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Δευτέρα 13 Φεβρουαρίου 2023

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

AlexandrosSfakianakis shared this article with you from Inoreader

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.
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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

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

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Thioredoxin 1 overexpression attenuated diabetes‐induced endoplasmic reticulum stress in Müller cells via apoptosis signal‐regulating kinase 1

AlexandrosSfakianakis shared this article with you from Inoreader

Abstract

As one of the common and serious chronic complications of diabetes mellitus (DM), the related mechanism of diabetic retinopathy (DR) has not been fully understood. Müller cell reactive gliosis is one of the early pathophysiological features of DR. Therefore, exploring the manner to reduce diabetes-induced Müller cell damage is essential to delay DR. Thioredoxin 1 (Trx1), one of the ubiquitous redox enzymes, plays a vital role in redox homeostasis via protein–protein interactions, including apoptosis signal-regulating kinase 1 (ASK1). Previous studies have shown that upregulation of Trx by some drugs can attenuate endoplasmic reticulum stress (ERS) in DR, but the related mechanism was unclear. In this study, we used DM mouse and high glucose (HG)-cultured human Müller cells as models to clarify the effect of Trx1 on ERS and the underlying mechanism. The data showed that the diabetes-induced Müller cell damage was increased significantly. Moreover, the expression of ERS and re active gliosis was also upregulated in diabetes in vivo and in vitro. However, it was reversed after Trx1 overexpression. Besides, ERS-related protein expression, reactive gliosis, and apoptosis were decreased after transfection with ASK1 small-interfering RNA in stable Trx1 overexpression Müller cells after HG treatment. Taken together, Trx1 could protect Müller cells from diabetes-induced damage, and the underlying mechanism was related to inhibited ERS via ASK1.
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Characterization of Microvascular Invasion in Hepatocellular Carcinoma Using Computational Modeling of Interstitial Fluid Pressure and Velocity

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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.
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Multiple slot modules for high field magnetic resonance imaging array coils

AlexandrosSfakianakis shared this article with you from Inoreader

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.
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Concerns on Bebtelovimab (LY‐CoV1404) used to neutralize Omicron subvariants

AlexandrosSfakianakis shared this article with you from Inoreader

Abstract

Bebtelovimab (LY-CoV1404) is a monoclonal antibody showing remarkable neutralizing capacity against all SARS-CoV-2 variants of concern (VOCs) as of June 2022, including the Omicron variant and its subvariants

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Nasal mucosa is much more susceptible than oral mucosa to infection of SARS‐CoV‐2 Omicron subvariants: wearing nasal masks where facial masks cannot be used

AlexandrosSfakianakis shared this article with you from Inoreader

Abstract

we analyzed airway tissue tropism of SARS-CoV-2 and found that the nasal mucosa is much more susceptible than oral mucosa to infection of SARS-CoV-2 Omicron variant and subvariants, suggesting the importance of protecting nasal epithelium from Omicron variant infection. We have designed a bifunctional mask that can be used as a facial mask under regular conditions and a nasal mask in some settings (e.g., eating and drinking) where facial mask cannot be used

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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

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.

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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

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.
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