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1.  A Pharmacokinetic/Pharmacodynamic Model of Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia Patients Treated with Flavopiridol 
Purpose
Flavopiridol, the first clinically evaluated cyclin dependent kinase inhibitor, demonstrates activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.
Experimental Design
A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates.
Results
Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy < 10 cm or > 10 cm during the first two treatments was 0.111 (SE% 13.0%) and 0.265, (SE% 17.9%) respectively, when flavo-G area under the plasma concentration vs. time curve was at its median value in whole patient group.
Conclusions
This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine if the associations between TLS, gender and glucuronide metabolites are relevant in CLL patients treated with other cyclin dependent kinase inhibitors.
doi:10.1158/1078-0432.CCR-12-1092
PMCID: PMC3845832  PMID: 23300276
chronic lymphocytic leukemia; flavopiridol; tumor lysis syndrome; population pharmacokinetics; glucuronide metabolite; logistic regression model
2.  Prognosis of patients with gastric cancer and solitary lymph node metastasis 
AIM: To investigate the relationship of solitary lymph node metastasis (SLNM) and age with patient survival in gastric cancer (GC).
METHODS: The medical records databases of China’s Beijing Cancer Hospital at the Peking University School of Oncology and Shanghai Tenth People’s Hospital affiliated to Tongji University were searched retrospectively to identify patients with histologically proven GC and SLNM who underwent surgical resection between October 2003 and December 2012. Patients with distant metastasis or gastric stump carcinoma following resection for benign disease were excluded from the analysis. In total, 936 patients with GC + SLNM were selected for analysis and the recorded parameters of clinicopathological disease and follow-up (range: 13-2925 d) were collected. The Kaplan-Meier method was used to stratify patients by age (≤ 50 years-old, n = 198; 50-64 years-old, n = 321; ≥ 65 years-old, n = 446) and by metastatic lymph node ratio [MLR < 0.04 (1/25), n = 180; 0.04-0.06 (1/25-1/15), n = 687; ≥ 0.06 (1/15), n = 98] for 5-year survival analysis. The significance of intergroup differences between the survival curves was assessed by a log-rank test.
RESULTS: The 5-year survival rate of the entire GC + SLNM patient population was 49.9%. Stratification analysis showed significant differences in survival time (post-operative days) according to age: ≤ 50 years-old: 950.7 ± 79.0 vs 50-64 years-old: 1697.8 ± 65.9 vs ≥ 65 years-old: 1996.2 ± 57.6, all P < 0.05. In addition, younger age (≤ 50 years-old) correlated significantly with mean survival time (r = 0.367, P < 0.001). Stratification analysis also indicated an inverse relationship between increasing MLR and shorter survival time: < 0.04: 52.8% and 0.04-0.06: 51.1% vs ≥ 0.06: 40.5%, P < 0.05. The patients with the shortest survival times and rates were younger and had a high MLR (≥ 0.06): ≤ 50 years-old: 496.4 ± 133.0 and 0.0% vs 50-65 years-old: 1180.9 ± 201.8 and 21.4% vs ≥ 65 years-old: 1538.4 ± 72.4 and 37.3%, all P < 0.05. The same significant trend in shorter survival times and rates for younger patients was seen with the mid-range MLR group (0.04-0.06), but the difference between the two older groups was not significant. No significant differences were found between the age groups of patients with MLR < 0.04. Assessment of clinicopathological parameters identified age group, Borrmann type, histological type and tumor depth as the most important predictors of the survival rates and times observed for this study population.
CONCLUSION: GC patients below 51 years of age with MLR of SLNM above 0.06 have shorter life expectancy than their older counterparts.
doi:10.3748/wjg.v19.i46.8611
PMCID: PMC3870506  PMID: 24379578
Gastric cancer; Solitary lymph node metastasis; Age; Metastatic lymph node ratio; Survival
3.  Intestinal stem cell marker LGR5 expression during gastric carcinogenesis 
AIM: To investigate the differential expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in gastric cancer tissues and its significance related to tumor growth and spread.
METHODS: Formalin-fixed biopsy specimens of intestinal metaplasia (n = 90), dysplasia (n = 53), gastric adenocarcinoma (n = 180), metastases in lymph nodes and the liver (n = 15), and lesion-adjacent normal gastric mucosa (controls; n = 145) were obtained for analysis from the Peking University Cancer Hospital’s Department of Pathology and Gastrointestinal Surgery tissue archives (January 2003 to December 2011). The biopsied patients’ demographic and clinicopathologic data were retrieved from the hospital’s medical records database. Each specimen was subjected to histopathological typing to classify the tumor node metastasis (TNM) stage and to immunohistochemistry staining to detect the expression of the cancer stem cell marker LGR5. The intergroup differences in LGR5 expression were assessed by Spearman’s rank correlation analysis, and the relationship between LGR5 expression level and the patients’ clinicopathological characteristics was evaluated by the χ2 test or Fisher’s exact test.
RESULTS: Significantly more gastric cancer tissues showed LGR5+ staining than normal control tissues (all P < 0.01), with immunoreactivity detected in 72.2% (65/90) and 50.9% (27/53) of intestinal metaplasia and dysplasia specimens, respectively, 52.8% (95/180) of gastric adenocarcinoma specimens, and 73.3%% (11/15) of metastasis specimens, but 26.9% (39/145) of lesion-adjacent normal gastric mucosa specimens. Comparison of the intensity of LGR5+ staining showed an increasing trend that generally followed increasing dedifferentiation and tumor spread (normal tissue < dysplasia, < gastric adenocarcinoma < metastasis; all P < 0.001), with the exception of expression level detected in intestinal metaplasia which was higher than that in normal gastric tissues (P < 0.001). Moreover, gastric cancer-associated enhanced expression of LGR5 was found to be significantly associated with age, tumor differentiation, Lauren type and TNM stage (I + II vs III + IV) (all P < 0.05), but not with sex, tumor site, location, size, histology, lymphovascular invasion, depth of invasion, lymph node metastasis or distant metastasis. Patients with LGR5+ gastric cancer specimens and without signs of metastasis from the original biopsy experienced more frequent rates of recurrence or metastasis during follow-up than patients with LGR5- specimens (P < 0.05).
CONCLUSION: Enhanced LGR5 is related to progressive dedifferentiation and metastasis of gastric cancer, indicating the potential of this receptor as an early diagnostic and prognostic biomarker.
doi:10.3748/wjg.v19.i46.8714
PMCID: PMC3870519  PMID: 24379591
Leucine-rich repeat-containing G protein-coupled receptor 5; Cancer stem cell; Gastric cancer; Intestinal metaplasia; Tumorigenesis
4.  Imatinib mesylate in clinically suspected gastric stromal tumors 
Gastrointestinal stromal tumors (GISTs) occur most frequently in the stomach. Diagnosis of gastric GIST is not always clear before surgery. Flexible endoscopy may suggest the nature of the lesion (a bulky tumor with preserved mucosa); however, biopsy is rarely diagnostic. Therefore, diagnostic medication with safe drugs may provide a feasible way under such conditions after an informed consent is obtained. Based on the excellent efficacy of imatinib mesylate (IM) in the treatment of GIST, we successfully applied it in the diagnostic medication of two patients with clinically suspected gastric stromal tumors. In conclusion, the diagnostic medication with IM can be an alternative option for patients with suspected GIST that can not be confirmed pathologically.
doi:10.3978/j.issn.1000-9604.2013.10.14
PMCID: PMC3828431  PMID: 24255585
Gastrointestinal stromal tumors (GISTs); imatinib mesylate (IM); magnetic resonance imaging (MRI)
5.  Therapeutic Efficacy of Fuzheng-Huayu Tablet Based Traditional Chinese Medicine Syndrome Differentiation on Hepatitis-B-Caused Cirrhosis: A Multicenter Double-Blind Randomized Controlled Trail 
Aim. To evaluate and predict the therapeutic efficacy of Fuzheng-Huayu tablet (FZHY) based traditional Chinese Medicine (TCM) syndrome differentiation or TCM symptoms on chronic hepatitis B caused cirrhosis (HBC). Methods. The trial was designed according to CONSORT statement. It was a multi-center, double-blind, randomized, placebo-controlled trail. Several clinical parameters, Child-Pugh classification and TCM symptoms were detected and evaluated. The FZHY efficacy was predicted by an established Bayes forecasting method following the Bayes classification model. Results. The levels of HA and TCM syndrome score in FZHY group were significantly decreased (P < 0.05) compared to placebo group, respectively. The efficacy of FZHY on TCM syndrome score in HBC patients with some TCM syndromes was better. In TCM syndrome score evaluation, there were 53 effective and 22 invalid in FZHY group. TCM symptoms predicted FZHY efficacy on HBC were close to Child-Pugh score prediction. Conclusion. FZHY decreases the levels of HA and TCM syndrome scores, improves the life quality of HBC patients. Moreover, there were different therapeutic efficacies among different TCM syndromes, indicating that accurate TCM syndrome differentiation might guide the better TCM treatment. Furthermore, the FZHY efficacy was able to predict by Bayes forecasting method through the alteration of TCM symptoms.
doi:10.1155/2013/709305
PMCID: PMC3606729  PMID: 23533516
6.  Age-Specific Human Papillomavirus Antibody and DNA Prevalence: A Global Review 
Purpose
Global data on human papillomavirus serological and DNA prevalence are essential to optimize HPV prophylactic vaccination strategies.
Methods
We conducted a global review of age-specific HPV antibody and studies with both antibody and DNA prevalence for HPV types 16, 18, 6 and 11.
Results
One hundred-seventeen studies were included; participants’ ages ranged from several hours to over 90 years. HPV 16 seroprevalence was generally higher in Africa, Central and South America, and North America, more prevalent among women than men, and peaked around ages 25-40 years. HPV 18 seroprevalence was generally lower than HPV 16 with a later age peak. Data were limited for HPV 6 and 11, which both peaked at ages similar to HPV 18. In 9-26 year-old females, HPV 16 seroprevalence ranged from 0-31% in North America, 21-30% in Africa, 0-23% in Asia/Australia, 0-33% in Europe, and 13-43% in Central and South America. HPV 16/18 DNA prevalence peaked 10-15 years before corresponding HPV 16/18 antibody prevalence.
Conclusions
Females within the HPV-vaccine eligible age group (9-26 years) had a range of dual HPV 16 DNA and serology negativity from 81-87%, whereas 90-98% were HPV 16 DNA negative. Serology and DNA data are lacking worldwide for females younger than age 15 years, the prime target group for vaccination.
doi:10.1016/j.jadohealth.2011.10.010
PMCID: PMC3572199  PMID: 22265107
Global; Human papillomavirus; Serology; DNA; prevalence; immunology; antibodies
7.  Evolution of viral RNA in a Chinese patient to interferon/ribavirin therapy for hepatitis C 
Objective
The combination of interferon (IFN) and ribavirin (RBV) is the standard therapy for hepatitis C virus (HCV) infection. HCV genotype 2a has proved more amenable to the therapy, but its efficacy is yet limited. This study aimed to investigate the mechanism of the poor response in a case of HCV genotype 2a infection.
Methods
We analyzed dynamic change of HCV RNA from a patient, infected with HCV genotype 2a, showing a poor virological response to IFN/RBV as judged 12 weeks after initiation of the therapy by HCV clone sequencing. Then we constructed subgenomic Japanese fulminant hepatitis-1 (JFH1) replicon and different chimeric replicons with humanized Gaussia luciferase gene. The chimeric replicons were derived from subgenomic JFH1 replicon, in which the NS5A region was replaced by the patient’s sequence from the pre/post-treatment, and the chimeric replicons’ susceptibility to IFN were evaluated by relative Gausia Luciferase activity.
Results
The pretreatment HCV sequences appeared almost uniform, and the quasispecies variation was further more simplified after 12 weeks of therapy. Besides, the quasispecies variation seemed to be more diversified in the NS5A, relatively, a region crucial for IFN response, and each of chimeric replicons exhibited distinct response to IFN.
Conclusions
During the course of the chronic infection, HCV population seems to be adapted to the patient’s immunological system, and further to be selected by combination of IFN/RBV therapy, indicating quasispecies may completely eliminated by addition of other drugs with targets different from those of IFN. In addition, each different response of chimeric replicon to IFN is most likely related to amino acid changes in or near the IFN-sensitivity determining region (ISDR) of NS5A during chronic infection and IFN/RBV therapy.
doi:10.3978/j.issn.1000-9604.2012.10.01
PMCID: PMC3551335  PMID: 23359634
HCV-2a; IFN; poor response; JFH1; chimeric replicon
8.  Myofibrillogenesis regulator-1 overexpression is associated with poor prognosis of gastric cancer patients 
AIM: To investigate the expression of myofibrillogenesis regulator-1 (MR-1) in relation to clinicopathological parameters and postoperative survival in a group of Chinese patients with gastric cancer.
METHODS: In our previous study of human whole-genome gene expression profiling, the differentially expressed genes were detected in the gastric cancer and its adjacent noncancerous mucosa. We found that MR-1 was associated with the location and differentiation of tumors. In this study, MR-1 protein expression was determined by immunohistochemistry in specimens of primary cancer and the adjacent noncancerous tissues from gastric cancer patients. A set of real-time quantitative polymerase chain reaction assays based on the Universal ProbeLibrary-a collection of 165 presynthesized, fluorescence-labeled locked nucleic acid hydrolysis probes-was designed specifically to detect the expression of MR-1 mRNA. The correlation was analyzed between the expression of MR-1 and other tumor characteristics which may influence the prognosis of gastric cancer patients. A retrospective cohort study on the prognosis was carried out and clinical data were collected from medical records.
RESULTS: MR-1 mRNA and protein could be detected in gastric cancer tissues as well as in matched noncancerous tissues. MR-1 was up-regulated at both mRNA (5.459 ± 0.639 vs 1.233 ± 0.238, P < 0.001) and protein levels (34.2% vs 13.2%, P = 0.003) in gastric cancer tissues. Correlation analysis demonstrated that high expression of MR-1 in gastric cancer was significantly correlated with clinical stage (P = 0.034). Kaplan-Meier analysis showed that the postoperative survival of the MR-1 positive group tended to be poorer than that of the MR-1 negative group, and the difference was statistically significant (P = 0.002). Among all the patients with stage I-IV carcinoma, the 5-year survival rates of MR-1 positive and negative groups were 50.40% and 12.70%, respectively, with respective median survival times of 64.27 mo (95%CI: 13.41-115.13) and 16.77 mo (95%CI: 8.80-24.74). Univariate and multivariate analyses were performed to compare the impact of MR-1 expression and other clinicopathological parameters on prognosis. In a univariate analysis on all 70 specimens, 6 factors were found to be significantly associated with the overall survival statistically: including MR-1 expression, depth of invasion, distant metastasis, lymph node metastasis, vascular invasion and the tumor node metastasis (TNM) stage based on the 7th edition of the International Union against Cancer TNM classification. To avoid the influence caused by univariate analysis, the expressions of MR-1 as well as other parameters were examined in multivariate Cox analysis. Clinicopathological variables that might affect the prognosis of gastric cancer patients were analyzed by Cox regression analysis, which showed that MR-1 expression and TNM stage were independent predictors of postoperative survival. The best mathematical multivariate Cox regression model consisted of two factors: MR-1 expression and TNM stage. Our results indicated that MR-1 protein could act as an independent marker for patient overall survival [Hazard ratio (HR): 2.215, P = 0.043].
CONCLUSION: MR-1 is an important variable that can be used to evaluate the outcome, prognosis and targeted therapy of gastric cancer patients.
doi:10.3748/wjg.v18.i38.5434
PMCID: PMC3471113  PMID: 23082061
Myofibrillogenesis regulator-1; Gastric cancer; Real-time quantitative reverse transcriptase-polymerase chain reaction; Immunohistochemistry; Poor prognosis
9.  Phase I Trial of Lenalidomide and CCI-779 in Patients With Relapsed Multiple Myeloma: Evidence for Lenalidomide–CCI-779 Interaction via P-Glycoprotein  
Journal of Clinical Oncology  2011;29(25):3427-3434.
Purpose
Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.
Patients and Methods
A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions.
Results
Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate.
Conclusion
The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp–based drug-drug interaction with lenalidomide.
doi:10.1200/JCO.2010.32.4962
PMCID: PMC3164245  PMID: 21825263
10.  Presence of S100A9-positive inflammatory cells in cancer tissues correlates with an early stage cancer and a better prognosis in patients with gastric cancer 
BMC Cancer  2012;12:316.
Background
S100A9 was originally discovered as a factor secreted by inflammatory cells. Recently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in gastric cancer and explore its role in cancer progression.
Methods
S100A9 expression in gastric tissue samples from 177 gastric cancer patients was assessed by immunohistochemistry. The expression of its dimerization partner S100A8 and the S100A8/A9 heterodimer were also assessed by the same method. The effect of exogenous S100A9 on motility of gastric cancer cells AGS and BGC-823 was then investigated.
Results
S100A9 was specifically expressed by inflammatory cells such as macrophages and neutrophils in human gastric cancer and gastritis tissues. Statistical analysis showed that a high S100A9 cell count (> = 200) per 200x magnification microscopic field in cancer tissues was predictive of early stage gastric cancer. High S100A9-positive cell count was negatively correlated with lymph node metastasis (P = 0.009) and tumor invasion (P = 0.011). S100A9 was identified as an independent prognostic predictor of overall survival of patients with gastric cancer (P = 0.04). Patients with high S100A9 cell count were with favorable prognosis (P = 0.021). Further investigation found that S100A8 distribution in human gastric cancer tissues was similar to S100A9. However, the number of S100A8-positive cells did not positively correlate with patient survival. The inflammatory cells infiltrating cancer were S100A8/A9 negative, while those in gastritis were positive. Furthermore, exogenous S100A9 protein inhibited migration and invasion of gastric cancer cells.
Conclusions
Our results suggested S100A9-positive inflammatory cells in gastric cancer tissues are associated with early stage of gastric cancer and good prognosis.
doi:10.1186/1471-2407-12-316
PMCID: PMC3476982  PMID: 22838504
Gastric cancer; S100A9; Inflammatory cells; Tumor staging; Survival
11.  Seroprevalence of Human Papillomavirus Types 6, 11, 16 and 18 in Chinese Women 
BMC Infectious Diseases  2012;12:137.
Background
Human papillomavirus (HPV) seroprevalence data have not previously been reported for different geographical regions of China. This study investigated the cross-sectional seroprevalence of antibodies to HPV 6, 11, 16, and 18 virus-like particles in Chinese women.
Methods
Population-based samples of women were enrolled from 2006 to 2007 in 3 rural and 2 urban areas of China. Each consenting woman completed a questionnaire and provided a blood sample. Serum antibodies were detected using a competitive Luminex immunoassay that measures antibodies to type-specific, neutralizing epitopes on the virus-like particles.
Results
A total of 4,731 women (median age 35, age range 14-54) were included, of which 4,211 were sexually active women (median age 37) and 520 virgins (median age 18). Low risk HPV 6 was the most common serotype detected (7.3%), followed by HPV 16 (5.6%), HPV 11 (2.9%), and HPV 18 (1.9%). Overall HPV seroprevalence to any type was significantly higher among sexually active women (15.8%) than virgins (2.5%) (P = 0.005). Overall seroprevalence among sexually active women gradually increased with age. Women from rural regions had significantly lower overall seroprevalence (Odds Ratio (OR) = 0.7; 95% CI: 0.6-0.9, versus metropolitan regions, P < 0.001). With increasing number of sexual partners, women were at higher risk of seropositivity of any type (OR = 2.6; 95% CI: 1.7-3.9 for > = 4 partners versus 1 partner, P < 0.001). Wives were at higher risk of seropositivity for HPV 16/18/6/11 when reporting having a husband who had an extramarital sexual relationship (OR = 2.0; 95% CI: 1.6-2.5, versus those whose husbands having no such relationship, P < 0.001). There was a strong association between HPV 16 seropositivity and presence of high-grade cervical lesions (OR = 6.5; 95% CI: 3.7-11.4, versus normal cervix, P < 0.001).
Conclusions
HPV seroprevalence differed significantly by age, geography, and sexual behavior within China, which all should be considered when implementing an optimal prophylactic HPV vaccination program in China.
doi:10.1186/1471-2334-12-137
PMCID: PMC3482566  PMID: 22715915
Human papillomavirus; Seroprevalence; China
12.  Risk Factors for Tumor Lysis Syndrome in patients with Chronic Lymphocytic Leukemia Treated with the Cyclin Dependent Kinase Inhibitor, Flavopiridol 
Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia (CLL) treated with the cyclin dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36%-55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III-IV, adenopathy ≥ 10 cm, splenomegaly, del(11q), decreased albumin, and increased absolute lymphocyte count, white blood cell count (WBC), β2-microglobulin, and lactate dehydrogenase (LDH) were associated (p<0.05) with TLS. In multivariable analysis, female gender, adenopathy ≥ 10 cm, elevated WBC, increased β2-microglobulin, and decreased albumin were associated with TLS (p<0.05). With respect to patient outcomes, 49% and 44% of patients with and without TLS, respectively, responded to flavopiridol (p=0.71). In a multivariable analysis controlling for number of prior therapies, cytogenetics, Rai stage, age, and gender, progression-free survival (PFS) was inferior in patients with TLS (p=0.01). Female patients and patients with elevated β2-microglobulin, increased WBC, adenopathy ≥ 10 cm, and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol.
doi:10.1038/leu.2011.109
PMCID: PMC3162125  PMID: 21606960
chronic lymphocytic leukemia; flavopiridol; tumor lysis syndrome
13.  Attributable Causes of Breast Cancer and Ovarian Cancer in China: Reproductive Factors, Oral Contraceptives and Hormone Replacement Therapy 
Objective
To provide an evidence-based, consistent assessment of the burden of breast cancer attributable to reproductive factors (RFs, including nulliparity, mean number of children, age at first birth and breastfeeding), use of oral contraceptives (OCs, restricted to the age group of 15-49 years), and hormone replacement therapy (HRT), as well as of the burden of ovarian cancer attributable to the mean number of children in China in 2005.
Methods
We derived the prevalence of these risk factors and the relative risk of breast and ovarian cancer from national surveys or large-scale studies conducted in China. In the case of RFs, we compared the exposure distributions in 2001 and counterfactual exposure.
Results
Exposure of RFs in 2001 was found to account for 6.74% of breast cancer, corresponding to 9,617 cases and 2,769 deaths, and for 2.78% of ovarian cancer (711 cases, 294 deaths). The decrease in mean number of children alone was responsible for 1.47% of breast cancer and 2.78% of ovarian cancer. The prevalence of OC use was 1.74% and the population attributable fraction (PAF) of breast cancer was 0.71%, corresponding to 310 cases and 90 deaths. The PAF of breast cancer due to HRT was 0.31%, resulting in 297 cases and 85 deaths.
Conclusion
RFs changes in China contributed to a sizable fraction of breast and ovarian cancer incidence and mortality, whereas HRT and OCs accounted for relatively low incidence of breast cancer in China.
doi:10.1007/s11670-012-0009-y
PMCID: PMC3555252  PMID: 23359757
Reproductive factors; Oral contraceptives; Hormone replacement therapy; Cancer; Population attributable fraction
14.  Neoadjuvant chemotherapy for locally advanced gastric cancer: With or without radiation 
The role of perioperative chemotherapy for gastric cancer has been established for gastric cancers in their advanced stage. In most parts of the world, even in Japan and Korea, local recurrence of gastric cancer following curative resection remains a problem. Should radiation be added to chemotherapy to achieve better local and regional control? What is the current evidence? What are the concerns regarding neoadjuvant chemoradiation in terms of safety, efficacy and survival benefit? After a serious review of the literature, the authors conclude that it is still too early to get a definitive answer but radiation seems promising. It may bring a higher pathological response rate. Rationally, more high level clinical trials are needed to confirm the role of radiotherapy in the neoadjuvant setting or to ascertain subsets of patients who may benefit from it. It is of note that surgeons should pay attention to possible complicated circumstances following radiotherapy, maintain proper nutrition status and minimize the occurrence of postoperative complications. As few data are available in Japan and Korea, interpretation and implementation of neoadjuvant radiation or chemoradiation should be done with caution.
doi:10.4240/wjgs.v4.i2.27
PMCID: PMC3297664  PMID: 22408715
Stomach; Neoplasm; Treatment; Radiation; Neoadjuvant
15.  Complications after radical gastrectomy following FOLFOX7 neoadjuvant chemotherapy for gastric cancer 
Background
This study assessed the postoperative morbidity and mortality occurring in the first 30 days after radical gastrectomy by comparing gastric cancer patients who did or did not receive the FOLFOX7 regimen of neoadjuvant chemotherapy.
Methods
We completed a retrospective analysis of 377 patients after their radical gastrectomies were performed in our department between 2005 and 2009. Two groups of patients were studied: the SURG group received surgical treatment immediately after diagnosis; the NACT underwent surgery after 2-6 cycles of neoadjuvant chemotherapy.
Results
There were 267 patients in the SURG group and 110 patients in the NACT group. The NACT group had more proximal tumours (P = 0.000), more total/proximal gastrectomies (P = 0.000) and longer operative time (P = 0.005) than the SURG group. Morbidity was 10.0% in the NACT patients and 17.2% in the SURG patients (P = 0.075). There were two cases of postoperative death, both in the SURG group (P = 1.000). No changes in complications or mortality rate were observed between the SURG and NACT groups.
Conclusion
The FOLFOX7 neoadjuvant chemotherapy is not associated with increased postoperative morbidity, indicating that the FOLFOX7 neoadjuvant chemotherapy is a safe choice for the treatment of local advanced gastric cancer.
doi:10.1186/1477-7819-9-110
PMCID: PMC3204253  PMID: 21942969
Gastric cancer; neoadjuvant chemotherapy; complication; FOLFOX7; surgery
16.  Over-expression of Metastasis-associated in Colon Cancer-1 (MACC1) Associates with Better Prognosis of Gastric Cancer Patients 
Objective
The aim of this study was to detect metastasis-associated in colon cancer-1 (MACC1) expression in Chinese gastric cancer and analyze the relationship between MACC1 expression and postoperative survival.
Methods
The expression of MACC1 and c-MET protein in a sample of 128 gastric cancer tissues was detected by immunohistochemistry. A retrospective cohort study on the prognosis was carried out and data were collected from medical records.
Results
The positive rate of MACC1 protein expression in gastric cancer was 47.66%, higher than that in adjacent noncancerous mucosa (P<0.001). MACC1 protein expression was not related to the clinicopathological variables involved. Kaplan-Meier analysis revealed that the survival of MACC1 positive group tended to be better than that of MACC1 negative group, particularly in patients with stage III carcinoma (P=0.032). Cox regression analysis revealed that MACC1 protein over-expression in gastric cancer tended to be a protective factor with hazard ratio of 0.621 (P=0.057). Immunohistochemical analysis showed that the positive rate of c-MET protein expression was much higher in cases with positive MACC1 expression in gastric cancer (P=0.002), but P53 expression was not associated with MACC1 expression.
Conclusion
MACC1 over-expression implies better survival and may be an independent prognostic factor for gastric cancer in Chinese patients.
doi:10.1007/s11670-011-0153-9
PMCID: PMC3587544  PMID: 23483020
MACC1; Gastric cancer; Prognosis
17.  Discovery and validation of prognostic markers in gastric cancer by genome-wide expression profiling 
AIM: To develop a prognostic gene set that can predict patient overall survival status based on the whole genome expression analysis.
METHODS: Using Illumina HumanWG-6 BeadChip followed by semi-supervised analysis, we analyzed the expression of 47 296 transcripts in two batches of gastric cancer patients who underwent surgical resection. Thirty-nine samples in the first batch were used as the training set to discover candidate markers correlated to overall survival, and thirty-three samples in the second batch were used for validation.
RESULTS: A panel of ten genes were identified as prognostic marker in the first batch samples and classified patients into a low- and a high-risk group with significantly different survival times (P = 0.000047). This prognostic marker was then verified in an independent validation sample batch (P = 0.0009). By comparing with the traditional Tumor-node-metastasis (TNM) staging system, this ten-gene prognostic marker showed consistent prognosis results. It was the only independent prognostic value by multivariate Cox regression analysis (P = 0.007). Interestingly, six of these ten genes are ribosomal proteins, suggesting a possible association between the deregulation of ribosome related gene expression and the poor prognosis.
CONCLUSION: A ten-gene marker correlated with overall prognosis, including 6 ribosomal proteins, was identified and verified, which may complement the predictive value of TNM staging system.
doi:10.3748/wjg.v17.i13.1710
PMCID: PMC3072635  PMID: 21483631
Gastric cancer; Gene expression profiling; Survival markers; Prognosis; Ribosomal proteins
18.  Genome Sequence of the Milbemycin-Producing Bacterium Streptomyces bingchenggensis▿  
Journal of Bacteriology  2010;192(17):4526-4527.
Streptomyces bingchenggensis is a soil-dwelling bacterium producing the commercially important anthelmintic macrolide milbemycins. Besides milbemycins, the insecticidal polyether antibiotic nanchangmycin and some other antibiotics have also been isolated from this strain. Here we report the complete genome sequence of S. bingchenggensis. The availability of the genome sequence of S. bingchenggensis should enable us to understand the biosynthesis of these structurally intricate antibiotics better and facilitate rational improvement of this strain to increase their titers.
doi:10.1128/JB.00596-10
PMCID: PMC2937363  PMID: 20581206
19.  Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition 
PLoS ONE  2010;5(11):e13792.
Background
Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.
Methodology/Principal Findings
Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.
Conclusions/Significance
Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy.
doi:10.1371/journal.pone.0013792
PMCID: PMC2967470  PMID: 21072184
20.  Methylation of GATA-4 and GATA-5 and development of sporadic gastric carcinomas 
AIM: To understand the implication of GATA-4 and GATA-5 methylation in gastric carcinogenesis.
METHODS: Methylation status of GATA-4 and GATA-5 CpG islands in human gastric mucosa samples, including normal gastric biopsies from 45 outpatients, gastric dysplasia [low-grade gastric intraepithelial neoplasia (GIN), n = 30; indefinite, n = 77], and 80 paired sporadic gastric carcinomas (SGC) as well as the adjacent non-neoplastic gastric tissues was analyzed by methylation specific polymerase chain reaction (MSP) and confirmed by denatured high performance liquid chromatography (DHPLC). Immunohistochemical staining was used to detect protein expression. The correlation between GATA-4 and GATA-5 methylation and clinicopathological characteristics of patients including Helicobacter pylori (H. pylori) infection was analyzed.
RESULTS: GATA-4 and GATA-5 methylation was frequently observed in SGCs (53.8% and 61.3%, respectively) and their corresponding normal tissues (41.3% and 46.3%) by MSP. The result of MSP was consistent with that of DHPLC. Loss of both GATA-4 and GATA-5 proteins was associated with their methylation in SGCs (P = 0.01). Moreover, a high frequency of GATA-4 and GATA-5 methylation was found in both gastric low-grade GIN (57.1% and 69.0%) and indefinite for dysplasia (42.9% and 46.7%), respectively. However, GATA-4 and GATA-5 methylation was detected only in 4/32 (12.5%) and 3/39 (7.7%) of normal gastric biopsies. GATA-4 methylation in both normal gastric mucosa and low-grade GIN was also significantly associated with H. pylori infection (P = 0.023 and 0.027, two-sides).
CONCLUSION: Epigenetic inactivation of GATA-4 (and GATA-5) by methylation of CpG islands is an early frequent event during gastric carcinogenesis and is significantly correlated with H. pylori infection.
doi:10.3748/wjg.v16.i10.1201
PMCID: PMC2839171  PMID: 20222162
Dysplasia; Gastric carcinoma; GATA-4; GATA-5; Helicobacter pylori; Methylation
21.  The Genomes of Oryza sativa: A History of Duplications 
Yu, Jun | Wang, Jun | Lin, Wei | Li, Songgang | Li, Heng | Zhou, Jun | Ni, Peixiang | Dong, Wei | Hu, Songnian | Zeng, Changqing | Zhang, Jianguo | Zhang, Yong | Li, Ruiqiang | Xu, Zuyuan | Li, Shengting | Li, Xianran | Zheng, Hongkun | Cong, Lijuan | Lin, Liang | Yin, Jianning | Geng, Jianing | Li, Guangyuan | Shi, Jianping | Liu, Juan | Lv, Hong | Li, Jun | Wang, Jing | Deng, Yajun | Ran, Longhua | Shi, Xiaoli | Wang, Xiyin | Wu, Qingfa | Li, Changfeng | Ren, Xiaoyu | Wang, Jingqiang | Wang, Xiaoling | Li, Dawei | Liu, Dongyuan | Zhang, Xiaowei | Ji, Zhendong | Zhao, Wenming | Sun, Yongqiao | Zhang, Zhenpeng | Bao, Jingyue | Han, Yujun | Dong, Lingli | Ji, Jia | Chen, Peng | Wu, Shuming | Liu, Jinsong | Xiao, Ying | Bu, Dongbo | Tan, Jianlong | Yang, Li | Ye, Chen | Zhang, Jingfen | Xu, Jingyi | Zhou, Yan | Yu, Yingpu | Zhang, Bing | Zhuang, Shulin | Wei, Haibin | Liu, Bin | Lei, Meng | Yu, Hong | Li, Yuanzhe | Xu, Hao | Wei, Shulin | He, Ximiao | Fang, Lijun | Zhang, Zengjin | Zhang, Yunze | Huang, Xiangang | Su, Zhixi | Tong, Wei | Li, Jinhong | Tong, Zongzhong | Li, Shuangli | Ye, Jia | Wang, Lishun | Fang, Lin | Lei, Tingting | Chen, Chen | Chen, Huan | Xu, Zhao | Li, Haihong | Huang, Haiyan | Zhang, Feng | Xu, Huayong | Li, Na | Zhao, Caifeng | Li, Shuting | Dong, Lijun | Huang, Yanqing | Li, Long | Xi, Yan | Qi, Qiuhui | Li, Wenjie | Zhang, Bo | Hu, Wei | Zhang, Yanling | Tian, Xiangjun | Jiao, Yongzhi | Liang, Xiaohu | Jin, Jiao | Gao, Lei | Zheng, Weimou | Hao, Bailin | Liu, Siqi | Wang, Wen | Yuan, Longping | Cao, Mengliang | McDermott, Jason | Samudrala, Ram | Wang, Jian | Wong, Gane Ka-Shu | Yang, Huanming | Bennetzen, Jeff
PLoS Biology  2005;3(2):e38.
We report improved whole-genome shotgun sequences for the genomes of indica and japonica rice, both with multimegabase contiguity, or almost 1,000-fold improvement over the drafts of 2002. Tested against a nonredundant collection of 19,079 full-length cDNAs, 97.7% of the genes are aligned, without fragmentation, to the mapped super-scaffolds of one or the other genome. We introduce a gene identification procedure for plants that does not rely on similarity to known genes to remove erroneous predictions resulting from transposable elements. Using the available EST data to adjust for residual errors in the predictions, the estimated gene count is at least 38,000–40,000. Only 2%–3% of the genes are unique to any one subspecies, comparable to the amount of sequence that might still be missing. Despite this lack of variation in gene content, there is enormous variation in the intergenic regions. At least a quarter of the two sequences could not be aligned, and where they could be aligned, single nucleotide polymorphism (SNP) rates varied from as little as 3.0 SNP/kb in the coding regions to 27.6 SNP/kb in the transposable elements. A more inclusive new approach for analyzing duplication history is introduced here. It reveals an ancient whole-genome duplication, a recent segmental duplication on Chromosomes 11 and 12, and massive ongoing individual gene duplications. We find 18 distinct pairs of duplicated segments that cover 65.7% of the genome; 17 of these pairs date back to a common time before the divergence of the grasses. More important, ongoing individual gene duplications provide a never-ending source of raw material for gene genesis and are major contributors to the differences between members of the grass family.
Comparative genome sequencing of indica and japonica rice reveals that duplication of genes and genomic regions has played a major part in the evolution of grass genomes
doi:10.1371/journal.pbio.0030038
PMCID: PMC546038  PMID: 15685292

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