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1.  Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies 
Cell Death & Disease  2013;4(10):e828-.
Accumulating evidence indicates that cancer-initiating cells (CICs) are responsible for cancer initiation, relapse, and metastasis. Colorectal carcinoma (CRC) is typically classified into proximal colon, distal colon, and rectal cancer. The gradual changes in CRC molecular features within the bowel may have considerable implications in colon and rectal CICs. Unfortunately, limited information is available on CICs derived from rectal cancer, although colon CICs have been described. Here we identified rectal CICs (R-CICs) that possess differentiation potential in tumors derived from patients with rectal adenocarcinoma. The R-CICs carried both CD44 and CD54 surface markers, while R-CICs and their immediate progenies carried potential epithelial–mesenchymal transition characteristics. These R-CICs generated tumors similar to their tumor of origin when injected into immunodeficient mice, differentiated into rectal epithelial cells in vitro, and were capable of self-renewal both in vitro and in vivo. More importantly, subpopulations of R-CICs resisted both 5-fluorouracil/calcium folinate/oxaliplatin (FolFox) and cetuximab treatment, which are the most common therapeutic regimens used for patients with advanced or metastatic rectal cancer. Thus, the identification, expansion, and properties of R-CICs provide an ideal cellular model to further investigate tumor progression and determine therapeutic resistance in these patients.
doi:10.1038/cddis.2013.337
PMCID: PMC3824647  PMID: 24091671
rectal adenocarcinoma; cancer-initiating cells (CICs); chemoresistance; CD44; CD54
3.  ER stress-mediated apoptosis induced by celastrol in cancer cells and important role of glycogen synthase kinase-3β in the signal network 
Feng, L | Zhang, D | Fan, C | Ma, C | Yang, W | Meng, Y | Wu, W | Guan, S | Jiang, B | Yang, M | Liu, X | Guo, D
Cell Death & Disease  2013;4(7):e715-.
HeLa cells treated with celastrol, a natural compound with inhibitive effect on proteasome, exhibited increase in apoptotic rate and characteristics of apoptosis. To clarify the signal network activated by celastrol to induce apoptosis, both the direct target proteins and undirect target proteins of celastrol were searched in the present study. Proteasome catalytic subunit β1 was predicted by computational analysis to be a possible direct target of celastrol and confirmed by checking direct effect of celastrol on the activity of recombinant human proteasome subunit β1 in vitro. Undirect target-related proteins of celastrol were searched using proteomic studies including two-dimensional electrophoresis (2-DE) analysis and iTRAQ-based LC-MS analysis. Possible target-related proteins of celastrol such as endoplasmic reticulum protein 29 (ERP29) and mitochondrial import receptor Tom22 (TOM22) were found by 2-DE analysis of total cellular protein expression profiles. Further study showed that celastrol induced ER stress and ER stress inhibitor could ameliorate cell death induced by celastrol. Celastrol induced translocation of Bax into the mitochondria, which might be related to the upregulation of BH-3-only proteins such as BIM and the increase in the expression level of TOM22. To further search possible target-related proteins of celastrol in ER and ER-related fractions, iTRAQ-based LC-MS method was use to analyze protein expression profiles of ER/microsomal vesicles-riched fraction of cells with or without celastrol treatment. Based on possible target-related proteins found in both 2-DE analysis and iTRAQ-based LC-MS analysis, protein–protein interaction (PPI) network was established using bioinformatic analysis. The important role of glycogen synthase kinase-3β (GSK3β) in the signal cascades of celastrol was suggested. Pretreatment of LiCL, an inhibitor of GSK3β, could significantly ameliorate apoptosis induced by celastrol. On the basis of the results of the present study, possible signal network of celastrol activated by celastrol leading to apoptosis was predicted.
doi:10.1038/cddis.2013.222
PMCID: PMC3730400  PMID: 23846217
celastrol; apoptosis; endothelium reticulum; proteomics; bioinformatics
4.  Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species 
Cell Death & Disease  2013;4(6):e681-.
Lon protease is a multifunction protein and operates in protein quality control and stress response pathways in mitochondria. Human Lon is upregulated under oxidative and hypoxic stresses that represent the stress phenotypes of cancer. However, little literature undertakes comprehensive and detailed investigations on the tumorigenic role of Lon. Overexpression of Lon promotes cell proliferation, apoptotic resistance to stresses, and transformation. Furthermore, Lon overexpression induces the production of mitochondrial reactive oxygen species (ROS) that result from Lon-mediated upregulation of NDUFS8, a mitochondrial Fe-S protein in complex I of electron transport chain. Increased level of mitochondrial ROS promotes cell proliferation, cell survival, cell migration, and epithelial–mesenchymal transition through mitogen-activated protein kinase (MAPK) and Ras-ERK activation. Overall, the present report for the first time demonstrates the role of Lon overexpression in tumorigenesis. Lon overexpression gives an apoptotic resistance to stresses and induces mitochondrial ROS production through Complex I as signaling molecules to activate Ras and MAPK signaling, giving the survival advantages and adaptation to cancer cells. Finally, in silico and immunohistochemistry analysis showed that Lon is overexpressed specifically in various types of cancer tissue including oral cancer.
doi:10.1038/cddis.2013.204
PMCID: PMC3702277  PMID: 23788038
lon protease; cell survival; mitochondria; reactive oxygen species (ROS); tumorigenesis
5.  PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer 
It has recently been proposed that a three-gene model (SCMGENE) that measures ESR1, ERBB2, and AURKA identifies the major breast cancer intrinsic subtypes and provides robust discrimination for clinical use in a manner very similar to a 50-gene subtype predictor (PAM50). However, the clinical relevance of both predictors was not fully explored, which is needed given that a ~30 % discordance rate between these two predictors was observed. Using the same datasets and subtype calls provided by Haibe-Kains and colleagues, we compared the SCMGENE assignments and the research-based PAM50 assignments in terms of their ability to (1) predict patient outcome, (2) predict pathological complete response (pCR) after anthracycline/taxane-based chemotherapy, and (3) capture the main biological diversity displayed by all genes from a microarray. In terms of survival predictions, both assays provided independent prognostic information from each other and beyond the data provided by standard clinical–pathological variables; however, the amount of prognostic information was found to be significantly greater with the PAM50 assay than the SCMGENE assay. In terms of chemotherapy response, the PAM50 assay was the only assay to provide independent predictive information of pCR in multivariate models. Finally, compared to the SCMGENE predictor, the PAM50 assay explained a significantly greater amount of gene expression diversity as captured by the two main principal components of the breast cancer microarray data. Our results show that classification of the major and clinically relevant molecular subtypes of breast cancer are best captured using larger gene panels.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-012-2143-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-012-2143-0
PMCID: PMC3413822  PMID: 22752290
Breast cancer; Microarrays; PAM50; Prognosis; Gene expression
6.  Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen 
Annals of Oncology  2012;23(11):2866-2873.
Background
ER-positive (ER+ ) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only.
Methods
Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan–Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance.
Results
All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%–100%).
Conclusions
Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone.
doi:10.1093/annonc/mds080
PMCID: PMC3477878  PMID: 22532584
breast cancer; genomics; luminal; mammaprint; oncotype; PAM50
7.  An unusual cause of epigastric pain in a diabetic patient 
Gut  2006;55(4):477.
doi:10.1136/gut.2005.076091
PMCID: PMC1856199  PMID: 16531528
pyogenic liver abscess; epigastric pain; diabetes mellitus
8.  Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome 
Journal of medical genetics  2003;40(3):e29.
doi:10.1136/jmg.40.3.e29
PMCID: PMC1618877  PMID: 12624158
9.  Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations 
Thorax  2003;58(4):348-351.
Methods: Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6–8 weeks of clinical stability.
Results: Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510–1865) to 1914.5 (1065–3205) x 103/ml (p<0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4–92.3)%) and macrophages (14.7 (2.6–21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7–24)% to 41.4 (6–69)% (p<0.05).
Conclusions: NF-κB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD
doi:10.1136/thorax.58.4.348
PMCID: PMC1746629  PMID: 12668802
10.  Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome 
Journal of Medical Genetics  2003;40(3):e29.
doi:10.1136/jmg.40.3.e29
PMCID: PMC1618877  PMID: 12624158
11.  Serum concentrations of cartilage oligomeric matrix protein and bone sialoprotein in hip osteoarthritis: A one year prospective study 
Annals of the Rheumatic Diseases  1998;57(9):527-532.
OBJECTIVE—To evaluate serum concentations of cartilage oligomeric matrix protein (COMP) and bone sialoprotein (BSP) as predictors of disease progression in hip osteoarthrtitis (OA).
METHODS—Forty eight consecutive patients, referred to hospital for symptomatic hip OA, (ACR criteria) were monitored in a one year prospective trial with radiographs and serum samples. The radiographs were graded for joint space narrowing, osteophytes, and sclerosis and the joint space width was measured by a digitised image analyser. Serum COMP and BSP were quantified by immunoassays.
RESULTS—The COMP concentrations at baseline correlated with the joint space width at entry and with its yearly mean narrowing (r = 0.38, p = 0.002) but not with joint space narrowing grade progression. The concentrations were higher in patients with bilateral hip OA (p = 0.03). The serum BSP concentrations at baseline were unrelated to OA progression but correlated inversely to the osteophyte grade (r = −0.36, p = 0.004) and sclerosis grade ( r = −0.42, p = 0.0004).
CONCLUSION—Serum COMP seems to be a surrogate marker of OA and may be of interest for the detection of patients at risk of rapidly progressing disease in hip OA. Serum BSP changes seem to reflect alterations in the subchondral bone turnover in hip OA. Measurement of joint space width using a digitised image analyser is a sensitive way of assessing OA progression that facilitates evaluation of tissue markers in relation to anatomical changes in the joint.

 Keywords: osteoarthritis; hip; cartilage oligomeric matrix protein; bone sialoprotein
PMCID: PMC1752738  PMID: 9849311
12.  Processing of lipid-modified prolipoprotein requires energy and sec gene products in vivo. 
Journal of Bacteriology  1993;175(19):6113-6117.
The kinetics of processing of glyceride-modified prolipoprotein that accumulated in globomycin-treated Escherichia coli has been found to be affected by sec mutations, i.e., secA, secE, secY, secD, and secF, and by metabolic poisons which affect proton motive force (PMF). The effect of sec mutations on processing of glyceride-modified prolipoprotein in vivo was not due to a secondary effect on PMF. Neither a secF mutation nor metabolic poisons affected the processing of previously accumulated proOmpA protein in vivo, suggesting that the requirements for functional sec gene products and PMF are specific to the processing of lipoprotein precursors by signal peptidase II.
PMCID: PMC206704  PMID: 8407783
13.  Immunohistological examination of the inter- and intracellular distribution of O6-alkylguanine DNA-alkyltransferase in human liver and melanoma. 
British Journal of Cancer  1992;66(2):355-360.
The tissue and cellular distribution of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase) is an important question in relation to the response of tumour and normal tissues to chemotherapeutic regimes employing alkylating agents such as methyltriazenes and nitrosoureas. In order to examine this issue by immunostaining, we have raised a rabbit antiserum to apparently pure recombinant human enzyme. The antiserum is highly specific and sensitive, detecting a band at 24 kDa on western blots of crude extracts of ATase-expressing human lymphoblastoid cells, liver and melanoma. Adjacent sections of acetone or formalin fixed normal human liver and subcutaneous malignant melanoma were reacted with preimmune serum or antiserum and an immunoperoxidase detection system with silver enhancement was used to locate binding of the primary antibody to the antigen. In sections reacted with preimmune serum or with antigen-preadsorbed antiserum, only faint cytoplasmic and little or no nuclear staining was seen. In contrast, using antiserum, the reaction in positively staining cells was very intense and predominantly nuclear. In the liver, there was interindividual variation in the cellular distribution of reaction with staining present in all discernable cell types in most samples but confined to the hepatocytes and bile duct epithelial cells in others. In the melanoma sections, all discernable cell types showed mainly nuclear staining: the intensity of staining varied between tissue samples and there was evidence of a range of intermediate staining intensities with some melanoma cells showing no detectable reaction.
Images
PMCID: PMC1977793  PMID: 1503911
14.  Transcription mapping of the varicella-zoster virus genome. 
Journal of Virology  1985;56(2):600-606.
RNA was isolated from varicella-zoster virus-infected Flow 5000 cells (diploid fibroblasts) at late times after infection. With the use of overlapping DNA probes representing all regions of the varicella-zoster genome, an extensive Northern blot analysis of the RNA was carried out. The analysis revealed at least 58 discrete transcripts ranging in size from approximately 0.8 to 6.5 kilobases. RNAs were found to be homologous to all probes used except for those mapping at approximately map unit 0.3, where no RNA transcripts could be detected. Comparison of the sizes and locations of RNA transcripts mapping in the right-hand ends of the varicella-zoster virus and the herpes simplex virus DNAs shows a number of striking analogies, suggesting their similar genomic organization.
Images
PMCID: PMC252617  PMID: 2997479
15.  Physiological consequences of starvation in Pseudomonas putida: degradation of intracellular protein and loss of activity of the inducible enzymes of L-arginine catabolism. 
Journal of Bacteriology  1975;124(3):1302-1311.
We investigated the degradation of radioisotopically labeled intracellular protein in starved, intact cells of Pseudomonas putida P2 (ATCC 25571) and the regulation of this process. Intracellular protein isotopically labeled with L-[4,5-3H]leucine during log-phase growth at 30 C is degraded at rates of 1 to 2%/h in log-phase cells and 7 to 9%/h in starved cells. Rifampin, chloramphenicol, and tosyllysine chloromethylketone lower the rate of protein degradation by starved cells. Addition to starved cells of a nutrient upon which the culture is induced for growth rapidly lowers the rate of protein degradation from 7 to 9%/h to less than 1.5%/h. A nutrient that is oxidized but that cannot immediately support growth also lowers the rate of starvation-induced protein degradation. Proteolytic activity of cell extracts requires a divalent metal ion and may be inhibited up to 60% by tosyllysine chloromethylketone or p-toluenesulfonyl fluoride. Rifampin and chloramphenicol have no effect. In contrast to intact cells, extracts of growing or starving cells degrade protein at equivalent rates. We also investigated the stabilities of the inducible transport system and of four inducible intracellular enzymes of L-arginine catabolism. These include: the membrane-associated, L-arginine-specific transport system; L-arginine oxidase (oxidase); alpha-ketoarginine decarboxylase (decarboxylase); gamma-guanidinobutyraldehyde dehydrogenase ( dehydrogenase); and gamma-guanidinobutyrate amidinohydrolase (hydrolase). In starved cells, the rates of loss of activities were: transport and dehydrogenase activities, stable; oxidase and decarboxylase activities, 20 to 30%/h; hydrolase activity, 5 to 8%/h. Chloramphenicol decreases the rate of loss of oxidase, decarboxylase, and hydrolase activity, whereas p-toluenesulfonyl fluoride lowers the rate of loss of decarboxylase but not of oxidase or hydrolase activity. Addition to starved cells of a nutrient for which they are already induced for growth (e.g., malate, a noninducer of arginine catabolic enzymes) decreases the rate of loss of oxidase and decarboxylase activity but not that of the hydrolase.
PMCID: PMC236042  PMID: 1194237
16.  Expression of a human O6-alkylguanine-DNA-alkyltransferase cDNA in human cells and transgenic mice. 
Nucleic Acids Research  1990;18(19):5723-5727.
A truncated human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA was ligated into an expression vector under the control of the mouse metallothionein-1 gene promotor and upstream of part of the human growth hormone gene to provide splice and polyadenylation signals. Transfection of this construct into human cells resulted in very high levels of ATase expression (more than 300 fmoles/mg protein versus less than 2 fm/mg protein in parent vector transfected control cells). Microinjection of a 4.2 kb fragment of this vector into B6D2F2 mouse embryos and implantation of survivors into pseudopregnant females has so far generated 35 offspring. Southern analysis of tail tip DNA has shown that 11 of the offspring are transgenic for the human ATase gene, between 1 and at least 30 copies of the gene being detected. Human ATase transcripts were detected in total RNA extracted from liver obtained from two male transgenic mice by partial hepatectomy. Cell free extracts of liver samples from five transgenic mice showed up to 4 times higher ATase levels than control livers.
Images
PMCID: PMC332306  PMID: 2216765
17.  AN EXPERIMENTAL SEPARATION OF OXYGEN LIBERATION FROM CARBON DIOXIDE FIXATION IN PHOTOSYNTHESIS BY CHLORELLA 
Using intact cells of Chlorella pyrenoidosa it is possible to obtain oxygen by the reduction of certain reducible materials other than carbon dioxide. Of these, benzaldehyde was studied in some detail. This reduction does not involve the production of carbon dioxide from the benzaldehyde. Stoichiometrical relationships as expressed by the following equation: 2C6H5CHO + 2H2O → 2C6H5CH2OH + O2 are somewhat difficult to obtain because the benzaldehyde can disappear from the reaction mixtures by dark reactions. The technique is now available which permits detailed studies of the oxygen-liberating mechanisms in photosynthesis.
PMCID: PMC2142580  PMID: 19873369

Results 1-17 (17)