Biomedical subjects

Huiling Li

Publications and source records attributed to Huiling Li.

13 recordsLinked to original sources

PubMed2006

Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer.

PURPOSE: Vascular endothelial growth factor receptor-1 (VEGFR-1) plays important roles in promotion of tumor growth by mediating cellular functions in tumor vascular endothelium and cancer cells. Blockade of VEGFR-1 activation has been shown to inhibit pathologic angiogenesis and tumor growth, implicating VEGFR-1 as a potential therapeutic target for the treatment of cancer. We have thus developed a VEGFR-1 antagonist human monoclonal antibody designated as IMC-18F1 and evaluated its antitumor activity in preclinical experimental models to show the therapeutic potential of the antibody for cancer treatment in clinic. EXPERIMENTAL DESIGN: Human IgG transgenic mice were used for generation of anti-VEGFR-1 antibodies. Anti-VEGFR-1-specific blocking antibodies were identified using solid-phase binding and blocking assays. Inhibitory antitumor cell activity of IMC-18F1 was assessed in cell-based kinase and growth assays. Pharmacokinetic/pharmacodynamic studies were done to determine the association of antibody blood level with antitumor efficacy of the antibody in vivo. Antitumor efficacy of the anti-VEGFR-1 antibodies as monotherapy and in combination with cytotoxic agents was evaluated in human breast cancer xenograft models. RESULTS: A fully human neutralizing antibody, IMC-18F1, was shown to be a high-affinity (KD=54 pmol) inhibitor of VEGFR-1 ligand binding (VEGF-A, VEGF-B, and placental growth factor). IMC-18F1 inhibited ligand-induced intracellular activation of VEGFR-1 and mitogen-activated protein kinase signaling and prevented ligand-stimulated in vitro growth of breast cancer cells. In vivo, IMC-18F1 suppressed the growth of human breast tumor xenografts in association with reduced mitogen-activated protein kinase and Akt activation, reduced tumor cell proliferation, and increased tumor cell apoptosis. Pharmacokinetic/pharmacodynamic studies established a plasma elimination half-life of 5 days for IMC-18F1 and a steady-state trough plasma therapeutic threshold of 88 microg/mL. Importantly, inhibition of mouse and human VEGFR-1 with MF1 and IMC-18F1, respectively, enhanced the antitumor efficacy of cytotoxic agents commonly used to treat breast cancer. CONCLUSIONS: Based on preclinical validation studies, IMC-18F1 anti-VEGFR-1 has potential to provide clinical benefit to cancer patients.

Animals↗

PubMed2006

Hypogonadism in male patients with cancer.

BACKGROUND: Patients with cancer often develop anorexia, fatigue, and decreased muscle mass. These signs and symptoms are nonspecific, and they frequently occur in other conditions, including hypogonadism. METHODS: The objectives of this study were 1) to measure testosterone levels in patients with cancer and 2) to examine the correlations between testosterone, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), ghrelin levels, and appetite in patients with cancer patients and in a noncancer control group. This was designed as a cross-sectional study in the setting of a university-affiliated Veterans Affairs Medical Center. The study population included 31 male patients with cancer and 25 gender-matched noncancer controls of similar age. The variables total testosterone (TT), calculated free testosterone (cFT), calculated bioavailable testosterone (cBT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), TNF-alpha, IL-6, IGF-1, and active ghrelin were measured in fasting morning plasma samples. Appetite was measured according to a visual analog scale. The main outcome measures were cFT and cBT. RESULTS: Cancer patients had mean TT levels similar to levels in the noncancer control group but significantly lower levels of cFT, cBT, IGF-1, and appetite. SHBG, LH, TNF-alpha, IL-6, and ghrelin levels were increased in patients with cancer compared with the control group. cFT and cBT levels were correlated inversely with IL-6 and ghrelin levels and were correlated directly with IGF-1 levels and appetite. CONCLUSIONS: Patients with cancer had lower levels of biologically active testosterone. TT was not adequate for the evaluation of hypogonadism, because SHBG levels were increased. A reliable measurement of FT and/or BT should be used. LH was elevated in the patients with cancer, indicating that low FT levels were caused by primary testicular dysfunction. The authors postulated that high IL-6 or ghrelin levels inhibit testosterone synthesis, although a secondary effect at the hypothalamic-pituitary levels cannot be excluded.

Aged↗

PubMed2006

A pattern-mixture model for the analysis of censored quality-of-life data.

We propose a pattern-mixture model for describing the joint distribution of incomplete repeated measurements of quality of life (QoL) and right-censored survival times. The model assumes that the survival times follow a multinomial distribution and that the quality of life outcome follows a multivariate normal distribution conditional on the survival time. We estimate the model using a Bayesian approach by importance sampling. We then use simulated parameters to create multiple imputations of the censored QoL outcomes, which can then be used to calculate individual values of quality-adjusted life-years (QALYs). We apply the method to data from the Randomized Evaluation of Mechanical Assistance in the Treatment of Congestive Heart Failure (REMATCH) clinical trial.

Bayes Theorem↗

PubMed2006

Breast biopsy and race/ethnicity among women without breast cancer.

BACKGROUND: Breast biopsy is essential for definitive breast cancer diagnosis, but may also play a role in determining eligibility for breast cancer preventive measures or clinical trials. In addition, the prevalence of a history of negative breast biopsy can be viewed as an indicator of the adequacy or intensity of health care in a given population. We therefore analyzed the association of a history of breast biopsy with race/ethnicity and other factors in a cohort of women without a cancer diagnosis who completed a risk assessment form for participation in the Study of Tamoxifen and Raloxifene (STAR) and a sociodemographic questionnaire. METHODS: Subjects were recruited at our large, urban teaching hospital. We developed a logistic regression model with biopsy (ever/never) as the outcome and age, race/ethnicity, educational attainment, and insurance coverage as the independent variables. RESULTS: Among 805 unaffected predominantly minority subjects, white women were more than three times as likely as black and Hispanic women (OR=3.3, 95% CI 1.9-5.9), and insured women were twice as likely as uninsured women (OR=2.0, 95% CI 1.4-2.9) to have had a biopsy. Biopsy results were also associated with race/ethnicity. DISCUSSION: We view these observations as hypothesis-generating rather than definitive. If confirmed, the associations we observed between negative biopsies and insurance status may reflect disparities in the timeliness and effectiveness of follow-up of suspicious lesions found via mammography. Our findings may also be relevant to the well-known association of breast cancer stage at diagnosis with low income and minority race/ethnicity.

Adult↗

PubMed2006

Synergistic antitumor effects of combined epidermal growth factor receptor and vascular endothelial growth factor receptor-2 targeted therapy.

PURPOSE: Combination therapies that target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways, are being actively tested for the treatment of cancer. In evaluating combination strategies, the ideal combination would be one in which the treatments interact in a way that is synergistic with regard to antitumor effects. Here, we have evaluated the interaction between anti-EGFR antibody Erbitux (cetuximab) and anti-VEGFR2 antibody, DC101, in preclinical models of pancreatic (BxPC-3) and colon (GEO) cancer. EXPERIMENTAL DESIGN: Analysis of the interaction between cetuximab and DC101 in vivo used a novel method for establishing the upper 95% confidence limits for the combination index (CI) of isobologram analyses, where CI < 1 indicates synergy. Assessment of tumor cell proliferation, apoptosis, VEGF production, and hypoxia, as well as tumor vascularization, was performed to gain insights into the mechanistic basis for synergy between agents targeting different tumor compartments. RESULTS: Monotherapy ED(50) values for tumor growth inhibition ranged from 1.8 to 2.3 mg/kg and 10.5 to 16.6 mg/kg for cetuximab and DC101, respectively. From the dose response of the combination treatment, it was determined that cetuximab and DC101 are synergistic in the BxPC-3 (CI = 0.1, P < 0.01) and GEO (CI = 0.1, P < 0.01) models. Overlapping effects on the tumor cell and vascular compartments form a basis for the interaction, with VEGF production and hypoxia-inducible factor 1alpha potentially acting as molecular links between EGFR and VEGFR2 inhibition. CONCLUSIONS: Results show antitumor synergy for combined EGFR and VEGFR2 targeted therapy, supporting the significant therapeutic potential of this combination strategy.

Adenocarcinoma↗

PubMed2005

Genetic polymorphisms in arginase I and II and childhood asthma and atopy.

BACKGROUND: A recent microarray study implicated arginase I (ARG1) and arginase II (ARG2) in mouse allergic asthma models and human asthma. OBJECTIVES: To examine the association between genetic variation in ARG1 and ARG2 and childhood asthma and atopy risk. METHODS: We enrolled 433 case-parent triads, consisting of patients with asthma 4 to 17 years old and their biologic parents, from the allergy clinic of a public hospital in Mexico City between 1998 and 2003. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped 4 single nucleotide polymorphisms (SNPs) of ARG1 and 4 SNPs of ARG2 with minor allele frequencies higher than 10% by using the TaqMan assay (Roche Molecular Systems, Pleasanton, Calif). RESULTS: ARG1 SNPs and haplotypes were not associated with asthma, but all 4 ARG1 SNPs were associated with the number of positive skin tests (P = .007-.018). Carrying 2 copies of minor alleles for either of 2 highly associated ARG2 SNPs was associated with a statistically significant increased relative risk (RR) of asthma (1.5, 95% CI = 1.1-2.1 for arg2s1; RR = 1.6, 95% CI = 1.1-2.3 for arg2s2). The association was slightly stronger among children with a smoking parent (arg2s1 RR = 2.1, 95% CI = 1.2 - 3.9 with a smoking parent; RR = 1.2, 95% CI = 0.8-1.9 without; interaction P = .025). Haplotype analyses reduced the sample size but supported the single SNP results. One ARG2 SNP was related to the number of positive skin tests (P = .027). CONCLUSION: Variation in arginase genes may contribute to asthma and atopy in children.

Adolescent↗

PubMed2005

[Risk factors of retinal redetachment after expected silicone oil removal].

PURPOSE: To analyze the clinical risk factors of the occurrence of retinal redetachment after expected silicone oil removal. METHODS: Clinical data were studied retrospectively. A total of 105 eyes of 104 consecutive patients were enrolled according to the criteria as follows: the expected intraocular silicone oil removal was performed after pars plana vitrectomy for complicated rhegmatogenous retinal detachment (RRD); the retina was flat during silicone oil tampanade; the patients were dealt with by the same surgeon. RESULTS: With a mean postoperative follow-up of 310 days, 11 of 105 eyes (10.4%) developed retinal redetachment after silicone oil removal. The redetachment rate was higher in the aphakic eyes (21.1%) than in the phakic/pseudophakic eyes (4.5%) (OR 5.69, P < 0.05). However, the factors, including giant tear, PVR grade C3 and D, previous failed retinal detachment surgery, high myopia, had no significance with retinal redetachment (Ps > 0.05). Among the 77 eyes undergoing prophylactic 360 degree laser retinopexy before silicone oil removal, 4 eyes had retinal redetachment (5.2%). The redetachment ratio was lower than those without prophylactic laser retinopexy (OR 0.16, P < 0.05). CONCLUSION: Aphakia is a risk factor of retinal detachment after removal of silicone oil. Prophylactic 360 degree laser retinopexy can reduce the incidence of retinal redetachment.

Adolescent↗

PubMed2004

Bayesian estimation of cost-effectiveness from censored data.

We describe a Bayesian methodology for estimating the cost-effectiveness of a new treatment compared to a standard in a clinical trial, when censoring of survival, the effectiveness variable, induces censoring of total cost. The statistical model assumes that survival follows a Weibull distribution and that total health care cost follows a gamma distribution whose mean has a linear regression on survival time. We summarize the posterior distributions of key parameters by importance sampling. We illustrate the method with an analysis of data from a randomized clinical trial of a treatment for cardiovascular disease.

Bayes Theorem↗

PubMed2004

Men with breast cancer have better disease-specific survival than women.

HYPOTHESIS: Male breast cancer patients have better disease-specific survival than carefully matched female breast cancer patients. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS AND METHODS: Each man in the breast cancer database at Columbia-Presbyterian Medical Center (New York, NY) between the years 1980 and 1998 was matched with a woman. Matching was done based on age and date of diagnosis, stage, and primary histologic findings. MAIN OUTCOME MEASURES: The overall survivals and disease-specific survivals of the male breast cancer group and female breast cancer group were compared. RESULTS: Fifty-three male patients were matched with an equal number of female breast cancer patients. The Kaplan-Meier curves demonstrated that there was no significant difference in overall survival. The 5- and 10-year survivals for women were 0.77 and 0.51, and for men 0.77 and 0.56. When the Kaplan-Meier curves for breast cancer-specific survival were compared, however, there was a significant difference in the 5- and 10-year survivals (P = .05, log-rank test). For women, the 5- and 10-year disease-specific survival was 0.81 and 0.7, respectively, while for men it was 0.9 and 0.9, respectively. In a Cox regression analysis for time to death from breast cancer, stage was the only predictor of death that approached significance (P = .06). CONCLUSIONS: While the overall survivals were equivalent, male breast cancer patients had significantly better disease-specific survivals compared with their female counterparts. Male patients were 4 times more likely to die of other causes than their breast cancer.

Aged↗

PubMed2004

Bayesian estimation of cost-effectiveness: an importance-sampling approach.

We describe a method for estimating the cost-effectiveness of a new treatment compared to a standard, using data from a comparative clinical trial. We quantify the clinical effectiveness as a binary variable indicating success or failure. The underlying statistical model assumes that costs are uncensored and follow separate gamma distributions in each of the groups defined by the four possible combinations of treatment arm and effectiveness outcome. The method is subjectivist, in that it represents prior uncertainty about model parameters with a probability distribution, which we update via Bayes's theorem to produce a posterior distribution. We approximate the posterior by importance sampling, a straightforward simulation method. We illustrate the method with an analysis of cost (derived from resource usage data) and effectiveness (measured by one-year survival) in a clinical trial in heart disease. The example demonstrates that the method is practical and provides for a flexible data analysis.

Bayes Theorem↗

PubMed2003

In vivo preservation of steroid specificity in CWR22 xenografts having a mutated androgen receptor.

BACKGROUND: In vitro studies of CWR22 tumor cells lack steroid specificity. We sought to determine if CWR22 xenografts also lack steroid specificity. METHODS: We injected castrated nude mice with CWR22 tumor cells (6 x 10(6) cells) and implanted Alzet osmotic pumps that delivered approximately 1 mg steroid/kg body weight/day. RESULTS: Serum PSA levels were detectable in intact mice and castrated mice treated with testosterone (T), but not in those treated with estradiol (E(2)), progesterone (P), or flutamide (F). T maintained mean tumor weight similar to that in intact mice (P = NS). We observed no tumors in castrated mice or mice treated with E(2), P, or F, and tumor histology was consistent with weights. CONCLUSIONS: The mutation of the androgen receptor (H874Y) that occurs in the CWR22 xenograft model of human prostate cancer does not significantly affect in vivo steroid specificity for E(2), P, or F.

Androgen Antagonists↗

PubMed2003

Disparities in use of lipid-lowering medications among people with type 2 diabetes mellitus.

BACKGROUND: People with diabetes are at high risk for cardiovascular events regardless of known heart disease. Physicians may underrecognize the excess cardiovascular risk conferred by diabetes alone, without a recent cardiovascular event. Other disparities in the receipt of lipid-lowering medications (LLMs) may exist. METHODS: We studied veterans with diabetes in fiscal years 1998 and 1999 cross-sectionally. We used administrative data (demographic information, International Classification of Diseases, Ninth Revision [ICD-9] codes, utilization information, medications, and laboratory tests) to evaluate associations between use of LLMs and age, ethnicity, sex, marital status, Charlson Index, heart disease ICD-9 codes, oral agents and insulin, hospitalization status, and low-density lipoprotein cholesterol levels. We constructed separate logistic regression models to evaluate associations between low-density lipoprotein cholesterol and similar predictor variables. RESULTS: Odds ratios were similar in both years. For fiscal year 1999, patients without recent ICD-9 codes in their administrative data indicating heart disease were 0.35 times less likely to be given LLMs than those with such codes. Individuals older than 75 years were 0.65 times less likely to be given LLMs than those younger than 65 years. African Americans were 0.72 times less likely than whites to be given LLMs. In fiscal years 1999 and 1998, 27% and 36% of individuals given LLMs had low-density lipoprotein cholesterol levels higher than 130 mg/dL (3.37 mmol/L). CONCLUSIONS: Veterans with diabetes but no recently coded heart disease, older individuals, and African Americans could benefit from programs targeted to introduce LLMs. Up to one third of individuals given LLMs remained above the target level of 130 mg/dL for low-density lipoprotein cholesterol.

Aged↗

PubMedDate not supplied

Cyclin D1 overexpression is associated with estrogen receptor expression in Caucasian but not African-American breast cancer.

BACKGROUND: African-American (AA) breast cancer patients consistently show a shortened survival when compared with Caucasian patients. This worse prognosis is most likely due to a combination of socioeconomic factors and differences in tumor biology. Previous studies have demonstrated that cyclin D1 overexpression is strongly associated with estrogen receptor (ER) expression in breast cancer, but these series either included primarily Caucasian patients or did not specify race. MATERIALS AND METHODS. We analyzed 200 breast cancer cases obtained from AA and Caucasian patients who were matched on age, stage, ER status, and year of diagnosis. We examined expression levels of cyclin D1, p53, p27Kip1 (p27), and p21Cip1 (p21), and correlated their expression with ER status. RESULTS: Cyclin D1, p53, p27, and p21 expression rates were similar in matched cases of AA and Caucasian breast cancer (p values>0.05). However, cyclin D1 overexpression was significantly associated with ER status in only the Caucasian (p=0.0005), and not the AA cases (p=0.07). CONCLUSION: This finding suggests a novel biological difference, which may contribute to the more aggressive phenotype of AA breast cancer.

Adult↗