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Transcriptomic and proteomic characterization of cell and protein biomarkers of checkpoint inhibitor-induced liver injury
Get PDFImmune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 have shown remarkable antitumor efficacy, but can also cause immune-related adverse events, including checkpoint inhibitor-induced liver injury (ChILI). This multi-omic study aimed to investigate changes in blood samples from treated cancer patients who developed ChILI. PBMCs were sequenced for by transcriptomic and T cell receptor repertoire (bulk and single-cell immune profiling), and extracellular vesicle (EV) enrichment from plasma was analyzed by mass spectroscopy proteomics. Data were analyzed by comparing the ChILI patient group to the control group who did not develop ChILI and by comparing the onset of ChILI to pre-ICI treatment baseline. We identified significant changes in T cell clonality, gene expression, and proteins in peripheral blood mononuclear cells (PBMCs) and plasma in response to liver injury. Onset of ChILI was accompanied by an increase in T cell clonality. Pathway analysis highlighted the involvement of innate and cellular immune responses, mitosis, pyroptosis, and oxidative stress. Single-cell RNA sequencing revealed that these changes were primarily found in select T cell subtypes (including CD8 + effector memory cells), while CD16 + monocytes exhibited enrichment in metabolic pathways. Proteomic analysis of plasma extracellular vesicles showed enrichment in liver-associated proteins among differentially expressed proteins. Interestingly, an increase in PBMC PD-L1 gene expression and plasma PD-L1 protein was also found to be associated with ChILI onset. These findings provide valuable insights into the immune and molecular mechanisms underlying ChILI as well as potential biomarkers of ChILI. Trial registration number NCT04476563
A Time‐ and Cost‐Effective eDNA Protocol to Survey Freshwater Mussels (Bivalvia: Unionida) in Tropical Rivers
Get PDFTropical freshwater mussels (Bivalvia: Unionida) are one of the most endangered groups of animals globally, but conservation is hindered by a lack of species distribution data. Traditional hand-sampling is time- and cost-intensive and not always possible, for example, because of the presence of crocodiles. Surveying freshwater mussel populations by environmental DNA (eDNA) could potentially rapidly increase data availability, but no published study and protocols targeted towards tropical freshwater mussels are available to date. We aimed to develop a reliable and cost-efficient eDNA protocol for surveying tropical freshwater mussels. We first developed and validated a qPCR primer-probe assay within the cytochrome c oxidase subunit 1 (COI) gene for Rectidens sumatrensis. We applied this assay in a controlled laboratory setting on eDNA collected from lake and river water, respectively, at two different R. sumatrensis densities in order to test a set of 18 different protocols for capturing, preserving, and extracting freshwater mussel eDNA. All protocols use equipment that is readily available and reusable. Our results revealed that samples stored in Longmire's buffer (at 4°C) yielded more mussel DNA than when stored in absolute ethanol (at −20°C), with 0.45 μm, and eDNA extracted with the Qiagen DNeasy Blood & Tissue Kit rather than the PowerSoil ProKit (albeit latter exhibiting fewer instances of amplification in negative controls). The assay detailed here was capable of detecting down to R. sumatrensis eDNA concentrations of 6.38 × 10−7 ng/μL and reflected the difference in stocking density
Clinico-pathological features predicting indication to mastectomy in breast cancer patients achieving complete response after neoadjuvant therapy: a retrospective analysis of the EUSOMA database
No full textAims: We investigated factors related to the type of surgery, i.e. mastectomy versus breast conserving surgery (BCS), in breast cancer (BC) patients with complete pathologic response in the breast (ypT0) after neoadjuvant therapy (NAT). Methods: A retrospective analysis from the EUSOMA database was performed using data from 55 certified centers across 14 European countries, including ypT0 BC patients (i.e., neither invasive nor in situ residuals), treated between 2017 and 2022. Variables analyzed included year of surgery, age, number and distribution of tumor focality, extent, clinical and pathological stages, and biologic subtype. Logistic regression was used to identify predictors of surgical choice. The Kaplan-Meier method was used for comparison of local recurrence-free survival (LRFS) between surgical groups. Results: Of 1416 BC patients included, 67.5 % underwent BCS and 32.5 % mastectomy. At multivariable analysis, factors increasing the likelihood of mastectomy included: more recent year of surgery [odds ratio (OR) 2.61, 95 % confidence interval (95%CI): 1.51–4.51,p = 0.001], younger age (OR: 0.96, 95%CI: 0.95–0.97,p < 0.001), multifocality (OR: 2.20, 95%CI: 1.61–3.00,p < 0.001) and multicentricity (OR: 12.66, 95%CI: 6.82–23.49,p < 0.001), advanced clinical tumor stage (OR: 14.54, 95%CI: 5.80–36.47,p < 0.001), and baseline axillary nodal involvement (OR: 1.56, 95%CI: 1.12–2.17,p = 0.009). Comparison between groups did not show a significant difference in LRFS (p = 0.389). Conclusion: Many BC patients undergo mastectomy despite achieving complete response of primary tumor after NAT. Patients-related and tumor-related features, as well as having surgery in more recent years, seems to influence this choice. Our findings suggest the need for an optimized decision-making to spare unnecessary mastectomies
The usability and feasibility of the Person Attuned Musical Interactions intervention – modified version (PAMI-M) for UK care home staff working with residents with dementia
Get PDFIntroductionResearch on music interventions in care homes to improve social interactions has shown inconsistent results, potentially due to insufficient guidelines and staff training. Person Attuned Musical Interactions (PAMI), an evidence-based music therapy skill-sharing training package, aims to integrate non-verbal and musical interactions into care routines with residents with dementia. A modified version (PAMI-M) was developed to make PAMI accessible to a wider UK care home population.MethodTwo studies evaluated PAMI-M to assess clinical appropriateness, usability, and readability. Study 1 assessed the feasibility of the study design and manual, and Study 2 evaluated the revised manual on feedback from Study 1. Care staff were trained in PAMI-M and applied the skills with a resident with dementia over 8 weeks in Study 1 and 18 weeks in Study 2, with fortnightly reflective sessions supervised by a music therapist. Data collection included reflective session transcripts and post-intervention staff interviews.ResultsFive dyads completed Study 1, and 10 completed Study 2. Staff demonstrated the tailoring of skills to meet their residents’ needs. The intervention materials were readable and usable despite implementation barriers, such as time restraints, staff illness and COVID-19. Staff recommended shortening the manual, dividing the training into small sessions, and in-person observations for better usability.DiscussionThe studies highlighted the plausibility of delivering PAMI-M remotely, though staff would prefer a hybrid approach with observational elements for practical assessment and support. While this paper evaluated PAMI-M’s usability and feasibility, findings could inform the development of other psychosocial interventions in care homes
Differentiated yet common sentiments: UK news coverage on the Biden–Xi summit meeting
Get PDFBritain’s policy on China fluctuated from positive engagement to China scepticism between 2015 and 2023, influenced by geopolitical and domestic politics and economic concerns. British media coverage of US–China interactions and rivalry therefore warrants scrutiny. The US–China summit meeting of November 2023 offered such an opportunity. This article uses a critical discourse analysis approach to analyse UK coverage of Xi Jinping’s US visit. Portrayals of the summit are examined in terms of differing tones and stances adopted by The Guardian, the BBC, and the Daily Mail news outlets. It is found that while the Daily Mail’s tone toward the summit meeting was overwhelmingly negative, that of The Guardian was moderately positive and the BBC’s tone was mostly neutral. Narratives reveal that Britain positioned itself between the two rivalries through an inclusion of diverse, elite perspectives and that its framing of China cohered with Anglo–American ideological norms and special relations
Collagen composition in equine exuberant granulation tissue reflects tissue immaturity
Get PDFExuberant granulation tissue (EGT) is a second intention wound healing disorder. It commonly occurs in the distal limb of horses. EGT causes significant increase in the duration and cost of treatment, potentially leading to the decision not to pursue treatment and euthanize the patient. The underlying pathomechanisms of this fibroproliferative disorder remain unclear, particularly in terms of collagen composition and the association between myofibroblasts and blood vessels. This study investigated the collagen composition in naturally occurring EGT following trimming in 19 horses (EGT group). In both the superficial and deep wound beds of EGT-affected horses, the collagen distribution was assessed and compared to control wounds (n=6 horses, control group, punch biopsies) using histology. Immunofluorescence was performed to colocalize activated alpha smooth muscle actin-positive myofibroblasts in EGT as well as angiogenic markers. Our histological findings showed significantly higher amounts of immature collagen (type III) in the superficial and deep regions of EGT compared to the controls while the total amount of collagen in both groups did not differ significantly. In EGT, occluded microvessels and endothelial cell hypertrophy were present in the deep layer and myofibroblasts were ubiquitously found in the whole wound bed. Markers for intermediate filaments were reduced in the superficial region. In conclusion, collagen composition in EGT differed significantly from control wounds, indicating tissue immaturity. Consequently, promoting tissue maturation towards a more mature ECM composition could serve as a valuable target for future therapeutic interventions enabling better regeneration
Archives as worldmaking
Get PDFThis paper introduces the special issue ‘Archives as worldmaking’. Moving beyond the traditional focus on archives as tools of nation- or empire-building, the special issue posits archiving as a foundational practice of political worldmaking. It therefore emphasises the mechanics of worldmaking, as much as its diverse political manifestations. The paper first provides an overview of recent scholarship on archives and worldmaking within geography and related fields. It then presents the specific contributions to the special issue, organised around the key themes of worldmaking's plurality, its situated nature, and its connection to institution-building. The paper concludes by outlining four future research directions: colonial logics, racial capitalism, misinformation, and the role of archivists
Multisystemic resilience and its impact on youth mental health: reflections on co-designing a multi-disciplinary, participatory study
Get PDFYouth depression is a global emergency. Redressing this emergency requires a sophisticated understanding of the multisystemic risks and biopsychosocial, economic, and environmental resources associated with young people's experiences of no/limited versus severe depression. Too often, however, personal risks and a focus on individual-level protective resources dominate accounts of young people's trajectories towards depression. Further, studies of depression in high-income countries (i.e., “western”) typically inform these accounts. This article corrects these oversights. It reports on the methodology of the Wellcome-funded R-NEET study: a multidisciplinary, multisystemic, mixed method longitudinal study of resilience among African youth whose status as “not in education, employment or training” (NEET) makes them disproportionately vulnerable to depression. Co-designed by academics, community-based service providers and youth in South Africa and Nigeria, with partnerships in the United Kingdom, Canada and the United States, the R-NEET study is identifying the physiological, psychological, social, economic, institutional, and environmental risks and resources associated with distinct trajectories of depression. Using the methodology of the R-NEET study as exemplar, this article advances an argument for understanding resilience as a contextually and culturally rooted capacity that draws on the multiple, co-occurring systems that young people depend upon to support their wellbeing. Acknowledging and harnessing the multiple systems implicated in resilience is critical to researchers and mental health providers who seek to support young people to thrive, and to young people themselves when protecting or promoting their mental wellbeing
Ex Vivo investigation of a Smart Endotracheal Tube for Identifying Oesophageal Intubation
Get PDFSignificanceUnrecognized intubation of the esophagus instead of the trachea results in rapid and severe consequences for the patient. Utilizing the spectral properties of the tissues could reduce incidents of these events.AimWe aim to investigate the design and implementation of a smart endotracheal tube (ETT) with integrated optical fiber sensors to distinguish esophageal and tracheal tissues.ApproachComputational methods are investigated to characterize and classify nine pairs of ex vivo porcine organs using spectral properties. Two classifiers [K-nearest neighbor and linear discriminant analysis (LDA)] are investigated.ResultsOf the tissues sampled, 100% are correctly distinguished, with LDA being the preferred choice when considering both performance and applicability.ConclusionsIn clinical practice, this approach offers a method for confirming correct tracheal intubation using the spectral properties of the tissues, performed in a single step with no other invasive medical device than the ETT required to detect the spectral measurements
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