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Curriculum↗
Biomedical subjects
E White
Publications and source records attributed to E White.
Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advanced malignancies.
PURPOSE: Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFNalpha) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFNalpha, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFNalpha could modulate bcl-2 expression in vitro and in patients. PATIENTS AND METHODS: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFNalpha and escalating doses of TAX. The effect of CRA/IFNalpha on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFNalpha on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting. RESULTS: CRA 1 mg/kg on days 1 to 4, IFNalpha 6 MU/m(2) subcutaneously on days 1 to 4, and TAX 175 mg/m(2) on day 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFNalpha caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFNalpha decreased bcl-2 expression in vitro and in PBMCs. CONCLUSION: CRA/IFNalpha and TAX is a well-tolerated regimen. CRA/IFNalpha increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFNalpha can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFNalpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.
Adult↗
Ethnicity and birthplace in relation to tumor size and stage in Asian American women with breast cancer.
OBJECTIVES: This study examined whether Asian American women with breast cancer have tumor characteristics associated with delayed detection of their disease. METHODS: Breast cancer size and stage were examined in relation to subjects' ethnic group and birthplace, on the basis of Surveillance, Epidemiology, and End Results program data. RESULTS: Asian-born Asian American women with breast cancer had a greater proportion of tumors larger than 1 cm at diagnosis (79%) than did US White women (70%) (P < .001). In contrast, the proportion of tumors larger than 1 cm among Asian American women born in the United States (67%) did not differ significantly from that among US White women. CONCLUSIONS: Lower utilization of breast cancer screening by Asian-born Asian American women is probably responsible for their greater proportion of tumors larger than 1 cm relative to US White women in the study population. Interventional measures should be taken to increase the use of mammographic screening by first-generation Asian American women.
Adult↗
Effect of age and breast density on screening mammograms with false-positive findings.
OBJECTIVE: The objective of this study was to examine the effect of breast density and age on screening mammograms with false-positive findings. MATERIALS AND METHODS: The study sample was taken from the Washington State Mammography Tumor Registry, which links data from participating radiologists with the Puget Sound Cancer Surveillance System and the Washington State Cancer Registry. Participants (n = 73,247) were women 35 years old and older who underwent screening mammography for which an assessment and a four-category density rating were coded. A total of 46,340 mammograms were sampled to avoid interpreter bias. In this study of false-positive mammograms, only women with no diagnosis of breast cancer within 12 months of the index mammogram were included. Logistic regression was used to estimate the odds ratios of a false-positive mammogram being associated with each category of breast density or age, adjusting for the other factor as a covariate. RESULTS: After controlling for breast density, we found that the risk of a false-positive mammogram was not affected by age (p = 27). However, the trend of increasing risk of a false-positive mammogram with increasing breast density was highly significant (p < .001). Women with extremely dense breast tissue were almost two times more likely to have a false-positive mammogram than were women with fatty breast tissue. This effect persisted after controlling for age. CONCLUSION: Breast density, not age, is an important factor when predicting risk of a false-positive mammogram. Breast density should be considered when educating individual women on the risks and benefits of screening mammography.
Adult↗
Hyperoxic myopia in a closed-circuit mixed-gas scuba diver.
A myopic shift occurred in a closed-circuit mixed-gas scuba diver using a 1.3 atm abs constant partial pressure of oxygen in a nitrogen-oxygen mix. This change was noticed after approximately 18 days of diving with a mean dive time of 4.04 h each day. The observed myopic shift was due to hyperoxic myopia, one sign of lenticular oxygen toxicity, and resolved over a 1 mo. period after diving was completed. On a subsequent drive trip, a myopic shift was found in both the index diver as well as two other divers breathing the same gasmix on similar profiles. Diving communities should be aware of the risk of both lenticular and pulmonary oxygen toxicity when conducting intensive diving at oxygen partial pressures in the 1.3-1.6 atm abs range.
Atmospheric Pressure↗
Interaction of E1B 19K with Bax is required to block Bax-induced loss of mitochondrial membrane potential and apoptosis.
The Bcl-2 homologous region 3 (BH3) is sufficient for interaction of pro-apoptotic with anti-apoptotic Bcl-2 family members, and functional antagonism may determine whether cell survival or death is the outcome of this protein-protein interaction. To address the biological role of BH3, two Bax-Bcl2 chimeras were generated in which 13 amino acids encompassing BH3 was swapped between anti-apoptotic Bcl-2 and pro-apoptotic Bax, thereby generating Bax with BH3 of Bcl-2 (Bax-BH3Bcl2), and Bcl-2 with BH3 of Bax (Bcl2-BH3Bax). Function and binding of the chimeras was then assessed utilizing the adenoviral Bcl-2 homologue, E1B 19K, which blocks apoptosis, and interacts with Bax, but not with Bcl-2. E1B 19K did not interact with Bax-BH3Bcl2 but did interact with Bcl2-BH3Bax. Bax-BH3Bcl2 retained pro-apoptotic function, while Bcl2-BH3Bax did not exhibit either pro- or anti-apoptotic activity. Thus, BH3 of Bcl-2 encodes binding specificity but not the apoptotic propensity. E1B 19K could not block Bax-BH3Bcl2-induced apoptosis, suggesting that E1B 19K may act to antagonize pro-apoptotic proteins rather than as an effector of survival. Furthermore, Bax expression disrupted the mitochondrial membrane potential, which could be rescued by E1B 19K expression. Thus, BH3 controls the binding specificity among Bcl-2 family members, and direct interaction between pro-apoptotic and anti-apoptotic proteins is a mechanism to regulate mitochondrial membrane potential and apoptosis.
Adenovirus E1B Proteins↗
Validity of methods used to assess vitamin and mineral supplement use.
Assessing vitamin and mineral supplement use is important because supplement use per se is an exposure of interest for the risk of several chronic diseases and because supplements contribute a large proportion of total (diet plus supplement) micronutrient intake, another important exposure in epidemiologic research. Unfortunately, little is known about methods for obtaining valid information about supplement use. The authors conducted a validation study in 1996 comparing supplement data collected in a telephone interview and from a self-administered questionnaire with data derived from a detailed, in-person interview and transcription of the labels of supplement bottles (i.e., a gold standard) among adult supplement users in Washington State (n = 104). Spearman correlation coefficients comparing average daily supplemental vitamin and mineral intake from the interview or questionnaire with the gold standard ranged from 0.76 (95% confidence interval 0.66-0.83) for vitamin C to 0.08 (95% confidence interval -0.14 to 0.29) for iron, with a mean of about 0.5. The principal sources of error were inaccurate assumptions about the micronutrient composition of multiple vitamins and respondent confusion regarding the distinction between multiple vitamins and single supplements. These results suggest that commonly used epidemiologic methods of assessing supplement use may incorporate significant amounts of error in estimates of some nutrients.
Adult↗
Preservation of the in vivo phosphorylation status of phospholamban in the heart: evidence for a site-specific difference in the dephosphorylation of phospholamban.
The phosphorylation status of the cardiac sarcoplasmic reticular (SR) protein phospholamban determines the activity of the SR Ca(2+)-ATPase. In order to predict SR Ca2+ transport in vivo, it is vital that techniques used to measure the phosphorylation status of phospholamban adequately clamp the endogenous kinases and phosphatases which modify phosphorylation during sample preparation. A recent study (Boateng, S., Seymour, A-M., Dunn, M., Yacoub, M., and Boheler, K. (1997) Biochem. Biophys. Res. Comm. 239, 701-705) has suggested that phosphatase inhibitors must be present in quenching media to prevent almost total dephosphorylation of phospholamban. We addressed this issue by assessing the effect of both kinase and phosphatase inhibition on site-specific phosphorylation of phospholamban in ferret ventricular muscle and isolated rat ventricular myocytes quenched with Laemmli sample buffer. Under these clearly defined quenching conditions in isolated myocytes, we demonstrated that the phosphorylation status of phospholamban was low under basal conditions, and high following exposure to the beta-agonist isoprenaline. The only significant effect of inhibitor inclusion in the quench solution was in isolated myocyte preparations where phosphatase inhibition increased phosphorylation at Ser16 by about a third. The differential effect of phosphatase inclusion on phosphorylation at Ser16 and Thr17 may indicate that different enzymes are involved in dephosphorylation of the two sites.
Amino Acid Sequence↗
Suppression of the p300-dependent mdm2 negative-feedback loop induces the p53 apoptotic function.
The p53 tumor suppressor gene product interacts with the p300 transcriptional coactivator that regulates the transactivation of p53-inducible genes. The adenovirus E1A protein has been shown to bind to p300 and inhibit its function. E1A inhibits p53 transactivation and also promotes p53 accumulation by a p300-dependent mechanism. Murine double minute 2 (Mdm2) is a transcriptional target of p53 that binds to p53 and inhibits its transcriptional activity. E1A inhibited mdm2 transactivation without affecting the expression of p21(WAF1) or Bax, which resulted in high levels of p53 accumulation and apoptosis. Ectopic expression of p300 restored Mdm2 levels and inhibited p53-dependent apoptosis, as did ectopic expression of Mdm2. Thus, p300 is required for mdm2 induction by p53 and the subsequent inhibition of p53 stabilization. Inhibition of p300 by E1A results in stabilization of p53 and causes apoptosis. Moreover, E1B 19K or Bcl-2 expression in E1A-transformed cells abrogated p53-dependent apoptosis by restoring mdm2 transactivation by p53. Hence, p300 regulation of mdm2 expression controls apoptotic activity of p53, and 19K or Bcl-2 bypass E1A inhibition of p300 transactivation of Mdm2.
Adenovirus E1B Proteins↗
Variation in mammographic breast density by time in menstrual cycle among women aged 40-49 years.
BACKGROUND: Mammography is less effective for women aged 40-49 years than for older women, which has led to a call for research to improve the performance of screening mammography for younger women. One factor that may influence the performance of mammography is breast density. Younger women have greater mammographic breast density on average, and increased breast density increases the likelihood of false-negative and false-positive mammograms. We investigated whether breast density varies according to time in a woman's menstrual cycle. METHODS: Premenopausal women aged 40-49 years who were not on exogenous hormones and who had a screening mammogram at a large health maintenance organization during 1996 were studied (n = 2591). Time in the menstrual cycle was based on the woman's self-reported last menstrual bleeding and usual cycle length. RESULTS: A smaller proportion of women had "extremely dense" breasts during the follicular phase of their menstrual cycle (24% for week 1 and 23% for week 2) than during the luteal phase (28% for both weeks 3 and 4) (two-sided P = .04 for the difference in breast density between the phases, adjusted for body mass index). The relationship was stronger for women whose body mass index was less than or equal to the median (two-sided P<.01), the group who have the greatest breast density. CONCLUSIONS/IMPLICATIONS: These findings are consistent with previous evidence suggesting that scheduling a woman's mammogram during the follicular phase (first and second week) of her menstrual cycle instead of during the luteal phase (third and fourth week) may improve the accuracy of mammography for premenopausal women in their forties. Breast tissue is less radiographically dense in the follicular phase than in the luteal phase.
Adult↗
E1B 19K inhibits Fas-mediated apoptosis through FADD-dependent sequestration of FLICE.
E1B 19K, the adenovirus Bcl-2 homologue, is a potent inhibitor of apoptosis induced by various stimuli including Fas and tumor necrosis factor-alpha. Fas and TNFR-1 belong to a family of cytokine-activated receptors that share key components in their signaling pathways, Fas-associating protein with death domain (FADD) and FADD-like interleukin-1beta-converting enzyme (FLICE), to induce an apoptotic response. We demonstrate here that E1B 19K and Bcl-xL are able to inhibit apoptosis induced by FADD, but not FLICE. Surprisingly, apoptosis was abrogated by E1B 19K and Bcl-xL when FADD and FLICE were coexpressed. Immunofluorescence studies demonstrated that FADD expression produced large insoluble death effector filaments that may represent oligomerized FADD. E1B 19K expression disrupted FADD filament formation causing FADD and FLICE to relocalize to membrane and cytoskeletal structures where E1B 19K is normally localized. E1B 19K, however, does not detectably bind to FADD, nor does it inhibit FADD and FLICE from being recruited to the death-inducing signaling complex (DISC) when Fas is stimulated. Thus, E1B 19K may inhibit Fas-mediated cell death downstream of FADD recruitment of FLICE but upstream of FLICE activation by disrupting FADD oligomerization and sequestering an essential component of the DISC.
Actin Cytoskeleton↗
Inhibition of ICE-like proteases inhibits apoptosis and increases virus production during adenovirus infection.
Interleukin-1b converting enzyme (ICE)-related cysteine proteases are required for E1A-induced, p53-dependent apoptosis in baby rat kidney (BRK) cells. Adenovirus E1B 19K protein, which is a potent inhibitor of apoptosis, inhibits activation of these proteases in BRK cells. E1A expression induces apoptosis during infection of human cells by mutant adenoviruses which contain nonfunctional E1B 19K. The question arises as to whether ICE-related proteases are involved in E1A-induced apoptosis during mutant adenovirus infection of human cells. To test the involvement of the cysteine proteases in E1A-induced apoptosis during productive adenovirus infection of HeLa cells, we examined whether Z-VAD-FMK, an inhibitor of ICE-related proteases, can inhibit apoptosis induced by mutant adenovirus which lacks functional E1B 19K. Z-VAD-FMK inhibited E1A-induced apoptosis in adenovirus-infected Hela cells, suggesting that the ICE family proteases are involved in this apoptosis pathway. Z-VAD-FMK also inhibited cleavage of substrates such as cysteine protease CPP32 and nuclear lamins, whereas cleavage of poly(ADP-ribose) polymerase was partially inhibited during infection with an E1B 19K mutant. Inhibition of apoptosis by Z-VAD-FMK significantly enhanced production of infectious adenovirus and attenuated virus release. Thus apoptosis may be a method for the host cell to limit virus production and release at the end of the infection cycle.
Adenovirus E1A Proteins↗
The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells.
Mutations in p53 change the sensitivity to cancer chemotherapeutic drugs. Whereas many drugs, including the vinca alkaloids, often become less effective when p53 is transcriptionally inactivated, several, most notably paclitaxel, may become more effective. In studying the underlying mechanism(s), we found that increased MAP4 expression, which occurs with transcriptionally silent p53, is associated with increased sensitivity to paclitaxel and decreased sensitivity to vinca alkaloids. Using murine fibroblasts transfected with MAP4, we directly demonstrated that the changes in drug sensitivity were associated with parallel alterations in drug-induced apoptosis and cell-cycle arrest. Immunofluorescent staining of the microtubule network revealed that cells with increased MAP4 expression displayed an increase in polymerized microtubules and an increased binding of fluorsceinated paclitaxel. Since MAP4 stabilizes polymerized microtubules, overexpression of this gene provides a plausible mechanism to explain the altered sensitivity to microtubule-active drugs in the presence of mutant p53.
3T3 Cells↗
Effect of asthma and its treatment on growth: four year follow up of cohort of children from general practices in Tayside, Scotland.
OBJECTIVE: To investigate whether asthma or its treatment impairs children's growth, after allowing for socioeconomic group. DESIGN: 4 year follow up of a cohort of children aged 1-15. SETTING: 12 general practices in the Tayside region of Scotland. SUBJECTS: 3347 children with asthma or features suggestive of asthma registered with the general practices. MAIN OUTCOME MEASURES: Height and weight standard deviation scores. RESULTS: Children who lived in areas of social deprivation (assessed by postcode) had lower height and weight than their contemporaries (mean standard deviation score -0.26 (SD 1.02) and -0.18 (1.15) respectively, P < 0.001 for both). Children who were receiving > or = 400 micrograms daily of inhaled steroids and who were attending both hospital and general practice for asthma care had lower height and weight than average, independent of the effect of deprivation (mean standard deviation score -0.62 (1.01), P = 0.002, for height and -0.58 (0.94), P = 0.005, for weight). Children receiving high doses of inhaled corticosteroids also showed lower growth rates (mean change in standard deviation score -0.19 (0.51), P = 0.003). However, no other children with asthma showed growth impairment. CONCLUSION: Most children with asthma were of normal height and weight and had normal growth rates. However, children receiving high doses of inhaled steroids and requiring both general practice and hospital services had a significant reduction in their stature. This effect was independent from but smaller than the effect of socioeconomic group on stature.
Adolescent↗
Validity and reliability of subject and mother reporting of perinatal factors.
The authors used data from a population-based case-control study of breast cancer in women aged < or = 44 years (cases, n = 975; controls, n = 866) conducted between 1994 and 1996 in three counties of western Washington state to assess the validity and reliability of reported perinatal factors. For a sample of participants, exposure information from self-administered questionnaires was validated with information from birth certificates (cases, n = 378; controls, n = 283). Detailed information regarding perinatal characteristics of their daughters was also collected from subjects' mothers (case mothers, n = 510; control mothers, n = 436) to assess the reliability of subjects' reporting of these events. Although reporting of birth weight by subjects (cases, r = 0.83; controls, r = 0.80) and their mothers (case mothers, r = 0.89; control mothers, r = 0.84) was highly correlated with the birth certificates, there was differential measurement error by subjects; cases reported birth weight accurately on average, but controls tended to underestimate their birth weight. Agreement between the subject and mother report was excellent for birth weight (cases, r = 0.85; controls, r = 0.87) and good for other perinatal factors, but birth order and maternal diethylstilbestrol use were underreported among cases and reported accurately among controls. Differential measurement error of birth weight by case-control status resulted in biased odds ratios for breast cancer risk.
Birth Weight↗
Rapid effects of cytochalasin-D on contraction and intracellular calcium in single rat ventricular myocytes.
Contraction and intracellular calcium ([Ca2+]i) transients were recorded using a video edge detector and fluorescence spectrophotometry, respectively, in rat ventricular myocytes at 22-24 degreesC stimulated at a frequency of 1 Hz. Application of the F-actin disrupter cytochalasin-D (Cyt-D) caused a large reduction in the amplitude of contraction and a small increase in the [Ca2+]i transient. These responses began within a few seconds of application and were complete after 2 min of exposure. Phase-plane relationships of contraction and [Ca2+]i were consistent with cytochalasin-D causing a decrease in myofilament responsiveness to Ca2+.
Actins↗
Co-ordinated changes in cAMP, phosphorylated phospholamban, Ca2+ and contraction following beta-adrenergic stimulation of rat heart.
Concentration-dependent changes in cyclic AMP (cAMP), site-specific phosphorylation of phospholamban, the intracellular calcium ([Ca2+]i) transient and contraction were measured in isolated rat ventricular myocytes exposed to the beta-adrenoceptor agonist isoprenaline. Cyclic AMP was measured by [125I]-cAMP scintillation proximity assay, phosphorylation of phospholamban at Ser16 and Thr17 was assessed using a pair of site-specific polyclonal antibodies, and [Ca2+]i was monitored with the fluorescent dye fura 2. Cyclic AMP rose to twice basal levels in the presence of 10(-6) M isoprenaline. The maximum increase in phosphorylation at Ser16 and Thr17 of phospholamban was seen at 10(-7) M isoprenaline. At this stage Ser16 phosphorylation was six times higher, and Thr17 phosphorylation was three times higher than that recorded in the absence of isoprenaline. Phosphorylation at Ser16 correlated more closely with changes in the [Ca2+]i transient and contraction than did phosphorylation at Thr17. This is the first study of its kind to measure simultaneous changes in cAMP, the phosphorylation of phospholamban, the [Ca2+]i transient and contraction over a range of concentrations of beta-agonist. The results suggest that phosphorylation of phospholamban at Thr17 is of lesser physiological relevance to the effects of beta-adrenergic stimulation on the heart than phosphorylation at Ser16.
Adrenergic beta-Agonists↗
Local side effects of subcutaneous and intramuscular urinary gonadotropins for ovarian stimulation in in vitro fertilization: a prospective, randomized study.
OBJECTIVE: To compare the incidence and severity of local side effects of urinary-derived gonadotropins administered s.c. and i.m.. DESIGN: Prospective randomized study of women undergoing IVF treatment. SETTING: Tertiary referral center for assisted reproduction. PATIENT(S): A total of 71 patients were randomized to receive gonadotropins by the s.c. (n = 41) or i.m. (n = 30) route. INTERVENTION(S): One cycle of IVF with gonadotropins administered either s.c. or i.m. for ovarian stimulation. MAIN OUTCOME MEASURE(S): Incidence and severity of local side effects, such as redness, itching, swelling, pain, and bruising. RESULT(S): Pain was the most common side effect, with 55.3% and 70.1% of i.m. and s.c. injections, respectively, resulting in pain. There were no statistically significant differences in the incidence of itching or bruising after i.m. and s.c. injections. Although there was a higher incidence of redness and swelling in the s.c. group compared with the i.m. group, most cases were classified as mild. CONCLUSION(S): There was a significantly higher incidence of some local side effects after s.c. gonadotropin administration but most of these were mild and well tolerated by patients.
Adolescent↗