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1.  Diabetes Promotes DMH-Induced Colorectal Cancer by Increasing the Activity of Glycolytic Enzymes in Rats 
PLoS ONE  2014;9(10):e110455.
The objective of the present study was to investigate the association between diabetes mellitus and colorectal carcinogenesis as well as the possible mechanism involved in this interaction. Diabetes rat models were induced with a low dose of STZ followed by a low dose of DMH to induce colorectal cancer. The formation of ACF in the colon and the incidence, number and size of tumors were measured. The activity of glycolytic enzymes in colonic tissues was also measured. The results demonstrated that both the total number of ACF and the number of foci that contain a different number of crypts were increased in diabetic rats. At the end of the experimental treatment, the incidence, number and size of tumors were also increased in diabetic rats. Overall, these data indicated that diabetes increased the risk of colorectal cancer. The activity of HK and PK in colonic tissues was increased in diabetic rats, whereas the activity of PDH was decreased. In addition, the activities of these enzymes in intratumor were higher than that of in peritumor. These data indicated that the high rate of glycolysis may play a role in colorectal carcinogenesis in diabetic rats.
PMCID: PMC4201553  PMID: 25329503
2.  Breast Cancer with Neoductgenesis: Histopathological Criteria and Its Correlation with Mammographic and Tumour Features 
Introduction. Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis. We developed histopathological criteria for neoductgenesis in order to study reproducibility and correlation with other tumour markers. Methods. 74 cases of grades 2 and 3 DCIS, with or without an invasive component, were selected. A combined score of the degree(s) of concentration of ducts, lymphocyte infiltration, and periductal fibrosis was used to classify cases as showing neoductgenesis, or not. Diagnostic reproducibility, correlation with tumour markers, and mammographic features were studied. Results. Twenty-three of 74 cases were diagnosed with neoductgenesis. The kappa value between pathologists showed moderate reproducibility (0.50) (95% CI; 0.41–0.60). Neoductgenesis correlated significantly with malignant type microcalcifications and TN-C expression (P = 0.008 and 0.04) and with ER, PR, and HER2 status (P < 0.00001 for all three markers). Conclusions. We developed histological criteria for breast cancer with neoductgenesis. Neoductgenesis, by our applied histopathological definition was related to more aggressive tumour biology and malignant mammographic calcifications.
PMCID: PMC4220584  PMID: 25400950
3.  Fast presurgical functional mapping using task-related intracranial high gamma activity 
Journal of neurosurgery  2013;119(1):26-36.
Electrocorticography (ECoG) is a powerful tool for presurgical functional mapping. Power increase in the high gamma band has been observed from ECoG electrodes on the surface of the sensory motor cortex during the execution of body movements. In this study the authors aim to validate the clinical usage of high gamma activity in presurgical mapping by comparing ECoG mapping with traditional direct electrical cortical stimulation (ECS) and functional MRI (fMRI) mapping.
Seventeen patients with epilepsy participated in an ECoG motor mapping experiment. The patients executed a 5-minute hand/tongue movement task while the ECoG signal was recorded. All 17 patients also underwent extraoperative ECS mapping to localize the motor cortex. Eight patients also participated in a presurgical fMRI study. The high gamma activity on ECoG was modeled using the general linear model (GLM), and the regions showing significant gamma power increase during the task condition compared with the rest condition were localized. The maps derived from GLM-based ECoG mapping, ECS, and fMRI were then compared.
High gamma activity in the motor cortex can be reliably modulated by motor tasks. Localization of the motor regions achieved with GLM-based ECoG mapping was consistent with the localization determined by ECS. The maps also appeared to be highly localized compared with the fMRI activations. Using the ECS findings as the reference, GLM-based ECoG mapping showed a significantly higher sensitivity than fMRI (66.7% for ECoG, 52.6% for fMRI, p < 0.05), while the specificity was high for both techniques (> 97%). If the current-spreading effect in ECS is accounted for, ECoG mapping may produce maps almost identical to those produced by ECS mapping (100% sensitivity and 99.5% specificity).
General linear model–based ECoG mapping showed a superior performance compared to traditional ECS and fMRI mapping in terms of efficiency and accuracy. Using this method, motor functions can be reliably mapped in less than 5 minutes.
PMCID: PMC3746067  PMID: 23600935
epilepsy surgery; functional mapping; high gamma activity; motor cortex
4.  BIIB021, an Hsp90 inhibitor, effectively kills a myelodysplastic syndrome cell line via the activation of caspases and inhibition of PI3K/Akt and NF-κB pathway proteins 
The novel orally available inhibitor of the molecular chaperone heat shock protein 90 (Hsp90), BIIB021, induces the apoptosis of various types of tumor cell in vitro and in vivo. However, the effects and mechanisms of this agent on myelodysplastic syndrome (MDS) cell lines remain unknown. The aim of this study was to investigate the effects of BIIB021 on SKM-1 cells (a MDS cell line) and examine its mechanisms of action. The results showed that BIIB021 inhibited the growth of SKM-1 cells effectively in vitro. The treatment of SKM-1 cells with BIIB021 resulted in the inhibition of cell growth through G0/G1-phase cell cycle arrest and induced apoptosis by activating caspase-3, -8 and -9. Furthermore, this study also demonstrated that the mechanisms of apoptosis in SKM-1 cells were associated with the suppression of the phosphatidylinositide 3-kinase/Akt and nuclear factor-κB signaling pathways. Therefore, the findings indicate a novel approach for the treatment of high-risk MDS.
PMCID: PMC4043628  PMID: 24926340
BIIB021; myelodysplastic syndrome cell line; caspases; PI3K/Akt; NF-κB pathway proteins
5.  A Comparison of Tumor Biology in Primary Ductal Carcinoma In Situ Recurring as Invasive Carcinoma versus a New In Situ 
Introduction. About half of all new ipsilateral events after a primary ductal carcinoma in situ (DCIS) are invasive carcinoma. We studied tumor markers in the primary DCIS in relation to type of event (invasive versus in situ). Methods. Two hundred and sixty-six women with a primary DCIS from two source populations, all with a known ipsilateral event, were included. All new events were regarded as recurrences. Patient and primary tumor characteristics (estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, and Ki67) were evaluated. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses. Results. One hundred and thirty-six of the recurrences were invasive carcinoma and 130 were in situ. The recurrence was more often invasive if the primary DCIS was ER+ (OR 2.5, 95% CI 1.2–5.1). Primary DCIS being HER2+ (OR 0.5, 95% CI 0.3–0.9), EGFR+ (OR 0.4, 95% CI 0.2–0.9), and ER95−/HER2+ (OR 0.2, 95% CI 0.1–0.6) had a lower risk of a recurrence being invasive. Conclusions. In this study, comparing type of recurrence after a DCIS showed that the ER−/HER2+ tumors were related to a recurrence being a new DCIS. And surprisingly, tumors being ER+, HER2−, and EGFR− were related to a recurrence being invasive cancer.
PMCID: PMC3893751  PMID: 24490077
6.  Molecular subtypes in ductal carcinoma in situ of the breast and their relation to prognosis: a population-based cohort study 
BMC Cancer  2013;13:512.
Different molecular subtypes of breast cancer have been identified based on gene expression profiling. Treatment suggestions based on an approximation of these subtypes by immunohistochemical criteria have been published by the St Gallen international expert consensus panel. Ductal carcinoma in situ (DCIS) can be classified into the same molecular subtypes. Our aim was to study the relation between these newly defined subtypes and prognosis in DCIS.
TMA including 458 women from a population-based cohort with DCIS diagnosed 1986–2004 was used. Stainings for ER, PR, HER2 and Ki67 were used to classify the surrogate molecular subtypes according to the St Gallen criteria from 2011. The associations with prognosis were examined using Kaplan-Meier analyses and Cox proportional hazards regression models.
Surrogate molecular subtyping could be done in 381 cases. Mean follow up was 164 months. Of the classified DCIS 186 were Luminal A (48.8%), 33 Luminal B/HER2- (8.7%), 74 Luminal B/HER2+ (17.4%), 61 HER2+/ER- (16.0%) and 27 Triple Negative (7.1%). One hundred and two women had a local recurrence of which 58 were invasive. Twenty-two women had generalised disease, 8 without a prior local recurrence. We could not find a prognostic significance of the molecular subtypes other than a higher risk of developing breast cancer after more than 10 years of follow-up among women with a Triple Negative DCIS (OR 3.2; 95% CI 1.1-9.8).
The results from this large population-based cohort, with long-term follow up failed to demonstrate a prognostic value for the surrogate molecular subtyping of DCIS using the St Gallen criteria up to ten years after diagnosis. More than ten years after diagnosis Triple Negative DCIS had an elevated risk of recurrence.
PMCID: PMC4228470  PMID: 24171825
7.  Molecular characterization of rifampicin-resistant Staphylococcus aureus isolates in a Chinese teaching hospital from Anhui, China 
BMC Microbiology  2012;12:240.
Staphylococcus aureus (S. aureus) is a major nosocomial pathogen that causes a variety of infections and toxicoses. In recent years, the percentage of rifampicin-resistant S. aureus has increased rapidly in China. The aims of this study were to analyze 1) the level of rifampicin resistance in S. aureus and its correlation with mutations in the rpoB gene, and 2) the molecular characterization of rifampicin-resistant S. aureus isolates.
88 rifampicin-resistant S. aureus isolates were collected for this study. Of the 88 isolates, 83 (94.3%) were high-level rifampicin resistant (MIC≥8 mg/L) while the remaining 5 isolates (5.7%) had a low-level resistance to rifampicin (MIC, 2 to 4 mg/L). Four amino acid substitutions were found in the 88 isolates, which were 481His/Asn (95.5%), 466Leu/Ser (87.5%), 477Ala/Asp (6.8%) and 486Ser/Leu (4.5%) respectively. All mutations were found to be present in cluster I of the rpoB gene. The low-level resistant isolates were found to have only one mutation, while the high-level resistant isolates had at least two or more mutations. The most common multiple mutations were 481His/Asn+466Leu/Ser(92.8%,77/83). The other multiple mutations found were 481His/Asn+477Ala/Asp (6.0%,5/83), and 481His/Asn+466Leu/Ser+477Ala/Asp (1.2%,1/83). Out of 28 high-level rifampicin-resistant S. aureus isolates, three molecular types were found, namely, ST239-MRSA-III-spa t030 (25/28, 89.3%), ST239-MRSA-III-spa t021 (2/28, 7.1%), and ST239-MRSA-III-spa t045 (1/28, 3.6%).
Rifampicin resistance in S. aureus was closely associated with mutations in the rpoB gene. High-level rifampicin-resistant S. aureus is one of the most important features in Anhui Provincial Hospital, and high-level rifampicin resistance in S. aureus is associated with multiple mutations of rpoB gene. The prevalence of high-level rifampicin-resistant S. aureus in Anhui may be associated with the spread of the ST239-MRSA III-spa t030 clone.
PMCID: PMC3485161  PMID: 23082766
Staphylococcus aureus; MRSA; Rifampicin resistance; rpoB gene; MLST
8.  Sequential Neural Processes in Abacus Mental Addition: An EEG and fMRI Case Study 
PLoS ONE  2012;7(5):e36410.
Abacus experts are able to mentally calculate multi-digit numbers rapidly. Some behavioral and neuroimaging studies have suggested a visuospatial and visuomotor strategy during abacus mental calculation. However, no study up to now has attempted to dissociate temporally the visuospatial neural process from the visuomotor neural process during abacus mental calculation. In the present study, an abacus expert performed the mental addition tasks (8-digit and 4-digit addends presented in visual or auditory modes) swiftly and accurately. The 100% correct rates in this expert’s task performance were significantly higher than those of ordinary subjects performing 1-digit and 2-digit addition tasks. ERPs, EEG source localizations, and fMRI results taken together suggested visuospatial and visuomotor processes were sequentially arranged during the abacus mental addition with visual addends and could be dissociated from each other temporally. The visuospatial transformation of the numbers, in which the superior parietal lobule was most likely involved, might occur first (around 380 ms) after the onset of the stimuli. The visuomotor processing, in which the superior/middle frontal gyri were most likely involved, might occur later (around 440 ms). Meanwhile, fMRI results suggested that neural networks involved in the abacus mental addition with auditory stimuli were similar to those in the visual abacus mental addition. The most prominently activated brain areas in both conditions included the bilateral superior parietal lobules (BA 7) and bilateral middle frontal gyri (BA 6). These results suggest a supra-modal brain network in abacus mental addition, which may develop from normal mental calculation networks.
PMCID: PMC3344852  PMID: 22574155
9.  Effect of the Citrus Lycopene β-Cyclase Transgene on Carotenoid Metabolism in Transgenic Tomato Fruits 
PLoS ONE  2012;7(2):e32221.
Lycopene β-cyclase (LYCB) is the key enzyme for the synthesis of β-carotene, a valuable component of the human diet. In this study, tomato constitutively express Lycb-1 was engineered. The β-carotene level of transformant increased 4.1 fold, and the total carotenoid content increased by 30% in the fruits. In the transgenic line, the downstream α-branch metabolic fluxes were repressed during the three developmental stages while α-carotene content increased in the ripe stage. Microarray analysis in the ripe stage revealed that the constitutive expression of Lycb-1 affected a number of pathways including the synthesis of fatty acids, flavonoids and phenylpropanoids, the degradation of limonene and pinene, starch and sucrose metabolism and photosynthesis. This study provided insight into the regulatory effect of Lycb-1 gene on plant carotenoid metabolism and fruit transcriptome.
PMCID: PMC3286453  PMID: 22384184
10.  Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study 
BMC Cancer  2010;10:653.
Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort.
All 458 women with a primary DCIS diagnosed between 1986 and 2004, in Uppland and Västmanland, Sweden were included. TMA blocks were constructed. To classify the DCIS tumors, we used immunohistochemical (IHC) markers (estrogen-, progesterone-, HER2, cytokeratin 5/6 and epidermal growth factor receptor) as a surrogate for the gene expression profiling. The association with prognosis was examined for basal-like DCIS and other subtypes using Kaplan-Meier survival analyses and Cox proportional hazards regression models.
IHC data were complete for 392 women. Thirty-two were basal-like (8.2%), 351 were luminal or HER2-positive (89.5%) and 9 unclassified (2.3%). Seventy-six women had a local recurrence of which 34 were invasive. Another 3 women had general metastases as first event. Basal-like DCIS showed a higher risk of local recurrence and invasive recurrence 1.8 (Confidence interval (CI) 95%, 0.8-4.2) and 1.9 (0.7-5.1), respectively. However, the difference was not statistically significant. Also, no statistically significant increased risk was seen for triple-negative or high grade DCIS.
Basal-like DCIS showed about a doubled, however not statistically significant risk for local recurrence and developing invasive cancer compared with the other molecular subtypes. Molecular subtyping was a better prognostic parameter than histopathological grade.
PMCID: PMC3001723  PMID: 21118480
11.  The CTCF Insulator Protein Is Posttranslationally Modified by SUMO▿  
Molecular and Cellular Biology  2008;29(3):714-725.
The CTCF protein is a highly conserved zinc finger protein that is implicated in many aspects of gene regulation and nuclear organization. Its functions include the ability to act as a repressor of genes, including the c-myc oncogene. In this paper, we show that the CTCF protein can be posttranslationally modified by the small ubiquitin-like protein SUMO. CTCF is SUMOylated both in vivo and in vitro, and we identify two major sites of SUMOylation in the protein. The posttranslational modification of CTCF by the SUMO proteins does not affect its ability to bind to DNA in vitro. SUMOylation of CTCF contributes to the repressive function of CTCF on the c-myc P2 promoter. We also found that CTCF and the repressive Polycomb protein, Pc2, are colocalized to nuclear Polycomb bodies. The Pc2 protein may act as a SUMO E3 ligase for CTCF, strongly enhancing its modification by SUMO 2 and 3. These studies expand the repertoire of posttranslational modifications of CTCF and suggest roles for such modifications in its regulation of epigenetic states.
PMCID: PMC2630690  PMID: 19029252
12.  Transcriptome analysis of a spontaneous mutant in sweet orange [Citrus sinensis (L.) Osbeck] during fruit development 
Journal of Experimental Botany  2009;60(3):801-813.
Bud mutations often arise in citrus. The selection of mutants is one of the most important breeding channels in citrus. However, the molecular basis of bud mutation has rarely been studied. To identify differentially expressed genes in a spontaneous sweet orange [C. sinensis (L.) Osbeck] bud mutation which causes lycopene accumulation, low citric acid, and high sucrose in fruit, suppression subtractive hybridization and microarray analysis were performed to decipher this bud mutation during fruit development. After sequencing of the differentially expressed clones, a total of 267 non-redundant transcripts were obtained and 182 (68.2%) of them shared homology (E-value ≤1×10−10) with known gene products. Few genes were constitutively up- or down-regulated (fold change ≥2) in the bud mutation during fruit development. Self-organizing tree algorithm analysis results showed that 95.1% of the differentially expressed genes were extensively coordinated with the initiation of lycopene accumulation. Metabolic process, cellular process, establishment of localization, response to stimulus, and biological regulation-related transcripts were among the most regulated genes. These genes were involved in many biological processes such as organic acid metabolism, lipid metabolism, transport, and pyruvate metabolism, etc. Moreover, 13 genes which were differentially regulated at 170 d after flowering shared homology with previously described signal transduction or transcription factors. The information generated in this study provides new clues to aid in the understanding of bud mutation in citrus.
PMCID: PMC2652045  PMID: 19218315
Bud mutation; candidate genes; cDNA microarray; Citrus; real-time RT-PCR; suppression subtractive hybridization (SSH)
13.  Myosin VI Is a Mediator of the p53-Dependent Cell Survival Pathway 
Molecular and Cellular Biology  2006;26(6):2175-2186.
Myosin VI is an unconventional motor protein, and its mutation is responsible for the familiar conditions sensorineural deafness and hypertrophic cardiomyopathy. Myosin VI is found to play a key role in the protein trafficking and homeostasis of the Golgi complex. However, very little is known about how myosin VI is regulated and whether myosin VI has a function in the DNA damage response. Here, we found that myosin VI is regulated by DNA damage in a p53-dependent manner and possesses a novel function in the p53-dependent prosurvival pathway. Specifically, we show that myosin VI is induced by p53 and DNA damage in a p53-dependent manner. We found that p53 directly binds to, and activates, the promoter of the myosin VI gene. We also show that the intracellular localization of myosin VI is substantially altered by p53 and DNA damage in a p53-dependent manner such that the pool of myosin VI in endocytic vesicles, membrane ruffles, and cytosol migrates to the Golgi complex, perinuclear membrane, and nucleus. Furthermore, we show that knockdown of myosin VI attenuates activation of p53 and impairs Golgi complex integrity, which makes myosin VI-deficient cells susceptible to apoptosis upon DNA damage. Taken together, we found a novel function for p53 in the maintenance of Golgi complex integrity and for myosin VI in the p53-dependent prosurvival pathway.
PMCID: PMC1430268  PMID: 16507995

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