The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Background: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. Methods: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. Results: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). Conclusion: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection

Psychometric properties of the Fear of Birth Scale in women in the perinatal period: A multicountry study.

Assessing Fear of Birth Scale's (FOBS) psychometric properties in the perinatal period using multicountry data is a step toward effectively screen clinically significant fear of childbirth (FOC) in maternal healthcare settings. FOBS psychometric properties were analyzed in women in the perinatal period using data from Australia, Germany, Lithuania, Poland, and Portugal. FOBS' reliability, criterion (known group and convergent), concurrent, predictive, and clinical validity were analyzed. FOBS was completed by 3431 women in pregnancy (n = 2984) or postpartum (n = 447). Sociodemographic, obstetric, neonatal, and mental health-related data, depressive and anxiety symptoms, and tokophobia severity were self-reported. FOBS has good reliability. Known-group validity was established based on differences in sociodemographic, obstetric, neonatal, and mental health-related variables. Convergent validity was found with depressive and anxiety symptoms, and birth trauma. Concurrent validity was found with tokophobia severity. FOBS scores in pregnancy predicted elective cesarean section, and postpartum depressive and anxiety symptoms. FOBS discriminates between women with and without clinically significant FOC in pregnancy and postpartum, with optimal cut-offs across countries. This multicountry study suggested that FOBS is a psychometrically strong measure that can be an effective tool to screen clinically significant FOC in the perinatal period

Going through it together: Dyadic associations between parents' birth experience, relationship satisfaction, and mental health

BACKGROUND: Previous research suggests that a negative birth experience is associated with symptoms of postpartum depression and anxiety in mothers and partners. However, this has mostly been investigated within the first year postpartum and research on the long-term effects is lacking. Additionally, the role of relationship satisfaction and the interdependence between parents have not been considered so far. METHODS: Couples (N = 1992) completed questionnaires on their birth experience, relationship satisfaction, and symptoms of depression and anxiety at two months, 14 months, and two years after birth, respectively. RESULTS: Actor-Partner Interdependence Mediation Models indicated no partner effects, but several significant actor and indirect effects. A more positive birth experience was associated with higher relationship satisfaction and less depression and anxiety symptoms for both parents. Higher relationship satisfaction was in turn associated with less depression (mothers and partners) and anxiety symptoms (mothers). The association between birth experience and depression symptoms was partially mediated by relationship satisfaction for mothers and partners, while the association between birth experience and anxiety symptoms was partially mediated by relationship satisfaction only for mothers. LIMITATIONS: Due to the highly educated, very healthy sample with low levels of depression and anxiety as well as high relationship satisfaction, results cannot be generalized to less privileged parents. Moreover, all effects were very small. CONCLUSIONS: Results highlight the importance of a positive birth experience for parents' relationship satisfaction and mental health. Negative birth experiences need to be avoided to prevent a negative impact on the whole family

Birth expectations, birth experiences and childbirth‐related post‐traumatic stress symptoms in mothers and birth companions: Dyadic investigation using response surface analysis

Objectives During the perinatal period, women and their birth companions form expectations about childbirth. We aimed to examine whether a mismatch between birth expectations and experiences predict childbirth‐related post‐traumatic stress symptoms (CB‐PTSS) for mothers and birth companions. We also explored the influence of the mismatch between mothers' and birth companions' expectations/experiences on CB‐PTSS. Design Dyadic longitudinal data from the Self‐Hypnosis IntraPartum Trial. Methods Participants (n = 469 mothers; n = 358 birth companions) completed questionnaires at 27 and 36 weeks of gestation and 2 and 6 weeks post‐partum. We used the measures of birth expectations (36 weeks gestation), birth experiences (2 weeks post‐partum) and CB‐PTSS (6 weeks post‐partum). Results Correlations revealed that birth expectations were associated with experiences for both mothers and birth companions but were not consistently associated with CB‐PTSS. Birth experiences related to CB‐PTSS for both mothers and birth companions. The response surface analysis results showed no support for the effect of a mismatch between expectations and experiences on CB‐PTSS in mothers or birth companions. Similarly, a mismatch between mothers' and birth companions' expectations or experiences was unrelated to CB‐PTSS. Conclusions Following previous literature, birth expectations were associated with experiences, and experiences were associated with CB‐PTSS. By testing the effect of the match between birth experiences and expectations using an advanced statistical method, we found that experiences play a more substantial role than the match between experiences and expectations in CB‐PTSS. The impact of birth experiences on CB‐PTSS highlights the importance of respectful and supportive maternity care

A brief international screening tool for traumatic birth and childbirth-related PTSD: the city BiTS-short form

Introduction Screening to identify traumatic births and childbirth-related post-traumatic stress disorder (CB-PTSD) is critical for reducing the global burden of maternal mental health challenges. Despite this, no brief, validated tools exist for international use. This study therefore developed and validated a short version of the City Birth Trauma Scale (City BiTS) to provide a brief, globally relevant screening tool. Methods The City BiTS-Short was developed in three stages. In stage 1, exclusive lasso statistical analyses were conducted on survey data of 11 302 postpartum women in 31 countries to identify the most effective items for the City BiTS-Short, ensuring all four CB-PTSD symptom domains were represented. In stage 2, stakeholder reviews were conducted with researchers, health professionals (midwives, health visitors, psychiatrist, psychologist) and representatives of women who experienced traumatic birth. In stage 3, the City BiTS-Short was finalised and psychometric properties examined across diverse geographical settings. Results The City BiTS-Short comprises one item assessing traumatic birth and four items assessing CB-PTSD symptoms: re-experiencing, avoidance, negative cognitions and mood and hyperarousal. The scale had strong psychometric properties, including good internal consistency (α=0.78) and high correlations with the original City BiTS (r=0.90), birth trauma ratings (r=0.50), distress (r=0.56), impairment (r=0.47) and CB-PTSD diagnoses (r=0.54). It identified 90% of participants with a CB-PTSD diagnosis. Women who had operative births (F(3,2174)=127.38, p<0.001), maternal complications (F(2,2163)=212.84, p<0.001), infant complications (F(2,1100)=138.93, p<0.001) or depression (t(3209.5)=−30.96, p<0.001) had higher scores. Psychometric properties were consistent across most international contexts, with stakeholders affirming its utility. Conclusion The City BiTS-Short offers a brief, validated screening tool for identifying birth trauma and CB-PTSD symptoms. Its widespread adoption can enhance early detection and support for women, potentially reducing the global burden of birth trauma and improving maternal mental health outcomes worldwide. Further research is needed to explore its use in specific contexts

Methyl-binding domain protein-based DNA isolation from human blood serum combines DNA analyses and serum-autoantibody testing

<p>Abstract</p> <p>Background</p> <p>Circulating cell free DNA in serum as well as serum-autoantibodies and the serum proteome have great potential to contribute to early cancer diagnostics via non invasive blood tests. However, most DNA preparation protocols destroy the protein fraction and therefore do not allow subsequent protein analyses. In this study a novel approach based on methyl binding domain protein (MBD) is described to overcome the technical difficulties of combining DNA and protein analysis out of one single serum sample.</p> <p>Methods</p> <p>Serum or plasma samples from 98 control individuals and 54 breast cancer patients were evaluated upon silica membrane- or MBD affinity-based DNA isolation via qPCR targeting potential DNA methylation markers as well as by protein-microarrays for tumor-autoantibody testing.</p> <p>Results</p> <p>In control individuals, an average DNA level of 22.8 ± 25.7 ng/ml was detected applying the silica membrane based protocol and 8.5 ± 7.5 ng/ml using the MBD-approach, both values strongly dependent on the serum sample preparation methods used. In contrast to malignant and benign tumor serum samples, cell free DNA concentrations were significantly elevated in sera of metastasizing breast cancer patients. Technical evaluation revealed that serum upon MBD-based DNA isolation is suitable for protein-array analyses when data are consistent to untreated serum samples.</p> <p>Conclusion</p> <p>MBD affinity purification allows DNA isolations under native conditions retaining the protein function, thus for example enabling combined analyses of DNA methylation and autoantigene-profiles from the same serum sample and thereby improving minimal invasive diagnostics.</p

An untargeted multi-technique metabolomics approach to studying intracellular metabolites of HepG2 cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

<p>Abstract</p> <p>Background</p> <p><it>In vitro </it>cell systems together with omics methods represent promising alternatives to conventional animal models for toxicity testing. Transcriptomic and proteomic approaches have been widely applied <it>in vitro </it>but relatively few studies have used metabolomics. Therefore, the goal of the present study was to develop an untargeted methodology for performing reproducible metabolomics on <it>in vitro </it>systems. The human liver cell line HepG2, and the well-known hepatotoxic and non-genotoxic carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), were used as the <it>in vitro </it>model system and model toxicant, respectively.</p> <p>Results</p> <p>The study focused on the analysis of intracellular metabolites using NMR, LC-MS and GC-MS, with emphasis on the reproducibility and repeatability of the data. State of the art pre-processing and alignment tools and multivariate statistics were used to detect significantly altered levels of metabolites after exposing HepG2 cells to TCDD. Several metabolites identified using databases, literature and LC-nanomate-Orbitrap analysis were affected by the treatment. The observed changes in metabolite levels are discussed in relation to the reported effects of TCDD.</p> <p>Conclusions</p> <p>Untargeted profiling of the polar and apolar metabolites of <it>in vitro </it>cultured HepG2 cells is a valid approach to studying the effects of TCDD on the cell metabolome. The approach described in this research demonstrates that highly reproducible experiments and correct normalization of the datasets are essential for obtaining reliable results. The effects of TCDD on HepG2 cells reported herein are in agreement with previous studies and serve to validate the procedures used in the present work.</p

Desenvolvimento e avaliação de uma fonte DC de alta tensão para utilização em sistema de deposição de filmes finos por pulverização catódica

RESUMO O trabalho em questão está relacionado ao projeto e construção de uma fonte de alta tensão em corrente contínua utilizando materiais e dispositivos adquiridos no comércio local visando sua aplicação no processo de pulverização catódica. Essa técnica permite a deposição de filmes finos de metais, óxidos e nitretos sobre substratos sólidos. Como teste de funcionamento e aplicação da fonte DC, com a mesma instalada em canhão de pulverização em alto vácuo, filmes finos de diferentes espessuras de cobre, aço inoxidável 304 e tungstênio foram depositados e estudados. Análise de espessura, morfologia, e resistência elétrica e resistividade foram conduzidas. Filmes com resistividade elétrica dependente das espessuras foram obtidos. A fonte DC se mostrou confiável em operação e permite a deposição de uma infinidade de materiais nas mais diferentes espessuras sobre vários tipos de substratos