Publications by authors named "Minghao Song"

9 Publications

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Accurate prediction of mega-electron-volt electron beam properties from UED using machine learning.

Sci Rep 2021 Jul 6;11(1):13890. Epub 2021 Jul 6.

Condensed Matter Physics and Materials Science Division, Brookhaven National Laboratory, Upton, NY, 11973, USA.

To harness the full potential of the ultrafast electron diffraction (UED) and microscopy (UEM), we must know accurately the electron beam properties, such as emittance, energy spread, spatial-pointing jitter, and shot-to-shot energy fluctuation. Owing to the inherent fluctuations in UED/UEM instruments, obtaining such detailed knowledge requires real-time characterization of the beam properties for each electron bunch. While diagnostics of these properties exist, they are often invasive, and many of them cannot operate at a high repetition rate. Here, we present a technique to overcome such limitations. Employing a machine learning (ML) strategy, we can accurately predict electron beam properties for every shot using only parameters that are easily recorded at high repetition rate by the detector while the experiments are ongoing, by training a model on a small set of fully diagnosed bunches. Applying ML as real-time noninvasive diagnostics could enable some new capabilities, e.g., online optimization of the long-term stability and fine single-shot quality of the electron beam, filtering the events and making online corrections of the data for time-resolved UED, otherwise impossible. This opens the possibility of fully realizing the potential of high repetition rate UED and UEM for life science and condensed matter physics applications.
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July 2021

Galectin-3 inhibition attenuates doxorubicin-induced cardiac dysfunction by upregulating the expression of peroxiredoxin-4.

Can J Physiol Pharmacol 2020 Oct 9;98(10):700-707. Epub 2020 Jun 9.

Department of Cardiology, Tongji Hospital of Tongji University, Shanghai 200003, People's Republic of China.

Doxorubicin (DOX) is a highly efficient chemotherapeutic drug limited by its cardiotoxicity. Galectin-3 (Gal-3) overexpression is associated with several cardiovascular diseases. In this study, the in vivo models of DOX-treated rats and the in vitro model of DOX-treated H9C2 cells were used. DOX induced cardiac injury and dysfunction accompanied with the upregulation of Gal-3 at the end of the experiment, while inhibition of Gal-3 with modified citrus pectin (MCP) exhibited a dramatic improvement in cardiac function of the DOX-treated rats, as manifested by increased left ventricular systolic pressure and ±d/d and decreased left ventricular end-diastolic pressure. The plasma levels of myocardial injury markers such as lactate dehydrogenase, creatine kinase, creatine kinase-MB, and cardiac troponin I were decreased after MCP treatment. In parallel, MCP attenuated myocardial tissue markers of oxidative stress such as hydrogen peroxide and malondialdehyde restored the activities of superoxide dismutase, catalase, and glutathione peroxidase and upregulated antioxidant peroxiredoxin-4 (Prx-4). To further verify the role of Prx-4, it was downregulated by siRNA-mediated knockdown in H9C2 cells. MCP could not reverse DOX-induced oxidative stress in Prx-4-knock-down cells. In conclusion, Gal-3 mediated DOX-induced cardiotoxicity and Gal-3 inhibition attenuated DOX-induced cardiac dysfunction by upregulating the expression of Prx-4 to reduce myocardial oxidative stress.
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October 2020

Epidermal growth factor receptor (EGFR) amplification rates observed in screening patients for randomized trials in glioblastoma.

J Neurooncol 2019 Aug 4;144(1):205-210. Epub 2019 Jul 4.

Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Purpose: Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world.

Methods: EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography.

Results: EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases).

Conclusions: EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.
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August 2019

Comparison of Biomarker Assays for : Implications for Precision Medicine in Patients with Glioblastoma.

Clin Cancer Res 2019 06 22;25(11):3259-3265. Epub 2019 Feb 22.

Erasmus MC Cancer Center, Rotterdam, the Netherlands.

Purpose: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing amplification by multiple assays. Specifically, we evaluated correlation among fluorescence hybridization (FISH), a standard assay for detecting amplification, with other methods. Formalin-fixed, paraffin-embedded tumor samples were used for all assays. amplification was detected using FISH ( = 206) and whole-exome sequencing (WES, = 74). mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, = 206) and transcriptome profiling (RNAseq, = 64). EGFR protein expression was determined by immunohistochemistry (IHC, = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61-0.80 defines substantial agreement) or statistics.

Results: mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating amplification.

Conclusions: Methods for assessing mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.
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June 2019

Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification.

BMC Cancer 2016 Feb 16;16:105. Epub 2016 Feb 16.

AbbVie, North Chicago, IL, USA.

Background: c-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity.

Method: We generated and tested a bivalent anti-c-Met monoclonal antibody ABT-700 in vitro for binding potency and antagonistic activity and in vivo for antitumor efficacy in human tumor xenografts. Human cancer cell lines and gastric cancer tissue microarrays were examined for MET amplification by fluorescence in situ hybridization (FISH).

Results: ABT-700 exhibits a distinctive ability to block both HGF-independent constitutive c-Met signaling and HGF-dependent activation of c-Met. Cancer cells addicted to the constitutively activated c-Met signaling driven by MET amplification undergo apoptosis upon exposure to ABT-700. ABT-700 induces tumor regression and tumor growth delay in preclinical tumor models of gastric and lung cancers harboring amplified MET. ABT-700 in combination with chemotherapeutics also shows additive antitumor effect. Amplification of MET in human cancer tissues can be identified by FISH.

Conclusions: The preclinical attributes of ABT-700 in blocking c-Met signaling, inducing apoptosis and suppressing tumor growth in cancers with amplified MET provide rationale for examining its potential clinical utility for the treatment of cancers harboring MET amplification.
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February 2016

Analysis of genetic copy number changes in cervical disease progression.

BMC Cancer 2010 Aug 16;10:432. Epub 2010 Aug 16.

Abbott Molecular Inc, 1300 E, Touhy Ave, Des Plaines, IL 60018, USA.

Background: Cervical dysplasia and tumorigenesis have been linked with numerous chromosomal aberrations. The goal of this study was to evaluate 35 genomic regions associated with cervical disease and to select those which were found to have the highest frequency of aberration for use as probes in fluorescent in-situ hybridization.

Methods: The frequency of gains and losses using fluorescence in-situ hybridization were assessed in these 35 regions on 30 paraffin-embedded cervical biopsy specimens. Based on this assessment, 6 candidate fluorescently labeled probes (8q24, Xp22, 20q13, 3p14, 3q26, CEP15) were selected for additional testing on a set of 106 cervical biopsy specimens diagnosed as Normal, CIN1, CIN2, CIN3, and SCC. The data were analyzed on the basis of signal mean, % change of signal mean between histological categories, and % positivity.

Results: The study revealed that the chromosomal regions with the highest frequency of copy number gains and highest combined sensitivity and specificity in high-grade cervical disease were 8q24 and 3q26. The cytological application of these two probes was then evaluated on 118 ThinPrep samples diagnosed as Normal, ASCUS, LSIL, HSIL and Cancer to determine utility as a tool for less invasive screening. Using gains of either 8q24 or 3q26 as a positivity criterion yielded specificity (Normal +LSIL+ASCUS) of 81.0% and sensitivity (HSIL+Cancer) of 92.3% based on a threshold of 4 positive cells.

Conclusions: The application of a FISH assay comprised of chromosomal probes 8q24 and 3q26 to cervical cytology specimens confirms the positive correlation between increasing dysplasia and copy gains and shows promise as a marker in cervical disease progression.
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August 2010

Dysplastic cells in cytological cervical samples show a high incidence of chromosomal abnormalities.

Diagn Cytopathol 2010 Jan;38(1):28-33

Abbott Molecular, Inc., Des Plaines, Illinois 60018, USA.

Chromosomal abnormalities are frequent in most cervical cancers. Amplifications of both the 3q26 (TERC) and 8q24 (MYC) loci have been shown to be prevalent in both high-grade lesions and invasive cervical carcinoma. Most of these studies have looked at either the histological sample or at the entire cytological population of cells. We have developed a Papanicolaou (Pap) destaining method that allows for the accurate analysis of individual cells that were previously identified by cytopathology as dysplastic. The application of fluorescence in situ hybridization (FISH) was then implemented to determine the chromosomal status of the dysplastic cells in the samples and correlate the two events. Chromosomal abnormality is over a thousand times more frequent in dysplastic cells compared with their morphologically normal counterparts.
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January 2010

Chromosomal biomarkers for detection of human papillomavirus associated genomic instability in epithelial cells of cervical cytology specimens.

J Mol Diagn 2007 Nov;9(5):604-11

Abbott Molecular Inc., 1300 E. Touhy Avenue, Des Plaines, IL 60018, USA.

The goal of this study was to compare how accumulation of chromosomal aberrations in human papillomavirus (HPV)-infected cells correlates with the severity of cervical dysplastic lesions. We assessed the frequency of genomic alterations for 35 different loci in a pilot biopsy study and selected two loci (3q26 and 8q24) with the highest frequency of copy number gains found in high-grade dysplasia and cancer. These probes were labeled with gold and red fluorophores and combined with HPV biotin-labeled probes for subsequent detection using a tyramide signal amplification system with a green fluorophore. Cells that were both HPV positive and chromosomally abnormal were designated as "double-positive cells." Cervical cytology specimens from 235 patients were used for this blinded study. The average number of double-positive cells increased from two cells in patients with a cytological interpretation of atypical squamous cells of undetermined significance to 22 cells in low-grade squamous intraepithelial lesion and 99 cells in high-grade squamous intraepithelial lesion, reflecting an accumulation of chromosomal abnormality with disease progression. Using a cutoff of four or more double-positive cells as the criterion for the presence of a cervical intraepithelial neoplasia 2 or 3 lesion, we demonstrated that low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion cytology specimens with underlying cervical intraepithelial neoplasia 2/3 histology showed positive test results in more than 80% of cases. Correlation of 3q26 and 8q24 aneusomy with concurrent HPV infection may thus serve as a biomarker of genetic instability in HPV-infected cells.
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November 2007

Evaluation of quantity and staining pattern of human papillomavirus (HPV)-infected epithelial cells in thin-layer cervical specimens using optimized HPV-CARD assay.

Cancer 2007 Oct;111(5):330-8

Research and Development, Abbott Molecular, Inc., Des Plaines, Illinois 60018, USA.

Background: Testing for human papillomavirus (HPV) is used in the triage of women with a cervical cytology of atypical squamous cells of undetermined significance (ASCUS). A fluorescent in situ hybridization assay was developed for the detection of HPV using the catalyzed receptor deposition technique (HPV-CARD). In this study, the utility of this assay was tested for the detection of HPV in liquid-based cervical cytology specimens.

Methods: A total of 195 liquid-based cytology specimens were analyzed using the HPV-CARD assay. The results from the assay were compared with HPV polymerase chain reaction (PCR) and typing results. The number of HPV-infected cells and the staining pattern was correlated with the cytology classification.

Results: A 91% concordance between HPV-CARD and PCR was observed for the detection of high-risk HPV viruses. A 78% concordance was observed for specimens that were negative for HPV. In ASCUS, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) categories, the average number of HPV-positive cells per slide was 19 cells, 127 cells, and 450 cells, respectively. The number of cells with a punctate staining, suggestive of HPV integration, was 21% in ASCUS, 34% in LSIL, and 46% in HSIL specimens.

Conclusions: The results of the current study indicate positive correlations between the severity of the disease and the increased overall quantity of HPV-positive epithelial cells in cervical cytology specimens and accumulation of cells with punctate staining suggestive of integrated HPV. In summary, the developed HPV-CARD assay was found to provide novel information regarding the proportion and staining pattern of HPV-infected epithelial cells in different cytologic categories of cervical specimens.
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October 2007