Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk

AlexandrosSfakianakis shared this article with you from Inoreader Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk via International Journal of Cancer Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, which is featured by systematic metabolism. Thus, a better understanding of metabolic dysregulation in PDAC is important to better characterize its etiology. Here, we performed a large metabolome-wide association study (MWAS) to systematically explore associations between genetically predicted metabolite levels in blood and PDAC risk. Using data from 881 subjects of European descent in the TwinsUK Project, comprehensive genetic models were built to predict serum metabolite levels. These prediction models were applied to the genetic data of 8,280 cases and 6,728 controls included in the PanScan (I, II, and III) and PanC4 consortia. After assessing the metabolite-PDAC risk associations by a slightly modified TWAS/FUSION framework, we identified five metabolites (including two dipeptides) showing significant associations with PDAC risk at false discovery rate (FDR)<0.05. Integrated with gut m icrobial information, two-sample Mendelian randomization (MR) analyses were further performed to investigate the relationship among serum metabolites, gut microbiome features, and PDAC. The flavonoid-degrading bacteria Flavonifractor sp90199495 was found to be associated with metabolite X – 21849, and it was also shown to be associated with PDAC risk. Collectively, our study identified novel candidate metabolites for PDAC risk, which could lead to new insights into the etiology of PDAC and improved treatment options. View on Web

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Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data

AlexandrosSfakianakis shared this article with you from Inoreader Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data via International Journal of Cancer Abstract Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1,142 circulating proteins with breast cancer risk in 133,384 cases and 113,789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) <0.05, including nine proteins encoded by genes located at least 500kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR <0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling, and NF-κB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk. View on Web

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Neonatal intestinal obstruction in Hoyeraal–Hreidarsson syndrome with novel RTEL1 variants

AlexandrosSfakianakis shared this article with you from Inoreader Neonatal intestinal obstruction in Hoyeraal–Hreidarsson syndrome with novel RTEL1 variants via Pediatric Blood & Cancer View on Web

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Effectiveness and Accuracy of MRI‐Ultrasound Fusion Targeted Biopsy Based on PI‐RADS v2.1 Category in Transition/Peripheral Zone of the Prostate

AlexandrosSfakianakis shared this article with you from Inoreader Effectiveness and Accuracy of MRI‐Ultrasound Fusion Targeted Biopsy Based on PI‐RADS v2.1 Category in Transition/Peripheral Zone of the Prostate via Journal of Magnetic Resonance Imaging Background MRI-ultrasound fusion targeted biopsy (MRI-TBx) improves the clinically significant prostate cancer (csPCa) detection with fewer cores. However, whether systematic biopsy-guided by transrectal ultrasound (TRUS-SBx) can be omitted when undergoing MRI-TBx in transition zone (TZ) and peripheral zone (PZ) remains unclear. Purpose To assess the performance and effectiveness of MRI-TBx based on PI-RADS v2.1 for csPCa diagnosis in TZ and PZ, respectively. Study Type Retrospective. Subjects A total of 309 selected cases (median age 70 years) with 356 lesions who underwent both MRI-TBx and TRUS-SBx were enrolled. Field Strength/Sequence A 3.0 T, multiparametric MRI (mp-MRI) including T2-weighted turbo-spin echo imaging (T2WI), diffusion-weighted spin-echo echo planar imaging (DWI), dynamic contrast-enhanced MRI with time-resolved T1-weighted imaging (DCE). Assessment Mp-MRI was assessed by two radiologists using PI-RADS v2.1. The csPCa detection rates provided by MRI-TBx, TRUS-SBx and combined biopsy in TZ and PZ were calculated, respectively. Statistical Tests McNemar test was used to compare the csPCa detection rates in TZ and PZ, respectively. The frequencies and distribution of all detected prostate cancers by different biopsy methods were also compared. P < 0.05 was considered statistically significant. Results Among 356 lesions in 309 patients, 208 (68 in TZ, 140 in PZ) were pathologically confirmed as csPCa. In TZ, there were significant differences for csPCa detection with PI-RADS 3 between combined biopsy and TRUS-SBx (23.5% vs. 15.3%), MRI-TBx (23.5% vs. 16.3%), respectively. MRI-TBx detected 23% (19/83) cases missed by TRUS-SBx in which 68% (13/19) were csPCa. In PZ, there were no statistical differences between MRI-TBx and combined biopsy with PI-RADS 3–5 (P = 0.21, 0.25, 0.07, respectively). In 9% (14/152) cases only detected by MRI-TBx, 86% (12/14) were clinically significant. Five percent (7/152) of cases only detected by TRUS-SBx were completely nonclinically significant. Data Conclusion MRI-TBx played a positive role on csPCa diagnosis in TZ, but combined biopsy might be the best choice especially in the subgroup PI-RADS 3. In PZ, MRI-TBx had an advantage over TRUS-SBx for csPCa detection. Evidence Level 2. Technical Efficacy Stage 2. View on Web

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Characterization of Microvascular Invasion in Hepatocellular Carcinoma Using Computational Modeling of Interstitial Fluid Pressure and Velocity

AlexandrosSfakianakis shared this article with you from Inoreader Characterization of Microvascular Invasion in Hepatocellular Carcinoma Using Computational Modeling of Interstitial Fluid Pressure and Velocity via Journal of Magnetic Resonance Imaging Background Most solid tumors show increased interstitial fluid pressure (IFP), and this increased IFP is an obstacle to treatment. A noninvasive model for measuring IFP in hepatocellular carcinoma (HCC) is an unresolved issue. Purpose To develop a noninvasive model to measure IFP and interstitial fluid velocity (IFV) in HCC and to characterize the microvascular invasion (MVI) status by using this model. Study Type Retrospective. Population A total of 97 HCC patients (mean age 57.6 ± 10.9 years, 77.3% males), 53 of them with MVI and 44 of them without MVI. Field Strength/Sequence A 3-T, three-dimensional spoiled gradient-recalled echo. Assessment MVI was defined as microscopic vascular invasion of small vessels within the peritumoral liver tissue. The volumes of interest (VOIs) were manually delineated and enclosed the tumor lesion and healthy liver parenchyma, respectively. The extended Tofts model (ETM) was used to estimate permeability parameters from all the VOIs. Subsequently, the continuity partial differential equation (PDE) was implemented and IFP and IFV were acquired. Statistical Tests Wilcoxon signed-ranks tests, histogram analysis, Mann–Whitney U test, Fisher's exact test, least absolute shrinkage and selection operator (LASSO) logistic regression, receiver operating characteristic (ROC) curve analysis with the area under the curve (AUC), Youden index, DeLong test, and Benjamini–Hochberg correction. A P value <0.05 was considered statistically significant. Results The HCC lesions exhibited elevated IFP and reduced IFV. There were no significant differences in any measured demographic and clinical features between the MVI-positive and MVI-negative groups, except for tumor size. Nine IFP histogram analysis-derived parameters and seven IFV histogram analysis-derived parameters could be used to characterize the MVI status. LASSO regression selected five features: IFP maximum, IFP 10th percentile, IFP 90th percentile, IFV SD, and IFV 10th percentile. The combination of these features showed the highest AUC (0.781) and specificity (77.3%). Data Conclusion A noninvasive IFP and IFV measurement model for HCC was developed. Specific IFP- and IFV-derived parameters exhibited significant association with the MVI status. Evidence Level 3. Technical Efficacy Stage 2. View on Web

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MP‐RAVE: IR‐Prepared T1‐Weighted Radial Stack‐of‐Stars 3D GRE imaging with retrospective motion correction

AlexandrosSfakianakis shared this article with you from Inoreader MP‐RAVE: IR‐Prepared T1‐Weighted Radial Stack‐of‐Stars 3D GRE imaging with retrospective motion correction via Magnetic Resonance in Medicine Purpose To describe an inversion-recovery T1-weighted radial stack-of-stars 3D gradient echo (GRE) sequence with comparable image quality to conventional MP-RAGE and to demonstrate how the radial acquisition scheme can be utilized for additional retrospective motion correction to improve robustness to head motion. Methods The proposed sequence, named MP-RAVE, has been derived from a previously described radial stack-of-stars 3D GRE sequence (RAVE) and includes a 180° inversion recovery pulse that is generated once for every stack of radial views. The sequence is combined with retrospective 3D motion correction to improve robustness. The effectiveness has been evaluated in phantoms and healthy volunteers and compared to conventional MP-RAGE acquisition. Results MP-RAGE and MP-RAVE anatomical images were rated "good" to "excellent" in overall image quality, with artifact level between "mild" and "no artifacts", and with no statistically significant difference between methods. During head motion, MP-RAVE showed higher inherent robustness with artifacts confined to local brain regions. In combination with motion correction, MP-RAVE provided noticeably improved image quality during different head motion and showed statistically significant improvement in image sharpness. Conclusion MP-RAVE provides comparable image quality and contrast to conventional MP-RAGE with improved robustness to head motion. In combination with retrospective 3D motion correction, MP-RAVE can be a useful alternative to MP-RAGE, especially in non-cooperative or pediatric patients. View on Web

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Multiple slot modules for high field magnetic resonance imaging array coils

AlexandrosSfakianakis shared this article with you from Inoreader Multiple slot modules for high field magnetic resonance imaging array coils via Magnetic Resonance in Medicine Purpose Mitigating coupling effects between coil elements represents a continuing challenge. Here, we present a 16-bowtie slot volume coil arranged in eight independent dual-slot modules without the use of any decoupling circuits. Methods Two electrically short "bowtie" slot antennas were used to form a "module." A bowtie configuration was chosen because electromagnetic modeling results show that bowtie slots exhibit improved B1+Pin$$ \frac{B_1^{+}}{\sqrt{P_{in}}} $$ efficiency when compared to thin rectangular slots. An eight-module volume coil was evaluated through electromagnetic modeling, bench tests, and MRI experiments at 4.7 T. Results Bench tests indicate that worst-case coupling between modules did not exceed −14.5 dB. MR images demonstrate well-localized patterns about single excited modules confirming the low coupling between modules. Homogeneous MR images were acquired from a synthesized quadrature birdcage transmit mode. MRI experiments show that the RF power requirements for the proposed coil are 9.2 times more than a birdcage coil. Whereas from simulations performed to assess the proposed coil losses, the total power dissipated in the phantom was 1.1 times more for the birdcage. Simulation results at 7 T reveal an equivalent B1 + homogeneity when compared with an eight-dipole coil. Conclusion Although exhibiting higher RF power requirements, as a transmit coil when the power availability is not a restriction, the inherently low coupling between electrically short slots should enable the use of many slot elements around the imaging volume. The slot module described in this paper should be useful in the design of multi-channel transmit coils. View on Web

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Oxidative stress – a key determinant of complications and negative outcome in Hepatitis E virus infected pregnancies: a comprehensive account involving cases from northeast India

AlexandrosSfakianakis shared this article with you from Inoreader Oxidative stress – a key determinant of complications and negative outcome in Hepatitis E virus infected pregnancies: a comprehensive account involving cases from northeast India via Journal of Medical Virology Abstract Background Regulated oxidative stress (OS) is important during pregnancy. Sporadic studies suggest the significance of deregulated OS in Hepatitis E virus (HEV) infected pregnancy, but with limited reactive oxygen species (ROS) or antioxidant markers. The present novel study therefore aimed to evaluate the significance of ROS-antioxidant imbalance and resulting altered OS in HEV infected pregnancy complications like preterm delivery (PTD) and outcome. Methodology Difference in serum levels of ROS and antioxidant panel of markers were evaluated by ELISA for HEV IgM RNA positive genotype 1 cases [including acute (AVH) and fulminant (FHF) cases] and healthy term delivery subjects, and analyzed statistically. Results Direct ROS marker H2O2 levels and indirect OS marker for DNA damage 8-OHdG was significantly increased in HEV-cases compared to controls, and was associated and prognostic factor for PTD and fetal death in HEV cases. A comparatively lower total serum antioxidant capacity was observed in the FHF cases compared to the control subjects and the AVH cases. GSH levels and SOD activity were significantly associated with PTD in the FHF sub-cohorts (p=0.017) and AVH sub-cohorts (p<0.001) respectively, and was associated with poor prognosis in HEV cases. The serum H2O2 levels were found to be negatively correlated with SOD activity (p=0.016) and GSH levels (p=0.001) in the HEV-AVH cases; and positively correlated with the viral load in HEV cases (p=0.023). Conclusions The ROS-antioxidant imbalance resulting OS plays a detrimental associative role in HEV infected pregnancy complications like PTD and adverse pregnancy outcomes; and holds therapeutic significance. This article is protected by copyright. All rights reserved. View on Web

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Hypoxia‐induced oxidative stress promotes therapy resistance via upregulation of heme oxygenase‐1 in multiple myeloma

AlexandrosSfakianakis shared this article with you from Inoreader Hypoxia‐induced oxidative stress promotes therapy resistance via upregulation of heme oxygenase‐1 in multiple myeloma via Cancer Medicine By examining in detail the function of genes that are highly expressed in side population (SP) cells exposed to hypoxia, we clarified the contribution of the hypoxia-ROS-HMOX1 axis to proteasome inhibitor resistance in hypoxic environments. This axis might also be involved in hypoxia-induced MafB expression. Abstract Background Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments. Methods We performed cDNA microarray analysis for SP and non-SP obtained from RPMI-8226 and KMS-11 cell lines cultured for 48 h in normoxic and hypoxic conditions (1% O2). Genes specifically upregulated in hypoxic SP were examined. Results Our comprehensive gene expression analysis identified HMOX1, BACH2, and DUX4 as protein-coding genes that are specifically highly expressed in SP cells under hypoxic conditions. We have shown that HMOX1/heme oxygenase-1 (HMOX1/HO-1) is induced by hypoxia-inducible reactive oxygen species (ROS) and reduces ROS levels. Furthermore, we found that HMOX1 contributes to hypoxia-induced resistance to proteasome inhibitors in vitro and in vivo. Excessive ROS levels synergistically enhance bortezomib sensitivity. In clinical datasets, HMOX1 had a strong and significantly positive correlation with MAFB but not MAF. Interestingly, hypoxic stimulation increased MAFB/MafB expression in myeloma cells; in addition, the knockdown of MAFB under hypoxic conditions suppressed HMOX1 expression. Conclusion These results suggest that the hypoxia-ROS-HMOX1 axis and hypoxia-induced MafB may be important mechanisms of proteasome inhibitor resistance in hypoxic microenvironments. View on Web

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An fNIRS-Based Dynamic Functional Connectivity Analysis Method to Signify Functional Neurodegeneration of Parkinson’s Disease

AlexandrosSfakianakis shared this article with you from Inoreader An fNIRS-Based Dynamic Functional Connectivity Analysis Method to Signify Functional Neurodegeneration of Parkinson’s Disease via Neural Systems and Rehabilitation Engineering, IEEE Transactions on - new TOC Parkinson's disease (PD) is a prevalent brain disorder, and PD diagnosis is crucial for treatment. Existing methods for PD diagnosis are mainly focused on behavior analysis, while the functional neurodegeneration of PD has not been well investigated. This paper proposes a method to signify functional neurodegeneration of PD with dynam ic functional connectivity analysis. A functional near-infrared spectroscopy (fNIRS)-based experimental paradigm was designed to capture brain activation from 50 PD patients and 41 age-matched healthy controls in clinical walking tests. Dynamic functional connectivity was constructed with sliding-window correlation analysis, and k-means clustering was applied to generate the key brain connectivity states. Dynamic state features including state occurrence probability, state transition percentage and state statistical features were extracted to quantify the variations of brain functional networks. A support vector machine was trained to classify PD patients and healthy controls. Statistical analysis was conducted to investigate the difference between PD patients and healthy controls as well as the relationship between dynamic state features and the MDS-UPDRS sub-score of gait. The results showed that PD patients had a higher probability of transiting to brain connectivity states with high levels of information transmission compared with healthy controls. The MDS-UPDRS sub-score of gait and the dynamics state features showed a significant correlation. Moreover, the proposed method had better classification performances than the available fNIRS-based methods in terms of accuracy and F1 score. Thus, the proposed method well signified functional neurodegeneration of PD, and the dynamic state features may serve as promising functional biomarkers for PD diagnosis. View on Web

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