Δευτέρα 13 Φεβρουαρίου 2023

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

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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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Exosomes: Mediators in Microenvironment of Colorectal Cancer

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Abstract

Tumor microenvironment, the soil where tumor thrives, plays a critical role in the development and progression of colorectal cancer (CRC). Various cell signaling molecules in the environment promote tumor angiogenesis, immune tolerance and facilitate immune escape. Exosomes, as messengers between tumor and host cells, are considered key mediators involved in the tumor-accelerating environment. However, the exosome-mediated communication networks in the CRC microenvironment are still largely unclear. In this review, we summarized the relationship between TME and CRC based on recent literature. Then, we revealed the unique impacts and signal molecules of exosomes on account of their regulatory role in the flora, hypoxia, inflammatory, and immunological microenvironment of CRC. Finally, we summarized the therapeutically effective of exosomes in CRC microenvironment and discussed their current status and prospects, aiming to provide new molecular targets and a theoretical basis for th e CRC treatment.
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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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Pain mitigation and management strategies for anti‐GD2 infusions: An expert consensus

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Abstract

Monoclonal antibodies (mAbs) targeting disialoganglioside 2 (GD2) are an important treatment advance for high-risk neuroblastoma, including in patients with refractory or relapsed disease. Dinutuximab and dinutuximab beta are administered for ≥8 hours (and up to 10 days for dinutuximab beta), whereas naxitamab is administered over 0.5 to 2 hours as tolerated. As acute pain is a class effect of anti-GD2 mAbs, effective pain management is crucial to successful treatment. Here, we provide an overview of current pain-management strategies for anti-GD2 mAb infusions, with a focus on strategies suitable for naxitamab infusions, which cause a more rapid onset of often severe pain. We discuss opioid analgesics, ketamine, gabapentin, and other similar agents and nonpharmacologic approaches. Potential future pain-management options are also discussed, in addition to the use of sedatives to reduce the anxiety that may be associated with infusion-related pain. In this expert conse nsus paper, specific guidance for pain management during naxitamab infusions is provided, as these infusions are administered over 0.5 to 2 hours and may not need overnight hospitalization based on the physician's assessment, and require rapid-onset analgesia options suitable for potential outpatient administration.
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Neonatal intestinal obstruction in Hoyeraal–Hreidarsson syndrome with novel RTEL1 variants

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

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

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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

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

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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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