Single Cell Transcriptomics Implicate Novel Monocyte and T Cell Immune Dysregulation in Sarcoidosis

Sarcoidosis is a systemic inflammatory disease characterized by infiltration of immune cells into granulomas. Previous gene expression studies using heterogeneous cell mixtures lack insight into cell-type-specific immune dysregulation. We performed the first single-cell RNA-sequencing study of sarcoidosis in peripheral immune cells in 48 patients and controls. Following unbiased clustering, differentially expressed genes were identified for 18 cell types and bioinformatically assessed for function and pathway enrichment. Our results reveal persistent activation of circulating classical monocytes with subsequent upregulation of trafficking molecules. Specifically, classical monocytes upregulated distinct markers of activation including adhesion molecules, pattern recognition receptors, and chemokine receptors, as well as enrichment of immunoregulatory pathways HMGB1, mTOR, and ephrin receptor signaling. Predictive modeling implicated TGFβ and mTOR signaling as drivers of persistent monocyte activation. Additionally, sarcoidosis T cell subsets displayed patterns of dysregulation. CD4 naïve T cells were enriched for markers of apoptosis and Th17/T(reg) differentiation, while effector T cells showed enrichment of anergy-related pathways. Differentially expressed genes in regulatory T cells suggested dysfunctional p53, cell death, and TNFR2 signaling. Using more sensitive technology and more precise units of measure, we identify cell-type specific, novel inflammatory and regulatory pathways. Based on our findings, we suggest a novel model involving four convergent arms of dysregulation: persistent hyperactivation of innate and adaptive immunity via classical monocytes and CD4 naïve T cells, regulatory T cell dysfunction, and effector T cell anergy. We further our understanding of the immunopathology of sarcoidosis and point to novel therapeutic targets

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease

© 2020, The Author(s). Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation

Navigational Bronchoscopy with Cryobiopsy for Diagnosis of ILD

Background. Interstitial lung diseases (ILDs) are a group of parenchymal pulmonary diseases in which pathologic diagnosis is essential. Although cryobiopsy has a high diagnostic yield, the complication rate remains high. Case Presentation. We report two cases of lung cryobiopsy guided by navigational bronchoscopy (LCB) for the diagnosis of ILD. In both cases, a CT chest angiogram (CTA) using a navigational protocol was performed. Targets were premarked and reached with the navigational system. Radial ultrasound (RU) was applied in combination with fluoroscopy guidance (FG) prior to sampling. Both patients achieved a final diagnosis; they were discharged home after procedure and no complications were noted. Discussion. By using a CTA with navigational guidance, we were able to perform cryobiopsy in areas with most disease activity and least vascularization. Conclusion. LCB used with navigational guidance for the diagnosis of ILD provides may be a safe and effective procedure that provides high diagnostic yield. Limitations include cost, availability, and expertise. Larger trials are needed to confirm the additional benefit

Transudative pleural effusion of malignant etiology: Rare but real

A 62-year-old female presented to the emergency room with one-month history of epigastric abdominal pain, nausea and vomiting. She endorsed progressive dyspnea over two weeks. CT of the abdomen demonstrated bilateral pleural effusions and pancreatic inflammation, so the working diagnosis was pancreatitis. A diagnostic thoracentesis was performed and the pleural fluid analysis was classified as transudate by Light's criteria. Given the atypical features in history and concern for malignancy, fluid was sent for cytological examination and immunohistochemistry which suggested a mucinous malignancy. EGD revealed poorly differentiated signet ring cell adenocarcinoma of stomach. Patient underwent placement of indwelling pleural catheters for symptomatic improvement and was discharged to hospice. The decision whether to routinely send transudative effusions for cytological evaluation remains controversial. This case demonstrates the importance of using clinical judgement to guide that decision

Fig 2 -

Kaplan-Meier survival curves a. in high-dose and low-dose groups and b. for subgroups with OSCI = 5 at randomization.</p

Hyperglycemia and infection events in the low-dose group and high-dose group.

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Clinical improvement using the WHO-Ordinal scale for clinical improvement (WHO-OSCI).

Clinical improvement using the WHO-Ordinal scale for clinical improvement (WHO-OSCI).</p

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease.

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer’s disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM3 gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation

A lipidomic based metabolic age score captures cardiometabolic risk independent of chronological ageResearch in context

Summary: Background: Metabolic ageing biomarkers may capture the age-related shifts in metabolism, offering a precise representation of an individual’s overall metabolic health. Methods: Utilising comprehensive lipidomic datasets from two large independent population cohorts in Australia (n = 14,833, including 6630 males, 8203 females), we employed different machine learning models, to predict age, and calculated metabolic age scores (mAge). Furthermore, we defined the difference between mAge and age, termed mAgeΔ, which allow us to identify individuals sharing similar age but differing in their metabolic health status. Findings: Upon stratification of the population into quintiles by mAgeΔ, we observed that participants in the top quintile group (Q5) were more likely to have cardiovascular disease (OR = 2.13, 95% CI = 1.62–2.83), had a 2.01-fold increased risk of 12-year incident cardiovascular events (HR = 2.01, 95% CI = 1.45–2.57), and a 1.56-fold increased risk of 17-year all-cause mortality (HR = 1.56, 95% CI = 1.34–1.79), relative to the individuals in the bottom quintile group (Q1). Survival analysis further revealed that men in the Q5 group faced the challenge of reaching a median survival rate due to cardiovascular events more than six years earlier and reaching a median survival rate due to all-cause mortality more than four years earlier than men in the Q1 group. Interpretation: Our findings demonstrate that the mAge score captures age-related metabolic changes, predicts health outcomes, and has the potential to identify individuals at increased risk of metabolic diseases. Funding: The specific funding of this article is provided in the acknowledgements section