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author:("Ma, qianlong")
1.  Predicting Prostate Biopsy Results Using a Panel of Plasma and Urine Biomarkers Combined in a Scoring System 
Journal of Cancer  2016;7(3):297-303.
Background: Determining the need for prostate biopsy is frequently difficult and more objective criteria are needed to predict the presence of high grade prostate cancer (PCa). To reduce the rate of unnecessary biopsies, we explored the potential of using biomarkers in urine and plasma to develop a scoring system to predict prostate biopsy results and the presence of high grade PCa.
Methods: Urine and plasma specimens were collected from 319 patients recommended for prostate biopsies. We measured the gene expression levels of UAP1, PDLIM5, IMPDH2, HSPD1, PCA3, PSA, TMPRSS2, ERG, GAPDH, B2M, AR, and PTEN in plasma and urine. Patient age, serum prostate-specific antigen (sPSA) level, and biomarkers data were used to develop two independent algorithms, one for predicting the presence of PCa and the other for predicting high-grade PCa (Gleason score [GS] ≥7).
Results: Using training and validation data sets, a model for predicting the outcome of PCa biopsy was developed with an area under receiver operating characteristic curve (AUROC) of 0.87. The positive and negative predictive values (PPV and NPV) were 87% and 63%, respectively. We then developed a second algorithm to identify patients with high-grade PCa (GS ≥7). This algorithm's AUROC was 0.80, and had a PPV and NPV of 56% and 77%, respectively. Patients who demonstrated concordant results using both algorithms showed a sensitivity of 84% and specificity of 93% for predicting high-grade aggressive PCa. Thus, the use of both algorithms resulted in a PPV of 90% and NPV of 89% for predicting high-grade PCa with toleration of some low-grade PCa (GS <7) being detected.
Conclusions: This model of a biomarker panel with algorithmic interpretation can be used as a “liquid biopsy” to reduce the need for unnecessary tissue biopsies, and help to guide appropriate treatment decisions.
PMCID: PMC4747884  PMID: 26918043
RNA; Cell-free; Gleason; scoring; high-grade; algorithm.
2.  Synonymous Polymorphisms in HOXB13 as a Protective Factor for Prostate Cancer 
Journal of Cancer  2015;6(5):409-411.
Background: Genomic association and linkage studies, as well as epidemiological data have implicated both the HOXB13 gene and single nucleotide polymorphisms (SNPs) in the development of prostate cancer (PCa). The recent association between the G84E polymorphism in the HOXB13 gene and PCa has been shown to result in a more aggressive cancer with an earlier onset of the disease. We examined the frequency of this mutation and other recurrent HOXB13 SNPs in patients with PCa and those with benign prostatic hyperplasia (BPH) or no cancer.
Methods: Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on exons 1 and 2 of HOXB13 gene, followed by bidirectional Sanger Sequencing on peripheral blood from 232 PCa (age 46-92) and 110 BPH (age 45-84) patients. Statistical analysis was used to correlate between recurrent SNPs and PCa.
Results: The G84E mutation was found at a low frequency in randomly selected PCa and BPH (both 0.9%). Two recurrent, synonymous SNPs, rs8556 and rs900627, were also detected. rs8556 was detected in 48 PCa (20.7%) and 26 BPH (23.6%) subjects; rs9900627was detected in 27 PCa (11.6%) and 19 BPH (17.3%) subjects. Having both rs8556 and rs9900627 or being homozygous for either one was associated with being 2.9 times less likely to develop PCa (p=0.05).
Conclusions: Although a larger study in order to confirm our findings, our data suggests a significant negative correlation between two SNPs, rs8556 and rs9900627, and the presence of PCa.
PMCID: PMC4392048  PMID: 25874003
prostate cancer; HOXB13; polymorphism; SNP; benign prostatic hyperplasia; G84E
3.  Circulating Ki-67 protein in plasma as a biomarker and prognostic indicator of acute lymphoblastic leukemia 
Leukemia research  2009;34(2):173-176.
Tissue-based determination of Ki-67, a marker of cellular proliferation, has shown prognostic value in solid tumors and hematological malignancies. We developed and validated an electrochemiluminescence-based method for sensitive measurement of circulating Ki-67 in plasma (cKi-67). This assay demonstrated significantly higher levels of cKi-67 in patients with newly diagnosed acute lymphoblastic leukemia (ALL) (n=27; median, 762; range, 0-4574 U/100 μL) than in healthy control subjects (n=114; median, 399; range, 36-2830 U/100 μL). Moreover, elevated plasma cKi-67 was associated with significantly shorter survival in ALL patients (P=0.05). These findings suggest that Ki-67 can be detected in circulation and has potential for use as a biomarker for predicting clinical behavior in ALL.
PMCID: PMC4132892  PMID: 19679351
Acute lymphoblast leukemia; circulating KI-67; Plasma
4.  Circulating Ki-67 Index in Plasma as a Biomarker and Prognostic Indicator in Chronic Lymphocytic Leukemia 
Leukemia research  2010;34(10):1320-1324.
Ki-67 is a nuclear antigen that is expressed in all stages of the cell cycle, except G0, and is widely used as a marker of cellular proliferation in human tumors. We recently showed that elevated levels of Ki-67 circulating in plasma (cKi-67) are associated with shorter survival in patients with acute lymphoblastic leukemia. The study included 194 patients with CLL and 96 healthy control subjects. cKi-67 levels in plasma were determined using an electrochemiluminescent immunoassay. We normalized the cKi-67 level to the absolute number of lymphocytes in the patient's peripheral blood to establish the plasma cKI-67 index. The cKi-67 index showed significant correlation with lymph node involvement and Rai stage (P = 0.05). Higher cKi-67 index values were significantly associated with shorter survival. Multivariate Cox proportional hazards regression analysis demonstrated that the association of the cKi-67 index with shorter survival was independent of IgVH mutation status. In a multivariate model incorporating the cKi-67 index with B2M and IgVH, only cKi-67 index and B2M levels remained as independent predictors of survival. The results of this study suggest that the plasma cKi-67 index, along with B2M level, is a strong predictor of clinical behavior in CLL
PMCID: PMC4108997  PMID: 20362333
cKi-67 Index; Plasma; Chronic Lymphocytic Leukemia
5.  Proteasome Enzymatic Activities in Plasma as Risk Stratification of Patients with Acute Myeloid Leukemia and Advanced Myelodysplastic Syndrome 
Cytogenetic abnormalities are currently the most important predictors of response and clinical outcome for patients with acute myeloid leukemia (AML) or advanced-stage myelodysplastic syndrome (MDS). Because clinical outcomes vary markedly within cytogenetic subgroups, additional biological markers are needed for risk stratification.
Experimental Design
We assessed the utility of measuring pretreatment proteasome chymotrypsin-like (Ch-L), caspase-like (Cas-L), and trypsin-like (Tr-L) activities in plasma to predict response and survival of patients with AML (n=174) or advanced-stage MDS (n=52).
All three enzymatic activities were significantly (P<0.001) increased in the plasma of patients with AML and MDS as compared with normal controls. Both Ch-L and Cas-L activities, but not Tr-L activity correlated with outcome. Ch-L and Cas-L activities, but not Tr-L activity predicted response in univariate analysis (P = 0.002). However, only Ch-L activity was independent predictor of response from age grouping (< vs ≥70 years), cytogenetics, and BUN in multivariate analysis. Similarly, both Ch-L and Cas-L activities, but not Tr-L activity were predictors of overall survival in univariate analysis (P <0.0001), but only Ch-L activity was independent of cytogenetics, age, performance status, BUN, and beta-2 microglobulin in multivariate Cox regression models. Ch-L activity was also a strong independent predictor of survival in patients with intermediate karyotype (n=124).
Measuring plasma chymotrypsin-like activity may provide a powerful biomarker for risk stratification in patients with AML and advanced-stage MDS, including those with normal karyotype.
PMCID: PMC4091712  PMID: 19458051
acute myeloid leukemia; myelodysplastic syndrome; proteasome, chymotrypsin-like activity; survival; response; nomogram
6.  Ubiquitin-Proteasome System Profiling in Acute Leukemias and its Clinical Relevance 
Leukemia research  2010;35(4):526-533.
The ubiquitin-proteasome system (UPS) plays a major role in the homeostasis of cellular protein. We demonstrate that each of the major hematologic diseases (AML, ALL, and MDS) has a specific and different plasma profile of UPS protein and enzymatic activities. While high levels of proteasome and ubiquitin proteins and enzymatic activities are detected in the plasma samples from patients, normalizing enzymatic activities, show that each proteasome has lower enzymatic activities in these diseases as compared with normal controls. Proteasome protein levels in AML are strong predictor of survival independently of cytogenetics, performance status and age. The Ch-L activity when normalized to the level of proteasome protein show significant negative correlation with survival in ALL.
PMCID: PMC4051750  PMID: 20951430
acute myeloid leukemia; acute lymphoblastic leukemia; myelodysplastic syndrome; proteasome, ubiquitin; chymotrypsin-like activity; survival; response
7.  BCR-JAK2 fusion as a result of a translocation (9;22)(p24;q11.2) in a patient with CML-like myeloproliferative disease 
Translocation (9;22)(q34;q11.2) resulting in BCR/ABL1 fusion at the molecular level is the hallmark of chronic myelogenous leukemia (CML). Variants of the Philadelphia translocation and complex translocations involving BCR have been reported in myeloproliferative disorders (MPD). A rare translocation, t(9;22)(p24;q11.2), resulting in a novel BCR-JAK2 fusion has been reported in a handful of cases of CML and acute myelogenous leukemia (AML). We present clinical-pathological and cytogenetic evaluation of a patient with Philadelphia-chromosome negative CML/MPD harboring a t(9;22)(p24;q11.2) resulting in BCR-JAK2 fusion. Fluorescence in situ hybridization and molecular characterization of the translocation confirmed a BCR-JAK2 fusion and helped delineate the breakpoints upstream of exon 1 of minor cluster region of BCR gene and likely intron 18 of the JAK2 gene, resulting in an in-frame transcript This case provides convincing support, along with two previous case-reports, for a role for activation of the Janus kinase 2 in evolution of myeloproliferative disease. The recurrent, albeit rare, nature of the breakpoints within BCR and JAK2 suggests a potential new diagnostic target that should be interrogated in Ph-negative CML/MPD patients.
PMCID: PMC3467166  PMID: 22549126
CML; JAK2; BCR; Translocation; t(9;22)
8.  Effects of Clinically Relevant MPL Mutations in the Transmembrane Domain Revealed at the Atomic Level through Computational Modeling 
PLoS ONE  2011;6(8):e23396.
Mutations in the thrombopoietin receptor (MPL) may activate relevant pathways and lead to chronic myeloproliferative neoplasms (MPNs). The mechanisms of MPL activation remain elusive because of a lack of experimental structures. Modern computational biology techniques were utilized to explore the mechanisms of MPL protein activation due to various mutations.
Transmembrane (TM) domain predictions, homology modeling, ab initio protein structure prediction, and molecular dynamics (MD) simulations were used to build structural dynamic models of wild-type and four clinically observed mutants of MPL. The simulation results suggest that S505 and W515 are important in keeping the TM domain in its correct position within the membrane. Mutations at either of these two positions cause movement of the TM domain, altering the conformation of the nearby intracellular domain in unexpected ways, and may cause the unwanted constitutive activation of MPL's kinase partner, JAK2.
Our findings represent the first full-scale molecular dynamics simulations of the wild-type and clinically observed mutants of the MPL protein, a critical element of the MPL-JAK2-STAT signaling pathway. In contrast to usual explanations for the activation mechanism that are based on the relative translational movement between rigid domains of MPL, our results suggest that mutations within the TM region could result in conformational changes including tilt and rotation (azimuthal) angles along the membrane axis. Such changes may significantly alter the conformation of the adjacent and intrinsically flexible intracellular domain. Hence, caution should be exercised when interpreting experimental evidence based on rigid models of cytokine receptors or similar systems.
PMCID: PMC3157383  PMID: 21858098
9.  Significant association between polymorphism of the erythropoietin gene promoter and myelodysplastic syndrome 
BMC Medical Genetics  2010;11:163.
Myelodysplastic syndrome (MDS) may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP) rs1617640 in the erythropoietin (EPO) promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS.
We genotyped the EPO rS1617640 SNP in 189 patients with MDS, 257 with acute myeloid leukemia (AML), 106 with acute lymphoblastic leukemia, 97 with chronic lymphocytic leukemia, 353 with chronic myeloid leukemia, and 95 healthy controls.
The G/G genotype was significantly more common in MDS patients (47/187; 25.1%) than in controls (6/95; 6.3%) or in patients with other leukemias (101/813; 12.4%) (all P < 0.001). Individuals with the G/G genotype were more likely than those with other genotypes to have MDS (odd ratio = 4.98; 95% CI = 2.04-12.13). Clinical and follow up data were available for 112 MDS patients and 186 AML patients. There was no correlation between EPO promoter genotype and response to therapy or overall survival in MDS or AML. In the MDS group, the GG genotype was significantly associated with shorter complete remission duration, as compared with the TT genotype (P = 0.03). Time to neutrophils recovery after therapy was significantly longer in MDS patients with the G/G genotype (P = 0.02).
These findings suggest a strong association between the rs1617640 G/G genotype and MDS. Further studies are warranted to investigate the utility of screening for this marker in individuals exposed to environmental toxins or chemotherapy.
PMCID: PMC2992491  PMID: 21078205
10.  JAK2 Exon 14 Deletion in Patients with Chronic Myeloproliferative Neoplasms 
PLoS ONE  2010;5(8):e12165.
The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs); deletion of the entire exon 14 is rarely detected. In our previous study of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by reverse transcription-PCR (RT-PCR) with direct sequencing, complete deletion of exon 14 (Δexon14) constituted <1% of JAK2 mutations. This appears to be an alternative splicing mutation, not detectable with DNA-based testing.
Methodology/Principal Findings
We investigated the possibility that MPN patients may express the JAK2 Δexon14 at low levels (<15% of total transcript) not routinely detectable by RT-PCR with direct sequencing. Using a sensitive RT-PCR–based fluorescent fragment analysis method to quantify JAK2 Δexon14 mRNA expression relative to wild-type, we tested 61 patients with confirmed MPNs, 183 with suspected MPNs (93 V617F-positive, 90 V617F-negative), and 46 healthy control subjects. The Δexon14 variant was detected in 9 of the 61 (15%) confirmed MPN patients, accounting for 3.96% to 33.85% (mean  = 12.04%) of total JAK2 transcript. This variant was also detected in 51 of the 183 patients with suspected MPNs (27%), including 20 of the 93 (22%) with V617F (mean [range] expression  = 5.41% [2.13%–26.22%]) and 31 of the 90 (34%) without V617F (mean [range] expression  = 3.88% [2.08%–12.22%]). Immunoprecipitation studies demonstrated that patients expressing Δexon14 mRNA expressed a corresponding truncated JAK2 protein. The Δexon14 variant was not detected in the 46 control subjects.
These data suggest that expression of the JAK2 Δexon14 splice variant, leading to a truncated JAK2 protein, is common in patients with MPNs. This alternatively spliced transcript appears to be more frequent in MPN patients without V617F mutation, in whom it might contribute to leukemogenesis. This mutation is missed if DNA rather than RNA is used for testing.
PMCID: PMC2921382  PMID: 20730051
11.  Structural effects of clinically observed mutations in JAK2 exons 13-15: comparison with V617F and exon 12 mutations 
The functional relevance of many of the recently detected JAK2 mutations, except V617F and exon 12 mutants, in patients with chronic myeloproliferative neoplasia (MPN) has been significantly overlooked. To explore atomic-level explanations of the possible mutational effects from those overlooked mutants, we performed a set of molecular dynamics simulations on clinically observed mutants, including newly discovered mutations (K539L, R564L, L579F, H587N, S591L, H606Q, V617I, V617F, C618R, L624P, whole exon 14-deletion) and control mutants (V617C, V617Y, K603Q/N667K).
Simulation results are consistent with all currently available clinical/experimental evidence. The simulation-derived putative interface, not possibly obtained from static models, between the kinase (JH1) and pseudokinase (JH2) domains of JAK2 provides a platform able to explain the mutational effect for all mutants, including presumably benign control mutants, at the atomic level.
The results and analysis provide structural bases for mutational mechanisms of JAK2, may advance the understanding of JAK2 auto-regulation, and have the potential to lead to therapeutic approaches. Together with recent mutation profiling results demonstrating the breadth of clinically observed JAK2 mutations, our findings suggest that molecular testing/diagnostics of JAK2 should extend beyond V617F and exon 12 mutations, and perhaps should encompass most of the pseudo-kinase domain-coding region.
PMCID: PMC2749040  PMID: 19744331

Results 1-12 (12)