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Articles by C Li
Total Records ( 22 ) for C Li
  C Zhang , Y Tan , W Guo , C Li , S Ji , X Li and L. Cai
 

Renal protection against diabetes-induced pathogenic injuries by multiple exposures to low-dose radiation (LDR) was investigated to develop a novel approach to the prevention of renal disease for diabetic subjects. C57BL/6J mice were given multiple low-dose streptozotocin (STZ; 60 x 6 mg/kg) to produce a type 1 diabetes. Two weeks after diabetes onset, some of diabetic mice and age-matched nondiabetic mice were exposed whole body to 25 mGy X-rays every other day for 2, 4, 8, 12, and 16 wk. Diabetes caused a significant renal dysfunction, shown by time-dependent increase in urinary microalbumin (Malb) and decrease in urinary creatinine (Cre), and pathological changes, shown by significant increases in renal structural changes and PAS-positive staining. However, diabetes-induced renal dysfunction and pathological changes were significantly, albeit partially, attenuated by multiple exposures to LDR. Furthermore, LDR protection against diabetes-induced renal dysfunction and pathological changes was associated with a significant suppression of diabetes-increased systemic and renal inflammation, shown by significant increases in serum and renal TNF, ICAM-1, IL-18, MCP-1, and PAI-1 contents. To further explore the mechanism by which LDR prevents diabetes-induced renal pathological changes, renal oxidative damage was examined by Western blotting and immunohistochemical staining for 3-nitrotyrosine and 4-hydroxynonenal. Significant increase in oxidative damage was observed in diabetic mice, but not diabetic mice, with LDR. Renal fibrosis, examined by Western blotting of connective tissue growth factor and Masson's trichrome staining, was also evident in the kidneys of diabetic mice but not diabetic mice with LDR. These results suggest that multiple exposures to LDR significantly suppress diabetes-induced systemic and renal inflammatory response and renal oxidative damage, resulting in a prevention of the renal dysfunction and fibrosis.

  D. A Solomon , A. C Leon , W. H Coryell , J Endicott , C Li , J. G Fiedorowicz , L Boyken and M. B. Keller
 

Context  The phenomenology of bipolar I disorder affects treatment and prognosis.

Objective  To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes.

Design  Subjects with Research Diagnostic Criteria bipolar I disorder were prospectively followed up for as long as 25 years. The probability of recovery over time from multiple successive mood episodes was examined with survival analytic techniques, including a mixed-effects grouped-time survival model.

Setting  Five US academic medical centers.

Participants  Two hundred nineteen subjects with bipolar I disorder.

Main Outcome Measures  Level of psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation every 6 months for the first 5 years of follow-up and annually thereafter.

Results  The median duration of bipolar I mood episodes was 13 weeks. More than 75% of the subjects recovered from their mood episodes within 1 year of onset. The probability of recovery was significantly less for an episode with severe onset (psychosis or severe psychosocial impairment in week 1 of the episode) (hazard ratio [HR] = 0.746; 95% confidence interval [CI], 0.578-0.963; P = .02) and for subjects with greater cumulative morbidity (total number of years spent ill with any mood episode) (HR = 0.917; 95% CI, 0.886-0.948; P < .001). Compared with the probability of recovery from a major depressive episode, there was a significantly greater probability of recovery from an episode of mania (HR = 1.713; 95% CI, 1.373-2.137; P < .001), hypomania (HR = 4.502; 95% CI, 3.466-5.849; P < .001), or minor depression (HR = 2.027; 95% CI, 1.622-2.534; P < .001) and, conversely, a significantly reduced probability of recovery from a cycling episode (switching from one pole to the other without an intervening period of recovery) (HR = 0.438; 95% CI, 0.351-0.548; P < .001).

Conclusions  The median duration of bipolar I mood episodes was 13 weeks, and the probability of recovery was significantly decreased for cycling episodes, mood episodes with severe onset, and subjects with greater cumulative morbidity.

  P. W. H Peng , C Li , E Farcas , A Haley , W Wong , J Bender and F. Chung
  Background

The objective of this study was to examine the effects of low-dose pregabalin on the analgesic efficacy, side-effects, and recovery profile in patients undergoing laparoscopic cholecystectomy.

Methods

One hundred and sixty-two patients aged 18–65 yr, of ASA physical status I–III, undergoing elective outpatient laparoscopic cholecystectomy were recruited and randomized in this prospective, placebo-controlled, double-blind study to receive one of the following study medications orally: pregabalin 50 mg, pregabalin 75 mg, or placebo, 1 h before surgery and then every 12 h after operation for a total of three doses. Postoperative numeric pain scores, analgesic consumption, recovery score (QoR-40), and side-effects (opioid-related symptom distress scale) were assessed in the early postoperative period (every 15 min during the first hour, at 90, 120 min, 6, and 12 h) and at days 1, 2, and 7. Data were analysed using an intention-to-treat method.

Results

Compared with the placebo group, the pain scores were lower in the pregabalin 75 mg group in the first 90 min after surgery (P<0.05). Pregabalin 50 mg resulted in pain reduction at 30 and 45 min (P<0.05) relative to placebo. The analgesic consumption, side-effects, and recovery scores were similar among the three groups.

Conclusions

Perioperative administration of pregabalin 75 mg provided limited analgesic benefit in the postoperative period. An updated meta-analysis confirms this finding (see Supplementary material).

  C Li , J Lu , Z Liu , L. E Wang , H Zhao , A. K El Naggar , E. M Sturgis and Q. Wei
 

Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion (–652 6N ins/del) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 –652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 –652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 –652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 –652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted. Cancer Prev Res; 3(2); 246–53

  T Holopainen , H Huang , C Chen , K. E Kim , L Zhang , F Zhou , W Han , C Li , J Yu , J Wu , G. Y Koh , K Alitalo and Y. He
 

The angiopoietin-1 (Ang1)/Tie2 signaling pathway is known to play an important role in the regulation of vascular maturation and maintenance of vessel integrity. In this study, we have investigated the effect of systemic Tie2 activation or inhibition on tumor growth and metastasis. We found that treatment with Ang1 delivered via an adenoviral vector promoted s.c. implanted tumor metastasis to the lungs. Ang1 treatment did not significantly increase vascular density in the tumors but induced enlargement of blood vessels in both the tumor and normal tissues, which increased tumor cell dissemination into the blood circulation. Ang1 also enhanced the formation of metastatic foci in the lungs when tumor cells were injected into the circulation via the tail vein. The effect of Ang1 on metastasis was validated by a simultaneous treatment with a soluble form of Tie2 (sTie2), which led to the suppression of Ang1-induced increase of tumor metastasis. Furthermore, using a highly metastatic tumor model, we confirmed that systemic treatment with sTie2 suppressed tumor metastasis to the lungs and lymph nodes, whereas tumor-associated angiogenesis and lymphangiogenesis were not significantly affected. This suggests that the Ang1/Tie2 signals contribute to tumor progression by increasing vascular entry and exit of tumor cells to facilitate tumor dissemination and establishment of metastases. [Cancer Res 2009;69(11):4656–64]

  R. J Leeman Neill , S. E Wheeler , S. V Singh , S. M Thomas , R. R Seethala , D. B Neill , M. C Panahandeh , E. R Hahm , S. C Joyce , M Sen , Q Cai , M. L Freilino , C Li , D. E Johnson and J. R. Grandis
 

Treatment of human head and neck squamous cell carcinoma (HNSCC) cell lines with guggulsterone, a widely available, well-tolerated nutraceutical, demonstrated dose-dependent decreases in cell viability with EC50s ranging from 5 to 8 µM. Guggulsterone induced apoptosis and cell cycle arrest, inhibited invasion and enhanced the efficacy of erlotinib, cetuximab and cisplatin in HNSCC cell lines. Guggulsterone induced decreased expression of both phosphotyrosine and total signal transducer and activator of transcription (STAT)-3, which contributed to guggulsterone's growth inhibitory effect. Hypoxia-inducible factor (HIF)-1 was also decreased in response to guggulsterone treatment. In a xenograft model of HNSCC, guggulsterone treatment resulted in increased apoptosis and decreased expression of STAT3. In vivo treatment with a guggulsterone-containing natural product, Guggulipid, resulted in decreased rates of tumor growth and enhancement of cetuximab's activity. Our results suggest that guggulsterone-mediated inhibition of STAT3 and HIF-1 provide a biologic rationale for further clinical investigation of this compound in the treatment of HNSCC.

  Y He , H Zhang , J Yin , J Xie , X Tan , S Liu , Q Zhang , C Li , J Zhao , H Wang and G. Cao
 

Genetic predisposition of nuclear factor-kappa B (NF-B)-signaling pathways linking inflammation to hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remains unresolved. We conducted a case–control study to determine the associations of the polymorphisms within the promoter regions of NFKB1 encoding NF-B1 and NFKBIA encoding IkappaBalpha with the development of HCC. A total of 404 healthy controls, 482 non-HCC subjects with HBV infection and 202 patients with HCC were included. NFKB1 –94ATTG2 allele and GG allele in the 3'-untranslated region of NFKBIA were more prevalent in HCC patients than in the healthy controls. NFKBIA –826CT and NFKBIA –881AG allelic carriages were more prevalent in HCC patients than in the non-HCC subjects with HBV infection. The estimated haplotype frequency of NFKBIA promoter –881G–826T–519C was significantly higher in the patients with HCC than in the HBV-infected subjects without HCC (odds ratio = 3.142, P = 0.002). As compared with the HBV-infected subjects without HCC, NFKBIA –826 T and NFKBIA –881AG allelic carriages were only associated with HCC risk in the subjects with HBV genotype C. The association of NFKBIA –881AG allelic carriage with HCC risk was not affected by liver cirrhosis (LC) status, alanine aminotransferase level and hepatitis B e antigen status. By multivariate regression analysis, NFKB1 –94ATTG2, NFKBIA –826T, NFKBIA –881AG and HBV genotype C were independently associated with an increased risk of HCC. In conclusion, NFKB1 –94ATTG2 allele and haplotype –881G–826T–519C in NFKBIA promoter were associated with hepatocarcinogenesis. NFKBIA –826T and –881AG were associated with the risk of HCC in the subjects infected with HBV genotype C.

  X Sun , C Li , C Zhuang , W. C Gilmore , E Cobos , Y Tao and Z. Dai
 

Abl interactor 1 (Abi1) is a key regulator of actin polymerization/depolymerization. The involvement of Abi1 in the development of abnormal cytoskeletal functions of cancer cells has recently been reported. It remains unclear, however, how Abi1 exerts its effects in tumor cells and whether it contributes to tumor progression in vivo. We report here a novel function for Abi1 in the regulation of invadopodia formation and Src-inhibitor of differentiation protein 1 (Id1)-matrix metalloproteinase (MMP)-9 pathway in MDA-MB-231 human breast cancer cells. Abi1 is found in the invadopodia of MDA-MB-231 cells. Epigenetic silencing of the Abi1 gene by short hairpin RNA in MDA-MB-231 cells impaired the formation of invadopodia and resulted in downregulation of the Src activation and Id1/MMP-9 expression. The decreased invadopodia formation and MMP-9 expression correlate with a reduction in the ability of these cells to degrade extracellular matrix. Remarkably, the knockdown of Abi1 expression inhibited tumor cell proliferation and migration in vitro and slowed tumor growth in vivo. Taken together, these results indicate that the Abi1 signaling plays a critical role in breast cancer progression and suggest that this pathway may serve as a therapeutic target for the treatment of human breast cancer.

  L Liu , Y. H Li , Y. B Niu , Y Sun , Z. J Guo , Q Li , C Li , J Feng , S. S Cao and Q. B. Mei
 

Evidence strongly supported a link between inflammation and cancer. Patients with colitis have high risk for development of colon cancer. Nuclear factor-kappa B (NF-B), partially induced by lipopolysaccharide (LPS) binding to Toll-like receptor (TLR) 4, is a vital molecule in supervising the transformation of colitis to colon cancer. It could be a good strategy to prevent colitis carcinogenesis for targeting LPS/TLR4/NF-B pathway. In the present study, we obtained an oligogalactan composed of five galacturonic acids from apple pectin and evaluated its protective efficacy on intestinal toxicities and carcinogenesis in a mouse model of colitis-associated colon cancer induced by 1,2-dimethylhydrazine and dextran sodium sulfate (DSS). The apple oligogalactan (AOG) was highly effective against intestinal toxicities and carcinogenesis and decreased the elevated levels of TLR4 and tumor necrosis factor- (TNF-) induced by inflammation in vivo in this model system. In vitro studies, AOG alone only slightly increased the levels of protein expression and messenger RNA of TLR4, phosphorylation of IB and production of TNF- in HT-29 cells. However, AOG significantly decreased the elevation of all the biomarkers induced by LPS when it was combined with LPS. The effect of AOG may be related to membrane internalization and redistribution of TLR4 from cell membrane to cytoplasm. AOG is active against inflammation and carcinogenesis through targeting LPS/TLR4/NF-B pathway. Both AOG and LPS are agonists of TLR4 for sharing the same ligand but AOG has a much lower intrinsic activity than that of LPS. AOG may be useful for treatment of colitis and prevention of carcinogenesis in the clinics.

  E. S Ford , C Li , G Zhao , W. S Pearson and S. Capewell
 

Background— Cohorts consistently show that individuals with low levels of cardiovascular risk factors experience low rates of subsequent cardiovascular events. Our objective was to examine the prevalence and trends in low risk factor burden for cardiovascular disease among adults in the US population.

Methods and Results— We used data from adults 25 to 74 years of age who participated in 4 national surveys. We created an index of low risk from the following variables: not currently smoking, total cholesterol <5.17 mmol/L (<200 mg/dL) and not using cholesterol-lowering medications, systolic blood pressure <120 mm Hg and diastolic blood pressure <80 mm Hg and not using antihypertensive medications, body mass index <25 kg/m2, and not having been previously diagnosed with diabetes mellitus. The age-adjusted prevalence of low risk factor burden increased from 4.4% during 1971 to 1975 to 10.5% during 1988 to 1994 before decreasing to 7.5% during 1999 to 2004 (P for nonlinear trend <0.001). The patterns were similar for men and women, although the prevalence among women exceeded that among men in each survey (P<0.001 for each survey). In addition, whites had a significantly higher prevalence of low risk factor burden than blacks during each survey except during 1976 to 1980 (1971 to 1975, 1988 to 1994, 1999 to 2004: P<0.001; 1976 to 1980: P=0.154). Furthermore, a larger percentage of whites had a low risk factor burden than Mexican Americans during 1988 to 1994 (P<0.001) and 1999 to 2004 (P=0.001).

Conclusions— The prevalence of low risk factor burden for cardiovascular disease is low. The progress that had been made during the 1970s and 1980s reversed in recent decades.

  A. J Saltzman , D Mancini DiNardo , C Li , W. K Chung , C. Y Ho , S Hurst , J Wynn , M Care , R. M Hamilton , G. W Seidman , J Gorham , B McDonough , E Sparks , J. G Seidman , C. E Seidman and H. L. Rehm
 

Rationale: The myosin-binding protein C isoform 3 (MYBPC3) variant Arg502Trp has been identified in multiple hypertrophic cardiomyopathy (HCM) cases, but compelling evidence to support or refute the pathogenicity of this variant is lacking.

Objective: To determine the prevalence, origin and clinical significance of the MYBPC3 Arg502Trp variant.

Methods and Results: The prevalence of MYBPC3 Arg502Trp was ascertained in 1414 sequential HCM patients of primarily European descent. MYBPC3 Arg502Trp was identified in 34 of these 1414 unrelated HCM patients. Segregation of MYBPC3 Arg502Trp with clinical status was assessed in family members. Disease haplotypes were examined in 17 families using two loci flanking MYBPC3. Family studies identified an additional 43 variant carriers, many with manifest disease, yielding a calculated odds ratio of 11 000:1 for segregation of MYBPC3 Arg502Trp with HCM. Analyses in 17 families showed at least 4 independent haplotypes flanked MYBPC3 Arg502Trp. Eight individuals (4 probands and 4 family members) also had another sarcomere protein gene mutation. Major adverse clinical events occurred in approximately 30% of MYBPC3 Arg502Trp carriers by age 50; these were significantly more likely (P<0.0001) when another sarcomere mutation was present.

Conclusions: MYBPC3 Arg502Trp is the most common and recurrent pathogenic mutation in a diverse primarily European descent HCM cohort, occurring in 2.4% of patients. MYBPC3 Arg502Trp conveys a 340-fold increased risk for HCM by 45 years of age, when more than 50% of carriers have overt disease. HCM prognosis worsens when MYBPC3 Arg502Trp occurs in the setting of another sarcomere protein gene mutation.

  K Beck , B. J Wu , J Ni , F. S Santiago , K. P Malabanan , C Li , Y Wang , L. M Khachigian and R. Stocker
  Rationale:

Induction of heme oxygenase (HO)-1 protects against experimental atherosclerotic diseases, and certain pharmacological HO-1 inducers, like probucol, inhibit the proliferation of vascular smooth muscle cells and, at the same time, promote the growth of endothelial cells in vivo and in vitro.

Objective:

Because such cell-specific effects are reminiscent of the action of the transcription factor Yin Yang (YY)1, we tested the hypothesis that there is a functional relationship between HO-1 and YY1.

Methods and Results:

We report that probucol increases the number of YY1+ cells in rat carotid artery following balloon injury at a time coinciding with increased HO-1 expression. The drug also induces the expression of YY1 mRNA and protein in rat aortic smooth muscle cells (RASMCs) in vitro, as do other known HO-1 inducers (tert-butylhydroquinone and hemin) and overexpression of HO-1 using a human HMOX1 cDNA plasmid. Conversely, overexpression of YY1 induces expression of HO-1 in RASMCs. Induction of YY1 expression is dependent on HO-1 enzyme activity and its reaction product CO, because pharmacological inhibition of heme oxygenase activity or CO scavenging block, whereas exposure of RASMCs to a CO-releasing molecule increases, YY1 expression. Furthermore, RNA interference knockdown of YY1 prevents probucol or adeno–HO-1 from inhibiting RASMC proliferation in vitro and neointimal formation in vivo.

Conclusions:

Our findings show, for the first time, that HO-1 functionally interplays with the multifunctional transcription factor YY1 and that this interplay explains some of the protective activities of HO-1.

  C Li , M Kuchimanchi , D Hickman , L Poppe , M Hayashi , Y Zhou , R Subramanian , G Kumar and S. Surapaneni
 

Motesanib diphosphate is a novel, investigational, highly selective oral inhibitor of the receptor tyrosine kinases vascular endothelial growth factor receptors 1, 2, and 3, the platelet-derived growth factor receptor, and the stem cell factor receptor (Kit). The in vitro metabolic profiles of [14C]motesanib were examined by using microsomes and hepatocytes from preclinical species and humans. Several oxidative metabolites were observed and characterized by tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and coinjection with authentic standards. Cytochrome P450 (P450) 3A4 is the major isozyme involved in the oxidative biotransformation of motesanib, but the CYP2D6 and CYP1A isozymes also make minor contributions. In hepatocyte incubations, oxidative and conjugative pathways were observed for all species examined, and indoline N-glucuronidation was the dominant pathway. Three less common and novel phase II conjugates of the indoline nitrogen were detected in hepatocytes and in microsomes supplemented with specific cofactors, including N-carbamoyl glucuronide, N-glucose, and N-linked β-N-acetylglucosamine. An N-glucuronide metabolite was the most frequently observed phase II conjugate in liver microsomes of all species, whereas the N-acetylglucosamine conjugate was observed only in monkey liver microsomes. Incubations with recombinant human UDP-glucuronosyltransferases (UGTs) and inhibition by the UGT1A4 and UGT1A1 substrates/inhibitors imipramine and bilirubin suggested that UGT1A4 is the major UGT isozyme catalyzing the N-glucuronidation of motesanib, with a minor contribution from UGT1A1. The in vitro metabolic profiles were similar between the human and preclinical species examined. All metabolites found in humans were also detected in other species.

  C Li , M Kuchimanchi , D Hickman , L Poppe , M Hayashi , Y Zhou , R Subramanian , G Kumar and S. Surapaneni
 

Motesanib diphosphate is a novel, investigational, highly selective oral inhibitor of the receptor tyrosine kinases vascular endothelial growth factor receptors 1, 2, and 3, the platelet-derived growth factor receptor, and the stem cell factor receptor (Kit). The in vitro metabolic profiles of [14C]motesanib were examined by using microsomes and hepatocytes from preclinical species and humans. Several oxidative metabolites were observed and characterized by tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and coinjection with authentic standards. Cytochrome P450 (P450) 3A4 is the major isozyme involved in the oxidative biotransformation of motesanib, but the CYP2D6 and CYP1A isozymes also make minor contributions. In hepatocyte incubations, oxidative and conjugative pathways were observed for all species examined, and indoline N-glucuronidation was the dominant pathway. Three less common and novel phase II conjugates of the indoline nitrogen were detected in hepatocytes and in microsomes supplemented with specific cofactors, including N-carbamoyl glucuronide, N-glucose, and N-linked β-N-acetylglucosamine. An N-glucuronide metabolite was the most frequently observed phase II conjugate in liver microsomes of all species, whereas the N-acetylglucosamine conjugate was observed only in monkey liver microsomes. Incubations with recombinant human UDP-glucuronosyltransferases (UGTs) and inhibition by the UGT1A4 and UGT1A1 substrates/inhibitors imipramine and bilirubin suggested that UGT1A4 is the major UGT isozyme catalyzing the N-glucuronidation of motesanib, with a minor contribution from UGT1A1. The in vitro metabolic profiles were similar between the human and preclinical species examined. All metabolites found in humans were also detected in other species.

  X Lu , J. A Shapiro , C. T Ting , Y Li , C Li , J Xu , H Huang , Y. J Cheng , A. J Greenberg , S. H Li , M. L Wu , Y Shen and C. I. Wu
 

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

  C Li , Z Chen , Z Liu , J Huang , W Zhang , L Zhou , D. L Keefe and L. Liu
 

Mammalian parthenogenetic embryos (pE) are not viable due to placental deficiency, presumably resulting from lack of paternally expressed imprinted genes. Pluripotent parthenogenetic embryonic stem (pES) cells derived from pE could advance regenerative medicine by avoiding immuno-rejection and ethical roadblocks. We attempted to explore the epigenetic status of imprinted genes in the generation of pES cells from parthenogenetic blastocysts, and its relationship to pluripotency of pES cells. Pluripotency was evaluated for developmental and differentiation potential in vivo, based on contributions of pES cells to chimeras and development to day 9.5 of pES fetuses complemented by tetraploid embryos (TEC). Consistently, pE and fetuses failed to express paternally expressed imprinted genes, but pES cells expressed those genes in a pattern resembling that of fertilized embryos (fE) and fertilized embryonic stem (fES) cells derived from fE. Like fE and fES cells, but unlike pE or fetuses, pES cells and pES cell–fetuses complemented by TEC exhibited balanced methylation of Snrpn, Peg1 and U2af1-rs1. Coincidently, global methylation increased in pE but decreased in pES cells, further suggesting dramatic epigenetic reprogramming occurred during isolation and culture of pES cells. Moreover, we identified decreased methylation of Igf2r, Snrpn, and especially U2af1-rs1, in association with increased contributions of pES cells to chimeras. Our data show that in vitro culture changes epigenetic status of imprinted genes during isolation of pES cells from their progenitor embryos and that increased expression of U2af1-rs1 and Snrpn and decreased expression of Igf2r correlate with pluripotency of pES cells.

  W Zheng , W Wen , Y. T Gao , Y Shyr , Y Zheng , J Long , G Li , C Li , K Gu , Q Cai , X. O Shu and W. Lu
  Background

Most of the genetic variants identified from genome-wide association studies of breast cancer have not been validated in Asian women. No risk assessment model that incorporates both genetic and clinical predictors is currently available to predict breast cancer risk in this population.

Methods

We analyzed 12 single-nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies mostly of women of European ancestry as being associated with the risk of breast cancer in 3039 case patients and 3082 control subjects who participated in the Shanghai Breast Cancer Study. All participants were interviewed in person to obtain information regarding known and suspected risk factors for breast cancer. The c statistic, a measure of discrimination ability with a value ranging from 0.5 (random classification) to 1.0 (perfect classification), was estimated to evaluate the contribution of genetic and established clinical predictors of breast cancer to a newly established risk assessment model for Chinese women. Clinical predictors included in the model were age at menarche, age at first live birth, waist-to-hip ratio, family history of breast cancer, and a previous diagnosis of benign breast disease. The utility of the models in risk stratification was evaluated by estimating the proportion of breast cancer patients in the general population that could be accounted for above a given risk threshold as predicted by the models. All statistical tests were two-sided.

Results

Eight SNPs (rs2046210, rs1219648, rs3817198, rs8051542, rs3803662, rs889312, rs10941679, and rs13281615), each of which reflected a genetically independent locus, were found to be associated with the risk of breast cancer. A dose–response association was observed between the risk of breast cancer and the genetic risk score, which is an aggregate measure of the effect of these eight SNPs (odds ratio for women in the highest quintile of genetic risk score vs those in the lowest = 1.85, 95% confidence interval = 1.58 to 2.18, Ptrend = 2.5 x 10–15). The genetic risk score, the waist-to-hip ratio, and a previous diagnosis of benign breast disease were the top three predictors of the risk of breast cancer, each contributing statistically significantly (P < .001) to the full risk assessment model. The model, with a c statistic of 0.6295 after adjustment for overfitting, showed promise for stratifying women into different risk groups; women in the top 30% risk group accounted for nearly 50% of the breast cancers diagnosed in the general population.

Conclusion

A risk assessment model that includes both genetic markers and clinical predictors may be useful to classify Asian women into relevant risk groups for cost-efficient screening and other prevention programs.

  Z Xiao , G Li , Y Chen , M Li , F Peng , C Li , F Li , Y Yu , Y Ouyang and Z. Chen
 

Formalin-fixed, paraffin-embedded (FFPE) tissue specimens represent a potentially valuable resource for protein biomarker investigations. In this study, proteins were extracted by a heat-induced antigen retrieval technique combined with a retrieval solution containing 2% SDS from FFPE tissues of normal nasopharyngeal epithelial tissues (NNET) and three histological types of nasopharyngeal carcinoma (NPC) with diverse differentiation degrees. Then two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling was employed to quantitatively identify the differentially expressed proteins among the types of NPC FFPE tissues. Our study resulted in the identification of 730 unique proteins, the distributions of subcellular localizations and molecular functions of which were similar to those of the proteomic database of human NPC and NNET that we had set up based on the frozen tissues. Additionally, the relative expression levels of cathepsin D, keratin8, SFN, and stathmin1 identified and quantified in this report were consistent with the immunohistochemistry results acquired in our previous study. In conclusion, we have developed an effective approach to identifying protein changes in FFPE NPC tissues utilizing iTRAQ technology in conjunction with an economical and easily accessible sample preparation method. (J Histochem Cytochem 58:517–527, 2010)

  C Li , B. B Sadi , G Moodie , J. N Daka , E. P. C Lai and G. H. Kramer
 

Rapid bioassay is very important for immediate and near-term consequence management, which includes identifying contaminated individuals and providing necessary medical intervention during a radiological or nuclear emergency. This paper reports the application of a newly developed bioassay technique for 90Sr in urine on a field deployable instrument, the Triathler®. Performance of this field technique for sensitivity, accuracy and repeatability is evaluated against bioassay criteria (ANSI N13.30). This field technique offers the following analytical merits: (1) minimum detectable activity of 121 Bq l–1 when 20 ml of urine is used; (2) relative bias of 11.1 % and relative precision of 3.2 % at the level of 45 Bq per 20 ml of urine and (3) sample turnaround time of less than 1 h. The technique meets the requirements for emergency bioassay when a committed effective dose of 0.5 Sv is used as the action dose threshold for medical intervention. Sample throughput can be significantly improved if this technique is automated.

  D. A Solomon , A. C Leon , J Endicott , W. H Coryell , C Li , J. G Fiedorowicz and M. B. Keller
 

Background

Much remains unknown about the phenomenology of bipolar I disorder.

Aims

To determine the type of bipolar I mood episodes that occur over time, and their relative frequency.

Method

A total of 219 individuals with Research Diagnostic Criteria bipolar I disorder were prospectively followed for up to 25 years (median 20 years). Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation.

Results

Overall, 1208 mood episodes were prospectively observed. The episodes were empirically classified as follows: major depression, 30.9% (n = 373); minor depression, 13.0% (n = 157); mania, 20.4% (n = 246); hypomania, 10.4% (n = 126); cycling, 17.3% (n = 210); cycling plus mixed state, 7.8% (n = 94); and mixed, 0.2% (n = 2).

Conclusions

Cycling episodes constituted 25% of all episodes. Work groups revising ICD–10 and DSM–IV should add a category for bipolar I cycling episode.

  W Cao , L Bover , M Cho , X Wen , S Hanabuchi , M Bao , D. B Rosen , Y. H Wang , J. L Shaw , Q Du , C Li , N Arai , Z Yao , L. L Lanier and Y. J. Liu
 

Plasmacytoid dendritic cells (pDCs) produce copious type I interferon (IFN) upon sensing nucleic acids through Toll-like receptor (TLR) 7 and TLR9. Uncontrolled pDC activation and IFN production are implicated in lymphopenia and autoimmune diseases; therefore, a mechanism controlling pDC IFN production is essential. Human pDCs specifically express an orphan receptor, immunoglobulin-like transcript 7 (ILT7). Here, we discovered an ILT7 ligand expressed by human cell lines and identified it as bone marrow stromal cell antigen 2 (BST2; CD317). BST2 directly binds to purified ILT7 protein, initiates signaling via the ILT7–FcRI complex, and strongly inhibits production of IFN and proinflammatory cytokines by pDCs. Readily induced by IFN and other proinflammatory cytokines, BST2 may modulate the human pDC’s IFN responses through ILT7 in a negative feedback fashion.

 
 
 
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