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1.  Targeted sequencing using a 47 gene multiple myeloma mutation panel (M3P) in -17p high risk disease 
British journal of haematology  2014;168(4):507-510.
Summary
We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.
doi:10.1111/bjh.13171
PMCID: PMC4314325  PMID: 25302557
myeloma; cancer genetics; DNA mutation; DRUG resistance; genetic analysis
2.  Immunophenotypes and Immune Markers Associated with Acute Promyelocytic Leukemia Prognosis 
Disease Markers  2014;2014:421906.
CD2+, CD34+, and CD56+ immunophenotypes are associated with poor prognoses of acute promyelocytic leukemia (APL). The present study aimed to explore the role of APL immunophenotypes and immune markers as prognostic predictors on clinical outcomes. A total of 132 patients with de novo APL were retrospectively analyzed. Immunophenotypes were determined by flow cytometry. Clinical features, complete remission (CR), relapse, and five-year overall survival (OS) rate were assessed and subjected to multivariate analyses. The CD13+CD33+HLA-DR-CD34− immunophenotype was commonly observed in patients with APL. Positive rates for other APL immune markers including cMPO, CD117, CD64, and CD9 were 68.7%, 26%, 78.4%, and 96.6%, respectively. When compared with patients with CD2− APL, patients with CD2+ APL had a significantly higher incidence of early death (50% versus 15.7%; P = 0.016), lower CR rate (50% versus 91.1%; P = 0.042), and lower five-year OS rate (41.7% versus 74.2%; P = 0.018). White blood cell (WBC) count before treatment was found to be the only independent risk factor of early death, CR failure, and five-year mortality rate. Flow cytometric immunophenotype analysis can facilitate prompt APL diagnosis. Multivariate analysis has demonstrated that WBC count before treatment is the only known independent risk factor that predicts prognosis for APL in this study population.
doi:10.1155/2014/421906
PMCID: PMC4089198  PMID: 25045197
4.  Whole Genome Analyses of a Well-Differentiated Liposarcoma Reveals Novel SYT1 and DDR2 Rearrangements 
PLoS ONE  2014;9(2):e87113.
Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.
doi:10.1371/journal.pone.0087113
PMCID: PMC3914808  PMID: 24505276
5.  The clinical significance of cereblon expression in multiple myeloma 
Leukemia research  2013;38(1):23-28.
Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). We demonstrate here that no patient with very low CRBN expression responded to IMiD plus dexamethasone therapy. In 53 refractory MM patients treated with pomalidomide and dexamethasone, CRBN levels predict for decreased response rates and significant differences in PFS (3.0 vs. 8.9 months, p < 0.001) and OS (9.1 vs. 27.2 months, p = 0.01) (lowest quartile vs. highest three quartiles). While higher CRBN levels can serve as a surrogate for low risk disease, our study demonstrates that low CRBN expression can predict resistance to IMiD monotherapy and is a predictive biomarker for survival outcomes.
doi:10.1016/j.leukres.2013.08.015
PMCID: PMC3905958  PMID: 24129344
Multiple myeloma; Cereblon; Gene expression profiling; Immunomodulatory drugs; Biological markers
6.  Obligate mutualism within a host drives the extreme specialization of a fig wasp genome 
Genome Biology  2013;14(12):R141.
Background
Fig pollinating wasps form obligate symbioses with their fig hosts. This mutualism arose approximately 75 million years ago. Unlike many other intimate symbioses, which involve vertical transmission of symbionts to host offspring, female fig wasps fly great distances to transfer horizontally between hosts. In contrast, male wasps are wingless and cannot disperse. Symbionts that keep intimate contact with their hosts often show genome reduction, but it is not clear if the wide dispersal of female fig wasps will counteract this general tendency. We sequenced the genome of the fig wasp Ceratosolen solmsi to address this question.
Results
The genome size of the fig wasp C. solmsi is typical of insects, but has undergone dramatic reductions of gene families involved in environmental sensing and detoxification. The streamlined chemosensory ability reflects the overwhelming importance of females finding trees of their only host species, Ficus hispida, during their fleeting adult lives. Despite long-distance dispersal, little need exists for detoxification or environmental protection because fig wasps spend nearly all of their lives inside a largely benign host. Analyses of transcriptomes in females and males at four key life stages reveal that the extreme anatomical sexual dimorphism of fig wasps may result from a strong bias in sex-differential gene expression.
Conclusions
Our comparison of the C. solmsi genome with other insects provides new insights into the evolution of obligate mutualism. The draft genome of the fig wasp, and transcriptomic comparisons between both sexes at four different life stages, provide insights into the molecular basis for the extreme anatomical sexual dimorphism of this species.
doi:10.1186/gb-2013-14-12-r141
PMCID: PMC4053974  PMID: 24359812
7.  Inhibition of NADPH Oxidase Mediates Protective Effect of Cardiotonic Pills against Rat Heart Ischemia/Reperfusion Injury 
Cardiotonic pill (CP) is a compound Chinese medicine currently used in China for treatment of ischemic angina pectoris. Our previous results indicated that a single dosing of CP pretreatment at 0.8 g/kg attenuates ischemia/reperfusion- (I/R-) induced myocardial injury and cardiac microcirculatory disturbance. The present study aimed to investigate the effect of CP at low dosage in a multiple dosing manner and to uncover the mechanism of antioxidative activity of CP. Male Sprague-Dawley rats were subjected to left anterior descending artery occlusion for 30 min followed by 60 min reperfusion. CP was administrated daily by gavage for six days at 0.1, 0.4, and 0.8 g/kg/day before I/R. Results showed that multiple dosing of CP at three doses significantly reduced I/R-induced myocardial injury, microcirculatory disturbance, and oxidative stress. CP dramatically inhibited I/R-induced nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase subunit gp91phox expression and p67phox and p47phox translocation from cytosol to cell membrane. Translocation of cytosolic subunits to membrane is required for the activation of NADPH oxidase. These data suggested that multiple dosing of CP at doses ranging from 0.1 to 0.8 g/kg/day reduced I/R-induced rat myocardial injury and microcirculatory disturbance, which was mediated by inhibition of NADPH oxidase activation.
doi:10.1155/2013/728020
PMCID: PMC3690747  PMID: 23840265
8.  Poly[diaqua­[μ-1,4-bis­(1H-imidazol-1-yl)benzene-κ2 N 3:N 3′](μ-fumarato-κ2 O 1:O 4)nickel(II)] 
In the title compound, [Ni(C4H2O4)(C12H10N4)(H2O)2]n, the NiII ion has a distorted octa­hedral coordination geometry. The asymmetric unit is composed of an Ni2+ ion, located on a twofold rotation axis, one half of a 1,4-bis­(1H-imidazol-1-yl)benzene (BIMB) ligand and one half of a fumarte (fum2−) dianion, both ligands being located about inversion centers, and a coordinating water mol­ecule. The NiII ions are linked by two BIMB ligands and two fum2− dianions, forming a four-connected layered structure parallel to (010) with a 44-sql topology. Within each layer, there are rhombic grids with dimensions of ca 13.5 × 9.0 Å and approximate angles of 109 and 70°. The crystal packing features a two-dimensional → two-dimensional parallel/parallel interpenetration in which one undulating layer is catenated to another equivalent one, forming a new bilayer. Moreover, the entangled two-dimensional layers are connected by O—H⋯O and C—H⋯O hydrogen bonds, generating a three-dimensional structure.
doi:10.1107/S1600536812038895
PMCID: PMC3470161  PMID: 23125605
9.  Emergence and Continuous Evolution of Genotype 1E Rubella Viruses in China 
Journal of Clinical Microbiology  2012;50(2):353-363.
In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.
doi:10.1128/JCM.01264-11
PMCID: PMC3264136  PMID: 22162559
10.  The effects of berberine on hyperhomocysteinemia and hyperlipidemia in rats fed with a long-term high-fat diet 
Background
The study was undertaken to examine the effects of berberine (BBR) on serum homocysteine, lipids and the aortic lesion in Sprague–Dawley (SD) rats fed with a long-term high-fat diet (HFD).
Methods
Healthy male SD rats weighing 190-210 g received randomly standard diet or a high-fat diet for 24 weeks. After 8 weeks of feeding, rats fed with HFD were randomized to receive berberine (200 mg · kg-1· day-1) or vehicle by gavage for 16 weeks. After overnight fasting, all rats were sacrificed and total blood samples were also collected for determinant of fasting serum homocysteine (Hcy), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-c) levels. The aorta was stained with hematoxylin and eosin (HE) and Sudan Ш to evaluate aortic lesion. The livers were dissected out and snap-frozen in liquid nitrogen for hepatic TC content and molecular analysis. 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), Lipoprotein receptors and apolipoproteins gene expression in the liver were determined by real-time PCR.
Results
Intragastrical administration with berberine for 16 weeks lowered serum Hcy in rats fed with a high-fat diet. In parallel, it also decreased body weight and improved serum TC and LDL-c. Berberine also tended to decrease hepatic cholesterol. Consistently, berberine also upregulated LDL receptor (LDLR) mRNA level and suppressed HMGR gene expression. Meanwhile, upon berberine-treated rats, there was a significant increase in apolipoprotein E (apoE) mRNA, but no change in apoAI and scavenger receptor (SR) mRNA in the liver. Further, no atherosclerotic lesions were developed in berberine-treated rats for 16 weeks.
Conclusion
Berberine can counteract HFD-elicited hyperhomocysteinemia and hyperlipidemia partially via upregulating LDLR and apoE mRNA levels and suppressing HMGR gene expression.
doi:10.1186/1476-511X-11-86
PMCID: PMC3475055  PMID: 22762542
Berberine; Hyperhomocysteinemia; Hyperlipidemia
11.  Development of a class-specific polyclonal antibody-based indirect competitive ELISA for detecting fluoroquinolone residues in milk*  
Modified 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) method was employed to synthesize the artificial antigen of norfloxacin (NOR), and New Zealand rabbits were used to produce anti-NOR polyclonal antibody (pAb). Based on the checkerboard titration, an indirect competitive enzyme-linked immunosorbent assay (icELISA) standard curve was established. This assay was sensitive and had a working range from 0.12 to 68.40 ng/ml, with the half maximal inhibitory concentration (IC50) and limit of detection (LOD) values of 2.7 ng/ml and 0.06 ng/ml, respectively. The produced pAb exhibited high cross-reactivity to fluoroquinolones (FQs) tested, and the IC50 values to enoxacin, ciprofloxacin, and pefloxacin were 3.1, 3.4, and 4.1 ng/ml, respectively. It also indicated that the concentrations of NaOH and methanol in assay buffer should not be higher than 10% and 30%. When spiked in milk at 5, 20, and 50 ng/ml, the recoveries for NOR, enoxacin, ciprofloxacin, and pefloxacin ranged 90.5%–98.0%, 84.0%–95.2%, 94.0%–106.0%, and 89.5%–100.0%, respectively. The results suggest that this class-specific pAb-based icELISA could be utilized for the primary screening of FQ residues in animal-original products.
doi:10.1631/jzus.B1200001
PMCID: PMC3390712  PMID: 22761246
Norfloxacin; Fluoroquinolones; Indirect competitive ELISA; Class-specificity; Milk
12.  Paraneoplastic syndrome mimicking adult-onset Still's disease caused by advanced lung cancer: a case report 
BMC Cancer  2011;11:487.
Background
Paraneoplastic syndromes (PNSs) are common complications of lung cancer and often develop preceding the diagnosis of primary malignancy. Rheumatologic PNSs mimicking Adult-Onset Still' s Disease (AOSD) is a rare condition with only a limited number of cases reported in the literature, none of which was associated with lung cancer. It is often difficult to differentiate AOSD-like paraneoplasia from coincidental AOSD based on the clinical manifestations.
Case presentation
Here we present a 56-year-old man with advanced lung adenocarcinoma who developed a remittent fever together with pharyngodynia and joint pain after first cycle of chemotherapy with paclitaxel plus carboplatin. Although a leukocytosis was detected, no evidence of infection was acquired and empirical antibiotic treatment was ineffective. A temple skin rash, abnormal hepatic function and a remarkable elevated level of serum ferritin occurred later in this patient, which highly supported a potential diagnosis of AOSD. The patient was finally diagnosed as AOSD-like PNS considering the good and prompt response to a short-term administration of non-steroidal anti-inflammatory drug and subsequent cycles of effective chemotherapy with pemetrexed plus cisplatin.
Discussion and conclusions
Though rare, AOSD-like PNS can be one of the potential diagnoses in lung cancer patients with fever of undetermined origin, especially those having no response to antibiotic treatment. Management consists of control of the underlying malignancy and symptomatic treatment of the syndromes with non-steroidal anti-inflammatory drugs or corticosteroids.
doi:10.1186/1471-2407-11-487
PMCID: PMC3232026  PMID: 22085873
13.  Development of an indirect competitive ELISA for simultaneous detection of enrofloxacin and ciprofloxacin*  
Modified 1-ethyl-3-(3-dimethylaminopropy) carbodiimide (EDC) method was employed to synthesize the artificial antigen of enrofloxacin (ENR), and New Zealand rabbits were used to produce anti-ENR polyclonal antibody (pAb). Based on the checkerboard titration, an indirect competitive enzyme-linked immunosorbent assay (ELISA) standard curve was established. This assay was sensitive and had a linear range from 0.6 to 148.0 μg/kg (R 2=0.9567), with the half maximal inhibitory concentration (IC50) and limit of detection (LOD) values of 9.4 μg/kg and 0.2 μg/kg, respectively. Of all the competitive analogues, the produced pAb exhibited a high cross-reactivity to ciprofloxacin (CIP) (87%), the main metabolite of ENR in tissues. After optimization, the matrix effects can be ignored using a 10-fold dilution in beef and 20-fold dilution in pork. The overall recoveries and coefficients of variation (CVs) were in the ranges of 86%–109% and 6.8%–13.1%, respectively. It can be concluded that the established ELISA method is suitable for simultaneous detection of ENR and CIP in animal tissues.
doi:10.1631/jzus.B1100076
PMCID: PMC3208167  PMID: 22042652
Enrofloxacin; Ciprofloxacin; Indirect competitive ELISA; Animal tissues
14.  Abnormal Brain Default-Mode Network Functional Connectivity in Drug Addicts 
PLoS ONE  2011;6(1):e16560.
Background
The default mode network (DMN) is a set of brain regions that exhibit synchronized low frequency oscillations at resting-state, and is believed to be relevant to attention and self-monitoring. As the anterior cingulate cortex and hippocampus are impaired in drug addiction and meanwhile are parts of the DMN, the present study examined addiction-related alteration of functional connectivity of the DMN.
Methodology
Resting-state functional magnetic resonance imaging data of chronic heroin users (14 males, age: 30.1±5.3 years, range from 22 to 39 years) and non-addicted controls (13 males, age: 29.8±7.2 years, range from 20 to 39 years) were investigated with independent component analysis to address their functional connectivity of the DMN.
Principal Findings
Compared with controls, heroin users showed increased functional connectivity in right hippocampus and decreased functional connectivity in right dorsal anterior cingulate cortex and left caudate in the DMN.
Conclusions
These findings suggest drug addicts' abnormal functional organization of the DMN, and are discussed as addiction-related abnormally increased memory processing but diminished cognitive control related to attention and self-monitoring, which may underlie the hypersensitivity toward drug related cues but weakened strength of cognitive control in the state of addiction.
doi:10.1371/journal.pone.0016560
PMCID: PMC3027699  PMID: 21298074
15.  Addiction Related Alteration in Resting-state Brain Connectivity 
NeuroImage  2009;49(1):738-744.
It is widely accepted that addictive drug use is related to abnormal functional organization in the user’s brain. The present study aimed to identify this type of abnormality within the brain networks implicated in addiction by resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI). With fMRI data acquired during resting state from 14 chronic heroin users (12 of whom were being treated with methadone) and 13 non-addicted controls, we investigated the addiction related alteration in functional connectivity between the regions in the circuits implicated in addiction with seed-based correlation analysis. Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), and orbital frontal cortex (OFC), between amygdala and OFC; and reduced functional connectivity between prefrontal cortex and OFC, and ACC. These observations of altered resting-state functional connectivity suggested abnormal functional organization in the addicted brain and may provide additional evidence supporting the theory of addiction that emphasizes enhanced salience value of a drug and its related cues but weakened cognitive control in the addictive state.
doi:10.1016/j.neuroimage.2009.08.037
PMCID: PMC2764798  PMID: 19703568
16.  Total salvianolic acid improves ischemia-reperfusion-induced microcirculatory disturbance in rat mesentery 
AIM: To investigate the effect of total salvianolic acid (TSA) on ischemia-reperfusion (I/R)-induced rat mesenteric microcirculatory dysfunctions.
METHODS: Male Wistar rats were randomly distributed into 5 groups (n = 6 each): Sham group and I/R group (infused with saline), TSA group, TSA + I/R group and I/R + TSA group (infused with TSA, 5 mg/kg per hour). Mesenteric I/R were conducted by a ligation of the mesenteric artery and vein (10 min) and subsequent release of the occlusion. TSA was continuously infused either starting from 10 min before the ischemia or 10 min after reperfusion. Changes in mesenteric microcirculatory variables, including diameter of venule, velocity of red blood cells in venule, leukocyte adhesion, free radicals released from venule, albumin leakage and mast cell degranulation, were observed through an inverted intravital microscope. Meanwhile, the expression of adhesion molecules CD11b/CD18 on neutrophils was evaluated by flow cytometry. Ultrastructural evidence of mesenteric venules damage was assessed after microcirculation observation.
RESULTS: I/R led to multiple responses in mesenteric post-capillary venules, including a significant increase in the adhesion of leukocytes, production of oxygen radicals in the venular wall, albumin efflux and enhanced mast cell degranulation in vivo. All the I/R-induced manifestations were significantly reduced by pre- or post-treatment with TSA, with the exception that the I/R-induced increase in mast cell degranulation was inhibited only by pre-treatment with TSA. Moreover, pre- or post-treatment with TSA significantly attenuated the expression of CD11b/CD18 on neutrophils, reducing the increase in the number of caveolae in the endothelial cells of mesentery post-capillary venules induced by I/R.
CONCLUSION: The results demonstrated that TSA protects from and ameliorates the microcirculation disturbance induced by I/R, which was associated with TSA inhibiting the production of oxygen-free radicals in the venular wall and the expression of CD11b/CD18 on neutrophils.
doi:10.3748/wjg.v16.i42.5306
PMCID: PMC2980679  PMID: 21072893
Salvia miltiorrhiza; Leukocyte adherence; Oxygen-free radicals; Albumin leakage; Ischemia-reperfusion
17.  Poly[bis­[μ2-2-(2-pyridylmethyl­amino)ethanesulfonato]cadmium(II)] 
The title compound [Cd(C8H11N2O3S)2]n, is a two-dimensional coordination polymer based on a Cd2+ atom and deprotonated 2-(2-pyridylmethyl­amino)ethanesulfonic acid (Hpmt). The complex has mol­ecular symmetry C i as a consequence of the CdII being located on an inversion centre. Two N atoms of each pmt− ligand coordinate to the Cd2+ ion and its sulfonate O atom bonds to an adjacent Cd2+ ion. 24-membered (–Cd—N—C—C—S—O–)4 rings are formed between neighbouring Cd2+ ions; these are inter­connected, forming a two-dimensional layer structure. In respect to stereogenic amino N atom and the inversion symmetry of the complex, the compound is a 1:1 racemate. The crystal packing is stabilized by inter­molecular N—H⋯O hydrogen bonds and further connected by π–π stacking inter­actions between the pyridyl rings [average inter­planar distance and centroid–centroid separation = 3.582 (1) and 3.634 (1)Å, respectively], forming a three-dimensional supra­molecular architecture.
doi:10.1107/S1600536809049162
PMCID: PMC2971805  PMID: 21578666
18.  2,5-Bis[2-(2-methoxy­ethoxy)phen­yl]-1,3,4-oxadiazole 
In the title compound, C20H22N2O5, the central 1,3,4-oxadiazole ring is essentially planar [r.m.s. deviation from the best plane of 0.0011 Å] and makes dihedral angles of 4.10 (3) and 13.32 (4)° with the two benzene rings. In the crystal structure, the packing is stabilized by weak non-classical inter­molecular C—H⋯N hydrogen bonds, which link the mol­ecules into an extended network.
doi:10.1107/S1600536809028931
PMCID: PMC2977367  PMID: 21583681
19.  Promiscuous Mutations Activate the Non-Canonical NF-kB Pathway in Multiple Myeloma 
Cancer cell  2007;12(2):131-144.
Summary
Activation of NF-kB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2, and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the non-canonical NF-kB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kB pathway in the pathogenesis of multiple myeloma.
doi:10.1016/j.ccr.2007.07.003
PMCID: PMC2083698  PMID: 17692805
20.  Poly[disodium [diaqua­tri-μ2-oxalato-dimagnesium(II)]] 
The title compound, {Na2[Mg2(C2O4)3(H2O)2]}n, is isotypic with its Co analogue. There are two crystallographically independent oxalate groups in the asymmetric unit, one lying on an inversion center and the other on a general position. Mg2+ ions are ligated by H2O mol­ecules and bridged by tri- and tetra­dentate oxalate ligands, forming ladder-like double chains that are held together via O—H⋯O hydrogen bonds, with Na+ cations located between the chains to balance the charge.
doi:10.1107/S1600536808019508
PMCID: PMC2961912  PMID: 21203081
21.  A new polymorph of magnesium oxalate dihydrate 
In the asymmetric unit of the title compound, catena-poly[[diaqua­magnesium(II)]-μ-oxalato], [Mg(C2O4)(H2O)2]n, there is one Mg atom in an octa­hedral coordination with site symmetry 222, a unique C atom of the oxalate anion lying on a twofold axis, an O atom of the anion in a general position and a water O atom at a site with imposed twofold rotation symmetry. The Mg2+ ions are ligated by water mol­ecules and bridged by the anions to form chains that are held together by O—H⋯O hydrogen bonds. The structure of the title compound has already been reported in a different space group [Lagier, Pezerat & Dubernat (1969 ▶). Rev. Chim. Miner. 6, 1081–1093; Levy, Perrotey & Visser (1971 ▶). Bull. Soc. Chim. Fr. pp. 757–761].
doi:10.1107/S1600536808015870
PMCID: PMC2961852  PMID: 21202738
22.  Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity  
The Journal of Clinical Investigation  2008;118(5):1750-1764.
Knockout and transgenic studies in mice demonstrate that normal somatic tissues redundantly express 3 cyclin D proteins, whereas tumor cells seem dependent on a single overexpressed cyclin D. Thus, selective suppression of the individual cyclin D deregulated in a tumor represents a biologically valid approach to targeted cancer therapy. In multiple myeloma, overexpression of 1 of the cyclin D proteins is a ubiquitous feature, unifying at least 7 different initiating genetic events. We demonstrate here that RNAi of genes encoding cyclin D1 and cyclin D2 (CCND1 and CCND2, respectively) inhibits proliferation and is progressively cytotoxic in human myeloma cells. By screening a chemical library using a cell-based assay for inhibition of CCND2 trans-activation, we identified the plant cytokinin kinetin riboside as an inhibitor of CCND2 trans-activation. Kinetin riboside induced marked suppression of CCND2 transcription and rapidly suppressed cyclin D1 and D2 protein expression in primary myeloma cells and tumor lines, causing cell-cycle arrest, tumor cell–selective apoptosis, and inhibition of myeloma growth in xenografted mice. Mechanistically, kinetin riboside upregulated expression of transcription repressor isoforms of cAMP-response element modulator (CREM) and blocked both trans-activation of CCND2 by various myeloma oncogenes and cis-activation of translocated CCND1, suggesting induction of an overriding repressor activity that blocks multiple oncogenic pathways targeting cyclin D genes. These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies.
doi:10.1172/JCI34149
PMCID: PMC2323188  PMID: 18431519
23.  Identification of the functional role of peroxiredoxin 6 in the progression of breast cancer 
Introduction
The molecular mechanisms involved in breast cancer metastasis still remain unclear to date. In our previous study, differential expression of peroxiredoxin 6 was found between the highly metastatic MDA-MB-435HM cells and their parental counterparts, MDA-MB-435 cells. In this study, we investigated the effects of peroxiredoxin 6 on the proliferation and metastatic potential of human breast cancer cells and their potential mechanism.
Methods
Expression of peroxiredoxin 6 in the highly metastatic MDA-MB-231HM cells was investigated by RT-PCR, real-time PCR and western blot. A recombinant expression plasmid of the human peroxiredoxin 6 gene was constructed and transfected into MDA-MB-231 and MDA-MB-435 cells. The effects of peroxiredoxin 6 on the proliferation and invasion of MDA-MB-231 and MDA-MB-435 cells were investigated by the Cell Counting Kit-8 method, colony-formation assay, adhesion assay, flow cytometry and invasion assay in vitro. miRNA was used to downregulate the expression of peroxiredoxin 6. Genes related to the invasion and metastasis of cancer were determined by RT-PCR, real-time PCR and western blot. The tumorigenicity and spontaneously metastatic capability regulated by peroxiredoxin 6 were determined using an orthotopic xenograft tumor model in athymic mice.
Results
Overexpression of peroxiredoxin 6 in MDA-MB-231HM cells compared with their parental counterparts was confirmed. Upregulation of peroxiredoxin 6 enhanced the in vitro proliferation and invasion of breast cancer cells. The enhancement was associated with decreasing levels of tissue inhibitor of matrix metalloproteinase (TIMP)-2 and increasing levels of the urokinase-type plasminogen activator receptor (uPAR), Ets-1 (E26 transformation-specific-1), matrix metalloproteinase (MMP)-9 and RhoC (ras homolog gene family, member C) expression. The results were further demonstrated by RNA interference experiments in vitro. In an in vivo study, we also demonstrated that peroxiredoxin 6-transfected breast cancer cells grew much faster and had more pulmonary metastases than control cells. By contrast, peroxiredoxin 6 knockdown breast cancer cells grew more slowly and had fewer pulmonary metastases. Effects similar to those of peroxiredoxin 6 on the uPAR, Ets-1, MMP-9, RhoC and TIMP-2 expression observed in in vitro studies were found in the in vivo study.
Conclusion
Overexpression of peroxiredoxin 6 leads to a more invasive phenotype and metastatic potential in human breast cancer, at least in part, through regulation of the levels of uPAR, Ets-1, MMP-9, RhoC and TIMP-2 expression.
doi:10.1186/bcr1789
PMCID: PMC2246172  PMID: 17980029
24.  Compound Danshen injection improves endotoxin-induced microcirculatory disturbance in rat mesentery 
AIM: To investigate the effect of compound Danshen injection on lipopolysaccharide (LPS)-induced rat mesenteric microcirculatory dysfunctions and the underlying possible mechanism by an inverted intravital microscope and high-speed video camera system.
METHODS: LPS was continuously infused through the jugular artery of male Wistar rats at the dose of 2 mg/kg per hour. Changes in mesenteric microcirculation, such as diameters of arterioles and venules, velocity of RBCs in venules, leukocyte rolling, adhesion and emigration, free radicals released from post-capillary venules, FITC-albumin leakage and mast cell degranulation, were observed through an inverted intravital microscope assisted with CCD camera and SIT camera. Meanwhile, the expression of adhesion molecules CD11b/CD18 and the production of free radical in neutrophils, and the expression of intercellular adhesion molecule 1 (ICAM-1) in human umbilical vein endothelial cells (HUVECs) were quantified by flow cytometry (FACS) in vitro.
RESULTS: The continuous infusion with LPS resulted in a number of responses in microcirculation, including a significant increase in the positive region of venule stained with Monastral blue B, rolling and adhesion of leukocytes, production of oxygen radical in venular wall, albumin efflux and enhanced mast cell degranulation in vivo, all of which, except for the leukocyte rolling, were attenuated by the treatment with compound Danshen injection. Experiments performed in vitro further revealed that the expression of CD11b/CD18 and the production of oxygen free radical in neutrophils, and the expression of ICAM-1 in HUVECs were increased by exposure to LPS, and they were attenuated by compound Danshen injection.
CONCLUSION: These results suggest that compound Danshen injection is an efficient drug with multi-targeting potential for improving the microcirculatory disturbance.
doi:10.3748/wjg.v13.i26.3581
PMCID: PMC4146797  PMID: 17659708
Compound Danshen; Mesenteric microci-rculation; Oxygen-free radical; Adhesion molecules; Lipopolysaccharide
25.  Docetaxel shows radiosensitization in human hepatocellular carcinoma cells 
AIM: To determine the radiosensitizing potential of docetaxel in human hepatocellular carcinoma SMMC-7721 cells and its mechanisms.
METHODS: SMMC-7721 cells were incubated with docetaxel at 0.125, 0.25, and 0.5 nmoL/L for 24 h and at 0.125 and 0.25 nmol/L for 48 h before irradiation. Radiation doses were given from 0 to 10 Gy. Cell survival was measured by a standard clonogenic assay after a 9-d incubation. The reactive oxygen species (ROS) and glutathione (GSH) are detected after being given the same dose of docetaxel for the same time.
RESULTS: The sensitization enhancement ratios (SER) for SMMC-7721 cells determined at the 50% survival level were 1.15, 1.21 and 1.49 at 0.125, 0.25, and 0.5 nmol/L for pre-incubation of 24 h, respectively; the SER were 1.42, 1.67 at 0.125 and 0.25 nmol/L, for pre-incubation of 48 h, respectively. The ROS of SMMC-7721 cells increased and GSH decreased after pretreatment with the same doses of docetaxel for 24 or 48 h.
CONCLUSION: A radiosensitizing effect of docetaxel could be demonstrated unambiguously in this cell line used. In addition, our data showed that the mechanism of radiopotentiation by docetaxel probably does not involve a G2/M block in SMMC-7721 cells, and ROS generation and GSH deletion may play a key role in the radiosensitizing effect of docetaxel.
doi:10.3748/wjg.v11.i19.2990
PMCID: PMC4305674  PMID: 15902743
Docetaxel; Hepatocellular carcinoma; SMMC-7721cell line; Radiosensitization; Reactive oxygen species

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