Publications by authors named "Xinyu Wen"

70 Publications

BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma.

Nat Commun 2021 Nov 26;12(1):6924. Epub 2021 Nov 26.

Genetics Branch, NCI, NIH, Bethesda, MD, USA.

Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.
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http://dx.doi.org/10.1038/s41467-021-27176-wDOI Listing
November 2021

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Cell Rep 2021 Nov;37(8):110047

University of Toronto Musculoskeletal Oncology Unit, Sinai Health System; Department of Surgery, University of Toronto, Toronto, ON, Canada.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
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http://dx.doi.org/10.1016/j.celrep.2021.110047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642810PMC
November 2021

Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.

Cancer Res 2021 Dec 5;81(23):5818-5832. Epub 2021 Oct 5.

Translational Genomics Research Institute (TGen), Phoenix, Arizona.

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1033DOI Listing
December 2021

Polychlorinated naphthalene concentrations in human serum caused by unintentional production and emissions, and potential effects of polychlorinated naphthalenes on thyroid hormones.

Sci Total Environ 2022 Feb 25;806(Pt 1):150546. Epub 2021 Sep 25.

College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China; Engineering Research Center of Food Environment and Public Health, Beijing 100081, China. Electronic address:

The concentrations of 75 polychlorinated naphthalene (PCN) congeners in 95 human serum samples from the Fengjiang electronic waste dismantling area and Huangyan District in Taizhou City (Zhejiang Province, China) were determined. Thyroid hormone (FT3, FT4, TSH, and TRH) concentrations in the samples were also determined. The total PCN concentrations in the samples from Fengjiang and Huangyan were 1.29 × 10-4.28 × 10 and 8.29 × 10-6.45 × 10 pg/g lipid, respectively. The less-chlorinated (Cl) PCN concentrations were relatively high in all of the samples, and the concentrations in the samples from the two areas were not significantly different. The sums of the combustion-related PCN congener concentrations were significantly higher in the samples from Fengjiang than in the samples from Huangyan, and the sums of the more-chlorinated (Cl) PCNs were slightly higher in the samples from Fengjiang than in the samples from Huangyan. The relationship between the PCN concentration and age indicated that electronic waste controls have decreased human exposure to PCNs but that attention should still be paid to exposure to less-chlorinated PCNs. The main PCN congeners that contributed to the toxic equivalent concentrations were markedly different for the samples from Fengjiang and Huangyan. CN-66/67 was dominant for the Fengjiang samples and CN-10 was dominant for the Huangyan samples. Attention should be paid to the risks posed by less-chlorinated PCNs to human health. CN-1, CN-2, and CN-20 concentrations are related to human thyroid hormone levels, and the relationships between less-chlorinated PCN concentrations and thyroid hormone concentrations should be further studied.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150546DOI Listing
February 2022

Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.

J Clin Oncol 2021 09 24;39(26):2859-2871. Epub 2021 Jun 24.

Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA.

Purpose: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome.

Patients And Methods: Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed.

Results: DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. (15%), (15%), and (13%) mutations were found at a higher incidence than previously reported and mutations were associated with worse outcomes in both fusion-negative and fusion-positive cases. Interestingly, mutations in isoforms predominated in infants < 1 year (64% of cases). Mutation of was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data.

Conclusion: This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.
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http://dx.doi.org/10.1200/JCO.20.03060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425837PMC
September 2021

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

JCO Precis Oncol 2021 11;5. Epub 2021 Jan 11.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts.

Materials And Methods: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort.

Results: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (, ) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with fusion-negative RMS patients versus the patients with fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (, , , mismatch repair genes), rarely (, , , ), or never () reported in RMS. Numerous genes (, , mismatch repair) were on the ACMG Secondary Findings 2.0 list.

Conclusion: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.
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http://dx.doi.org/10.1200/PO.20.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169077PMC
January 2021

Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies.

Sci Transl Med 2021 01;13(578)

Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA.

Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (), checkpoint kinase 1 (), breast cancer 2 (), and mutY DNA glycosylase () pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, = 0.008; and 2.60, = 0.028), and longer recurrence-free survival after platinum-based chemotherapy ( = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of interacting protein C-terminal helicase 1 (), a homologous recombination-related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.
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http://dx.doi.org/10.1126/scitranslmed.abc7488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489678PMC
January 2021

Development and Evaluation of a Combined Immunoassay Method Based on a Stable Isotope Tagging Strategy and Inductively Coupled Plasma Mass Spectrometry for Detecting Human Chorionic Gonadotropin.

Clin Lab 2020 Nov;66(11)

Background: The development of a combined immunoassay method, based on a stable isotope tagging strategy and inductively coupled plasma mass spectrometry (ICP-MS), has created options for quantitative bioanalysis. The aim of the study was to develop a combined immunoassay, featuring ICP-MS and a stable element labeling strategy, for the detection of human chorionic gonadotropin (HCG), and developed methodology applicable for clinical practice.

Methods: In accordance with guidelines published by the Clinical and Laboratory Standards Institute (CLSI), we developed our assay and then evaluated its analytical performance, including the limit of detection (LOD), the upper limit of quantification (ULoQ), linearity, precision, recovery, cross reactivity, and interference. Next, we collected 130 clinical samples for analysis with the new assay. The data derived from our assay were then compared with those derived by an existing electrochemiluminescence immunoassay (ECLIA).

Results: The LOD of the assay was 0.33 mIU/mL and the ULoQ was 11,300 mIU/mL. The coefficient of determina-tion of linearity was higher than 0.99 in the range of 1 to 8,917 mIU/mL (R2 = 0.9964). The obtained recoveries ranged from 97.08% to 103.50%, while the intra-assay imprecision of high value samples and low value samples were 2.97% and 6.08%, respectively. The inter-assay imprecision of high value samples and low value samples were 3.98% and 7.08%, respectively. Interference test results deviated by less than ± 10% in the presence of hemoglobin ≤ 2 g/L, bilirubin ≤ 274 mol/L, or triglycerides ≤ 37 mmol/L. Compared with the commercial ECLIA method for clinical sample detection, the proposed method showed a significant correlation (R2 = 0.9770) and satisfactory agreement.

Conclusions: The combination of ICP-MS and a stable element labeling based immunoassay for HCG detection was established successfully and the general performance of this system was acceptable, thus indicating that the assay has potential for the clinical application.
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http://dx.doi.org/10.7754/Clin.Lab.2020.191207DOI Listing
November 2020

Proteome profiling of gestational diabetes mellitus at 16-18 weeks revealed by LC-MS/MS.

J Clin Lab Anal 2020 Sep 15;34(9):e23424. Epub 2020 Jun 15.

Medical School of Chinese PLA & Medical Laboratory Center, First Medical Center of Chinese PLA General Hospital, Beijing, China.

Background: The practices used to diagnose gestational diabetes mellitus (GDM) could only be carried out around the time of detectable symptoms, and predictive capacity is little.

Methods: LC-MS/MS was conducted to explore overview proteomics for GDM complicated pregnant woman at 16-18 gestation weeks, while normal pregnant for control. Enzyme-linked immunosorbent assay was further applied in an independent cohort of 15 GDM cases and 15 controls for verification.

Results: The results indicated that 24 protein expression levels were significantly changed in GDM group samples, and inflammation, oxidative stress, insulin resistance, blood coagulation, and lipid homeostasis were associated with GDM. The abnormal expression of CRP and IGFBP2 was verified in the first-trimester maternal plasma in women who subsequently developed GDM.

Conclusions: This study not only identified 24 potential predictive biomarkers for GDM also provided a global overview of protein rearrangements induced by GDM.
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http://dx.doi.org/10.1002/jcla.23424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521232PMC
September 2020

Screening and identification of serum biomarkers of osteoarticular tuberculosis based on mass spectrometry.

J Clin Lab Anal 2020 Jul 12;34(7):e23297. Epub 2020 Mar 12.

School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.

Background: In view of the current difficulty of clinically diagnosing osteoarticular tuberculosis, our aim was to use mass spectrometry to establish diagnostic models and to screen and identify serum proteins which could serve as potential diagnostic biomarkers for early detection of osteoarticular tuberculosis.

Methods: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to select an osteoarticular tuberculosis-specific serum peptide profile and establish diagnostic models. Further, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify potential serum biomarkers that could be used for auxiliary diagnosis of osteoarticular tuberculosis, and then clinical serum samples were used to verify these biomarkers by enzyme-linked immunosorbent assay (ELISA).

Results: We established four diagnostic models that can distinguish osteoarticular tuberculosis from rheumatoid arthritis, ankylosing spondylitis, osteoarticular infections, and healthy adults. The models were osteoarticular tuberculosis-rheumatoid arthritis, osteoarticular tuberculosis-ankylosing spondylitis, osteoarticular tuberculosis-osteoarticular infections, and osteoarticular tuberculosis-healthy adult, and their accuracy was 76.78%, 79.02%, 83.77%, and 88.16%, respectively. Next, we selected and identified 18 proteins, including complement factor H-related protein 1 (CFHR1) and complement factor H-related protein 2 (CFHR2), which were upregulated in the tuberculosis group only.

Conclusions: We successfully established four diagnostic models involving osteoarticular tuberculosis, rheumatoid arthritis, ankylosing spondylitis, osteoarticular infections, and healthy adults. Furthermore, we found that CFHR1 and CFHR2 may be two valuable auxiliary diagnostic indicators for osteoarticular tuberculosis. These results provide reference values for rapid and accurate diagnosis of osteoarticular tuberculosis.
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http://dx.doi.org/10.1002/jcla.23297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370717PMC
July 2020

Simultaneous determination of gastric cancer biomarkers pepsinogen PGI/PGII using element tagged immunoassay coupled with inductively coupled plasma mass spectrometry detection.

J Clin Lab Anal 2020 Jul 9;34(7):e23287. Epub 2020 Mar 9.

Department of Clinical Laboratory Medicine, Chinese People's Liberation Army General Hospital & Postgraduate Medical School, Beijing, China.

Objectives: In this study, a new immunoassay for the simultaneous determination of pepsinogen I (PGI) and pepsinogen II (PGII) in serum based on element labeling strategy coupled with inductively coupled plasma mass spectrometry (ICP-MS) detection was proposed.

Methods: The sandwich-type immunoassay was used to simultaneously detect PGI and PGII in serum. PGI and PGII were captured by anti-PGI and anti-PGII antibody immobilized on the magnetic beads and then banded with Eu labeled anti-PGI detection antibody and Sm labeled anti-PGII detection antibody, followed by ICP-MS detection.

Results: The linear correlation coefficient (R ) of PGI and PGII standard curves was .9938 and .9911, with the dynamic range of 0-200 ng/mL and 0-60 ng/mL, respectively. The limit of detection for PGI and PGII was 1.8 ng/mL and 0.3 ng/mL, respectively. The average recovery was 101.41% ± 6.74% for PGI and 101.47% ± 4.20% for PGII. Good correlations were obtained between the proposed method and CLIA (r = .9588 for PGI, r = .9853 for PGII).

Conclusions: We established a mass spectrometry-based immunoassay for the simultaneous detection of PGI and PGII in a single analysis. The element tagged immunoassay coupled with ICP-MS detection has high sensitivity, accuracy, and specificity in clinical serum sample analysis.
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http://dx.doi.org/10.1002/jcla.23287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370713PMC
July 2020

Effect of ferric ions on the anaerobic bio-dissolution of jarosites by Acidithiobacillus ferrooxidans.

Sci Total Environ 2020 Mar 28;710:136334. Epub 2019 Dec 28.

CAS Key Laboratory for Urban Pollutant Conversion, Department of Applied Chemistry, University of Science and Technology of China, Hefei 230026, China; Centre of Wastewater Resource Recovery, College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, China. Electronic address:

Large amounts of jarosites are produced during zinc hydrometallurgy and bioleaching, as well as in acid sulfate soils and acid mine drainage environments. As such, understanding the behavior of jarosite dissolution is important for analyzing the iron cycle process and promoting the control and treatment of jarosites. In general, soluble ferric ions and jarosites coexist in acid environments; however, the relationship between soluble ferric ions and jarosites under anaerobic reductive conditions is still not well understood. In this study, the effect of adding Fe on the promotion of the bio-dissolution of jarosites using Acidithiobacillus ferrooxidans is investigated. With the addition of 12 mM Fe, the efficiency and maximum rate of jarosite bio-dissolution were found to reach 84.1% and 2.66 mmol/(L·d), respectively. The addition of Fe at concentrations higher than 12 mM did not further improve the jarosite bio-dissolution. These results indicate that the mechanisms underlying these improvements include: (i) the reduction of the zeta potential due to the compression of the diffusion layer of the electric double layer by Fe; (ii) bacteria growth enhancement and the stabilization of the pH of cultures via the reduction of soluble Fe. Based on these observations, this study serves to promote the development of jarosite bio-dissolution using Acidithiobacillus ferrooxidans and challenges the idea that soluble Fe suppresses the bio-dissolution reaction of solid Fe substances such as jarosite when soluble ferric ions and jarosite coexist.
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http://dx.doi.org/10.1016/j.scitotenv.2019.136334DOI Listing
March 2020

Back recursive estimation of unknown frequency sinusoidal disturbance in superconducting RF cavities.

ISA Trans 2020 Jun 6;101:204-210. Epub 2020 Feb 6.

Institute of Energy Science, Nanjing University, Nanjing 210046, China.

A novel back recursive estimation (BRE) scheme is proposed for superconducting radio frequency (SRF) cavities. Microphonic,the main source of cavities detuning is modeled as unknown frequency sinusoidal disturbance. The disturbance property is excited by an auxiliary filter and the frequency information is estimated in observer framework. Furthermore, the sinusoidal disturbance is rearranged as a series of dynamics form using virtual disturbances. Back recursive signal is calculated according to the correlation between virtual disturbance and equivalent input disturbance. As a result, the asymptotic stability of estimation error can be obtained based on Lyapunov function, and robustness can be obtained if another external bounded disturbance exists. Simulations verify the effectiveness of the proposed method.
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http://dx.doi.org/10.1016/j.isatra.2020.02.001DOI Listing
June 2020

A preliminary study for the establishment of a reference interval for vitamin B12 in China after performance verification of a second-generation ECLIA kit.

J Clin Lab Anal 2020 May 6;34(5):e23165. Epub 2020 Jan 6.

Department of Clinical Laboratory Medicine, Chinese People's Liberation Army General Hospital & Postgraduate Medical School, Beijing, China.

Background: The second-generation electrochemiluminescence immunoassay (ECLIA) kit of vitamin B12 is widely used in clinical laboratories, and the establishment of a reference interval (RI) is essential to provide the basis for clinical monitoring. The purpose of this study was to establish a laboratory RI for vitamin B12 in China and at the same time verify the method performance of the second-generation kit.

Methods: The verification of the method performance was conducted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Based on these guidelines, a total of 580 serum samples were collected, and 391 serum samples were used for the establishment of the RI according to CLSI guidelines. The subjects were grouped by sex and age. The age groups were as follows: 21-40, 41-60, and 61-80 years. The RI was defined by nonparametric 2.5th and 97.5th percentile intervals.

Results: The performance of the second-generation kit of vitamin B12 from the Roche Cobas E602 system was in compliance with laboratory requirements. Serum vitamin B12 levels conformed to a non-Gaussian distribution. Harris-Boyd's test did not indicate partitioning for different age and gender group. Besides, there was no significant difference between different age groups (P = .07) and gender groups (P = .2002). The RI for healthy Chinese adults (aged 21-80 years) calculated by the nonparametric method was 250.8-957.1 pg/mL.

Conclusions: The reference range of vitamin B12 was established, which provided a theoretical basis for the clinical application and monitoring of vitamin B12 detection.
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http://dx.doi.org/10.1002/jcla.23165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246358PMC
May 2020

Rejection of time-varying frequency sinusoidal disturbance using refined observer for a class of uncertain systems.

ISA Trans 2020 May 9;100:136-144. Epub 2019 Dec 9.

School of Automation Sciences and Electrical Engineering, Beihang University, 100044, China.

The time-varying frequency disturbance rejection problem is addressed for a class of nonlinear uncertain system. A novel refined disturbance observer (RDO) is developed composed of auxiliary observer and calibration observer. At first, the disturbance is redescribed using auxiliary observer after coordinate transformation, which contains a parametric form about frequency and a decay term. The derivative of frequency and system uncertain are absorbed in the decay term, furthermore, the correlation between disturbance frequency and disturbance can be derived. Then the key parameter, i.e. frequency factor is estimated by calibration observer characteristic with two-degree-freedom, the decay term associated with derivative of frequency can be attenuated in feedback control loop. Thus, the composite controller including a refined disturbance observer (RDO) and a robust feedback controller is designed, which inherits the elegant feature of disturbance observer based control (DOBC). The H∞ index performance can be guaranteed to attenuate the estimation error driven by disturbance time-varying frequency together with system uncertainty.
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http://dx.doi.org/10.1016/j.isatra.2019.11.039DOI Listing
May 2020

Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma.

Nat Genet 2019 12 29;51(12):1714-1722. Epub 2019 Nov 29.

Genetics Branch, NCI, NIH, Bethesda, MD, USA.

Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma and identify critical CR TF dependencies. These CR TFs build SEs that have the highest levels of histone acetylation, yet paradoxically the same SEs also harbor the greatest amounts of histone deacetylases. We find that hyperacetylation selectively halts CR TF transcription. To investigate the architectural determinants of this phenotype, we used absolute quantification of architecture (AQuA) HiChIP, which revealed erosion of native SE contacts, and aberrant spreading of contacts that involved histone acetylation. Hyperacetylation removes RNA polymerase II (RNA Pol II) from core regulatory genetic elements, and eliminates RNA Pol II but not BRD4 phase condensates. This study identifies an SE-specific requirement for balancing histone modification states to maintain SE architecture and CR TF transcription.
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http://dx.doi.org/10.1038/s41588-019-0534-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886578PMC
December 2019

Development and evaluation of an element-tagged immunoassay coupled with inductively coupled plasma mass spectrometry detection: can we apply the new assay in the clinical laboratory?

Clin Chem Lab Med 2020 Jun;58(6):873-882

Department of Clinical Laboratory Medicine, Chinese People's Liberation Army General Hospital and Postgraduate Medical School, Fuxing Road 28, Haidian District, Beijing 100853, P.R. China, Phone: +15901056535, Fax: 010-66937771.

Introduction Element-tagged immunoassay coupled with inductively coupled plasma-mass spectrometry (ICP-MS) detection has the potential to revolutionize immunoassay analysis in clinical detection; however, a systematic evaluation with the standard guidelines of the assay is needed to ensure its performance meets the requirements of the clinical laboratory. Methods Carcinoembryonic antigen (CEA) was chosen for analysis using the proposed method. A systematic evaluation of the proposed assay was carried out according to the Clinical and Laboratory Standards Institute (CLSI). The 469 clinical samples were analyzed using the new method and compared with the electrochemiluminescent immunoassay (ECLIA) method. Results The measurement range of the assay was 1-900 ng/mL, with a detection limit of 0.83 ng/mL. The inter-assay and intra-assay imprecision were 4.67% and 5.38% with high concentration samples, and 9.27% and 17.64% with low concentration samples, respectively. The cross-reactivity (%) for different antigens was less than 0.05%, and the recovery was between 94% and 108%. Percentage deviation of all the dilutions was less than 12.5% during linearity estimation. The interference bias caused by different substances was less than 10%. The reference interval of the assay was 0-4.442 ng/mL. Comparison with the commercial ECLIA method for clinical sample detection, the proposed method showed a correlation of 0.9878 and no significant differences between the methods were observed (p = 0.6666). Conclusions The ICP-MS based immunoassay was successfully developed, and the analytical performance of the assay met the requirements of the CLSI, which fully proved the clinical transferability and application of the new method.
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http://dx.doi.org/10.1515/cclm-2019-0566DOI Listing
June 2020

Therapeutic applications of adipose-derived mesenchymal stem cells on acute liver injury in canines.

Res Vet Sci 2019 Oct 12;126:233-239. Epub 2019 Sep 12.

College of Veterinary Medicine, Shaanxi Stem Cell Engineering and Technology Research Center, Northwest A&F University, Yangling 712100, China. Electronic address:

In this study, canine adipose-derived mesenchymal stem cells (cADSCs) therapeutic potential was investigated in artificially induced acute liver injury model by CCl in canines. The primary cADSCs cells were cultured and then intravenously administered into the canine animal model. Six cross-breed dogs were divided into three groups including blank control group, CCl model group, CCl induced cADSCs transplantation group. The results showed that after intraperitoneal injection of CCl solution, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Albumin (ALB) in peripheral blood of experimental canines confirmed the correct induction of acute liver injury. Moreover, the liver structure showed clear macroscopic damage. The cADSCs were homed in the liver of the administered animals. The AST, ALT and ALB in the peripheral blood rapidly decreased. H&E and PAS histological evaluation showed that both the structure of canine liver tissue and the ability to synthesize hepatic glycogen could be restored to the control level after cADSCs transplantation. Therefore, cADSCs can play a therapeutic role in the recovery of liver injury. Overall, this study demonstrates that the primary cADSCs transplantation into the acute liver injury model induced by intravenous injection can play a certain therapeutic role in the recovery of liver in canines. These results may provide a new treatment idea for acute liver disease in pets clinically.
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http://dx.doi.org/10.1016/j.rvsc.2019.09.004DOI Listing
October 2019

Identification of New Peptide Biomarkers for Bacterial Bloodstream Infection.

Proteomics Clin Appl 2020 03 10;14(2):e1900075. Epub 2019 Dec 10.

Department of Clinical Laboratory, The PLA General Hospital, Beijing, 100853, China.

Purpose: Due to a lack of effective early diagnostic measures, new diagnostic methods for bacterial bloodstream infections (BSIs) are urgently needed. A protein-peptide profiling approach can be used to identify novel diagnostic biomarkers of BSIs.

Experimental Design: In this study, MALDI-TOF MS and nano-LC/ESI-MS/MS are used to analyze serum peptides. In addition, GO and network analyses are conducted as a means of analyzing these potential protein markers. Finally, the potential biomarkers are verified in independent clinical samples via ELISA.

Results: m/z 1533.8, 2794.3, 3597.3, 5007.3, and 7816.7 reveal an identical trend; the intensity of m/z 1533.8, 2794.3, and 3597.3 are higher in the infection group relative to controls, whereas the intensity of m/z 5007.3 and 7816.7 are lower in the infection group. Four peaks are successfully identified including ITIH4, KNG1, SAA2, and C3. GO and network analyses find these proteins to form an interaction network, which may be correlated with BSI. ELISA results indicate that ITIH4, KNG1, and SAA2 are effective in differentiating infected from normal control group and the febrile group.

Conclusions And Clinical Relevance: These biomarkers have the potential to offer new insights into the signaling networks underlying the development and progression of BSI.
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http://dx.doi.org/10.1002/prca.201900075DOI Listing
March 2020

Perfluorooctanoic acid induces migration and invasion and inhibits apoptosis through the PI3K/AKT signaling pathway in human rhabdomyosarcoma cells.

Oncol Rep 2019 Oct 6;42(4):1558-1568. Epub 2019 Aug 6.

Chinese PLA Department of Clinical Laboratory Medicine and Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, P.R. China.

The present study aimed to investigate the effects of perfluorooctanoic acid (PFOA) on tumor cell migration, invasion and apoptosis by activation of the PI3K/AKT signaling pathway in human rhabdomyosarcoma (RMS). PFOA is a persistent, synthetic organic environment pollutant, which has been previously associated with multiple diseases, including cancer. The present study aimed to confirm whether PFOA can elicit cell growth in the RD subline of RBS. RD cells were treated with different concentrations of PFOA. Cell proliferation was evaluated using Cell Counting Kit‑8 and cell cycle assays. Cell migration and invasion were determined using wound healing and Transwell assays. Apoptotic rates were estimated by Annexin V‑FITC/propidium iodide staining. The expression levels of vimentin, serum/glucocorticoid‑regulated kinase 1 (SGK1), cyclin E2, cyclin dependent kinase (CDK)2, p53, p21, p27, phosphatidylinositol‑3 kinase (PI3K) and protein kinase B (AKT), and apoptosis‑associated genes and proteins (including Bcl‑2 and Bax) were detected by reverse transcription‑PCR and western blot analyses. The results showed that PFOA significantly promoted RD cell proliferation, migration and invasion and significantly inhibited RD cell apoptosis. Exposure to PFOA also induced the expression of vimentin, SGK1, cyclin E2, CDK2, AKT, PI3K and Bcl‑2, but suppressed the expression of Bax in the RD cells. The treatment of RD cells with BEZ235, a PI3K inhibitor, antagonized the effects of PFOA on metastatic formation and apoptosis. The results obtained show that the PI3K/AKT signaling pathway is implicated in mediating the pro‑neoplastic effects of PFOA. The data suggests that PFOA is a carcinogen capable of promoting RD cell migration and invasion and inhibiting apoptosis through the PI3K/AKT signaling pathway.
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http://dx.doi.org/10.3892/or.2019.7265DOI Listing
October 2019

Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress.

Aging (Albany NY) 2018 10;10(10):2954-2972

College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering and Technology, Northwest A and F University, Yangling, Shaanxi Province, China.

Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can aid in the treatment of numerous diseases in animals. However, natural aging during expansion of ADMSCs prior to their use in transplantation restricts their beneficial effects. Melatonin is reported to exert biorhythm regulation, anti-oxidation, and anti-senescence effects in various animal and cell models. Herein, by using a senescent canine ADMSCs (cADMSCs) cell model subjected to multiple passages , we investigated the effects of melatonin on ADMSCs senescence. We found that melatonin alleviates endoplasmic reticulum stress (ERS) and cell senescence. MT1/MT2 melatonin receptor inhibitor, luzindole, diminished the mRNA expression levels and rhythm expression amplitude of Bmal1 and Nrf2 genes. Nrf2 knockdown blocked the stimulatory effects of melatonin on endoplasmic reticulum-associated degradation (ERAD)-related gene expression and its inhibitory effects on ERS-related gene expression. At the same time, the inhibitory effects of melatonin on the NF-κB signaling pathway and senescence-associated secretory phenotype (SASP) were blocked by Nrf2 knockdown in cADMSCs. Melatonin pretreatment improved the survival of cADMSCs and enhanced the beneficial effects of cADMSCs transplantation in canine acute liver injury. These results indicate that melatonin activates Nrf2 through the MT1/MT2 receptor pathway, stimulates ERAD, inhibits NF-κB and ERS, alleviates cADMSCs senescence, and improves the efficacy of transplanted cADMSCs.
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http://dx.doi.org/10.18632/aging.101602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224246PMC
October 2018

Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk -Not-Amplified Human Neuroblastoma.

Clin Cancer Res 2018 11 21;24(22):5673-5684. Epub 2018 May 21.

Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease, including a focus on tumor-infiltrating lymphocytes (TIL). We performed deep RNA-seq on pretreatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters, including patient outcome. The expression profiles of 190 additional pretreatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings. We found that -not-amplified (-NA) tumors had significantly higher cytotoxic TIL signatures compared with -amplified (-A) tumors. A reported MYCN activation signature was significantly associated with poor outcome for high-risk patients with -NA tumors; however, a subgroup of these patients who had elevated activated natural killer (NK) cells, CD8 T cells, and cytolytic signatures showed improved outcome and expansion of infiltrating TCR clones. Furthermore, we observed upregulation of immune exhaustion marker genes, indicating an immune-suppressive microenvironment in these neuroblastomas. This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK/T cells and improved outcomes in high-risk neuroblastoma patients harboring -NA tumors. Our findings suggest that these high-risk patients with -NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504934PMC
November 2018

Toward Subtle Manipulation of Fine Dendritic β-Nucleating Agent in Polypropylene.

ACS Omega 2017 Oct 26;2(10):7230-7238. Epub 2017 Oct 26.

State Key Laboratory of Polymer Materials Engineering, Polymer Research Institute of Sichuan University, Chengdu 610065, China.

Dendritic β-nucleating agent (β-NA) can readily manipulate the formation of dendritic β-crystal with a unique toughening effect on polypropylene (PP) to drastically enhance the ductility. However, by the current method, the geometric size is too large to fully perform the nucleating efficiency. In this study, by comparatively investigating the effect of molecular weight of PP and diffusion of β-NAs in a PP melt, we proposed a novel carrier strategy that selective enrichment of β-NAs in a PP carrier was followed by directed migration into polymer matrix. Accordingly, the growth of NAs was controlled by the release from the PP carrier, which decreased the available amount of β-NAs during the growth stage. In this case, the viscosity difference between PP carrier and matrix determined the interfacial movement of β-NAs. When the PP carrier and matrix had same molecular weight, the diffusion and release became favorable to facilitate the formation of the dense and fine dendritic aggregates. As a result, the relative content of β-crystals reached 92%, with a drastic increase of ∼82% in the optimal condition compared to the directed compounded PP/β-NAs sample. This study can open a new avenue to tailor the topologies of β-NAs and the ensuing β-crystals for high-performance PP products.
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http://dx.doi.org/10.1021/acsomega.7b01036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645093PMC
October 2017

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer.

Cell Rep 2017 Sep;20(10):2408-2423

Regulatory RNAs and Cancer Section, Genetics Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD 20892, USA. Electronic address:

Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.
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http://dx.doi.org/10.1016/j.celrep.2017.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777516PMC
September 2017

Paired Expression Analysis of Tumor Cell Surface Antigens.

Front Oncol 2017 21;7:173. Epub 2017 Aug 21.

Genetics Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States.

Adoptive immunotherapy with antibody-based therapy or with T cells transduced to express chimeric antigen receptors (CARs) is useful to the extent that the cell surface membrane protein being targeted is not expressed on normal tissues. The most successful CAR-based (anti-CD19) or antibody-based therapy (anti-CD20) in hematologic malignancies has the side effect of eliminating the normal B cell compartment. Targeting solid tumors may not provide a similar expendable marker. Beyond antibody to Her2/NEU and EGFR, very few antibody-based and no CAR-based therapies have seen broad clinical application for solid tumors. To expand the way in which the surfaceome of solid tumors can be analyzed, we created an algorithm that defines the pairwise relative overexpression of surface antigens. This enables the development of specific immunotherapies that require the expression of two discrete antigens on the surface of the tumor target. This dyad analysis was facilitated by employing the Hotelling's -squared test (Hotelling-Lawley multivariate analysis of variance) for two independent variables in comparison to a third constant entity (i.e., gene expression levels in normal tissues). We also present a unique consensus scoring mechanism for identifying transcripts that encode cell surface proteins. The unique application of our bioinformatics processing pipeline and statistical tools allowed us to compare the expression of two membrane protein targets as a pair, and to propose a new strategy based on implementing immunotherapies that require both antigens to be expressed on the tumor cell surface to trigger therapeutic effector mechanisms. Specifically, we found that, for MYCN amplified neuroblastoma, pairwise expression of ACVR2B or anaplastic lymphoma kinase (ALK) with GFRA3, GFRA2, Cadherin 24, or with one another provided the strongest hits. For MYCN, non-amplified stage 4 neuroblastoma, neurotrophic tyrosine kinase 1, or ALK paired with GFRA2, GFRA3, SSK1, GPR173, or with one another provided the most promising paired-hits. We propose that targeting these markers together would increase the specificity and thereby the safety of CAR-based therapy for neuroblastoma.
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http://dx.doi.org/10.3389/fonc.2017.00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566986PMC
August 2017

Preoperative Serum Carcinoembryonic Antigen as a Marker for Predicting the Outcome of Three Cancers.

Biomark Cancer 2017 16;9:1-7. Epub 2017 Feb 16.

Department of Clinical Biochemistry, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, Beijing, China.

Background: Serum levels of carcinoembryonic antigen (CEA) are associated with a variety of tumors.

Objective: This study evaluated the prognostic value of pretreatment serum CEA levels in predicting the outcomes of multiple tumors subjected to treatment.

Methods: Prior to therapy, serum samples from 71 prostate, 46 breast, 77 gastric, and 31 pancreatic cancer patients were collected to examine serum CEA levels. The cutoff value for CEA was set as determined by the maximum Youden index. The data were analyzed by the Kaplan-Meier curves generated by the log-rank test and Cox multivariate analysis.

Results: The overall survival rate for all the patients was 71.11%. The 3-year survival rate of patients with prostate, breast, gastric, and pancreatic cancers was 81.69%, 95.65%, 54.55%, and 51.61%, respectively. The 3-year survival rate showed significant statistical differences between patients with serum CEA levels <2.885 µg/L and those with serum CEA levels ⩾2.885 µg/L ( < .001). The statistical differences of the 3-year survival rate also existed in the men ( = .010) or women group ( < .001), as well as in the 3 different types of cancer, which include breast cancer ( = .025), gastric cancer ( = .001), and pancreatic cancer ( = .047).

Conclusions: Serum CEA levels can provide additional prognostic information and may be useful in treatment implementation for patients with breast, gastric, or pancreatic cancer.
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http://dx.doi.org/10.1177/1179299X17690142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345947PMC
February 2017

PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability.

Cancer Discov 2017 08 26;7(8):884-899. Epub 2017 Apr 26.

Genetics Branch, NCI, NIH, Bethesda, Maryland.

Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We find PAX3-FOXO1 reprograms the -regulatory landscape by inducing super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specific vulnerability that can be exploited for precision therapy. PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatin-level functions are critical to understanding its oncogenic activity. We find that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-1297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802885PMC
August 2017

Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma.

Genet Med 2017 08 26;19(8):955-958. Epub 2017 Jan 26.

Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

Purpose: Ewing sarcoma is a small round blue cell tumor that is highly malignant and predominantly affects the adolescent and young adult population. It has long been suspected that a genetic predisposition exists for this cancer, but the germ-line genetic underpinnings of this disease have not been well established.

Methods: We performed germline variant analysis of whole-genome or whole-exome sequencing of samples from 175 patients affected by Ewing sarcoma.

Results: We discovered pathogenic or likely pathogenic germline mutations in 13.1% of our cohort. Pathogenic mutations were highly enriched for genes involved with DNA damage repair and for genes associated with cancer predisposition syndromes.

Conclusion: Our findings reported here have important clinical implications for patients and families affected by Ewing sarcoma. Genetic counseling should be considered for patients and families affected by this disease to take advantage of existing risk management strategies. Our study also highlights the importance of germline sequencing for patients enrolled in precision-medicine protocols.Genet Med advance online publication 26 January 2017.
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http://dx.doi.org/10.1038/gim.2016.206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529247PMC
August 2017

Identification of MicroRNAs Involved in Growth Arrest and Apoptosis in Hydrogen Peroxide-Treated Human Hepatocellular Carcinoma Cell Line HepG2.

Oxid Med Cell Longev 2016 15;2016:7530853. Epub 2016 Aug 15.

Core Laboratory of Translational Medicine, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, Beijing 100853, China; Department of Clinical Biochemistry, Chinese PLA General Hospital, Beijing 100853, China.

Although both oxidative stress and microRNAs (miRNAs) play vital roles in physiological and pathological processes, little is known about the interactions between them. In this study, we first described the regulation of H2O2 in cell viability, proliferation, cycle, and apoptosis of human hepatocellular carcinoma cell line HepG2. Then, miRNAs expression was profiled after H2O2 treatment. The results showed that high concentration of H2O2 (600 μM) could decrease cell viability, inhibit cell proliferation, induce cell cycle arrest, and finally promote cell apoptosis. Conversely, no significant effects could be found under treatment with low concentration (30 μM). miRNAs array analysis identified 131 differentially expressed miRNAs (125 were upregulated and 6 were downregulated) and predicted 13504 putative target genes of the deregulated miRNAs. Gene ontology (GO) analysis revealed that the putative target genes were associated with H2O2-induced cell growth arrest and apoptosis. The subsequent bioinformatics analysis indicated that H2O2-response pathways, including MAPK signaling pathway, apoptosis, and pathways in cancer and cell cycle, were significantly affected. Overall, these results provided comprehensive information on the biological function of H2O2 treatment in HepG2 cells. The identification of miRNAs and their putative targets may offer new diagnostic and therapeutic strategies for liver cancer.
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http://dx.doi.org/10.1155/2016/7530853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5002491PMC
March 2017
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