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author:("Liu, synexin")
1.  Clinical Significance of CTNNB1 Mutation and Wnt Pathway Activation in Endometrioid Endometrial Carcinoma 
Endometrioid endometrial carcinoma (EEC) is the most common form of endometrial carcinoma. The heterogeneous clinical course of EEC is an obstacle to individualized patient care.
We performed an integrated analysis on the multiple-dimensional data types including whole-exome and RNA sequencing, RPPA profiling, and clinical data from 271 EEC cases in The Cancer Genome Atlas (TCGA) to identify molecular fingerprints that may account for this clinical heterogeneity. Significance analysis of microarray was used to identify marker genes of each subtype that were subject to pathway analysis. Association of molecular subtypes with clinical features and mutation data was analyzed with the Mann Whitney, Chi-square, Fisher’s exact, and Kruskal-Wallis tests. Survival analysis was evaluated with log-rank test. All statistical tests were two-sided.
Four transcriptome subtypes with distinct clinicopathologic characteristics and mutation spectra were identified from the TCGA dataset and validated in an independent sample cohort of 184 EEC cases. Cluster II consisted of younger, obese patients with low-grade EEC but diminished survival. CTNNB1 exon 3 mutations were present in 87.0% (47/54) of Cluster II (P < .001) that exhibited a low overall mutation rate; this was statistically significantly associated with Wnt/β-catenin signaling activation (P < .001). High expression levels of CTNNB1 (P = .001), MYC (P = .01), and CCND1 (P = .01) were associated with poorer overall survival in low-grade EEC tumors.
CTNNB1 exon 3 mutations are likely a driver that characterize an aggressive subset of low-grade and low-stage EEC occurring in younger women.
PMCID: PMC4200060  PMID: 25214561
2.  Broadband CARS spectral phase retrieval using a time-domain Kramers–Kronig transform 
Optics letters  2009;34(9):1363-1365.
We describe a closed-form approach for performing a Kramers–Kronig (KK) transform that can be used to rapidly and reliably retrieve the phase, and thus the resonant imaginary component, from a broadband coherent anti-Stokes Raman scattering (CARS) spectrum with a nonflat background. In this approach we transform the frequency-domain data to the time domain, perform an operation that ensures a causality criterion is met, then transform back to the frequency domain. The fact that this method handles causality in the time domain allows us to conveniently account for spectrally varying nonresonant background from CARS as a response function with a finite rise time. A phase error accompanies KK transform of data with finite frequency range. In examples shown here, that phase error leads to small (<1%) errors in the retrieved resonant spectra.
PMCID: PMC3960577  PMID: 19412273
3.  Transcriptome and Small RNA Deep Sequencing Reveals Deregulation of miRNA Biogenesis in Human Glioma 
The Journal of pathology  2013;229(3):10.1002/path.4109.
Altered expression of oncogenic and tumor-suppressing microRNAs (miRNAs) is widely associated with tumorigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumors. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and interrogated expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression.
PMCID: PMC3857031  PMID: 23007860
microRNA; biogenesis; glioma
4.  Tumour angiogenesis regulation by the miR-200 family 
Nature communications  2013;4:2427.
The miR-200 family is well known to inhibit the epithelial–mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent.
PMCID: PMC3904438  PMID: 24018975
5.  Integrated Analysis of Gene Expression and Tumor Nuclear Image Profiles Associated with Chemotherapy Response in Serous Ovarian Carcinoma 
PLoS ONE  2012;7(5):e36383.
Small sample sizes used in previous studies result in a lack of overlap between the reported gene signatures for prediction of chemotherapy response. Although morphologic features, especially tumor nuclear morphology, are important for cancer grading, little research has been reported on quantitatively correlating cellular morphology with chemotherapy response, especially in a large data set. In this study, we have used a large population of patients to identify molecular and morphologic signatures associated with chemotherapy response in serous ovarian carcinoma.
Methodology/Principal Findings
A gene expression model that predicts response to chemotherapy is developed and validated using a large-scale data set consisting of 493 samples from The Cancer Genome Atlas (TCGA) and 244 samples from an Australian report. An identified 227-gene signature achieves an overall predictive accuracy of greater than 85% with a sensitivity of approximately 95% and specificity of approximately 70%. The gene signature significantly distinguishes between patients with unfavorable versus favorable prognosis, when applied to either an independent data set (P = 0.04) or an external validation set (P<0.0001). In parallel, we present the production of a tumor nuclear image profile generated from 253 sample slides by characterizing patients with nuclear features (such as size, elongation, and roundness) in incremental bins, and we identify a morphologic signature that demonstrates a strong association with chemotherapy response in serous ovarian carcinoma.
A gene signature discovered on a large data set provides robustness in accurately predicting chemotherapy response in serous ovarian carcinoma. The combination of the molecular and morphologic signatures yields a new understanding of potential mechanisms involved in drug resistance.
PMCID: PMC3348145  PMID: 22590536
6.  Mitosis Phase Enrichment with Identification of Mitotic Centromere-Associated Kinesin As a Therapeutic Target in Castration-Resistant Prostate Cancer 
PLoS ONE  2012;7(2):e31259.
The recently described transcriptomic switch to a mitosis program in castration-resistant prostate cancer (CRPC) suggests that mitotic proteins may be rationally targeted at this lethal stage of the disease. In this study, we showed upregulation of the mitosis-phase at the protein level in our cohort of 51 clinical CRPC cases and found centrosomal aberrations to also occur preferentially in CRPC compared with untreated, high Gleason–grade hormone-sensitive prostate cancer (P<0.0001). Expression profiling of chemotherapy-resistant CRPC samples (n = 25) was performed, and the results were compared with data from primary chemotherapy-naïve CRPC (n = 10) and hormone-sensitive prostate cancer cases (n = 108). Our results showed enrichment of mitosis-phase genes and pathways, with progression to both castration-resistant and chemotherapy-resistant disease. The mitotic centromere-associated kinesin (MCAK) was identified as a novel mitosis-phase target in prostate cancer that was overexpressed in multiple CRPC gene-expression datasets. We found concordant gene expression of MCAK between our parent and murine CRPC xenograft pairs and increased MCAK protein expression with clinical progression of prostate cancer to a castration-resistant disease stage. Knockdown of MCAK arrested the growth of prostate cancer cells suggesting its utility as a potential therapeutic target.
PMCID: PMC3281954  PMID: 22363599
7.  Tumor-associated methylation of the putative tumor suppressor AJAP1 gene and association between decreased AJAP1 expression and shorter survival in patients with glioma 
Chinese Journal of Cancer  2011;30(4):247-253.
Allelic loss of the short arm of chromosome 1 has been observed frequently in a wide spectrum of cancers, most frequently in oligodendroglioma. In our previous studies, we evaluated 177 oligodendroglial tumor samples and identified the AJAP1 gene (formerly Shrew1) in the consensus region of deletion. AJAP1 is a transmembrane protein found in adheren junctions and functions to inhibit glioma cell adhesion and migration. Whereas a putative tumor suppressor gene, we did not detect AJAP1 gene mutations. In subsequent studies, we found that AJAP1 was underexpressed in oligodendrogliomas relative to normal brain tissues. Bioinformatic analysis revealed the presence of CpG islands in the promoter of AJAP1. Methylation analysis of the AJAP1 promoter identified hypermethylation in 21 % of oligodendrogliomas (n = 27), and the degree of methylation correlated with low levels of AJAP1 expression (P = 0.045). The AJAP1 promoter was also highly methylated in a wide spectrum of cell lines (n = 22), including cell lines of glioblastoma. Analysis of the National Cancer Institute's REMBRANDT dataset, which contains 343 glioma samples, indicated that low AJAP1 gene expression was associated with decreased survival. Thus, both genetic (gene deletion) and epigenetic alterations (promoter methylation) are likely mechanisms that inactivate the putative tumor suppressor AJAP1 in gliomas, which contributes to poor prognosis.
PMCID: PMC4013351  PMID: 21439246
Methylation; epigenetics; AJAP1(Shrew1); 1p36; glioblastoma; The Cancer Genome Atlas; survival
8.  Structural Basis of Fluorescence Fluctuation Dynamics of Green Fluorescent Proteins in Acidic Environments 
The journal of physical chemistry. B  2006;110(47):24138-24146.
Green fluorescent proteins (GFP) have become powerful markers for numerous biological studies due to their robust fluorescence properties, site-specific labeling, pH-sensitivity, and mutations for multiple-site labeling. Fluorescence correlation spectroscopy (FCS) studies have indicated that fluorescence blinking of anionic GFP mutants take place on a time scale of 45-300 μs, depending on pH, and have been attributed to external proton transfer. Here we present experimental evidence indicating that conformational change of the protein β-barrel is a determining step for such external protonation of GFP-S65T (at low pH) using time-resolved fluorescence and polarization anisotropy measurements. While the average anionic fluorescence lifetime of GFP-S65T is reduced by ∼18% over pH 3.6-10.0 range, the fluorescence polarization anisotropy decays mostly as a single-exponential with a rotational time, φ=17±1 ns, that indicates an intact β-barrel with a hydrodynamic volume of 78±5 nm3. In contrast, the total fluorescence (525±50 nm) of the excited neutral state of S65T reveals a strong correlation between the fluorescence lifetime, structural conformation, and pH. The average fluorescence lifetime of the excited neutral state of S65T as a function of pH yields a pKa≈5.9 in agreement with literature values using steady-state techniques. In contrast to the intact β-barrel at high pH, the anisotropy of neutral S65T (at pH≤pKa) decays as a biexponential (e.g., at pH 5.8, φ1=1.86 ns, β1=0.03, φ2=17.5 ns, and β2=0.25), which suggests a segmental mobility of the chromophore associated with conformational changes of the protein. The segmental motion of the S65T chromophore becomes faster with an enhanced amplitude ratio as pH is reduced. For comparative purposes, we also provide complementary FCS results on fluorescence blinking of the neutral-state of EGFP mutant (F64L/S65T), on a much slower time scale. Our results indicate that conformational rearrangement of the β-barrel and the amino acids surrounding the embedded chromophore is a rate determining step for external proton transfer and possibly cis/trans isomerization as non-radiative pathways that underlie fluorescence blinking of GFP mutants in acidic environment. In addition, the neutral-state transition is likely to be involved in the blinking process previously observed for the anionic-state transition in several GFP mutants.
PMCID: PMC2556077  PMID: 17125385
Green fluorescent protein; GFP-S65T; fluorescence blinking; fluorescence anisotropy; fluorescence correlation spectroscopy; structural conformation

Results 1-8 (8)