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Biomedical subjects

A Y Chen

Publications and source records attributed to A Y Chen.

At least 19 recordsLinked to original sources
PubMed2001

Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1.

A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). Structure-activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC(50) = 0.003 microM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide.

Administration, Oral↗
PubMed2001

The development of breast carcinoma in women with thyroid carcinoma.

BACKGROUND: Breast carcinoma and thyroid carcinoma are two malignancies that occur most commonly in women. An association between the incidence rates of thyroid and breast carcinoma in women after a diagnosis of the other malignancy has been suggested in a retrospective analysis of a single institution's tumor registry. In that study, an increased incidence of breast carcinoma in premenopausal women previously treated for thyroid carcinoma was observed. METHODS: The purpose of this study was to investigate further this relation utilizing a large database, the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. The SEER database is maintained by the National Cancer Institute, and it represents 11 population-based cancer registries covering approximately 14% of the United States population. The study was a population-based retrospective cohort analysis using external comparisons. From 1973 to 1994, 365 women in the SEER database were identified as having both thyroid and breast carcinomas. The SEER database from 1973 to 1994 was utilized to calculate age specific and calendar year specific incidence rates for each year for thyroid and breast carcinomas. The expected number of second cancers for each age group, calendar year, and follow-up period were determined by multiplying these incidence rates by the age specific and calendar year specific number of person-years at risk. The risk ratio (RR) was calculated by dividing the observed by the expected number of second cancers. Statistical significance was determined by the Poisson test. RESULTS: A total of 1,333,115 person-years were available for analysis. One hundred thirteen thyroid carcinoma cases were diagnosed after breast carcinoma cases (RR, 0.99; P = 0.576). Two hundred fifty-two breast carcinoma cases were diagnosed after thyroid carcinoma cases (RR, 1.18; P = 0.007). Premenopausal women (age 20-49 years) with an index thyroid carcinoma have a significantly increased risk of developing subsequent breast carcinoma (RR, 1.42; P = 0.001). Black premenopausal women with an index thyroid carcinoma do not have an increased risk of developing breast carcinoma, but the statistical power is lower due to low numbers. No women with index breast carcinoma have an increased risk of developing thyroid carcinoma. CONCLUSIONS: Women with a history of thyroid carcinoma have a greater than expected risk of developing breast carcinoma. This risk is most pronounced in premenopausal white women. The implications of this observation with respect to breast carcinoma screening guidelines and thyroid carcinoma treatment guidelines deserve further investigation.

Adult↗
PubMed2001

Stimulation of topoisomerase II-mediated DNA damage via a mechanism involving protein thiolation.

The breakage/reunion reaction of DNA topoisomerase II (TOP2) can be interrupted by DNA intercalators (e.g., doxorubicin), enzyme binders (e.g., etoposide), or DNA lesions (e.g., abasic sites) to produce TOP2-mediated DNA damage. Here, we demonstrate that thiol alkylation of TOP2 can also produce TOP2-mediated DNA damage. This conclusion is supported by the following observations using purified TOP2: (1) Thiol-reactive quinones were shown to induce TOP2-mediated DNA cleavage. (2) Thiol-reactive compounds such as N-ethylmaleimide (NEM), disulfiram, and organic disulfides [e.g., 2,2'-dithiobis(5-nitropyridine)] were also shown to induce TOP2-mediated DNA cleavage with similar reaction characteristics as thiol-reactive quinones. (3) TOP2-mediated DNA cleavage induced by thiol-reactive quinones was completely abolished using mutant yeast TOP2 with all cysteine residues replaced with alanine (cysteineless TOP2). These results suggest the possibility that cellular DNA damage could occur indirectly through thiolation of a nuclear protein, TOP2. The implications of this reaction in carcinogenesis and apoptotic cell death are discussed.

Alanine↗
PubMed2001

The significance of comorbidity in advanced laryngeal cancer.

INTRODUCTION: Cancer patients often have concurrent diseases and conditions known as comorbidities. The aim of this project is to demonstrate the significance of comorbidity in the treatment and outcomes of advanced laryngeal carcinoma. METHODS: A retrospective medical record review of 182 patients with previously untreated T3 or T4 squamous carcinomas of the larynx treated at M. D. Anderson between 1990 and 1995 was performed. Demographic, patient-specific, tumor-specific, and outcome measures information were collected. Comorbidity was coded using the Modified Medical Comorbidity Index. Univariate and multivariate analysis with the use of life survival analysis techniques and logistic regression were performed. RESULTS: The median age at diagnosis was 59.5 years. Most patients were men (69.2%) and Caucasian (73.1%). Laryngeal preservation was performed in 90 patients, and surgical resection was performed in 92 patients. Patients in the two treatment groups had similar comorbidity, locoregional control (65%), and 5-year survival (37.3%). Patients with either moderate or severe comorbidity had significantly worse overall survival (p = .00014) and worse 5-year survival than those with no or mild comorbidity (21.8% vs 46.3%, p = .003). CONCLUSIONS: This study demonstrates that comorbidity is significantly associated with survival in a group of patients with identical histology, site, and stage. Comorbid status should be incorporated into the assessment of prognosis and outcome to improve and optimize the management of head and neck cancer patients.

Adult↗
PubMed2001

Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity.

BACKGROUND: The purpose of this study was to determine whether coronary artery bypass grafting without cardiopulmonary bypass (off-pump CABG) decreases risk-adjusted operative death and major complications after coronary artery bypass grafting in selected patients. METHODS: Using The Society of Thoracic Surgeons (STS) National Adult Cardiac Surgery Database, procedural outcomes were compared for conventional and off-pump CABG procedures from January 1, 1998, through December 31, 1999. Mortality and major complications were examined, both as unadjusted rates and after adjusting for known base line patient risk factors. RESULTS: A total of 126 experienced centers performed 118,140 total CABG procedures. The number of off-pump CABG cases was 11,717 cases (9.9% of total cases). The use of an off-pump procedure was associated with a decrease in risk-adjusted operative mortality from 2.9% with conventional CABG to 2.3% in the off-pump group (p < 0.001). The use of an off-pump procedure decreased the risk-adjusted major complication rate from 14.15% with conventional CABG to 10.62% in the off-pump group (p < 0.0001). Patients receiving off-pump procedures were less likely to die (adjusted odds ratio 0.81, 95% CI 0.70 to 0.91) and less likely to have major complications (adjusted odds ratio 0.77, 95% CI 0.72 to 0.82). CONCLUSIONS: Off-pump CABG is associated with decreased mortality and morbidity after coronary artery bypass grafting. Off-pump CABG may prove superior to conventional CABG in appropriately selected patients.

Aged↗
PubMed2001

Pelvic embolization for treatment of hemorrhage related to spontaneous and induced abortion.

OBJECTIVE: Presentation of outcomes of pelvic arterial embolization for hemorrhage after spontaneous or induced abortion. STUDY DESIGN: We collected case reports of embolization after spontaneous or induced abortion from oral presentations and from members of the National Abortion Federation. RESULTS: Pelvic arterial embolization was performed for 11 women who had hemorrhage after spontaneous or induced abortion, and it was initially successful for all women. One woman ultimately required a hysterectomy after unsuccessful repeated embolization. Prophylactic embolization was done for 8 women who were at risk for hemorrhage from placenta accreta; 4 of these women had subsequent hysterectomies. CONCLUSIONS: Selective pelvic arterial embolization may be a successful treatment for hemorrhage associated with spontaneous and induced abortion. Embolization can be considered before hysterectomy is undertaken for control of hemorrhage. There may be a role for prophylactic catheterization or embolization when there is a risk of severe hemorrhage.

Abortion, Induced↗
PubMed2001

The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. Anderson dysphagia inventory.

OBJECTIVE: To design a reliable and validated self-administered questionnaire whose purpose is to assess dysphagia's effects on the quality of life (QOL) of patients with head and neck cancer. DESIGN: Cross-sectional survey study. METHODS: Focus groups were convened for questionnaire development and design. The M. D. Anderson Dysphagia Inventory (MDADI) included global, emotional, functional, and physical subscales. One hundred consecutive adult patients with a neoplasm of the upper aerodigestive tract who underwent evaluation by our Speech Pathology team completed the MDADI and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Speech pathologists completed the Performance Status Scale for each patient. Validity and reliability properties were calculated. Analysis of variance was used to assess how well the MDADI discriminated between groups of patients. RESULTS: The internal consistency reliability of the MDADI was calculated using the Cronbach alpha coefficient. The Cronbach alpha coefficients of the MDADI subscales ranged from 0.85 to 0.93. Test-retest reliability coefficients of the subscales ranged from 0.69 to 0.88. Spearman correlation coefficients between the MDADI subscales and the SF-36 subscales demonstrated construct validity. Patients with primary tumors of the oral cavity and oropharynx had significantly greater swallowing disability with an adverse impact on their QOL compared with patients with primary tumors of the larynx and hypopharynx (P<.001). Patients with a malignant lesion also had significantly greater disability than patients with a benign lesion (P<.001). CONCLUSIONS: The MDADI is the first validated and reliable self-administered questionnaire designed specifically for evaluating the impact of dysphagia on the QOL of patients with head and neck cancer. Standardized questionnaires that measure patients' QOL offer a means for demonstrating treatment impact and improving medical care. The development and validation of the MDADI and its use in prospective clinical trials allow for better understanding of the impact of treatment of head and neck cancer on swallowing and of swallowing difficulty on patients' QOL.

Adult↗
PubMed2000

The impact of clinical pathways on the practice of head and neck oncologic surgery: the University of Texas M. D. Anderson Cancer Center Experience.

OBJECTIVE: To assess the impact of clinical pathways on the practice of head and neck oncologic surgery in an academic center. DESIGN: Cross-sectional study. SETTING: Cancer treatment center. PATIENTS: The study population consisted of 3 groups of patients who underwent unilateral neck dissection and were treated in the Department of Head and Neck Surgery of the University of Texas M. D. Anderson Cancer Center, Houston. Additional procedures which may have been performed were direct laryngoscopy, rigid esophagoscopy, and/or dental extractions. Ninety-six patients treated during 1993-1994 prior to the implementation of the clinical pathway (historical control group) were compared with 94 patients treated during 1996-1998, 64 who were not (contemporaneous nonpathway group) and 30 who were managed on the clinical pathway (pathway group). Patients from 1995 were excluded since the pathway was in the planning stages then. MAIN OUTCOME MEASURES: Median length of stay; median total costs of care. RESULTS: The median length of hospital stay of the historical control, contemporaneous nonpathway, and pathway groups decreased from 4.0 to 2.0 days (P<.001). The total median costs of care were less in the pathway group as compared with the historical control group ($6,227 and $8,459, respectively, P<.001) and also less in the contemporaneous nonpathway group compared with the historical control group (S6885 and $8,459, respectively, P<.001). Mean and median length of hospital stay and costs were lower in the pathway group as compared with the nonpathway group but not significantly (P = .11 and P = .07, respectively) The contemporaneous nonpathway and pathway groups did not differ in complications or readmissions. CONCLUSIONS: Development and implementation of this clinical pathway played a statistically significant role in decreasing length of hospital stay and total costs of care associated with neck dissection between nonpathway and pathway patients. Thus, a more cost-effective practice environment has resulted for all of our patients.

Academic Medical Centers↗
PubMed2000

Cancer of the oral cavity.

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Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Generation of T-cell immunity to a murine melanoma using MART-1-engineered dendritic cells.

The murine melanoma B16 expresses the murine counterpart of the human MART-1/Melan-A (MART-1) antigen, sharing a 68.6% amino acid sequence identity. In this study, mice were vaccinated with bone marrow-derived murine dendritic cells genetically modified with a replication-incompetent adenoviral vector to express the human MART-1 gene (AdVMART1). This treatment generated a protective response to a lethal tumor challenge of unmodified murine B16 melanoma cells. The response was mediated by major histocompatibility complex class I-restricted cytotoxic T lymphocytes specific for MART-1 antigen, which produced high levels of interferon-gamma when reexposed to MART-1 in vitro and lysed targets in a calcium-dependent mechanism suggestive of perforin/granzyme B lysis. MART-1 was presented by the dendritic cells used for vaccination and not by epitopes cross-presented by host antigen-presenting cells. In conclusion, dendritic cells genetically modified to express the human MART-1 antigen generate potent murine MART-1-specific protective responses to B16 melanoma.

Animals↗
PubMed2000

Factors associated with age at operation for children with congenital heart disease.

OBJECTIVE: Previous studies have shown that children with congenital heart disease (CHD) who live in nonurban areas or who do not have private insurance are at risk for delayed referral to a pediatric cardiologist. However, the effect of these factors on the age at which cardiac surgery is performed has not been evaluated. This study is designed to evaluate the factors that influence the age at which definitive surgical repair is performed. METHODS: Data on hospital discharges for 1995 and 1996 in California were obtained from the Office of Statewide Health Planning and Development database. Children <18 years who underwent surgical repair for atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot (TOF), or atrioventricular canal (AVC) were included in the study. Age at surgery was evaluated using type of CHD, gender, race, type of insurance, surgical centers, urban or rural home location, and distance between home and surgical center as independent variables. RESULTS: In 1995-1996, 666 children underwent ASD closure (mean age: 5.1 years; median: 4.0 years), 582 VSD closure (mean age: 2.8; median: 1.1 years), 394 TOF repair (mean age: 1.7; median:.9 years), and 177 AVC repair (mean age: 1.1; median:.6 years). Comparing median and mean age at surgery, we found: AVC<TOF<VSD<ASD (< indicates younger than). A consistent trend for all 4 types of CHD was seen indicating that for median age at operation: private insurance<managed care<Medicaid. Gender or race had no effect on age at operation, although Asians tended to be older at surgery for all 4 types of CHD. There is a significant negative correlation between the case volume of surgical centers and median age at operation for ASD (r = -.37), VSD (r = -.49), TOF (r = -.63), and AVC (r = -.17). In addition, significant positive correlation was found between degree of urbanization of home locations (measured by population density) and median age at operation for ASD (r =.50), VSD (r =.77), and TOF (r =.18). No significant correlation was found between distance to surgical center and age at operation. CONCLUSIONS: Many medical and nonmedical variables play important roles in determining age for definitive repair of CHD in children. Type of insurance, a recognized surrogate for access to care, may play an important role. In addition, centers with higher surgical case volume were more likely to operate at a younger age. Finally, children in urban areas tend to be older at the time of surgery for ASD, VSD, and TOF.

Age Distribution↗
PubMed1999

p53 selective and nonselective replication of an E1B-deleted adenovirus in hepatocellular carcinoma.

An E1B gene-attenuated adenovirus (dl1520) has been proposed to have a selective cytolytic activity in cancer cells with a mutation or deletion in the p53 tumor suppressor gene (p53-null), a defect present in almost half of human hepatocellular carcinomas (HCCs). In this study, the in vitro and in vivo antitumor activity of dl1520 was investigated focusing on two human HCC cell lines, a p53-wild type (p53-wt) cell line and a p53-null cell line. dl1520 was tested for in vitro cytopathic effects and viral replication in the human HCC cell lines Hep3B (p53-null) and HepG2 (p53-wt). The in vivo antitumor effects of dl1520 were investigated in tumors grown s.c. in a severe combined immunodeficient mouse model. In addition, the combination of dl1520 infection with systemic chemotherapy was assessed in these tumor xenografts. At low multiplicities of infection, dl1520 had an apparent p53-dependent in vitro viral growth in HCC cell lines. At higher multiplicities of infection, dl1520 viral replication was independent of the p53 status of the target cells. In vivo, dl1520 significantly retarded the growth of the p53-null Hep3B xenografts, an effect augmented by the addition of cisplatin. However, complete tumor regressions were rare, and most tumors eventually grew progressively. dl1520 had no effect on the in vivo growth of the p53-wt HepG2 cells, with or without cisplatin treatment. The E1B-deleted adenoviral vector dl1520 has an apparent p53-dependent effect in HCC cell lines. However, this effect is lost at higher viral doses and only induces partial tumor regressions without tumor cures in a human HCC xenograft model.

Adenoviridae↗
PubMed1999

Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress.

Hydrogen peroxide (H2O2), a reactive oxygen species (ROS), is known to induce oxidative stress and apoptosis. U937 cells treated with H2O2 were shown to produce high molecular weight (HMW) DNA fragments approximately 50 to 100 kb in size in <1 min. The formation of these HMW DNA fragments is reversible and shown to be mediated by DNA topoisomerase II (TOP2). Following this initial event, formation of irreversible HMW DNA fragments and nucleosomal ladders occurs. Our results thus demonstrate a potential role of TOP2 in oxidative damage of DNA and apoptotic cell death.

DNA Damage↗
PubMed1999

Effect of temperature on lateral wall mechanics of the guinea pig outer hair cell.

The outer hair cell is thought to enhance the sensitivity of mammalian hearing. Its lateral wall consists of 3 concentric layers: an outermost plasma membrane, a cortical lattice, and an innermost collection of flattened membranes called the subsurface cisternae. The cytoplasm requires positive pressure for full expression of the outer hair cell's electromotility. Using micropipette aspiration, we investigated the mechanics of the guinea pig's outer hair cell lateral wall at room temperature (22 degrees C) and at the guinea pig's body temperature (39 degrees C). Although there was a 10% decrease in stiffness parameter with an increase from room to body temperature, the difference was not statistically significant; values ranged from 0.45 to 0.65 dyne/cm. With sufficient negative pressure, the cytoplasmic membrane is separated from the rest of the outer hair cell's lateral wall, a process that leads to vesiculation of the plasma membrane. Vesiculation occurs at a lower pressure than at body temperature. Our results demonstrate that the stiffness parameter of the outer hair cell lateral wall at body temperature is similar to that at room temperature. However, the plasma membrane's attachment to the cortical lattice is greatly altered by temperature. The decrease in strength of membrane attachment at body temperature may result from a change in membrane fluidity, making it more easy for membrane attachment sites to break free and permit vesiculation. Whether the tethering of the plasma membrane to the cortical lattice is lost under clinically pathologic conditions deserves future study.

Animals↗
PubMed1999

Establishing the etiology of childhood hearing loss.

The cause of hearing loss in children is often difficult to identify. We evaluated a cohort of 114 children (47 boys, 67 girls) referred with newly diagnosed hearing loss (non-otitis media) to identify factors predictive of etiology and type of hearing loss. Clinical (history and physical examination), laboratory, and radiographic data were collected. One hundred children (87.7%) had sensorineural hearing loss, and 14 (12.3%) had conductive or mixed hearing loss. The cause of hearing loss was identified in 54 children (48%). Patients with isolated aural atresia (n = 7) or with a known diagnosis of congenital cytomegalovirus infection (n = 21) were excluded from further data analysis. We conducted statistical analysis to identify factors predictive of the cause and type of hearing loss. Clinical factors that aided in identifying a cause included abnormal physical examination findings (p = 0.001) and craniofacial anomalies (p = 0.006). Computed tomography of the temporal bones was the only diagnostic test predictive of cause (p < 0.001). Factors predictive of the type of hearing loss detected (sensorineural vs. conductive or mixed) were abnormal physical examination findings (p = 0.01) and craniofacial anomalies (p = 0.004). An exhaustive laboratory or radiographic workup did not prove beneficial in identifying the etiology of hearing loss in our series.

Audiometry↗
PubMed1999

Cost-effectiveness of the diagnostic evaluation of vertigo.

OBJECTIVE: To evaluate the cost-effectiveness of several diagnostic tests used in the evaluation of vertigo. STUDY DESIGN: Cost-effectiveness analysis, using data from retrospective case review. METHODS: Charts and test results were reviewed from 192 outpatients seen in an academic tertiary referral center for evaluation of vertigo. Cost-effectiveness analysis was performed using decision analysis software, data from office and hospital charges, and expert-based estimations of the utility of different test outcomes. Sensitivity analysis was performed using standard algorithms and wide variable ranges. RESULTS: We found that audiologic testing, posturography, and electronystagmography were the most cost-effective tests, and that magnetic resonance imaging and blood tests had the lowest cost-effectiveness. The analysis was sensitive to the effects of financial costs of tests but, with a few exceptions, was typically not sensitive to the utility of test outcomes or the distribution of test results. CONCLUSIONS: The use of cost-effectiveness analysis, the estimation of utility of test outcomes, and techniques of sensitivity analysis should help guide the clinician's decision making on appropriate testing for patients with vertigo.

Audiometry, Pure-Tone↗