In the question put forward by Scott et al., implications about the role of immune activation in depressive or other mood disorders were suggested. Low-level inflammation, triggered by the release of inflammatory molecules such as cytokines, has been detected in individuals with major mood disorders. These markers can be present in very low concentrations, posing a significant analytical challenge and complicating their use as reliable biomarkers. In this Perspective, we discuss the potential promise in leveraging nanotechnology and trace-level analysis of biomarkers of immune activation to enhance our molecular understanding of the immune system’s functioning and its association with depressive and other mood disorders. This Perspective critically discusses the analytical challenges of trace biomarker detection, highlighting issues with variability in study methodologies and cohort heterogeneity and emphasising the need for diurnal and longitudinal sampling to study circadian disruption and immune activation. Profiling inflammatory markers in this manner could create individualised molecular fingerprints, revealing disruptions in immune synchronisation with circadian rhythms and detecting abnormalities linked to specific mood disorder subtypes, and particularly ‘circadian depression’. As the profiling of general inflammatory markers may not be sufficient to study any causative relationship between immune activation and major mood disorders, we propose the exploration of novel biomarkers such as extracellular vesicles to support these investigations. The use of nanotechnologies for trace profiling of diurnal variations of inflammatory molecules, in combination with novel biomarkers, offers a promising strategy to develop a molecular understanding of the role of immune activation in depressive and other mood disorders.

Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform. With mRNAs packaged in a myriad of extracellular vesicles and particles, these signals may be used to develop clinically actionable, non-invasive disease biomarkers. Here, we summarize the recent scientific developments of extracellular mRNA, biology of extracellular mRNA carriers, clinical utility of cf-mRNA as disease biomarkers, as well as proposed functions in cell and tissue pathophysiology.

The aim of liquid biopsies is to obtain tumor information via the molecular interrogation of liquid samples, including blood and urine. As a minimally invasive procedure, liquid biopsies have attracted attention. A series of studies have reported associations of biomarkers such as circulating tumor DNA, cell-free DNA and extracellular vesicles with urological cancers, especially prostate cancer (PCa), and demonstrated the promising potential of liquid biopsies. In this review, we summarize recent clinical translational studies of liquid biopsies in PCa and other urological cancers, including bladder cancer and renal cell carcinoma. The number of translational studies was limited, and most of the studies focused on PCa. Biomarkers isolated from blood by different detection methods could be applied in clinical practice to predict prognosis and treatment response in advanced PCa. The other applications in urological cancers identified in previous studies remain to be explored further. Current studies are limited due to the lack of ideal standard detection methods for biomarkers. In the future, with advances in methodology, more translational studies will be conducted to identify potential applications of liquid biopsies in urological cancers.

Burkitt lymphoma (BL) has a cure rate of around 95% when treated with chemo-immunotherapy that is standard of care in high-income countries (Minard-Colin et al., 2020, New England Journal of Medicine 382, 2207–2219), but currently, more than 50% of children and young adults with endemic BL (Epstein Barr virus driven BL) in sub-Saharan Africa (SSA) do not survive. Treatment for BL is largely free of charge, but there is limited access to reliable diagnostic services leading to significant delays and misdiagnoses. Innovations in histopathology such as whole slide imaging and the use of novel diagnostic approaches, in particular using circulating cell-free viral and/or lymphoma DNA (liquid biopsy), could increase access to timely and reliable diagnosis and improve outcomes in SSA.

Circulating cell-free DNA (cfDNA) consists of small fragments of DNA that circulate freely in the bloodstream. In cancer patients, a fraction of cfDNA is derived from tumour cells, therefore containing the same genetic and epigenetic alterations, and is termed circulating cell-free tumour DNA. The potential use of cfDNA, the so-called ‘liquid biopsy’, as a non-invasive cancer biomarker has recently received a lot of attention. The present review will focus on studies concerning the potential clinical applications of cfDNA in ovarian cancer patients.