Encoding Enhanced Complex CNN for Accurate and Highly Accelerated MRI

Magnetic resonance imaging (MRI) using hyperpolarized noble gases provides a way to visualize the structure and function of human lung, but the long imaging time limits its broad research and clinical applications. Deep learning has demonstrated great potential for accelerating MRI by reconstructing images from undersampled data. However, most existing deep conventional neural networks (CNN) directly apply square convolution to k-space data without considering the inherent properties of k-space sampling, limiting k-space learning efficiency and image reconstruction quality. In this work, we propose an encoding enhanced (EN2) complex CNN for highly undersampled pulmonary MRI reconstruction. EN2 employs convolution along either the frequency or phase-encoding direction, resembling the mechanisms of k-space sampling, to maximize the utilization of the encoding correlation and integrity within a row or column of k-space. We also employ complex convolution to learn rich representations from the complex k-space data. In addition, we develop a feature-strengthened modularized unit to further boost the reconstruction performance. Experiments demonstrate that our approach can accurately reconstruct hyperpolarized 129Xe and 1H lung MRI from 6-fold undersampled k-space data and provide lung function measurements with minimal biases compared with fully-sampled image. These results demonstrate the effectiveness of the proposed algorithmic components and indicate that the proposed approach could be used for accelerated pulmonary MRI in research and clinical lung disease patient care

CypA, a gene downstream of HIF-1α, promotes the development of PDAC.

Hypoxia-inducible factor-1α (HIF-1α) is a highly important transcription factor involved in cell metabolism. HIF-1α promotes glycolysis and inhibits of mitochondrial respiration in pancreatic ductal adenocarcinoma (PDAC). In response to tumor hypoxia, cyclophilin A (CypA) is over-expressed in various cancer types, and is associated with cell apoptosis, tumor invasion, metastasis, and chemoresistance in PDAC. In this study, we showed that both HIF-1α and CypA expression were significantly associated with lymph node metastasis and tumor stage. The expression of CypA was correlated with HIF-1α. Moreover, the mRNA and protein expression of CypA markedly decreased or increased following the suppression or over-expression of HIF-1α in vitro. Chromatin immunoprecipitation analysis showed that HIF-1α could directly bind to the hypoxia response element (HRE) in the CypA promoter regions and regulated CypA expression. Consistent with other studies, HIF-1α and CypA promoted PDAC cell proliferation and invasion, and suppressed apoptosis in vitro. Furthermore, we proved the combination effect of 2-methoxyestradiol and cyclosporin A both in vitro and in vivo. These results suggested that,CypA, a gene downstream of HIF-1α, could promote the development of PDAC. Thus, CypA might serve as a potential therapeutic target for PDAC

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Validation of expression of HIF-lα and CypA in PDAC tissues and analysis of the clinical significance.

<p><b>A.</b> The IHC results of HIF-lα and CypA. CypA protein expression was significantly correlated with HIF-lα, as detected by immunohistochemical staining on PDAC. Left panels: various expression levels of HIF-lα protein. Right panels: expression of CypA protein of the same samples in the adjacent section. <b>B.</b> Cross tabulation of HIF-lα and CypA expression levels in 158 cases of PDAC. Expression of CypA was correlated with HIF-1α (P = 0.002). <b>C.</b> The survival analysis of HIF-lα IHC results. PDAC patients (n = 158) with mild positive HIF-lα protein expression (−/+/++, n = 119) had significantly better total survival than those with strong positive expression (+++, n = 39). HIF-1α expression was prognostic for overall survival. The two- and three-year survival rates were 25.2% and 13.4%, respectively, in patients with mild HIF-1α, but decreased to 7.7% or 2.6%, respectively, in patients with strong expression of HIF-1α. (P<0.001) <b>D.</b> The survival analysis of CypA IHC results. The same PDAC patients (n = 158) with negative CypA protein expression (−, n = 65) had significantly better total survival than those with positive expression (+, n = 93). Patients with negative CypA had two- and three-year survival rates of 32.3% and 20%, respectively, which significantly decreased to 12.9% and 4.3% in patients with positive CypA (P<0.001). <b>E.</b> The survival analysis of HIF-lα and CypA IHC results. The same PDAC patients (n = 158) with mild positive HIF-1α and negative CypA protein expression (n = 57) had significantly better total survival than those with strong positive HIF-1α and positive CypA expression (n = 31), the two- or three-year survival rate between them was significantly different, respectively (P<0.001). Besides, the same PDAC patients (n = 158) with mild positive HIF-1α and positive CypA protein expression (n = 62) or with strong positive HIF-1α and negative CypA protein expression (n = 8) had significantly better total survival than those with strong positive HIF-1α and positive CypA expression (n = 31), and had worse total survival than those with mild positive HIF-1α and negative CypA expression (n = 57). The two- or three-year survival rate between the above every combination of two groups was significantly different, respectively (P<0.05).</p

CypA expression is regulated by HIF-lα.

<p><b>A.</b> HIF-lα and CypA relative mRNA expression levels in different groups. HIF-lα and CypA relative mRNA expression levels in pancreatic cancer cell lines Mia-paca-2 and BXPC3 were determined by real-time PCR analysis. β-actin cDNA served as the internal control. Expression levels in both untransfected cell lines were set as 1. Columns, mean of triplicate samples from two different experiments; bars, SE. *: P<0.05. <b>B.</b> HIF-lα and CypA protein expression levels in different groups. HIF-lα and CypA protein expression levels were determined by western blot analysis. β-actin served as the loading control. Expression levels in both untransfected cell lines were set as 1. Columns, mean of triplicate samples from two different experiments; bars, SE. *: P<0.05. <b>C.</b> Binding of HIF-lα to the CypA promoter in BXPC3.: screening of the 5-flanking region of the CypA gene revealed 3 potential HIF-1α binding sites (−32∼−36 −311∼−315 −1269∼−1273) relative to the start site of transcription. D. ChIP results in different groups. ChIP assay was performed and the promoter fragment binding sites (−311∼−315) was specifically co-immuno-precipitated by anti-HIF-lα but not the control IgG or non-antibody. In chromatin fraction pulled down by anti-HIF-1α antibody, the CypA promoter PCR fragments binding sites (−32∼−36 or −1269∼−127) hardly has been detected. E. Dual luciferase results in different groups. The results showed that the full-length CypA promoter activity (CypA-promotor) increased significantly after over expression of HIF-1α compared to that treated with plasmids alone (P<0.05). But the mutant CypA promoter (CypA-promotor-mutation) had not increased, which was used as negative control. VEGF luciferase reporter construct (VEGF-promotor) was used as positive control for the HIF-1α response. Over-expression of HIF-1α increased about 3-fold of the VEGF promoter activity compared to controls (P<0.05).</p

Association between HIF-1α, CypA expression levels and the clinical factors.

<p>Association between HIF-1α, CypA expression levels and the clinical factors.</p

Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 15%-20% are eligible for radical surgery. Gemcitabine is an important chemotherapeutic agent for patients with PDAC; however, the efficacy of gemcitabine is limited due to resistance. Therefore, reducing gemcitabine resistance is essential for improving survival of patients with PDAC. Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC. Methods: We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome sequencing, and qPCR were used to determine the specific mechanism by which phospholipase D1 (PLD1) confers resistance to gemcitabine. Results: PLD1 combines with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein, BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. Conclusions: PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity