Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide ...(LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-kappaB in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold (P<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-alpha and IL-6 secretion (IL-6, CONTROL: 2.7+/-0.5 vs. LPS: 4.8+/-0.3 ng/ml; P<0.001; TNF-alpha,
1.0+/-0.83 vs. LPS: 32.8+/-6.23 pg/ml; P<0.001). NF-kappaB inhibitor reduced IL-6 in AbdSc adipocytes (
2.7+/-0.5 vs. NF-kappaB inhibitor: 2.1+/-0.4 ng/ml; P<0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF-kappaB was increased in T2DM patients (P<0.05), and TLR-2, TRAF-6, and NF-kappaB were increased in LPS-treated adipocytes (P<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, P<0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P=0.0395) and serum LPS (reduced by 35%, P=0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.
Abstract
Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells ...(mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (T
reg
) cell development
1–4
. Within weeks of birth, a separate wave of T
reg
cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota
5–8
, yet the cell types responsible for the generation of peripheral T
reg
(pT
reg
) cells have not been identified. Here we describe the identification of a class of RORγt
+
antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pT
reg
cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pT
reg
generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pT
reg
differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt
+
group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pT
reg
generation, further implicating TC IV as the tolerogenic RORγt
+
antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.
Mutation in the CHMP2B gene has been implicated in frontotemporal dementia. The authors screened CHMP2B in patients with ALS and several cohorts of control samples. They identified mutations (Q206H; ...I29V) in two patients with non-SOD1 ALS. Neuropathology of the Q206H case showed lower motor neuron predominant disease with ubiquitylated inclusions in motor neurons. Antibodies to p62 (sequestosome 1) showed novel oligodendroglial inclusions in the motor cortex.
A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or ...placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence. Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation. One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab 0·82 0·71-0·95, p = 0·008 and sarilumab 0·80 0·61-1·04, p = 0·09 compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 95%CI 0·81-1·32, p = 0·80. The p-value for the global test of inconsistency was 0·28. Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.
Sequence stratigraphy emphasizes facies relationships and stratal architecture within a chronological framework. Despite its wide use, sequence stratigraphy has yet to be included in any ...stratigraphic code or guide. This lack of standardization reflects the existence of competing approaches (or models) and confusing or even conflicting terminology. Standardization of sequence stratigraphy requires the definition of the fundamental model-independent concepts, units, bounding surfaces and workflow that outline the foundation of the method. A standardized scheme needs to be sufficiently broad to encompass all possible choices of approach, rather than being limited to a single approach or model.
A sequence stratigraphic framework includes genetic units that result from the interplay of accommodation and sedimentation (i.e., forced regressive, lowstand and highstand normal regressive, and transgressive), which are bounded by ‘sequence stratigraphic’ surfaces. Each genetic unit is defined by specific stratal stacking patterns and bounding surfaces, and consists of a tract of correlatable depositional systems (i.e., a ‘systems tract’). The mappability of systems tracts and sequence stratigraphic surfaces depends on depositional setting and the types of data available for analysis. It is this high degree of variability in the precise expression of sequence stratigraphic units and bounding surfaces that requires the adoption of a methodology that is sufficiently flexible that it can accommodate the range of likely expressions. The integration of outcrop, core, well-log and seismic data affords the optimal approach to the application of sequence stratigraphy. Missing insights from one set of data or another may limit the ‘resolution’ of the sequence stratigraphic interpretation.
A standardized workflow of sequence stratigraphic analysis requires the identification of all genetic units and bounding surfaces that can be delineated objectively, at the selected scale of observation, within a stratigraphic section. Construction of this model-independent framework of genetic units and bounding surfaces ensures the success of the sequence stratigraphic method. Beyond this, the interpreter may make model-dependent choices with respect to which set of sequence stratigraphic surfaces should be elevated in importance and be selected as sequence boundaries. In practice, the succession often dictates which set of surfaces are best expressed and hold the greatest utility at defining sequence boundaries and quasi-chronostratigraphic units. The nomenclature of systems tracts and sequence stratigraphic surfaces is also model-dependent to some extent, but a standard set of terms is recommended to facilitate communication between all practitioners.
Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We ...investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma.
We carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial.
Mutant BRAF or NRAS ctDNA was detected (≥1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79–5.47; P < 0.0001 and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80–5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83–5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88–6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%–55%) versus 65% (95% CI 56%–72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40–4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32–4.74, P = 0.005).
ctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy.
ISRCTN 81261306
Pediatric brain tumors have diverse pathologic features, which poses diagnostic challenges. Although perfusion evaluation of adult tumors is well established, hemodynamic properties are not well ...characterized in children. Our goal was to apply arterial spin-labeling perfusion for various pathologic types of pediatric brain tumors and evaluate the role of arterial spin-labeling in the prediction of tumor grade.
Arterial spin-labeling perfusion of 54 children (mean age, 7.5 years; 33 boys and 21 girls) with treatment-naive brain tumors was retrospectively evaluated. The 3D pseudocontinuous spin-echo arterial spin-labeling technique was acquired at 3T MR imaging. Maximal relative tumor blood flow was obtained by use of the ROI method and was compared with tumor histologic features and grade.
Tumors consisted of astrocytic (20), embryonal (11), ependymal (3), mixed neuronal-glial (8), choroid plexus (5), craniopharyngioma (4), and other pathologic types (3). The maximal relative tumor blood flow of high-grade tumors (grades III and IV) was significantly higher than that of low-grade tumors (grades I and II) (P < .001). There was a wider relative tumor blood flow range among high-grade tumors (2.14 ± 1.78) compared with low-grade tumors (0.60 ± 0.29) (P < .001). Across the cohort, relative tumor blood flow did not distinguish individual histology; however, among posterior fossa tumors, relative tumor blood flow was significantly higher for medulloblastoma compared with pilocytic astrocytoma (P = .014).
Characteristic arterial spin-labeling perfusion patterns were seen among diverse pathologic types of brain tumors in children. Arterial spin-labeling perfusion can be used to distinguish high-grade and low-grade tumors.
Myeloproliferative neoplasms (MPNs) feature a malignant clone containing the JAK2 V617F mutation, or another mutation causing dysregulated JAK2 kinase activity. The multiple disease phenotypes of ...MPNs, and their tendency to transform phenotypically, suggest pathophysiologic heterogeneities beyond a common phenomenon of JAK2 hyperactivation. JAK2 has the potential to activate multiple other signaling molecules, either directly through downstream effectors, or indirectly through induction of target gene expression. We have interrogated myeloproliferative signaling in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) patient samples using mass cytometry, which allows the quantitative measurement of multiple signaling molecules simultaneously at the single-cell level, in cell populations representing a nearly complete spectrum of hematopoiesis. MF and sAML malignant cells demonstrated a high prevalence of hyperactivation of the JAK-STAT, MAP kinase, PI3 kinase and NFκB signaling pathways. Constitutive NFκB signaling was evident across MF and sAML patients. A supporting gene set enrichment analysis (GSEA) of MF showed many NFκB target genes to be expressed above normal levels in MF patient CD34+ cells. NFκB inhibition suppressed colony formation from MF CD34+ cells. This study indicates that NFκB signaling contributes to human myeloproliferative disease and is abnormally activated in MF and sAML.
Distinct molecular subgroups of pediatric medulloblastoma confer important differences in prognosis and therapy. Currently, tissue sampling is the only method to obtain information for ...classification. Our goal was to develop and validate radiomic and machine learning approaches for predicting molecular subgroups of pediatric medulloblastoma.
In this multi-institutional retrospective study, we evaluated MR imaging datasets of 109 pediatric patients with medulloblastoma from 3 children's hospitals from January 2001 to January 2014. A computational framework was developed to extract MR imaging-based radiomic features from tumor segmentations, and we tested 2 predictive models: a double 10-fold cross-validation using a combined dataset consisting of all 3 patient cohorts and a 3-dataset cross-validation, in which training was performed on 2 cohorts and testing was performed on the third independent cohort. We used the Wilcoxon rank sum test for feature selection with assessment of area under the receiver operating characteristic curve to evaluate model performance.
Of 590 MR imaging-derived radiomic features, including intensity-based histograms, tumor edge-sharpness, Gabor features, and local area integral invariant features, extracted from imaging-derived tumor segmentations, tumor edge-sharpness was most useful for predicting sonic hedgehog and group 4 tumors. Receiver operating characteristic analysis revealed superior performance of the double 10-fold cross-validation model for predicting sonic hedgehog, group 3, and group 4 tumors when using combined T1- and T2-weighted images (area under the curve = 0.79, 0.70, and 0.83, respectively). With the independent 3-dataset cross-validation strategy, select radiomic features were predictive of sonic hedgehog (area under the curve = 0.70-0.73) and group 4 (area under the curve = 0.76-0.80) medulloblastoma.
This study provides proof-of-concept results for the application of radiomic and machine learning approaches to a multi-institutional dataset for the prediction of medulloblastoma subgroups.
The critical importance of membrane‐bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric ...Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.
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