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The transfer of a small number of cells between parent and offspring during pregnancy, commonly referred to as microchimerism, is thought to occur in all human pregnancies. The impact of microchimeric cells on health outcomes in mothers and offspring with respect to cancer, remains unknown. Molecular and epidemiological studies yield conflicting results on the link between microchimerism and cancer, underscoring the complexity of this phenomenon. Further, most studies on microchimerism and cancer focus on the relationship between circulating fetal cells in parous women. Given that the cellular exchange between the mother and offspring is thought to have arisen due to the evolution of internal gestation, we provide an evolutionary perspective on how internal gestation may impact the risk of cancer in humans. We highlight the potential mechanisms that may play a role in cancer vulnerability in mammals, such as genomic conflict and placental invasion. We then review the literature to investigate the effects of microchimerism on cancer outcomes in parous women, highlighting each study's interpretation of the role microchimeric cells play in cancer development, whether it is a protective or contributing role. We conclude that our current understanding of the relationship between microchimerism and cancer is poorly understood and propose mechanisms for when we would expect to see microchimerism contribute to a role in protecting the host from cancer and when microchimerism may contribute to tumor development. Future studies, including more advanced methods to detect and identify microchimerism, will be important for elucidating the link between microchimerism and cancer initiation and progression., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Microchimerism is defined as the presence of a small population of genetically distinct cells within a host that is derived from another individual. Throughout pregnancy, maternal and fetal cells are known to traffic across the feto-maternal interface and result in maternal and fetal microchimerism, respectively. However, the routes of cell transfer, the molecular signaling as well as the timing in which trafficking takes place are still not completely understood. Recently, the presence of inflammation at the feto-maternal interface has been linked with maternal microchimeric cells modulating organ development in the fetus. Here, we review the current literature and suggest that inflammatory processes at the feto-maternal interface tissues are a physiological prerequisite for the establishment of microchimerism. We further propose a spatio-temporal corridor of microchimeric cell migration to potentially explain some biological effects of microchimerism. Additionally, we elaborate on the possible consequences of a shift in this spatio-temporal corridor, potentially responsible for the development of pathologies in the neonate., Competing Interests: Declarations. Competing interests: The authors declare no competing interest., (© 2025. The Author(s).)

Background: Metastatic prostate cancer is a highly heterogeneous and dynamic disease and practicable tools for patient stratification and resistance monitoring are urgently needed. Liquid biopsy analysis of circulating tumor cells (CTCs) and circulating tumor DNA are promising, however, comprehensive testing is essential due to diverse mechanisms of resistance. Previously, we demonstrated the utility of mRNA-based in situ padlock probe hybridization for characterizing CTCs., Methods: We have developed a novel combinatorial dual-color (CoDuCo) assay for in situ mRNA detection, with enhanced multiplexing capacity, enabling the simultaneous analysis of up to 15 distinct markers. This approach was applied to CTCs, corresponding tumor tissue, cancer cell lines, and peripheral blood mononuclear cells for single-cell and spatial gene expression analysis. Using supervised machine learning, we trained a random forest classifier to identify CTCs. Image analysis and visualization of results was performed using open-source Python libraries, CellProfiler, and TissUUmaps., Results: Our study presents data from multiple prostate cancer patients, demonstrating the CoDuCo assay's ability to visualize diverse resistance mechanisms, such as neuroendocrine differentiation markers (SYP, CHGA, NCAM1) and AR-V7 expression. In addition, druggable targets and predictive markers (PSMA, DLL3, SLFN11) were detected in CTCs and formalin-fixed, paraffin-embedded tissue. The machine learning-based CTC classification achieved high performance, with a recall of 0.76 and a specificity of 0.99., Conclusions: The combination of high multiplex capacity and microscopy-based single-cell analysis is a unique and powerful feature of the CoDuCo in situ assay. This synergy enables the simultaneous identification and characterization of CTCs with epithelial, epithelial-mesenchymal, and neuroendocrine phenotypes, the detection of CTC clusters, the visualization of CTC heterogeneity, as well as the spatial investigation of tumor tissue. This assay holds significant potential as a tool for monitoring dynamic molecular changes associated with drug response and resistance in prostate cancer., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the ethics committee (EK 31–353 ex 18/19) and written informed consent was obtained from all patients and healthy controls. Consent for publication All patients gave written informed consent for publication. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce., Methods: To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation., Results: We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis., Conclusions: This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.

Foetal cells are detectable in women decades postpartum, a state termed foetal microchimerism. The interplay between these semi-allogeneic foetal cells and the mother could be affected by genetic mismatches in the HLA loci. Here, we relate HLA allele and molecular mismatch values to the presence and quantity of foetal microchimerism in the maternal circulation during pregnancy and postpartum. A total of 76 pregnant women were included, of which 59 were followed up 1-8 years postpartum. Maternal and foetal DNA was genotyped for HLA class I and II loci. Foetal cells in maternal buffy coat were detected by qPCR, targeting inherited paternal alleles. Antibody-verified eplet mismatch and Predicted Indirectly Recognisable HLA Epitopes (PIRCHE) scores were calculated to quantify foetal-maternal histocompatibility from the mother's perspective. Circulating foetal cells were detected in 50.0% (38/76) of women during pregnancy, and 25.4% (15/59) postpartum. During pregnancy, HLA class II antibody-verified eplet mismatch load and PIRCHE scores correlated negatively with the presence and quantity of foetal cells in the maternal circulation. Postpartum, HLA class I allele mismatches correlated negatively with foetal microchimerism presence, while HLA class II allele mismatches, HLA class I and II antibody-verified eplet mismatch load, and PIRCHE-I and PIRCHE-II scores correlated negatively with both microchimerism presence and quantity. The correlation between mismatch parameters aimed at evaluating the risk of humoral and T cell-mediated allorecognition and foetal microchimerism was more evident postpartum than during pregnancy. The observed predictive effect of foetal-maternal histocompatibility on foetal microchimerism suggests that circulating foetal cells are subject to clearance by the maternal immune system. We propose that allorecognition of foetal cells in the maternal circulation and tissues influences any long-term effect that foetal microchimerism may have on maternal health., (© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Background: Liquid biopsies are emerging as valuable clinical biomarkers for cancer monitoring. Although International Organization for Standards (ISO) and Technical Specifications from the European Committee for Standardization (CEN/TS) standardized workflows exist, their implementation in clinical practice is underdeveloped. We aimed to assess the applicability of ISO and CEN/TS standards in a real-world clinical setting, with a particular focus on evaluating the impact of preanalytical parameters and hemolysis on liquid biopsy analysis., Methods: We evaluated 659 peripheral blood samples from advanced prostate cancer patients against ISO and CEN/TS standards and documented all essential criteria, including tube draw order, filling level, temperature, and time tracking from blood draw to storage. We assessed hemolysis and its effect on circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) analysis., Results: Our results demonstrated a high compliance rate, with 96.2% (634/659) of samples meeting essential ISO and CEN/TS criteria. We did not observe a significant impact on ctDNA or CTC detection rates between hemolytic and nonhemolytic samples. Hemolysis was identified in 12.9% (40/311) of plasma samples from our advanced prostate cancer cohort, and within the draw order of 5 blood collection tubes, hemolysis did not significantly increase from tube 1 to 5. In total, 83.8% (552/659) of blood collection tubes had high fill levels above 80% of nominal filling level., Conclusions: Our study demonstrates the feasibility and benefits of adhering to ISO and CEN/TS standards in a clinical liquid biopsy study. The standards revealed that hemolysis occurred frequently but did not impair downstream ctDNA and CTC analysis in our cohort of advanced prostate cancer patients., (© Association for Diagnostics & Laboratory Medicine 2024.)

Background: Pregnant women have an increased risk of getting infected with SARS-CoV-2 and are more prone to severe illness. Data on foetal demise in affected pregnancies and its underlying aetiology is scarce and pathomechanisms remain largely unclear., Case: Herein we present the case of a pregnant woman with COVID-19 and intrauterine foetal demise. She had no previous obstetric or gynaecological history, and presented with mild symptoms at 34 + 3 weeks and no signs of foetal distress. At 35 + 6 weeks intrauterine foetal death was diagnosed. In the placental histopathology evaluation, we found inter- and perivillous fibrin depositions including viral particles in areas of degraded placental anatomy without presence of viral entry receptors and SARS-CoV-2 infection of the placenta., Conclusion: This case demonstrates that maternal SARS-CoV-2 infection in the third trimester may lead to an unfavourable outcome for the foetus due to placental fibrin deposition in maternal COVID-19 disease possibly via a thrombogenic microenvironment, even when the foetus itself is not infected., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Opting for or against the administration of adjuvant chemotherapy in therapeutic management of stage II colon cancer remains challenging. Several studies report few survival benefits for patients treated with adjuvant therapy and additionally revealing potential side effects of overtreatment, including unnecessary exposure to chemotherapy-induced toxicities and reduced quality of life. Predictive biomarkers are urgently needed. We, therefore, hypothesise that the spatial tissue composition of relapsed and non-relapsed colon cancer stage II patients reveals relevant biomarkers., Methods: The spatial tissue composition of stage II colon cancer patients was examined by a novel spatial transcriptomics technology with sub-cellular resolution, namely in situ sequencing. A panel of 176 genes investigating specific cancer-associated processes such as apoptosis, proliferation, angiogenesis, stemness, oxidative stress, hypoxia, invasion and components of the tumour microenvironment was designed to examine differentially expressed genes in tissue of relapsed versus non-relapsed patients. Therefore, FFPE slides of 10 colon cancer stage II patients either classified as relapsed (5 patients) or non-relapsed (5 patients) were in situ sequenced and computationally analysed., Results: We identified a tumour gene signature that enables the subclassification of tissue into neoplastic and non-neoplastic compartments based on spatial expression patterns obtained through in situ sequencing. We developed a computational tool called Genes-To-Count (GTC), which automates the quantification of in situ signals, accurately mapping their position onto the spatial tissue map and automatically identifies neoplastic and non-neoplastic tissue compartments. The GTC tool was used to quantify gene expression of biological processes upregulated within the neoplastic tissue in comparison to non-neoplastic tissue and within relapsed versus non-relapsed stage II colon patients. Three differentially expressed genes (FGFR2, MMP11 and OTOP2) in the neoplastic tissue compartments of relapsed patients in comparison to non-relapsed patients were identified predicting recurrence in stage II colon cancer., Conclusions: In depth spatial in situ sequencing showed potential to provide a deeper understanding of the underlying mechanisms involved in the recurrence of disease and revealed novel potential predictive biomarkers for disease relapse in colon cancer stage II patients. Our open-access GTC-tool allowed us to accurately capture the tumour compartment and quantify spatial gene expression in colon cancer tissue., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Non-coding natural antisense transcripts (ncNATs) are regulatory RNA molecules that are overlapping with as well as complementary to other transcripts. These transcripts are implicated in a broad variety of biological and pathological processes, including tumorigenesis and oncogenic progression. With this complex field still in its infancy, annotations, expression profiling and functional characterisations of ncNATs are far less comprehensive than those for protein-coding genes, pointing out substantial gaps in the analysis and characterisation of these regulatory transcripts. In this review, we discuss ncNATs from an analysis perspective, in particular regarding the use of high-throughput sequencing strategies, such as RNA-sequencing, and summarize the unique challenges of investigating the antisense transcriptome. Finally, we elaborate on their potential as biomarkers and future targets for treatment, focusing on cancer., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we (1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, (2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR -splice variant 7) in lysed whole blood, and (3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44-53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches.