An extension of the U ⁣(1)\mathrm{U}\!\left(1\right) BF theory, Turaev-Viro invariant and Drinfeld center construction. Part I: Quantum fields, quantum currents and Pontryagin duality

In this first of a series of articles dedicated to natural extensions of the U(1) BF theory, abelian Turaev-Viro (TV) construction and corresponding Drinfeld center construction for any closed oriented smooth manifolds, we present the mathematical background that will be used.Comment: 58 pages, 2 figure

Impact of segmentation and discretization on radiomic features in 68Ga-DOTA-TOC PET/CT images of neuroendocrine tumor

OBJECTIVE: To identify the impact of segmentation methods and intensity discretization on radiomic features (RFs) extraction from 68Ga-DOTA-TOC PET images in patients with neuroendocrine tumors.METHODS: Forty-nine patients were retrospectively analyzed. Tumor contouring was performed manually by four different operators and with a semi-automatic edge-based segmentation (SAEB) algorithm. Three SUVmax fixed thresholds (20, 30, 40%) were applied. Fifty-one RFs were extracted applying two different intensity rescale factors for gray-level discretization: one absolute (AR60 = SUV from 0 to 60) and one relative (RR = min-max of the VOI SUV). Dice similarity coefficient (DSC) was calculated to quantify segmentation agreement between different segmentation methods. The impact of segmentation and discretization on RFs was assessed by intra-class correlation coefficients (ICC) and the coefficient of variance (COVL). The RFs' correlation with volume and SUVmax was analyzed by calculating Pearson's correlation coefficients.RESULTS: DSC mean value was 0.75 ± 0.11 (0.45-0.92) between SAEB and operators and 0.78 ± 0.09 (0.36-0.97), among the four manual segmentations. The study showed high robustness (ICC >0.9): (a) in 64.7% of RFs for segmentation methods using AR60, improved by applying SUVmax threshold of 40% (86.5%); (b) in 50.9% of RFs for different SUVmax thresholds using AR60; and (c) in 37% of RFs for discretization settings using different segmentation methods. Several RFs were not correlated with volume and SUVmax.CONCLUSIONS: RFs robustness to manual segmentation resulted higher in NET 68Ga-DOTA-TOC images compared to 18F-FDG PET/CT images. Forty percent SUVmax thresholds yield superior RFs stability among operators, however leading to a possible loss of biological information. SAEB segmentation appears to be an optimal alternative to manual segmentation, but further validations are needed. Finally, discretization settings highly impacted on RFs robustness and should always be stated

Diagnostic Value of FDG PET-CT Quantitative Parameters and Deauville-Like 5 Point-Scale in Predicting Malignancy of Focal Thyroid Incidentaloma

Objective: To evaluate the diagnostic value of FDG PET-CT metabolic parameters and Deauville-like 5 point-scale to predict malignancy in a population of patients presenting focal thyroid incidentaloma (fTI).Design: This retrospective study included 41 fTI, classified according to cytological and histological data as benign (BL) or malignant lesion (ML). FDG PET-CT semi-quantitative parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG), tumor to liver SUVmean ratio (TLRmax and TLRmean), tumor to blood-pool SUVmean ratio (TBRmax and TBRmean) were calculated. Each fTI was also classified on a Deauville-like 5-point scale (DS) currently used in lymphoma. Comparison between BL and ML was performed for each parameter and a ROC analysis was conducted.Results: All quantitative PET metabolic parameters (SUV parameters, volume based parameters and SUV ratio) were higher in ML compared with BL, yet no significant difference was reported. fTI (uptake) malignancy rate according to DS grades 2, 3, 4, and 5 was, respectively, 25% (1 of 4), 28.6% (2 of 7), 8.3% (1 of 12), and 33.3% (6 of 18) with no significant difference between ML and BL groups. Results of ROC analysis showed that mean TBR had the highest AUC in our cohort (0.66 95%CI [0.41; 0.91]) with a cut-off value of 2.2. Specificity of MTV and TLG was 100% (cut-off values: MTV 9.6 ml, TLG 22.9 g) and their sensitivity was 30 and 40%, respectively.Conclusion: Our study did not highlight any FDG PET/CT parameter predictor of fTI malignancy

Prognostic Value of Whole-Body PET Volumetric Parameters Extracted from 68Ga-DOTATOC PET/CT in Well-Differentiated Neuroendocrine Tumors

Our objective was to evaluate the prognostic value of somatostatin receptor tumor burden on Ga-68-DOTATOC PET/CT in patients with well-differentiated (WD) neuroendocrine tumors (NETs). Methods: We retrospectively analyzed the 68Ga-DOTATOC PET/CT scans of 84 patients with histologically confirmed WD NETs (51 grade 1, 30 grade 2, and 3 grade 3). For each PET/CT scan, all Ga-68-DOTATO-Cavid lesions were independently segmented by 2 operators using a customized threshold based on the healthy liver SUVmax (LIFEx, version 5.1). Somatostatin receptor-expressing tumor volume (SRETV) and total lesion somatostatin receptor expression (TLSRE = SRETV X SUVmean) were extracted for each lesion, and then whole-body SRETV and TLSRE (SRETVwb and TLSREwb, respectively) were defined as the sum of SRETV and TLSRE, respectively, for all segmented lesions in each patient. Time to progression (TTP) was defined as the combination of disease-free survival in patients undergoing curative surgery (n = 10) and progression-free survival for patients with unresectable or metastatic disease (n = 74). TTP and overall survival were calculated by Kaplan-Meier analysis, log-rank testing, and the Cox proportional-hazards regression model. Results: After a median follow-up of 15.5 mo, disease progression was confirmed in 35 patients (41.7%) and 14 patients died. A higher SRETVwb (>39.1 cm(3)) and TLSREwb (>306.8 g) correlated significantly with a shortermedian TTP (12 mo vs. not reached; P < 0.001). In multivariate analysis, SRETVwb (P = 0.005) was the only independent predictor of TTP regardless of histopathologic grade and TNM staging. Conclusion: According to our results, SRETVwb and TLSREwb extracted from Ga-68-DOTATOC PET/CT could predict TTP or overall survival and might have important clinical utility in the management of patients with WD NETs

Transcriptomic responses of Phanerochaete chrysosporium to oak acetonic extracts: focus on a new glutathione transferase.

The first steps of wood degradation by fungi lead to the release of toxic compounds known as extractives. To better understand how lignolytic fungi cope with the toxicity of these molecules, a transcriptomic analysis of Phanerochaete chrysosporium genes was performed in presence of oak acetonic extracts. It reveals that in complement to the extracellular machinery of degradation, intracellular antioxidant and detoxification systems contribute to the lignolytic capabilities of fungi presumably by preventing cellular damages and maintaining fungal health. Focusing on these systems, a glutathione transferase (PcGTT2.1) has been selected for functional characterization. This enzyme, not characterized so far in basidiomycetes, has been first classified as a GTT2 in comparison to the Saccharomyces cerevisiae isoform. However, a deeper analysis shows that GTT2.1 isoform has functionally evolved to reduce lipid peroxidation by recognizing high-molecular weight peroxides as substrates. Moreover, the GTT2.1 gene has been lost in some non-wood decay fungi. This example suggests that the intracellular detoxification system could have evolved concomitantly with the extracellular ligninolytic machinery in relation to the capacity of fungi to degrade wood

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci

CART Peptide Is a Potential Endogenous Antioxidant and Preferentially Localized in Mitochondria

The multifunctional neuropeptide Cocaine and Amphetamine Regulated Transcript (CART) is secreted from hypothalamus, pituitary, adrenal gland and pancreas. It also can be found in circulatory system. This feature suggests a general role for CART in different cells. In the present study, we demonstrate that CART protects mitochondrial DNA (mtDNA), cellular proteins and lipids against the oxidative action of hydrogen peroxide, a widely used oxidant. Using cis-parinaric acid as a sensitive reporting probe for peroxidation in membranes, and a lipid-soluble azo initiator of peroxyl radicals, 2,2′-Azobis(2,4-dimethylvaleronitrile) we found that CART is an antioxidant. Furthermore, we found that CART localized to mitochondria in cultured cells and mouse brain neuronal cells. More importantly, pretreatment with CART by systemic injection protects against a mouse oxidative stress model, which mimics the main features of Parkinson's disease. Given the unique molecular structure and biological features of CART, we conclude that CART is an antioxidant peptide (or antioxidant hormone). We further propose that it may have strong therapeutic properties for human diseases in which oxidative stress is strongly involved such as Parkinson's disease

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract: Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease