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1.  Demographic and Placement Variables Associated with Overweight and Obesity in Children in Long-Term Foster Care 
Maternal and child health journal  2013;17(9):10.1007/s10995-012-1181-x.
Overweight and obesity is a growing problem for children in foster care. This study describes the prevalence of overweight and obesity in an urban, ethnic minority population of children ages 2–19 in long-term foster care (N = 312) in Los Angeles, California. It also investigates whether demographics or placement settings are related to high body mass index.
The estimates of prevalence of overweight/obesity (≥ 85th percentile) and obesity (≥ 95th percentile) were presented for gender, age, ethnicity, and placement type. Multiple logistic regression was used to examine potential associations between demographic and placement variables and weight status.
The prevalence of overweight/obesity was 40% and obesity was 23% for the study population. Children placed in a group home had the highest prevalence of overweight/obesity (60%) and obesity (43%) compared to other types of placement. Within this study, older children (ages 12–19) were more likely to be overweight/obese than normal weight compared to children between 2 and 5 years old when controlling for gender, ethnicity and placement (OR = 2.10, CI =1.14–3.87).
These findings suggest that older age and long-term foster care in general may be risk factors for obesity. Child welfare agencies and health care providers need to work together to train caregivers with children in long-term foster care in obesity treatment interventions and obesity prevention strategies.
PMCID: PMC3586377  PMID: 23124799
childhood obesity; overweight; long-term foster care; group home
2.  Weight changes in children in foster care for 1 year 
Child abuse & neglect  2013;37(10):832-840.
The aims of this study of predominately racial/ethnic minority children in foster care (N = 360, birth to 19 years old) in Los Angeles, CA were to examine the (1) prevalence of obesity (≥ 95 percentile) and overweight/obese(≥ 85 percentile) upon entrance to foster care (T1) and after 1 year in foster care (T2); (2) comparison of high weight categories to national statistics; (3) relationship of changes in weight status to age, reason for entry into foster care, and placement.
Chi-square test and McNemar test comparing paired proportions were used to determine whether there were significant changes in the proportion of high weight categories between T1 and T2. Chi-square test or Fisher’s exact test were used to evaluated the association between age, placement, and reason for foster care with the change in weight category. Changes in weight were categorized as (1) decreased in weight, (2) remained at overweight or obese, (3) increased in weight, or (4) remained normal.
The proportion of obese and obese/overweight children between age 2 and 5 were significantly lower at T2 than T1. There were no significant changes in the prevalence of obesity for the total population at T2. Children age 6 or older had a higher prevalence of obesity and overweight/obesity compared to national statistics. Of children at all ages, 64.7% of children of all ages entered foster care with a normal weight and stayed in the normal range during their first year in foster care, 12.2% decreased their weight, 15.4% remained overweight or obese, and 7.7% increased their weight. Age and parental substance use was related to change in weight category from T1 to T2.
Children did not become more overweight or obese in foster care; however 28% of the children were obese or overweight upon entry into foster care. Children who are 6 years or older and obese upon entering foster care should be targeted for weight reduction. The pediatric community and child welfare system need to work together by including weight percentiles in the foster care file and training/monitoring child welfare caregivers in weight reduction interventions.
PMCID: PMC3713178  PMID: 23499524
3.  Clinicopathological and prognostic role of MMP-9 in esophageal squamous cell carcinoma: a meta-analysis 
Many studies reported that matrix metalloproteinase-9 (MMP-9) participated in the development of esophageal squamous cell carcinoma (ESCC) and resulted in poor prognosis, however, they all included few patients and had inconsistent results. So we conducted a meta-analysis to explore the correlation between overexpression of MMP-9 and the clinicopathological characteristics and overall survival (OS) of ESCC.
PubMed, EMBASE, Web of Science, Chinese Biomedical Literature Database, Google Scholar and other databases were searched for relevant studies. The Newcastle-Ottawa quality assessment scale was used to assess the methodological quality of included study and RevMan 5.2 software was used to conduct meta-analysis.
A total of 35 studies were included, and the results of meta-analysis showed that overexpression of MMP-9 was associated with grade of differentiation [well/moderate vs. poor: odds ratio (OR): 0.39, 95% confidence interval (CI): 0.29-0.52; P<0.00001], lymph node metastasis (negative vs. positive: OR: 0.24, 95% CI: 0.16-0.34; P<0.00001), TNM stage (T1/T2 vs. T3/T4: OR: 0.28, 95% CI: 0.14-0.54; P=0.0002), the depth of invasion (T1/T2 vs. T3/T4: OR: 0.29, 95% CI: 0.17-0.49; P<0.00001), and vascular invasion of ESCC (negative vs. positive: OR: 0.35, 95% CI: 0.21-0.58; P<0.0001), and also associated with poor overall survival of ESCC (HR: 2.17, 95% CI: 1.32-3.57; P=0.002). Subgroup analysis showed that more than 10% of carcinoma cell staining was associated with significant increase of mortality risk (HR: 2.44, 95% CI: 1.16-5.15; P=0.02), and sensitive analysis suggested that MMP-9 was an independent prognostic factor in ESCC (HR: 1.49, 95% CI: 1.16-1.91; P=0.002).
On the basis of limited evidence, overexpression of MMP-9 may be a potential independent prognosis factor of ESCC patients in Asia, and high-quality studies assessing the prognostic significance of MMP-9 for ESCC patients are still needed.
PMCID: PMC3872548  PMID: 24385690
Matrix metalloproteinase-9 (MMP-9); esophageal squamous cell carcinoma (ESCC); overall survival (OS); meta-analysis
4.  Maternal HIV Serostatus, Mother–Daughter Sexual Risk Communication and Adolescent HIV Risk Beliefs and Intentions 
AIDS and behavior  2013;17(7):2540-2553.
Daughters of HIV-positive women are often exposed to the same factors that placed their mothers at risk. This cross-sectional study (N = 176 dyads) examined HIV status, parent-teen sexual risk communication (PTSRC), and daughters’ abstinence and condom use beliefs and intentions. Maternal HIV status was not associated with PTSRC. Path analyses show that maternal depression was associated with PTSRC behavioral and normative beliefs; relationship satisfaction was associated with PTSRC normative and control beliefs. Control beliefs were solely predictive of maternal PTSRC intention. PTSRC was associated with adolescent behavioral and normative beliefs. Abstinence beliefs were associated with abstinence intentions; condom beliefs were associated with condom use intentions. Relationship satisfaction was associated with adolescent control beliefs about both abstinence and condom use. There is a need for interventions that help HIV-positive mothers recognize their daughter’s HIV risk and provide them with relationship building and parent process skills to help reduce these risks.
PMCID: PMC3458119  PMID: 22677973
Parent–child sexual risk communication; Adolescent sexual risk; Maternal HIV; Relationship satisfaction
5.  A Scan Statistic for Binary Outcome Based on Hypergeometric Probability Model, with an Application to Detecting Spatial Clusters of Japanese Encephalitis 
PLoS ONE  2013;8(6):e65419.
As a useful tool for geographical cluster detection of events, the spatial scan statistic is widely applied in many fields and plays an increasingly important role. The classic version of the spatial scan statistic for the binary outcome is developed by Kulldorff, based on the Bernoulli or the Poisson probability model. In this paper, we apply the Hypergeometric probability model to construct the likelihood function under the null hypothesis. Compared with existing methods, the likelihood function under the null hypothesis is an alternative and indirect method to identify the potential cluster, and the test statistic is the extreme value of the likelihood function. Similar with Kulldorff’s methods, we adopt Monte Carlo test for the test of significance. Both methods are applied for detecting spatial clusters of Japanese encephalitis in Sichuan province, China, in 2009, and the detected clusters are identical. Through a simulation to independent benchmark data, it is indicated that the test statistic based on the Hypergeometric model outweighs Kulldorff’s statistics for clusters of high population density or large size; otherwise Kulldorff’s statistics are superior.
PMCID: PMC3681795  PMID: 23785424
6.  Bilateral oophorectomy is not associated with increased mortality: the California Teachers Study 
Fertility and sterility  2011;97(1):111-117.
To investigate the effect of surgical menopause due to bilateral oophorectomy on mortality, in light of evidence that bilateral oophorectomy among premenopausal women rapidly reduces endogenous hormone levels thereby modifying risks of cardiovascular disease and breast cancer.
The California Teachers Study (CTS) is a prospective cohort study of 133,479 women initiated in 1995–1996 through a mailed, self-administered questionnaire. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression.
CTS participants who, at baseline, reported having surgical menopause due to bilateral oophorectomy (n=9,785), were compared to participants with natural menopause (n=32,219).
Main outcome measures
We investigated whether bilateral oophorectomy was associated with all-cause, cardiovascular, or cancer mortality, overall and by menopausal hormone therapy (HT) use status.
Among participants younger than 45 years of age at menopause, multivariable relative risks were 0.86 (95% CI, 0.74–1.00), 0.85 (95% CI, 0.66–1.11) and 0.91 (95% CI, 0.67–1.23) for all-cause mortality, cardiovascular mortality and cancer mortality, respectively. Among participants with an age at menopause of 45 years or later, multivariable relative risks were 0.87 (95% CI, 0.80–0.94), 0.83 (95% CI, 0.71–0.96) and 0.84 (95% CI, 0.72–0.98) for all-cause, cardiovascular and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of HT use.
Surgical menopause due to bilateral oophorectomy vs. natural menopause does not increase all-cause, cardiovascular, or cancer mortality.
PMCID: PMC3245786  PMID: 22088205
surgical menopause and mortality; bilateral oophorectomy; mortality; California Teachers Study
7.  Oral contraceptives, menopausal hormone therapy use and risk of B-cell non-Hodgkin lymphoma in the California Teachers Study 
We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and stratified Cox proportional hazards models were fit to estimate relative risks (RR) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95%CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95%CI=0.83-1.33) overall, or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95%CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk.
PMCID: PMC3258672  PMID: 20957632
non-Hodgkin lymphoma; oral contraceptives; menopausal hormonal therapy; hysterectomy; bilateral oophorectomy
8.  Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway 
ACS Medicinal Chemistry Letters  2010;1(9):454-459.
Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers with constitutively active STAT3. In this study, we report the identification of niclosamide, an FDA-approved anthelmintic drug, as a new small-molecule inhibitor of the STAT3 signaling pathway. This compound potently inhibited the activation and transcriptional function of STAT3 and consequently induced cell growth inhibition, apoptosis, and cell cycle arrest of cancer cells with constitutively active STAT3. Our study provides a new promising lead compound with a salicylic amide scaffold for the development of STAT3 pathway inhibitors as novel molecularly targeted anticancer drugs.
PMCID: PMC4007964  PMID: 24900231
STAT3 signaling pathway; inhibitor; niclosamide; apoptosis; cell cycle arrest
9.  Continuous requirement of ErbB2 kinase activity for loss of cell polarity and lumen formation in a novel ErbB2/Neu-driven murine cell line model of metastatic breast cancer 
Well over a quarter of human breast cancers are ErbB2-driven and constitute a distinct subtype with substantially poorer prognosis. Yet, there are substantial gaps in our understanding of how ErbB2 tyrosine kinase activity unleashes a coordinated program of cellular and extracellular alterations that culminate in aggressive breast cancers. Cellular models that exhibit ErbB2 kinase dependency and can induce metastatic breast cancer in immune competent hosts are likely to help bridge this gap.
Materials and Methods:
Here, we derived and characterized a cell line model obtained from a transgenic ErbB2/Neu-driven mouse mammary adenocarcinoma.
The MPPS1 cell line produces metastatic breast cancers when implanted in the mammary fat pads of immune-compromised as well as syngeneic immune-competent hosts. MPPS1 cells maintain high ErbB2 overexpression when propagated in DFCI-1 or related media, and their growth is ErbB2-dependent, as demonstrated by concentration-dependent inhibition of proliferation with the ErbB kinase inhibitor Lapatinib. When grown in 3-dimensional (3-D) culture on Matrigel, MPPS1 cells predominantly form large irregular cystic and solid structures. Remarkably, low concentrations of Lapatinib led to a switch to regular acinar growth on Matrigel. Immunofluorescence staining of control vs. Lapatinib-treated acini for markers of epithelial polarity revealed that inhibition of ErbB2 signaling led to rapid resumption of normal mammary epithelium-like cell polarity.
The strict dependence of the MPPS1 cell system on ErbB2 signals for proliferation and alterations in cell polarity should allow its use to dissect ErbB2 kinase-dependent signaling pathways that promote loss of cell polarity, a key component of the epithelial mesenchymal transition and aggressiveness of ErbB2-driven breast cancers.
PMCID: PMC3243085  PMID: 22190871
3-D Matrigel; EMT; ErbB2/Her2/Neu; lapatinib; mouse models; syngeneic xenografts
10.  Associations Between Family Structure, Family Functioning, and Substance Use Among Hispanic/Latino Adolescents 
This study examined the role of family structure and functioning in predicting substance use among Hispanic/Latino adolescents, surveyed in 9th and 10th grade. The sample (N=1433) was half female, mostly of Mexican descent, and the majority was born in the U.S. Living with a single father was associated with less parental monitoring and less family cohesion (γ = −0.07, −0.06, respectively). Living with a single mother was associated with less parental monitoring (γ = −0.10). Living with neither parent was associated with less communication (γ = −0.08), less parental monitoring (γ = −0.09), more family conflict (γ = 0.06), and less family cohesion (γ = −0.06). Less monitoring was associated with substance use at follow-up (β = −0.17). Low rates of parental monitoring appear to mediate the association between parental family structure and substance use. Results suggest that improving basic parenting skills, and offering additional social support and resources to assist parents in monitoring adolescents may help prevent substance use. These interventions may be particularly beneficial for single parents.
PMCID: PMC2849874  PMID: 20307116
Adolescents; Hispanic/Latino; Family function; Family structure; Structural Equation Modeling
11.  Menopausal Hormone Therapy Use and Risk of Invasive Colon Cancer 
American Journal of Epidemiology  2010;171(4):415-425.
Results from epidemiologic studies of hormone therapy use and colon cancer risk are inconsistent. This question was investigated in the California Teachers Study (1995–2006) among 56,864 perimenopausal or postmenopausal participants under 80 years of age with no prior colorectal cancer by using Cox proportional hazards regression. Incident invasive colon cancer was diagnosed among 442 participants. Baseline-recent hormone therapy users were at 36% lower risk for colon cancer versus baseline-never users (baseline-recent users: relative risk (RR) = 0.64, 95% confidence interval (CI): 0.51, 0.80). Results did not differ by formulation. Estimated risk was lower among baseline-recent hormone therapy users with increasing duration between 5 and 15 years of use (RR = 0.49, 95% CI: 0.35, 0.68), but the trend did not persist in the longest duration group, more than 15 years of use (RR = 0.69, 95% CI: 0.52, 0.92; Ptrend = 0.60). Long-term recreational physical activity, obesity, regular use of nonsteroidal antiinflammatory medications, and daily alcohol intake did not modify these effects; baseline-recent use was more strongly associated with colon cancer risk among women with a family history of colorectal cancer (Pheterogeneity = 0.04). Baseline-recent hormone therapy use was inversely associated with invasive colon cancer risk among perimenopausal and postmenopausal women in the California Teachers Study.
PMCID: PMC2842195  PMID: 20067917
colonic neoplasms; hormone replacement therapy; lung neoplasms; parity; prospective studies; reproduction; smoking
12.  Anticancer activity of celastrol in combination with ErbB2-targeted therapeutics for treatment of ErbB2-overexpressing breast cancers 
Cancer Biology & Therapy  2011;11(2):263-276.
The receptor tyrosine kinase ErbB2 is overexpressed in up to a third of breast cancers, allowing targeted therapy with ErbB2-directed humanized antibodies such as Trastuzumab. Concurrent targeting of ErbB2 stability with HSP90 inhibitors is synergistic with Trastuzumab, suggesting that pharmacological agents that can inhibit HSP90 as well as signaling pathways activated by ErbB2 could be useful against ErbB2-overexpressing breast cancers. The triterpene natural product Celastrol inhibits HSP90 and several pathways relevant to ErbB2-dependent oncogenesis including the NFκB pathway and the proteasome, and has shown promising activity in other cancer models. Here, we demonstrate that Celastrol exhibits in vitro antitumor activity against a panel of human breast cancer cell lines with selectivity towards those overexpressing ErbB2. Celastrol strongly synergized with ErbB2-targeted therapeutics Trastuzumab and Lapatinib, producing higher cytotoxicity with substantially lower doses of Celastrol. Celastrol significantly retarded the rate of growth of ErbB2-overexpressing human breast cancer cells in a mouse xenograft model with only minor systemic toxicity. Mechanistically, Celastrol not only induced the expected ubiquitinylation and degradation of ErbB2 and other HSP90 client proteins, but it also increased the levels of reactive oxygen species (ROS). Our studies show that the Michael Acceptor functionality in Celastrol is important for its ability to destabilize ErbB2 and exert its bioactivity against ErbB2-overexpressing breast cancer cells. These studies suggest the potential use of Michael acceptor-containing molecules as novel therapeutic modalities against ErbB2-driven breast cancer by targeting multiple biological attributes of the driver oncogene.
PMCID: PMC3047084  PMID: 21088503
ErbB2; Her2/Neu; 17-AAG; celastrol; trastuzumab; targeted therapy; drug interaction; ubiquitin; proteasome; HSP90; ROS
13.  Negative Regulation of EGFR-Vav2 Signaling Axis by Cbl Ubiquitin Ligase Controls EGF Receptor-mediated Epithelial Cell Adherens Junction Dynamics and Cell Migration* 
The Journal of Biological Chemistry  2010;286(1):620-633.
The E3 ubiquitin ligase Casitas B lymphoma protein (Cbl) controls the ubiquitin-dependent degradation of EGF receptor (EGFR), but its role in regulating downstream signaling elements with which it associates and its impact on biological outcomes of EGFR signaling are less clear. Here, we demonstrate that stimulation of EGFR on human mammary epithelial cells disrupts adherens junctions (AJs) through Vav2 and Rac1/Cdc42 activation. In EGF-stimulated cells, Cbl regulates the levels of phosphorylated Vav2 thereby attenuating Rac1/Cdc42 activity. Knockdown of Cbl and Cbl-b enhanced the EGF-induced disruption of AJs and cell motility. Overexpression of constitutively active Vav2 activated Rac1/Cdc42 and reorganized junctional actin cytoskeleton; these effects were suppressed by WT Cbl and enhanced by a ubiquitin ligase-deficient Cbl mutant. Cbl forms a complex with phospho-EGFR and phospho-Vav2 and facilitates phospho-Vav2 ubiquitinylation. Cbl can also interact with Vav2 directly in a Cbl Tyr-700-dependent manner. A ubiquitin ligase-deficient Cbl mutant enhanced the morphological transformation of mammary epithelial cells induced by constitutively active Vav2; this effect requires an intact Cbl Tyr-700. These results indicate that Cbl ubiquitin ligase plays a critical role in the maintenance of AJs and suppression of cell migration through down-regulation of EGFR-Vav2 signaling.
PMCID: PMC3013022  PMID: 20940296
Actin; Breast Cancer; Epithelial Cell; Receptor Tyrosine Kinase; Rho; Ubiquitination; Adherens Junctions; Cbl; EGFR; Vav2
14.  Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort 
Although pregnancy-related factors such as nulliparity and late age at first full-term pregnancy are well-established risk factors for invasive breast cancer, the roles of these factors in the natural history of breast cancer development remain unclear.
Among 52,464 postmenopausal women participating in the California Teachers Study (CTS), 624 were diagnosed with breast carcinoma in situ (CIS) and 2,828 with invasive breast cancer between 1995 and 2007. Multivariable Cox proportional hazards regression methods were used to estimate relative risks associated with parity, age at first full-term pregnancy, breastfeeding, nausea or vomiting during pregnancy, and preeclampsia.
Compared with never-pregnant women, an increasing number of full-term pregnancies was associated with greater risk reduction for both breast CIS and invasive breast cancer (both P trend < 0.01). Women having four or more full-term pregnancies had a 31% lower breast CIS risk (RR = 0.69, 95% CI = 0.51 to 0.93) and 18% lower invasive breast cancer risk (RR = 0.82, 95% CI = 0.72 to 0.94). Parous women whose first full-term pregnancy occurred at age 35 years or later had a 118% greater risk for breast CIS (RR = 2.18, 95% CI = 1.36 to 3.49) and 27% greater risk for invasive breast cancer (RR = 1.27, 95% CI = 0.99 to 1.65) than those whose first full-term pregnancy occurred before age 21 years. Furthermore, parity was negatively associated with the risk of estrogen receptor-positive (ER+) or ER+/progesterone receptor-positive (PR+) while age at first full-term pregnancy was positively associated with the risk of ER+ or ER+/PR+ invasive breast cancer. Neither of these factors was statistically significantly associated with the risk of ER-negative (ER-) or ER-/PR- invasive breast cancer, tests for heterogeneity between subtypes did not reach statistical significance. No clear associations were detected for other pregnancy-related factors.
These results provide some epidemiologic evidence that parity and age at first full-term pregnancy are involved in the development of breast cancer among postmenopausal women. The role of these factors in risk of in situ versus invasive, and hormone receptor-positive versus -negative breast cancer merits further exploration.
PMCID: PMC2917030  PMID: 20565829
15.  Overexpression of RhoA Induces Preneoplastic Transformation of Primary Mammary Epithelial Cells 
Cancer research  2009;69(2):483-491.
Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions, including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably used immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMEC). We show here that ectopic expression of wild-type (WT) RhoA as well as a constitutively active RhoA mutant (G14V) in two independent primary hMEC strains led to their immortalization and preneoplastic transformation. These cells have continued to grow over 300 population doublings (PD) with no signs of senescence, whereas cells expressing the vector or dominant-negative RhoA mutant (T19N) senesced after 20 PDs. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well-known Rho effectors including Rho kinase, PKN, mDia1, and mDia2, was also capable of immortalizing hMECs. Notably, similar to parental normal cells, Rho-immortalized cells have WT p53 and intact G1 cell cycle arrest on Adriamycin treatment. Rho-immortalized cells were anchorage dependent and were unable to form tumors when implanted in nude mice. Lastly, microarray expression profiling of Rho-immortalized versus parental cells showed altered expression of several genes previously implicated in immortalization and breast cancer progression. Taken together, these results show that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked to cellular transformation and breast cancer.
PMCID: PMC2792911  PMID: 19147561

Results 1-15 (15)