Unravelling the biological and clinical challenges of circulating tumour cells in epithelial ovarian carcinoma.

Epithelial ovarian carcinoma (EOC) is the eighth most common cancer in women and the leading cause of gynaecological cancer death, predominantly due to the absence of effective screening tools, advanced stage at diagnosis, and high rates of recurrence. Circulating tumour cells (CTCs), are a rare subset of tumour cells that disseminate from a tumour and migrate into the circulation, play a pivotal role in the metastatic cascade, and therefore hold promise as biomarkers for disease monitoring and prognostication. Exploring CTCs from liquid biopsies is an appealing approach for research and clinical practice, given it is minimally invasive, facilitates serial sampling and enables the capture of the entire spectrum of cancer cells circulating in the blood. The prognostic utility of CTC enumeration has been FDA-approved for clinical use in metastatic breast, prostate, and colorectal cancers. However, the unique biology of EOC, discussed herein, compounds the detection and characterisation complexities already inherent in CTC research, consequently hindering progress towards clinical applications. The aim of this review is to provide an overview of both the biological and clinical challenges encountered in harnessing the power of CTCs in EOC.

A comparative study of circulating tumor cell isolation and enumeration technologies in lung cancer.

Circulating tumor cells (CTCs) have potential as diagnostic, prognostic, and predictive biomarkers in solid tumors. Despite Food and Drug Administration (FDA) approval of CTC devices in various cancers, the rarity and heterogeneity of CTCs in lung cancer make them technically challenging to isolate and analyze, hindering their clinical integration. Establishing a consensus through comparative analysis of different CTC systems is warranted. This study aimed to evaluate seven different CTC enrichment methods across five technologies using a standardized spike-in protocol: the CellMag™ (EpCAM-dependent enrichment), EasySep™ and RosetteSep™ (blood cell depletion), and the Parsortix® PR1 and the new design Parsortix® Prototype (PP) (size- and deformability-based enrichment). The Parsortix® systems were also evaluated for any differences in recovery rates between cell harvest versus in-cassette staining. Healthy donor blood (5 mL) was spiked with 100 fluorescently labeled EpCAMhigh H1975 cells, processed through each system, and the isolation efficiency was calculated. The CellMag™ had the highest recovery rate (70 ± 14%), followed by Parsortix® PR1 in-cassette staining, while the EasySep™ had the lowest recovery (18 ± 8%). Additional spike-in experiments were performed with EpCAMmoderate A549 and EpCAMlow H1299 cells using the CellMag™ and Parsortix® PR1 in-cassette staining. The recovery rate of CellMag™ significantly reduced to 35 ± 14% with A549 cells and 1 ± 1% with H1299 cells. However, the Parsortix® PR1 in-cassette staining showed cell phenotype-independent and consistent recovery rates among all lung cancer cell lines: H1975 (49 ± 2%), A549 (47 ± 10%), and H1299 (52 ± 10%). Furthermore, we demonstrated that the Parsortix® PR1 in-cassette staining method is capable of isolating heterogeneous single CTCs and cell clusters from patient samples. The Parsortix® PR1 in-cassette staining, capable of isolating different phenotypes of CTCs as either single cells or cell clusters with consistent recovery rates, is considered optimal for CTC enrichment for lung cancer, albeit needing further optimization and validation.

Mediators of socioeconomic differences in overweight and obesity among youth in Ireland and the UK (2011-2021): a systematic review.

BACKGROUND: By 2025, adult obesity prevalence is projected to increase in 44 of 53 of European-region countries. Childhood obesity tracks directly onto adult obesity, and children of low socioeconomic position families are at disproportionately higher risk of being obese compared with their more affluent peers. A previous review of research from developed countries identified factors mediating this relationship. This systematic review updates and extends those findings specifically within the context of Ireland and the United Kingdom. OBJECTIVE: The aim of this systematic review is to summarise peer-reviewed research completed in Ireland and the United Kingdom between 2011-2021 examining mediators of socioeconomic differentials in adiposity outcomes for youth. DESIGN: An electronic search of four databases, Ovid MEDLINE, Embase, Web of Science and EBSCOhost was conducted. Quantitative studies, published in the English language, examining mediators of socioeconomic differentials in adiposity outcomes in youth, and conducted in Ireland and the United Kingdom between 2011-2021 were included. An appraisal of study quality was completed. The systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Following screening, a total of 23 papers were eligible for inclusion. Results indicate socioeconomic differentials for Ireland and the United Kingdom follow similar patterns to other developed countries and have similar mediating factors including early life and parent-level factors. However, this review identified additional factors that mediate the relationship, namely access to green space and favorable neighborhood conditions. Identifying these factors present further opportunities for potential interventions and confirm the requirement for tailored and appropriate research and interventions for Ireland and the United Kingdom. CONCLUSION: This review identified several modifiable factors that should be considered when planning interventions aimed at reducing socioeconomic differentials in adiposity among youth in Ireland and the United Kingdom. Support was found for interventions to be made as early as possible in an at-risk child's life, with the prenatal and preschool periods considered the most efficacious. Results were equivocal about the role of physical activity in the risk of childhood overweight and obesity. While multi-country analyses provide excellent overviews, country- or area-specific research may produce more nuanced, and potentially more powerful findings, which can help better inform policy responses and interventions.

The Dynamics of Platelet Activation during the Progression of Streptococcal Sepsis.

Platelets contribute to inflammation however, the role of platelet activation during the pathophysiological response to invasive bacterial infection and sepsis is not clear. Herein, we have investigated platelet activation in a mouse model of invasive Streptococcus pyogenes infection at 5, 12, and 18 hours post infection and correlated this to parameters of infection. The platelet population in ex-vivo blood samples showed no increased integrin activation or surface presentation of CD62P, however platelet-neutrophil complex formation and plasma levels of CD62P were increased during bacterial dissemination and the progression of sepsis, indicating that platelet activation had occurred in vivo. Platelet-neutrophil complex formation was the most discriminatory marker of platelet activation. Platelet-neutrophil complexes were increased above baseline levels during early sepsis but decreased to significantly lower levels than baseline during late sepsis. The removal of these complexes from the circulation coincided with a significant increase in organ damage and the accumulation of platelets in the liver sinusoids, suggesting that platelet activation in the circulation precedes accumulation of platelets in damaged organs. The results demonstrate that monitoring platelet activation using complementary methods may provide prognostic information during the pathogenesis of invasive S. pyogenes infection.

Platelet-Dependent Neutrophil Function Is Dysregulated by M Protein from Streptococcus pyogenes.

Platelets are rapidly responsive sentinel cells that patrol the bloodstream and contribute to the host response to infection. Platelets have been reported to form heterotypic aggregates with leukocytes and may modulate their function. Here, we have investigated platelet-neutrophil complex formation and neutrophil function in response to distinct agonists. The endogenous platelet activator thrombin gave rise to platelet-dependent neutrophil activation, resulting in enhanced phagocytosis and bacterial killing. Streptococcus pyogenes is an important causative agent of severe infectious disease, which can manifest as sepsis and septic shock. M1 protein from S. pyogenes also mediated platelet-neutrophil complex formation; however, these neutrophils were dysfunctional and exhibited diminished chemotactic ability and bacterial killing. This reveals an important agonist-dependent neutrophil dysfunction during platelet-neutrophil complex formation and highlights the role of platelets during the immune response to streptococcal infection.

Active but inoperable thrombin is accumulated in a plasma protein layer surrounding Streptococcus pyogenes.

Activation of thrombin is a critical determinant in many physiological and pathological processes including haemostasis and inflammation. Under physiological conditions many of these functions are involved in wound healing or eradication of an invading pathogen. However, when activated systemically, thrombin can contribute to severe and life-threatening conditions by causing complications such as multiple multi-organ failure and disseminated intravascular coagulation. In the present study we investigated how the activity of thrombin is modulated when it is bound to the surface of Streptococcus pyogenes. Our data show that S. pyogenes bacteria become covered with a proteinaceous layer when incubated with human plasma, and that thrombin is a constituent of this layer. Though the coagulation factor is found attached to the bacteria with a functional active site, thrombin has lost its capacity to interact with its natural substrates and inhibitors. Thus, the interaction of bacteria with human plasma renders thrombin completely inoperable at the streptococcal surface. This could represent a host defense mechanism to avoid systemic activation of coagulation which could be otherwise induced when bacteria enter the circulation and cause systemic infection.

Platelets promote bacterial dissemination in a mouse model of streptococcal sepsis.

Platelets have been reported to contribute to inflammation and inflammatory disorders. In the present study, we demonstrate that platelets contribute to the acute response to bacterial infection in a mouse model of invasive Streptococcus pyogenes infection. Thrombocytopenia occurred rapidly in infected animals and this was associated with platelet activation, formation of platelet-neutrophil complexes and neutrophil activation. In order to assess the role of platelets during infection, platelets were depleted prior to infection. Platelet-depleted animals had significantly decreased platelet-neutrophil complex formation and neutrophil activation in response to infection. Importantly, significantly fewer bacteria disseminated to the blood, lungs, and spleen of platelet-depleted animals. Platelet-depleted animals did not decrease as significantly in weight as the infected control animals. The results demonstrate a previously unappreciated role for platelets during the pathophysiological response to infection, whereby S. pyogenes bacteria bind to platelets and platelets facilitate bacterial dissemination.