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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl3), pp.iii25-iii25
    Description: Despite landmark advances in the genomics of medulloblastoma, significant ambiguity exists in the translation these findings into therapeutic advances. We propose that quantitative proteomics can be used to better discern driver aberrations and more directly view the functional, and therefore targetable, biology of this disease. METHODS: We created a Stable isotope Labeling of Amino acids in cell Culture (SILAC) reference atlas of proteins from 4 medulloblastoma cell lines and spiked it into cell lysates of low passage medulloblastoma cultures. A Hybrid LTQ-Orbitrap mass spectrometer was used to quantitate proteins relative to the atlas. RESULTS AND DISCUSSION: We used the SILAC reference atlas to quantitate the proteome of myc-amplified and non-myc-amplified group 3 low passage medulloblastoma cells. Accurate quantitation was achieved for an average of 1215 proteins per primary cell line. Technical replicates resulted in r2 values between 0.91 and 0.98. The differentially abundant proteins myc-amplified tumors reveal protein-protein connectivity networks associated with alternative splicing, ribosome biogenesis and metabolism. At the junction of splicing and metabolism, we confirmed the upregulation of specific splicing factors (HNRNPs) in the myc-amplified group. We demonstrate the HNRNP control of PKM isoform generation and the subsequent effect upon tumor cell metabolism and resistance to hypoxia. Furthermore, we confirm these proteomic findings using independent medulloblastoma tissue samples and show they are conserved in low passage primary tumor cultures. CONCLUSIONS: Our results demonstrate the advantages of quantitative proteomic profiling to discover oncogenic driver molecules. This is particularly significant given the emerging evidence of the poor correlation between mRNA abundance and protein abundance. Ultimately, insight into the protein level biology provided by these types of studies will yield more readily accessible therapeutic targets and allow clearer inferences of disease biology.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Neuro-Oncology, 2016, Vol. 18(suppl3), pp.iii106-iii106
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 3
    Language: English
    In: Acta Neuropathologica Communications, 01 June 2018, Vol.6(1), pp.1-19
    Description: Abstract Genomic characterization has begun to redefine diagnostic classifications of cancers. However, it remains a challenge to infer disease phenotypes from genomic alterations alone. To help realize the promise of genomics, we have performed a quantitative proteomics investigation using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and 41 tissue samples spanning the 4 genomically based subgroups of medulloblastoma and control cerebellum. We have identified and quantitated thousands of proteins across these groups and find that we are able to recapitulate the genomic subgroups based upon subgroup restricted and differentially abundant proteins while also identifying subgroup specific protein isoforms. Integrating our proteomic measurements with genomic data, we calculate a poor correlation between mRNA and protein abundance. Using EPIC 850 k methylation array data on the same tissues, we also investigate the influence of copy number alterations and DNA methylation on the proteome in an attempt to characterize the impact of these genetic features on the proteome. Reciprocally, we are able to use the proteome to identify which genomic alterations result in altered protein abundance and thus are most likely to impact biology. Finally, we are able to assemble protein-based pathways yielding potential avenues for clinical intervention. From these, we validate the EIF4F cap-dependent translation pathway as a novel druggable pathway in medulloblastoma. Thus, quantitative proteomics complements genomic platforms to yield a more complete understanding of functional tumor biology and identify novel therapeutic targets for medulloblastoma.
    Keywords: Silac ; Proteomics ; Medulloblastoma ; Pediatric Brain Tumor ; Medicine
    E-ISSN: 2051-5960
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  • 4
    Language: English
    In: Oncotarget, 10 June 2015, Vol.6(16), pp.14584-95
    Description: Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior.
    Keywords: Cmyc ; Cancer ; Glycolysis ; Medulloblastoma ; Proteomics ; Biomarkers, Tumor -- Genetics ; Cerebellar Neoplasms -- Genetics ; Medulloblastoma -- Genetics ; Proteomics -- Methods
    E-ISSN: 1949-2553
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 5
    Language: English
    In: Neuro-Oncology, 06/2017, 06/01/2017, Vol.19(suppl_4), pp.iv39-iv39
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press (via CrossRef)
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  • 6
    Language: English
    In: Oncotarget, 06/10/2015, Vol.6(16)
    Description: Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior.
    ISSN: Oncotarget
    E-ISSN: 1949-2553
    Source: CrossRef
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  • 7
    Language: English
    In: Journal of the American College of Cardiology, 27 March 2012, Vol.59(13), pp.E854-E854
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/S0735-1097(12)60855-9 Byline: Liang Zhong, Yee How Lau, Ling Ling Sim, David Sim, Bernard Kwok, Terrance Chua, Raymond Lee, Ru-San Tan Author Affiliation: National Heart Centre Singapore, Singapore, Singapore, Novena Heart Centre Singapore, Singapore Article Note: (footnote) ACC Oral Contributions McCormick Place South, S405 Saturday, March 24, 2012, 9:15 a.m.-9:30 a.m. Session Title: Predicting Outcomes in Heart Failure: Biomarkers and Beyond Abstract Category: 14. Heart Failure: Clinical Presentation Number: 905-8
    Keywords: Medicine
    ISSN: 0735-1097
    E-ISSN: 1558-3597
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  • 8
    Language: English
    In: International Journal of Cardiology, 03 October 2013, Vol.168(3), pp.1975-1983
    Description: There is a clinical need for a contractility index that reflects myocardial contractile dysfunction even when ejection fraction (EF) is preserved. We used novel relative load-independent global and regional contractility indices to compare left ventricular (LV) contractile function in three groups: heart failure (HF) with preserved ejection fraction (HFPEF), HF with reduced ejection fraction (HFREF) and normal subjects. Also, we determined the associations of these parameters with 3-month and 1-year mortality in HFPEF patients. 199 HFPEF patients [median age (IQR): 75 (67–80) years] and 327 HFREF patients [69 (59–76) years] were recruited following hospitalization for HF; 22 normal control subjects [65 (54–71) years] were recruited for comparison. All patients underwent standard two-dimensional Doppler and tissue Doppler echocardiography to characterize LV dimension, structure, global and regional contractile function. The median (IQR) global LV contractility index, was 4.30 s (3.51–4.57 s ) in normal subjects but reduced in HFPEF [2.57 (2.08–3.64)] and HFREF patients [1.77 (1.34–2.30)]. Similarly, median (IQR) regional LV contractility index was 99% (88–104%) in normal subjects and reduced in HFPEF [81% (66–96%)] and HFREF [56% (41–71%)] patients. Multi-variable logistic regression analysis on HFPEF identified sc-mFS 〈 76% as the most consistent predictor of both 3-month (OR = 7.15, p 〈 0.05) and 1-year (OR = 2.57, p 〈 0.05) mortality after adjusting for medical conditions and other echocardiographic measurements. Patients with HFPEF exhibited decreased LV global and regional contractility. This population-based study demonstrated that depressed regional contractility index was associated with higher 3-month and 1-year mortality in HFPEF patients.
    Keywords: Heart Failure ; Contractility ; Normalized Wall-Stress ; Pathophysiology ; Prognosis ; Medicine
    ISSN: 0167-5273
    E-ISSN: 1874-1754
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  • 9
    Language: English
    In: Phytotherapy Research, April, 2013, Vol.27(4), p.581(7)
    Description: Byline: Patrick Kwok-Kin Lai, Judy Yuet-Wa Chan, Ling Cheng, Ching-Po Lau, Simon Quan-Bin Han, Ping-Chung Leung, Kwok-Pui Fung, Clara Bik-San Lau Foot ulceration, if not treated properly, will eventually result in amputation. Inflammation may impede the wound healing process if not properly controlled. The root of Astragalus membranaceus (AR) is one of the Chinese herbs commonly found in Chinese herbal formulae used for treating foot ulcer. In this study, we aimed to identify the active fractions and/or compounds from AR aqueous extract, which are responsible for the anti-inflammatory effect using in vitro bioassay-guided fractionation. The anti-inflammatory effect was monitored by the inhibition of nitric oxide (NO) released from lipopolysaccharide-stimulated mouse macrophage RAW 264.7 cells after treated with AR aqueous extract or its fractions and isolated components. Two major active fractions (P2-3-2-2-2 and P2-3-2-2-3) were found to significantly inhibit NO production at 0.156 mg/mL (p〈0.01). In addition, three chemical components (formononetin, calycosin and astragaloside IV) were successfully isolated from P2-3-2-2-3. Only formononetin could significantly inhibit NO production (p〈0.01), whereas the other two components had no significant effects at concentrations ranging from 0.039 to 0.156 mg/mL. In conclusion, two major anti-inflammatory active fractions that may enhance wound healing were identified, and formononetin was one of the active ingredients in the active fractions. Copyright A[c] 2012 John Wiley & Sons, Ltd. Correspondence: Correspondence to: Clara Bik San Lau, Institute of Chinese Medicine, E205, Science Centre East Block, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China. E-mail: claralau@cuhk.edu.hk Supporting information: Additional Supporting Information may be found in the online version of this article Additional supporting information may be found in the online version of this article.
    ISSN: 0951-418X
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  • 10
    Language: English
    In: American Journal of Chinese Medicine, Sept, 2010, Vol.38(5), p.1005(10)
    Keywords: Antifungal Agents -- Research ; Antifungal Agents -- Identification And Classification ; Legumes -- Chemical Properties ; Legumes -- Health Aspects ; Legumes -- Research ; Eucalyptus -- Chemical Properties ; Eucalyptus -- Health Aspects ; Eucalyptus -- Research ; Chinese Herbal Medicine -- Research ; Dermatophytes -- Care And Treatment ; Dermatophytes -- Research ; Microbiological Assay -- Usage ; Microbiological Assay -- Research
    ISSN: 0192-415X
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