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4.  A comprehensive database of Duchenne and Becker muscular dystrophy patients (0–18 years old) in East China 
Currently, there is no cure for Duchenne and Becker muscular dystrophies (DMD/BMD). However, clinical trials with new therapeutic strategies are being conducted or considered. A comprehensive database is critical for patient recruitment and efficacy evaluation. China has the largest population, yet, no comprehensive database for DMD/BMD is available. Our study registered the data of the DMD/BMD patients in East China.
A modified registry form of Remudy ( was applied to Chinese DMD/BMD patients through the outpatient clinic at Children’s Hospital of Fudan University, Shanghai during the period of August 2011 to December 2013. The data included geographic distribution of patients, age at diagnosis, clinical manifestation, genetic analysis and treatment status.
194 DMD and 35 BMD patients were registered. Most patients lived in East China, namely Jiangsu province, Anhui province, Zhejiang province, Jiangxi province, Shanghai, Fujian province and Shandong province. All individuals aged less than 18 years (age limit to a children’s hospital). Diagnosis was made for a majority of patients during the age of 3–4 (16.6%) and 7–8 (14.8%) years old. Exon deletion was the most frequent genetic mutations (65.5% and 74.3%) followed by point mutations (14.4% and 11.4%), duplications (9.8% and 8.6%) and small insertion/deletion (9.3% and 2.9%) for DMD and BMD, respectively. 82.5% of DMD registrants were ambulatory, and all the BMD registrants were able to walk. 26.3% of DMD registrants have been treated with steroids. Cardiac functions were examined for 46.4% DMD boys and 45.7% BMD boys and respiratory functions were examined for 18.6% DMD boys and 14.3% BMD boys. Four boys with abnormal cardiac function were prescribed for treatment with cardiac medicine. 33.2% of DMD patients are eligible for exon skipping therapy, and among them 9.2% and 4.3% patients are eligible for skipping exon 51 and 53, respectively.
The database is the first linking accurate genetic diagnosis with clinical manifestation and treatment status of dystrophinopathy patients in East China. It provides comprehensive information essential for further patient management, especially for promotion of international cooperation in developing experimental therapies such as exon skipping and read-through of nonsense mutations targeting a subgroup of DMD patient population.
PMCID: PMC4323212  PMID: 25612904
Duchenne and Becker muscular dystrophy; The CHFU database; Patient management
5.  Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(48):18404-18412.
AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer.
METHODS: We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7th edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed.
RESULTS: ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51).
CONCLUSION: ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.
PMCID: PMC4277979  PMID: 25561809
AT-rich interactive domain 1A; Switching defective/sucrose non-fermenting complexes; Colorectal cancer; Clinicopathologic characteristics; Prognosis
6.  Consolidated bioprocessing performance of Thermoanaerobacterium thermosaccharolyticum M18 on fungal pretreated cornstalk for enhanced hydrogen production 
Biological hydrogen production from lignocellulosic biomass shows great potential as a promising alternative to conventional hydrogen production methods, such as electrolysis of water and coal gasification. Currently, most researches on biohydrogen production from lignocellulose concentrate on consolidated bioprocessing, which has the advantages of simpler operation and lower cost over processes featuring dedicated cellulase production. However, the recalcitrance of the lignin structure induces a low cellulase activity, making the carbohydrates in the hetero-matrix more unapproachable. Pretreatment of lignocellulosic biomass is consequently an extremely important step in the commercialization of biohydrogen, and for massive realization of lignocellulosic biomass as alternative fuel feedstock. Thus, development of a pretreatment method which is cost efficient, environmentally benign, and highly efficient for enhanced consolidated bioprocessing of lignocellulosic biomass to hydrogen is essential.
In this research, fungal pretreatment was adopted for enhanced hydrogen production by consolidated bioprocessing performance. To confirm the fungal pretreatment efficiency, two typical thermochemical pretreatments were also compared side by side. Results showed that the fungal pretreatment was superior to the other pretreatments in terms of high lignin reduction of up to 35.3% with least holocellulose loss (the value was only 9.5%). Microscopic structure observation combined with Fourier transform infrared spectroscopy (FTIR) analysis further demonstrated that the lignin and crystallinity of lignocellulose were decreased with better holocellulose reservation. Upon fungal pretreatment, the hydrogen yield and hydrogen production rate were 6.8 mmol H2 g-1 pretreated substrate and 0.89 mmol L-1 h-1, respectively, which were 2.9 and 4 times higher than the values obtained for the untreated sample.
Results revealed that although all pretreatments could contribute to the enhancement of hydrogen production from cornstalk, fungal pretreatment proved to be the optimal method. It is apparent that besides high hydrogen production efficiency, fungal pretreatment also offered several advantages over other pretreatments such as being environmentally benign and energy efficient. This pretreatment method thus has great potential for application in consolidated bioprocessing performance of hydrogen production.
PMCID: PMC4296546  PMID: 25648837
Consolidated bioprocessing; Thermoanaerobacterium thermosaccharolyticum M18; Pretreatment; Hydrogen production; Cornstalk
7.  Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei 
Bioorganic & medicinal chemistry letters  2013;23(24):10.1016/j.bmcl.2013.09.101.
Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series.
PMCID: PMC3874807  PMID: 24157367
Fragment screening; MEP pathway; IspF; Non-mevalonate; Anti-infective; SPR
8.  The programmed death-1 gene polymorphism (PD-1.5 C/T) is associated with non-small cell lung cancer risk in a Chinese Han population 
It has been proposed that genetic factors contribute to the susceptibility of non-small cell lung cancer (NSCLC). The programmed death-1 (PD1) is an immunoinhibitory receptor belonging to the CD28/B7 family. The aim of this study is to investigate the relationship between PD-1.5 C/T and NSCLC risk in a Chinese population. A population-based case-control study was conducted in 324 NSCLC patients and 330 cancer-free controls. The genotype of the PD-1.5 C/T was determined by using a polymerase chain reaction assay. Statistically significant difference was observed when the patients and controls were compared according to CC+CT versus TT (OR=2.34, 95% CI 1.35-4.06, P=0.003). The C allele was significantly associated with NSCLC risk (OR=1.421, 95% CI 1.10-1.82, P=0.006). Compared to TNM stage I+II, PD-1.5 C/T significantly increased advanced NSCLC risk (OR=2.66, 95% CI 1.07-6.63, P=0.03). The results from this study suggested that PD-1.5 C/T was potentially related to NSCLC susceptibility in Chinese Han population.
PMCID: PMC4307562  PMID: 25664115
Non-small cell lung cancer; programmed death-1; polymorphism; genetics
9.  Management of isolated superior mesenteric artery dissection 
World Journal of Gastroenterology : WJG  2014;20(45):17179-17184.
AIM: To evaluate our experience of the clinical management of spontaneous isolated superior mesenteric artery dissection (ISMAD).
METHODS: From January 2008 to July 2013, 18 patients with ISMAD were retrospectively analyzed, including 7 patients who received conservative therapy, 9 patients who received reconstruction with bare stents, and 2 patients who underwent surgical treatment. The decision to intervene was based on anatomic suitability, patient comorbidities and symptoms.
RESULTS: Intestinal ischemia-related symptoms completely resolved in 7 patients who received conservative therapy. Stent placement was successful in 9 patients. Of the 9 patients who received endovascular stenting, abdominal pain was alleviated after the procedure and gradually disappeared within 3 d. Follow-up computed tomography and computed tomography angiography were available in all patients during the first month and the first year after the procedure, which revealed patent stent and patent involved superior mesenteric artery branches with complete obliteration of the dissection lesion. In the 2 patients who underwent surgical treatment, good clinical efficacy was also observed.
CONCLUSION: ISMAD may be managed successfully in a variety of ways based on the clinical symptoms. ISMAD should be treated by conservative management as the first-line option, however, in those with bowel necrosis or imminent arterial rupture during conservative therapy, endovascular or surgical therapy is indicated.
PMCID: PMC4258589  PMID: 25493033
Intestine; Superior mesenteric artery; Dissection; Therapy; Endovascular reconstruction
10.  Efficacy and prognostic analysis of chemoradiotherapy in patients with thoracic esophageal squamous carcinoma with cervical lymph nodal metastasis alone 
The prognostic factors of thoracic esophageal squamous carcinoma with cervical lymph nodal metastasis (CLNM) have not been specifically investigated. This study was performed to analyze the efficacy and prognostic factors of chemoradiotherapy for thoracic esophageal carcinoma with CLNM alone.
From 2002 to 2011, 139 patients with inoperable esophageal cancer who underwent chemoradiotherapy at the Sun Yat-Sen University were retrospectively analyzed. Median radiation doses were 60 Gy (range: 50–68 Gy). Univariate and multivariate analyses were performed to compare overall survival (OS) and progression-free survival (PFS).
The 1- and 3-year OS rates were 68.2% and 27.9%, respectively. The 1- and 3-year PFS rates were 51.9% and 20.1%, respectively. The multivariate analysis demonstrated that response to treatment, T stage, pathological grade, and laterality of cervical lymph nodal metastases were independent prognostic factors for thoracic esophageal carcinoma with CLNM.
Concurrent chemoradiotherapy is an important and hopeful treatment option for patients with esophageal cancer with CLNM alone. Our study has revealed that response to treatment, T stage, pathological grade and laterality of cervical lymph nodal metastases are significant prognostic factors for long-term survival.
PMCID: PMC4251839  PMID: 25424871
Chemoradiotherapy; Esophageal cancer; Prognosis; Cervical lymph nodal metastasis
11.  MicroRNA-383 Regulates the Apoptosis of Tumor Cells through Targeting Gadd45g 
PLoS ONE  2014;9(11):e110472.
MicroRNAs (miRNAs) are a class of small non-coding single-stranded RNA molecules that inhibit gene expression at post-transcriptional level. Gadd45g (growth arrest and DNA-damage-inducible 45 gamma) is a stress-response protein, which has been implicated in several biological processes, including DNA repair, the cell cycle and cell differentiation.
In this work, we found that miR-383 is a negative regulator of Gadd45g. Forced expression of miR-383 decreased the expression of Gadd45g through binding to the 3′ untranslated region (3′-UTR), whereas inhibition of miR-383 increased Gadd45g expression. The presence of miR-383 increased the cellular sensitivity to DNA damage in breast cancer cells, which was rescued by ectopic expression of Gadd45g without the 3′-UTR. miR-383 also regulates the expression of Gadd45g in embryonic stem (ES) cells, but not their apoptosis under genotoxic stress. miR-383 was further showed to negatively regulate ES cell differentiation via targeting Gadd45g, which subsequently modulates the pluripotency-associated genes. Taken together, our study demonstrates that miR-383 is a negative regulator of Gadd45g in both tumor cells and ES cells, however, has distinct function in regulating cell apoptosis. miR-383 may be used as antineoplastic agents in cancer chemotherapy.
We demonstrate for the first time that miR-383 can specifically regulates the expression of Gadd45g by directly targeting to the 3-UTR region of Gadd45g mRNA, a regulatory process conserved in human tumor cells and mouse embryonic stem cells. These two compotents can be potentially used as antineoplastic agents in cancer chemotherapy.
PMCID: PMC4240536  PMID: 25415264
12.  Time course change of COX2-PGI2/TXA2 following global cerebral ischemia reperfusion injury in rat hippocampus 
Neuroinflammation plays pivotal roles in the progression of cerebral ischemia injury. Prostaglandins (PGs) as the major inflammatory mediators in the brain participate in the pathophysiological processes of cerebral ischemia injury. Cyclooxygenase-2 (COX2) is the rate-limiting enzyme of PGs, and thus it is necessary to characterize of the expression patterns of COX2 and its downstream products at the same time in a cerebral ischemia/reperfusion (I/R) model.
The levels of prostacyclin (PGI2) and thromboxane (TXA2) and the expression of COX2 were detected in the rat hippocampus at different time points after reperfusion (30 min, 2 h, 6 h, 24 h, 48 h, 7 d, and 15 d).
The COX2 mRNA and protein expressions in hippocampus both remarkably increased at 30 min, and peaked at 7 d after global cerebral I/R compared with the sham-operated group. The level of PGI2 significantly increased at 2 h after reperfusion, with a peak at 48 h, but was still significantly higher than the sham-operated animals at 15 d. TXA2 level decreased at 30 min and 2 h after reperfusion, but significantly increased at 6 h and peaked at 48 h. PGI2/TXA2 ratio increased at 30 min after reperfusion, and peaked at 48 h compared with the sham-operated animals.
I/R injury significantly increased the COX2 expression, PGI2 and TXA2 levels, and the PGI2/TXA2 ratio in rat hippocampus in a time-dependent manner. As a consequence, the increased PGI2 level and PGI2/TXA2 ratio may represent a physiological mechanism to protect the brain against the neuronal damage produced by I/R injury.
PMCID: PMC4240876  PMID: 25388440
Global cerebral ischemia reperfusion; PGI2; TXA2; COX2; PGI2/TXA2; Neuroinflammation
13.  Insulin-like growth factor-I induces epithelial to mesenchymal transition via GSK-3β and ZEB2 in the BGC-823 gastric cancer cell line 
Oncology Letters  2014;9(1):143-148.
Metastasis is the most common cause of mortality in patients with gastric cancer. Epithelial-to-mesenchymal transition (EMT), which may be stimulated by insulin-like growth factor-I (IGF-I) is involved in the metastasis of numerous tumors; however, the molecular mechanism by which IGF-I may induce tumor cell EMT remains to be elucidated in gastric cancer. The present study aimed to investigate the induction of EMT in BGC-823 gastric cancer cells. It was identified that IGF-I induced EMT by upregulating the levels of ZEB2 transcription factor, and this was dependent on the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in these cells. In addition, glycogen synthase kinase 3β (GSK-3β), an intracellular downstream effector of PI3K/Akt, sustained the epithelial phenotype by repressing ZEB2 expression and the subsequent inhibition of EMT induced by IGF-I, suggesting the involvement of a potential PI3K/Akt-GSK-3β-ZEB2 signaling pathway in IGF-I-induced EMT in gastric cancer BGC-823 cells. Overall, the results of the present study suggest that IGF-I induced EMT by the activation of a PI3K/Akt-GSK-3β-ZEB2 signaling pathway in gastric cancer BGC-823 cells. Therefore, this study may provide more useful information regarding the mechanism of gastric cancer metastasis.
PMCID: PMC4246767  PMID: 25435948
epithelial-to-mesenchymal transition; insulin-like growth factor-I; insulin-like growth factor-I receptor; ZEB2; GSK-3β
14.  Effects of miR-33a-5P on ABCA1/G1-Mediated Cholesterol Efflux under Inflammatory Stress in THP-1 Macrophages 
PLoS ONE  2014;9(10):e109722.
The present study is to investigate whether inflammatory cytokines inhibit ABCA1/ABCG1-mediated cholesterol efflux by regulating miR-33a-5P in THP-1 macrophages. We used interleukin-6 and tumor necrosis factor-alpha in the presence or absence of native low density lipoprotein (LDL) to stimulate THP-1 macrophages. THP-1 macrophages were infected by either control lentivirus vectors or lentivirus encoding miR-33a-5P or antisense miR-33a-5P. The effects of inflammatory cytokines, miR-33a-5P and antisense miR-33a-5P on intracellular lipids accumulation and intracellular cholesterol contents were assessed by oil red O staining and quantitative intracellular cholesterol assay. ApoA-I-mediated cholesterol efflux was examined using the fluorescent sterol (BODIPY-cholesterol). The gene and protein expressions of the molecules involved in cholesterol trafficking were examined using quantitative real-time polymerase chain reaction and Western blotting. Inflammatory cytokines or miR-33a-5P increased intracellular lipid accumulation and decreased apoA-I-mediated cholesterol efflux via decreasing the expression of ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. However, antisense miR-33a-5P reversed the effects of inflammatory cytokines on intracellular lipid accumulation, cholesterol efflux, and the expression of miR-33a-5P, ABCA1 and ABCG1 in the absence or presence of LDL in THP-1 macrophages. This study indicated that inflammatory cytokines inhibited ABCA1/ABCG1-mediated cholesterol efflux by up-regulating miR-33a-5P in THP-1 macrophages.
PMCID: PMC4201478  PMID: 25329888
15.  A Feasibility Study of an Intravascular Imaging Antenna to Image Atherosclerotic Plaques in Swine Using 3.0 T MRI 
PLoS ONE  2014;9(9):e108301.
To investigate the feasibility of an intravascular imaging antenna to image abdominal aorta atherosclerotic plaque in swine using 3.0T magnetic resonance imaging (MRI).
Atherosclerotic model was established in 6 swine. After 8 months, swine underwent an MR examination, which was performed using an intravascular imaging guide-wire, and images of the common iliac artery and the abdominal aorta were acquired. Intravascular ultrasound (IVUS) was performed in the right femoral artery; images at the same position as for the MR examination were obtained. The luminal border and external elastic membrane of the targeted arteries were individually drawn in the MR and IVUS images. After co-registering these images, the vessel, lumen, and vessel wall areas and the plaque burden in the same lesions imaged using different modalities were calculated and compared. The diagnostic accuracy of intravascular MR examination in delineating the vessel wall and detecting plaques were analyzed and compared using IVUS.
Compared with IVUS, good agreement was found between MRI and IVUS for delineating vessel, lumen, and vessel wall areas and plaque burden (r value: 0.98, 0.95, 0.96 and 0.91, respectively; P<0.001).
Compared with IVUS, using an intravascular imaging guide-wire to image deep seated arteries allowed determination of the vessel, lumen and vessel wall areas and plaque size and burden. This may provide an alternative method for detecting atherosclerotic plaques in the future.
PMCID: PMC4178132  PMID: 25259585
16.  Reduced expression of p21-activated protein kinase 1 correlates with poor histological differentiation in pancreatic cancer 
BMC Cancer  2014;14(1):650.
P21-activated protein kinase 1 (PAK1), a main downstream effector of small Rho GTPases, is overexpressed in many malignancies. PAK1 overexpression is associated with poor prognosis in some tumor types, including breast cancer, gastric cancer, and colorectal cancer. However, the expression and clinical relevance of PAK1 expression in human pancreatic cancer remains unknown.
The present study investigated the clinical and prognostic significance of PAK1 expression in pancreatic carcinoma. We examined and scored the expression of PAK1 by immunohistochemistry in 72 primary pancreatic carcinoma samples and 20 liver metastatic samples. The relationships between PAK1 and clinicopathological parameters and prognosis in primary and metastatic pancreatic cancer were analyzed.
Among the total 92 cases, primary pancreatic cancer samples had a significantly higher rate (38/72, 52.8%) of high PAK1 expression than liver metastatic samples (5/20, 25.0%) (P = 0.028). Among the 72 primary pancreatic cancer patients, high PAK1 expression was associated with younger age (P = 0.038) and moderately or well differentiated tumor (P = 0.007). Moreover, a positive relationship was found between high PAK1 expression and overall survival (OS) (P < 0.005). Patients with high PAK1 expression had a better OS than those with low PAK1 expression. Univariate and multivariate analysis by Cox regression including PAK1 and other prognostic pathological markers demonstrated high PAK1 immunostaining as a prognostic factor for survival in pancreatic cancer patients (P < 0.005).
We report for the first time that PAK1 is a novel prognostic marker for pathologically confirmed human pancreatic cancer. Reduced expression of PAK1 correlates with poor histological differentiation in pancreatic cancer.
PMCID: PMC4242600  PMID: 25182632
P21-activated protein kinase 1 (PAK1); Pancreatic cancer; Immunohistochemistry; Prognosis
17.  Is There a Benefit in Receiving Concurrent Chemoradiotherapy for Elderly Patients with Inoperable Thoracic Esophageal Squamous Cell Carcinoma? 
PLoS ONE  2014;9(8):e105270.
Background and purpose
The benefit of concurrent chemoradiotherapy (CCRT) in elderly patients with inoperable esophageal squamous cell carcinoma (SCC) is controversial. This study aimed to assess the efficiency and safety of CCRT in elderly thoracic esophageal cancer patients.
Methods and materials
Between January 2002 and December 2011, 128 patients aged 65 years or older treated with CCRT or radiotherapy (RT) alone for inoperable thoracic esophageal SCC were analyzed retrospectively (RT alone, n = 55; CCRT, n = 73).
No treatment-related deaths occurred and no patients experienced any acute grade 4 non-hematologic toxicities. Patients treated with CCRT developed more severe acute toxicities than patients who received RT alone. The 3-year overall survival (OS) rate was 36.1% for CCRT compared with 28.5% following RT alone (p = 0.008). Multivariate analysis identified T stage and treatment modality as independent prognostic factors for survival. Further analysis revealed that survival was significantly better in the CCRT group than in the RT alone group for patients ≤ 72 years. Nevertheless, the CCRT group had a similar OS to the RT group for patients > 72 years.
Our results suggest that elderly patients with inoperable thoracic esophageal SCC could benefit from CCRT, without major toxicities. However, for patients older than 72 years, CCRT is not superior to RT alone in terms of survival benefit.
PMCID: PMC4136816  PMID: 25133495
18.  Demonstrating the feasibility of large-scale development of standardized assays to quantify human proteins 
Nature methods  2013;11(2):149-155.
The successful application of MRM in biological specimens raises the exciting possibility that assays can be configured to measure all human proteins, resulting in an assay resource that would promote advances in biomedical research. We report the results of a pilot study designed to test the feasibility of a large-scale, international effort in MRM assay generation. We have configured, validated across three laboratories, and made publicly available as a resource to the community 645 novel MRM assays representing 319 proteins expressed in human breast cancer. Assays were multiplexed in groups of >150 peptides and deployed to quantify endogenous analyte in a panel of breast cancer-related cell lines. Median assay precision was 5.4%, with high inter-laboratory correlation (R2 >0.96). Peptide measurements in breast cancer cell lines were able to discriminate amongst molecular subtypes and identify genome-driven changes in the cancer proteome. These results establish the feasibility of a scaled, international effort.
PMCID: PMC3922286  PMID: 24317253
19.  Inflammatory Stress Increases Hepatic CD36 Translational Efficiency via Activation of the mTOR Signalling Pathway 
PLoS ONE  2014;9(7):e103071.
Inflammatory stress is an independent risk factor for the development of non-alcoholic fatty liver disease (NAFLD). Although CD36 is known to facilitate long-chain fatty acid uptake and contributes to NAFLD progression, the mechanisms that link inflammatory stress to hepatic CD36 expression and steatosis remain unclear. As the mammalian target of rapamycin (mTOR) signalling pathway is involved in CD36 translational activation, this study was undertaken to investigate whether inflammatory stress enhances hepatic CD36 expression via mTOR signalling pathway and the underlying mechanisms. To induce inflammatory stress, we used tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) stimulation of the human hepatoblastoma HepG2 cells in vitro and casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress increased hepatic CD36 protein levels but had no effect on mRNA expression. A protein degradation assay revealed that CD36 protein stability was not different between HepG2 cells treated with or without TNF-α or IL-6. A polysomal analysis indicated that CD36 translational efficiency was significantly increased by inflammatory stress. Additionally, inflammatory stress enhanced the phosphorylation of mTOR and its downstream translational regulators including p70S6K, 4E-BP1 and eIF4E. Rapamycin, an mTOR-specific inhibitor, reduced the phosphorylation of mTOR signalling pathway and decreased the CD36 translational efficiency and protein level even under inflammatory stress resulting in the alleviation of inflammatory stress-induced hepatic lipid accumulation. This study demonstrates that the activation of the mTOR signalling pathway increases hepatic CD36 translational efficiency, resulting in increased CD36 protein expression under inflammatory stress.
PMCID: PMC4105654  PMID: 25048611
20.  Low expression of RSK4 predicts poor prognosis in patients with colorectal cancer 
Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related death all over the world. Ribosomal s6 kinase4 (RSK4), an X-linked gene, firstly was found as to be a potential tumor suppressive gene in a variety of cancers and is widely participated in signaling pathway. However its role in CRC is unclear. This study is to explore the correlation between the protein expression of RSK4 and clinical pathologic characteristics in colorectal tumors, which might serve as a prognostic determinant of colorectal cancers. Methods: Biopsies of 103 colorectal cancer and 46 matched adjacent noncancerous tissues were collected for analysis of RSK4 protein by immunohistochemistry. The correlation between RSK4 protein expression and the clinical pathological features of colorectal cancers were evaluated by Chi-square test and Fisher’s exact test. The survival rates were analyzed by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was analyzed by the Cox proportional hazard models. Results: RSK4 was conversely correlated with some pathological classifications (P<0.05 for N, G and clinical staging), and there were no statistically significant differences in age, CEA expression in blood, CA199 and tumors t-staging (x2 test, P>0.05 for all categories) respectively. Furthermore, patients with high protein level of RSK4 showed prolonged overall survivals (P<0.05). Moreover, multivariate analysis showed that low expression level of RSK is an independent risk factor for high mortality in colorectal cancer. Conclusions: Low RSK4 expression is correlated with advanced clinical pathologic classifications and is a poor overall survival in colorectal cancer patients. These findings suggest that RSK4 may serve as a useful marker in prognostic evaluation for patients with colorectal cancer.
PMCID: PMC4152057  PMID: 25197367
Colorectal cancer; RSK4; immunohistochemistry; survival analysis
21.  Absolute Quantitation of Met Using Mass Spectrometry for Clinical Application: Assay Precision, Stability, and Correlation with MET Gene Amplification in FFPE Tumor Tissue 
PLoS ONE  2014;9(7):e100586.
Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for ‘high Met’ expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue.
After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH).
Proteomic mapping of recombinant Met identified 418TEFTTALQR426 as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/µg tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (<150 amol/µg to 4669.5 amol/µg. High correlation was observed between SRM Met expression and both MET GCN and MET/CEP7 ratio as determined by FISH (n = 30; R2 = 0.898). IHC did not correlate well with SRM (n = 44; R2 = 0.537) nor FISH GCN (n = 31; R2 = 0.509). A Met SRM level of ≥1500 amol/µg was 100% sensitive (95% CI 0.69–1) and 100% specific (95% CI 0.92–1) for MET amplification.
The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET tumors. These results demonstrate a novel clinical tool for efficient tumor expression profiling, potentially leading to better informed therapeutic decisions for patients with GEC.
PMCID: PMC4077664  PMID: 24983965
22.  Circulating Muscle-specific miRNAs in Duchenne Muscular Dystrophy Patients 
Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for Duchenne muscular dystrophy (DMD) patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the serum levels of six muscle-specific miRNAs (miR-1/206/133/499/208a/208b, also known as myomiRs) were all elevated in DMD patients (P < 0.01). The receiver operating characteristic curves of circulating miR-206, miR-499, miR-208b, and miR-133 levels reflected strong separation between Becker's muscular dystrophy (BMD) and DMD patients (P < 0.05). miR-206, miR-499, and miR-208b levels were positively correlated with both age and type IIc muscle fiber content in DMD patients (2–6 years), indicating that they might represent the stage of disease as well as the process of regeneration. miR-499 and miR-208b levels were correlated with slow and fast fiber content and might reflect the ratio of slow to fast fibers in DMD patient (>6 years). Fibroblast growth factor, transforming growth factor-β, and tumor necrosis factor-α could affect the secretion of myomiRs, suggesting that circulating myomiRs might reflect the effects of cytokines and growth factors on degenerating and regenerating muscles. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for DMD diagnosis and disease progression.
PMCID: PMC4121518  PMID: 25050825
biomarkers; Duchenne muscular dystrophy; secretion; serum miRNAs
23.  Morphology and Quantitative Monitoring of Gene Expression Patterns during Floral Induction and Early Flower Development in Dendrocalamus latiflorus 
The mechanism of floral transition in bamboo remains unclear. Dendrocalamus latiflorus (Bambusease, Bambusoideae, Poaceae) is an economically and ecologically important clumping bamboo in tropical and subtropical areas. We evaluated morphological characteristics and gene expression profiling to study floral induction and early flower development in D. latiflorus. The detailed morphological studies on vegetative buds and floral organography were completed using paraffin sectioning and scanning electron microscopy. The 3 mm floral buds commence the development of stamen primordia and pistil primordium. Furthermore, homologs of floral transition-related genes, including AP1, TFL1, RFL, PpMADS1, PpMADS2, SPL9, FT, ID1, FCA, and EMF2, were detected and quantified by reverse transcriptase PCR and real-time PCR in vegetative and floral buds, respectively. Distinct expression profiles of ten putative floral initiation homologues that corresponded to the developmental stages defined by bud length were obtained and genes were characterized. Six of the genes (including DlTFL1, DlRFL, DlMADS2, DlID1, DlFCA, DlEMF2) showed statistically significant changes in expression during floral transition. DlAP1 demonstrated a sustained downward trend and could serve as a good molecular marker during floral transition in D. latiflorus. The combined analysis provided key candidate markers to track the transition from the vegetative to reproductive phase.
PMCID: PMC4139830  PMID: 25003644
Dendrocalamus latiflorus; floral induction; early floral development; morphological characteristics; gene expression profiling; molecular marker
24.  Unilateral Cervical Nodal Metastasis Is an Independent Prognostic Factor for Esophageal Squamous Cell Carcinoma Patients Undergoing Chemoradiotherapy: A Retrospective Study 
PLoS ONE  2014;9(6):e101332.
To determine the prognostic significance of unilateral cervical lymph nodal metastasis (CLNM) in patients with inoperable thoracic esophageal squamous cell carcinoma (SCC) and to identify significant prognostic factors in these patients.
Patients and methods
This retrospective study involved 395 patients with inoperable esophageal SCC treated with concurrent chemoradiotherapy. The patients were classified into three groups according to their cervical lymph node status: group A, no evidence of CLNM; group B, unilateral CLNM; group C, other distant metastases. Overall survival (OS) and progression-free survival (PFS) were calculated. Significant prognostic factors were identified using univariate and multivariate analyses.
The 3-year OS rates in groups A, B and C were 46.7%, 33.5% and 8.3%, respectively (p<0.001, log-rank test). The corresponding PFS rates were 40.7%, 26.4% and 4.7% (p<0.001, log-rank test). Group B had a similar prognosis to that of group A and better 3-year OS (p = 0.009) and PFS (p = 0.006) rates than those of group C. Multivariate analysis demonstrated that T stage, chemotherapy regimen and cervical lymph node involvement were independent prognostic factors affecting OS and PFS.
Compared to other distant metastases, unilateral CLNM is associated with longer OS in esophageal SCC and should be regarded as a regional disease. Sex, T stage, concurrent chemotherapy modality and cervical lymph node involvement are independent predictors of survival in esophageal SCC.
PMCID: PMC4076311  PMID: 24979040
25.  Intraspinal leiomyoma: A case report and literature review 
Oncology Letters  2014;8(3):1380-1384.
Leiomyomas are benign tumors which are predominantly found in the genitourinary and gastrointestinal tracts. Leiomyomas in the spine are extremely rare. The current study presents a case of a 35-year-old female with intraspinal leiomyoma who presented with low back pain and weakness in the left leg of two months. Computerized tomography and magnetic resonance imaging revealed an epidural mass at the T11–12 levels. The patient underwent a T11–12 laminectomy through posterior approach, achieving total removal of the tumor with a well-demarcated dissection plane. Pathological examination demonstrated a leiomyoma. Postoperatively, the patient showed a significant improvement in neurological function. Although intraspinal leiomyoma is extremely rare, it should be considered in the differential diagnosis of spinal lesions in females. The diagnosis is predominantly dependent on a pathological examination. Gross total resection is recommended for its treatment, however the prognosis remains poor. Post-operative hormonal therapy may be useful in controlling tumor recurrence.
PMCID: PMC4114636  PMID: 25120728
leiomyoma; spinal

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