Browsing by Author "Zhang, Qiang"

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    Artificial Intelligence for Contrast-Free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-Based Virtual Native Enhancement
    (American Heart Association, 2022-11-15) Zhang, Qiang; Burrage, Matthew K.; Shanmuganathan, Mayooran; Gonzales, Ricardo A.; Lukaschuk, Elena; Thomas, Katharine E.; Mills, Rebecca; Pelado, Joana Leal; Nikolaidou, Chrysovalantou; Popescu, Iulia A.; Lee, Yung P.; Zhang, Xinheng; Dharmakumar, Rohan; Myerson, Saul G.; Rider, Oliver; Oxford Acute Myocardial Infarction (OxAMI) Study; Channon, Keith M.; Neubauer, Stefan; Piechnik, Stefan K.; Ferreira, Vanessa M.; Medicine, School of Medicine
    Background: Myocardial scar is currently assessed non-invasively using cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) as an imaging gold-standard. However, a contrast-free approach would provide many advantages, including a faster and cheaper scan, without contrast-associated problems. Methods: Virtual Native Enhancement (VNE) is a novel technology that can produce virtual LGE-like images, without the need for contrast. VNE combines cine imaging and native T1-maps to produce LGE-like images using artificial intelligence (AI). VNE was developed for patients with prior myocardial infarction on 4271 datasets (912 patients), where each dataset is comprised of slice position-matched cine, T1-maps and LGE images. After quality control, 3002 datasets (775 patients) were used for development, and 291 datasets (68 patients) for testing. The VNE generator was trained using generative adversarial networks, employing two adversarial discriminators to improve the image quality. The left ventricle was contoured semi-automatically. Myocardial scar volume was quantified using the full width at half maximum method. Scar transmurality was measured using the centerline chord method and visualized on bull’s eye plots. Lesion quantification by VNE and LGE were compared using linear regression, Pearson correlation (R) and intraclass correlation coefficients (ICC). Proof-of-principle histopathological comparison of VNE in a porcine model of myocardial infarction was also performed. Results: VNE provided significantly better image quality than LGE on blinded analysis by 5 independent operators on 291 datasets (all p<0.001). VNE correlated strongly with LGE in quantifying scar size (R=0.89, ICC=0.94) and transmurality (R=0.84, ICC=0.90) in 66 patients (277 test datasets). Two CMR experts reviewed all test image slices and reported an overall accuracy of 84% of VNE in detecting scar when compared with LGE, with specificity of 100% and sensitivity of 77%. VNE also showed excellent visuospatial agreement with histopathology in 2 cases of a porcine model of myocardial infarction. Conclusions: VNE demonstrated high agreement with LGE-CMR for myocardial scar assessment in patients with prior myocardial infarction in visuospatial distribution and lesion quantification, with superior image quality. VNE is a potentially transformative AI-based technology, with promise to reduce scan times and costs, increase clinical throughput, and improve the accessibility of CMR in the very-near future.
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    Circulating tumour DNA characterisation of invasive lobular carcinoma in patients with metastatic breast cancer
    (Elsevier, 2022) Davis, Andrew A.; Gerratana, Lorenzo; Clifton, Katherine; Medford, Arielle J.; Velimirovic, Marko; Hensing, Whitney L.; Bucheit, Leslie; Shah, Ami N.; D’Amico, Paolo; Reduzzi, Carolina; Zhang, Qiang; Dai, Charles S.; Denault, Elyssa N.; Bagegni, Nusayba A.; Opyrchal, Mateusz; Ademuyiwa, Foluso O.; Bose, Ron; Gradishar, William J.; Behdad, Amir; Ma, Cynthia X.; Bardia, Aditya; Cristofanilli, Massimo; Medicine, School of Medicine
    Background: Limited data exist to characterise molecular differences in circulating tumour DNA (ctDNA) for patients with invasive lobular carcinoma (ILC). We analysed metastatic breast cancer patients with ctDNA testing to assess genomic differences among patients with ILC, invasive ductal carcinoma (IDC), and mixed histology. Methods: We retrospectively analysed 980 clinically annotated patients (121 ILC, 792 IDC, and 67 mixed histology) from three academic centers with ctDNA evaluation by Guardant360™. Single nucleotide variations (SNVs), copy number variations (CNVs), and oncogenic pathways were compared across histologies. Findings: ILC was significantly associated with HR+ HER2 negative and HER2 low. SNVs were higher in patients with ILC compared to IDC or mixed histology (Mann Whitney U test, P < 0.05). In multivariable analysis, HR+ HER2 negative ILC was significantly associated with mutations in CDH1 (odds ratio (OR) 9.4, [95% CI 3.3-27.2]), ERBB2 (OR 3.6, [95% confidence interval (CI) 1.6-8.2]), and PTEN (OR 2.5, [95% CI 1.05-5.8]) genes. CDH1 mutations were not present in the mixed histology cohort. Mutations in the PI3K pathway genes (OR 1.76 95% CI [1.18-2.64]) were more common in patients with ILC. In an independent cohort of nearly 7000 metastatic breast cancer patients, CDH1 was significantly co-mutated with targetable alterations (PIK3CA, ERBB2) and mutations associated with endocrine resistance (ARID1A, NF1, RB1, ESR1, FGFR2) (Benjamini-Hochberg Procedure, all q < 0.05). Interpretation: Evaluation of ctDNA revealed differences in pathogenic alterations and oncogenic pathways across breast cancer histologies with implications for histologic classification and precision medicine treatment.
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    CNC-bZIP protein NFE2L1 regulates osteoclast differentiation in antioxidant-dependent and independent manners
    (Elsevier, 2021-11-06) Liu, Zhiyuan; Wang, Huihui; Hou, Yongyong; Yang, Yang; Jia, Jingkun; Wu, Jinzhi; Zuo, Zhuo; Gao, Tianchang; Ren, Suping; Bian, Yiying; Liu, Shengnan; Fu, Jingqi; Sun, Yongxin; Li, Jiliang; Yamamoto, Masayuki; Zhang, Qiang; Xu, Yuanyuan; Pi, Jingbo; Biology, School of Science
    Fine-tuning of osteoclast differentiation (OD) and bone remodeling is crucial for bone homeostasis. Dissecting the mechanisms regulating osteoclastogenesis is fundamental to understanding the pathogenesis of various bone disorders including osteoporosis and arthritis. Nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as NRF1), which belongs to the CNC-bZIP family of transcription factors, orchestrates a variety of physiological processes and stress responses. While Nfe2l1 gene may be transcribed into multiple alternatively spliced isoforms, the biological function of the different isoforms of NFE2L1 in bone metabolism, osteoclastogenesis in particular, has not been reported. Here we demonstrate that knockout of all isoforms of Nfe2l1 transcripts specifically in the myeloid lineage in mice [Nfe2l1(M)-KO] results in increased activity of osteoclasts, decreased bone mass and worsening of osteoporosis induced by ovariectomy and aging. In comparison, LysM-Cre-mediated Nfe2l1 deletion has no significant effect on the osteoblast and osteocytes. Mechanistic investigations using bone marrow cells and RAW 264.7 cells revealed that deficiency of Nfe2l1 leads to accelerated and elevated OD, which is attributed, at least in part, to enhanced accumulation of ROS in the early stage of OD and expression of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1α (Nfatc1/α). In addition, NFE2L1 regulates the transcription of multiple antioxidant genes and Nfatc1/α and OD in an isoform-specific manner. While long isoforms of NFE2L1 function as accelerators of induction of Nfatc1/α and antioxidant genes and OD, the short isoform NFE2L1-453 serves as a brake that keeps the long isoforms’ accelerator effects in check. These findings provide a novel insight into the regulatory roles of NFE2L1 in osteoclastogenesis and highlight that NFE2L1 is essential in regulating bone remodeling and thus may be a valuable therapeutic target for bone disorders.
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    Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation
    (Cell Press, 2017-03-16) Cheung, Ka Lung; Zhang, Fan; Jaganathan, Anbalagan; Sharma, Rajal; Zhang, Qiang; Konuma, Tsuyoshi; Shen, Tong; Lee, June-Yong; Ren, Chunyan; Chen, Chih-Hung; Lu, Geming; Olson, Matthew R.; Zhang, Weijia; Kaplan, Mark H.; Littman, Dan R.; Walsh, Martin J.; Xiong, Huabao; Zeng, Lei; Zhou, Ming-Ming; Pediatrics, School of Medicine
    The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T-helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclinT1/Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity., , Cheung et al. uncover both separate and interdependent Brd2 and Brd4 genomic functions in potentiating the genetic program required for Th17 cell development and adaptive immunity. Brd2 interacts with transcription factor Stat3 and chromatin insulator CTCF/cohesin complex to support enhancer assembly, whereas Brd4 temporally controls RNA PolII for transcription elongation.
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    Polyhedral Distortions and Unusual Magnetic Order in Spinel FeMn2O4
    (American Chemical Society, 2023-03-14) Zhang, Qiang; Tian, Wei; Nepal, Roshan; Huq, Ashfia; Nagler, Stephen; DiTusa, J. F.; Jin, Rongying; Physics, School of Science
    Spinel compounds AB2X4 consist of both tetrahedral (AX4) and octahedral (BX6) environments with the former forming a diamond lattice and the latter a geometrically frustrated pyrochlore lattice. Exploring the fascinating physical properties and their correlations with structural features is critical in understanding these materials. FeMn2O4 has been reported to exhibit one structural transition and two successive magnetic transitions. Here, we report the polyhedral distortions and their correlations to the structural and two magnetic transitions in FeMn2O4 by employing the high-resolution neutron powder diffraction. The cation distribution is found to be (Mn0.92+Fe0.13+)A(Mn3+Fe0.93+Mn0.12+)BO4. While large trigonal distortion is found even in the high-temperature cubic phase, the first-order cubic-tetragonal structural transition associated with the elongation of both tetrahedra and octahedra with shared oxygen atoms along the c axis occurs at TS ≈ 750 K, driven by the Jahn-Teller effect of the orbital active B-site Mn3+ cation. Strong magnetoelastic coupling is unveiled at TN1 ≈ 400 K as manifested by the appearance of Néel-type collinear ferrimagnetic order, an anomaly in both tetrahedral and octahedral distortions, as well as an anomalous decrease of the lattice constants c and a weak anomaly of a. Upon cooling to TN2 ≈ 65 K, it evolves to a noncollinear ferrimagnetic order accompanied by the different moments at the split magnetic sites B1 and B2. Only one-half of the B-site Mn3+/Fe3+ spins, i.e., the B2-site spins in the pyrochlore lattice, are canted, which is a unique magnetic order among spinels. The canting angle between A-site and B2-site moments is ∼25°, but the B1-site moment stays antiparallel to the A-site moment even at 10 K. This noncollinear order is accompanied by a modification of the O-B-O bond angles in the octahedra without significant change in lattice constants or tetrahedral/octahedral distortion parameters, indicating a distinct magnetoelastic coupling. We demonstrate distinct roles of the A-site and B-site magnetic cations in the structural and magnetic properties of FeMn2O4. Our study indicates that FeMn2O4 is a wonderful platform to unveil interesting magnetic order and to investigate their correlations with polyhedral distortions and lattice.