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Tissue-resident macrophages are heterogeneous as a consequence of anatomical niche–specific functions. Many populations self-renew independently of bone marrow in the adult, but the molecular mechanisms of this are poorly understood. We determined a transcriptional profile for the major self-renewing population of peritoneal macrophages in mice. These cells specifically expressed the transcription factor Gata6. Selective deficiency of Gata6 in myeloid cells caused substantial alterations in the transcriptome of peritoneal macrophages. Gata6 deficiency also resulted in dysregulated peritoneal macrophage proliferative renewal during homeostasis and in response to inflammation, which was associated with delays in the resolution of inflammation. Our investigations reveal that the tissue macrophage phenotype is under discrete tissue-selective transcriptional control and that this is fundamentally linked to the regulation of their proliferation renewal.

Systemic arterial air embolism is an uncommon but potentially fatal complication of CT-guided transthoracic lung biopsy. Although rare, it carries significant morbidity due to cerebral and coronary ischaemia. We report two cases of systemic arterial air embolism occurring during CT-guided percutaneous lung biopsies. Both patients developed acute neurological deficits immediately following the procedure, attributed to cerebral air embolism. Imaging confirmed the presence of intracranial air in subarachnoid spaces. Neurological symptoms improved with supportive management, including oxygen administration and positioning. Histopathology in both cases revealed pulmonary adenocarcinoma. These cases highlight the importance of prompt recognition and appropriate management of systemic air embolism. Risk mitigation strategies include careful patient positioning, minimisation of intrapulmonary pressure gradients, and maintenance of needle occlusion. Although rare, this complication must be anticipated by interventionalists and managed promptly to avoid permanent neurological damage.

BackgroundTobacco smoke exposure (TSE) through secondhand and thirdhand smoke is a modifiable risk factor that contributes to childhood morbidity. Limited research has assessed surface TSE pollution in children’s environments as a potential source of thirdhand smoke exposure, and none have examined levels of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on surfaces.ObjectiveThis study measured surface NNK and nicotine in children’s homes and associations with sociodemographics and parent-reported TSE behaviors. We assessed correlations of surface NNK and nicotine with dust NNK, dust nicotine, and child cotinine.MethodsHome surface wipe NNK and nicotine data from 84 children who lived with smokers were analyzed. Tobit and simple linear regression analyses were conducted to assess associations of surface NNK and nicotine with child characteristics. Spearman’s (ρ) correlations assessed the strength of associations between environmental markers and child cotinine.ResultsNearly half (48.8%) of children’s home surfaces had detectable NNK and 100% had detectable nicotine. The respective geometric means (GMs) of surface NNK and nicotine loadings were 14.0 ng/m2 and 16.4 µg/m2. Surface NNK positively correlated with surface nicotine (ρ = 0.54, p < 0.001) and dust NNK (ρ = 0.30, p = 0.020). Surface nicotine positively correlated with dust NNK (ρ = 0.42, p < 0.001) and dust nicotine (ρ = 0.24, p = 0.041). Children with household incomes ≤ $15,000 had higher surface NNK levels (GM = 18.7 ng/m2, p = 0.017) compared to children with household incomes >$ 15,000 (GM = 7.1 ng/m2). Children with no home smoking bans had higher surface NNK (GM = 18.1 ng/m2, p = 0.020) and surface nicotine (GM = 17.7 µg/m2, p = 0.019) levels compared to children with smoking bans (GM = 7.5 ng/m2, 4.8 µg/m2, respectively).ImpactAlthough nicotine on surfaces is an established marker of thirdhand smoke pollution, other thirdhand smoke contaminants have not been measured on surfaces in the homes of children living with smokers. We provide evidence that the potent carcinogenic tobacco-specific nitrosamine NNK was detectable on surfaces in nearly half of children’s homes, and nicotine was detectable on all surfaces. Surface NNK was positively correlated with surface nicotine and dust NNK. Detectable surface NNK levels were found in homes with indoor smoking bans, indicating the role of NNK as a persistent thirdhand smoke pollutant accumulating on surfaces as well as in dust.

Are the Writings a miscellaneous collection of books, as is so often asserted, or do they have a purposeful design or arrangement? Over the past 35 years, there has been a significant amount of scholarly interest in the shape of the Law, Former Prophets, Twelve Minor Prophets and the Psalms, while examinations of the shape of the Writings were almost nonexistent until very recently. The 11 essays in this volume explore this often-neglected issue from a variety of critical perspectives—reader-centered approaches, canonical, structural-canonical, and redactional—made more robust by the mix of German- and English-language scholarship on this question, including 4 articles translated from German into English. Essays range from the historical development of the collection, to analysis of the collection's different arrangements, to the relationship of books and subcollections within the Writings, to the reception of the collection in Jewish and Christian sources. Every book in the Writings is discussed, with particular attention given to Job, Ruth, and 1 and 2 Chronicles. The volume closes with 3 critical responses from John Barton, Tamara Cohn Eskenazi, and Christopher Seitz.

The discovery of disease biomarkers, along with the use of \"liquid biopsies\" as a minimally invasive source of biomarkers, continues to be of great interest. In inflammatory diseases of the central nervous system (CNS), cerebrospinal fluid (CSF) is the most obvious biofluid source. Extracellular vesicles (EVs) are also present in CSF and are thought to be potential \"biomarker treasure chests\". However, isolating these CSF-derived EVs remains challenging. This small-scale pilot study developed and tested a protocol to enrich for CSF-EVs, both in relapsing remitting multiple sclerosis (RRMS) CSF and controls. These were subsequently compared, using an aptamer based proteomics array, SOMAscan™. EVs were enriched from RRMS patient (n = 4) and non-demyelinating control (idiopathic intracranial hypertension (IIH) (n = 3)) CSF using precipitation and mini size-exclusion chromatography (SEC). EV-enriched fractions were selected using pre-defined EV characteristics, including increased levels of tetraspanins. EVs and paired CSF were analysed by SOMAscan™, providing relative abundance data for 1128 proteins. CSF-EVs were characterised, revealing exosome-like features: rich in tetraspanins CD9 and CD81, size ~100 nm, and exosome-like morphology by TEM. Sufficient quantities of, SOMAscan™ compatible, EV material was obtained from 5 ml CSF for proteomics analysis. Overall, 348 and 580 proteins were identified in CSF-EVs and CSF, respectively, of which 50 were found to be significantly (t-test) and exclusively enriched in RRMS CSF-EVs. Selected proteins, Plasma kallikrein and Apolipoprotein-E4, were further validated by western blot and appeared increased in CSF-EVs compared to CSF. Functional enrichment analysis of the 50 enriched proteins revealed strong associations with biological processes relating to MS pathology and also extracellular regions, consistent with EV enrichment. This pilot study demonstrates practicality for EV enrichment in CSF derived from patients with MS and controls, allowing detailed analysis of protein profiles that may offer opportunities to identify novel biomarkers and therapeutic approaches in CNS inflammatory diseases.

BackgroundMetformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).MethodsPeripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses.ResultsIncreased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1.ConclusionsOur data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.

Background and aims: Despite recent advances in advanced prostate cancer treatments, clinical biomarkers or treatments for men with such cancers are imperfect. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterise BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA M.expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression, and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signalling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available.

There is widespread transcriptional dysregulation in Huntington’s disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that are dysfunctional in HD, could act as a surrogate for brain tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD cohorts, and performed gene set enrichment analysis using public databases and weighted correlation network analysis modules from HD and control brain datasets. We identified dysregulated gene sets in blood that replicated in the independent cohorts, correlated with disease severity, corresponded to the most significantly dysregulated modules in the HD caudate, the most prominently affected brain region, and significantly overlapped with the transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and use of gene sets likely surmounted the limitations of previously inconsistent HD blood expression studies. Our results suggest transcription is disrupted in peripheral cells in HD through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with Alzheimer’s disease, suggesting a common pathogenic mechanism involving macrophage phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic approaches.

Background Early detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity. Results Here we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett’s Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status. Conclusions Given our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum , a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.

The COVID-19 pandemic has led to restrictions such as social distancing and mandatory wearing of face masks. Singing and religious gatherings have been linked to infection clusters, and between 2020 and 2021 indoor congregational singing and chanting were prohibited in the United Kingdom. We evaluated attitudes to face mask use and their acceptability as well as changes within places of worship since their reopening in July up to autumn 2020. In this cross-sectional study, participants were recruited using convenience sampling through selective targeting of religious organisations and social media. Participants self-enrolled and completed an online questionnaire, which included open and closed questions. We used multivariable logistic regression to identify factors associated with face mask acceptability. We performed thematic analysis to evaluate responses to open questions. A total of 939 participants were included in the analysis. Median age was 52.7 years and 66.1% were female, while 80.7% identified as Christian. A majority (672/861; 78.0%) of participants would find it acceptable to wear a face mask and reduce their singing or chanting volume if required, even though 428/681 (49.1%) found face masks to be uncomfortable. Multivariable regression found that younger age was associated with a higher acceptability of face masks (adjusted OR (aOR): 0.98 (95% confidence interval (95% CI) 0.96–1.00), p  = 0.0218). The majority of respondents stated that religious services had become shorter, attended by fewer people and with reduced singing or chanting. Most (869/893, 97.3%) stated their place of worship complied with government guidelines, with 803/887 (90.5%) reported that their place of worship enforced face mask wearing and 793/887 (89.4%) at least moderately happy with precaution measures. Our study demonstrates the significant impact of COVID-19 in places of worship but a high degree of compliance with guidelines. Face masks, despite practical difficulties, appeared to be more acceptable if there was an incentive of being able to sing and chant.