Magnetic resonance tissue phase mapping demonstrates altered left ventricular diastolic function in children with chronic kidney disease

Abstract

Background

Echocardiographic examinations have revealed functional cardiac abnormalities in children with chronic kidney disease.

Objective

To assess the feasibility of MRI tissue phase mapping in children and to assess regional left ventricular wall movements in children with chronic kidney disease.

Materials and methods

Twenty pediatric patients with chronic kidney disease (before or after renal transplantation) and 12 healthy controls underwent tissue phase mapping (TPM) to quantify regional left ventricular function through myocardial long (Vz) and short-axis (Vr) velocities at all 3 levels of the left ventricle.

Results

Patients and controls (age: 8 years—20 years) were matched for age, height, weight, gender and heart rate. Patients had higher systolic blood pressure. No patient had left ventricular hypertrophy on MRI or diastolic dysfunction on echocardiography. Fifteen patients underwent tissue Doppler echocardiography, with normal z-scores for mitral early diastolic (V_E), late diastolic (V_A) and peak systolic (V_S) velocities. Throughout all left ventricular levels, peak diastolic Vz and Vr (cm/s) were reduced in patients: Vz_base -10.6 ± 1.9 vs. -13.4 ± 2.0 (P < 0.0003), Vz_mid -7.8 ± 1.6 vs. -11 ± 1.5 (P < 0.0001), Vz_apex -3.8 ± 1.6 vs. -5.3 ± 1.6 (P = 0.01), Vr_base -4.2 ± 0.8 vs. -4.9 ± 0.7 (P = 0.01), Vr_mid -4.7 ± 0.7 vs. -5.4 ± 0.7 (P = 0.01), Vr_apex -4.7 ± 1.4 vs. -5.6 ± 1.1 (P = 0.05).

Conclusion

Tissue phase mapping is feasible in children and adolescents. Children with chronic kidney disease show significantly reduced peak diastolic long- and short-axis left ventricular wall velocities, reflecting impaired early diastolic filling. Thus, tissue phase mapping detects chronic kidney disease-related functional myocardial changes before overt left ventricular hypertrophy or echocardiographic diastolic dysfunction occurs.

http://ift.tt/2gWWF20

Three-dimensional surface and ultrasound imaging for daily IGRT of prostate cancer

Image guided radiotherapy (IGRT) is an essential pre-requisite for delivering high precision radiotherapy. We compared daily variation detected by two non-ionizing imaging modalities (surface imaging and trans...

http://ift.tt/2hBUNji

Erratum to: Trends in Media Reports of Celebrities’ Breast Cancer Treatment Decisions

http://ift.tt/2hKfYLO

Intravital FRET imaging reveals osteopontin-mediated polymorphonuclear leukocyte activation by tumor cell emboli

Abstract

Myeloid-derived suppressor cells (MDSCs) cause paraneoplastic leukemoid reactions and facilitate tumor cell metastasis. However, the interaction of MDSCs with tumor cells in live tissues has not been adequately visualized. To accomplish this task, we developed an intravital imaging protocol to observe metastasized tumor cells in mouse lungs. For visualization of the activation of MDSCs, bone marrow cells derived from transgenic mice expressing a Förster resonance energy transfer (FRET) biosensor for extracellular signal-regulated kinase (ERK) were implanted into host mice. Under a two-photon excitation microscope, numerous polymorphonuclear cells (PMNs) were found to infiltrate the lungs of tumor-bearing mice in which 4T1 mammary tumor cells were implanted into the footpads. By FRET imaging, we found that ERKs in PMNs were activated around the 4T1 tumor emboli in the lungs. Because antibody array analysis implied the involvement of osteopontin (OPN) in the metastasis of 4T1 cells, we further analyzed the effect of OPN knockdown. The OPN knockdown in 4T1 cells did not affect the cell growth, but markedly suppressed lung metastasis of 4T1 cells and ERK activation in PMNs in the lung. Intravenous injection of recombinant OPN restored the lung metastasis of OPN-deficient 4T1 cells, suggesting that OPN functioned in a paracrine manner. It has been reported that ERK activation of neutrophils causes NETosis and that PMNs promote metastasis of tumor cells by NETosis. In agreement with the previous reports, the NETosis inhibitor DNase I inhibited lung metastasis of 4T1 cells. These observations suggest that OPN promotes metastasis of 4T1 cells by activating PMNs and inducing NETosis.

This article is protected by copyright. All rights reserved.

http://ift.tt/2gIIlww

Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population

Summary

Genome-wide association studies (GWAS) have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. Here we evaluated the genetic variants at 9p21.3 reported in cancer GWAS with case-control study including 2,139 ESCC cases and 2,273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele odds ratio (OR) of 0.84 (95% confidence interval (CI), 0.77-0.91; P=2.95×10^-5). The rs7023329-G allele was related to a high expression of MTAP (P=0.020). The rs1679013-C allele was independently associated with an increased risk of ESCC with a per-allele OR of 1.12 (95% CI, 1.01-1.24; P=0.039). We also found that the carriers of the risk allele rs1679013-C had lower expressions of CDKN2B than non-carriers (P=0.035). CDKN2B was also significantly down-regulated in ESCC tumor tissues as compared with adjacent normal tissues (P=3.50×10^-5). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of 9p21.3 locus in cancer development.

This article is protected by copyright. All rights reserved.

http://ift.tt/2gIM9hf

Prediction and prioritization of neoantigens: integration of RNA-Seq data with whole-exome sequencing

Abstract

The importance of neoantigens for cancer immunity is now well-acknowledged. However, there are diverse strategies for predicting and prioritizing candidate neoantigens, and thus neoantigen loads reported in the literature vary a great deal. To clarify this issue, we compared the numbers of neoantigen candidates predicted by four currently utilized strategies. Whole-exome sequencing (WES) and RNA-Seq of 4 non-small cell lung cancer patients was performed. We identified 361 somatic missense mutations from which 224 candidate neoantigens were predicted using MHC class I binding affinity prediction software (Strategy I). Of these, 207 exceeded the set threshold of gene expression (fragments per kilobase of transcript per million fragments mapped (FPKM) ≥1) resulting in 124 candidate neoantigens (Strategy II). To verify mutant mRNA expression, sequencing of amplicons from tumor cDNA including each mutation was performed; 204 of the 207 mutations were successfully sequenced, yielding 121 mutant mRNA sequences, resulting in 75 candidate neoantigens (Strategy III). Sequence information was extracted from RNA-Seq to confirm the presence of mutated mRNA. Variant allele frequencies ≥0.04 in RNA-Seq were found for 117 of the 207 mutations and regarded as expressed in the tumor, and finally, 72 candidate neoantigens were predicted (Strategy IV). Without additional amplicon sequencing of cDNA, Strategy IV was comparable to Strategy III. We therefore propose Strategy IV as a practical and appropriate strategy to predict candidate neoantigens fully utilizing currently available information. At any rate, it is of note that different neoantigen loads were deduced from the same tumors depending on the strategies applied.

This article is protected by copyright. All rights reserved.

http://ift.tt/2hKQ0rJ

A leukemogenic kinase, FIP1L1-PDGFRA, and a SUMO E3 ligase, PIAS1, form a positive crosstalk via their enzymatic activities

Abstract

Fusion tyrosine kinases play a crucial role in the development of hematological malignancies. FIP1L1-PDGFRA is a leukemogenic fusion kinase that causes chronic eosinophilic leukemia. As a constitutively active kinase, FIP1L1-PDGFRA stimulates downstream signaling molecules, leading to cellular proliferation and the generation of an anti-apoptotic state. Contribution of the N-terminal FIP1L1 portion is necessary for FIP1L1-PDGFRA to exert its full transforming activity, but the underlying mechanisms have not been fully characterized. We identified PIAS1 as a FIP1L1-PDGFRA-association molecule by yeast two-hybrid screening. Our analyses indicate that the FIP1L1 portion of FIP1L1-PDGFRA is required for efficient associatiation with PIAS1. As a consequence of the association, FIP1L1-PDGFRA phosphorylates PIAS1. Moreover, the kinase activity of FIP1L1-PDGFRA stabilizes PIAS1. Therefore, PIAS1 is one of the downstream targets of FIP1L1-PDGFRA. Moreover, we found that PIAS1, as a SUMO E3 ligase, sumoylates and stabilizes FIP1L1-PDGFRA. In addition, suppression of PIAS1 activity by a knockdown experiment resulted in destabilization of FIP1L1-PDGFRA. Therefore, FIP1L1-PDGFRA and PIAS1 form a positive crosstalk via their enzymatic activities. Suppression of sumoylation by ginkgolic acid, a small molecule compound inhibiting a SUMO E1-activating enzyme, also destabilizes FIP1L1-PDGFRA, and while the tyrosine kinase inhibitor imatinib suppresses FIP1L1-PDGFRA-dependent cell growth, ginkgolic acid or siRNA of PIAS1 has a synergistic effect with imatinib. In conclusion, our results suggest that sumoylation by PIAS1 is a potential target in the treatment of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.

This article is protected by copyright. All rights reserved.

http://ift.tt/2gIGNSV