matched tissues compared to less variable CpGs. These sites were enriched for CpGs under genetic influence, suggesting that a substantial proportion of DNAm covariation between tissues can be attributed to genetic variation. Finally, we demonstrated the relevance of our findings to human epigenetic studies by categorizing CpGs from published DNAm association studies of pediatric BECs and peripheral blood. Conclusions Taken together, our results highlight a number of important considerations and practical implications in the design and interpretation of EWAS analyses performed in pediatric peripheral tissues.

Background A family of parsimonious Gaussian mixture models for the biclustering of gene expression data is introduced. Biclustering is accommodated by adopting a mixture of factor analyzers model with a binary, row-stochastic factor loadings matrix. This particular form of factor loadings matrix results in a block-diagonal covariance matrix, which is a useful property in gene expression analyses, specifically in biomarker discovery scenarios where blood can potentially act as a surrogate tissue for other less accessible tissues. Prior knowledge of the factor loadings matrix is useful in this application and is reflected in the one-way supervised nature of the algorithm. Additionally, the factor loadings matrix can be assumed to be constant across all components because of the relationship desired between the various types of tissue samples. Parameter estimates are obtained through a variant of the expectation-maximization algorithm and the best-fitting model is selected using the Bayesian information criterion. The family of models is demonstrated using simulated data and two real microarray data sets. The first real data set is from a rat study that investigated the influence of diabetes on gene expression in different tissues. The second real data set is from a human transcriptomics study that focused on blood and immune tissues. The microarray data sets illustrate the biclustering family’s performance in biomarker discovery involving peripheral blood as surrogate biopsy material. Results The simulation studies indicate that the algorithm identifies the correct biclusters, most optimally when the number of observation clusters is known. Moreover, the biclustering algorithm identified biclusters comprised of biologically meaningful data related to insulin resistance and immune function in the rat and human real data sets, respectively. Conclusions Initial results using real data show that this biclustering technique provides a novel approach for biomarker discovery by enabling blood to be used as a surrogate for hard-to-obtain tissues.

Among gynecologic malignancies, ovarian cancer (OC) has the poorest survival rate, and its clinical management remains challenging due to the high rate of recurrence and chemoresistance. Improving survival for these patients is critical, although this requires the ability to translate preclinical studies to actual patient care: bench to bedside and back. Our objective was to develop a preclinical model that accurately represents tumor biology and its microenvironment. We utilized SKOV-3, OVCAR-8, and CS-99 cell lines to show that this model was suitable for in vitro assessment of cell proliferation. We tested OC cells independently and in co-culture with cancer associated fibroblasts (CAFs) or immune cells. Additionally, we used patient-derived ovarian carcinoma and carcinosarcoma samples to show that the system maintains the histologic morphology of the primary tissue after 7 days. Moreover, we tested the response to chemotherapy using both cell lines and patient-derived tumor specimens and confirmed that cell death was significantly higher in the treated group compared to the vehicle group. Finally, we immune profiled the 3-D model containing patient tissue after several days in the bioreactor system and revealed that the immune populations are still present. Our data suggest that this model is a suitable preclinical model to aid in research that will ultimately impact the treatment of patients with gynecologic cancer.

Epigenetics has an important role in the regulation of metabolic adaptation to environmental modifications. In this sense, the determination of epigenetic changes in non-invasive samples during the development of metabolic diseases could play an important role in the procedures in primary healthcare practice. To help translate the knowledge of epigenetics to public health practice, the present study aims to explore the parallelism of methylation levels between white blood cells and buccal samples in relation to obesity and associated disorders. Blood and buccal swap samples were collected from a subsample of the Spanish cohort of the Food4Me study. Infinium HumanMethylation450 DNA Analysis was carried out for the determination of methylation levels. Standard deviation for β values method and concordance correlation analysis were used to select those CpG which showed best parallelism between samples. A total of 277 CpGs met the criteria and were selected for an enrichment analysis and a correlation analysis with anthropometrical and clinical parameters. From those selected CpGs, four presented high associations with BMI (cg01055691 in GAP43 ; r  = −0.92 and rho = −0.84 for blood; r  = −0.89 and rho = −0.83 for buccal sample), HOMA-IR (cg00095677 in ATP2A3 ; r  = 0.82 and rho = −0.84 for blood; r  = −0.8 and rho = −0.83 for buccal sample) and leptin (cg14464133 in ADARB2 ; r  = −0.9182 and rho = −0.94 for blood; r  = −0.893 and rho = −0.79 for buccal sample). These findings demonstrate the potential application of non-invasive buccal samples in the identification of surrogate epigenetic biomarkers and identify methylation sites in GAP43 , ATP2A3 and ADARB2 genes as potential targets in relation to overweight management and insulin sensibility.

This chapter contains sections titled: Introduction Studies with FFPE Cell Blocks and Gel‐Embedded Proteins Studies with Tissue Surrogates Evaluation of the Effects of Histological Processing on Tissue Surrogates Effects of Detergent and Temperature on Recovery Efficiency Effects of Other Buffer Formulations on Recovery Efficiency Studies with Tissue Surrogates Formed from Other Proteins Conclusion References